Extended Abstracts of the XIX National Congress of the Italian Society of Neonatology

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Contents

ScientificProgramme,XIXNationalCongressoftheItalianSocietyofNeonatology...... vii

Term pregnancy and mode of delivery A.Spinillo,C.CassaniandS.Bogliolo(Italy)...... S1

Term of pregnancy and mode of delivery: the neonatologist’s point of view M.PezzatiandB.Gambi(Italy) ...... S3

Hearing and vision screening G.Gargano(Italy)...... S5

Pulse oximetry newborn screening for congenital heart defects. Is it really useful? F.Schena,E.Ciarmoli,A.Mayer,A.Cappelleri,L.Bassi,M.FumagalliandF.Mosca(Italy)...... S8

Metabolic newborn screening: between past and future M.A.Donati,L.Padrini,G.LaMarcaandE.Pasquini(Italy)...... S10

Rooming-in: an update L.D.Serpero,M.Sabatini,M.ColivicchiandD.Gazzolo(Italy)...... S12

Microbiota in healthy term infant F.Indrio,A.DiMauro,G.Riezzo,F.DiMauroandR.Francavilla(Italy)...... S15

Gastro-oesophageal reflux: pathogenesis, symptoms, diagnostic and therapeutic management L.Corvaglia,S.MartiniandG.Faldella(Italy)...... S18

Breastfeeding promotion and neonatological practices R.DavanzoandA.DeCunto(Italy)...... S20

Rooming-in care of newborn infants G.MangiliandI.C.Formica(Italy)...... S23

Sudden unexpected perinatal collapse and sudden unexpected early neonatal death N.Nassi,R.Piumelli,V.Nardini,P.Toti,A.M.Buccoliero,G.LiccioliandG.Donzelli(Italy)...... S25

Discharge of the newborn: timing, mode and controls P.L.Vasarri(Italy)...... S27

The newborn with “few red blood cells” and the newborn with “too many red blood cells” M.Motta,A.DelVecchioandR.D.Christensen(Italy,USA)...... S29

The neonate at risk for thrombocytopenia A.DelVecchio,M.MottaandR.D.Christensen(Italy,USA)...... S33

The neonatal heart murmur S.Mannarino,A.C.Codazzi,A.Diouf,R.FalconeandS.Chiapedi(Italy) ...... S37

Long QT interval in the newborn A.B.Delogu,R.Iannotta,A.Saracino,G.BaroneandC.Romagnoli(Italy) ...... S39

Medical–legal aspects of neonatal transport R.Paludetto,A.DiFiore,J.Cerullo,G.Mansi,J.VanDenHeuvelandA.Umbaldo(Italy) ...... S41

Newborn at social risk R.Lucchini,E.Bacchio,S.GiampietroandM.DeCurtis(Italy)...... S43

Abandoned newborn: neglected phenomenon? P.Ferrara,A.Gatto,P.Paolillo,F.Vena,F.IannielloandC.Romagnoli(Italy)...... S45 iv Contents / Early Human Development 89S4 (2013) iii–v

The umbilical cord: a source of great richness G.Chirico(Italy) ...... S47

Use of allogenic umbilical cord blood for red cells transfusion in premature infants: utopia or reality? P. Papacci, M. Fioretti, C. Giannantonio, A. Molisso, M.G. Tesfagabir, A. Tornesello, M. Bianchi, L. Teofili and C. Romagnoli (Italy) . . . . S49

Cord blood banks: organizational aspects L.Salvaneschi(Italy)...... S52

Alternative birthing ways: the neonatologist’s point of view C.V.Bellieni(Italy)...... S54

Bonding and breastfeeding after a cesarean delivery V.Zanardo,A.Canella,R.MaoneandG.Straface(Italy)...... S56

Neonatal neurobehavioral assessment in healthy and at-risk infants G.CalciolariandR.Montirosso(Italy) ...... S58

Infants from medically assisted procreation M.G.DeLuca,L.Orfeo,A.Casani,F.Cocca,C.Coletta,G.DiManso,L.Grappone,N.Pozzi,A.Scoppa,N.LecciaandA.Salerno(Italy) . . S60

Discordant twins: obstetric risk factors and neonatal outcomes A.A.Zuppa,V.Cardiello,P.Catenazzi,A.D’Antuono,M.CavaniandC.Romagnoli(Italy)...... S62

Newborn from mother with disorders of glucose homeostasis E.Bertino,M.Raia,F.Cresi,E.Maggiora,A.CosciaandG.Gilli(Italy) ...... S64

Babies born to mothers with thyroid disease P.Ghirri,F.DiniandA.Boldrini(Italy)...... S66

Newborn of mother with syphilis in pregnancy P.Valentini(Italy) ...... S68

Congenital toxoplasmosis L.Bollani,L.StrocchioandM.Stronati(Italy)...... S70

Neonatal herpes simplex infection F.Natale,B.Bizzarri,A.Castronovo,A.Russo,M.Bartolucci,R.PedicinoandM.DeCurtis(Italy)...... S73

The infant born to a mother with infectious disease risk M.G.CaprettiandG.Faldella(Italy)...... S76

The floppy newborn S.Orcesi(Italy)...... S79

Obstetrical brachial plexus injury L.Memo,S.Caminiti,A.Memo,D.GarozzoandS.Ferraresi(Italy)...... S82

Neonatal abstinence syndrome I.Bersani,M.Corsello,M.Mastandrea,V.Patacchiola,S.Foligno,V.GarofaloandA.Dotta(Italy)...... S85

Risk factors of hospitalization for lower respiratory tract infections in infants with 33 weeks of gestational age or more: a prospective Italian cohort study on 2210 newborns M. Lanari, F. Prinelli, F. Adorni, S. Di Santo, M. Musicco and the “Italian Study Group on Risk Factors for RSV Hospitalization” (Italy) . . S88

The guidelines for the prophylaxis of RSV: the need to upgrade A.Dall’Agnola,E.GirardiandR.Beghini(Italy)...... S91

Bronchiolitis: update on the management E.Baraldi,D.ElMazloum,M.Maretti,F.TirelliandL.Moschino(Italy) ...... S94

Management of acute lung injury and acute respiratory distress syndrome in infants C.Moretti,P.Papoff,C.S.Barbàra,E.Caresta,C.LiberatiandF.Midulla(Italy) ...... S96

Cerebral ultrasound in full term neonates: why and when? L.Bartalena,M.Giampietri,M.Bernardini,P.Biver,F.DeCesaris,E.Fiorentini,V.MadrigaliandA.Boldrini(Italy)...... S99

Developmental dysplasia of the hip: to screen or not to screen with ultrasound A.ChiaraandM.DePellegrin(Italy) ...... S102

How has research changed our clinical practice in the last years? F.Mosca,M.Colnaghi,L.Giannì,P.Roggero,I.Sirgiovanni,M.AgostiandM.Fumagalli(Italy)...... S104

Preventing errors in neonatology N.A.RomeoandE.Muccioli(SanMarino)...... S109 Contents / Early Human Development 89S4 (2013) iii–v v

Synthetic surfactant: primary data T.Curstedt(Sweden)...... S111

Surfactant therapies to treat pulmonary disorders in young infants P.Biban,S.Spaggiari,L.Andaloro,F.Sacco,D.Silvagni,M.GaffuriandP.Bonetti(Italy)...... S113

Sustained lung inflation to manage preterm infants (25–29 weeks’ gestation) in the delivery room: the Italian SLI study G. Lista, C. Dani, L. Boni, F. Cavigioli, S. Pratesi, M. Agosti, M. Bellettato, P. Biban, A. Del Vecchio, D. Gazzolo, C. Gizzi, R. Magaldi, H.Messner,F.Mosca,F.Sandri,F.Scopesi,D.Trevisanuto,G.VentoandA.Boldrin(Italy)...... S115

Chemical contaminants in breast milk S.PiconeandP.Paolillo(Italy)...... S117

Human milk in the neonatal intensive care unit: good practices S.DiFabio,C.DiNataleandL.DiVentura(Italy)...... S119

Vitamin D and fluoride: in order to prevent, not to cure S.Lacerenza,M.Stronati,P.PaolilloandC.Romagnoli(Italy) ...... S121

Is sucrose useful in neonatal medicine? R.AntonucciandL.Antonucci(Italy)...... S123

The ideal formula for healthy term infants G.Francescato,F.Mosca,C.AgostoniandM.Agosti(Italy)...... S126

The detection of oxygen saturation in the healthy newborn M.RavaniandM.Fornaciari(Italy)...... S129 © 2013 Elsevier Ireland Ltd. All rights reserved.

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28 Ottobre 2013

15.00 - 16.50 Sala Palazzo Affari Sessione Parallela L'impostazione nutrizionale neonatale tra normalità e problemi PROGRAMMAPresidente: Mario De Curtis (Roma) Moderatori: Luca Bernardo (Milano), Gustavo Caoci (Roma) 28 Ottobre 2013 15.00 Microbiota intestinale nel nato a termine Flavia Indrio (Bari) 15.00 - 16.50 Auditorium 15.20Sessione Ruolo Parallela epigenetico dell'alimentazione neonatale L'eventoUmberto parto nel Simeoni terzo (Marsiglia)millennio Presidente: Gian Paolo Salvioli (Bologna) 15.40Moderatori: Il reflusso Lino Chiandetti gastro-esofageo (Padova), nel Maria neonato Pia De Carolis (Roma) Luigi Tommaso Corvaglia (Bologna) 15.00 Termine di gravidanza e modalità del parto: il punto di vista ostetrico 16.00 ComeArsenio e Spinilloperché (Pavia)incentivare la produzione del latte materno Riccardo Davanzo (Trieste) 15.20 Termine di gravidanza e modalità del parto: il punto di vista neonatologico 16.20 DiscussioneMarco Pezzati (Firenze)

15.40 La placenta: grande assente, sempre presente Tullia Todros (Torino)

17.0016.00 - 1Responsabilità8.50 Auditorium medico -legale in sala parto SessioneErnesto Parallela D'Aloja (Cagliari) Il neonato tra normalità e imprevisti Presidente:16.20 Discussione Paolo Giliberti (Napoli) Mo deratori: Carlo Giannini (Roma), Giuseppe Presta (Tricase)

17.00 Il concetto di "normalità" del neonato: dall'anamnesi all'esame obiettivo Gherardo Rapisardi (Firenze) 15.00 - 16.50 Sala Verde 17.20Sessione Assistenza Parallela neonatale in rooming-in Il presenteGiovanna e il futuro Mangili degli (Bergamo) screening neonatali Presidente: Vassilios Fanos (Cagliari) 17.40Moderatori: ALTE Giancarlo in rooming-in: Barboni un (Perugia) pericolo, Salvinoreale? Marcello Vitaliti (Palermo) Niccolò Nassi (Firenze) 15.00 Screening audiologico ed oculistico 18.00 DimissioneGiancarlo Gargano del neonato: (Reggio tempi, Emilia) modalità e controlli Pier Luigi Vasarri (Prato) 15.20 Pulsiossimetria per lo screening delle cardiopatie: è veramente utile? 18.20 DiscussioneFederico Schena (Milano)

15.40 Screening metabolico: tra presente e futuro Alice Donati (Firenze)

16.00 L'organizzazione del Nido/Rooming-in nel terzo millennio Diego Gazzolo (Alessandria)

16.20 Discussione

viii Programma XIX Congresso Nazionale della Società Italiana di Neonatologia

28 Ottobre 2013 28 Ottobre 2013

15.00 - 16.50 Sala Palazzo Affari Sessione15.00 - 16.50 Parallela Sala Palazzo Affari L'impoSessionestazione Parallela nutrizionale neonatale tra normalità e problemi Presidente:L'impostazione Mario nutrizionale De Curtis (Roma) neonatale tra normalità e problemi Moderatori:Presidente: MarioLuca Bernardo De Curtis (Milano) (Roma) , Gustavo Caoci (Roma) Moderatori: Luca Bernardo (Milano), Gustavo Caoci (Roma) 15.00 Microbiota intestinale nel nato a termine 15.00 FlaviaMicrobiota Indrio intestinale (Bari) nel nato a termine Flavia Indrio (Bari) 15.20 Ruolo epigenetico dell'alimentazione neonatale 15.20 UmbertoRuolo epigenetico Simeoni (Marsiglia) dell'alim entazione neonatale Umberto Simeoni (Marsiglia) 15.40 Il reflusso gastro-esofageo nel neonato 15.40 LuigiIl reflusso Tommaso gastro-esofageo Corvaglia (Bologna) nel neonato Luigi Tommaso Corvaglia (Bologna) 16.00 Come e perché incentivare la produzione del latte materno 16.00 RiccardoCome e perché Davanzo incentivare (Trieste) la produzione del latte materno Riccardo Davanzo (Trieste) 16.20 Discussione 16.20 Discussione

17.00 - 18.50 Auditorium Sessione17.00 - 1 8.50Parallela Auditorium IlSessione neonato Parallela tra normalità e imprevisti Presidente:Il neonato tra Paolo normalità Giliberti e (Napoli)imprevisti MoPresidente:deratori: PaoloCarlo GianniniGiliberti (Roma)(Napoli), Giuseppe Presta (Tricase) Moderatori: Carlo Giannini (Roma), Giuseppe Presta (Tricase) 17.00 Il concetto di "normalità" del neonato: dall'anamnesi all'esame obiettivo 17.00 GIl herardoconcetto Rapisardi di "normalità" (Firenze) del neonato: dall'anamnesi all'esame obiettivo Gherardo Rapisardi (Firenze) 17.20 Assistenza neonatale in rooming-in 17.20 GiovannaAssistenza Mangili neonatale (Bergamo) in rooming- in Giovanna Mangili (Bergamo) 17.40 ALTE in rooming-in: un pericolo reale? 17.40 NiccolòALTE in Nassi rooming-in: (Firenze) un pericolo reale? Niccolò Nassi (Firenze) 18.00 Dimissione del neonato: tempi, modalità e controlli 18.00 PierDimissione Luigi Vasarri del neonato: (Prato) tempi, modalità e controlli Pier Luigi Vasarri (Prato) 18.20 Discussione 18.20 Discussione

Programma XIX Congresso Nazionale della Società Italiana di Neonatologia ix

28 Ottobre 2013 28 Ottobre 2013

17.00 - 18.50 Sala Verde 15.00Sessione - 16.50 Parallela Sala Palazzo Affari SessioneIl neonato Parallela con rischio ematologico cardiologico L'impoPresidente:stazione Angelo nutrizionale Colombo (Bergamo)neonatale tra normalità e problemi Presidente:Moderatori: MarioUgo Bottone De Curtis (Massa) (Roma), Ambrogio Di Paolo (Roma) Moderatori: Luca Bernardo (Milano), Gustavo Caoci (Roma) 17.00 Il neonato con "pochi globuli rossi" e il neonato con "troppi globuli rossi" 15.00 MicrobiotaMario Motta intestinale (Brescia) nel nato a termine Flavia Indrio (Bari) 17.20 Il neonato a rischio di piastrinopenia 15.20 RuoloAntonio epigenetico Del Vecchio dell'alim (Bari) entazione neonatale Umberto Simeoni (Marsiglia) 17.40 Il neonato con il "soffio cardiaco" 15.40 IlSavina reflusso Mannarino gastro-esofageo (Pavia) nel neonato Luigi Tommaso Corvaglia (Bologna) 18.00 Il QT lungo nel periodo neonatale 16.00 ComeAngelica e perché Bibiana incentivare Delogu (Roma) la produzione del latte materno Riccardo Davanzo (Trieste) 18.20 Discussione 16.20 Discussione

17.00 - 18.50 Sala Palazzo Affari 17.00Sessione - 18.50 Parallela Auditorium SessioneI neonati Parallelaa rischio "non medico" IlPresidente: neonato tra Giorgio normalità Rondini e imprevisti (Pavia) Presidente:Moderatori: PaoloMaurizio Giliberti Gente (Napoli) (Roma), Angela Motta (Catania) Mo deratori: Carlo Giannini (Roma), Giuseppe Presta (Tricase) 17.00 Il trasporto neonatale: situazione attuale 17.00 IlStefano concetto Martinelli di "normalità" (Milano) del neonato: dall'anamnesi all'esame obiettivo Gherardo Rapisardi (Firenze) 17.20 Problemi medico-legali del trasporto neonatale 17.20 AssistenzaRoberto Paludetto neonatale (Napoli) in rooming- in Giovanna Mangili (Bergamo) 17.40 Il neonato a rischio sociale Renato Lucchini (Roma) 17.40 ALTE in rooming-in: un pericolo reale? 18.00 NiccolòIl neonato Nassi abbandonato (Firenze) Pietro Ferrara (Roma) 18.00 Dimissione del neonato: tempi, modalità e controlli 18.20 Discussione Pier Luigi Vasarri (Prato)

18.20 Discussione 19.00 - 21.00 Auditorium Cerimonia Inaugurale

Presentazione del Congresso

Saluto delle Autorità

Lettura Magistrale: La realtà aumentata Gianfranco Gensini (Firenze)

x Programma XIX Congresso Nazionale della Società Italiana di Neonatologia

29 Ottobre 2013 28 Ottobre 2013

09.00 - 10.50 Auditorium Se15.00ssione - 16.50 Parallela Sala Palazzo Affari IlSessione cordone Parallela ombelicale Presidente:L'impostazione Giuseppe nutrizionale Buonocore neonatale (Siena) tra normalità e problemi Moderatori:Presidente: MarioLuca Antonio De Curtis Ramenghi (Roma) (Genova), Antonio G. Spagnolo (Roma) Moderatori: Luca Bernardo (Milano), Gustavo Caoci (Roma) 09.00 Il cordone ombelicale: fonte di grande ricchezza 15.00 GaetanoMicrobiota Chirico intestinale (Brescia) nel nato a termine

09.20 LaFlavia trasfusione Indrio (Bari) autologa Patrizia Papacci (Roma) 15.20 Ruolo epigenetico dell'alimentazione neonatale 09.40 LaUmberto banca Simeonidel cordone: (Marsiglia) aspetti organizzativi Laura Salvaneschi (Pavia) 15.40 Il reflusso gastro-esofageo nel neonato 10.00 LaLuigi banca Tommaso del cordone: Corvaglia aspetti (Bologna) normativi Giuliano Grazzini (Roma) 16.00 Come e perché incentivare la produzione del latte materno 10.20 DiscussioneRiccardo Davanzo (Trieste)

16.20 Discussione

09.00 - 10.50 Sala Verde Sessione Parallela Dal17.00 part - 1o8.50 al rooming-in Auditorium con piccoli e grandi dubbi Presidente:Sessione Parallela Claudio Fabris (Torino) ModerIl neonatoatori: tra Mario normalità Barbarini e imprevisti (Como), Rinaldo Zanini (Lecco) Presidente: Paolo Giliberti (Napoli) 09.00Moderatori: Modalità Carlo alternative Giannini (Roma) di parto:, Giuseppe il parere Presta del (Tricase)neonatologo Carlo Valerio Bellieni (Siena)

09.2017.00 Il reconcetto-bonding di nei"normalità" nati da taglio del neonato: cesareo dall'anamnesi all'esame obiettivo VincenzoGherardo ZanardoRapisardi (Padova) (Firenze)

09.4017.20 EsameAssistenza neurocomportamentale neonatale in rooming- delin nato a termine GuidoGiovanna Calciolari Mangili (Lugano) (Bergamo)

10.00 Succhiotto si, succhiotto no 17.40 NestorALTE in Vain rooming-in: (Argentina) un pericolo reale? Niccolò Nassi (Firenze) 10.20 Discussione 18.00 Dimissione del neonato: tempi, modalità e controlli Pier Luigi Vasarri (Prato)

18.20 Discussione

Programma XIX Congresso Nazionale della Società Italiana di Neonatologia xi

29 Ottobre 2013 28 Ottobre 2013

09.00 - 11.30 Sala Palazzo Affari 15.00Simposio - 16.50 Educazionale Sala Palazzo Affari SessioneIl surfattante Parallela tra presente e futuro L'impoCon il contributostazione nutrizionale non condizionato neonatale di Chiesi tra normalitàFarmaceutici e problemi Presidente: Mario De Curtis (Roma) Moderatori:Presidente: VirgilioLuca Bernardo Carnielli (Milano) (Ancona), Gustavo Caoci (Roma) Moderatori: Fabrizio Sandri (Bologna), Giovanni Vento (Roma) 15.00 Microbiota intestinale nel nato a termine 09.00 FlaviaSommi Indrionistrazione (Bari) del surfattante con tecnica LISA Egbert Herting (Lübeck) 15.20 Ruolo epigenetico dell'alimentazione neonatale 09.20 UmbertoIl surfattante Simeoni sintetico: (Marsiglia) primi dati Tore Curstedt (Sweden) 15.40 Il reflusso gastro-esofageo nel neonato 09.40 LuigiIl surfattante Tommaso nella Corvaglia patologia (Bologna) respiratoria del lattante Paolo Biban (Verona) 16.00 Come e perché incentivare la produzione del latte materno 10.00 RiccardoStudio farmaco-economico Davanzo (Trieste) sul surfattante Carlo Dani (Firenze) 16.20 Discussione 10.20 Risultati dello studio SLI Gianluca Lista (Milano)

10.50 Discussione 17.00 - 18.50 Auditorium Sessione Parallela Il neonato tra normalità e imprevisti Presidente:11.00 - 13.30 Paolo Auditorium Giliberti (Napoli) MoSessionederatori: Plenaria Carlo Giannini (Roma), Giuseppe Presta (Tricase) Saranno Famosi 17.00Presidente: Il concetto Costantino di "normalità" Romagnoli (Roma)del neonato: dall'anamnesi all'esame obiettivo Moderatori:Gherardo Umberto Rapisardi Simeoni (Firenze) (Marsigl ia), Nestor Vain (Argentina)

17.20 Assistenza neonatale in rooming-in Giovanna Mangili (Bergamo)

17.4012.30 - 13.30ALTE in Sala rooming-in: Onice un pericolo reale? SimposioNiccolò Educazionale Nassi (Firenze) Prevenzione della perdita di calore nel neonato pretermine 18.00Con il contributoDimissione non del condizionato neonato: tempi, di GE modalitàHealthcare e controlli Pier Luigi Vasarri (Prato) Conduce: Francesco Messina Napoli) 18.20 Discussione 12:30 Ipotermia e VLBW Luca Antonio Ramenghi (Genova)

12:45 Prevenzione della perdita di calore alla nascita: quali evidenze Daniele Trevisanuto (Padova)

13:15 Discussione

13.30 - 14.30 Lunch

xii Programma XIX Congresso Nazionale della Società Italiana di Neonatologia

29 Ottobre 2013 28 Ottobre 2013

14.30 - 16.20 Auditorium 15.00 - 16.50 Sala Palazzo Affari Sessione Parallela IlSessione neonato Parallela da gravidanze complicate Presidente:L'impostazione Giacomo nutrizionale Faldella neonatale(Bologna) tra normalità e problemi Presidente: Mario De Curtis (Roma) Moderatori: Caterina Cacace (Patti), Lidia Decembrino (Pavia) Moderatori: Luca Bernardo (Milano), Gustavo Caoci (Roma) 14.30 Nati da gravidanze assistite 15.00 MariaMicrobiota Gabriella intestinale De Luca nel (Benevento) nato a termine Flavia Indrio (Bari)

14.50 Gemelli discordanti 15.20 AntonioRuolo epigenetico Alberto Zuppa dell'alim (Roma)entazione neonatale Umberto Simeoni (Marsiglia)

15.10 Neonato da madre con disturbi dell'omeostasi glicemica 15.40 EnricoIl reflusso Bertino gastro-esofageo (Torino) nel neonato Luigi Tommaso Corvaglia (Bologna) 15.30 Neonato da madre con patologia tiroidea 16.00 PaoloCome Ghirrie perché (Pisa) incentivare la produzione del latte materno Riccardo Davanzo (Trieste)

15.50 Discussione 16.20 Discussione

14.30 - 16.20 Sala Verde 17.00 - 18.50 Auditorium Sessione Parallela IlSessione neonato Parallela con piccoli/grandi problemi chirurgici Presidente:Il neonato tra Alberto normalità Villani e (Roma)imprevisti Moderatori:Presidente: PaoloGuglielmo Giliberti Paradies, (Napoli) Vittoria Pascale (Catanzaro) Moderatori: Carlo Giannini (Roma), Giuseppe Presta (Tricase)

14.30 Gestione del neonato con segnalazione prenatale di CAKUT 17.00 RinoIl concetto Agostiniani di "normalità" (Pistoia) del neonato: dall'anamnesi all'esame obiettivo Gherardo Rapisardi (Firenze) 14.50 Le emergenze chirurgiche neonatali 17.20 AntoniAssistenzano Morabito neonatale (Manchester) in rooming- in Giovanna Mangili (Bergamo) 15.10 L'ipoplasia mandibolare 17.40 AALTElberto in Bozzettirooming-in: (Monza) un pericolo reale? Niccolò Nassi (Firenze) 15.30 Gli angiomi: come comportarsi 18.00 ErnestoDimissione Bonifazi del neonato: (Bari) tempi, modalità e controlli Pier Luigi Vasarri (Prato) 15.50 Discussione 18.20 Discussione

Programma XIX Congresso Nazionale della Società Italiana di Neonatologia xiii

29 Ottobre 2013 28 Ottobre 2013

14.30 - 16.20 Sala Palazzo Affari Simposio15.00 - 16.50 Educazionale Sala Palazzo Affari DubSessionebi e certezze Parallela in nutrizione ConL'impo il contributostazione nutrizionale non condizionato neonatale di Milte tra normalità e problemi Presidente: Mario De Curtis (Roma) Presidente:Moderatori: IgnazioLuca Bernardo Barberi (Milano)(Messina), Gustavo Caoci (Roma) Moderatori: Giorgio Bracaglia (Tivoli), Massimo Palumbo (Viterbo) 15.00 Microbiota intestinale nel nato a termine 14.30 FlaviaI contaminanti Indrio (Bari) del latte: quale rischio per il neonato Simonetta Picone (Roma) 15.20 Ruolo epigenetico dell'alimentazione neonatale 14.50 UmbertoIl latte materno Simeoni in (Marsiglia) TIN: le buone pratiche Sandra Di Fabio (L'Aquila) 15.40 Il reflusso gastro-esofageo nel neonato 15.10 LuigiProfilo Tommaso di sicurezza Corvaglia ed efficacia (Bologna) della melatonina in età neonatale Angelo Massagli (Brindisi) 16.00 Come e perché incentivare la produzione del latte materno 15.20 RiccardoLa melatonina Davanzo in neonatologia(Trieste) Carmine D'Incecco (Pescara) 16.20 Discussione 15.40 Vitamina D e Fluoro: prevenire per non curare Serafina Lacerenza (Pavia)

16.00 Discussione 17.00 - 18.50 Auditorium Sessione Parallela Il neonato tra normalità e imprevisti Presidente: Paolo Giliberti (Napoli) Mo16.30deratori: - 18.20 Carlo Auditorium Giannini (Roma), Giuseppe Presta (Tricase) Sessione Parallela 17.00Il nato daIl concettomadre con... di "normalità" del neonato: dall'anamnesi all'esame obiettivo Presidente:Gherardo Maurizio Rapisardi De Martino (Firenze) (Firenze) Moderatori: Patrizio Fiorini (Firenze) , Pina Timpani (Reggio Calabria)

17.2016.30 AssistenzaInfezione luetica neonatale in rooming-in GiovannaPiero Valentini Mangili (Roma) (Bergamo)

17.4016.50 ALTEInfezione in rooming-in: da Toxoplasma un pericolo reale? NiccolòLina Bollani Nassi (Pavia) (Firenze)

17.10 Infezione Erpetica 18.00 Dimissione Fabio Natale del (Roma) neonato: tempi, modalità e controlli Pier Luigi Vasarri (Prato) 17.30 Rischio infettivologico 18.20 DiscussioneMaria Grazia Capretti (Bologna)

17.50 Discussione

xiv Programma XIX Congresso Nazionale della Società Italiana di Neonatologia

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16.30 - 18.20 Sala Verde Sessione15.00 - 16.50 Parallela Sala Palazzo Affari IlSessione neonato Parallela a rischio neurologico Presidente:L'impostazione Giovanni nutrizionale Cioni (Pisa) neonatale tra normalità e problemi Moderatori:Presidente: MarioElsa Buffone De Curtis (Roma) (Roma), Fabrizio Ferrari (Modena) Moderatori: Luca Bernardo (Milano), Gustavo Caoci (Roma) 16.30 Esame obiettivo neurologico di screening 15.00 EugenioMicrobiota Mercuri intestinale (Roma) nel nato a termine Flavia Indrio (Bari) 16.50 Il neonato con tremori e il neonato ipotonico 15.20 SimonaRuolo epigenetico Orcesi (Pavia) dell'alim entazione neonatale Umberto Simeoni (Marsiglia) 17.10 Il neonato con lesione del plesso brachiale 15.40 LuigiIl reflusso Memo gastro-esofageo (Belluno) nel neonato Luigi Tommaso Corvaglia (Bologna) 17.30 Sindrome da astinenza neonatale da farmaci e sostanze psicotropi 16.00 AndreaCome e Dotta perché (Roma) incentivare la produzione del latte materno Riccardo Davanzo (Trieste) 17.50 Discussione 16.20 Discussione

16.30 - 18.20 Sala Palazzo Affari Simposio17.00 - 18.50 Educazionale Auditorium PiccoleSessione e Parallelagrandi novità per il neonato ConIl neonato il contributo tra normalità non condizionato e imprevisti di DMF Presidente: Paolo Giliberti (Napoli) Presidente:Moderatori: BartolomeoCarlo Giannini Spinella (Roma) (Palermo), Giuseppe Presta (Tricase) Moderatori: Maurizio Finocchi (Roma), Rosario Magaldi (Foggia) 17.00 Il concetto di "normalità" del neonato: dall'anamnesi all'esame obiettivo 16.30 IlG herardosaccarosio Rapisardi in neonatologia: (Firenze) è utile? Roberto Antonucci (Cagliari) 17.20 Assistenza neonatale in rooming-in 16.50 LoGiovanna Zinco: Mangiliquesto (Bergamo)illustre sconosciuto Luca Maggio (Roma) 17.40 ALTE in rooming-in: un pericolo reale? 17.10 FortificazioneNiccolò Nassi (Firenze) del latte materno dopo la dimissione

18.00 PaolaDimissione Roggero del (Milano) neonato: tempi, modalità e controlli

Pier Luigi Vasarri (Prato) 17.30 Come formulare un latte ideale per il neonato normale

Massimo Agosti (Varese) 18.20 Discussione

17.50 Discussione

18.30 - 20.30 Auditorium

Assemblea dei Soci SIN

Programma XIX Congresso Nazionale della Società Italiana di Neonatologia xv

30 Ottobre 2013 28 Ottobre 2013

09.00 - 10.50 Auditorium Sessione15.00 - 16.50 Parallela Sala Palazzo Affari LaSessione patologia Parallela respiratoria grave del lattante Presidente:L'impostazione Giovanni nutrizionale Paolo Gancia neonatale (Cuneo) tra normalità e problemi ModeratoPresidente:ri: MarioFrancesco De Curtis Raimondi (Roma) (Napoli), Paolo Emilio Tagliabue (Monza) Moderatori: Luca Bernardo (Milano), Gustavo Caoci (Roma) 09.00 Il rischio di infezione da VRS nei neonati di età gestazionale 33-35 settimane 15.00 MicrobiotaMarcello Lanari intestinale (Imola) nel nato a termine Flavia Indrio (Bari) 09.20 Le linee guida per la profilassi dell'infezione da VRS: necessità di aggiornamento? 15.20 RuoloAlberto epigenetico Dall'Agnola dell'alim(Bussolengo)entazione neonatale Umberto Simeoni (Marsiglia) 09.40 Il trattamento della bronchiolite nei primi mesi di vita 15.40 IlEugenio reflusso Baraldi gastro-esofageo (Padova) nel neonato Luigi Tommaso Corvaglia (Bologna) 10.00 Il trattamento della patologia respiratoria grave nei primi mesi di vita 16.00 ComeCorrado e perchéMoretti incentivare(Roma) la produzione del latte materno Riccardo Davanzo (Trieste) 10.20 Discussione 16.20 Discussione

09.00 - 10.50 Sala Verde

Sessione Parallela 17.00 - 18.50 Auditorium Il neonato a "rischio" ecografico Sessione Parallela Presidente: Onofrio Sergio Saia (Treviso) Il neonato tra normalità e imprevisti Moderatori: Rita Luciano (Roma), Carlo Poggiani (Cremona) Presidente: Paolo Giliberti (Napoli)

Moderatori: Carlo Giannini (Roma), Giuseppe Presta (Tricase) 09.00 Ecografia cerebrale nel nato a termine: perché e quando?

Laura Bartalena (Pisa) 17.00 Il concetto di "normalità" del neonato: dall'anamnesi all'esame obiettivo

Gherardo Rapisardi (Firenze) 09.20 Pneumotorace e pneumomediastino asintomatici: che fare?

Nicola Cassata (Palermo) 17.20 Assistenza neonatale in rooming-in

Giovanna Mangili (Bergamo) 09.40 Ecografia delle anche: pro e contro

Alberto Chiara (Voghera) 17.40 ALTE in rooming-in: un pericolo reale?

Niccolò Nassi (Firenze) 10.00 Ecografia del rachide per disrafismi spinali

Claudia Rendeli (Roma) 18.00 Dimissione del neonato: tempi, modalità e controlli

Pier Luigi Vasarri (Prato) 10.20 Discussione

18.20 Discussione

xvi Programma XIX Congresso Nazionale della Società Italiana di Neonatologia

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09.00 - 11.10 Sala Palazzo Affari Sessione15.00 - 16.50 Infermieristica Sala Palazzo Affari CareSessione e Rooming-in Parallela da oggi al futuro Presidente:L'impostazione Antonella nutrizionale Maini (Pavia) neonatale tra normalità e problemi ModeratPresidente:ori: MarioRoberta De Guardione Curtis (Roma) (Torino), Denis Pisano (Cagliari) Moderatori: Luca Bernardo (Milano), Gustavo Caoci (Roma) 09.00 Profili professionali al nido 15.00 AnnamMicrobiotaaria Battanintestinale (Monza) nel, natoRemo a Galavernatermine (Cuneo) Flavia Indrio (Bari) 09.20 Ruolo e competenze dell'nfermiere nell'ambulatorio infermieristico 15.20 DonatellaRuolo epigenetico Trapanelli dell'alim (Milano)entazione neonatale Umberto Simeoni (Marsiglia) 09.40 La cultura della nascita 15.40 ElisabettaIl reflusso Dionigastro-esofageo (Brescia), Cristina nel neonato Tantere (Brescia) Luigi Tommaso Corvaglia (Bologna) 10.00 Il counselling infermieristico come strumento per comprendere gli eventuali disagi familiari 16.00 postCome-partum e perché incentivare la produzione del latte materno AntonellaRiccardo Davanzo Pelliccione (Trieste) (L'Aquila)

10.2016.20 CareDiscussione e neonato sano Giovanna Cuomo (Modena)

10.40 Discussione

17.00 - 18.50 Auditorium Sessione Parallela Il neonato tra normalità e imprevisti 11.20 - 13.20 Sala Palazzo Affari Presidente: Paolo Giliberti (Napoli) Sessione Infermieristica Moderatori: Carlo Giannini (Roma), Giuseppe Presta (Tricase) Care e Rooming-in da oggi al futuro

Presidente: Gianna Rossi (Bologna) 17.00 Il concetto di "normalità" del neonato: dall'anamnesi all'esame obiettivo Moderatori: Maria Grazia Cristofori (Ferrara) , Fabrizia Stizzoli (Varese) Gherardo Rapisardi (Firenze)

11.20 La rilevazione della saturazione nel neonato fisiologico 17.20 Assistenza neonatale in rooming-in Monica Ravani (Cremona) Giovanna Mangili (Bergamo)

11.40 Gestione del cordone ombelicale: stato dell'arte 17.40 ALTE in rooming-in: un pericolo reale? Elena Bernabei (Aversa) Niccolò Nassi (Firenze)

12.00 Trattamento routinario del moncone ombelicale vs. nessun trattamento: studio RC 18.00 Dimissione del neonato: tempi, modalità e controlli Carla Fusetti (Milano), Mariateresa Garavaglia (Milano) Pier Luigi Vasarri (Prato)

12.20 Allattamento al seno in madri con fattori di rischio 18.20 Discussione Elena Vagli (Pisa)

12.40 Efficacia della saturazione sensoriale durante l'esecuzione di procedure invasive minori:

esperienza triennale

Maria Di Ventura (Roma), Assunta Fabi (Roma)

13.00 Discussione

Programma XIX Congresso Nazionale della Società Italiana di Neonatologia xvii

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11.00 - 12.50 Auditorium 15.00Sessione - 16.50 Plenaria Sala Palazzo Affari SessioneNeonatologia Parallela tra medicina legale e ricerca clinica L'impoPresidente:stazione Daniele nutrizionale Farina (Torino) neonatale tra normalità e problemi Presidente:Moderatori: Mario Armando De Curtis Cuttano (Roma) (Pisa) , Lucio Giordano (Napoli) Moderatori: Luca Bernardo (Milano), Gustavo Caoci (Roma) 11.00 La tutela assicurativa e medico-legale in Neonatologia 15.00 MicrobiotaPaolo D'agost intestinaleino (Torino) nel nato a termine Flavia Indrio (Bari) 11.20 Il ruolo delle Società scientifiche 15.20 RuoloGiovanni epigenetico Corsello (Palermo)dell'alimentazione neonatale Umberto Simeoni (Marsiglia) 11.40 Come la ricerca negli ultimi anni ha modificato la nostra pratica clinica 15.40 IlFabio reflusso Mosca gastro-esofageo (Milano) nel neonato Luigi Tommaso Corvaglia (Bologna) 12.00 La prevenzione degli errori in neonatologia 16.00 ComeNicola e Antonio perché Romeoincentivare (S. Marino) la produzione del latte materno Riccardo Davanzo (Trieste) 12.20 Discussione 16.20 Discussione

13.00 - 13.30 Auditorium Chiusura dei lavori

17.00 - 18.50 Auditorium Sessione Parallela Il neonato tra normalità e imprevisti Presidente: Paolo Giliberti (Napoli) Moderatori: Carlo Giannini (Roma), Giuseppe Presta (Tricase)

17.00 Il concetto di "normalità" del neonato: dall'anamnesi all'esame obiettivo Gherardo Rapisardi (Firenze)

17.20 Assistenza neonatale in rooming-in Giovanna Mangili (Bergamo)

17.40 ALTE in rooming-in: un pericolo reale? Niccolò Nassi (Firenze)

18.00 Dimissione del neonato: tempi, modalità e controlli Pier Luigi Vasarri (Prato)

18.20 Discussione

Early Human Development 89S4 (2013) S1–S2

Term pregnancy and mode of delivery

Arsenio Spinillo *, Chiara Cassani, Stefano Bogliolo

Department of Obstetrics and Gynaecology, IRCCS-Fondazione Policlinico San Matteo and University of Pavia, Pavia, Italy

1. Defining term pregnancy: need for a rethinking? prevalence between different countries in consequence of different policies of labor induction and methods for assessing gestational Traditionally, pregnancy is considered "at term" when gestation age. While pathophysiology of prolongation of pregnancy is largely has lasted 37 completed weeks (260 days) but less than 42 weeks unknown, some risk factors are identified such as pre-pregnancy (294 days) since the first day of last menstrual period. Only in obesity, nulliparity, maternal age over 30 years, fetal abnormality the recent years a growing number of evidence suggest that a and also placental senescence and placental sulphatase deficiency. significant differences exist in neonatal morbidity and mortality of Post-term pregnancy seems to be associated with a increased rate infants delivered within the 5-week interval classically considered of fetal, maternal and neonatal morbidity and mortality, even if term gestation. According to available data it plausible to introduce thereisnoconclusiveevidenceinliteraturethatprolongationof a subcategory of term births defining infants delivered from 37 pregnancy per se is the major risk factor. Fetal complications include before 39 weeks, called “early term” [1]. Short term morbidity such stillbirth, intrauterine growth restriction, oligohydramnios, meco- as respiratory distress, neonatal infection, rates of mechanical ven- nium aspiration, macrosomia. Most common maternal complication tilation and intensive care is increased in neonates born before 39 such as dysfunctional labor, shoulder dystocia, obstetric trauma and weeks’ gestation compared with those born beyond. Also neonatal post-partum hemorrhage are associated with increased newborns mortality rate and sudden infant death increased for births between weight which in observed in 26% of births at 41 weeks. Neonatal 37 and 38 week’s compared with birth at 39 and beyond and mortality is associated with SGA (small for gestational age) and remained stable till 40 completed weeks (Table 1) [2]. Moreover, major congenital malformation. Neonatal morbidity includes low even if no long-term studies exist comparing neurological capacity Apgar scores, meconium aspiration syndrome, shoulder dystocia of “early term” infant to those born at 39–40 weeks, we might and Erb’s palsy. Up to date in order to avoid post-term pregnancy expect higher incidence of learning impairment in infant delivered complications routine induction before 42 weeks is proposed and at 37–38 weeks due to the continuum growth evident in human this policy is associate with fewer perinatal deaths and fewer brain. A further issue is the accurate assessment of gestational cesarean section compared to expectant management [3]. Labor age based on early US confirmation of fetal biometry since the induction policy reduces also the rate of newborns greater than estimated delivery date based on menstrual history only might 4000 gr but increases the rate of operative vaginal birth. Up to have a high variability. date the optimal timing of labor induction is still unknown but the option of labor induction should be offered at 41 to 42 weeks. For 2. Elective induction of labor: when, why, how? women choosing expectant management fetal monitoring should be started at 41 weeks also to identify fetuses at high risk. There According to FIGO and ACOG a pregnancy reaching 42 com- is no agreement on a specific fetal surveillance technique for pleted weeks (294 days) is defined as post-term. About 4% to 10% post-term pregnancies capable to predict acute adverse events. of all pregnancies last beyond 42 weeks with a wide variation of None of the most commonly used tests such as cardiotocography, amniotic fluid volume assessment, fetal biophysical profile and Table 1 Doppler ultrasound, have shown good predictive value. The success Perinatal mortality at term pregnancy (modified by Clark et al. [1]. of labor induction is dependent on different factors, first of all on Week of birth Cumulative probability of Perinatal mortality the characteristics of the cervix commonly evaluated using Bishop’s perinatal death rate score. Almost 30 percent of women with a Bishop score of 3 or 37 2–3/1000 9–10/1000 less at time of labor induction have a cesarean delivery compared 38 1–2/1000 4–5/1000 with a rate of cesarean birth of only 4 percent in women with 39 1–2/1000 2–3/1000 Bishop score of 8 or more. Many methods are used for elective 40 2–3/1000 2–3/1000 41 1–2/1000 1–2/1000 induction of labor. The available evidence suggest that membrane 42 2–3/1000 2–3/1000 sweeping near term could reduce the use of more formal methods 43 3–4/1000 3–4/1000 of induction [4]. Unfavorable cervix requires cervical ripening using mechanical device as trans-cervical catheter or pharmacological methods such as prostaglandins (PGE2, PGE1,PGF2a) in different * Corresponding author: Arsenio Spinillo, Department of Obstetrics and Gynae- cology, IRCCS-Fondazione Policlinico San Matteo and University of Pavia, 19 Viale vaginal preparations including gels, tablets, suppositories and pes- Camillo Golgi, 27100 Pavia, Italy. saries. Oxytocin infusion with or without amniotomy can be used

0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. S2 A. Spinillo et al. / Early Human Development 89S4 (2013) S1–S2 for labor induction in case of favorable bishop score. Concurrent abnormality such malformation and fibroids, breech delivery in use of oxytocin and prostaglandin is associated with higher risk previous pregnancy. Since the publication in 2000 of the results of a of hyperstimulation and non reassuring cardiotocography. Further large randomised controlled study assessing the benefit of cesarean research is need to assess the best method and vehicle for labour section for breech presentation compared with vaginal birth, the induction [5]. rate of cesarean birth has increased markedly [9]. Consequently obstetricians are loosing the skill of supporting women having 3. Cesarean section on maternal request: too posh to push? vaginal breech birth. External cephalic version should be proposed to reduces the incidence of noncephalic presentation at delivery and Delivery by cesarean section continue to increase in both so reduce the rate of avoidable caesarean section. Evidences from developed and developing countries. Although difficult to quantify, literature demonstrate that external cephalic version significantly it has been estimated that nearly 4% to 18% of all cesarean section reduce the chance of caesarean section; the success rate, with a worldwide are done on maternal request [6]. Patients who require trained operator, range from 50 to 80 percent depending on race, cesarean section and even caregivers cite the fear of perineal parity, uterine tone, liquor volume, engagement of the breech and injury such anal and urinary incontinence, postpartum hemorrhage, whether the head is palpable, and the use of tocolysis. Tocolytic sexual dysfunction, pain, loss of control, fetal injury and mortality. drugs, in particular betastimulants, were effective in increasing Moreover popular press stories of celebrities requiring cesarean cephalic presentations in labour and in reducing the number of section might influence other women’s decision over mode of birth. caesarean sections [10]. External cephalic version should be offered Up to date no randomized controlled trials exists which make from 36 weeks in nulliparous and from 37 weeks in multiparous a comparison of maternal and neonatal morbidity and mortality women. Since this manipulations have a risk, even if very low, between elective cesarean section on maternal request and vaginal of complications such as placental abruption, uterine rupture and delivery. fetomaternal haemorrhage, external cephalic version should be Caesarean section is a risk factor for the development of neona- performed where facilities for monitoring and immediate delivery tal respiratory complications, mostly respiratory distress syndrome are available. (RDS) and transient tachypnoea of the newborn, but also severe No evidence supported the use of postural management or persistent pulmonary hypertension and hypoxic respiratory failure moxibustion to promote spontaneous version of the breech, further both in term and preterm infants [7]. Several studies have shown studies are needed. that respiratory morbidity and need of intensive care in infants born by elective cesarean section at term are inversely related to Conflict of interest gestational age and this trend is particularly pronounced for RDS. In an effort to reduce this morbidity ACOG and NICE recommends The authors have no conflict of interest to declare. delaying elective cesarean section at 39 weeks or later, or waiting for the onset of spontaneous labor. Pathophysiology of respiratory References complications seems to be different in term-birth compared to [1] Clark SL, Fleischman AR. Term pregnancy: time for a redefinition. Clin preterm-birth: a key role is performed by lung epithelial sodi- Perinatol 2011;38:557–64. umchannel that switch from a chloride secretory to a sodium [2] Reddy UM, Ko CW, Willinger M. “Early” term birth (37–38 weeks) are reabsorption mode promoting alveolar fluid drainage. Although associated with increased mortality Am J Obstet Gynecol 2006;195:S202. little is known about the precise mechanisms underpinning this [3] Gulmezoglu AM, Crowther CA, Middleton P, Heatley E. Induction of labour physiologic changes in lung epithelia, the process of labor seems to for improving birth outcomes for women at or beyond term (Review). The Cochrane Collaboration 2012. be necessary for complete lung maturation. Glucocorticoids appear [4] Boulvain M, Stan CM, Irion O. Membrane sweeping for induction of labour to increase the number and function of sodium channels accel- (Review). The Cochrane Collaboration 2010. erating reabsorption of fetal lung fluid. In view of this evidence, [5] Kelly AJ, Malik S, Smith L, Kavanagh J, Thomas J. Vaginal prostaglandin Stutchfield and coworkers demonstrated the efficacy, in elective (PGE2 and PGF2a) for induction of labor at term (Review). The Cochrane Collaboration 2012. cesarean section at term, of antepartum course of betamethasone [6] Wax JR, Cartin A, Pinette MG, et al. Patient choice cesarean: an evidence- given 48 hours before delivery in reducing admission in neonatal based review. Obstet Gynecol Surv 2004;59:601. intensive unit for respiratory distress [8]. In absence of trail data [7] Ramachandrappa A, Jain L. Elective cesarean section: it’s impact on neonatal comparing elective cesarean section and vaginal delivery good qual- respiratory outcome. Clin Perinatol 2008;35(2):373-vii. ity prospective studies of short and long term neonatal morbidity [8] Stutchfield P, Whitaker R, Russell I. Antenatal betamethasone and incidence of neonatal respiratory distress after elective caesarean section: pragmatic are needed in order to better counselling women choice. randomized trial. BMJ 2005;331:662. [9] Hannah ME, Hannah WJ, Hewson SA, Hodnett ED, Saigal S, Willan AR. Planned 4. External cephalic version: safety and harms caesarean section versus planned vaginal birth for breech presentation at term: a randomised multicentre trial. Term Breech Trial Collaborative Group. Lancet 2000;356:1375–83. Breech presentation complicates 3–4% of all pregnancies at [10] Cluver C, Hofmeyr GJ, Gyte GM, Sinclair M. Interventions for helping to turn term and a higher proportion of preterm delivery. Major risk term breech babies to head first presentation when using external cephalic factors for breech presentation are premature labor, multiple version. The Cochrane Collaboration 2012. pregnancy, polyhydramnios, hydrocephaly, placenta praevia, uterin Early Human Development 89S4 (2013) S3

Term of pregnancy and mode of delivery: the neonatologist’s point of view

Marco Pezzati *, Beatrice Gambi

Neonatology and NICU, Ospedale San Giovanni di Dio, ASL 10, Firenze, Italy

At all gestational ages, the risks of continuing a pregnancy 6/7 weeks gestation and comprised 70% of all preterm births [3]. must be carefully balanced against the risk of delivery and the Compared with those born at term, LPT infants are at increased associated risk of prematurity. The American College of Obstetrics risk of neonatal mortality and morbidity [4] including hyperbiliru- and Gynecology (ACOG) and the American Academy of Pediatrics binemia, hypoglycemia, feeding and respiratory problems [5]. The (AAP) define term pregnancy as one that has completed 37 weeks last few weeks of gestation are critical for fetal development and of gestation and that delivers after the first day of the 38th week of maturation, gradually preparing the fetus for a safe landing [6]. pregnancy [1]. Consequently LPT must not be considered a “near term” infant and This definition is wholly usable for physiological pregnancy, in since respiratory morbidity in elective section is related inversely the absence of maternal/fetal pathology and in the absence of risk to gestational age at the time of surgery [7], the ACOG [1] recom- factors. There are conditions that can somehow change the concept mends scheduling elective cesarean section at 39 weeks or waiting, of term of pregnancy as intrauterine growth restriction (IUGR), if possible, for the onset of spontaneous labor. twin pregnancy, fetal macrosomia, poorly controlled diabetes with If literature regarding complications of LPT birth is becoming excess of fetus growth and so on. Not least, the proper management well established, there is also growing awareness about the risks both of late preterm infant and early term infant must carefully ob being born on the earlier end of term gestation [8]. Even if consider the choice of the appropriate timing and mode of delivery. term gestation has been traditionally considered an homogeneous In IUGR the concept of term pregnancy can be extremely category regarding neonatal outcomes, many recent studies are variable in direct relationship both of fetal growth rate and degree showing that infants born at early term (37 0/7–38 6/7 weeks) have of uterine-placental level compensation monitored by placental a greater risk of complications than term infants 39 0/7–41 6/7 flow controls in the uterine, umbilical, cerebral arteries and venous [9–11] both during hospital care and in the home setting [8]. To duct and it influences the appropriate timing and modality of date, there are no studies that show a benefit to cesarean delivery delivery. over vaginal delivery for the late preterm and early term infants. There has been a lot of discussion of the utility of preterm Therefore, it remains the recommendation to perform cesarean delivery for multiplies pregnancy. The logic behind the debate is delivery for standard indications in these groups [2]. that the risk of fetal death increases at an earlier gestational age for multiplies than for singletons. It is necessary to analyze where Conflict of interest the risks of neonatal death and fetal death intersect. For twins, this is at 39 weeks, but for triplets it is at 36 weeks [2]. The The authors have no conflict of interest to declare. biamniotic, monochorionic pregnancy presents beyond the 36–37 weeks gestation a high risk for placental problems so it appears References prudent to regard this time as the term of pregnancy. In multi- [1] American Academy of Pediatrics and the American College of Obstetricians and ple gestations with more than 2 fetuses the delivery should be Gynecologist. Guidelines for Perinatal Care. 5th ed. Elk Grove Village, IL; 2005. prudentially programmed around 34–35 weeks while in monoam- [2] Dobak WJ, Gardner MO. Late Pretrm Gestation: Physiology of Labor and niotic pregnancy the term of pregnancy should be considered at Implications fo Delivery. Clin Perinatol 2006;33;765–76. 34 weeks. [3] Martin JA, Hamilton BE, Ventura SJ, et al. Births: final data for 2009. Nat Vital Stat Rep 2011;60(1):1–70. On the contrary, there are conditions where to change the [4] Tomashek KM, Shapiro-Mendoza CK, Davidoff MJ, Petrini JR. Differences in concept of term of pregnancy may be contraindicated. This is for mortality between late-preterm and term singleton infants in the United some maternal illnesses that do not find advantage in anticipate States, 1995–2002. J Pediatr 2007;151(5):450–6. the timing of delivery: grave myopia, multiple sclerosis, epilepsy, [5] Escobar GJ, McCormick MC, Zupancic JA. Unstudied infants: outcomes of paroxystic arrythmia, gestational and mellitus diabetes if well moderately premature infants in the neonatal intensive care unit. Arch Dis Child Fetal Neonatal Ed 2006;91:F238–44. controlled an so on. It is instead uncertain the mode of delivery in [6] Dudell GG, Jain L. Hypoxic Respiratory Failure in the Late Preterm Infant Clin case of poorly controlled diabetes with fetus in excess of growth Perinatol 2006;33:803–30. because of possible both fetal and neonatal consequences. [7] Morrison JJ, Rennie JM, Milton PJ. Neonatal respiratory morbidity and mode Late-preterm (LPT) birth is defined as delivery at 34 0/7 to 36 of delivery at term : influence of timing of elective cesarean section. Br J Obstetric Gynaecol 1995;102(2):101–6. [8] Hwang SS, Barfield WD, Smith RA, Morrow B, Shapiro-Mendoza CK, Prince CB, Smith VC, McCormick MC. Discharge Timing, Outpatient Follow-up, and Home * Corresponding author. Care of Late-Preterm and Early-Term Infants. Pediatrics 2013;132:101–8.

0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. S4 M. Pezzati, B. Gambi / Early Human Development 89S4 (2013) S3–S4

[9] Reddy UM, Bettegowda VR, Dias T, Yamada-Kushnir T, Ko CW, Willinger M. Medicine Units Network. Timing of elective repeat cesarean delivery at term Term pregnancy: a period of heterogeneous risk for infant mortality. Obstet and neonatal outcomes. N Engl J Med 2009;360(2):111–20. Gynecol 2011;117:1279–87. [11] Dietz PM, Rizzo JH, England LJ. Early term delivery and health care utilization [10] Tita AT, Landon MB, Spong CY; Eunice Kennedy Shriver NICHD Maternal-Fetal in the first year of life. J Pediatr 2012;161(2):234–9. Early Human Development 89S4 (2013) S5–S7

Hearing and vision screening

Giancarlo Gargano

Neonatal Intensive Care Unit (NICU), Arcispedale S. Maria Nuova, IRCCS, Reggio Emilia, Italy

The aim of neonatal screening is to identify real or potential Table 1 health problems at the earliest possible time in order to promote Risk indicators associated with permanent congenital hearing loss (from JCIH 2007 –modified). early intervention and to assure optimum health in neonates, infants and children. Among the different newborn screening Neonatal intensive care of more 5 days: < programs in recent years, hearing and vision screening have gained – Preterm birth (GA 34 ws) –Lowbirthweight(<1500 g) importance and widespread acceptance. – Assisted ventilation and ECMO – Neonatal meningitis or sepsis 1. Newborn hearing screening (NHS) – Birth asphyxia/(APGAR <7at5’) – Hyperbylirubinemia and exchange-transfusion Congenital hypoacusis is a very serious handicap with an – Seizure – Exposure to ototoxic medications (AMG, furosemide) exceptionally high social cost and it is estimated that in Europe the Intrauterine infections (TORCH) cost of hearing loss not subjected to therapy varies between 170 Craniofacial anomalies and 220 billion euro. Syndromes associated with hearing loss Every year in Italy 1500–2000 babies suffer hearing loss. Ap- Family history of permanent childhood hearing loss proximately 25,000 children under 10 years have communicative disorders caused by hearing impairment of varying degrees and 6500–7000 school children required special education. on Infant Hearing (JCIH), the American Academy of Pediatrics (AAP) It has been found that the earlier the onset and the later the released statements that recommended newborn hearing screening diagnosis, the more serious the prognosis of hearing loss, therefore and intervention. Healthy People 2010 proposed an ambitious pro- congenital forms are always very severe. Diagnosis and treatment gramme with three objectives: “to increase hearing loss screening are often delayed until the age of 1 or 2 years in children with at one month, to increase audiological evaluation at 3 months, hearing loss, particularly among those at low risk. and to increase enrolment in appropriate healthcare services at 6 The failure to identify moderate or severe congenital hearing months.” [4]. loss is associated with delayed language, speech and learning Despite the high prevalence of hearing loss and its real impact development resulting in serious neurobehavioral sequelae. on spoken language and cognitive development, accessible reli- As first shown by Yoshinaga-Itano [1], and later confirmed by able screening methods and effective management strategies for numerous other studies, early identification of congenital hearing neonatal hearing screening programs have not yet been universally loss (within 6 months), allows, through the adoption of timely and adopted appropriate treatment programs and follow-up, a proper language NHS was introduced in Italy in 1997, but actual employment has development thus significantly improving the neuro-psychological been very slow. In 2003 only 29.3% of public hospitals performed prognosis. NHS. In 2008, only 60% of Italian newborns underwent NHS In The prevalence of permanent childhood hearing impairment is 2011, the NHS framework was improved and the figure for infants approximately 1.3/1000 [2], several times more prevalent in new- screened at birth rose to about 80% borns than other routinely screened disorders such as phenilke- Audiological screening can be implemented by adopting dif- tomuria (1.10/20,000), congenital adrenal hyperplasia (1/12,000), ferent protocols and strategies, but everyone agrees that at birth hypothyroidism, cystic fibrosis and drepanocytosis (1/4000). These low-risk infants should be differentiated from high-risk ones. data alone would justify the adoption of universal audiological screening. A. In low-risk infants (well-infant nurseries) audiological screening In some categories, the prevalence of hearing impairment is can be carried out either with the use of: even greater, in particular, the NICU rate is estimated at 2–4%. In – Evoked otoacoustic emissions (transient evoked otoacoustic VLBW patients, neurosensory testing has revealed that occurrence emissions – TEOAE) is increasing continuously and currently hearing loss in distance – Auditory evoked potentials (ABR screening or automated ABR). stands at about 7% [3]. Otoacoustic emissions, describing cochlea response, are emitted The most important risk indicators [4] associated with congeni- in the form of acoustic energy and measure the contractile activity tal hearing loss are showed in Table 1. of external ciliate cells and are used as an objective indicator of In 1999 and again in 2007, together with the Joint Committee cochlear pathology. To perform this test, a miniature earphone and

0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. S6 G. Gargano / Early Human Development 89S4 (2013) S5–S7 microphone are placed in the ear, sounds are played and a response all childhood blindness [6]. In Europe and in USA prevalence of is measured. If a baby hears normally, an echo is reflected back into congenital and infantile cataract has been estimated to be about the ear canal and is measured by the microphone. When a baby has 1/10,000 births [7]. The optimal time to remove congenital cataracts a hearing loss, no echo can be measured on the OAE test. Since the and initiate optical treatment appears to be between 4 and 6 weeks analysis is reproducible, diagnostically accurate, easy to perform of age; this fact has been related to the developmental physiology and minimally invasive, the use of transient evoked otoacoustic of the human visual system, which becomes sensitive to visual emissions (TEOAEs) is presently the method of choice for neonatal deprivation at 6 weeks after birth. Therefore, delayed diagnosis and audiological screening in the general population. treatment for congenital cataract may result in abnormal visual Auditory brainstem response (ABR) can also be used as a screening development with irreversible amblyopia. In spite of this in USA test in newborn hearing screening programs. To perform this test, 38% of congenital cataract were diagnosed after age 6 weeks in sounds are played to the baby’s ears. Band-aid like electrodes are 2003. placed on the baby’s head to detect responses. This test measures In the 2008, AAP established the necessity of vision screening how the hearing nerve responds to sounds and can identify babies [8] and declared that: “all neonates, infants and children should who have a hearing loss. have an examination of the red reflex of eyes performed by ABR is a very precise test but is too complex for universal a pediatrician or other primary care clinician trained in this screening. TEOAE is generally easier to administer and faster. examination technique before discharge from the neonatal nursery TEOAE has very good sensitivity and specificity with a very low and during all subsequent routine health supervision visits.” The number of false negative and false positive rates (about 2–5%) [5]. “RED Reflex Examination” has been strongly recommended as screening test. B. In high-risk individuals, particularly NICU patients, it is instead This test has, in fact, proved to be extremely effective and sensi- recommended to carry out the audiological screening using tABR or tive in precociously identifying all the situations that can potentially even better by combining the two techniques. impair the vision or the life of subjects, such as: cataracts glaucoma In fact, a great number of preterm infants are at risk of retinoblastoma, the retinal abnormalities, systemic diseases with developing “Auditory Neuropathy”, a condition characterized by the ocular manifestations and high refractive errors. presence and normo-functionality of outer hair cells of the cochlea, Certain categories of persons are considered at high risk of but where noise impulses are not accurately transmitted to the visual impairment and require examinations by specialists such as auditory nerve (Retrocochlear S.). These individuals present normal ophthalmologists experienced in pediatric assessment (referral to TEOAEs, while their ABRs are pathological. an ophthalmologist who has experience in examining children for In the province of Reggio Emilia (Fig. 1) an audiological neonatal a complete eye examination) regardless of the outcome of the red screening program has been in operation since 2009 and in the reflex examination. These categories include: last 4 years 19,803 infants, representing a coverage of 99.94%, were 1. Premature babies screened The percentage of referr sent to the 3rd level was 1.19%. 2. Family history of congenital cataracts, retinoblastoma, glau- 34 subjects with hearing loss, equal to 1.44‰ were thus identified. coma, retinal abnormalities and metabolic or genetic diseases A profound hearing loss was found in 0.72‰ of the cases. 3. Newborns with significant developmental delay or neurologic It is important to point out, however, that some forms of hearing difficulties loss are post-natal and late-onset so an appropriate audiological 4. Babies with systemic disease associated with eye abnormali- surveillance program after the neonatal period is necessary. ties The red reflex examination uses the transmission of light by 2. Vision screening an ophthalmoscope, through all the normal transparent part of the eyes (tear film, cornea, aqueous humor, crystalline lens, and The incidence of childhood blindness due to congenital causes vitreous humor) and evaluates the quality of the transparent media. has been reported as 1.6/10,000 live births; etiologies include The light reflected off the ocular fundus, is transmitted back and intrauterine infections, metabolic disorders, chromosomal abnor- is imaged in the eye of the examiner. If there is any alteration, malities and inheritance [6]. Congenital cataract is the leading the quality will be bad and it will not be possible to observe the cause of preventable childhood blindness or vision deficit. In some reflection. reports untreated congenital cataracts are responsible for 10% of The test is considered normal if a regular and symmetrical red reflex can be observed in both eyes and is considered pathological if any “dark spots in the red reflex, a marked diminished reflex, the presence of a white reflex, or asymmetry of the reflex” is observed. Any of these conditions should lead to an “urgent” examination by an ophthalmologist who is a experienced in treating children. Despite the above recommendations, the red reflex has not yet entered into clinical practice and the coverage of this test is not very high in Italy. There are no definitive data on the true extent of screening. In 2008, Tuscany was the first Italian region, followed by Umbria, to make testing mandatory, but the adoption of this test throughout the country is extremely variable.

Conflict of interest

The author has no conflict of interest to declare.

References

[1] Yoshinaga-Itano C. Benefits of early intervention for children with hearing loss. Figure 1 Otolaryngol Clin North Am 1999;32(6):1089–102. G. Gargano / Early Human Development 89S4 (2013) S5–S7 S7

[2] O’Connor A, O’Sullivan PG, Behan L, Norman G, Murphy B. Initial results from compared with diagnostic test of auditory test brain stem response in Tehran the newborn hearing screening programme in Ireland. Ir J Med Sci. 2013 Mar hospital. Iran J Pediatr 2013;23(2):199–204. 2[Epubaheadofprint]. [6] Eventov-Friedman S, Leiba H, Flidel-Rimon O, Juster-Reicher A, Shinwell ES. [3] Wilson-Costello D, Friedman H, Minich N, Fanaroff AA, Hack M. Improved The red reflex examination in neonates: an efficient tool for early diagnosis of survival rates with increased neurodevelopmental disability for extremely low congenital ocular diseases. Isr Med Assoc J 2010;12:259–61. birth weight infants in the 1990s. Pediatrics 2005;115(4):997–1003. [7] Litmanovitz I, Dolfin T. Red reflex examination in neonates: the need for early [4] American Academy of Pediatrics. Position Statement: Principles and guide- screening. Isr Med Assoc J. 2010;12(5):301–2. lines for early hearing detection and intervention programs. Pediatrics 2007; [8] American Academy of Pediatrics, American Association for Pediatric Oph- 120:898–921. thalmology and Strabism, American Academy of Ophthalmology, American [5] Yousefi J, Ajalloueyan M, Amirsalari S, Hassanali Fard M. The specificity and Association of certified Orthoptists. Red reflex examination in neonates, infants sensitivity of transient otoacustic emission in neonatal hearing screening and children. Pediatrics 2008;122:1401–4. Early Human Development 89S4 (2013) S8–S9

Pulse oximetry newborn screening for congenital heart defects. Is it really useful?

Federico Schena *, Elena Ciarmoli, Alessandra Mayer, Alessia Cappelleri, Laura Bassi, Monica Fumagalli, Fabio Mosca

Neonatal Intensive Care Unit, Department of Clinical Science and Comunity Health, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy

Congenital heart diseases (CHDs) are the most common birth The reported sensitivity and specificity of pulse oximetry differ defects, occurring in 8–9/1,000 live births and they represent one of among studies depending on the timing of the test and the oxygen theleadingcauseofinfantdeath in the developed countries. saturation threshold. According to a recent metanalysis, based on A timely diagnosis is beneficial as even most critical cases the results of 11 published study, the overall sensitivity of pulse can be successfully repaired by cardiac surgery or interventional oximetry for detection of critical congenital heart defects is 76.5% catheterization procedures or may undergo a satisfactory palliation. while specificity is 99.9% [3]. Conversely, a delayed diagnosis may expose patients to the detri- The authors concluded that pulse oximetry meets the criteria to mental effects of prolonged hypoxia or hypoperfusion, worsen the become an universal neonatal screening. preoperative condition and ultimately increase the risk of death or In 2011 in the United States, the Secretary of Health and Human neurological sequelae [1]. Services (HHS) with the endorsement of the American Accademy With the advances in prenatal care many cases of CHDs are of Pediatrics recommended the universal implementation of pulse nowadays detected before birth. Nevertheless, the effectiveness of oximetry screening for critical CHDs and since then all birthing antenatal ultrasound screening is still not optimal and the detection facilities countrywide are gearing up to put the exam into routine rate of CHDs currently does not exceed 70% in the best case series. clinical practice [4]. At the present time CHDs that grossly alter the size of the four However, a well-recognized limitation of this screening tool cardiac chambers are easily recognized by fetal ultrasound while is the low sensitivity in detecting CHDs with obstruction to other severe defects such as aortic coarctation, transposition of the systemic circulation (i.e. aortic coarctation, interrupted aortic the great arteries and anomalous pulmonary venous return are arch, hypoplastic left heart syndrome) as oxygen saturation can identified in less than half of the cases. remain within normal limits while the systemic perfusion may be Early clinical diagnosis of undetected CHDs may also be a insidiously compromised. It is therefore necessary that efforts to difficult task for the neonatologist. A patent ductus arteriosus can implement a more efficient screening test for CHDs are aimed to mask an underlying structural defect in the first few days of life improve the recognition of this type of defect. and therefore elude clinical examination so that CHDs may become Recently, some new generation pulse oximeters have been evident with profound cyanosis, heart failure or cardiovascular manufactured providing along with the oxygen saturation value, collapse only after discharge from the newborn nursery. The rate of the peripheral perfusion index (PPI) a parameter that assesses the undetected CHD mainly depends on the time of hospital discharge: relative amount of arterial blood at the probe site. the sooner the babies are discharged the lower the detection rate. In 2007 De Wahl-Granelli and Östman-Smith established refer- A recent study from a population registry in Tennessee reports an ence values for PPI in healthy newborns in the first 5 days of life incidence of unrecognized critical CHD of 15 cases per 100,000 [5]. Median PPI measured at foot was 1.71 with interquartile range discharged newborns [2]. These patients represent the target for a 1.20–2.50. They also measured PPI in a cohort of newborns with left potential neonatal screening program for CHDs heart obstruction and found that it was below the 5th percentile Since most critical CHDs have a degree of hypoxaemia that in 5 out of 9 patients; PPI was therefore proposed as a promising would not necessarily produce visible cyanosis and therefore might tool to improve the detection of congenital heart defects with low not be clinically detectable, pulse oximetry has been proposed as a systemic perfusion but it has never been systematically assessed so screening test for the detection of potentially life-threatening heart far. diseases in the newborns. On behalf of the Neonatal Cardiology Study Group of the Italian Pulse oximetry is a rapid, accurate and low-cost method to Society of Neonatology, we planned to perform a prospective multi- measure arterial oxygen saturation and since it is completely center, national study to assess the effectiveness of combined pulse painless and harmless, it is well accepted by parents. oximetry and PPI as screening test for CHDs. The study will enroll Several studies have been conducted in the last 10 years on the 44,000 newborns. Arterial oxygen saturation and PPI are tested effectiveness of pulse oximetry as a screening tool for CHDs, some between 48 and 72 hours of life and measured from both preductal of them including a large population of neonates. and postductal sites The test is considered positive when at least one of the following criteria is present: arterial oxygen saturation ≤95% at either upper or lower limb; a difference between upper * Corresponding author. and lower saturation >3%; PPI ≤0.9. When the test is positive, it

0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. F. Schena et al. / Early Human Development 89S4 (2013) S8–S9 S9 is repeated after a 15 minutes interval to minimize false positive Italian neonatal setting and the potential additional value of PPI cases due to movement artifacts or transitory environmental con- measurement. dition (cold extremities, crying): if the positive result is confirmed the baby undergoes a cardiac ultrasound as a definitive diagnostic Conflict of interest exam. Fifteen Italian centers are involved in the study and approxi- The authors have no conflict of interest to declare. mately 31,000 infants have been enrolled so far. Our preliminary data show a low number of heart malformations detected by the References screening compared to previously reported studies as most cases are identified antenatally or early after birth on the bases of clinical [1] Ewer AK, Furmston AT, Middleton AJ, et al. Pulse oximetry as a screening signs. One case of aortic coarctation was identified exclusively by test for congenital heart defects in newborn infants: a test accuracy study a low PPI. On the other hand, the screening failed to identify with evaluation of acceptability and cost-effectiveness. Health Technol Assess 2012;16:1–184. two cases of left heart obstruction that were discharged undiag- [2] Mouledoux JH Walsh AX. Evaluating the diagnostic gap: statewide incidence of nosed. undiagnosed critical congenital heart disease before newborn screening with These preliminary results may be partly explained by the recent pulse oximetry. Ped Cardiol 2013 18 Apr; doi 10.1007/s00246-013-0697-1 improvement in prenatal diagnosis together with a “late screening” [Epub ahead of print]. (>48 hours of life) compared to previous studies; after 48 hours of [3] Thangaratinam S, Brown K, Zamora J, Khan KS, Ewer AK. Pulse oximetry screening for critical congenital heart defects in asymptomatic newborn babies: life most of these cardiac defects become clinically evident and can a systematic review and meta-analysis. Lancet 2012;379:2459–64. be diagnosed before the screening is performed. [4] Mahle WT, Newburger JW, Matherne GP, et al. Role of pulse oximetry However, 13,000 newborns still need to be enrolled and further in examining newborns for congenital heart disease: a scientific statement analyses have to be carried on before final consideration can be from the American Heart Association and American Academy of Pediatrics. Circulation 2009;120:447–58. drawn. [5] De Wahl-Granelli A, Ostman-Smith I. Noninvasive peripheral perfusion index Aftercompletionofthestudywehopetobeabletoprovidea as a possible tool for screening for critical left heart obstruction. Acta Paediatr deeper evaluation of the effectiveness of the CHD screening in the 2007;96:1455–9. Early Human Development 89S4 (2013) S10–S11

Metabolic newborn screening: between past and future

M.A. Donati *, L. Padrini, G. La Marca, E. Pasquini

Metabolic and Muscular Diseases Unit, Department of Neurosciences, Anna Meyer Children’s Hospital, Florence, Italy

ARTICLE INFO ABSTRACT

Keywords: The introduction of new technologies such as tandem mass spectrometry (MS/MS) has lead to a major rev- Newborn screening olution in newborn screening for metabolic diseases: from “a test for a disease” (i.e. Guthrie test) to “a test Tandem mass spectrometry (MS/MS) for many diseases”. On a single drop of blood it is now possible to analyze and quantify various metabo- lites, not only acylcarnitines and amino acids, but also adenosine and 2’-deoxyadenosine (for the detection of ADA-SCID) and lysosomal enzymes. Therefore a great potential can be seen in near future for the diagnosis of diseases for which there may be a specific and effective therapy. © 2013 Elsevier Ireland Ltd. All rights reserved.

The introduction of new technologies such as tandem mass (medium chain acylCoA dehydrogenase) deficiency. This condition spectrometry (MS/MS) has lead to a major revolution in newborn can be associated to death after an acute illness, i.e. for Reye screening programs: from the old wiew “a test for a disease” syndrome, or even to Sudden infant death syndrome (SIDS). In (i.e. Guthrie test) to the new concept “a test for many diseases”. non-screened newborns and childrens, it is possible to hypotize a Using a single drop of blood on Guthrie card (DBS, dried blood missed diagnosis whenever a sudden and unexpected death occurs. spot), indeed, it is now possible to search and quantify various In Tuscany and Umbria (two regions in central side of Italy) MCAD metabolites (acylcarnitines, amino acids) at the same time, thus deficiency shows an incidence of 1:27,000 screened newborns; diagnosing numerous metabolic diseases: organic acidurias, fatty diagnosed infants maintain to date good clinical condition by acids beta-oxidation defects, aminoacidopathies, urea cycle defects. following a simple dietary regime (regular meals and avoidance From the late Nineties newborn screening programs experiences in of prolonged fasting, expecially during acute infectious illness). various Countries (Australia, USA, United Kingdom, Germany) made Newborn metabolic screening programs are at the moment carried possible the diagnosis of metabolic diseases in neonatal age, often on in numerous others italian regions, with full or partial coverage: in a pre-symptomatic phase [1]. Liguria, Emilia Romagna, Campania, Sardinia, Lazio and Sicily. These diseases are rare individually, but show a high frequency Moreover, newborn screening in LC-MS/MS allows the diagnosis when considering them as a group. If not correctely diagnosed, they of some inherited or acquired metabolic defects in the mother, i.e. can lead quickly to death, or cause severe neurologic impairment. sistemic carnitine’s defect (which can be associated to cardiomy- Early diagnosis by newborn screening allows the begin of the opathy) so maternal diagnosis can be considered another beneficial therapy in a pre-symptomatic phase, than to performing a genetic effect of newborn screening programs. This is the case of maternal counseling. For these group of diseases, therapy consists in avoiding methilmalonic acidaemia with hyperomocisteinaemia due to vita- prolonged fast (i.e. beta oxidation defects) and/or following a mine B12 deficit. Propionylcarnitine (C3) is a metabolite included dietary regime (i.e. low provision of natural protein or fat) and, in newborn screening programs for the detection of propionic/ in some cases, supplementation with specific formulas. Other methilmalonic acidaemia and disorders of cobalamine metabolism. possibles therapies are vitamines and/or drugs [2]. In mothers, vitamin B12 deficiency may be due to malabsorption After a pilot study performed in 2002, Metabolic diseases or vegan diet. In newborns and infants, cobalamin deficiency is Unit at Meyer Children’s hospital in Florence started to manage mainly due to maternal vitamin deficiency and may be wors- the neonatal screening program using MS/MS since November ened by prolonged exclusive breastfeeding. Severe haematologic, 2004, for all the babies born in Tuscany. Since 2010, we also metabolic and neurological disorders may occur in infants exclu- provide neonatal newborn screening for all the babies born in sively breastfeed by mothers who follow a strict vegetarian diet. Umbria, with a total amount of 45,000 newborns screened per We underline the importance of newborn screening with second year. To date, over 350,000 newborns had been analyzed, with tier test (search for free methilmalonic acid on DBS) and combined a diagnostic rate of 1:1800. In our experience, some diseases analysis of acylcarnitines and omocisteine on mother’s blood in all considerated rare or non esistent show conversely an high incidence cases of elevated C3. This approach allows a properly diagnosis in italian population. This is the case, for istance, of MCAD of unrecognized vitamin B12 deficiency in the mother. Therapy with i.m. hydroxocobalamin in newborn and in the mother may prevent potential damages. There is a debate on how many and * Corresponding author. which diseases should be screened, but certainly the availability of

0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. M.A. Donati et al. / Early Human Development 89S4 (2013) S10–S11 S11 an effective therapy in early stage is an important prerequisite for a neonatal screening on DBS for four LSD (Pompe, Fabry, Gaucher introducing a disease in the panel. In 2006, The American College of and Niemann Pick A/B) was conducted in Austria from January 2010 Medical Genetics (ACMG), a group made up of specialists in public in 34,736 newborns [10]. The study identified positive samples health, health policy, ethics, and other sectors involved in neonatal whichwerethencorrelatedwithaspecific condition: 2 cases of screening, carried out a rewiew of theliteraturerelativetoneonatal Gaucher disease, 4 cases of Pompe disease and 9 cases of Fabry screening and indicated, among diseases that could be considered disease, with a complessive prevalence of 1:2315 births. Neonatal for the inclusion in screening programs, some lysosomal storage screening by LC-MS/MS requires great organizational commitment, diseases (LSD) such as mucopolysaccaridosis type I (MPS I), Fabry and high laboratoristic and clinical experience. A positive test must disease, Pompe disease and Krabbe disease [3]. Arguments in favor be followed by a rapid newborn recall, for laboratory confirmation of the inclusion of LSD in newborn screening panels have been test and clinical treatment and follow up. New test and protocols the increasing availability of therapies (i.e. enzyme replacement (i.e. for low birthweight newborns) have been developed and can theraphy, bone marrow transplant) [4] and the probable underesti- reduce the possibility of false positive and false negative tests, thus mation, in some cases very substantial, of the LDS’ real prevalence avoiding unnecessary stress or misdiagnosis. in world population [5]. In recent years, the widespread use of DBS combined with MS/MS has constituted a turning point for the Conflict of interest analysis of lysosomal enzymes associated to some storage diseases (Fabry, Gaucher, Pompe, Krabbe, Niemann-Pick A/B diseases and The authors have no conflict of interest to declare. Mucopolysaccharidosis I). It’s a strong, highly sensitive, rapid, cheap and non ivasive method; it’s suitable for screening projects both in References the neonatal population that in high-risk populations, both for the targeted analysis of patients with specific symptoms. A single DBS [1] Wilcken B, Wiley V, Hammond J, Carpenter K. Screening newborns for inborn errors of metabolism by tandem mass spectrometry. N Engl J Med allows multiple enzymatic analysis and, moreover, a high number 2003;348:2304–12. of samples can be analyzed simultaneously. In our laboratory whe [2] Saudubray JM, Van Den Berghe G, Walter JH. Inborn Metabolic Diseases: have therefore developed methods of enzyme assay using MS/MS Diagnosis and Treatment, Fifth edition. Berlin: Springer-Verlag, 2012. on DBS for the diagnosis of some LSD suitable to treatment: [3] American College of Medical Genetics Newborn Screening Expert Group. New- α α born screening: toward a uniform screening panel and system – executive Fabry disease ( -galactosidase), Pompe disease ( -glucosidase) and summary. Pediatrics 2006;117:S296–307. Mucopolysaccaridosis type I (α-iduronidase) [6]. Numerous expe- [4] Desnick RJ. Enzyme replacement and enhancement therapies for lysosomal riences of newborn screening for lysosomal diseases have already diseases. J Inherit Metab Dis 2004;27:385–410. been reported in international literature. A recent study of MS/MS [5] Spada M, Pagliardini S, Yasuda M, Tukel T, Thiagarajan G, Sakuraba H, enzyme assay for Fabry, Pompe and MPS I disease on 100,000 Ponzone A, Desnick RJ. High incidence of later-onset Fabry disease revealed by newborn screening. Am J Hum Genet 2006;79:31–40. DBS from anonymous newborn showed a combined prevalence of [6] La Marca G, Casetta B, Malvagia S, Guerrini R, Zammarchi E. New strategy 1:7500 (low enzyme activity confirmed with genetic molecular for the screening of lysosomal storage disorders: the use of the online test). [7]. The study concludes that simultaneous enzyme assay on trapping-and-cleanup liquid chromatography/mass spectrometry. Anal Chem MS/MS can be introduced into neonatal screening panel, and that 2009;81:6113–21. [7] Scott CR, Elliott S, Buroker N, Thomas LI, Keutzer J, Glass M, Gelb MH, this method has a predictive value equal to or better comparing Turecek F. Identification of infants at risk for developing fabry, pompe, or with the methods currently used for non-lysosomal diseases. In mucopolysaccharidosis-i from newborn blood spots by tandem mass spec- 2006, an italian study estimated the incidence of Fabry disease trometry. J Pediatr 2013;163(2):498–503. doi: 10.1016/j.jpeds.2013.01.031 diagnosed by newborn screening (fluorimetric test on DBS) to [Epub2013Mar1]. be 1:3100 (on a population consisting of 37,104 male infants) [8] Chien YH, Lee NC, Thurberg BL, Chiang SC, et al. Pompe disease in infants: improving the prognosis by newborn screening and early treatment. Pediatrics [5]. In Taiwan, Pompe disease was diagnosed by screening with 2009;124(6):1116–25. a prevalence of 1:33,333 (on a population of 132,000 screened [9] Chien YH, Hwu WL, Lee NC. Pompe disease: early diagnosis and early treat- newborns; age at diagnosis 9–22 days) [8]. From follow-up analysis ment make a difference. Pediatr Neonatol 201354(4):219–27. doi: 10.1016/ of patients with Pompe disease there is an evidence that 100% of j.pedneo.2013.03.009 [Epub 2013 Apr 28]. [10]MechtlerTP,SatryS,MetzTF,DeJesusVR,Greber-PlatzerS,PollakA, the patients diagnosed by screening in a presymptomatic phase are Herkner KR, Strenbel B, Kasper DC. Neonatal screening for lysosomal storage ventilator-free; on the contrary, 50% of the patients diagnosed in disorders: feasibility and incidence from a nationwide study in Austria. Lancet a symptomatic phase (even those diagnosed within six months of 2012;379(9813):335–41. age) are ventilator-dependent [9]. Regarding European experiences, Early Human Development 89S4 (2013) S12–S14

Rooming-in: an update

Laura D. Serpero a, Miriam Sabatini a, Micaela Colivicchi a, Diego Gazzolo a,b,* aDepartment of Maternal, Fetal and Neonatal Medicine, C. Arrigo Children’s Hospital Alessandria, Italy bDepartment of Cardiac Surgery S. Donato Milanese University Hospital, S. Donato Milanese, Italy

ABSTRACT

Rooming-in technique is a well-established and physiological procedure that is essential in the first hours from birth both for newborn and mother. However, there are several limitations especially for critical area that do not allow this procedure more effective. This holds for infrastructure limitations, medical and parents issues. In the present mini-review an overview of the state of art and further perspectives on rooming-in in NICU is offered as well as its empowerment in NICU/PICU post-surgical areas. © 2013 Elsevier Ireland Ltd. All rights reserved.

1. Introduction of neurons firing and wiring minute by minute. It’s an important step also in parents’ lives, because of their growing relationship The experience in animal model reports that separation of puppy with the baby. One of the major focuses of clinicians involved in this from the mother in the first minutes and hours after birth may area is the physical environment of the NICU itself and the effects of compromise the health and survival of the newborn. In this respect, mother and sick newborn separation at a stage when mother-baby it has been observed that human infants whose prematurity or nucleus should be empowered [7]. In addition, the impossibility of illness necessitated a prolonged separation from their mothers reproducing an environment as closest as possible to the in-utero resulted in mothering disorders [1]. sensory condition, rather than be into an incubator or warmer in Following this pioneering research, several studies have been which the baby may undergo procedures and interventions (in- conducted to investigate the effects of skin-to-skin contact on tubation, aspiration, catheterization, intravenous puncturing etc.) maternal-infant bonding, physiology and early breastfeeding be- constitute a relevant factor of stress/pain for the newborn and haviors. In the last decades when hospitals became the place of of anxiety for parents. Thus, the concept of rooming-in began in birth for babies, the practice of providing separate care for infant maternal and pediatric units as a response to consumer/patient and mother became established in industrial countries [2,3]. Babies request and has become an essential part of practice in those units. were kept securely in separate nursery and brought to the mother, In the present mini-review an overview of the state of art and for breastfeeding on demand or during scheduled feeding times, or further perspectives on rooming-in in NICU is offered. the baby’s mother walked to the nursery to breastfeed her infant. To date, in developed countries, since the advent of the WHO/ 2. Rooming-in and nursery UNICEF baby friendly hospital initiative in 1991, institutions have now started to keep the mother and the baby in the same room with Nursery care of normal newborn infants in hospitals nowadays the aim to promote skin-to-skin contact [4]. In this regard, bonding differs place to place. During hospitalization after the birth the soon after delivery has a positive effect on “neurobehavioral “rooming-in” allows a mother to stay with their child in the same responses” [5] including stabilization of heart rate and weight gain. room in the nurseries. This new trend has been developed to The neonatal intensive care unit (NICU) is an extraordinary place avoid any adverse psychological consequence on the mother–child especially for those who work there every day to understand how relationship. rooming-in might be important in newborns care [6]. For infants, Rooming-in is defined by WHO guideline and means that baby it is the environment in which brain growth and development pro- and mother stay together in the same room at night and day in the ceed at a pace unmatched at any other period in life, with millions hospital, and there should not be any limitation of direct contact between two of them. The recommendation of WHO encourages an Abbreviations: NICU, Neonatal Intensive Care Unit; PICU, Pediatric Intensive Care entire 24 hours of staying together [4]. Unit. The American Academy of Pediatrics and American College of * Author for correspondence, proofs and reprints: Diego Gazzolo, MD, PhD, Obstetricians and Gynecologist favor complete rooming-in over Department of Maternal, Fetal and Neonatal Medicine, C. Arrigo Children’s Hospital, separated nursery room. Spalto Marengo 46, 15100 Alessandria, Italy. Tel.: +39 0131 207241; fax: +39 0131 207268. There are three types of nursery care facilities usually prac- E-mail address: [email protected] (D. Gazzolo). tice today: (i) first, completely separated nursery room between

0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. L.D. Serpero et al. / Early Human Development 89S4 (2013) S12–S14 S13 mother’s and baby’s. In this case, mothers can spend time with their Besides the risk that the premature baby is naturally exposed babies in a limited schedule time for several minutes during the to, all the family members face other implications related to the hospital stay. The entire course of care is given in the nursery room intensive care treatment required during the prolonged hospital only; (ii) second, a partial rooming-in with mothers. Rooming-in stay [17]. nursery service offer chance for mothers to share time with their The concept of rooming-in began in maternal and pediatric babies during their hospital stay, and the partial rooming-in gives units as a response to consumer/patient request and has become not full time, but partial time in a day for them because main a normal part of practice in those units over the past twenty-five procedures are taken in the nursery room and not in mother’s years. The NICU has been slower in this transition, partly due to the room, and (iii) last type of care is complete rooming-in care of physical design of units, which were, until recently, ward style with babies and mothers. This nursery practice gives care for baby in the little or no space for parents to stay undisturbed. It was also unclear same room with mother from their time of birth to their discharge what role the parents could fulfill until the infant was closer to from the hospital. discharge. This can be very difficult for a patient who has recently It has been shown that the wider adoption of the “rooming-in” experienced a caesarean section or a complicated delivery. Often, a regimen in the maternity wards and early detection of hearing loss mother discharged from postpartum care must make the necessary could be vanished by dispersion of patients [8]. arrangements to visit her baby in the hospital as frequently as Rooming-in care it has been demonstrated to have many ad- possible. vantages; it has been identified as one of the essential steps to With the introduction of the private NICU room, parents are promoting long-term breastfeeding, thus increasing health benefits allowed to remain in the room with their baby throughout his or for mothers and babies [9]. In fact, the placement of the new- her NICU stay. This is the preferred option for most parents because born skin-to-skin on his or her mother’s chest, immediately after it allows more bonding time. It promotes infection control and birth, has been shown to have positive effects both on newborn environmental control, as each baby is kept in a separate room [18]. physiologic parameters, and on breastfeeding success. Moore and Private NICU room is a condition promoting privacy and allowing colleagues, have demonstrated that skin-to-skin contact in the new mothers the option of nursing or expressing breast milk for immediate post-delivery period increases the success of the first their babies directly in the NICU room. There is growing evidence breastfeed, and leads to more effective breastfeeding. Skin-to-skin that remaining mother and baby in the same room could promote contact have been demonstrated to diminish pain responses in better outcomes for the infant and mother. This refers to a reduced newborn during vaccines and pharmacological therapy administra- length of staying in hospital for the infant and decreases the tion, or blood sample collection [10,11]. potential guilt of mother separated from her infant and subsequent Abrahams and colleagues [12], shown that the effect of rooming- postpartum depression [19]. Another issue is the disappointing in, rather than standard nursery care, might be a safe and potent situation for a new mother to be discharged from postpartum care tool to reduce the severity of neonatal abstinence syndrome among directly into “visitor status” for her NICU baby. These circumstances opioid-exposed newborns and to promote more effective mothering may be even more complicated for the postpartum mother who in such newborns’ transition to extra-uterine life. requires an extended length of stay to recover after the delivery (i.e. The study of the habit of separation of the mother and baby after chronic illnesses, multiple births, caesarean section deliveries, etc.). birth, still persisting in many parts of the world, showed that a close Several studies showed that NICU babies whose parents were contact between mother and infant in the early “sensitive period” able to practice skin-to-skin contact have better recovery outcomes, (2 hours after birth) may induce a long-term (1 year) positive effect such as “a gain” in sleep time, decreased crying, improved oxygen on mother–infant interaction [13]. Of note, neonatal care with saturation levels [20,21]. In addition, skin-to-skin contact has been rooming-in mothers with type-1 diabetes and their newborn infants linked to increased confidence in parents, improved perceptions was associated with reduced neonatal morbidity when compared of their babies, and positive interaction between parents and with routine separation of infants from their mothers [14]. their infants [22]. Another well-known advantage resides in the effectiveness in keeping even the smallest infant as warm as or 3. Rooming-in and NICU warmer than the thermo-neutral setting of an incubator and with a built-in circadian rhythm [23]. Of note, rooming-in also promotes Throughout human history and in virtually all cultures until more family involvement in the patient’s care, which may decrease modern-day, mothers and their infants were an inseparable dyad the chances of medical error [24]. This is a very important step prior [15]. Only with the advent of NICU did the mother become no to the discharge of a preterm baby from a NICU, very convenient longer essential, in the early days, and even more considered a for parents that have the opportunity to develop their competence danger to her infant. Thus, the birth of a premature baby is a in caring for their baby. In this regard, the fact that, during baby’s distressing event in a woman’s life. Although no one plans on stay in the NICU, the staff worked with the mother to teach how having a premature baby it happens pretty often and having a child to assume total responsibility for thephysicalcareandsupervision in the NICU is stressful and confusing time for any parent [16]. of the child at home, has been positively experienced [25]. This A NICU is a high-tech nursery with special equipment and a especially holds for brain maturation in preterm infants as shown highly trained staff who care for preemies (born at 26 weeks gesta- by means of aEEG patterns [26], whilst Milgrom et al. [27] showed tion or less) and other newborns needing serious medical attention. that training parents about the neurosensory needs of their babies This situation is further complicated by the NICU hospitalization, enhanced white matter development. Indeed, Fifer et al. showed which is described as an additional stress factor by the mother. In that newborn infants learn to respond to an environmental stimulus this setting, the NICU mother is deprived of the opportunity to have even when asleep, emphasizing thecontinuous,intensenatureof her baby transported to her postpartum room and remain at her the learning process in newborns. bedside during the first few days of motherhood. NICU babies are In pediatric intensive care unit (PICU), several European coun- routinely transferred from the delivery room immediately following tries have adopted skin-to-skin contact practice in the last few birth with little or no time to bond with their parents, but the decades, showing that it is possible to adapt this practice to dif- initial bonding experience is critical for the infant and new mother. ferent contexts to neonatal care. In particular, it has a beneficial As opposed to well-baby care in a postpartum environment, the effect on the thermoregulatory and cardiovascular systems, exerting recovering mother must be healthy enough to visit her baby in the stabilizing activity through a more regular heart rate and providing NICU. a stable rate of blood flow-feeding to all tissues [28] that might be S14 L.D. Serpero et al. / Early Human Development 89S4 (2013) S12–S14 beneficial for oxygen support to the brain. In this regard, we con- [8] Grasso DL, Hatzopulos S, Cossu P, Ciarafoni F, Rossi M, Martini A, et al. ducted an observational study in which we investigated whether Role of the “rooming-in” on efficacy of universal neonatal hearing screening skin-to-skin contact could have been helpful in full term infants ad- programmes. Acta Otorhinolaryngol Ital 2008;28:243–6. [9] Murray EK, Ricketts S, Dellaport J. Hospital practices that increase breastfeed- mitted to PICU after congenital heart disease surgical repair. Results ing duration: results from a population-based study. Birth 2007;34:202–11. showed that in the skin-to-skin contact in the early post-extubation [10] Okan F, Ozdil A, Bulbul A, Yapici Z, Nuhoglu A. Analgesic effects of skin-to- phases had an impact on the quality, the therapy and the length of skin contact and breastfeeding in procedural pain in healthy term neonates. stay in PICU, with potential influences on management and costs Ann Trop Paediatr 2010;30:119–28. [11] Dilli D, Küçük IG, Dallar Y. Interventions to reduce pain during vaccination in [29]. infancy. J Pediatr. 2009;154:385-90. [12] Abrahams RR, Kelly SA, Payne S, Thiessen PN, Mackintosh J, Janssen PA. 4. Conclusions Rooming-in compared with standard care for newborns of mothers using methadone or heroin. Can Fam Physician 2007;53:1722–30. In humans, routine mother-infant separation shortly after birth [13] Bystrova K, Ivanova V, Edhborg M, Matthiesen AS, Ransjo-Arvidson AB, et al. Early contact versus separation: Eff ects on mother-infant interaction one is unique to the 20th century. This practice diverges from evo- year later. Birth 2009;36:97–109. lutionary history, where neonatal survival depended on close and [14] Stage E, Mathiesen ER, Emmersen PB, Greisen G, Damm P. Diabetic mothers virtually continuous maternal contact. Children make heavy use of and their newborn infants – rooming-in and neonatal morbidity. Acta Paediatr hospitals for pediatric and surgical inpatient care. Over half of all 2010;99:997–9. [15] Hodnett ED, Gates S, Hofmeyr GJ, Sakala C. Continuous support for women admissions for children are for surgical care. This proportion varies during childbirth. Cochrane Database Syst Rev. 2007;(3):CD003766. Review. according to age. To this regard, one of the most interesting new Update in: Cochrane Database Syst Rev. 2011;(2):CD003766. perspective in rooming-in consist in apply this practice not just [16]BuarqueV,LimaMC,ScottRP,VasconcelosMG.Theinfluenceofsupport in critic neonatal care, but also in post-surgical pediatric intensive groups on the family of risk newborns and on neonatal unit workers. J care. Pediatr (Rio J) 2006;82:295–301. [17] Hodnett ED, Gates S, Hofmeyr GJ, Sakala C. Continuous support for women during childbirth. Cochrane Database Syst Rev. 2003;(3):CD003766. Review. Acknowledgments Update in: Cochrane Database Syst Rev. 2007;(3):CD003766. [18] Floyd AMD. Challenging designs of neonatal intensive care units. Crit Care This work takes part to the I.O. PhD International Program and Nurse 2005;25:59–66. [19] Morawski Mew A, Holditch-Davis D, Belyea M, Miles M, Fishel A. Correlates was partially supported by grants to DG from Stella Cometa, I Colori of depressive symptoms in mothers of preterm infants. Neonatal Netw della Vita Foundations, Italy. The funding sources had no role in the 2003;22:51–60. study design, data collection, data interpretation, data analysis, or [20] Föhe K, Kropf S, Avenarius S. Skin-to-skin contact improves gas exchange in writing of this manuscript. premature infants. J Perinatol 2000;20:311–5. [21] Stremler R, Dhukai Z, Wong L, Parshuram C. Factors influencing sleep for parents of critically ill hospitalised children: a qualitative analysis. Intensive Conflict of interest Crit Care Nurs 2011;27:37–45. [22] Feldman R, Eidelman AI, Sirota L, Weller A. Comparison of skin-to-skin The authors have no conflict of interest to declare. (kangaroo) and traditional care: parenting outcomes and preterm infant development. Pediatrics 2002;110:16–26. [23] Ludington-Hoe SM, Nguyen N, Swinth JY, et al. Kangaroo care compared to References incubators in maintaining body warmth in preterm infants. Biol Res Nurs 2000;2:60–73. [1] Kennell, JH, Klaus, MH. Early mother-infant contact. Bull Menninger Clinic [24] Pearson, J., Andersen, K. Evaluation of a program to promote positive parent- 1979;43,69–77. ing in the neonatal intensive care unit. Neonatal Netw 2001;20:43–48. [2] Bauer K, Uhrig C, Sperling P, Pasel K, Wieland C, Versmold HT. Body temper- [25] Costello A, Chapman J. Mothers’ perceptions of the care-by-parent pro- atures and oxygen consumption during skin-to-skin (kangaroo) care in stable gram prior to hospital discharge of their preterm infants. Neonatal Netw preterm infants weighing less than 1500 grams. J Pediatr 1997;130:240–4. 1998;17:37–42. [3] Acolet D, Sleath K, Whitelaw A. Oxygenation, heart rate and temperature in [26] Scher MS, Ludington-Hoe S, Kaffashi F, Johnson MW, Holditch-Davis D, Loparo very low birthweight infants during skin-to-skin contact with their mothers. KA. Neurophysiologic assessment of brain maturation after an 8-week trial of Acta Paediatr Scand 1989;78:189–93. skin-to-skin contact on preterm infants. Clin Neurophysiol 2009;120:1812–8. [4] “Baby friendly” hospitals: new WHO/UNICEF initiative to promote breast- [27] Milgrom J, Newnham C, Anderson P, et al. Early sensitivity training for feeding. Midwives Chron 1991;104:298. parents of preterm infants: impact on the developing brain. Pediatr Res [5] Ferber SG, Makhoul IR. The effect of skin-to-skin contact (kangaroo care) 2010;67:330–335. shortly after birth on the neurobehavioral responses of the term newborn: a [28]HeimannK,VaessenP,PeschgensT,StanzelS,WenzlTG,OrlikowskyT. randomized, controlled trial. Pediatrics 2004;113:858–65. Impact of skin to skin care, prone and supine positioning on cardiorespi- [6] White RD. The newborn intensive care unit environment of care: how we got ratory parameters and thermoregulation in premature infants. Neonatology here, where we’re headed, and why. Semin Perinatol 2011;35:2–7. 2010;97:311–7. [7] Cesario SK: Designing health care environments, Part I. Basic concepts, [29] Gazzolo D, Masetti P, Meli M. Kangaroo care improves post-extubation principles, and issues related to evidence-based design. J Contin Educ Nurs cardiorespiratory parameters in infants after open heart surgery. Acta Paediatr 2009;40:280–288. 2000;89:728–9. Early Human Development 89S4 (2013) S15–S17

Microbiota in healthy term infant

Flavia Indrio a,*, Antonio Di Mauro a, Giuseppe Riezzo b, Federica Di Mauro c, Ruggiero Francavilla a aDepartment of Pediatrics, University of Bari, Bari, Italy bLaboratory of Experimental Pathophysiology, IRCCS Castellana Grotte, Italy cSchool of Medicine, University of Bari, Bari, Italy

ARTICLE INFO ABSTRACT

Keywords: Development of intestinal microbiota after birth is related to health throughout life. A healthy and balanced Term newborn gut microbiota profile in infancy is shaped and modulated by different factors as mode of delivery and feed- Intestinal microbiota ing type. An aberrant compositional development of gut microbiota in early life can be linked to the risk of Intestinal function intestinal or extraintestinal immune-mediated disease later in life. Brain development Considering the importance of the reciprocal interaction of the intestinal microbiota with the immune, metabolic, and neurological systems of the host, understand the dynamics of a “healty” neonatal colonization is now foundamental and can offer opportunities for developing specific therapies aimed to manipulate a delayed or aberrant colonization at birth or a dysbiotic microbiota later. © 2013 Elsevier Ireland Ltd. All rights reserved.

1. Introduction 2. Gut microbiota establishment in healthy term neonates

Every one of us have left a sterile existence in the womb to The initial colonization by pioneer bacteria, mainly facultative deal with an extra-uterine environment filled with microbes. At anaerobes bacteria as Staphylococcus, Streptococcus, Enterococcus birth and soon after that a complex community of microbes from and Enterobacteriaceas spp., and successive modification in obligate mother and surrounding environment start the colonization of the anaerobes strain population, influence gut and systemic health gastrointestinal tract, until a large, active and dense community throughout life [2]. Although the correct order of this bacterial of bacteria, fungi and protozoa, is established. The total of these succession isn’t yet well known, it can be considered that delay or microorganisms, estimated to be approximately 100 trillion, is aberration of the gut colonization process at birth could have an called microbiota and is dominated by numerous genera, species impact later in life [3]. and strains of bacteria. In everybody’s gut, inhabits a roughly 15% In the first period of life the acquisition and the development of the 1,000 or more intestinal bacteria that have been isolated, of gut microbiota is dynamic and is influenced by different deter- underling how variable and complex is the microbiota composition minants as mode of delivery and feeding type [4]. For example, between individuals. a caesarean section avoids normal colonization of neonatal gut Furthermore, the intestinal microbiota outnumbers 10-fold the by preventing exposure to vaginal and faecal maternal microbiota, total cells of the human body and the expression of microbiota whereas breastfeeding contributes in developing of a “healthy” genes, that are estimated about 2–4 million, exceeding the number microbiota by providing metabolic substrates for beneficial strain of our human genes 100-fold, is considered a parallel genome with and through cross-contamination with the mammary glands and its own functions [1]. Through expression of this exceptional quan- maternal skin. tity of genes, whose totality is termed microbiome,thesymbiotic Long-term consequences of mode of delivery and feeding type and generally mutualistic interaction between the microbiota and may be partially attributable to differences in gut microbiota its host play a fundamental role in human health by promoting gut establishment in the early colonization. The establishment of a homeostasis, enhancing gut mucosal structure and immune system population pattern of a healthy, term, vaginally-delivered, exclu- development, providing prevention from pathogens colonization, sively breast-fed newborn is assumed to be the most desirable stimulating intestinal motor function, contributing to digestive according to low incidence of morbidity and mortality throughout processes and to brain development (Fig. 1). life, compared to other delivery and feeding modes. Neonatal period is thought to be a critical time windows to acquire the beneficial functions of microbiota–host interaction and, although the classical colonization dogma is still widely accepted, further studies about population dynamics of pioneer bacteria are needed to direct bac- * Corresponding author. Tel. and fax: +39 08 05593624. terial assembly if delayed or to manipulate a dysbiotic microbiota E-mail address: [email protected] (F. Indrio). throughout life with pre/pro/antibiotics.

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Fig. 1. Factors influencing the establishment of the intestinal microbiota in infancy and related effect on intestinal and brain function and development.

Using culture dependent methods and new gene sequencing the intestinal content: it prevents the entrance in the systemic techniques, different studies have characterized the intestinal mi- circulation of potentially harmful intestinal antigens through the crobiota of healthy term infants and reported differences according gut mucosal barrier while induces systemic tolerance against to mode of delivery and feeding type. food and microbiota luminal antigens. Thus, first contact with While, term vaginally-born, breastfed newborn have been found bacterial species could be deterministic and have long lasting to acquire a relatively simple microbiota dominated by Bifidobac- effect on the immune response and a late acquisition of microbial terium species during the second week of life, sterile formula-fed stimulation or a reduced complexity of the microbiota during newborn shown a more diverse microbiota including Enterobacteri- infancy may delay the post-natal immune system maturation with aceae, Enterococcus and Bacterioides. This is generally attributable to consequent difficulties in the capacity to differentiate potentially the presence of antimicrobial protein and specific oligosaccharides dangerous from harmless antigens. Delayed and somewhat aberrant in breast milk, which represent a selective substrates for limited microbiota development can perturb immune regulatory networks number of gut microbial strain. Furthermore, breast milk contains that normally modulate intestinal inflammation, contributing to a sIgA, whose specificities have been shaped by maternal microbiota. number of intestinal or extraintestinal immune-mediated disease The presence of sIgA could modulate breast-fed infants colonization [8]. through a mucosal immune memory, transmitted from the mother to the offsprings [5]. 4. Microbiota and the developing brain According to delivery mode, in contrast to vaginally delivered, newborns born by caesarian sections shown a delayed increase Furthermore, recent studies revealed that the bacterial content in gut-associated anaerobe population density and lower ratios of the gut can modulate also brain developmental pathways. of anaerobes to facultative anaerobes during infancy. Probably In the early postnatal period, gut microbiota might modulate the vertical transmission of microbiota at birth from maternal synaptogenesis through changes in the expression of genes that vaginal and intestinal flora provides resistance to pathogen early affect neuronal circuits involved in motor and sensitive control. colonization with competitive mechanisms in the first weeks of Changes in interaction between microbiota and brain have been life. While vaginally-born infants acquire their microbiota from implicated in the pathophysiology of functional gastrointestinal mothers with a less diverse and relatively stable composition over disorders, such as infantile colic or irritable bowel syndrome later time, caesarian sections-born are susceptible to the colonization by in life. bacterial species of epidermal origin or by undesired microbes from Recently, aberrancies in the newborn intestinal colonization the environment [6,7]. have been proposed to affect gut motor function and visceral These studies have shown how microbiota establishment in hyperalgesia, inducing the neurogenic inflammation of sensory term neonates can be influenced by parental and medical decision neurons in the gut that leading, in turn, to abdominal pain and concerning mode of delivery and infant diet. colicky behaviour [9]. In a recent paper by de Weerth et al, was Despite gut microbiota pattern varied widely in the first year of identified a specific microbial signatures of infants with colic during live, according to delivery mode and infant diet, and is characterized the intestinal colonization [10]. Infants with colic showed lower by an high interindividual variability, it converge toward a more microbiota diversity and stability than did control infants in the first stable and adult-like microbiota in early stage of life. weeks of life. These microbial pattern possibly explain the excessive crying of the colic infants and give a theoretical explanation to 3. Microbiota and the developing immune system administration of probiotics as therapeutical strategy that result in decreased colic symptoms. The human immune system is the most elaborate example of the symbiotic relationship between the microbiota and the 5. Conclusion host. During the first colonization, the intestinal mucosa and its neonatal immune system (GALT, gut-associated lymphoid tissue) Althought the acquisition and development of gut microbiota mature under the influence of the microbiota. GALT samples is essential in life long health, its dynamic composition and its F. Indrio et al. / Early Human Development 89S4 (2013) S15–S17 S17 determinants factor remains poorly understood. Considering the [4] Isolauri E. Development of healty gut microbiota early in life. J Paediatr Child importance of the reciprocal interaction of the intestinal microbiota Health 2012,48(3):1–6. and the immune, metabolic, and neurological systems of the host, [5] Jost T, Lacroix C, Braegger CP, Chassard C. New insights in gut microbiota establishment in healthy breast fed neonates. PLoS One 2012;7(8):e44595. further studies are needed to understand the dynamics and driving [6] Azad MB, Konya T, Maughan H, Guttman DS, Field CJ, Chari RS, Sears MR, determinants of a “healty” neonatal colonization. Becker AB, Scott JA, Kozyrskyj AL; CHILD Study Investigators. Gut microbiota of healthy Canadian infants: profiles by mode of delivery and infant diet at 4 Conflict of interest months. CMAJ 2013;185(5):385–94. [7] Pandey PK, Verma P, Kumar H, Bavdekar A, Patole MS, Shouche YS. Com- parative analysis of fecal microflora of healthy full-term Indian infants born The authors have no conflict of interest to declare. with different methods of delivery (vaginal vs cesarean): Acinetobacter sp. prevalence in vaginally born infants. J Biosci 2012;37(6):989–98. References [8] Maynard CL, Elson CO, Hatton RD, Weaver CT. Reciprocal interactions of the intestinal microbiota and immune system. Nature 2012;489(7415):231–41. [1] Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, Nielsen T, Pons N, [9] Diamond B, Huerta PT, Tracey K, Volpe BT. It takes guts to grow a brain: In- Levenez F, Yamada T, et al. A human gut microbial gene catalogue established creasing evidence of the important role of the intestinal microflora in neuro- by metagenomic sequencing. Nature 2010;464:59–65. and immune-modulatory functions during development and adulthood. Bioes- [2] Saavedra JM, Dattilo AM. Early development of intestinal microbiota: implica- says 2011;33:588–91.2. tion for future health. Gastoenterol Clin North Am 2012;41(4):717–31. [10] de Weerth C, Fuentes S, Puylaert P, de Vos M. Intestinal microbiota of infants [3] Di Mauro A, Neu J, Riezzo G, Raimondi F, Martinelli D, Francavilla R, Indrio with colic: development and specific signatures. Pediatrics 2013;131.2:e550– F. Gastrointestinal function development and microbiota. Ital J Pediatr 2013; 8. 39:15. Early Human Development 89S4 (2013) S18–S19

Gastro-oesophageal reflux: pathogenesis, symptoms, diagnostic and therapeutic management

Luigi Corvaglia a,b,*, Silvia Martini a, Giacomo Faldella a,b aNeonatology and Neonatal Intensive Care Unit, S. Orsola-Malpighi Hospital, Bologna, Italy bDepartment of Medical and Surgical Sciences (DIMEC), University of Bologna, Italy

Gastro-oesophageal reflux (GOR) is very frequent in the first reflux episodes; hence, it is currently considered the best technique year of life; indeed, it has been reported that approximately 50% of to diagnose GOR and to monitor the effectiveness of anti-reflux babies up to 3 month regurgitate at least once per day [1]. therapies. The need for simpler and less invasive investigations to GOR might be elicited by several, physiological mechanisms: the diagnose GORD led to the development of a questionnaire expressly supine position, which promotes the rise of gastric content into addressed for the paediatric population and based on clinical oesophagus; the relatively abundant milk intakes; the immaturity observations [7], while a specific GOR scoring system, adapted of oesophageal motility, which entails a poor clearance of refluxate for hospitalized preterm infants has been recently proposed [4]. especially in the preterm population [2]. GOR is mainly due to However,theroleofrefluxquestionnaires in clinical practice is still the occurrence of transient lower oesophageal sphincter relaxations controversial, as some doubts have been raised on their capability (TLOSRs), unaccompanied by swallowing, that enhance the passage to correlate with the severity of GOR features and subsequent of gastric content in the oesophageal lumen [3], whereas in a few esophagitis. cases GOR follows a sudden increase of intra-abdominal pressure, Conceiving GOR therapeutic management, an increasing empir- not supported by a consensual augment of lower oesophageal ical use of anti-reflux drugs has been reported in the paediatric sphincter (LOS) pressure . population over the last decades; however, relevant adverse ef- In the majority of infants experiencing frequent regurgitations fects have been noticed in association with GOR pharmacological without clinical complications (the so-called “happy spitters”), GOR therapy. Hence, a step-wise therapeutic approach, firstly pro- can be considered a physiological and not harmful phenomenon. moting conservative measures in those infants with mild and Nevertheless, in moderate to severe cases, such complications as non-complicated GOR, is currently considered the most advisable feeding problems, failure to thrive, esophagitis, odynophagia or strategy to manage GOR [4], in order to avoid a potentially harmful lung aspiration [4] are commonly observed, thereby outlining the pharmacological overtreatment. profile of gastro-oesophageal reflux disease (GORD). Other atypical Among the main conservative strategies, body positioning is con- symptoms of GORD are bronchospasm, laryngitis, sinusitis, otitis, sidered a well-established and safe treatment for non-complicated unexplained irritability and, in a few number of infants, spastic GOR, especially in preterm infants. Indeed, whereas popular anti- torticollis and dystonic body movements, which characterize the reflux postures as head elevation or car-seat positioning were found “Sandifer syndrome”. to be ineffective on acid GOR features [8], both prone and left-side If pathological GOR is suspected, deepen diagnostic investiga- postures significantly decrease the number of acid and non-acid tions should be assessed to evaluate GOR severity and features, as GOR episodes [9]; however, in order to prevent sudden infant death the prevalence of acid or non-acid GOR entails different clinical and syndrome (SIDS), this measures should be limited to hospitalized therapeutic implications [2]. babies. Whereas pH monitoring effectively detects acid GOR, which Dietary interventions are likewise effective on GOR indexes. In a mainly occurs during the late post-prandial period [5] and is cohort of mildly symptomatic infants, frequent, small-volume feeds reported to play a role in the development of GORD, multiple have been shown to improve oesophageal acid exposure, but not intraluminal impedance (MII) is able to track down non-acid reflux, non-acid GOR features [3], whereas lower feeding flow rates, which which is more frequent in the early post-prandial period [5] and is result in a prolonged feeding duration, seem to be effective in suggested to represent a trigger stimulus for GOR-related apnoeas reducing non-acid GOR episodes [10]. in preterm infants [6]. Combined pH–MII monitoring is highly Feed thickening is a longstanding conservative strategy largely effective to assess acid, weakly acid and alkaline GOR features [5] adopted for GOR treatment. Human milk or standard formulas and to define the physical nature (gaseous, liquid or mixed) of might be home-thickened with specific thickening agents (i.e. rice, corn or potato starch), but the use of commercial anti- regurgitation (AR) formulas, industrially thickened with processed * Corresponding author: Luigi Corvaglia, Neonatologia e Terapia Intensiva Neona- rice, corn-starch or locust (carob) bean gum, has increasingly tale, Policlinico S. Orsola-Malpighi, Via Massarenti 11, 40138 Bologna, Italy. Tel./fax: +39 051-342754. spread. Although a significant reduction in the number of vomiting E-mail address: [email protected] (L. Corvaglia). and regurgitations has been widely observed, the effectiveness of

0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. L. Corvaglia et al. / Early Human Development 89S4 (2013) S18–S19 S19 feed thickening on GOR features, evaluated by means of either pH should be administered in the presence of GOR relevant complica or MII monitoring are still controversial. Hence, according to recent tions or after the failure of the conservative management, which practical guidelines, feed thickening should be addressed to infants might be routinely adopted as the first strategy for GOR manage- suffering from frequent vomiting and/or regurgitations and failure ment in infants and preterm babies with frequent regurgitations, to thrive due to the subsequent nutrient loss, in the absence of thereby allowing to treat the majority of them without resorting to other clinical complications which might underpin other diagnosis anti-reflux drugs. as, for instance, cow’s milk protein allergy (CMPA) [11]. In this regard, a 2- to 4-week trial of an extensively hydrolysed protein Conflict of interest (eHPF) or amino acid-based formula should be taken into account in formula-fed infants with frequent regurgitations and weight loss. The authors have no conflict of interest to declare. As we noticed in a recent trial, an eHPF resulted to be effective in reducing total acid GOR episodes and reflux index in preterm References infants with GOR symptoms and feeding intolerance [12]. Pharmacological therapy should be limited to infants suffering [1] Nelson SP, Chen EH, Syniar GM, Christoffel KK. Prevalence of symptoms of from GOR complications (i.e. esophagitis, lung aspiration, chronic gastroesophageal reflux during infancy. A pediatric practice-based survey. Pe- cough, weight loss) or after the failure of the conservative manage- diatric Practice Research Group. Arch Pediatr Adolesc Med 1997;151(6):569– 72. ment. Alginate-based formulations, proton pump inhibitors or H2 [2] Corvaglia L, Monari C, Martini S, Aceti A, Faldella G. Pharmacological ther- blockers are among the anti-reflux drugs most commonly used. apy of gastroesophageal reflux in preterm infants. Gastroenterol Res Pract On the basis of current evidences, alginate-based formulations 2013;2013:714564. appear to be a promising treatment for GORD. Indeed, thickening [3] Omari TI, Barnett CP, Benninga MA, Lontis R, Goodchild L, Haslam RR, et al. and buffering factors contained in these formulations seem to exert Mechanisms of gastro-oesophageal reflux in preterm and term infants with reflux disease. Gut 2002;51(4):475–9. a complementary effect in lowering acid GOR features, which are [4] Birch JL, Newell SJ. Gastrooesophageal reflux disease in preterm infants: known to be involved in GORD development [3]. However, further current management and diagnostic dilemmas. Arch Dis Child Fetal Neonatal trials are advisable to confirm these findings and to assess the safety Ed 2009;94(5):F379–83. of alginate-based medication before recommending their routine [5]CorvagliaL,MarianiE,AcetiA,CaprettiMG,AncoraG,FaldellaG.Combined oesophageal impedance–pH monitoring in preterm newborn: comparison of use, particularly in preterm infants [2]. two options for layout analysis. Neurogastroenterol Motil 2009;21(10):1027- Inhibitors of gastric acidity (IGA) are widely adopted as anti- e81. reflux drugs in the pediatric population. Due to their selective [6]CorvagliaL,ZamaD,SpizzichinoM,AcetiA,MarianiE,CaprettiMG,etal. action on histamine-2 (H2) receptors and gastric proton pump, as The frequency of apneas in very preterm infants is increased after non-acid H2-blockers or proton pump inhibitors (PPIs) are expressly effec- gastro-esophageal reflux. Neurogastroenterol Motil 2011;23(4):303–7, e152. [7] Orenstein SR, Cohn JF, Shalaby TM, Kartan R. Reliability and validity tive in reducing acid GOR; hence, a proper pH–MII monitoring to of an infant gastroesophageal reflux questionnaire. Clin Pediatr (Phila) assess GOR features should be carried out before starting IGA’s 1993;32(8):472–84. administration. Indeed, PPIs and H2 blockers are shown to be bur- [8] Orenstein SR, Whitington PF, Orenstein DM. The infant seat as treatment for dened by noticeable adverse effects as significantly increased rates gastroesophageal reflux. N Engl J Med 1983;309(13):760–3. [9] Corvaglia L, Rotatori R, Ferlini M, Aceti A, Ancora G, Faldella G. The effect of of pneumonia and gastroenteritis [13], thereby requiring a careful body positioning on gastroesophageal reflux in premature infants: evaluation evaluation of the risk–benefit balance. Conceiving preterm infants by combined impedance and pH monitoring. J Pediatr 2007;151(6):591–6, and neonates symptomatic for GORD, the overall available evi- 596.e1. dences regarding the efficacy of IGA are very few, whereas a higher [10] Jadcherla SR, Chan CY, Moore R, Malkar M, Timan CJ, Valentine CJ. Impact risk of necrotizing enterocolitis (NEC) and infections has been of feeding strategies on the frequency and clearance of acid and nonacid gastroesophageal reflux events in dysphagic neonates. JPEN J Parenter Enteral reported [14], thereby leading to an unfavorable risk–benefit ratio. Nutr 2012;36(4):449–55. Eventually, prokinetic agents (erythromycin, domperidone, [11] Vandenplas Y, Gutierrez-Castrellon P, Velasco-Benitez C, Palacios J, Jaen D, metoclopramide and cisapride) have been largely utilized in pedi- Ribeiro H, et al. Practical algorithms for managing common gastrointestinal atric practices to reduce GOR symptoms [2]. Even so, evidences on symptoms in infants. Nutrition 2013;29(1):184–94. the efficacy of metoclopramide in improving GORD symptoms are [12] Corvaglia L, Mariani E, Aceti A, Galletti S, Faldella G. Extensively hy- drolyzed protein formula reduces acid gastro-esophageal reflux in symp- still controversial, whereas other prokinetic agents, as domperidone tomatic preterm infants. Early Hum Dev 2013;89(7):453–5. and erythromycin, were reported to be ineffective in reducing GOR [13] Canani RB, Cirillo P, Roggero P, Romano C, Malamisura B, Terrin G, et features, against proven adverse events as dystonic reactions, oculo- al. Therapy with gastric acidity inhibitors increases the risk of acute gyric crisis, arrhythmias. In this regard, cisapride, which was widely gastroenteritis and community-acquired pneumonia in children. Pediatrics 2006;117(5):e817–20. employed to treat GORD up to a decade ago, has been gradually [14] Terrin G, Passariello A, De Curtis M, Manguso F, Salvia G, Lega L, et al. withdrawn due to its remarkable effects on QTc prolongation. Ranitidine is associated with infections, necrotizing enterocolitis, and fatal Thus, to avoid a risky overtreatment, pharmacological therapy outcome in newborns. Pediatrics 2012;129(1):e40–5. Early Human Development 89S4 (2013) S20–S22

Breastfeeding promotion and neonatological practices

Riccardo Davanzo, Angela De Cunto *

Division of Neonatology and NICU, Institute for Maternal and Child Health, IRCCS “Burlo Garofolo”, Trieste, Italy

ARTICLE INFO ABSTRACT

Keywords: Breastfeeding and human milk have been advocated as the normative standards for feeding infants of all Breastfeeding gestational ages, including the high risk newborn infants. Baby friendly hospital initiative Nevertheless, exclusive breastfeeding rates at hospital discharge in the general population of newborns Health promotion and in the subpopulation of high risk newborn infants are not yet satisfactory. Clinical practice A successful promotion of breastfeeding among both healthy and high risk newborn infants requires mul- ticomponent effective interventions. First, health professionals need to improve their knowledge on lactation, to acquire better skills to manage breastfeeding problems and to commit to preparing evidence based clinical protocols that would not hinder breastfeeding and the use of human milk in everyday hospital practices. Finally, we must recognize that all these efforts will be facilitated by an improved staff attitude towards breastfeeding. © 2013 Elsevier Ireland Ltd. All rights reserved.

1. Human milk for both the healthy and the sick newborn national figures on breastfeeding epidemiology are not available. Current limited information on breastfeeding rates is scattered and A wealth of scientific evidence shows that breastfeeding pro- shows a low exclusive breastfeeding rate at hospital discharge after motes both mother and child health. Advantages of breastfeeding birth and a rapid decrease in the first months of age (Table 1). for the child extend beyond the nursing period itself, as nutrition in According to a survey conducted by Radaelli [4], 95% of Italian the first years of life can permanently modify individual biological, paediatricians advice mothers to introduce complementary foods neurodevelopmental and social growth [1]. Consequently, breast- throughout 4–5.9 months, thus not following the recommendations feeding and human milk have been advocated as the normative on infant feeding from international health agencies (such as the standards for feeding infants of all gestational ages [2]. Actually, World Health Organization and UNICEF), Ministry of Health and although sucking at the breast competence are scarce or absent in pediatric societies who foster exclusive breastfeeding for 6 months, high-risk preterm infants cared for in neonatal intensive care units with continuation of partial breastfeeding for 1 year or longer (NICUs), the administration of human milk rather than preterm [2]. formula in this population improves outcomes, mainly reducing the risk of necrotizing enterocolitis. Eventually, mother’s own milk should be the first choice, with donor human milk representing a Table 1 second option. A synopsis of exclusive breastfeeding rates in Italy, expressed as percentage, using WHO feeding definitions. Data are derived from different Italian regions and from 2. Epidemiological data on breastfeeding in Italy and the need a national survey conduceted in 1999 in Italy. for breastfeeding promotion Region Year Reference At hospital Months of age discharge 356 Despite evidences on the relationship between breastfeeding Emilia Romagna 2005 Health Authority 44 26 – and health, breastfeeding rates at birth in healthy newborns are Statistics not yet satisfactory for developed countries, calling for a series Lombardia 2006 Pirola, Ricerca e 39 – 19.4 of multiple and integrated interventions to promote breastfeeding Pratica 2008 Liguria 2003 Santini, Acta Paediatr 50.3 – 9.5 [3]. In Italy, for example, there is no universal monitoring on 2008 feeding practice in the first year of life and consequently official Friuli Venezia 2006 Statistics from Health – 38 – Giulia Authority 2008 Cattaneo, Breastfeed – – 6 Med 2011 * Corresponding author: Angela De Cunto, Institute for Maternal and Child Italy 2003 Giovannini, Acta 77 5 Health, IRCCS “Burlo Garofolo”, Via dell’Istria 65/1, 34137 Trieste, Italy. Tel.: +39 Paediatr 2003 3493136915; fax: +39 040 3785239. ∼75% ∼40% ∼30% ∼10% E-mail address: [email protected] (A. De Cunto).

0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. R. Davanzo, A. De Cunto / Early Human Development 89S4 (2013) S20–S22 S21

3. Attitude and commitment of health professionals in 5. From tube to breast: the role of semi-demand feeding breastfeeding promotion The use of expressed breast milk for high risk preterm newborns Despite the well documented positive impact that breastfeeding during hospital stay should be ideally followed at the time of hospi- has on public health, health care workers hold a variety of tal discharge by direct breastfeeding. This should be considered as attitudes toward breastfeeding, depending on professional training a major goal by NICU’s staff, as it makes breastfeeding management background and interest, and personal reproductive history. easier, more practicable and sustainable. Health workers need to set their profession within a broader Demand feeding is known to be the preferred feeding pattern perspective in which their practice should be integrated with health for term babies, as its flexibility eases the physiology of lactation. promotion. Whatever the specific interests in medical care or the Obviously, demand feeding needs a competent baby as a prereq- place breastfeeding holds within a personal value system, health uisite. Consequently, although it is widely accepted as the current professionals should make an ethical commitment to promoting and recommendation for healthy term newborn infants, its use for protecting breastfeeding within the scope of her/his possibilities, the preterm population has been questioned due to the possible skills, role and competence [5]. scarce demand from the preterm baby and the risk of limited milk In everyday practice, health professionals should support breast- intake and poor growth. Eventually, to date, scheduled feeding still feeding through individual counselling and organized services and remains current standard practice for preterm infants feeding. care procedures for both healthy full-term infants with adequate Nevertheless, semi-demand feeding has been proposed for birth weight and infants with special needs. Knowledge of the preterm infants during the transition from scheduled to full demand biology and physiology of human lactation is therefore an essential feeding to promote the establishment of self-regulated oral feeding, prerequisite for setting medical interventions on firm ground in the particularly when the preterm newborn infant demonstrates to promotion and support of breastfeeding. meet well defined criteria according to a clinical protocol [10]. In developed countries, most deliveries take place in hospital Semi-demand feeding is reported to shorten time to oral feeding settings. Although the hospital setting might contrast breastfeeding without compromising weight gain. In semi-demand feeding the because of feeding patterns hindering physiology and obstetric free demand is intended as cautiously restricted in time and in pat- management of delivery, skilled professional help provided in tern. However, implement of this method relies on the recognized hospital and community settings during the first days of life have feeding competency of a preterm infant and a precise diagram for a strong positive influence on the start as well as the duration of the application of semi-demand feeding in preterm infants should breastfeeding and exclusivity of breastfeeding throughout the first be adopted to safely implement this practice. year of life. The Baby-friendly Hospital Initiative (BFHI) aimed to improve breastfeeding practices in maternity facilities is also an 6. Conclusion effective and cost-effective intervention [6]. Moreover, although breastfeeding is the natural norm, it needs A successful promotion of breastfeeding among both healthy to be trained and facilitated through appropriate environmental and high risk newborn infants requires multicomponent effective stimuli also in healthy term infant with a competent mother. Help- interventions by health professionals. First, health professionals ing mothers to breastfeed implies the ability to assess how good the need to improve their knowledge on lactation, to acquire better latch to the breast is, as it is related to the success of breastfeeding. skills to manage breastfeeding problems, to commit to preparing An accurate feeding assessment of infant position and latch on at evidence based breastfeeding protocols. Finally, we must recognize the breast represents an essential task of health professionals also that all these efforts will be more productive if coupled with the because it allows to determine the neuro-behavioural maturation development of an improved attitude of neonatology staff towards of the neonate, anticipates a proper milk intake and provides infor- breastfeeding. mation on maternal autonomy in the management of breastfeeding, which are factors to be considered for hospital discharge after Conflict of interest childbirth. In everyday practice maternity health professionals need reliable, reproducible tools to assess the effectiveness of breastfeed The authors have no conflict of interest to declare. in healthy newborns and to identify the mother–infant pairs in need of extra help and follow-up [7]. References

4. Nutrition with human milk of high risk infants [1]IpS,ChungM,RamanG,ChewP,MaculaN,DeVineD,TrikalinosT,Lau J. Breastfeeding and maternal and infant health outcomes in developed countries. Evidence report/technology assessment No. 153 (Prepared by Tufts- At discharge from NICU, rates of breastfeeding (feeding at the New England Medical Center Evidence-based Practice Center, under Contract breast) and the use of expressed human milk (mother’s and donor’s No. 290-02-0022). AHRQ Publications No. 07-E007. Rockville, MD: Agency for milk) are limited. Data from Italy show that only 28% of all infants Healthcare Research and Quality; April 2007. www.ahrq.gov. is fed exclusively with human milk at hospital discharge: 31%, 25%, [2] Section on Breastfeeding. Breastfeeding and the use of human milk. Pediatrics 22% and 33% respectively in the <1500 g, 1500–2000 g, 2000–2499 2012;129:e827–41. ≥ [3] Chung M, Raman G, Trikalinos T, Lau J, Ip S. Interventions in primary care gand 2500 g birth weight categories [8]. Infants with a birth to promote breastfeeding: an evidence review for the U.S. Preventive Services weight 1500–2499 g are fed exclusively with human milk less than Task Force. Ann Intern Med 2008;21;149(8):565–82. those in higher or lower birth weight categories. [4] Radaelli G, Riva E, Verduci E, Agosti M, Giovannini M. Attitudes and practices Actually, well-documented strategies effective at promoting of family paediatricians in Italy regarding infant feeding. Acta Paediatr breastfeeding and the use of human milk in NICUs are scarcely 2012;101(10):1063–8. doi: 10.1111/j.1651-2227.2012.02769.x [Epub 2012 Jul 17]. known and/or applied. Reported strategies include open access [5] Davanzo R. Pastore S. Promoting mother’s milk use in very low birth weight to NICU for both parents, specific knowledge of the science of infants: when nutritional hierarchy deals with the professional value system. lactation, multidisciplinary breastfeeding training, peer support in J Hum Lact 2011;27(4):329–30. doi: 10.1177/0890334411422705. hospital, breastmilk expression using simultaneous pumping with [6] Brodribb W, Kruske S, Miller YD. Baby-friendly hospital accreditation, in- hospital care practices, and breastfeeding. Pediatrics 2013;131(4):685–92. doi: an electric pump particularly in the first 2 weeks and kangaroo 10.1542/peds.2012-2556 [Epub 2013 Mar 11]. mother care [9]. [7] Tornese G, Ronfani L, Pavan C, Demarini S, Monasta L, Davanzo R. Does the LATCH score assessed in the first 24 hours after delivery predict non-exclusive S22 R. Davanzo, A. De Cunto / Early Human Development 89S4 (2013) S20–S22

breastfeeding at hospital discharge? Breastfeed Med. 2012;7(6):423–30. doi: [9] Davanzo R, Brovedani P, Travan L, Kennedy J, Crocetta A, Sanesi C, Strajn T, 10.1089/bfm.2011.0120 [Epub 2012 Feb 7]. De Cunto A. Intermittent Kangaroo Mother Care: A NICU Protocol. J Hum Lact [8] Davanzo R, Monasta L, Ronfani L, Brovedani P, Demarini S. Breastfeeding at 2013 Jun 4 [Epub ahead of print]. NICU discharge: a multicenter Italian study. J Hum Lact 2012; Jul 21 [Epub [10] Davanzo R, Strajn T, Kennedy J, Crocetta A, De Cunto A. From tube to breast: ahead of print]. the bridging role of semi-demand feeding. Unpublished. Early Human Development 89S4 (2013) S23–S24

Rooming-in care of newborn infants

G. Mangili *, I.C. Formica

Mother & Infant Department, Neonatal Intensive Care Unit, Papa Giovanni XXIII Hospital, Bergamo, Italy

In the early part of the twentieth century, when hospitals be- wards. In the hospital nursery there is tighter security as access to came the predominant sites for birth in industrialized countries, the infants is strictly limited to mothers and healthcare staff. One there was the practice of providing separate care for the infant ofthereasonsofthepracticeofseparatecareistheopinionthatit and mother. Babies were kept securely in a separate nursery. In would protect babies from infections. But according to rooming-in this circumstance mothers could spend time with their babies at supporters it is right to say that, during all the hospital stay, limited meeting times for several minutes during their hospital mother can have help and support when she meets difficulties, stay, walking to the nursery only to breastfeed their infants during from midwifes, nurses and other healthcare staff; moreover serious scheduled feeding times (“closed nursery”). Afterwards mothers outbreaks of nursery infection were reported, leading to a proposal were allowed to walk to the nursery to breastfeed “on demand” that keeping mother and baby together might prevent infection, or to attend to their infants during all the day. In this practice, in addition to other benefits. Rooming-in begins since the infant’s called “open nursery”, there is also the possibility to bring infants birth, when the baby remains with the mother in the delivery to the mothers’ room during the daily hours for breastfeeding, room: after delivery the newborn is put on mother’s chest (skin to but main procedures are taken in the nursery room and not in skin contact). Kangaroo mother intervention or kangaroo mother the mother’s room. More recently many hospitals have begun the care was introduced in 1978 in Colombia, which is characterized practice of keeping the mother and infant together in the same by direct skin-to-skin contact (kangaroo position), exclusive or room throughout their hospital stay; this last type of care has been nearly exclusive breastfeeding (kangaroo nutrition). Several studies termed rooming-in. It is defined by World Health Organization as showed that kangaroo mother intervention (KMI) has advantages the hospital practice where postnatal mothers with normal infants for the baby’s emotional stability, increased successful breastfeed- stay together in the same room twenty-four hours a day, from ing and decreased neonatal morbidity. In this aspect, rooming-in time they arrive in their room after delivery. They remain together circumstance is very important for successful KMI practice. “The until discharge, unless there is a specific medical indication which ten steps for successful breast feeding” from Baby-Friendly Hospital requires separation such as refusal by maternal condition or post- Initiative (BFHI), WHO/UNICEF, recommends early breast feeding partum diseases or as poor condition of babies (neonatal jaundice, within 30 minutes after birth with complete rooming-in care for the sepsis, hypoglycemia, cyanosis, vomiting). In these conditions the first 24 hours. And also, American Academy of Pediatrics and Amer- baby is transferred to nursery or to Neonatal Intensive Care Unit, ican College of Obstetricians and Gynecology recommend complete according to symptoms’ seriousness and to needful therapies. It is rooming-in. A lot of studies have demonstrated that the deep widely accepted that the rooming-in care has many advantages, but bond between mother and infant, termed “bonding”, is favored by the “open nursery” has still many supporters. They have the very protracted contact in the period immediately after delivery that diffused opinion that separate care is a hospital practice with both gives protection from infection, emotional stability and maximized maternal and infants benefits. Many mothers complain pain and mother to baby interaction with joy. Mother who can stay in contact discomfort after their delivery, distressed by physical effort or by with her baby is more relaxed, calm and self-confident for attending surgery in the case of caesarian section. Placing the infant in the infant during the hospital stay and can be more confident when hospital nursery after birth allows the mother to rest. Therefore the they go back home after discharge to raise their own baby. In the “open nursery” supporters think that it is opportune makes mother same time, after delivery, the baby that remains beside his mother to rest and recover for when she will come back home. While she at once is able to know mother’s smell and to close to the breast to is recuperating, she can either walk to the nursery whenever she suckle it. Breast milk production begins immediately after delivery. feels ready as frequently as she wishes or she can request the infant Its regulation is controlled by mother’s physical and psychological be brought to her room for demand breastfeeding. Alternatively all condition, the frequency of breastfeeding, effective infant’s suckling babies are brought from the nursery to their mother’s room. In fact of the breast, the stimulus of the sight and sound of the baby’s separate care may also be partial, for example it could be practiced cry. It’s proved that separating infant from his mother after birth during the night and rooming in during the day. In addition there is can reduce the frequency of breastfeeding and the amount of the also a security concern for infants when other patients and visitors breast milk a mother produces. Instead, considered that infant who have access to them, especially in hospitals with open maternity stays together with the mother has more frequent suckling of the breast, is demonstrated that rooming-in is associated with higher breastfeeding frequency, higher rate of exclusive breastfeeding and * Corresponding author. longer duration of breastfeeding. So rooming-in is suggested to

0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. S24 G. Mangili, I.C. Formica / Early Human Development 89S4 (2013) S23–S24 promote breastfeeding, reducing the need of supplement of liquids felt more useful and close to mothers and babies. In conclusion different from mother’s milk (dextrose water or formula milk) and nursery facilities should educate and encourage the advantages of represents a useful period of early knowledge between mother and rooming-in, including the good formation of attachment between infant and training of the mother in the newborn’s care. She will mother and infant, emotional stability, protection from infection, learn to be self-sufficient in facing and overcome the difficulties and increased breastfeeding rate so that rooming-in care can be (difficult suckling, times of suckling, crying, etc.). As regards the fully established. Rooming-in represents the evolution of healthy care offered in rooming-in the most important point is represented newborns’ care, but really it consist of a return to the past and by the change in the aims: the hygiene and the feeding of the physiology, when the delivery happened at home and the infant newborn don’t represent anymore the central point of the medical remained beside the mother since birth. and nursing tasks, but the main aim become the wealthy of the couple mother–baby. In fact instead to care only the newborn Conflict of interest and his needs, nurses help mothers to care own son and support them in breastfeeding: their roledoesn’treplacethemotheras The authors have no conflict of interest to declare. regards hygiene and watching of the newborn, but it wants to be a practical and psychological help which aims to self-confidence Selected bibliography of the mother in the daily care of the newborn. Furthermore rooming-in is associated with lower incidence of neonatal diarrhea, [1] Jaafar SH, Lee KS, Ho JJ. Separate care for new mother and infant versus weight decrease and significant jaundice; moreover some authors rooming-in for increasing the duration of breastfeeding (Review). Cochrane suggest that keeping mother and baby together might prevent Database Syst Rev 2012;9:CD006641. doi: 10.1002/14651858.CD006641.pub2. infections. For all these reasons the rooming-in is recommended by [2] Hill PD, Aldag JC, Chatterton RT, Zinaman M. Comparison of milk output between mothers of preterm and term infants: the first 6 weeks after birth. J World Health Organization and UNICEF “Ten Steps for Successful Hum Lact 2005;21(1):22–30. Breastfeeding” and this practice should be implemented in every [3] Lee YM, Song KH, Kim YM, Kang JS, Chang JY, Seol HJ, Choi YS, Bae CW. hospital. In our experience the complete rooming-in care practice Complete rooming-in care of newborn infants. Korean J Pediatr 2010 May; was introduced since when the new hospital was established, on 53(5):634–8 [Epub 2010 May 31]. [4] Dumas L, Lepage M, Bystrova K, Matthiesen AS, Welles-Nyström B, Widström December 2012. Efforts to rise rooming-in care success rate have AM. Influence of skin-to-skin contact and rooming-in on early mother–infant been undertaken in this period and it was made easier by larger interaction: a randomized controlled trial. Clin Nurs Res 2013; Jan 3 [Epub spaces and new wards disposition and organization. We observe ahead of print]. and monitor baby’s vital signs during the first hours in delivery [5] Charpak N, Ruiz-Peláez JG, Figueroa de Calume Z. Current knowledge of room until the first medical examination and after we take care of Kangaroo mother intervention. Curr Opin Pediatr 1996;8:108–12. [6] Charpak N, Ruiz-Pelaez JG, de Figueroa CZ, Charpak Y. A randomized, con- the normal baby in the same room of the mother During rooming-in trolled trial of kangaroo mother care: results of follow-up at 1 year of stay, routine procedures with pediatrician rounding everyday are corrected age. Pediatrics 2001;108:1072–9. given to the baby at each room. We noticed the advantages of [7] Moore ER, Anderson GC, Bergman N. Early skin-to-skin contact for mothers rooming-in, consisting of increasing of breastfeeding rate and per- and their healthy newborn infants. Cochrane Database Syst Rev 2007;(3): centage of exclusive breastfeeding (with consequential reduction CD003519. [8] WHO/UNICEF. Baby-Friendly Hospital Initiative. Revised, updated and ex- of mixed feeding with breast and formula feeding and exclusive panded for integrated care. Availalbe from http://www.who.int/nutrition/ formula feeding). In this respect, all healthcare staff was moti- topics/bfhi/en/index.html. vated and trained by the training program in accordance with to [9] Gartner LM, Morton J, Lawrence RA, Naylor AJ, O’Hare D, Schanler RJ, et al. World Health Organization and UNICEF guidelines about BFHI (Baby American Academy of Pediatrics Section on Breastfeeding. Breastfeeding and the use of human milk. Pediatrics 2005;115:496–506. Friendly Hospital Initiative). We experienced successful rooming-in [10] Committee on Health Care for Underserved Women; Committee on Obstetric care for the last six months, also in terms of satisfaction of the Practice. Breastfeeding: maternal and infant aspects. Int J Gynaecol Obstet mothers, that felt followed and supported during their hospital 2001;74:217–32. stay and of the nurses, that, in spite of the bigger workload, Early Human Development 89S4 (2013) S25–S26

Sudden unexpected perinatal collapse and sudden unexpected early neonatal death

Niccolò Nassi a,*, Raffaele Piumelli a, Vincenzo Nardini b,PaoloTotic, Anna Maria Buccoliero d,Giulia Liccioli e, Gianpaolo Donzelli e aSIDS Centre Meyer Children’s Hospital, Florence, Italy bPathology Unit II, Santa Chiara Hospital University of Pisa, Pisa, Italy cPathology Unit, Le Scotte Hospital, University of Siena, Siena, Italy d Pathology Unit, University of Florence, Florence, Italy eFetal-Neonatal Department, Meyer Children’s Hospital, University of Florence, Florence, Italy

ARTICLE INFO ABSTRACT

Keywords: Acute neonatal events, ranging from mild episodes (characterised by collapse) to deadly episodes, are re- Sudden infant death syndrome (SIDS) ported in literature more and more frequently. These events, which are defined as sudden unexpected peri- Apparent life-threatening event (ALTE) natal collapse (SUPC) and sudden unexpected early neonatal death (SUEND) respectively, mainly occur in the Sudden unexpected perinatal collapse first hours of life and usually affect infants from a first pregnancy who in most cases share the bed with their (SUPC) mothers. Due to the risks of severe neurological consequences or even death of the infant, it is essential for Sudden unexpected early neonatal death birth-centre staff to be adequately trained to ensure safe rooming-in. (SUEND) © 2013 Elsevier Ireland Ltd. All rights reserved.

1. Introduction syndrome (Ondine’s curse/CCHS), congenital heart disease, and cardiac arrhythmias. In 16% of cases, the cause is attributable The “sudden infant death syndrome” (SIDS) is the sudden to bacterial infections, while in 11% of cases the persistence of and unexpected death of an infant aged 1 to 12 months which pulmonary hypertension can give rise to acute events, and 42% remains unexplained after performing a thorough post-mortem of cases are idiopathic. The latter could be due to an imbalance examination. The acronym ALTE (apparent life-threatening event) in the autonomic nervous system characterised by a prevalence indicates an episode so frightening for the observer as to induce of the parasympathetic tone during the first hours of life. 27% him/her to believe the child is in danger of dying. These episodes of cases of SUPC are lethal and it is therefore crucial to ensure are clinically characterised by variable combinations of apnoea, “monitored and professional” rooming-in for all newborns and their change in skin colour (cyanosis, erythrosis, pallor) and muscle mothers, especially in the first hours after birth. The aim is to tone (hypotonia, hypertonia). The peak age for SIDS is between promote and encourage both skin-to-skin care and breastfeeding, the first and fourth month of life, while ALTEs primarily affect while also ensuring prompt intervention in case of an acute event. infants between 1 and 3 months of life. In 50% of cases, ALTEs The above-mentioned risk of congenital or metabolic disorders calls cannot be traced to any cause, and are called idiopathic ALTEs for strict multidisciplinary diagnostic processes in order to identify (IALTEs). While ALTEs and SIDS do not occur in the perinatal period, the cause of the event as early as possible. In case of death, the similar severe events during the first hours of life are reported infant should be subjected to a thorough post-mortem by trained and described increasingly more often. These critical events have pathologists according to specific protocols. been defined as sudden unexpected perinatal collapse (SUPC) and sudden unexpected early neonatal death (SUEND) respectively. 2. Experience in the Tuscany region The incidence of SUPC is between 0.03 and 0.08/1000 live births and affects apparently healthy term newborns, often from a first The regional network for the diagnostic examination of the pregnancy and in most cases (75%) the newborns share the bed cases of sudden unexpected infant deaths (SUDI) was set up in with the mother. A recent study also shows that about two-thirds the Tuscany region in 2009. A protocol was established and shared (66%) of infants with a history of SUPC were found in the prone by a multiagency taskforce. All cases of SUDI are examined by position, and in 40% of cases the mother was not aware of the acute three pathologists and the physicians of the emergency services event. Approximately 20% of neonatal collapses may be considered and the SIDS Centre of the Meyer Children’s Hospital. Between the very first sign of congenital anomalies such as prenatal cerebral 2009 and 2012, 34 cases of SUDI occurred in the Tuscany Region, damage, metabolic diseases, congenital central hypoventilation accounting for an incidence of less than 0.3‰ of live births. Autopsies were performed in 29 cases (85.2% of the total), however in 15 cases (57%) they failed to identify a specific cause of death. * Corresponding author. These cases were classified as SIDS. Two cases occurred during the

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first week of life and were therefore defined as SUENDs. In both The effectiveness of these measures will depend on their cases autopsies were performed by paediatric pathologists of two dissemination among professionals, as well as adequate training of specialist centres in our regional network according to a standard all the staff involved in the “birth environment”. protocol which includes ancillary investigations and case discussion with the clinicians. Conflict of interest The first case involved an 8-hour-old infant who died while breastfeeding. The autopsy revealed prenatal hypoxic–ischemic The authors have no conflict of interest to declare. lesions and a marked bilateral hypoplasia of the arcuate nuclei. The second case involved a 3-day-old infant who died suddenly Selected bibliography about 1 hour after feeding. The post-mortem revealed a unilateral [1] Becher JC, Bhushan SS, Lyon AJ. Unexpected collapse in apparently healthy hypoplasia of the arcuate nucleus. Arcuate nuclei are structures newborns – a prospective national study of a missing cohort of neonatal deaths belonging to the serotonergic network which plays a crucial role in and near-death events. Arch Dis Child Fetal Neonatal Ed 2012;97(1):F30–4. the control of breathing during sleep. Their malfunction seems to [2] Dageville C, Pignol J, De Smet S.Very. Early neonatal apparent life-threatening be involved in the pathomechanism of SIDS. Interestingly, similar events and sudden unexpected deaths: incidence and risk factors. Acta Paedi- brainstem lesions have also been found in cases of SIUDs, thus atr. 2008;866–9. [3] Fleming PJ. Unexpected collapse of apparently healthy newborn infants: the opening an intriguing scenario of a possible continuum among benefits and potential risks of skin-to-skin contact. Arch Dis Child Fetal SIUD, SUEND and SIDS. Neonatal Ed 2012;97(1):F2–3. [4] Guidelines for the Investigation of Newborn Infants who suffer a Sudden and 3. Conclusion Unexpected Postnatal Collapse In the First Week of Life. Recommendations from a Professional Group on Sudden Unexpected Postnatal Collapse. March 2011. Despite their rareness, SUPC and SUEND are two nosological [5] Krous HF, Beckwith JB, Byard RW, Rognum TO, Bajanowski T, Corey T, et entities which health professionals should be made aware of in al. Sudden infant death syndrome and unclassified sudden infant deaths: a order to ensure the necessary safety levels for mother and child. In definitional and diagnostic approach. Pediatrics 2004;114:234–8. this regard, we suggest implementing the following measures: [6] National Institutes of Health Consensus Development Conference on Infantile Apnea and Home Monitoring Consensus Statement. Pediatrics 1987. – informing the mother about rooming during the preparation [7] Poets A, Urschitz MS, Steinfeldt R, Poets CF. Risk factors for early sudden deaths for childbirth; and severe apparent life-threatening events. Arch Dis Child Fetal Neonatal Ed – discouraging bed sharing; 2012;97:F395–7. – assessing the level of the mother’s stress and fatigue; – laying infants in the supine position to sleep. Early Human Development 89S4 (2013) S27–S28

Discharge of the newborn: timing, mode and controls

Pier Luigi Vasarri

Prato, Italy

ARTICLE INFO ABSTRACT

Keywords: Many of the practices routinely used at birth centers are based more on habits developed through time, rather Newborn than the result of true scientific evidence. We have conducted a survey in the birth centers in Tuscany to verify Hospital the different care practices for healthy term newborn infants. Discharge © 2013 Elsevier Ireland Ltd. All rights reserved.

The decision regarding when to discharge a newborn is not as Table 1 simple as it may appear to a superficial analysis. The reduction of time spent in hospital is a benefit for the newborn and the family because it reduces the time of separation from parents and makes the birth of newborn less medicalized. The criteria of corporatization and the cost of the services of our hospitals however should lead to a rationalization of costs, but not to cut services for children and mothers. The choice of the discharge must meet this balance between well-being and safety of the newborn, needs and capacities of parents considering the availability and adequacy of services of local primary care and home care. Furthermore the discharge of the newborn should be based on available scientific evidence even though there are more and more economic reason that lead to anticipate the discharge as much as possible to reduce health care costs. The importance of this issue increases when the delivery is not physiological. The difficulties increase with the discharged of a pathological newborn due to the problems of these childrens. For example: low birth weight or preterm infants in intensive care have a higher risk of rehospitalization and death in the first year of life than full term infants. An increased risk of morbidity is also observed in late preterms who are the most numerous of all preterm infants. There are also infants with social problems that need to be discharged: children of drug-addicted mothers, homeless, handi- capped, etc. centers of the Tuscany region (currently 24, see Table 1) and to Careful preparation of the parents at discharge, an appropriate several major centers in other regions of Italy. The questions were follow-up and integration between hospital and primary care are related to: of particular significance in these patients to reduce the associated • compilation of the neonatal medical record risks. • exams on the umbilical cord The “complexity” of certain infants largely explains the diversity • type of prophylaxis against bleeding and ophthalmic prophylaxis ofthemodeofdischargebecauseeverychild,insomeways,isa • prevention of hypoglycemia and hyperbilirubinemia case in itself. • staff dedicated to the observation and observation mode However, there are significant differences among the birth • mode of assistance in the delivery room and subsequent visits centers on the management and discharge of newborns defined as • observation mode of breastfeeding “physiological” or “healthy”. • execution of metabolic screening, audiological screening and red In this regard, we administered a questionnaire to all the birth reflex

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• execution of screening for congenital heart disease using pulse discharge. The red reflex is performed at the birth center before oximetry the discharge, although with mydriasis obtained in different modes • times of discharge of vaginal delivery newborn and uncompli- (physiological/pharmacological) and the audiological screening by cated cesarean TOEA is performed in the totality of Tuscan centers. In some centers • protocols for GBS are also executed immediately AABR in the presence of risk factors. • management of particular categories of infants: late preterm, Almost all birth centers perform or are implementing the children of immigrants, children of mothers with poorly fol- screening test for congenital heart disease using pulse oximetry. lowed pregnancy, born with vacuum, etc. One aspect that emerged is the different prudential approach • ultrasound screening for congenital hip dysplasia of the various operators towards relatively frequent neonatal prob- • existence of a neonatal outpatients department run by doctors lems. The children of immigrants are often kept under prolonged and/or nurses. observation, they are subjected to a greater number of tests and a • existence of rooming-in. greater number of controls post-discharge; in the case of operative The questionnaire, although the data is not complete, has vaginal delivery with vacuum some centers prolong the period highlighted that there are significant differences in the management of observation, others perform a cerebral ultrasonography; late- of the newborn defined as “physiological” and in the mode of preterm infants are often kept with their mothers in rooming-in discharge between the birth centers of the region of Tuscany with with an average of 35 + 5 weeks of G.E. and weight of 2250 g but variability also linked to the number of newborns in each center. with widely differing margins in the various centers, ranging from In particular, some elements to think about are: G.E. 34 to 36 and 2000 to 2500 g for weight. The medical history of newborn was collected indirectly in the Based on this study it appears that, without shared guidelines, obstetric record and not directly from the neonatologist except in many of the practices routinely used at birth centers are based 4 cases out of 24. In most cases, the history, collected indirectly more on habits developed through time, rather than the result of from the obstetric record, it is missing of the important elements. true scientific evidence. The centers where the history is collected directly from the At a moment in time when “efficiency” is extremely important neonatologist are those with a low number of births, so the time and resources are scarce and prioritized on real needs, the increase factor is a limiting factor for a correct medical history. in the sharing of best practices and guidelines amongst health The majority of centers perform the test of the blood group operators (e.g. at a regional level) based on solid scientific evidence anddirectCoombstest,except3outof24whomakesuchtests becomes of paramount importance. if the mother is Rh neg. One center never executes these tests on umbilical cord but always performs an examination of EGA, Conflict of interest calcium and glucose. 14 out of 24 centers performs an EGA from the umbilical cord for each newborn, while 6 out of 24 only in The author has no conflict of interest to declare. cases of neonatal asphyxia and 4 out of 24 never. In various birth centers tests are performed in different ways, with the sampling Selected bibliography from the umbilical cord: bilirubin, thyroid hormones, CRP, blood [1] American Academy of Pediatrics Committee on Fetus and Newborn. Hospital count, hematocrit. discharge of the high risk neonate. Pediatrics 2008;122:1119–26. For the prevention of neonatal hypoglycemia in some birth [2] Doyle LW, Ford G, Davis N. Health and hospitalizations after discharge in centers the blood glucose test is performed in all infants, in others extremely low birth weight infants. Semin Neonatol 2003;8:137–45. only for populations at risk with differences in the time of execution [3] Lamarche-Vadel A, Blondel B, Truffert P, et al. Re-hospitalization in in- fant younger than 29 weeks’ gestation in the EPIPAGE study. Acta Paediatr of test and the interruption of the controls. For the prevention of 2004;93(10):1340–5. hyperbilirubinemia, in some centers all newborns are screened for [4] American Acdemy of Pediatrics Committee on Fetus and Newborn. Hospital bilirubin, with capillary or transcutaneous methodology, in other Stay for Healthy Term Newborns. Pediatricas 2010;125:405. these tests are performed only in the presence of jaundice or [5] Powell PJ, Powell CVE, Holli S, Robinson JM. When will my baby go home? clinical risk factors. Arch Dis Child 1992;67(10 Spec No):1214–6. [6] Rosen TS, Rosen J; American Academy of Pediatrics, Section on Home Health Other differences relate to the organizational aspects of manage- Care. Comprehensive home care program for the socially high risk infant. ment of the newborn, which is entrusted to different professionals Guidelines for Pediatric Home Health Care. Elk Grove Village, IL: American (midwives, nurses, social health workers) sometimes with standard- Academy of Pediatrics, 2002; pp 297–305. ized methods of observation (compilation of Check List: parenting [7] Rapisardi G., Pierattelli M., Tamburini G. Raccomandazioni per l’assistenza alla madre in puerperio e al neonato. Riv It Ped 2000;26:232–43. skills, breastfeeding, vital signs, ...) or sometimes based only on the [8] Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in operator experience. the newborn infant 35 or more weeks of gestation. Pediatrics 2004;114(1):297– Metabolic screenings have been implemented in the region of 316. Tuscany the and are currently performed in all newborns before Early Human Development 89S4 (2013) S29–S32

The newborn with “few red blood cells” and the newborn with “too many red blood cells”

Mario Motta a,*, Antonio Del Vecchio b, Robert D. Christensen c aNeonatal Intensive Care Unit, Children’s Hospital of Brescia, Brescia, Italy cDivision of Neonatology, Neonatal Intensive Care Unit, Di Venere Hospital, Bari, Italy cWomen and Newborns Program, Intermountain Healthcare, Salt Lake City, Utah, USA

ARTICLE INFO ABSTRACT

Keywords: Anemia and polycythemia are common hematologic problems in neonates. Although significant progress has Newborn been made in this field, some of the common interventions for these conditions are not yet supported by Anemia scientific evidence. With this manuscript we aim to define a structured approach for the diagnosis of these Polycythemia conditions and review their usual treatment. Blood transfusion © 2013 Elsevier Ireland Ltd. All rights reserved.

1. Neonatal reference range of erytrocytes count, RBC antibody by direct antiglobulin test and RBC antibody screen, and measurement of serum bilirubin. Additional testing Normal erythrocyte values in neonates differ significantly from may be helpful in identifying specific diagnoses, such as serologic those in older children and adults. Quantitative and qualita- tests to identify viral infections, blood cultures to identify bacterial tive differences of erythrocytes are present as a reflection of and fungal infections, a Heinz body preparation, and quantitative the physiologic developmental changes during fetal and neonatal assays for specific erythrocyte enzyme deficiencies. Kleihauer-Betke hematopoiesis. Therefore, a clear definition of the normal values testing of maternal blood can provide quantitative evidence of of erythrocytes is important for the proper evaluation and man- fetal-to-maternal transfusion. agement of neonatal anemia and polycythemia. However, since RBC transfusion in preterm or sick term neonates can be blood is not usually drawn on healthy, normal neonates, reference essential in the management of anemia. However, best practices in ranges (defined as the 5th to the 95th percentile values obtained neonatal transfusion medicine are largely undefined [3]. Therefore, from neonates with minimal pathology) are used instead of normal neonatal transfusion practice remains opinion based rather than ranges [1]. Reference ranges of erythrocyte values at various gesta- evidence based. The treatment of early-onset neonatal anemia due tional and postnatal age, obtained from a large cohort of neonates to the occurrence of acute, severe, life-threatening hemorrhage were recently published [1]. may necessitate emergency RBC transfusion without regard to the hemoglobin concentration. Packed red blood cells and saline 2. Neonatal anemia solution should be used to provide adequate and prompt volume expansion. Because a large volume transfusion (up to 40 ml/kg) Neonatal anemia is defined by a hemoglobin or hematocrit may be required to normalize blood volume, blood pressure, and below the 5th percentile lower reference ranges value, according hemoglobin levels, and because severely anemic infants are often to gestational age and postnatal age [2]. As shown in Table 1, the in incipient heart failure, care must be taken to prevent congestive pathogenesis of anemia at birth or appearing during the first few heart failure as a result of volume replacement. In such cases, weeks of life can be broadly categorized into three major groups; partial exchange transfusion (PET) can be considered as a means (1) blood loss, (2) hemolysis, or (3) production failure. A structured of increasing hemoglobin and oxygen-carrying capacity without approach to the diagnosis of anemia includes family and obstetric further increasing intravascular volume. history and physical examination. Diagnostic algorithms can be Apart from emergency transfusion for acute bleeding, assess- helpful (Fig. 1). These steps usually lead to the correct diagnosis. ment of the need for a RBC transfusion first requires consideration The initial laboratory evaluation includes a complete blood of the cause of the anemia. Special attention should be addressed count with red blood cell (RBC) indices, blood smear, reticulocyte to extremely low birth weight preterm neonates who typically develop the anemia of prematurity, a normocytic, normochromic, hypoproliferative anemia marked by inadequate production of ery- * Address correspondence to: Dr. Mario Motta, Neonatology and Neonatal Inten- thropoietin [4]. Additionally, extremely low birth weight neonates sive Care Unit, Children’s Hospital of Brescia, P. le Spedali Civili, 25123 Brescia, Italy. Tel +390303995219; Fax +390303700817. are exposed to frequent blood draws for laboratory testing, thus E-mail address: [email protected] (M. Motta). compounding their need for RBC transfusion. Current practice rec-

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Table 1 Classification of neonatal anemia.

Blood loss • Iatrogenic blood loss due to laboratory testing • Obstetric accidents (trauma of umbilical cord or placenta, prolonged positioning of the infant above the mother before cord clamping) • Malformations of the placenta or cord (velamentous insertion of the umbilical cord, vasa previa rupture) • Fetal-to-maternal transfusion • Donor of a twin-to-twin transfusion (only with monozygotic, monochorionic twinning) • Internal hemorrhage due to trauma or clotting disorders (intracranial, intrahepatic, cephalohematoma, subgaleal) Hemolysis • Immune hemolytic anemia – Rh, ABO, or minor group incompatibility – Maternal-fetal autoimmune hemolytic anemia – Drug-induced hemolytic anemia (penicillin, cephalothin, alpha-methyldopa, valproic acid) • Nonimmune – Acquired infection (bacterial or viral sepsis) – Congenital infection (rubella, herpes, syphilis, cytomegalovirus, toxoplasmosis, malaria, human immunodeficiency virus) – Vitamin E deficiency – Red cell membrane disorders (Hereditary spherocytosis, elliptocytosis, stomatocytosis, pyropoikilocytosis) – Disseminated intravascular coagulation – Red cell enzyme deficiencies (Glucose-6-phosphate dehydrogenase deficiency, Pyruvate kinase deficiency, other rare enzyme deficiencies) – Thalassemia syndromes (Alpha thalassemia, Gamma thalassemia) – Unstable hemoglobin (congenital Heinz body hemolytic anemias) – Inherited metabolic (Osteopetrosis, Galactosemia) Erythrocyte production failure • Bone marrow failure syndromes – Mainly involving erythroid cell line (Diamond-Blackfan anemia, transient erythropenia of childhood, congenital dyserythropoietic anemias) – Pancytopenias (reticular dysgenesis, refractory sideroblastosis syndrome “Pearson syndrome”, Fanconi anemia) • Infection – Acquired bacterial or viral sepsis – Congenital viral (rubella, parvovirus B19) • Anemia of prematurity • Nutritional deficiencies (protein, iron, folate, B12) • Transcobalamin II deficiency • Congenital leukemia

Fig. 1. Differential diagnosis of neonatal anemia. ommended for the prevention of anemia in extremely low birth 3. Neonatal polycythemia and hyperviscosity weight neonates includes: delayed clamping or stripping of the umbilical cord, obtaining the initial blood tests of neonates from Polycythemia is defined as a hemoglobin or hematocrit greater umbilical cord blood, limiting phlebotomy losses, implementing than the 95th percentile upper reference range limit for gestational written guidelines for transfusions, and selected use of recombinant age and postnatal age. For later preterm or term neonates in the first erythropoietin [5]. days after birth, this limit is a hemoglobin >22 g/dL or a hematocrit M. Motta et al. / Early Human Development 89S4 (2013) S29–S32 S31

Fig. 2. Algorithm for the diagnosis and treatment of neonatal polycythemia.

>65%, obtained from a venous blood sample. Clinical polycythemia other symptoms including respiratory distress, renal vein thrombo- may occur in 1 to 5% of otherwise healthy newborns and reflects sis, increased pulmonary vascular resistance, hypotonia, irritability the normal fetal adaptation to intrauterine hypoxia. However, the and seizures [8,9]. increased concentration of RBC is the primary determinant in Since measurement of viscosity is not widely available, the inducing hyperviscosity of blood and its related complications. hemoglobin or hematocrit remains the best surrogate tests for The pathogenesis of neonatal polycythemia involves two major diagnosing neonatal polycythemia. These values are often initially mechanisms: erythrocyte transfusion and increased intrauterine measured on a capillary blood sample and, if the hemoglobin is erythropoiesis (Table 2). >22 g/dL and or the hematocrit is >65%, a sample of venous Prospective studies indicate that the majority of polycythemic blood is needed to confirm the diagnosis. When a diagnosis of infants are asymptomatic [6,7]. When compared to matched con- polycythemia is made, infants should be evaluated for possible trols, symptomatic polycythemic neonates have a significantly etiologies (Table 2). All polycythemic neonates should be observed higher incidence of cyanosis, apnea, poor feeding or vomiting, and closely for neurologic and cardiovascular symptoms and evaluated hypoglycemia. The occurrence of necrotizing enterocolitis is similar for common complications, including hypoglycemia and hyperbili- between the two groups. Retrospective studies in neonates reported rubinemia. PET is traditionally used as the method to lower the hematocrit and thereby treat hyperviscosity; however its use is controversial. Table 2 Pathogenesis of neonatal polycythemia. Although PET improves cerebral blood flow and hemodynamic pa- rameters, there is no evidence that it improves long-term outcome, Erythrocyte transfusion and it may lead to an increase in the risk of necrotizing enterocolitis • Delayed clamping or stripping of the umbilical cord • Uncontrolled or precipitous delivery [10]. Considering the lack of evidence supporting the long-term • Intrapartum hypoxia benefits of PET but considering also the limited number of available • Recipient of twin-to-twin transfusion controlled studies, the standard of care in many neonatal intensive • Maternal-fetal transfusion care units continues to be PET for symptomatic infants with venous Increased intrauterine erythropoiesis hematocrits greater than 65%. Alternatively, a more conservative • Pregnancy-induced hypertension approach with intravenous hydration and close observation could • Cardiac or pulmonary disorders inducing maternal hypoxemia be adopted, limiting PET for those with worsening of symptoms • Large for gestational age infant • Maternal diabetes mellitus (Fig. 2). If necessary, isovolumic PET reduces the hyperviscosity by • Beckwith-Wiedemann syndrome lowering the hematocrit without causing hypovolemia. Since sys- • Endocrine abnormalities (congenital adrenal hyperplasia, hypothyroidism, tematic reviews showed that crystalloid solutions are as effective hyperthyroidism) as colloid solutions for PET, a normal saline solution should be used • Chromosomal anomalies (trisomy 21, 18, and 13) for this procedure [11,12]. S32 M. Motta et al. / Early Human Development 89S4 (2013) S29–S32

Conflict of interest [5] Christensen RD, Ilstrup S. Recent advances toward defining the benefits and risks of erythrocyte transfusions in neonates. Arch Dis Child Fetal Neonatal Ed The authors disclaim any competing interest. The authors have 2013;98(4):F365–72. [6] Black VD, Lubchenco LO, Luckey DW, Koops BL, McGuinness GA, Powell DP, not received any honorarium, grant, or other form of payment to Tomlinson AL. Developmental and neurologic sequelae of neonatal hypervis- produce the manuscript. cosity syndrome. Pediatrics 1982;69(4):426–31. [7] Black VD, Lubchenco LO, Koops BL, Poland RL, Powell DP. Neonatal hypervis- Funding cosity: randomized study of effect of partial plasma exchange transfusion on long-term outcome. Pediatrics 1985;75(6):1048–53. [8] Wiswell TE, Cornish JD, Northam RS.Neonatal polycythemia: frequency of clin- This research received no specific grant from any funding agency ical manifestations and other associated findings. Pediatrics 1986;78(1):26–30. in the public, commercial, or not-for-profit sectors. [9] Katz J, Rodriguez E, Mandani G, Branson HE. Normal coagulation find- ings, thrombocytopenia, and peripheral hemoconcentration in neonatal poly- cythemia. J Pediatr 1982;101(1):99–102. References [10] Ozek E, Soll R, Schimmel MS. Partial exchange transfusion to prevent neu- rodevelopmental disability in infants with polycythemia. Cochrane Database [1] Christensen RD, Henry E, Jopling J, Wiedmeier SE. The CBC: reference ranges Syst Rev 2010;1:CD005089. for neonates. Semin Perinatol 2009;33(1):3–11. [11] De Waal KA, Baerts, W, Offringa M. Systematic review of the optimal fluid [2] Venkatesh V, Khan R, Curley A, New H, Stanworth S. How we decide when a for dilutional exchange transfusion in neonatal polycythemia. Arch Dis Child neonate needs a transfusion. Br J Haematol 2013;160(4):421–33. Fetal Neonatal Ed 2006;91:F7–10. [3] Venkatesh V, Khan R, Curley A, Hopewell S, Doree C, Stanworth S. The safety [12] Dempsey EM, Barrington K. Crystalloid or colloid for partial exchange trans- and efficacy of red cell transfusions in neonates: a systematic review of fusion in neonatal polycythemia: a systematic review and meta-analysis. Acta randomized controlled trials. Br J Haematol 2012;158(3):370–85. Paediatr 2005;94:1650–5. [4] Bishara N, Ohls RK. Current controversies in the management of the anemia of prematurity. Semin Perinatol 2009;33(1):29–34. Early Human Development 89S4 (2013) S33–S36

The neonate at risk for thrombocytopenia

Antonio Del Vecchio a,*, Mario Motta b, Robert D. Christensen c aDivision of Neonatology, Neonatal Intensive Care Unit, Di Venere Hospital, Bari, Italy bNeonatal Intensive Care Unit, Children’s Hospital of Brescia, Brescia, Italy cWomen and Newborns Program, Intermountain Healthcare, Salt Lake City, Utah, USA

ABSTRACT

Thrombocytopenia is one of the commonest haematological problems of neonates. The incidence varies greatly depending on the patient population, and the pathogenesis involves various immune and non- immune mechanisms. Before birth, the risk of neonatal thrombocytopenia can be assessed by considering the maternal history, pregnancy complications, and family history. In non-thrombocytopenic neonates the risk that thrombocytopenia might subsequently develop during the hospital course can be assessed. In some cases this risk assessment allows prediction of the timing of presentation; early or late-onset. Early-onset (congenital) thrombocytopenia can be the kinetic result of either reduced platelet production or accelerated platelet consumption. In late-onset neonatal thrombocytopenia the principal kinetic mechanism is generally accelerated platelet consumption. © 2013 Elsevier Ireland Ltd. All rights reserved.

1. Introduction presentation; early (at birth or within the first 72 hours of life) or late (after 72 hours of life) onset thrombocytopenia. Thrombocytopenia affects up to 35% of neonates admitted to an First, we will briefly discuss the biological differences between intensive care unit [1,2]. It can occur in utero,atbirth,orinthe adult megakaryocytes and those of the newborn infant, which may hours or days after birth. It can be transient or prolonged, mild contribute to the increased susceptibility of neonates to developing or severe, and insignificant or life-threatening. The incidence of thrombocytopenia. We will focus also on those neonates at great neonatal thrombocytopenia depends on the patient population. As risk of thrombocytopenia, with a classification system based on the recently described by Wiedmeier and colleagues, thrombocytopenia timing of onset. is defined by a platelet count below the 5th percentile reference range, for gestational age and post-natal age [3]. In general, to 2. Neonatal platelet production qualify for the definition of neonatal thrombocytopenia, neonatolo- gists require two platelet counts below the lower range limit; this Platelet production, from megakaryocyte progenitors to double-check is to exclude the possibility of artifact. About 70% of megakaryocytes and then to platelets, is a complex process ini- ill or extremely low birth weight neonate will have two or more tiated early during fetal life. Megakaryocytes are first detected in platelet counts that fall into the thrombocytopenic range at some the liver and circulatory system at 8 weeks post-conception and point during their hospital course [4]. platelets increase in number during fetal life, reaching near adult Before birth, the risk of congenital thrombocytopenia can be concentrations in the blood around 22 weeks of gestation [6,7]. assessed by considering the maternal history, her pregnancy, and Sola-Visner schematically described the process of platelet pro- family history [5]. After birth, if needed, the platelet count can be duction as consisting of four steps: 1) Production of thrombopoietic conveniently, accurately, and rapidly measured. In those neonates factors (mainly thrombopoietin), 2) Proliferation of megakaryocyte discovered to have thrombocytopenia, a plan for evaluation can progenitors, 3) Maturation of megakaryocytes and 4) Production be made (Fig. 1), and among those with a normal platelet count, and release of platelets into the circulation. These four steps are the risk that they will subsequently develop thrombocytopenia can essentially the same in neonates and adults, even though sub- be assessed on the basis of clinical condition. In some cases this stantial developmental differences in megakaryocyte biology exist type of risk assessment allows prediction regarding the timing of and may be responsible for the diverse response of fetal/neonatal megakaryocyte to thrombocytopenia [8]. Plasma thrombopoietin concentrations are higher in healthy neonates than in healthy adults, but thrombocytopenic neonates * Address correspondence to: Antonio Del Vecchio, Division of Neonatology, usually have lower thrombopoietin concentrations than thrombo- Neonatal Intensive Care Unit, Di Venere Hospital, Via Ospedale Di Venere 1, 70121 Bari, Italy. Tel.: +39 080 5015012; fax: +39 080 5015016. cytopenic adults. Additionally, whereas neonatal megakaryocyte E-mail address: [email protected] (A. Del Vecchio). progenitors have a higher proliferative potential than those of

0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. S34 A. Del Vecchio et al. / Early Human Development 89S4 (2013) S33–S36

Fig. 1. Neonatal thrombocytopenia pathogenesis. adults and are more sensitive to thrombopoietin than adult progen- occurs in approximately 1% of these. Not uncommonly, the mother itors, neonatal megakaryocytes are smaller and of lower ploidy than is healthy without a history of ITP or other autoimmune disorder, adult megakaryocytes, and produce fewer platelets per megakary- but with a slight decrease of platelet count that resolves after ocyte. Thus, thrombocytopenic neonates can increase megakary- delivery. The neonate born to a mother with autoimmune disease ocyte number but not size. We hypothesize that this developmental should have platelet counts monitored for at least the first week. limitation contributes to the susceptibility of neonates to develop Neonatal thrombocytopenia usually persists 1 to 2 months with thrombocytopenia during illness [9,10]. spontaneous resolution [10,11]. Neonatal alloimmune thrombocytopenia (NAIT) is the platelet 3. The risk of early-onset thrombocytopenia counterpart of haemolytic disease of the neonate. NAIT is due to maternal antibodies generated against a specific fetal/neonatal Early thrombocytopenia is commonly associated with feto- platelet antigen (paternally inherited antigen) that differs from the maternal conditions. Infants born to mothers with pregnancy- maternal platelet antigen. Specific antigens appear on fetal platelets induced hypertension/preeclampsia or diabetes and those with early in gestation, and maternal antibodies can cross the placenta intrauterine growth restriction (all these conditions are associated early in the second trimester, thereby reacting with antigens with placental insufficiency and chronic intrauterine hypoxia) are at on fetal platelets, inducing severe fetal thrombocytopenia. These risk for developing thrombocytopenia. This variety is usually mild mothers have no history of abnormal bleeding and have normal to moderate, resolves spontaneously within 7 to 10 days, and does platelet counts. The severity of the neonatal thrombocytopenia is not generally warrant treatment. When early thrombocytopenia is unpredictable, but the platelet count usually continues to fall over severe (<50×103/μL) and/or persists more than 10 days, further the first days of life, and then increases over 1 to 4 weeks. ICH investigation is necessary (Fig. 1) [10,11]. occurs in approximately 10% to 15% of cases, and at least one half of To discover the cause of neonatal thrombocytopenia, it is im- these occur in utero, with death occurring in 10% of affected infants portant to consider the clinical condition of the neonate. Severe and neurologic sequelae in 20% [11,12]. early-onset thrombocytopenia in an otherwise healthy infant should Early onset thrombocytopenia of any severity in an ill term raise suspicion for an immune-mediated pathogenesis, either au- or preterm neonate should prompt an evaluation for viral, fungal, toimmune or alloimmune, from passive transfer of anti-platelet or bacterial sepsis, or disseminated intravascular coagulation; this antibodies from the maternal to the fetal circulation. latter mechanism can be associated with sepsis or with birth Autoimmune thrombocytopenia occurs in neonates born to asphyxia. The mechanism responsible for the thrombocytopenia mothers with idiopathic thrombocytopenic purpura (ITP), systemic after perinatal asphyxia is not completely known, but it has been lupus erythematosus (SLE), lymphoproliferative disorders, or hyper- hypothesized that the thrombocytopenia which complicates total thyroidism. Maternal autoantibodies are directed against an antigen body cooling of neonates with hypoxemic/ischemic encephalopathy on the mother’s own platelets and on the fetal platelets. They is due to significant changes in the composition of the surface cross the placenta and trigger the destruction of fetal platelets. antigens of platelets in response to hypothermia, resulting in their Thrombocytopenia occurs in approximately 10% of cases in which rapid removal from the circulation [13]. the mother has ITP or SLE, and intracranial haemorrhage (ICH) The pathophysiology of the thrombocytopenia associated with A. Del Vecchio et al. / Early Human Development 89S4 (2013) S33–S36 S35

Table 1 Severe congenital thrombocytopenia – genetic associations.

Small (<5–6 fL) Normal (7–12 fL) Large (>15 fL) No dysmorphic features • X-linked thrombocytopenia • CAMT • Bernard Soulier Xp11.23 1p34.2 homozygous or compound [3q21.3, 17p13.2 or 22q11.21] • Wiskott Aldrich syndrome heterozygous mutations in the • MYH9-related disorder Xp11.23 thrombopoietin receptor c-MPL [22q12.3] • Pseudo von Willebrand disease *These conditions result from different Thrombocytopenia 2 VWF [12p13.31] mutations in the same (WAS) gene ANKRD26 [10p12.2] Noonan-like features • Noonan-CAMT • Jacobsen syndrome with Paris- PTPN11 [c.218 C>T] Trousseau disorder [11q23.3] SGA, sometimes other features, • Braddock-Carey syndrome not Noonan-like microdeletion involving RUNX1 [21q22.11] Radioulnar synostosis • ATRUS HOXA11 [17p15.2] Absent radii • TAR compound heterozygote RBM8A [1q21.1] mutation plus allelic microdeletion

placental insufficiency is not completely understood, but Sola and for more than 2 weeks. Some of these patients receive multiple colleagues reported a decreased number of megakaryocyte in the platelet transfusions [18]. However, the benefits and risks of bone marrow [6] and Murray described a decreased concentration repeated transfusions for these patients are unclear. It may be that of megakaryocyte progenitors in these patients [14]. unless clinical bleeding problems are seen, prophylactic platelet Rarely, thrombocytopenia is congenital, severe, and persistent. transfusions of these patients, to keep their platelet count above a The genetic conditions causing selective failure of megakaryocy- rather arbitrary level, may impart greater risk than benefit [18]. topoies can be categorized according to platelet size (Table 1) [15]. Thrombocytopenia accompanying sepsis involves the reticule- Platelet size can be estimated electronically as the mean platelet endothelial removal of platelets activated by endothelial damage volume (MPV) or assessed microscopically and categorized as small [19]. Neonates respond to this by up-regulating thrombopoiesis, and (<5 or 6 fL), normal (8–12 fL), or large (generally >15 fL). Neonates thrombocytopenia develops only after platelet production cannot with persistently small platelets are likely to have X-linked throm- keep pace with platelet destruction, which is related to serum TPO bocytopenia (MIM #313900) or Wiskott Aldrich syndrome (MIM levels [20]. Conversely, CMV can directly infect megakaryocytes and #301000). Those with distinctive facial features, short stature, cause impaired platelet production and release. cryptorchidism and other anomalies are likely to have Noonan syn- Infants with NEC can develop thrombocytopenia, which approxi- drome, or Jacobsen syndrome with Paris-Trousseau disorder (MIM mately correlates with severity of the disease and can cause clinical #147791). However, the latter sometimes have large platelets. bleeding complications. It has been postulated that a platelet Neonates who are SGA but do not have Noonan-like facial features consumptive process or a combination of suppression of throm- (but might have other congenital problems like congenital heart bopoiesis and platelet adhesion to the necrotic areas of bowel are disease or small jaw) might have microdeletions on chromosome 21 mechanisms underlying this variety of thrombocytopenia [21,22]. involving RUNX1 causing the Braddock-Carey syndrome. Normally Late thrombocytopenia occurs also in neonates with renal vein grown neonates with no dysmorphic features may be more likely to thrombosis, or sagittal sinus thrombosis, or in association with have mutations in c-MPL (MIM #604498), while those with forearm a central venous or arterial catheter. In some cases a persistent anomalies are likely to have either with amegakaryocytic throm- thrombocytopenia can be the unique sign of a thrombus formation bocytopenia with radioulnar synostosis (ATRUS) (MIM #605432) or [17]. thrombocytopenia absent radius (TAR) syndrome (MIM #274000). Ultimately, drug-induced thrombocytopenia should be consid- Neonates with large platelets (typically >15 fL) might have one of ered in well appearing infants who assume some antibiotics, the familial macrothrombocytopenias such as Bernard Soulier (MIM phenobarbital and phenytoin, ibuprofen, hydrochlorotiazide, and in #231200), the MYH9-related disorder (MIM#600208), or platelet- whom NEC, infection, thrombosis and DIC have been ruled out [23]. type pseudo von Willebrand disease (type 2B, PGP1b mutation). 5. Pharmacological alternatives to platelet transfusion 4. The risk of late-onset thrombocytopenia In2008theUSFoodandDrugAdministration approved two Neonates who develop late-onset thrombocytopenia almost new medications for the treatment of chronic thrombocytopenia always have accelerated platelet destruction. The causative mech- associated with ITP. Both agents activate the C-MPL receptor on anisms include bacterial or fungal sepsis, necrotizing enterocolitis megakaryocytes in a manner similar to action of thrombopoietin. (NEC), Herpes Simplex virus, Cytomegalovirus or enterovirus infec- One agent, Romiplostim, is intended only for intravenous or sub- tions. If all these causes are ruled out, inborn errors of metabolism, cutaneous administration, and was developed by Amgen under thrombosis or drugs should be considered, which can be the pre- the trade-name Nplate. The other agent, Eltrombopag, is intended senting sign of the disease or indicate a particular clinical worsening only for oral use and was developed as collaboration between [16,17]. GlaxoSmithKline and Ligand Pharmaceuticals [24]. Late-onset sepsis is one of the most common causes of late-onset These medications have been used in very few neonates, all thrombocytopenia. Treatment of sepsis with appropriate antibiotics with chronic, transfusion-dependent, hyporegenerative thrombocy- or antifungals generally effectuates a slow rise in platelet count; topenias. We predict that they will have limited use treating the with the thrombocytopenia usually lasting about one week. In some common varieties of neonatal thrombocytopenia, but we support neonates with late sepsis, thrombocytopenia can be prolonged their testing in selected groups of neonates [15]. We base this pre- S36 A. Del Vecchio et al. / Early Human Development 89S4 (2013) S33–S36 diction on the fact that neither agent is rapid-acting, requiring about [9] Sola MC. Evaluation and treatment of severe and prolonged thrombocytopenia ten days or so before an increase in platelet count occurs. Since in neonates. Clin Perinatol 2004;31:1–14. the common varieties of neonatal thrombocytopenia do not persist [10] Fuchs DA, McGinn SG, Cantu CL, Klein RR, Sola-Visner MC, Rimsza LM. Developmental differences in megakaryocyte size in infants and children. Am for more than 10 to 14 days, pharmacological treatment with these J Clin Pathol 2012;138:140–5. new agents seems unwise. Also, these agents may not be effective [11] Bussel JB, Sola-Visner M. Current approaches to the evaluation and man- for cases of congenital thrombocytopenia due to C-MPL gene muta- agement of the fetus and neonate with immune thrombocytopenia. Semin tions, or due to mutations in down-stream activation, since these Perinatol 2009,33:35–42. [12] Black LV, Maheshwari A. Disorders of the fetomaternal unit: hematologic agents may not work any better than endogenous thrombopoietin. manifestations in the fetus and neonate. Semin Perinatol 2009;33:12–9. However, there may be some groups of thrombocytopenic neonates [13] Hoffmeister KM, Felbinger TW, Falet H, et al. The clearance mechanism of where Romiplostim or Eltrombopag are effective and preferable to chilled blood platelets. Cell 2003;112:87–97. repeated platelet transfusions. [14] Murray NA, Roberts IA. Circulating megakaryocytes and their progenitors in early thrombocytopenia in preterm neonates. Pediatr Res 1996;40:112–9. [15] Christensen RD, Yaish HM, Leon EL, Sola-Visner MC, Agrawal PB. A de novo Conflict of interest T73I mutation in PTPN11 in a neonate with severe and prolonged congenital thrombocytopenia and Noonan syndrome. Neonatology 2013;104:1–5. The authors have no conflict of interest to declare. [16] Holzhauer S, Zieger B. Diagnosis and management of neonatal thrombocy- topenia. Semin Fetal Neonatal Med 2011;16:305–10. [17] Sola-Visner M, Sallmon H, Brown R. New Insights into the Mechanisms of References Nonimmune Thrombocytopenia in Neonates. Semin Perinatol 2009;33:43–51. [18] Del Vecchio A, Sola MC, Theriaque DW, et al. Platelet transfusions in the [1] Sola MC, Del Vecchio A, Rimsza LM. Evaluation and treatment of thrombocy- neonatal intensive care unit: factors predicting which patients will require topenia in the neonatal intensive care unit. Clin Perinatol 2000;27:655–79. multiple transfusions. Transfusion 2001;41:803–8. [2] Roberts I, Stanworth S, Murray NA. Thrombocytopenia in the neonate. Blood [19] Brown RE, Rimsza LM, Pastos K, Young L, Saxonhouse MA, Bailey M, Lawrence Rev 2008;22:173–86. RM, Sola-Visner MC. Effects of sepsis on neonatal thrombopoiesis. Pediatr Res [3] Wiedmeier SE, Henry E, Sola-Visner MC, Christensen RD. Platelet reference 2008;64:399–404. ranges for neonates, defined using data from over 47,000 patients in a [20] Eissa DS, El-Farrash RA. New insights into thrombopoiesis in neonatal sepsis. multihospital healthcare system. J Perinatol 2009;29:130–6. Platelets 2013;24:122–8. [4] Christensen RD, Henry E, Wiedmeier SE, et al. Thrombocytopenia among [21] Christensen RD, Henry E, Del Vecchio A. Thrombocytosis and thrombocy- extremely low birth weight neonates: data from a multihospital healthcare topenia in the NICU: incidence, mechanisms and treatments. J Matern Fetal system. J Perinatol 2006;26:348–53. Neonatal Med 2012;25(Suppl 4):15–7. [5] Jensen JD, Wiedmeier SE, Henry E, Silver RM, Christensen RD. Linking [22] Cremer M, Weimann A, Szekessy D, Hammer H, Bührer C, Dame C. Low maternal platelet counts with neonatal platelet counts and outcomes using immature platelet fraction suggests decreased megakaryopoiesis in neonates the data repositories of a multihospital health care system. Am J Perinatol with sepsis or necrotizing enterocolitis. J Perinatol 2013;33:622–6. doi: 2011;28:597–604. 10.1038/jp.2013.21 [Epub 2013 Feb 28] [6] Sola-Visner MC, Christensen RD, Hutson AD, Rimsza LM. Megakaryocyte size [23] Sheffield MJ, Lambert DK, Baer VL, et al. Effect of ampicillin on bleeding and concentration in the bone marrow of thrombocytopenic and nonthrom- time in very low birth-weight neonates during the first week after birth. J bocytopenic neonates. Pediatr Res 2007;61:479–84. Perinatol 2011;31:477–80. [7] Ferrer-Marin F, Liu ZJ, Gutti R, Sola-Visner M. Neonatal thrombocytopenia and [24] Sallmon H, Gutti RK, Ferrer-Marin F, Liu ZJ, Sola-Visner MC. Increasing megakaryocytopoiesis. Semin Hematol 2010;47:281–8. platelets without transfusion: is it time to introduce novel thrombopoietic [8] Sola-Visner M. Platelets in the neonatal period: developmental differences agents in neonatal care? J Perinatol 2010;30:765–9. in platelet production, function, and hemostasis and the potential impact of therapies. Hematology Am Soc Hematol Educ Program 2012;2012:506–11. Early Human Development 89S4 (2013) S37–S38

The neonatal heart murmur

S. Mannarino a,*, A.C. Codazzi a,A.Dioufb,R.Falconeb,S.Chiapedib aPediatric Cardiology, Department of Pediatrics, Foundation IRCCS Policlinico S. Matteo, Pavia, Italy bDepartment of Pediatrics, University of Pavia, Pavia, Italy

1. Neonatal heart murmur Neonates have high heart rates, increasing the difficulty of auscul- tation. At birth, a rapid change within the cardiovascular system takes The red flags, prompting stronger consideration for a CHD, part to the adaptation to extrauterine life, sometimes producing include: diastolic murmur, harsh quality, grade ≥3, holosystolic murmurs that can be mistaken for heart disease. Similarly, if murmur, abnormal S2, maximal intensity at the upper left sternal transitional changes are slow to occur, presentation of congenital border (ULSB), presence of a systolic click. More likely associated heart disease (CHD) may be delayed. with an innocent murmur are: a soft systolic sound, short duration, A neonatal heart murmur (nhm) is frequently heard in neonatal musical or low pitch, intensity change by changing patient’s intensive care units and nurseries. Usually up to one in three position and with phases of respiration. Most of innocent nhm newborns will have a nhm in the first few days of life. Most of these are secondary to pulmonary artery branch stenosis (PPS), tricuspid originate through turbulent flow patterns due to hemodynamic regurgitation (TR) or patent ductus arteriosus (PDA). changes typical of transitional circulation and will spontaneously PPS may occur as a physiological benign feature or as a specific disappear. These murmurs are named “innocent” or “physiological”. pathological entity present in 2–3% of patients with CHD. In Conversely, a murmur may be the only manifestation of serious healthy infants murmur has the following features: ejection systolic CHD; however, not all neonates with CHD will be found to have a character, location in the pulmonary area, grade 1 to 2, low pitched, murmur at postnatal check. Timely recognition of a life-threatening extension just beyond S2, best heard in the axillae or back. This CHD(LT-CHD)iscrucialinordertoprovidepromptmanagement murmur usually disappears within the 6th month of life but it may before clinical deterioration ensues. In the evaluation of a newborn, reappear in older infants with respiratory tract infections because the clinician should stress that a large percentage of newborns of regional vascular reactivity and redistribution of blood flow. has nhm, of these, less than 1% present CHD. It is mandatory for At birth, the relative disparity in size between the main pul- neonatologists a complete assessment of the cardiovascular system monary artery trunk and its small branches, arising at sharp angles, – not just listen to the murmurs – in order to detect a potentially is thought to be the cause for this murmur. LT-CHD. Pathological PPS can occur as an isolated finding at single or Cardiac murmur is an audible heart sound in the range of multiple sites, in CHD such as Tetralogy of Fallot (TOF) variants or in 20–2000 Hz produced by a turbulent blood flow. Turbulent flow is syndromes (Williams, Alagille, Keutel, cutis laxa, Noonan, Rubella, intrinsically related with size of vessel, pressure gradient between Ehler-Danlos) and murmur differs from that of “physiological” PPS cardiac chamber or segment, critical velocity and viscosity of blood. for higher pitch and persistence in older age. The heart murmur is characterized by: timing during cardiac cycle TR refers to systolic failure of the heart’s tricuspid valve to close (systolic, diastolic or continuous); location (where it’s best heard), properly and may be associated with a low frequency pansystolic shape (crescendo, decrescendo or crescendo–decrescendo), quality murmur best heard under the lower left sternal border (LLSB). In the (blowing, harsh, rumbling or musical), pitch (low, medium or high) newborn the high pulmonary artery pressure increases the pressure and intensity (rated on a scale from grade 1 – barely audible – gradient between right ventricle and atrium and can result in a loud to 6 – loud enough to be heard with the stethoscope raised off pansystolic murmur. No structural deformity of the tricuspid valve the chest). Note that there is no relationship between the severity is found and murmur always disappears after the neonatal period of a CHD and the intensity of its murmur since low pressure due to the physiological fall of pulmunar resistances. gradient and wide communication cause low turbulence – faint Despite location and quality of this nhm might suggest a murmur, high pressure gradient and small communication cause ventricular septal defect (VSD), TR is the most likely finding in the higher turbulence – loud murmur. Also the presence or absence first day of life. of clicks has to be assessed. Radiation means where the murmur Neonates with Ebstein’s anomaly may have a persistent systolic spreads, that is according to the direction of blood flow. Detection thrill. Patients with mild displacement of valve leaflet may be of a murmur depends on the examiner’s skill and experience asymptomatic while those with severe forms, dependent on ductus and on the timing, frequency and conditions of examination. arteriosus for pulmonary blood flow, show extreme cyanosis. In preterm infants audible tricuspid regurgitation is often a sign of disease onset or persistence of pathological pulmonary * Corresponding author. hypertension.

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The most common murmur diagnosis in the neonatal intensive a low-pitched decrescendo diastolic component due to pulmonary care unit is PDA. In newborn a continuous “machinery” murmur incompetence. usually at the left ULSB is detected. It is characteristically loudest VSD, atrioventricular valve incompetence, pulmonary and aortic in systole and decreases during diastole because the persistent valve stenosis cause a systolic murmur. VSD is the most common pressure gradient between aorta and pulmonary arteries is greater congenital cardiac anomaly. Symptoms and murmur do not occur in systole. A small ductus is often asymptomatic while a large duct until pulmonary vascular resistances drop few days or weeks after may determine heart failure, poor growth and lower respiratory birth. Typically holosystolic (engulfs S1 and S2) murmur depending tract infections. In preterm, a continuous machinery murmur is on the abnormal flow from left to right ventricle, is loudest at LLSB; rarely heard: as the ductus begins to close (higher turbulence), there may be a thrill. Smaller holes (greater pressure difference) a rough systolic murmur is heard; when ductus is functionally have louder murmurs, largest defects (low pressure gradient) may or anatomically closed (low turbulence) the murmur become very be silent. The murmur disappears both if VSD closes (good clinical faint or absent. Ductus reopening by hypoxic insult restores the conditions of patient) both if Eisenmenger syndrome develops murmur; when pulmonary hypertension occurs no murmur is (patients with poor grow and severe symptoms). heard, but a desaturation at the lower limbs appears. Conversely a A significant regurgitation of the common atrioventricular valve continuous murmur is an index of low pulmonary resistances with causes a systolic cardiac murmur and gallop rhythm. In TOF, mur- a left-to-right shunt during all cardiac cycle. mur is not produced by VSD but by dynamic subvalvular and In CHD, less common continuous murmurs include coronary valvular pulmonary stenosis. During a cyanotic crisis pulmonary artery fistulas, pulmonary arteriovenous fistulas, systemic collateral infundibulum closes, with dramatic reduction of pulmonary blood arteries and pulmonary vessels arising from a truncus arteriosus. flow and murmur disappears. A reduction of intensity of murmur Usually murmur location corresponds to the site of lower indicates a worsening in the TOF when right obstruction increases pressure of the abnormal connection. and in the aortic stenosis at the failure of cardiac pump. Systolic A soft, high-pitched continuous murmur over the liver can ejection murmur, best heard in LUSB and over back, has to exclude appear in obstructed forms of total anomalous pulmonary venous aortic coarctation. Absence of femoral pulses, four-limb blood pres- return. sure (FLBP), pre and postductal pulse oximetry must be checked.

2. Red flags 3. Management of asymptomatic cardiac murmurs in newborn

Between S2 and S1, diastolic murmurs occur as a result of Various pragmatic guidelines have been proposed, with the aim incompetent semilunar valves. Aortic and pulmonary regurgitation to provide a pre-discharge diagnosis of LT-CHD. Collect medical produce a diastolic soft sound in decrescendo. In infants this history and investigations such as pulse oximetry, chest X-ray, murmur is difficult to recognize because of high heart frequency electrocardiogram, and FLBP are often performed in asymptomatic and irregular breathing. neonates with nhm. Echocardiography still remain the gold stan- Truncus arteriosus (TA) is a single arterial vessel giving rise dard, but it requires trained skilled personnel, is not readily coronary, pulmonary, and systemic arteries with a single semilunar available in all neonatal units and many authors amply demon- valve, very often incontinent, which can be from uni-commissural strated that is not required in all patients with nhm.Neonatologists to pentacuspid. TA has normal first heart sound frequently followed can easily acquire the ability to assess whether a murmur requires by a loud ejection click, which coincide with maximal opening a paediatric cardiologist’s examination. The paediatric cardiologists of the truncal valve and the second heart sound usually loud can assist neonatologists in more careful detection of CHD. For both and single. Truncal valve regurgitation produces a diastolic high- innocent and pathologic murmurs, referral to a paediatric cardiol- pitched murmur, best heard along the LSB. In addition the presence ogist for confirmation or clarification of the diagnosis is associated of truncal valve stenosis produces a loud pansystolic murmur with decreased parental anxiety. maximal at the LLSB and radiating to the entire precordium. A combination of a systolic (stenosis) and diastolic (regurgi- Conflict of interest tation) murmur identifies the so-called “to-and-fro”murmurthat differs from continuous murmur because the systolic component The authors have no conflict of interest to declare. ends prior to the start of the diastolic component. This murmur can be heard in TA and in the absence of the pulmonary valve (AVP). Selected bibliography In the AVP rudimentary pulmonary valve leads to severe regurgita- tion. Stenosis of orifice and aneurysmal dilatation of the pulmonary [1] Frank JE, Jacobe KM. Evaluation and management of heart murmurs in children. arteries with varying degrees of bronchial obstruction coexist. AVP Am Fam Physician 2011;84(7):793–800. [2] Shenvi A, Kapur J, Rasiah SV. Management of asymptomatic cardiac murmurs is most commonly associated with TOF with absence of ductus in term neonates. Pediatr Cardiol 2013;34(6):1438–46 [Epub 2013 Mar 10]. arteriosus The characteristic murmur “to-and-fro” consists of a [3] Moss & Adams’ Heart Disease in Infants, Children, and Adolescents: Including rough ejection systolic component due to valve ring stenosis and the Fetus and Young Adult. 8th Edition. Early Human Development 89S4 (2013) S39–S40

Long QT interval in the newborn

A.B. Delogu a,*, R. Iannotta a, A. Saracino a,G.Baroneb, C. Romagnoli b aPediatric Cardiology Unit, Department of Pediatrics, Università Cattolica del Sacro Cuore, Rome, Italy bDivision of Neonatology, Department of Pediatrics, Università Cattolica del Sacro Cuore, Rome, Italy

ABSTRACT

An understanding of the electrocardiogram in the newborn requires specific knowledge of the cardiac physi- ology and pathology before and shortly after birth. Many newborns may present with ventricular repolariza- tion abnormalities due to several acquired or congenital conditions which may cause prolonged QT interval. As the association between long QT interval and sudden infant death syndrome has been clearly established, the finding of ventricular repolarization abnormalities in the newborn is of special clinical relevance, with specific diagnostic, prognostic and therapeutic implications. © 2013 Elsevier Ireland Ltd. All rights reserved.

1. Introduction of QTc is 440 ms, which represents 2 standard deviations above the mean of a large population of newborns [3]. There are no sex There is no time in life when there is more variation of the differences in the normal QTc interval in neonates and children normal electrocardiogram (ECG) than in the neonatal period, with until puberty [2]. changes continuing from birth to adult life. The progression of the normal ECG is related to developmental changes in physiology, body 3. QT interval prolongation in the newborn size, and position and size of the cardiac chambers [1]. The major changes in the pediatric ECG occur in the first year of life with the QT interval prolongation represents a prolonged recovery from majority of normal adult values being abnormal in the newborn. electrical excitation, which contributes to an increased likelihood Likewise, many normal newborn values and patterns would be of dispersion of refractoriness, when some parts of myocardium abnormal in the adult. Normal electrocardiographic values in the might be refractory to subsequent depolarization. Consequently, pediatric population traditionally derive from those published in the wave of excitation may pursue a distinctive pathway around a 1979 by Davignon et al. [2]. focal point in the myocardium (circus reentry rhythm), leading to an arrhythmic response, such as ventricular tachycardia. 2. Measurement of the QT interval on the neonatal There are many possible causes underlying QT interval prolon- electrocardiogram gation in the newborn and some are similar to those responsible for ventricular abnormalities in children and in adults [4,5]. The QT interval on the ECG is the interval between the beginning of the QRS complex and the end of the T wave and represents the 4. Acquired QT prolongation in the newborn duration of activation and recovery of the ventricular myocardium. The QT measurement should be made in leads II, V5, and V6 with Electrolyte imbalances such as hypocalcaemia, hypokalemia, the longest value being used [1]. and hypomagnesaemia, often encountered in neonatal patients The QT interval duration changes with heart rate and it is and especially preterm infants in neonatal intensive care unit, usually corrected (QTc) by using Bazett’s formula, whereby QTc are known causes of acquired QT prolongation. Central nervous is equal to QT interval in seconds divided by the square root of system abnormalities can produce QT prolongation. Several drugs the preceding RR interval in seconds. Correction of the QT interval commonly used in the neonatal period and during infancy such requires a stable sinus rhythm without sudden changes in the RR as macrolide antibiotics and trimethoprim may induce QT interval interval. As recommended by guidelines for the interpretation of prolongation because they block IKr, one of the most important neonatal electrocardiogram of the European Society of Cardiology ionic currents involved in the control of ventricular repolarization. [1], heart rate in the newborn should not be too slow (lower than 80 In recent years, the medication cisapride was removed from the beats/min) or too fast (greater than 180 beats/min), because Bazett’s market for possible QT prolonging side effects, with preterm infants formula loses accuracy outside this range. The upper normal limit having increased susceptibility. Cases of QT prolongation have been reported with use of doxapram, a central respiratory stimulant used for apnea of prematurity, with anesthetics and with antiepileptic * Corresponding author. medications [4]. A more unusual route for substances affecting

0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. S40 A.B. Delogu et al. / Early Human Development 89S4 (2013) S39–S40 repolarization is via maternal, in utero exposure. Maternal usages exclude other causes of acquired QT interval prolongation and dis- of fluoxetine, methadone, and alcohol (causing alcohol withdrawal continuation of potentially QT-prolonging medications; a thorough in the infant) have been implicated in prolonged QT intervals in the family history (SIDS, LQTS); further evaluation and repeated future neonate. Neonates born from mothers with autoimmune diseases QT interval measurement; 24-h ECG Holter monitoring, echocardio and positive for the anti-Ro/SSA antibodies may also show QT gram and genetic screening. ECGs should be obtained also from the interval prolongation, which tends to be transient and to disappear parents and siblings of the neonate. by the sixth month of life, concomitantly with the disappearance of Some physicians continue to use a published clinical diagnostic the anti-Ro/SSA antibodies [1]. assessment score that incorporates personal and family history as well as ECG findings to compute “low”, “intermediate” and “high” 5. The congenital long QT syndrome in the newborn probabilities for the diagnosis of LQTS. Electrocardiographic abnor- malities present in long QT syndrome include prolongation of the Some of the neonates with QT interval prolongation may be QTc interval, sinus bradycardia and T-wave abnormalities. Genetic affected by congenital long QT syndrome (LQTS), implicated in heterogeneity makes genetic testing difficult for many patients. the pathogenesis of approximately 10% of sudden infant death Once diagnosis is established, initiation of therapy should be syndrome [3,6,7]. considered and beta-blocker therapy is recommended [8]. Congenital LQTS was first described clinically as Jervell and As the association between long QT interval and sudden infant Lange-Nielsen syndrome and Romano Ward syndrome in the late death syndrome has been clearly established [6,7], this raised the 1950s and early 1960s. The trademark event for the symptomatic question of whether routine neonatal ECG screening might identify LQTS patient is the potentially lethal ventricular dysrhythmia “vulnerable” infants at risk for SIDS [9]. However, up to this time, called torsades de pointes [8]. Symptoms of long QT syndrome this approach is still problematic [10]. in neonates include syncope, seizures, and sudden death. Syncope and seizures correlated with episodes of nonsustained torsade de Conflict of interest pointes, whereas sudden death likely results from a prolonged episodes. Importantly, in 12% of patients with LQTS, sudden death The authors have no conflict of interest to declare. was the first manifestation of the disease and in 4% this happened in the first year of life [6]. This point alone mandates the treatment References of all those diagnosed as affected, even if there are no symptoms. LQTS affects an estimated 1 in 2500 people and is understood [1] Schwartz PJ, Garson A, Paul T, et al. Guidelines for the interpretation of the neonatal electrocardiogram. A task force of the European Society of to be a collection of genetically distinct arrhythmogenic disorders Cardiology. European Society of Cardiology. Eur Heart J 2002;23:1329–44. resulting from genetic mutations in (primarily) cardiac potas- [2] Davignon A, Rautaharju P, Boisselle E, et al. Normal ECG standards for infants sium and sodium ion channels involved in the control of action and children. Pediatr Cardiol 1979;1:123–52. potential duration of ventricular repolarization, termed “cardiac [3] Schwartz PJ, Stramba-Badiale M, Segantini A, et al. Prolongation of the QT in- channelopathies”. Overall, 13 LQTS-susceptibility genes have been terval and the sudden infant death syndrome. N Engl J Med. 1998;338:1709– 14. discovered thus far. Mutations in the potassium channel genes [4] Schwartz PJ, Stramba-Badiale M. Repolarization abnormalities in the newborn. KCNQ1 (LQT1) and KCNH2 (LQT2) as well as the sodium channel J Cardiovasc Pharmacol 2010;55(6):539–43. gene SCN5A (LQT3) account for about 75% of all cases of clinically [5] Helfenbein ED, Ackerman MJ, Rautaharju PM, et al. An algorithm for QT definite LQTS and comprise over 95% of genetically identifiable interval monitoring in neonatal intensive care units. J Electrocardiol 2007;40(6 Suppl):S103–10. LQTS [8]. [6] Schwartz PJ, Priori SG, Dumaine R, et al. A molecular link between the sudden infant death syndrome and the long-QT syndrome. N Engl J Med 6. The diagnosis and management of the long QT interval in the 2000;343:262–7. newborn [7] Tester DJ, Ackerman MJ. Postmortem long QT syndrome genetic testing for sudden unexplained death in the young. J Am Coll Cardiol 2007;49:240–6. [8] Napolitano C, Bloise R, Monteforte N, et al. Sudden cardiac death and The diagnosis of LQTS continues to be difficult. Many neonates genetic ion channelopathies: long QT, Brugada, short QT, catecholaminergic may initially present with a somewhat prolonged QT in the first few polymorphic ventricular tachycardia, and idiopathic ventricular fibrillation. days of life, which eventually resolves after few weeks. This is likely Circulation 2012;125(16):2027–34. related to transient electrolyte abnormalities and /or to distur- [9] Quaglini S, Rognoni C, Spazzolini C, et al. Cost-effectiveness of neonatal ECG screening for the long QT syndrome. Eur Heart J 2006;27:1824–32. bances in autonomy control. Once an infant is identified as having [10] Berul CI, Perry JC. Contribution of long-QT syndrome genes to sudden an abnormally prolonged QT interval on at least two different ECG infant death syndrome: is it time to consider newborn electrocardiographic tracings, additional diagnostic procedures should be performed: screening? Circulation 2007;115(3):294–6. Early Human Development 89S4 (2013) S41–S42

Medical–legal aspects of neonatal transport

R. Paludetto *, A. Di Fiore, J. Cerullo, G. Mansi, J. Van Den Heuvel, A. Umbaldo

Neonatal Intensive Care Unit, Department of Pediatrics, AOU “Federico II”, Naples, Italy

In Italy since April 2000, we have a law , “Progetto Obiettivo The neonate must have appropriate identification band in place. Materno Infantile”, regarding the interhospital transport of pregnant Files and relevant information on mother’s pregnancy and delivery women and neonates as an essential component of regional peri- must be available. Accurate recording of each transport is essential natal care. Women with high-risk pregnancies or whose neonates to provide permanent documentation of the care provided. Good are likely to require intensive care should be admitted in Hospitals quality communication during the first call is determinant for that provide such level of care, bearing in mind that newborns born a successful transport as returning information to the referring to women transported during the antepartum period have better center. Informed consent from parents should be obtained before survival rates and decreased risks of long-term sequelae than those moving the newborn. who are transferred after birth [1–4]. After discussing the general issues including the defensive Some legal aspects are not yet defined, and each region or medicine and insurance that must be adequate to protect transport single hospital set standards and regulations that must be applied team members, we will present some clinical cases reported in by each local or regional transport system [5]. Many aspects of legal litigations or derived from the activity of the Regional System neonatal transport can be involved in legal litigations: organization of Neonatal Transport in Campania where since 1995 have been and administration, procedures of referring and receiving center, transported by the regional transport teams (Annunziata, Federico actions of the transport team. II and Caserta) about 1600 neonates each year. In summary the receiving center is responsible of the overall At the moment only few cases ended in court and are still organization of the transport system [6,7]. discussed. Local rules must be fixed to decide which newborn should be Recently we had a request from a first level Hospital to transport considered for transfer and which care-guidelines must be adopted; an alive newborn of 19 weeks gestational age. The neonatologist nevertheless most team provide neonatal transport for any baby, argued that he wasn’t sure of the real gestational age and the moving between neonatal units without strict limits for age or newborn was transported. The regional guidelines did not set rules weight. regarding the inferior limits of gestational age. Pretransport stabilization should aim to optimize the infant’s On the other hand we received calls to transport infants of 4–5 condition and must be accomplished by the referring center. Vehicle months of age for bronchiolitis and other conditions. and transport equipment must be prepared and checked by a formal Which neonate should be transported from a first or second checklist. Clinical care during transport requires observation and level to a third level of care is certainly an important issue to particular competence on ventilation, infusion and endotracheal be discussed and established between operators and institutions suction. involved in a local or regional system. Staff must be educated on technical issues regarding the trans- Years ago, during the night, we had six contemporary requests port vehicles, equipment, clinical care and communication with of transport with only two teams in call. The transport doctor on parents and operators. Numerous studies have demonstrated that call decided the priority on the basis of the clinical conditions, poor communication between both “physicians and physicians” and equipments and competence of neonatologists in the different “physicians and parents” is the determinant issue for medical- referring centers and distances of the receiving centers. This case is malpractice law suits [8]. now in court for legal litigation. Flaborius et al. indicated that the difficulties during the patients The time of the call, the birth time, clinical conditions and transport depended by equipments (37%), patient care (26%), trans- stabilization procedures, journey time of the ambulance are also port (11%), communication (9%), planning and training (9%), extra very important issues. staff (7%) and tasking (2%). According to the Authors it is possible to When the transport team arrives in the referring center, it avoid 91% of the failures [9]. should be the transport doctor to decide what to do, but in one Referring physician is responsible for evaluating and stabilizing case, after a decision of the transport doctor, the judge put the the newborn before transfer and for including correct information responsibility of the malpractice on the doctor in call at the hospital. on the newborn’s clinical condition during the telephone call. Good communication and documentation is a very important These information are finalized to establish a priority, in case of issue: the information about the clinical condition, the priority and contemporary calls. the procedures must be reported in the same way in the files of the referring center, the transport team and the receiving center. * Corresponding author.

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Conflict of interest [4] Insoft RM. Neonatal transport. In: Cloherty JP, Eichenwald EC, Stark AR (eds), Manual of Neonatal Care, 4th ed. Baltimore, MD: Lippincott Williams & Wilkins, The authors have no conflict of interest to declare. 2004; pp 147–53 [5] Console V., Brunelli A. Aspetti medico-legali ed assicurativi In: R. Agostino et al. Trasferimento Neonatale. Rome: Verduci Ed, 2002; pp 121–31. References [6] Kempley S, Ratnavel N. Neonatal Transport. In: Rennie JM (ed), Textbook of Neonatology. Amsterdam: Elsevier, 2012; pp 239–43. [1] AAP, ACOG. Guidelines for Perinatal Care. Interhospital Care of Perinatal Patient [7] Fineschi V, Turillazzi E. Neonatology and the law. In: G. Bonocore et al. (eds), 2002; pp 57–70. Neonatology. Springer, 2012; pp 192–6. [2] Gomella TL. Neonatology, Infant Transport. Lange Medical Books/McGraw-Hill [8] Agostino R, Aufieri R. Neonatal transport services. In: G. Bonocore et al. (eds), Medical Publishing Division, 2009; pp 131–3. Neonatology. Springer, 2012; pp 161–4. [3] Wood KS, Bose CL, Neonatal transport. In: MacDonald MC, Mullett MD, Sheshia [9] Flabouris A, Runciman WB, Levings B. Incidents During Out-of-Hospital Patient MMK (eds), Avery’s Neonatology, 6th ed. Baltimore, MD: Lippincott Williams & Transportation. Anaesth Intensive Care 2006;34:228–36. Wilkins, 2011; pp 40–53. Early Human Development 89S4 (2013) S43–S44

Newborn at social risk

Renato Lucchini *, Erica Bacchio, Silvia Giampietro, Mario De Curtis

Dipartimento di Pediatria, “Sapienza” Università di Roma, Rome, Italy

The birth of a child is a moment that marks great changes in the distress experienced due to their living conditions, out of fear parental couple and is usually accompanied by feelings of joy and (abuse, illegal immigration), embarrassment (poverty), or lack of positive expectations towards the future of the newborn. awareness of the problem. Conversely, sometimes birth is a socially problematic event in The current economic crisis is a new and widespread factor terms of psychosocial, economic and cultural distress. When this of increased risk of social problems of families with children [2]. is the case, the birth of a child is often not the product of a con- In Italy, the unemployment rate is rising, reaching 8. 4% in 2010. scious choice, but the consequence of inadequate information and Youth unemployment (15–24 years) is 27.8%, the highest in the last communication, or the concrete manifestation of unresolved issues. 10 years. Adequate and inadequate parenting are actually the opposite Today in Italy, about 1.8 million children and adolescents live extremes of conditions with infinite nuances, and it is not easy to in families who well in conditions of relative poverty and over define already in the neonatal stage which condition may affect 700 thousand children are growing up in extreme poverty, that future physical, mental and relational development. is, in families without the essential means to achieve a minimally Hertzman et al. argue that a good start in life is the key acceptable standard of living [3]. In 2011, compared to 2010, to reducing health and social inequalities and that governments families with children living in conditions of absolute poverty should invest more in programmes aimed to support early child increased from 365,000 to 440,000 [4]. A low family income does development [1]. not guarantee adequate physical, mental, intellectual or social We consider an infant at social risk any baby unlikely to receive development to minors, as a decreased purchasing power is likely from his family and/or environment in which he lives the moral, to have consequences on the nutritional status of the child. cultural and material resources necessary for proper development. Unemployment, precarious jobs, family stress, insufficient aid It is possible to identify many high-risk social factors, ranging to mothers and their children, and, therefore, lack of a long-term from the presence of parents with drug addiction, alcoholism, or perspective, are all conditions that contribute to a decline in psychiatric diseases, or in detention, to conditions of both economic educational opportunities and an increase in psychosocial problems and cultural poverty. and maltreatment. Other conditions of social risk are represented by lower maternal In the Lazio region about 2% of all infants are not acknowledged age (according to Italian law, a minor mother cannot acknowledge by either parent or are acknowledged only by the mother. Data her child unless she is at least 16 years), and the absence of a relating to our hospital (years 2005–2012) show a higher risk of partner (single parent). prematurity (28.8% vs 17.6%) and of very low birth weight (6.8% A special condition is finally represented by the abandonment vs 3.6%), but also of respiratory diseases (11% vs 6.2%) and need of the child at birth: this decision represents the most difficult for hospitalization in neonatal intensive care units (13.2% vs 7.3%) moment of a pregnancy and involves the early intervention of among babies only recognized by the mother. social services in order to protect the child and give him/her a Although immigration is a condition of increased risk of pre- minimum prospective of health, growth and development. maturity and neonatal disease, strong differences are evident in All these situations are more common among immigrant popu- lations, which are therefore seen as more at risk of social distress. Some of the phenomena described above have a dramatic Table 1 impact, but are infrequent. For example in the last 10 years (2003– Mother’s region of birth and perinatal outcomes: crude odds ratios and robust 95% 2012) in the Municipality of Rome 486 infants were abandoned and confidence intervals OR (95% CI). Lazio 2006–2008 (from L. Cacciani et al. [5] mod.). placed under protection (approximately 50 per year). The Italian detention centers currently houses about 60 children under 3 years All Regions EasternEurope Westand sub-Saharan Africa of age who live with their mothers. < However, the most frequent situations are often those that most Prematurity ( 31 weeks) 1.95 2.11 3.91 (1.72–2.21) (1.80–2.47) (2.85–5.35) likely escape the attention of health and social care workers, as Respiratory diseases 1.24 1.28 1.61 some women and their families may want to conceal the social (1.17–1.32) (1.22–1.34) (1.34–1.93) Special/intensive care 1.45 1.46 2.22 (1.34–1.57) (1.33–1.59) (1.89–2.60) * Corresponding author. Italy 1.00.

0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. S44 R. Lucchini et al. / Early Human Development 89S4 (2013) S43–S44 relation to the different geographical areas of origin, apparently (midwife, neonatologist, social worker) working in hospitals and due to the extent of social problems faced by some populations. the territory, aimed at supporting the most vulnerable ones. In a large study on nearly 300,000 infants born in our region has shown an increased risk of very preterm birth (<31 weeks) Conflict of interest among immigrant women from poorer regions of the world, such as West Africa and sub-Saharan Africa (Table 1) [5]. In addition, The authors have no conflict of interest to declare. immigrants, especially those with irregular status, referred less to health services, despite the Italian law guarantees equal access to References health care, particularly maternity services. [1] Hertzman C, Siddiqi A, Hertzman E, et al. Bucking the inequality gradient This is likely to be linked to the lack of information on the through early child development. BMJ. 2010 Feb 9;340:c468. doi: 10.1136/ services offered, the fear for illegal immigrants of being reported to bmj.c468. the police and of losing their jobs, as well as to cultural differences. [2] De Curtis M. Worrying increase in child poverty in Italy. BMJ 13 March 2013. In the maternity ward and neonatal unit, the contact with http://www.bmj.com/content/346/mbj.f1061/rr/635286 [3] http://istat.it/it/archivio/66983 situations that express social hardship is quite common, and it [4] http://atlante.savethechildren.it is important to know and be able to deal with the immediate [5] Cacciani L, Asole S, Polo A, et al. Perinatal outcomes among immigrant mothers problems, but also the possible risks from a distance, so as to cre- over two periods in a region of central Italy. BMC Public Health 2011, 11: 294 ate a network of collaboration between different professionals Early Human Development 89S4 (2013) S45–S46

Abandoned newborn: neglected phenomenon?

P. Ferrara a,*, A. Gatto a, P. Paolillo b,F.Venac, F. Ianniello a, C. Romagnoli d aInstitute of Pediatrics, Catholic University of Sacred Heart, Rome, Italy bDepartment of Neonatology, Neonatal Pathology, Neonatal Intensive Care Unit, Policlinico Casilino General Hospital, Rome, Italy cCampus Bio-Medico University, Rome, Italy d Division of Neonatology, Catholic University of Sacred Heart, Rome, Italy

Newborn abandonment is not a new phenomenon and in the the most vulnerable, in fact the newborns need particular attention humanistic and sacred literature there are reported many cases to the dynamics that characterized their assistance. This report of abandoned children after birth. As long ago as biblical times describe a phenomenon that in UK seems rare with high media and when baby Moses was placed among bulrushes, mothers who were social interest but we believe that is only the tip of iceberg because unable to keep their infants viewed abandonment as their only data are too small for a so large country. alternative [1]. About this topics the data on the scientific literature Another important aspect regards the places where these babies are very few and where the case series are described are very were abandoned. Forty-seven states across the United States have heterogeneous. passed legislation providing a mechanism by which parents can Although infant abandonment is a historical problem, we know legally surrender their unharmed and unwanted newborns at remarkably little about the conditions or effects of abandonment to designated locations [4]. States have defined Safe Havens to include guide evidence driven policies. hospitals, fire or police stations, age limits for surrender vary but Several definitions of modern baby abandonment are available. frequently are either 72 hr or 30 days, and the level of legal The US government has distinguished between “boarder babies”, protection and anonymity for the parent varies. The Safe Haven law “abandoned infants” and “discarded infants”. The first two abandon- is intended to provide an alternative path for desperate women, ment types refer to babies left in hospitals, with abandoned infants that includes provision of legal and anonymous surrender as an defined as newborn and boarder babies aged up to 12 months. Dis- alternative to illegal and unsafe abandonment. The premise behind carded infants are those abandoned in other public places without this idea is that women unsafely discard or abandon their infants care or supervision, and include neonaticide cases [1]. out of a fear of prosecution and lack of anonymity. Therefore, if a In an attempt to reduce the number of infanticides and aban- woman at risk of abandonment is made aware of this policy, she donment in unsafe places such as public restrooms, many states may instead decide against an illegal abandonment and choose to have enacted legislation to provide “safe places” for mothers to legally surrender her newborn to a designated Safe Haven. abandon their newborns. In Italy, like in other country, there are for the babies abandoned In Italy the data on these babies are not official. According to in the hospital the “baby hatch”, a comfortable space, usually near the latest survey of the Italian Society of Neonatology about 3000 the hospital, where mothers can leave their babies anonymously babies are abandoned every year (latest data of July 2012). Seventy- with the certainty that the baby will be cared for. Historically this threepercentarechildrenofItalian parents, 27% are children of practice was introduced in the 12th century by Pope Innocent III in immigrant parents. The parental age is between 20 and 40 years. the form of “foundling wheel”. He disposed to install in homes for Mothers under the age of 18 years old are only 6%. Four hundred foundlings a cylinder set upright in the outside wall of the building are the newborns abandoned in the hospital [2]. where the mothers placed the child, turned it around so that the In the UK the situation about the data is the same. The study baby was inside, rang a bell to alert caretakers and then she went of Sherr et al. describe the characteristics of this crime in UK by away anonymously. Actually in Italy there are some baby hatch in using the media reports to have information on abandoned babies particular: Mangiagalli Hospital in Milan, Hospital of the Innocents because of the absence of national policy or other official data. They in Florence, Sacra wheel of exposed in Naples, Casilino Hospital and collected the information between 1998 and 2005 and described an Santo Spirito Hospital (1th Italian wheel) in Rome. average number of 16 babies abandoned yearly [3]. In a period of Other countries where these structure were established are Ger- 7 years they observed 124 babies, 96 (77.4%) newborn babies (<1 many (more than 90 locations), Poland, Czech Republic, Hungary, week old) and 28 (22.6%) older infants. The 33.7% of abandoned Austria, USA, India and South Africa [5,6]. newborns died vs. 0% of older babies. This information is very Asai and Ishimoto in their article ask a question: “Should important to identify the importance of preventing this practice we maintain baby hatches in our society?” [7]. They describe the and to save the life of these babies. This particular population is reality of Jikei Hospital in Kumamoto City, Japan where in 5 years, since May 2007, 81 children (40 male and 41 female) were abandoned, 8 of which were disabled. Thirty parents provided * Corresponding author. reasons of this decision: poverty (9 cases), unmarried (9 cases),

0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. S46 P. Ferrara et al. / Early Human Development 89S4 (2013) S45–S46 public image/unwillingness to enter in family register (6 cases), treatment and then are put forward for adoption or placed with problems with partner (6 cases), and extramarital affair (4 cases). foster care by the local social services department. The first Italian They identified the most important objections to this practice: data published on this subject showed that, although the physical – the baby hatch violates a child’s right to know the identity of health of children in group homes is no worse than that of children his or her biological parents by allowing anonymous birth; living in their own homes, there are still serious deficiencies in – the baby hatch neglects fulfillment of the biological parents’ their overall health and well-being, particularly in emotional health basic obligation of to raise their child and the very availability and behavior. In any case foster care provides necessary conditions of the baby hatch induces abandonment of infants; to support the growth of the children and their physical, mental – some people abuse the baby hatch, using it for selfish reasons; and social needs [8]. – baby hatches cannot save babies’ lives; In conclusion considering that in Italy, as in many other – the rights of one parent can be ignored if the other surrenders developed States there is no national register recording the official a child without his or her consent; data for these infants, we think that an appropriate investigation – the baby hatch puts a baby in medical jeopardy; is most important to clarify the characteristics of this phenomenon – the baby hatch has no clear legal basis. to try stopping. Like all human dynamics in order to limit the Then we clarify all the positive aspect that we found in this pathological or negative ones we need to know them. In particular, institution so they explain that the baby hatches: can give children to implement preventive strategies must be clear the background the right to life and they can be saved; can protect vulnerable of the topic on we work. In this context it might be useful to have pregnant women who are mentally and economically desperate; data about the places where babies are abandoned more frequently, can uphold parent’s right to anonymity and both stigmatization and the time of year and more particular of the day when babies are discrimination against them can be avoided; can have the societal abandoned, the age of the mothers, the psychological condition function of serving as a last resort for desperate women and/or of parents, the economic conditions etc. All these data should be parents; can provide an alternative of social childcare organizations collected also to identify the categories of parents at risk and to give with only limited function; can serve as the emergency shelter role them a particular help. In particular we think that the prevention temporarily which accepts the baby of the mother and/or parents necessarily should begin before birth and the assistance must be who need time to think; can fulfill social responsibility to protect extended in the months after delivery, with structured strategies. and raise children by realizing a principle of solidarity; can offer All these proposals together with the establishment of a national pregnant women and/or parents an opportunity to drop off their register of the abandoned babies would have two principal objec- child at a safe place hoping that he or she survives; can serve tives: first of all to prevent the practice of abandon and second, as important local direct and upmost measures for women and/or when the first is failed, to save the life of these newborns. parents in trouble, by offering 24-hour preventive consultation and support system; can be a symbol embodying human compassion Conflict of interest which is a pure and natural feeling that it is unbearable and impossible to remain indifferent in the face of another’s misfortune; The authors have no conflict of interest to declare. can urge society as a whole to deliberate current situation in which child-rearing is difficult. References Another important point is the legislation that regulates this phenomenon in the different states. The Italian law allows women [1] Mueller J, Sherr L. Abandoned babies and absent policies. Health Policy. 2009 to give birth and to remain anonymous. They were assisted during Dec;93(2–3):157–64. the pregnancy and after the deliverytheycanrecognizeornot [2] http://www.aibi.it/ita/tremila-neonati-abbandonati-il-libro-nero-della- maternita/. recognize the newborn. The court can not try to find the biological [3] Sherr L, Mueller J, Fox Z. Abandoned babies in the UK – a review utilizing father of the baby but for the right of newborn to have a family media reports. Child Care Health Dev 2009;35(3):419–30. may initiate the procedures of adoptability. Although the law [4] Pruitt SL. The number of illegally abandoned and legally surrendered newborns fully protects the mothers very often due to problems of a social in the state of Texas, estimated from news stories, 1996–2006. Child Maltreat nature often or more often for problems of illegal immigration of 2008;13(1):89–93. [5] Okawa N, Ichiki S, Ito I, et al. Attitudes of newborn doctors towards baby hatch parents, who are afraid of being discovered, babies are abandoned “Stork’s Cradle”). J Jpn Soc Premature Newborn Med 2009;21:134–8. in dangerous conditions for life. Considering this situation and the [6] Evans S. The “baby box” returns to Europe. Berlin: BBC News Magazine, 2012; positive aspects highlighted by Asai and Ishimoto we believe that http://www.bbc.co.uk/news/magazine-18585020. the baby hatches are a valid instrument to limit the newborns’ risk [7] Asai A, Ishimoto H. Should we maintain baby hatches in our society? BMC Med Ethics 2013;14:9. of death. [8] Ferrara P, Romani L, Bottaro G, Ianniello F, Fabrizio GC, Chiaretti A, Alvaro F. An additional point is that usually, abandoned children are kept The physical and mental health of children in foster care. Iran J Public Health in hospital for a few days for observation and any necessary 2013;42(4):368–73. Early Human Development 89S4 (2013) S47–S48

The umbilical cord: a source of great richness

Gaetano Chirico

Neonatology and Neonatal Intensive Care, Children Hospital, Spedali Civili, Brescia, Italy

1. Introduction increased requirement of phototherapy, especially in settings where early discharge of term infants is a common practice [7]. Most of the components contained within the umbilical cord An additional utilization of the residual CB after delayed clamp- may represent a source of very useful factors for either the same ing or milking may be for the initial blood tests, in order to reduce infant or as a donation for the treatment of several diseases. the amount of blood firstly drawn from VLBW neonates [8]. Indeed, nowadays the umbilical cord, rather than discarded, is being increasingly used by two procedures adopted to better 3. Cord stem cells transplantation dispose of the beneficial effects of the cord factors: the delay of cord clamping, or the collection of cord blood (CB) to be stored in The other very important use of umbilical cord, that is rich the cord blood banks for subsequent utilization. in hematopoietic [9] and mesenchimal progenitor cells, is for the purpose of regenerative medicine. 2. Optimal timing of cord clamping Indeed, since 1988, the scientific community realized that cells derived from CB could be used as an alternative source, as The optimal timing of cord clamping has long been a matter compared to bone marrow, to realize stem cell transplantation. of debate. Guidelines tended to suggest an early clamping, before Compared with bone marrow, CB has shown many advantages 30 seconds from birth, in order to avoid a delay in performing such as quick availability, less risk of GHVD together with higher timely resuscitation when needed, or to prevent excessive passage compatibility rates and less risk of infections [10]. of CB to the fetus, leading to neonatal polycythemia, especially in Following the diffusion of the CB banks around the world, the pregnancies with risk factors, such as maternal diabetes, severe number of autologous or heterologous transplants is increasing intrauterine growth restriction, and living in high altitudes [1]. year after year for malignant and non-malignant conditions, both However, recent studies have clearly shown that, particularly in in children and adults. The limitation of the reduced volume and preterm infants, this is not the best choice. the relative low number of progenitor cells in the graft has been Several reports have demonstrated the short and long term overcome by the use of either double CB transplant, or single-unit favorable effects of delaying the umbilical cord clamping. The most intrabone injection [11], or ex vivo expansion of umbilical CB, consistent result is represented by the increase of circulating red although this last method may carry the risk for the acquisition of blood cell volume, hemoglobin and hematocrit in the neonate, and genomic imbalances [12]. the consequential reduced need of RBC transfusions, as confirmed More recently, new indications are emerging of diseases to by several trials [2]. be treated with CB components in the neonatal period. The However, the most important favorable effect reported in mostly awaited results of ongoing studies are undoubtedly those preterm infants may be considered the better hemodynamic stabi- concerning the treatment of brain injury, particularly subsequent lization soon after birth, with the improvement of mean systemic to perinatal hypoxic-ischemic encephalopathy (HIE). A series of blood pressure, urine output, improved superior vena cava blood experimental trials have shown the beneficial effects on brain flow, and cardiac function, and the reduced need for vasopressors. repair of therapies based on umbilical CB mononuclear cells, This may contribute to the reported reduction of the prevalence as hematopoietic stem/progenitor cells, endothelial progenitors, of intraventricular hemorrhage [3], necrotizing enterocolitis, and lymphocytes, monocytes and mesenchymal stem/progenitor cells sepsis [4], and to the long term protection against motor disability [13]. The neuroprotective effect of human cord cells may be [5]. due to several possible mechanisms of action, such as protection The need to rush when resuscitation is required, may be of neurons from glutamate-induced apoptosis and from oxygen– overcome by the use of cord milking. This fast method has glucose deprivation, the neurotrophic effect of soluble factors, and been shown to achieve a similar amount of blood transfusion, as the anti-inflammatory effect after stroke, probably mediated by compared with delaying clamping the cord for 30 seconds [6]. modulation of microglial cell function [13]. Although the superiority of delaying clamping or milking the Besides experimental studies, clinical trials have confirmed the cord in preterm infants is unanimously acknowledged, the same protective role of umbilical cord transplantation in neurodegener- procedure is still debated for term infants born in industrialized ative disorders, as in children with metachromatic leukodystrophy, countries, where its benefits, particularly the improvement of long or in Krabbe disease. term iron homeostasis, need to be weighed against the possible The first pilot studies of autologous CB infusion in neonates with

0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. S48 G. Chirico / Early Human Development 89S4 (2013) S47–S48

HIE and in children with cerebral palsy indicated no added risk Brighton Perinatal Study Group. Milking compared with delayed cord clamp- from the regimens used [14]. Therefore, controlled clinical trials ing to increase placental transfusion in preterm neonates: a randomized have been initiated of autologous CB infusions in term infants with controlled trial. Obstet Gynecol 2011;117:205–11. [7] Committee on Obstetric Practice, American College of Obstetricians and HIE, along with concurrent whole body cooling, or in children with Gynecologists. Committee Opinion No.543: Timing of umbilical cord clamping various acquired neurological injuries, including cerebral palsy [15]. after birth. Obstet Gynecol 2012;120:1522–6. Interesting data are also arising from studies aimed at the eval- [8] Baer VL, Lambert DK, Carroll PD, Gerday E, Christensen RD. Using umbilical uation of the effects of cord-derived mesenchimal or perivascular cord blood for the initial blood tests of VLBW neonates results in higher hemoglobin and fewer RBC transfusions. J Perinatol 2013;33:363–5. cells for the prevention or treatment of bronchopulmonary dyspla- [9] Gasparoni A, Ciardelli L, Avanzini MA, Bonfichi M, di Mario M, Piazzi G, sia. The reported outcomes in experimental models are Improved Martinotti L, Vanelli L, Rondini G, Chirico G. Immunophenotypic changes of survival and growth restriction, improved alveolar structure, at- fetal cord blood hematopoietic progenitor cells during gestation. Pediatr Res tenuated lung fibrosis, and inflammation [16], mainly favored by 2000;47:825–9. paracrine anti-inflammatory, antifibrotic and antioxidative effects, [10] Lanfranchi A, Porta F, Chirico G. Stem cells and the frontiers of neonatology. Early Hum Dev 2009;85:S15–8. rather than by cell engraftment [17]. [11] Rocha V, Labopin M, Ruggeri A, Podestà M, Gallamini A, Bonifazi F, Sanchez- Additional possible indications for cord blood cells under evalua- Guijo FM, Rovira M, Socie G, Baltadakis I, Michallet M, Deconinck E, Baci- tion are idiopathic osteoporosis, recessive dystrophic epidermolysis galupo A, Mohty M, Gluckman E, Frassoni F. Unrelated cord blood trans- bullosa, spinal cord injury, liver injury, HIV infections, and others. plantation: outcomes after single-unit intrabone injection compared with double-unit intravenous injection in patients with hematological malignan- Finally, it should be recalled that some studies have reported cies. Transplantation 2013;95:1284–91. unfavorable results [18], while others have outlined the risk long [12] Borghesi A, Avanzini MA, Novara F, Mantelli M, Lenta L, Achille V, Cerbo term occurrence of food allergy, or of potentially life-threatening RM, Tzialla C, Longo S, De Silvestri A, Zimmermann LJI, Manzoni P, Zecca M, autoimmune diseases. Spinillo A, Maccario R, Zuffardi O, Stronati M. Genomic alterations in human umbilical cord-derived mesenchymal stromal cells call for stringent quality control before any possible therapeutic approach. Cytotherapy 2013; in press. Conflict of interest [13] Pimentel-Coelho PM, Rosado-de-Castro PH, da Fonseca LM, Mendez-Otero R. Umbilical cord blood mononuclear cell transplantation for neonatal hypoxic- The author has no conflict of interest to declare. ischemic encephalopathy. Pediatr Res 2012;71:464–73. [14] Liao Y, Cotten M, Tan S, Kurtzberg J, Cairo MS. Rescuing the neonatal brain from hypoxic injury with autologous cord blood. Bone Marrow Transplant References 2013;48:890–900. [15] Sun J, Allison J, McLaughlin C, Sledge L, Waters-Pick B, Wease S, Kurtzberg J. [1] Raju TN, Singhal N. Optimal timing for clamping the umbilical cord after Differences in quality between privately and publicly banked umbilical cord birth. Clin Perinatol 2012;39:889–900. blood units: a pilot study of autologous cord blood infusion in children with [2] Rabe H, Diaz-Rossello JL, Duley L, Dowswell T. Effect of timing of umbilical acquired neurologic disorders. Transfusion 2010;50:1980–7. cord clamping and other strategies to influence placental transfusion at [16] O’Reilly M, Thébaud B. Using Cell-Based Strategies to Break the Link between preterm birth on maternal and infant outcomes. Cochrane Database Syst Rev Bronchopulmonary Dysplasia and the Development of Chronic Lung Disease 2012;8:CD003248. in Later Life. Pulm Med 2013;2013:874161. [3] Sommers R, Stonestreet BS, Oh W, Laptook A, Yanowitz TD, Raker C, Mercer [17] Pierro M, Ionescu L, Montemurro T, Vadivel A, Weissmann G, Oudit G, Emery J. Hemodynamic effects of delayed cord clamping in premature infants. D, Bodiga S, Eaton F, Péault B, Mosca F, Lazzari L, Thébaud B. Short-term, Pediatrics 2012;129:e667–72. long-term and paracrine effect of human umbilical cord-derived stem cells [4] Raju TN. Timing of umbilical cord clamping after birth for optimizing in lung injury prevention and repair in experimental bronchopulmonary placental transfusion. Curr Opin Pediatr 2013;25:180–7. dysplasia. Thorax 2013;68:475–84. [5] Mercer JS, Vohr BR, Erickson-Owens DA, Padbury JF, Oh W. Seven-month [18] Dalous J, Pansiot J, Pham H, Chatel P, Nadaradja C, D’Agostino I, Vottier G, developmental outcomes of very low birth weight infants enrolled in a Schwendimann L, Vanneaux V, Charriaut-Marlangue C, Titomanlio L, Gressens randomized controlled trial of delayed versus immediate cord clamping. J P, Larghero J, Baud O. Use of human umbilical cord blood mononuclear cells Perinatol 2010;30:11–6. to prevent perinatal brain injury: a preclinical study. Stem Cells Dev 2013; [6] Rabe H, Jewison A, Alvarez RF, Crook D, Stilton D, Bradley R, Holden D, 22:169–79. Early Human Development 89S4 (2013) S49–S51

Use of allogenic umbilical cord blood for red cells transfusion in premature infants: utopia or reality?

P. Papacci a,*, M. Fioretti a, C. Giannantonio a, A. Molisso a,M.G.Tesfagabira, A. Tornesello a, M. Bianchi b, L. Teofili b, C. Romagnoli a aIstituto di Pediatria, Divisione Neonatologia, Università Cattolica Saco Cuore,Rome, Italy bIstituto di Ematologia, UNICATT Cord Blood Bank, Italy

ARTICLE INFO ABSTRACT

Keywords: Extremely low birth weight (ELBW) infants almost always receive blood transfusions early in life. Newborn Autologous cord blood transfusions infants are currently transfused with leukocyte-depleted, irradiated red blood cells (RBCs) obtained from Allogenic cord blood transfusions adult donor, which contains adult hemoglobin. Adult hemoglobin affinity for oxygen is lower than fetal, Extremely low birth weight infants therefore red cell transfusion could be responsible for increased oxygen delivery to tissues increasing the Red blood cells transfusion risk of the “oxygen radicals disease of the newborn”. Though clinical studies have demonstrated that autol- Oxygen radicals disease ogous cord blood transfusions in newborns is feasible, the clinical use of umbilical cord blood (UCB) for RBC transfusion purposes is still limited, expecially because of the small volumes achieved after processing of the UCB unit. The preliminary results of the first clinical study assessing the feasibility and the effectiveness of a transfusional program in preterm infants with packed RBSs obtained from allogenic UCB are shown. © 2013 Elsevier Ireland Ltd. All rights reserved.

1. Introduction collection of cord blood as a source of haematopoietic progenitor cells and the development of modern techniques for the processing Extremely low birth weight (ELBW) infants represent a cat- and storage of blood products has raised the question as to whether egory of patients with very high transfusion requirements [1]. the RBCs discarded by the process of separation could not be Blood transfusions are a clinical practice almost indispensable in a useful blood product for autologous transfusion of premature preterm ELBW newborns because they are subject to anemia due newborns in the early stages of life. to decreased half-life of red blood cells (RBCs) containing fetal Umbilical cord blood (UCB) availability as a prospect for trans- hemoglobin, impaired erythropoietin response to anemia and iatro- fusional use was first reported in 1939 [2]. The preparation of genic blood loss. Despite the use of restrictive transfusion protocols, autologous RBCs from the UCB of preterm infants was negatively the reduction of phlebotomy loss and the use of erythropoietin, the affected in the past by the difficulties of collection of UBC units and transfusion rate remains very high and in Italy it is estimated that storage. Blood clotting was a main problem during the collection of 70–80% of infants weighing <1500 g receive RBCs transfusion, most cord blood units [3]; clots prevent to collect adequate volumes of of which is carried out in the first weeks of life. blood to be processed and separated in different blood components. Blood clotting can be also responsible of activating coagulation 2. Autologous cord blood transfusion for anemia of prematurity cascade in the RBCs unit. Refinements in techniques of umbilical blood processing for the purpose of recovering umbelical cord stem According to national and international guidelines newborn cells has gradually improved collection and storage of UBC and infants are currently transfused with leukocyte-depleted, irradiated several clinical trial have been performed with the aim to verify RBCs obtained from adult donor in a small volume (10–20 ml/kg). the coverage of transfusion need of preterm and the feasibility of The improvement of transfusion practices has ensured that the autologous RBC transfusion. risks associated with the use of RBCs is minimized. The screening Clinical studies have demonstrated that autologous cord blood of adult donors and the monitoring of infectious diseases of blood transfusions in newborns, although feasible, are not sufficient to components dramatically reduced the risks of transfusion by single entirely cover the early neonatal blood requests because of the donor. However to further limit the risks associated with multiple small volumes achieved after processing of the UCB unit, too often exposure to allogeneic donor, efforts have been made to verify the not adherent to the transfusion requirements of preterm infants feasibility of autologous placental blood transfusions. The increased [4]. Khodabux et al. [5] described the attempt to collect and process UCB in 176 deliveries <32 weeks’ GA into autologous RBC products, aiming to reduce allogenic transfusion. He declare that * Corresponding author. 57,6% of the collected UBC reached volumes >15 mL, able to be

0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. S50 P. Papacci et al. / Early Human Development 89S4 (2013) S49–S51 processed into RBC products and that after processing and quality 4.1. Methods control only 36,4% of suitable autologous products were available for transfusion. Considering low availability of autologous products Subject to acceptance of proper informed consent, packed RBSs due to a low number of successful UCB collections this randomized are elected to transfuse from UBC (ECC) infants with gestational clinical study was stopped before the enrollment of the sample size age ≤30 weeks and/or birth weight ≤1500 grams candidates for planned to demonstrate the primary outcome. transfusion therapy within four weeks after birth or up postnatal In addition, the high rate of bacterial contamination (1,9–8,6%) of age of the ˆ 32 weeks, in agreement with the national recommen- the harvested UCB units in the published clinical studies, probably dations [9]. In the absence of availability of group compatible, cord attributed mostly to non-sterile procedures for the collection of blood infants are assigned to receive packed RBSs from adult donor cord blood units, has been considered a major limitation for the (ECA). For each assignment group the characterization and biolog- actual use of these blood components [3–5]. ical qualification of blood units (obtained from donor and UBC) are carried out in accordance with the procedures in our Blood 3. Allogenic cord blood-derived RBCs for anemia of prematurity Transfusion Service and current legislation. Are excluded from this study infants with: isoimmunization maternal-fetal, fetal hydrops, The neonatal blood inside the placenta and the umbilical vessels congenital malformations and acute hemorrhage at birth. was initially used as a source of blood for adult allogeneic transfu- sions during the Second World War. In some hospitals in New York 4.2. Statistical analysis was used until the end of the sixties and, currently, it is reported its use in particular contexts, such as in developing countries [6]. Normally distributed continuous variables were expressed as No experience with allogeneic cord blood (ACB) RBC transfusion mean and standard deviation (SD). has been described until the preliminary results of a study carried The statistical evaluation was conducted using the software out to assess the feasibility of an ACB RBCs transfusion program for SPSS data mining, using for the analysis of continuous variables premature newborns in terms of preparation and yield of valid ACB the Mann-Whitney U test and Fisher’s exact test for dichotomous RBCs units [7]. The authors collected ACB units, that were not suit- variables. able for processing and storage for allogeneic transplant cord blood, The level of significance is for values of p < 0.05. in delivery ≥37 weeks’ GA, with absence of infection in the mother and no staining of the amniotic fluid. Forty-three percent of the 76 4.3. Results collections attempted was not suitable for subsequent processing because of the insufficient volume or of the presence of blood From 1 April 2013 to 1 July 2013 were elected to receive clots. The median volume after fractionation (31.2 ± 8.2 ml) of the cord blood transfusions 16 infants. Of these were enrolled, because remaining units appears to be greater than the volume of RBCs unit needed of transfusion, 8 infants of which 3 are assigned to the ECC from UCB for autologous use reported from literature and then it group and 5 assigned to the ECA (Table 1). is mostly sufficient to provide the coverage of a single transfusional The amount of blood transfused was 20 ml/kg at each event event of a ELBW infant. Biochemical, hematological parameters and transfusion. The characteristics of the pockets of RBSs from UBC microbiologic testing performed on the ABC RBC units proved that reflect those described by Bianchi et al. [7]. allunitscouldbeconsideredeligiblefortransfusion.Theauthors The feasibility, understood as the fulfilling of transfusion re- conclude that the preparation of RBCs from ACB is feasible and quirements of patients included in the study, is currently at 54.5%. convenient. This method does not reduce the risks associated with Currently the assessment of effectiveness can be performed allogenic transfusion but certainly allows to bypass the limits of only using the changes in hematocrit as a result of each transfu- cord blood collection for autologous use firstly the insufficiency of sional event. The hematocrit after transfusion, show no statistically blood volumes harvested at low gestational ages. The collection of significant differences between the two groups (Table 2). cord blood for allogeneic transfusion in deliveries of term neonates There were no adverse events referable to the transfusion of would then have the advantage to ensure a wider coverage trans- RBSs from UBC. fusion. This method could also reduce the risk of post-transfusion CMV infection that is currently connected to transfusions from adult donor, due to the guarantee of the search for antibodies against CMV, always performed on serum from the mother. The use of neonatal blood, although allogeneic, could theoretically result Table 1 in other benefits when administered to ELBW infants. Currently, Characteristics of the enrolled infants. newborns are transfused with RBSs from adult donor, which con- Cord group Adult group P value tains adult hemoglobin. Adult hemoglobin affinity for oxygen is N 35 substantially lower than fetal hemoglobin, therefore red cell trans- Male 2 4 1 fusion could be responsible for increased oxygen delivery to tissues EG 27.2 ± 3.7 27.1 ± 1.2 1 ± ± increasing the risk of the “oxygen radicals disease of the newborn”. PN 794.2 287.9 873 216.8 0.45 Twins 1 1 1 Many of the major complications of preterms, such as ROP, chronic APGAR 1 5.3 3.8 0.2 lung disease, IVH, necrotizing enterocolitis have been associated APGAR 5 8 6.6 0.34 with oxidative cellular damage mediated by oxygen radicals. In SGA 0 1 1 particular RBCs transfusions in the first month of life of prematures are one of the major risk factor for developing retinopathy [8]. Table 2 Hematological values (media ± SD). 4. Our experience Cord group Adult group P value At our NICU is ongoing a single center case control that aims Ht (%) 13.1 ± 4.2 14.1 ± 4.4 0.59 to define the feasibility and the effectiveness of a program of Ht at born (%) 54 ± 5.2 57 ± 8.4 0.65 transfusion therapy of preterm infants with packed RBSs obtained Blood loss by phlebotomy before each transfusion (ml) 15.2 ± 13.5 18.2 ± 13.1 0.39 from UBC allogeneic. P. Papacci et al. / Early Human Development 89S4 (2013) S49–S51 S51

4.4. Conclusions References

From the data available so far we can state that transfuse [1] Strauss RG. Anaemia of prematurity: pathophysiology and treatment. Blood homologous RBSs from cord blood is an eventuality possible. In our Rev 2010;24(6):221–5. [2] Halbrecht J. Transfusion with placental blood. Lancet 1939;233:202–203. reality, with the collaboration of UNICATT Cord Blood Bankwith, [3] Garritsen HS, et al. Autologous red cells derived from cord blood: collection, respect to transfusion requirements of infants the availability of preparation, storage and quality controls with optimal additive storage medium RBSs from UBC can cover the 55.5%. With regard to transfusional (Sag-mannitol). Transfus Med 2003;13:303–10. effectiveness, from currently collected data, we can state that [4] Eichler H, et al. Cord blood as a source of autologous RBCs for transfusion to preterm infants. Transfusion 2000;40(9):1111–7. the RBCs from UBC lead to an increase of the post-transfusion [5] Khodabux CM, et al. A clinical study on the feasibility of autologous cord blood hematocrit comparable to that produced by transfusions of RBSs transfusion for anemia of prematurity. Transfusion 2008;48(8):1634–43. from adult donor. The data represent a preliminary evaluation [6] Rubinstein P. Cord blood banking for clinical transplantation. Bone Marrow waiting to extend the analysis to a larger sample. Transplant 2009;44(10):635–42. [7] Bianchi M, et al. Allogeneic cord blood red cells for transfusion. Transfus Med Rev 2012;26(1):90–1; author reply 91–2. Conflict of interest [8] Giannantonio C, et al. Analysis of risk factors for progression to treatment- requiring ROP in a single neonatal intensive care unit: is the exposure time The authors have no conflict of interest to declare. relevant? J Matern Fetal Neonatal Med 2012;25(5):471–7. [9] The task force SIMTI and SIN. Recommendations on transfusion therapy in Neonatology. Blood Transfus 2006;4:158–80. Early Human Development 89S4 (2013) S52–S53

Cord blood banks: organizational aspects

L. Salvaneschi

Pavia CBB Director and Medical Director, Department of Transfusion Medicine, Fondazione IRCCS Policlinico “San Matteo”, University of Pavia, Pavia, Italy

Umbilical cord blood is known to contain a significant proportion and a cord blood unit from an unrelated individual should be started of pluripotent hematopoietic stem cells capable of completely contemporaneously, in order not to lose precious time. The decision repopulating the bone marrow following myeloablative therapy. to use one or other of the sources of hematopoietic stem cells, The unquestionable advantages of using this type of transplant if both are available, will be taken be each single Center and are: should ideally take into account the various parameters such as the • the low risk of viral contamination of cord blood, number of cord blood cells available, the degree of compatibility • the prompt availability of hematopoietic stem cells for trans- between the donor and recipient, the risk of immune-mediated plants between unrelated individuals, complications (i.e. GVHD) of the two types of transplant and the • a lower incidence of graft-versus-host disease (GVHD), time passed between the start of the search and the intended • the decreased immunological reactivity of the cord blood transplant in the context of the particular type of disease. cells, • the organization of banks of cryopreserved cord blood. 3. Recommended number of cord blood cells per kg of body However, an analysis of the patients who have so far received a weight for a transplant cord blood transplant shows that there are also some disadvantages: • the recipients of cord blood stem cell transplant have a higher Basing on the data so far available it is recommended that the risk of failed engraftment of donor hematopoiesis, a slight number of nucleated cells before thawing should be greater than delay in the kinetics of granulocyte recovery and a more 3×107/kg of the recipient’s body weight. The minimum threshold marked delay in the reconstitution of platelet counts than cell count to be able to carry out a cord blood transplant is esti- do corresponding subjects who have received a bone marrow mated to be 20–25×106 nucleated cells/kg of the recipient’s body transplant. weight, evaluated before the thawing procedure. No patient should • both the lower incidence of acute and chronic GVHD noted receive a transplant with a cell load below this minimum value. after a cord blood transplant and the use of steroids for prophylaxis against GVHD itself could theoretically diminish 4. The cord blood banks the graft-versus-leukemia (GVL) effect. In Italy cord blood cells can be collected when: 1. Criteria of compatibility between donor and recipient for the • a child with a disorder for which a transplant of hematopoi- performance of a cord blood transplant from an unrelated etic progenitor cells is indicated has the possibility of re- donor ceiving the cord blood obtained at the delivery of a sibling (dedicated donation), Since the data so far published on cord blood stem cell trans- • systematic collection and storage of allogeneic (unrelated) plants between unrelated individuals do not allow the risk of cord blood is organized by a regionally authorized structure, developing immune-mediated complication (GVHD) to be defined which assumes the function of a Cord Blood Bank, precisely, it is thought appropriate that the donor and recipient • restricted cases of autologous units. should not differ by more than 2 loci of HLA-A, B, DRB1 (identified Storage of cord blood for family use is not admitted; collection by high resolution molecular methods at low resolution for A and B may be performed but shall be transferred abroad to be stored in loci and at high resolution for DRB1). private CBBs. Private CBBs are not allowed in Italy.

2. Diseases which can be treated with a cord blood transplant 5. Fundamental principles underlying donation of cord blood

On the basis of the results so far obtained, the patients eligible • The donation is voluntary. for a cord blood transplant from an HLA-identical family donor are Cord blood cannot be collected without the informed consent of the same as those eligible for a bone marrow transplant from an the mother, since placental tissue is considered to belong to the HLA-compatible family donor. mother and neonate and the collection is carried out when the As far as concerns the alternative between using cord blood placenta is still in the uterus. or bone marrow stem cells from unrelated donors, it is worth • The donation is anonymous. emphasizing that the search for an unrelated bone marrow donor Protection of the identity of the mother and infant donor of

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umbilical cord blood units while at the same time maintaining The transport of the cord blood from the delivery room to the linkage of a particular unit to its mother/donor is of the highest cryopreservation center must be carried out in suitable conditions priority. and as quickly as possible, but in any case within 48 hours of • Infectious and genetic safety of the donation. collection. After a period of observation (quarantine) which lasts from two to six months, it must be confirmed that the cord blood unit is 7. Management of cord blood units arriving at the Bank not a source of genetic or viral diseases. • Protection of the pregnant women and staff. The Bank’s doctor organizes the last stages of the processing and The cord blood must be collected in the delivery room in an storage of the units on the basis of their qualitative and quantitative atmosphere of complete safety for both the woman in labor and characteristics. the staff. The mother’s consent to the donation does not oblige Before cryopreservation, the unit is examined, first by simple the staff to actually collect the cord blood if the circumstances visual inspection and then for the following parameters: evaluation at the moment of the birth are unfavorable. of maternal history, volume, total cell count, viability. If the unit • Lack of financial or commercial interests. is considered suitable, it is sent for freezing, and at this point Neither the donor nor the person collecting the cord blood must samples are taken for blood grouping, sterility tests, HLA typing, the have any financial interest in the donation. enumeration of CD34+ progenitor cells and NRBC, and cell cultures. A sample of maternal blood also undergoes HLA typing. 6. General plan for the collection and validation of cord blood The cord blood unit is cryopreserved within 48 hours of its collection. The units are stored in liquid nitrogen at a temperature The Cord Blood Bank has an integrated team of staff dealing with below −150°C in specific containers, reserved for cord blood in the the collection, processing, characterization, storage, selection and Bank, in assigned rooms with the necessary safety systems. distribution of the cord blood cells for allogeneic and/or autologous transplant of hematopoietic cord blood progenitor cells. The Bank 8. Sending data on the cord blood units to IBMDR is coordinated by the CBB Director. Other key-professional figures are the Processing Facility Director and the Quality Assurance Periodically a local file is generated containing information on Supervisor. the validated units of cord blood. This information is sent to IBMDR and then made available in NETCORD and BMDW. CB units are 6.1. Information assigned the status “Active”. If an “Active”unitiscompatibleata first level search, the requesting Transplant Center can ask for the A complete information to the mother is need; leaflet with clear, investigations to be continued and is put into contact with the CBB, easily understandable information can be provided, explaining the that assigns the unit chosen the status “Required”. methods and aims of cord blood donation as well as the indications If the requesting Center asks for the unit chosen to be reserved for using cord blood for transplantation purposes. for its patient, the CBB attributes the unit the status “Reserved”: in this way the unit can no longer be selected, usually for a period no 6.2. History longer than 60 days.

A detailed maternal history is an effective tool for screening 9. Organization of delivery and delivery of the unit donations for infectious and hereditary diseases which could poten- tially be transmitted to the recipient of the cord blood. The clinical If the requesting Transplant Center confirms that it wants to history taking is extended to siblings and the father of the unborn recruit the selected unit of cord blood, the delivery of the unit must baby. be arranged in agreement between the CBB and the requesting Center. 6.3. Informed consent The release of the CB unit is promptly notified to IBMDR.

The Cord Blood Bank has an outpatient clinic specifically devoted 10. Follow-up of patients transplanted with cord blood units to pregnant women who decide to adhere to the program of cord blood donation; the doctors working in this clinic deal with EUROCORD, through IBMDR, should supply the follow-up data taking the history, supplying correct information and obtaining on patients transplanted with the cord blood units issued. signed informed consent. The activities of the Cord Blood Donation outpatient clinic do not finish with the birth of the baby and Conflict of interest collection of the cord blood, but continue with the post-natal checks of the mother and baby six months after the birth. The author has no conflict of interest to declare. The procedure for obtaining consent is applied before the beginning of labor. Selected bibliography

6.4. The collection [1] Broxmeyer HE, Srour EF, Hangoc G, et al. Proc Natl Acad Sci U S A 2003;100: 645–50. The cord blood is collected at the time of the baby’s delivery, im- [2] Larghero J, Garcia J, Gluckman E. In: Apperly J, Carreras E, Gluckman E, mediately after the umbilical cord has been clamped and resected, Gratwohl A, Masszi T (eds), EBMT Hematopoietic Cell Transplantation, 5th edition. 2008; pp 112–27. by the appropriate person adequately trained in this procedure. This [3] Kim Y-J, Broxmeyer HE. Crit Rev Oncol/Hematol 2011;79(2):112–26. person may be the midwife in the delivery room, the obstetrician [4] Rocha V, Labopin M, Sanz G, et al. N Engl J Med 2004;351:2276–85. or a doctor specifically trained. Cord blood can also be collected in [5] Trenado A, Charlotte F, Fisson S, et al. J Clin Invest 2003;112:1688–96. thecaseofaCesareanbirth. Early Human Development 89S4 (2013) S54–S55

Alternative birthing ways: the neonatologist’s point of view

Carlo V. Bellieni *

Department of Mother-Infant Care, University Hospital, Siena, Italy

In western countries, pregnancy and birth have become a strictly Table 1 medical event, decreasing their physiological naturality. This has Maternal and neonatal outcomes in planned home birth versus planned hospital births [3]. led many to endorse a return to more intimate behaviors, rejecting traditional hospital delivery: is it safe? Neonatologists should be Planned Planned Odds 95% CI aware of pros and cons of these new tendencies to give appropriate home hospital ratio birth birth counseling and care. Neonatal death – all newborns 2.0/1,000 0.9/1,000 2.0 1.2–3.3 Neonatal death – nonanomalous 1.5/1,000 0.4/1,000 2.9 1.3–6.2 1. Home birth Episiotomy 7.0% 10.4% 0.26 0.24–0.28 Operative vaginal delivery 3.5% 10.2% 0.26 0.24–0.28 A recent Cochrane review [1] showed that “there is no strong Cesarean delivery 5% 9.3% 0.42 0.39–0.45 evidence from randomised trials to favour either planned hospital birth Third- or fourth-degree laceration 1.2% 2.5% 0.38 0.33–0.45 or planned home birth for low-risk pregnant women”. However, in Maternal infection 0.7% 2.6% 0.27 0.19–0.39 this review only one trial (involving 11 women) contributed data. CI, Confidence Interval. This did not allow conclusions to be drawn about safety. More information emerges from another recent review [2] that assessed Table 2 Recommendations when considering planned home birth candidate for home babies’ mortality differences between home birth and hospital birth delivery a. in studies published between 1996 and 2011; they selected 11 • studies, with no evidence of an increase of deaths in either group. Absence of preexisting maternal disease • Absence of significant disease occurring during the pregnancy However, these studies only included low-obstetrical-risk women • A singleton fetus estimated to be appropriate for gestational age from western countries. A wide metaanalysis [3] considered all • A cephalic presentation studies in this field published in 1947–2010 (Table 1); 12 studies • A gestation of 37 to <41 completed weeks of pregnancy • were retrieved and their conclusions were that, though perinatal Labor that is spontaneous or induced as an outpatient • A mother who has not been referred from another hospital mortality was similar between the two groups, “the overall neonatal death rate was almost twice as high in planned home vs planned Systems needed to support planned home birth • The availability of a certified nurse-midwife, certified midwife, or physician hospital births, and almost tripled among nonanomalous neonates”. practicing within an integrated and regulated health system On these bases, the American college of obstetricians and • Attendance by at least 1 appropriately trained individual whose primary gynecologists [4] affirmed that “reports suggesting that planned responsibility is the care of the newborn infant home births are safe involved only healthy pregnant women. Recent • Ready access to consultation • cohort studies reporting lower perinatal mortality rates with planned Assurance of safe and timely transport to a nearby hospital with a preexisting arrangement for such transfers home birth describe the use of strict selection criteria for appropriate a candidates (...). Failure to adhere to such criteria (because of postterm ACOG considers previous cesarean delivery to be an absolute contraindication to planned home birth. pregnancy, twins, or breech presentation) is clearly associated with a higher risk of perinatal death”. And added: “Another factor influencing the safety of planned home birth is the availability of safe and timely prophylaxis and screening tests, and general assessment in the first intrapartum transfer of the laboring patient”. few days. It also reviewed appropriate features for candidates for The American Academy of Pediatrics agreed with this statement home delivery (Table 2) and outlined that “there should be at least adding: “Geography also may adversely affect the safety of planned 1 person present at every delivery whose primary responsibility is home birth, because travel times >20 minutes have been associated the care of the newborn infant. Situations in which both the mother with increased risk of adverse neonatal outcomes, including mortality”. and the newborn infant simultaneously require urgent attention are AAP requires for these babies the same guarantees given to hospital infrequent but will nonetheless occur. Thus, each delivery should be births, with regard to birth assessment and resuscitation, due attended by 2 individuals, at least 1 of whom has the appropriate training, skills, and equipment to perform a full resuscitation of the infant in accordance of the principles of the Neonatal Resuscitation * Corresponding author: C.V. Bellieni, Neonatal Intensive Care Unit, Policlinico “Le Program. (...). In addition, a previous arrangement with a medical Scotte”, Viale M. Bracci, 53100 Siena, Italy. Tel.: +39 0577 586550; Fax: +39 0577 586182. facility needs to be in place to ensure a safe and timely transport in the E-mail address: [email protected] (C.V. Bellieni). event of an emergency”[5].

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2. Underwater birth Cochrane authors found no trials of freestanding birth centres, so they just evaluated studies comparing conventional institutional We should distinguish underwater labor and underwater birth, settings to alternative institutional settings. They found that the lat- when we give recommendations in this field, because the use of a ter were associated with reduced medical interventions, increased specific tub or shower can regard labor but not birth. spontaneous vaginal birth, maternal satisfaction, and breastfeeding So, while the AAP committee for fetus and newborn [6] in at one to two months postpartum, with no apparent risks to mother 2005 reported that “the safety and efficacy of underwater birth or baby. The authors concluded: “Hospital birth centres are associated for the newborn has not been established. There is no convincing with lower rates of medical interventions during labour and birth and evidence of benefit to the neonate but some concern for serious harm. higher levels of satisfaction, without increasing risk to mothers or Therefore, underwater birth should be considered an experimental babies.” Unfortunately, in several trials the design features of the procedure”, the 2009 Cochrane library performed a review [7] alternative setting were confounded by differences in the organiza- that “includes 11 trials none of which evaluated the management tional models of care (including separate staff and more continuity of third stage of labour.” Thus, “Results for the first stage of labour of caregiver in the alternative setting), and thus it is not possible to showed there was a significant reduction in the epidural/spinal/ draw conclusions about the independent effects of the design of the paracervical analgesia/anaesthesia rate amongst women allocated to birth environment. water immersion compared to controls. There was no difference in assisted vaginal deliveries, caesarean sections, perineal trauma or 4. Conclusion maternal infection. There were no differences for Apgar score less than seven at five minutes, neonatal unit admissions, or neonatal infection As babies’ advocates, neonatologists should clearly expose to rates.” Anyway they concluded that “water immersion during the first mothers-to-be the risks of the alternative birthing ways, when stage of labour reduces the use of epidural/spinal analgesia. There is present; they should also impose to follow all international guide- limited information for other outcomes related to water use during lines and recommendations, in the case of choosing an “alternative the first and second stages of labour, due to intervention and outcome birth”. This counseling should be strictly adherent to the precaution variability. There is no evidence of increased adverse effects to the principle: do not expose a patient to a risk, unless benefits outweigh fetus/neonate or woman from labouring in water or waterbirth.”. risks and without his/her consent. When a patient cannot give any ACOG’s Committee on Obstetric Practice (see www.emedicine. consent (and the fetus cannot), neonatologists should behave in its medscape.com/article/259724-overview#aw2aab6b9) is reported to best interest, choosing the less risky option. Anyway, neonatologists say that there are "insufficient data, especially concerning rates of cannot be blind about the progresses in safety made when all infection, to render an opinion on whether warm-water immersion the recommendations of international agencies are followed, with is a safe and appropriate birthing alternative." Therefore they did particular regard to hospital birth centres. neither back nor explicitly discourage this practice. The Committee also felt that "this procedure should be performed only if the Conflict of interest facility can be compliant with Occupational Safety and Health Act standards regarding infection" that include the specific tub and The author has no conflict of interest to declare. water recirculation systems used. The Royal College of Obstetricians and Gynaecologists and the References Royal College of Midwives numbered strict criteria [8] in this field; they “support labouring in water for healthy women with [1] Olsen O, Clausen JA. Planned hospital birth versus planned home birth. Cochrane Database Syst Rev 2012;9:CD000352. uncomplicated pregnancies. The evidence to support underwater birth [2] Faucon C, Brillac T. [Planned home versus planned hospital births: Adverse is less clear but complications are seemingly rare. If good practice outcomes comparison by reviewing the international literature]. Gynecol guidelines are followed (...), these complications should be further Obstet Fertil 2013;41(6):388–93. reduced”. [3] Wax JR, Lucas FL, Lamont M, Pinette MG, Cartin A, Blackstone J. Maternal and newborn outcomes in planned home birth vs planned hospital births: a A recent revision of international recommendations and studies metaanalysis. Am J Obstet Gynecol 2010;203(3):243.e1–8. [9] proposed an interesting worksheet for underwater birthing [4] American College of Obstetricians and Gynecologists. Planned Home safety, and concluded that “while the safety of hydrotherapy during birth. 2013. Available online: http://www.acog.org/∼/media/Committee%20 labor has support in the literature, question remain regarding the Opinions/Committee%20on%20Obstetric%20Practice/co476.pdf?dmc=1& safety of actually giving birth underwater”. ts=20130705T1209102031. [5] American Academy of Pediatrics, Committee on Fetus and Newborn. Policy Statement Planned Home Birth. Pediatrics 2013;131(5)1016–20. 3. Birth centers [6] Batton DG, Blackmon LR, Adamkin DH, Bell EF, Denson SE, Engle WA, Martin GI,StarkAR,BarringtonKJ,RajuTN,RileyL,TomashekKM,WallmanC, The authors of a recent Cochrane review [10] that analysed 10 Couto J. Committee on Fetus and Newborn, 2004–2005. Underwater births. trials, so wrote: “In an effort to support normal labour and birth Pediatrics 2005;115(5):1413–4. [7] Cluett ER, Burns E. Immersion in water in labour and birth. Cochrane Database for healthy childbearing women, a variety of institutional maternity Syst Rev 2009;(2):CD000111. care settings have been constructed. Some are ‘home-like’ bedrooms [8] Immersion in Water During Labour and Birth (RCOG/Royal College of Mid- within hospital labour wards. Others are ‘home-like’ birthing units wives Joint Statement No. 1). Available at http://www.rcog.org.uk/womens- adjacent to the labour wards. Others are freestanding birth centres. health/clinical-guidance/immersion-water-during-labour-and-birth. [9] Veltman L, Doherty D. Safety and underwater birth-what every risk manager More recently, ‘ambient’ and Snoezelen rooms have been constructed should know. J Healthc Risk Manag 2013;32(4):16–24. within labour wards; these rooms are not home-like but contain a [10] Hodnett ED, Downe S, Walsh D. Alternative versus conventional institutional variety of sensory stimuli and furnishings designed to promote feelings settings for birth. Cochrane Database Syst Rev 2012;8:CD000012. of calmness, control, and freedom of movement.” Early Human Development 89S4 (2013) S56–S57

Bonding and breastfeeding after a cesarean delivery

Vincenzo Zanardo *, Alessandra Canella, Rita Maone, Gianluca Straface

Division of Perinatal Medicine, Policlinico Abano Terme, Abano Terme, Italy

Breastfeeding is associated with benefits to lifelong health, exclusive breastfeeding remains suboptimal in many countries and yet the rate of exclusive breastfeeding remains low in many the use of breast milk substitutes is widespreading around the industrialized countries. In the United States, less than one half of world. These outcomes remain far short of both the WHO and the mothers breastfeed for 6 months, and only 15% do so exclusively American Academy of Pediatrics [4] recommendations for exclusive [1]. Similarly, while more than 80% of mothers who reside in Italy breastfeeding for the first 6 months and continued breastfeeding initiate breastfeeding [2], only 55% of mothers who exclusively or for up to 24 months of age. predominantly breastfeed during the postpartum hospital stay still Rapid, recent changes in modes of delivery, postnatal practices, breastfeed 6 months after delivery, and fewer than 40% practice parental expectations, and feeding options pose new important full breastfeeding within the first 6 months [3]. Mode of delivery, clinical and psychological challenges for the mother-infant dyad in particular cesarean delivery (CD), is widely believed to affect and for the breastfeeding success in most developed countries [15]. breastfeeding adversely. Some studies reported no association and Some studies have shown a negative impact of labor induction, others an inverse relation [4]. opioid pain medication, epidural administration assisted vaginal CD (prelabor or in-labor) has increased rapidly worldwide. It birth and cesarean birth on breastfeeding. [16] Other studies, accounts for 31.8% of all births [5], and it is even more widespread however, have been unable to show any impact or have had mixed in China and parts of South America, where rates are reported to findings [17,18]. be between 40% and 50% [6,7], figures far in excess of the WHO Existing data on whether intrapartum interventions affect recommended rate of 15% [8]. The rise in elective prelabor CD is breastfeeding outcomes is conflicting, and there has been no thus particularly concerning. In the United States, the number of consensus on the overall impact [19]. It is believed that there are elective CDs increased by 53% between 1996 and 2007 [9], whereas two biological mechanisms of the association between mode of in England there was a 250% increase between 1980 and 2010, delivery and breastfeeding. The first is associated with surgery, for and currently 40% of all CDs are prelabor [10]. The contribution of example, long duration of separation of mother and the newborn maternal choice to the increasing elective CD rate is important. In due to complications of the surgery, such as pain, hemorrhage, the United Kingdom, 6–8% of pregnant women express a preference and infections [19]. Thus, in-labor CD may follow a long, difficult for CD [11], whereas in Australia, an increase in elective CD has not labor and be associated to numerous factors such as confinement been accompanied by increases in potentially explanatory health to bed, fasting, analgesia and/or anesthetics for pain, oxytocin aug- related factors [12]. This finding should be interpreted with caution mentation, and anxiety and stress, all having a negative impact as maternal choice is not the only reason for elective CD, and there on breastfeeding: Even following a planned cesarean section, these are a wide range of medical reasons that obstetricians recommend interventions can be frightening, especially in first-time mothers. a prelabor CD [13]. Instead, in-labor cesarean delivery is often And the mother who has undergone a CD and is lacking support associated with the cumulative impact of different intrapartum and assistance is unable to hold her newborn baby for the frequent interventions, which may affect a woman’s decision and ability to periods necessary for breastfeeding. Bottle feeding has become a initiate breastfeeding. Therefore, better understanding of caesarean common clinical practice in these cases [20]. Bottle-feeding milk section rates, their consequences and their benefits will consent to based formulas will, however, reduce newborn sucking capacity as professionals to monitor the quality of their practice to ensure that well as mother’s lactation stimulus [21,22]. The other biological women can make the right feeding choice. mechanism is related to labor. Because emergency CD usually takes Breastfeeding is considered the ideal way to provide nutrition place after the onset of labor, this observation supports the con- to infants, and can significantly reduce infant morbidity. The tention that it is the metabolic or endocrine milieu of labor that is World Health Organization (WHO) has developed the “Ten Steps paramount to initiating lactation [23]. The magnitude of oxytocin to Successful Breastfeeding”, a strategy to support and improve and prolactin responses, which play important mediating roles in breastfeeding [14], suggesting the use of standard definitions milk ejection and in establishing mother–infant interaction, differs for breastfeeding outcomes. However, the duration of any and in mothers delivering by CD and vaginally [24]. Differences have also been shown in blood concentrations of appetite-regulating hormones in infants born by CD and vaginal delivery [25]. Rat pups * Corresponding author: Vincenzo Zanardo, Division of Perinatal Medicine, Poli- that undergo simulated VD by drawing them through a rubber ring clinico Abano Terme, Piazza Colombo 1, 35031 Abano Terme, Italy. Tel.:/fax: +39 049 720027. in utero before CD show earlier suckling than pups from the same E-mail address: [email protected] (Vincenzo Zanardo). litters delivered by CD without simulated VD [26]. Finally, acording

0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. V. Zanardo et al. / Early Human Development 89S4 (2013) S56–S57 S57 to Lagercrantz and Slotkin, it is actually important for infants to [10] Anon. HES Online. NHS: The Information Centre. NHS Maternity Statistics undergo the hormonal and physical stress of being born which 2009–2010. Available from: http://www.hesonline.nhs.uk seems to prepare them for bonding and feeding [27]. Human babies [11] National Collaborating Centre for Women’s and Children’s Health. Caesarean section. In: National Institute of Clinical Excellence, ed. London, U K: RCOG show a surge of plasma catecholamines associated with the “stress Press, 2004:37. of being born”, a physiological response to labor and squeezing [12] Janssens S, Wallace KL, Chang AM. Prepartum and intrapartum caesarean through the birth canal [27]. Vaginally delivered infants exhibit section rates at Mater Mothers’ Hospital Brisbane 1997–2005. Aust N Z J increased alertness compared to cesarean-delivered infants whose Obstet Gynaecol 2008;48:564–9. [13] Jackson NV, Irvine LM. The influence of maternal request on the elective mothers did not undergo full labor. Catecholamine concentrations caesarean section rate. J Obstet Gynaecol 1998;18:115–9. are higher in vaginally delivered human infants as compared to [14] Vallenas C, Savage-King F. Evidence for the Ten Steps to Successful Breast- cesarean-delivered infants. This is relevant, considering that elec- feeding. Geneva: World Health OrganizationChild Health and Development tive caesarean delivery is frequently performed before 39 weeks Unit; 1997. [28,29]. [15] McLeod SA. John Bowlby | Maternal Deprivation Theory – Simply Psychology. 2007; available from http://www.simplypsychology.org/bowlby.html In conclusion, available data analysis seems strongly support a [16] Riordan J, Gross A, Angeron J, Krumwiede B, Melin J. The effect of labor pain negative association between prelabor CD and early breastfeeding. relief medication on neonatal suckling and breastfeeding duration. J Hum Lact In the immediate postpartum period, it is important to iden- 2000;16:7–12. tify these women so that they can receive early and additional [17] Prior E, Santhakumaran S, Gale C, Philipps LH, Modi N, Hyde MJ. Breastfeeding after cesarean delivery: a systematic review and meta-analysis of world breastfeeding support to improve their breastfeeding [30]. literature. Am J Clin Nut 2012;95:1113–35. [18] Asole S, Spinelli A, Antinucci LE, Di Lallo D. Effect of hospital practices Conflict of interest on breastfeeding: a survey in the Italian region of Lazio. J Hum Lact 2009;25:333–40. The authors have no conflict of interest to declare. [19] Moore ER, Anderson GC, Bergman N, Dowswell T. Early skin-to-skin contact for mothers and their healthy newborn infants. Cochrane Database Syst Rev 2012;16;5:CD003519. References [20] American Academy of Pediatrics. Work group on breastfeeding: Breastfeeding and the use of human milk. Pediatrics 1997;100:1035–9. [1] Centers for Disease Control and Prevention. Breastfeeding Report Card – [21] Perez-Escamilla R, Maulen-Radovan I, Dewey KG. The association between United States, 2012. 2012; http://www.cdc.gov/breastfeeding/data/reportcard. cesarean delivery and breast-feeding outcomes among Mexican women. Am J htm. Pub Health 1996; 86:832–6. [2] Zanardo V, Svegliado G, Cavallin F, Giustardi A, Cosmi E, Litta P, et al. Elective [22] Forster DA, McLachlan HL. Breastfeeding initiation and birth setting practices: cesarean delivery: does it have a negative effect on breastfeeding? Birth a review of the literature. J Midw Womens Health 2007;52:273–80. 2010;37:275–9. [23] Hyde MJ, Mostyn A, Modi N, Kemp PR. The health implications of birth by [3] Giovannini M, Riva E, Banderali G, Salvioni M, Radaelli G, Agostoni C. caesarean section. Biol Rev Camb Philos Soc 2012;87:229–43. Exclusive versus predominant breastfeeding in Italian maternity wards and [24] Nissen E, Lilja G, Widstrom AM, Uvnas-Moberg K. Elevation of oxytocin levels feeding practices through the first year of life. J Hum Lact 2005,21:259–65. early post partum in women. Acta Obstet Gynecol Scand 1995;74:530–3. [4] American Academy of Pediatrics Section on Breastfeeding. Policy statement: [25] Yoshimitsu N, Douchi T, Kamio M, Nagata Y. Differences in umbilical venous Breastfeeding and the use of human milk. Pediatrics 2012;129:e827–41. and arterial leptin levels by mode of delivery. Obstet Gynecol 2000;96:342. [5] Martin JA, Hamilton BE, Sutton PD, Ventura SJ,Mathews TJ, Kirmeyer S, et al. [26] Perez-Escamilla R, Cobas JA, Balcazar H, Holland Benin M. Specifying the Births: final data for 2007. Natl Vital Stat Rep 2010; 58:1–85. antecedents of breast-feeding duration in Peru through a structural equation [6] Beliza’n JM, Althabe F, Barros FC, Alexander S. Rates and implications of model. Public Health Nutr 1999;2:461–7. caesarean sections in Latin America: ecological study. BMJ 1999;319:1397. [27] Lagercrantz H, Slotkin TA. The “stress” of being born. Sci Am 1986;254:100–7. [7] Lumbiganon P, Laopaiboon M, Gulmezoglu AM, Souza JP, Taneepanichskul S, [28] Zanardo V, Pigozzo A, Wainer G, Marchesoni D, Gasparoni A, Di Fabio S, et al. Ruyan P, et al. World Health Organization Global Survey on Maternal and Early lactation failure and formula adoption after elective caesarean delivery: Perinatal Health Research Group. Method of delivery and pregnancy outcomes cohort study. Arch Dis Child Fetal Neonatal Ed 2013;98:F37–41. in Asia: the WHO global survey on maternal and perinatal health 2007-08. [29] Ferber SG, Makhoul IR. The effect of skin-to-skin contact (kangaroo care) Lancet 2010;375:490–9. shortly after birth on the neurobehavioral responses of the term newborn: a [8] WHO. Appropriate technology for birth. Lancet 1985;2:436–7. randomized controlled trial. Pediatrics 2004,113:858–5. [9] Menacker F, Hamilton BE. Recent trends in cesarean delivery in the United [30] Klaus MH. Bonding: building the foundations of secure attachment and States. Hyattsville, MD: National Center for Health Statistics, 2010. independence. Perseus, 1995. Early Human Development 89S4 (2013) S58–S59

Neonatal neurobehavioral assessment in healthy and at-risk infants

Guido Calciolari a,*, Rosario Montirosso b aStudy Group on Developmental Care, Italian Society of Neonatology, Italy b0-3Centre for the Study of Social Emotional Development of the At-Risk Infant – Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy

Beyond the prematurity several factors can interfere with the babies. Furthermore a risk for developmental problems may be neurobehavioral responses of newborn infants in their early days related to the great psychic permeability that is observed in several of life [1]. Indeed, although the modern medicine have reduced the mothers of full-term and healthy infants, even when the birth impact of many pre- and peri-natal risks factors, there are many occurs after a low risk pregnancy, normal delivery and normal others – such as adverse effects of prenatal toxic substances, fetal transaction of the infant from the fetal to the extra-uterine life, growth problems, hyperbilirubinemia, perinatal asphyxia, acute in the protective environment of a hospital [9–11]. Mothers in fetal distress and gestational and pre-gestational diabetes – that the immediate postnatal period are indeed in search of answers remained unchanged [2]. The possible influence of these factors to many questions: this baby is really mine? Who is he? Shall I on infants’ behavioral response profiles suggests that, even if be able to love him? Does he love me? Shall I be a good enough born at term, these infants are at-risks of adverse outcomes mother? [9,10]. A positive response to these mother’s questions [3]. For istance, several studies about infants of drugs-addicted lets start a positive loop of interactions that continue to validate mothers indicate neurobehavioral problems in the neonatal period; her competencies as a mother and consequently allow mutually the most common findings in the infant’s neurobehavior are satysfyng experiences and promote mother’s ability to read and problems of states regulation, irritability, difficult consolability, respond to processes of change of the developing infant. On the instable motor control [1]. This neurobehavioral dysregulation contrary,when the answers are slow to emerge or do not come at predicts behavior problems in childhood and long term cognitive, all, maternal anxiety and concerns rise, their coregulation derails, emotional and behavioral disturbances [4]. It has been suggested tensions and stress for the family increase and consequently an that these behavior outcomes are originated by multiple pathways, adequate parent–infant relationship can easily be unlikely [10,11]. direct and indirect [5]: the direct path is tought to be a “true” If it’s true that the infant’s self-regulatory competence and general teratogenic drugs effect, including epigenetic mechanisms [6], behavior as well as parental sensitivity and responsiveness are whereas the indirect path is represented by a cascade of social, crucial for the quality of parent–infant interactions which, then it is environmental, maternal (e.g., mother’s psychic state) conditions important to define the neonatal neurobehavioral characteristics of that can interfere with a normal attacchment process [7]. Indeed, at-risk infants in order to formulate appropriate intervention plans newborn behavioral dysegulation may interfere with the first steps for their development [12]. Care plans that center on the neonatal of bonding because the parents may have difficulties to know behavioral organization of these infants facilitate development by the infant’s competencies or to be unable to see them for their enhancing skills, improving parental recognition of their infant’s emotional state: the inadequate capacity of understanding infants’ abilities and promoting the parent–infant relationship [12,13]. signals, the difficulty of effective soothing and regulating the infant The NICU Neonatal Neurobehavioral Scale (NNNS) designed by behavior may lead to increasing maternal stress and to lowered Lester and Tronick, has been used for this purpose [14]. While maternal self-esteem and, consequently, hamper a harmonious Brazelton’s NBAS (Neonatal Behavior Assessment Scale) [15] was mother–infant relation. Similar features emerge in the SGA/IUGR addressed to healty full-term infants, the target of the NNNS is population. These infants exhibit a reduced or instable motor the neurobehavioral assessment of preterm and at-risk infants, activity, lower capacity to respond to external stimuli, self-quieting with an initial focus on drug-exposed infants. For this purpose a difficulties, poor state regulation, more stress/abstinence signs stress/abstinence signs scoring were added to the neurologiocal [3]. These neurobehavioral features reduce, as in drug-addicted and behavioral items. Thus, the NNNS enables the professionals to mothers, the mothers’s ability “to understand” their baby and have a systematic profile of the infant neurobehavioral functioning: to establish a good relation with him/her. Mother–baby bonding spontaneous behavior and states, responses to handling, motor appears at risk even in the populations of adolescent mothers who spontaneous activity, self-shooting efforts and consolability, and are generally emotionally immature [8] and frequently affected by levels of stress. The use of NNNS assessment can help clinicians not psychiatric disorders, such as depression, anxiety, post-traumativ only to identifies neonates who are at risk of behavioral problems stress disorder. The bonding is further threatened since these in childhood, but also to develop individualized management infants are disorganized, excitable, harder to comfort than other protocols for infants at risk in order to prevent or reduce the strength of later childhood problems [5,16]. When the NNNS examination is administered to assess a high-risk infant, it can * Corresponding author. provide information to guide the clinician in planning intervention

0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. G. Calciolari, R. Montirosso / Early Human Development 89S4 (2013) S58–S59 S59 and can also support both infant and family by helping parents References recognize and understand their infant’s behavioral characteristics and needs [5]. NNNS-based intervention has beneficial effects on [1] Lester B, Tronick E, LaGasse L, Seifer R, Bauer C, Shankaran S, Bada, H, Wright neonatal organization of infants at-risk and on the quality in L, Smeriglio V, Lu J, Finnegan L, Maza P. The maternal lifestyle study: Effects of substance exposure during pregnancy on neurodevelopmental outcome in mother–infant interaction skills and maternal self-efficacy in caring 1-month-old infants. Pediatrics 2002;110:1182–92. for these infants. For example, a joint NNNS-based observation [2] Lester BM, Bagner DM, Liu J, La Gasse LL, Seifer R, Bauer CR, Shankaran S, Bada of infants born from drug-addicted mothers was seen to have H, Higgins RD, Das H. Infant neurobehavior dysregulation: Behavior problems a change in women’s ability to interact with their infants, to in children with prenatal substance exposure. Pediatrics 2009;124:1355–60. better organize the environment around the infant, to better [3] Als H, Tronick E, Adamson L, Brazelton TB. The behavior of the full-term but underweight newborn infant. Dev Med Child Neurol 1976;18:590–602. cope with their needs [5]. Moreover, a NNNS-based collaborative [4] Liu J, Bann C, Lester B, Tronick E, Das A, Lagasse L, Bauer C, Shankaran S, consultation help parent or other caregiver to better understand Bada H. Neonatal neurobehavior predicts medical and behavioral outcome. the meaning of their newborn behavior in the first steps of Pediatrics 2009;125:e90–8. attachment process and to promote a positive spiral of interactions [5] Boukydis Z, Lester B. Mother–infant consultation during drug treatment: research and innovative clinical practice. Harm Reduct J 2008;5:6–10. that improve the quality of the mother–infant relation. In this view, [6] Bromer C, Marsit CJ, Armstrong DA, Padbury JF, Lester B. Genetic and an approach called collaborative consultation has been recently epigenetic variation of the glucocorticoid receptor (NR3C1) in placenta and developed by Boukydis [17] in which infant behavior observation infant neurobehavior. Dev Psychobiol 2012 Jun 19. doi: 10.1002/dev.21061 is performed by a trained consultant with parents. This approach [Epub ahead of print]. is effective in helping parents recognize signs of infant stress, [7] Bruschweiler-Stern N. Neonatal interventions for relationship problems. In: Sameroff AJ, McDonough SC, Rosenblum KL (eds), Treating Parent Infant “shut-down” mechanisms, alert-and-available behavior, quality of Relationship Problems. New York: Guilford Press, 2004. motor behavior, facial expressions, posture/muscle tone and also [8] Moraes Barros MC, Guinsburg R, Mitsuhiro SS, Chalem E, Laranjeira RR. functions to optimize interactions and avoid overwhelming infants. Neurobehavioral profile of healthy full-term newborn infants of adolescent Moreover, the use of NNNS and the collaborative consultation mothers. Early Human Dev 2008;84: 281–7. [9] Bruschweiler-Stern N. The neonatal moment of meeting. Buiding the dialogue, promote a positive collaboration relationship between the clinician streghtening the bond. Adolesc Psychiatr Clin N Am 2009;18:533–44. and family. [10] Papousek HM. Intuitive parenting: A dialectic counterpart to the infant’s The possibility to assess which infants are most likely to show integrative competence. In: Osofsky J. (ed), Handbook of Infant Development, later developmental deficits is an critical aspect for a preventive 2nd edition. New York: Wiley, 1987. approach in neonatal period [4,12]. Consequently, the neonatal neu- [11] Sameroff AJ. Ports of entry and dinamics of mother–infants interactions. In: Sameroff AJ, McDonough SC, Rosenblum KL (eds), Treating parent infant robehavioral assessment might allow us to identify, in a population relationship problems, New York: Guilford Press, 2004. of infants at risk, which infants are at highest risk. This would make [12] El-Dib M, Massaro AN, Glass P, Alvy H. Neurodevelopmental assessment of the possible to develop preventive intervention programs to reduce or newborn: an opportunity for prediction of outcome. Brain Dev 2011;33:95– ameliorate these potential risks. Further, the possibility to early 105. [13] Boukydis Z. Working with parents and their infants in NICUs setting: use identify infants with special needs would allow to target them to of joint observations and neurobehavioral assessment. Early Chidhood Serv pediatric care, or referral to community-based intervention ser- 2008;2:42–57. vices, possibly reducing costs and using better the limited resources [14] Lester BM, Tronick EZ. NICU Network Neurobehavioral Scale. Pediatrics available. 2004;113:631–5. [15] Brazelton TB. Neonatal behavioral assessment scale. Clin Dev Med 1973;50:1– 66. Conflict of interest [16] Boukydis Z, Bigsby R, Lester BM. Clinical use of the Neonatal Intensive Care Unit Network Neurobehavioral Scale. Pediatrics 2004;113:679–89. The authors have no conflict of interest to declare. [17] Boukydis Z. Collaborative consultation with parents and infants in the perina- tal period. Baltimore, MD: Brookes Publishing Co., 2012. Early Human Development 89S4 (2013) S60–S61

Infants from medically assisted procreation

Maria Gabriella De Luca a,*, Luigi Orfeo a, Anna Casani a, Francesco Cocca a, Concettina Coletta a, Gaetano Di Manso a, Lidia Grappone a, Nicola Pozzi a, Alessandro Scoppa a, Nicola Leccia b, Annalisa Salerno b aNeonatal Intensive Care Unit, Gaetano Rummo Hospital, Benevento, Italy bPhysiopathology of Human Reproduction Unit, Gaetano Rummo Hospital, Benevento, Italy

In the last decades infertility has steadily increased, one in consequences such as aneuploidy and chromosomal abnormalities. every four couples in developing countries has been found to be However it is unclear whether the higher risk of birth defects affected by infertility. About 11% of women aged 15–44 in the after IVF or ICSI is due to parents characteristics. Chromosomal United States are unable to get pregnant. As a result many more abnormalities are more frequently detected in spermatozoa from couples resort to medically assisted procreation (MAP). The most azoospermic and oligospermic men. Deterioration in the quality of simple MAP consists in the introduction of a semen specimen into the ova with advancing maternal age is also responsible for the the uterine cavity (Intrauterine insemination, IUI) by means of a increasing risk of chromosomal abnormalities catheter. Before performing the insemination the semen must be Moreover, the recent increase in incidence of rare genetic im- “washed” in the laboratory, that is the sperm is separated from the printing diseases such as Beckwith-Wiedemann syndrome (BWS) other components of the semen and then concentrated in a small and Angelman syndrome (AS) in children conceived with ART, has volume. According to Centers for Disease Control and Prevention raised concerns for epigenetic effects of ART. The early stage of the definition of Assisted Reproductive Technologies (ARTs) includes mammalian development from fertilization to implantation is a all fertility treatments in which both egg and sperm are handled period in which the global changes in the epigenetic landscape take and it comprises various procedures. In “in vitro fertilization” (IVF) place. Genetic imprinting is the process by which certain genes are an egg is fertilized by sperm outside the body, the zygote is then expressed in a sex-specific manner. Only one allele (maternal or transferred to the patient’s uterus. The Intracytoplasmatic Sperm paternal) is active, and the inactive allele is epigenetically marked Injection (ICSI) is a more complex procedure where spermatozoon by histone modification, methylation or both. A demethylation of is injected directly into the cytoplasm of each oocyte. Zygote the genome occurs during germ cell and early embryonic develop- intrafallopian transfer (ZIFT) and Gamete intrafallopian transfer ment, a process that is sensitive to environmental factors. ART can (GIFT) are less used procedures. Today, over 1% of all babies born in alter the normal imprinting process during many steps. Hormonal the United States every year are conceived using ART. stimulation used to induce superovulation and in vitro maturation Children born via ART are at a higher risk of prematurity and of oocytes can disturb the natural process of remethylation dur- its sequelae, low or very low birth weight, intrauterine growth ing late-stage oocyte maturation. ICSI, in vitro culture of embryos retardation and birth defects. For some authors the risks identified preimplantation and cryopreservation of either gametes of embryos to date do not seem to be associated with the techniques, but rather are further factors that might alter the normal imprinting pro- as being due to parental characteristics and to clinical policies of cess. However little is known about whether these adverse effects transferring more than one embryo at a the time, which in turn are the result of ART or the consequence of parental subfertility. results in higher amounts of multiple pregnancies and deliveries. Male infertility may contribute to epigenetic effects, indeed al- Women who undergo ART procedures are more likely to deliver tered methylation patterns have been found in spermatozoa from multiple-births than those who conceive naturally (25% vs 1%). oligozoospermic men. Multiple births pose substantial risks to both mothers and infants, Italian legislation started in 2005 a National Register collecting including pregnancy complications, preterm delivery, and low birth data from 375 authorized Centers, regarding ART performed cycles. weight infants. That is why a policy of elective single embryo The number of couples who have recurred to an ART treatment transfer (eSET) has been adopted in many countries. has increased from 46,000 in 2005 to almost 68,000 in 2010. The increased risk of birth defects among births conceived with Accordingly to ART National Register last published data, regarding ART as compared with births from spontaneous conception seems 2010: 55 out 357 Centers did not performed any cycles; 302 Centers much more significant in ICSI. It reflects presumably the greater performed 19,707 intrauterine insemination (I level treatment); 174 gamete manipulation. The breaking of the oocyte membrane could out of 302 Centers performed 44,365 IVF/ICSI cycles. lead to injuries of internal structures of the oocyte with serious Of all treated couples, about 1 out of 4 fails to achieve a pregnancy; in 78% of cases pregnancies leads to one or more live births. In 2010 single pregnancies amounted to 12,506 (2.2% of total * Correspondence: Maria Gabriella De Luca, Azienda Ospedaliera Gaetanto Rummo, Via dell’Angelo 1, 82100 Benevento, Italy. Tel./fax: +39 0824-57798. births of the year), while in 2005 they were less of 5000. The 18.8% E-mail address: [email protected] (M.G. De Luca). of ART children were born from multiple pregnancies.

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Table 1 Table 2

Clinical data No. fetuses % Year Started Clinical Single Twin Triplets cycles pregnancies/ET pregnancies pregnancies (%) <32 w 21 6.73 (%) (%) (%) 32–36 w 31 9.93 ≥37 w 260 83.44 2005 46 37.5 73.33 26.66 0 >2500 g 208 66.6 2006 65 26.8 72.72 9 18.8 1500–2500 g 78 25 2007 124 29.4 68 20 12 <1500 g 28 8.9 2008 173 36.3 84.44 13.33 2.22 Abortion 21 6.2 2009 183 40.38 82.53 14.28 3.1 Malformation/genetic diseases * 4 1.1 2010 219 43.93 87.93 10.34 1.7 2011 223 42.8 88.85 5.8 4.3 * 1 Potter syndrome; 1 polycystic kidney; 1 urogenital malformation; 1 Beckwith- 2012 232 44.31 93.58 5.1 1.2 Wiedemann.

The mean age of women requiring ART is rising, a factor that Conflict of interest impacts negatively on the results of the techniques themselves, as > well as the number of cycles from patients 40 years. The authors have no conflict of interest to declare. Our Hospital run a Physiopathology of Human Reproduction Unit which has treated 1149 couples from 2007. Cumulative pregnancy rates is >40.5%/embryo transfer (Table 1). Multiple live-birth Selected bibliography deliveries ranged from 26% in 2005 to 0.063% in 2012 (Table 2). [1] Centers for Disease Control and Prevention. Assisted Reproductive Technology From January 2008 to December 2012, 153 very low birth weight Surveillance – United States, 2009 MMWR 2012;61(SS-7):16. (VLBW) newborns were admitted to our Neonatal Intensive Care [2] Davies JM, et al. Reproductive Technologies and the Risk of Birth Defects. N Unit, among these 40 (26.5% of total VLBW) were ART conceived Eng J Med 2012;366:1803–13. children and all of them were multiple births. The risk of birth [3] Dupont C, Sifer C A review of outcome data concerning children born following assisted reproductive technologies. Obstet Gynecol 2012;2012:405382 defects associated with ART was not different from the risk with [4] Iliadou AN, et al. Epigenetics and assisted reproductive technology. J Int Med spontaneous conception. The mean gestational age and birth weight 2011;270:414–20. were lower in ART children. We do not know to what extent our [5] Messerschmidt A et al. Perinatal outcome of preterm infants <1500 g after IVF data are influenced by the multiple births with their corresponding pregnancies compared with natural conception. Arch Dis Child Fetal Neonatal risks. On the contrary mortality and severe morbidities such as 2010;95:F225–9. [6] Scaravelli G, et al. Assisted reproductive technology in Italy: results from the bronchopulmonary dysplasia, severe brain injuries (intraventricular Italian ART Register 2005–2007. Minerva Ginecol 2012;64(6):521–9. haemorrhages gr. III–IV, periventricular leucomalacia), retinopathy [7] van Montfoort AP, et al. Assisted reproduction treatment and epigenetic of prematurity gr. III–V were similar in both groups. In conclusion inheritance. Hum Reprod Update 2012;18(2):171–97. ART should aim to promote singleton pregnancy in order to reduce multiple birth associated risks. Early Human Development 89S4 (2013) S62–S63

Discordant twins: obstetric risk factors and neonatal outcomes

Antonio Alberto Zuppa *, Valentina Cardiello, Piero Catenazzi, Annamaria D’Antuono, Maria Cavani, Costantino Romagnoli

Division of Neonatology, Department of Pediatrics, Catholic University of Sacred Heart, Rome, Italy

1. Introduction collected: maternal age, spontaneous or ART induced pregnancy, monochorionicity, diabetes, hypertension, pre-eclampsia, eclamp- After the 80s, there has been a significant increase in multi- sia. Neonatal clinical data were collected as well: sex, gestational ple pregnancies, particularly bigemine ones, by nearly 70%: this age (GA), birth weight (BW), length, head circumference (HC), mode phenomenon is mainly due to the increase of the use of assisted of delivery, small for gestational age (SGA), respiratory disease reproductive techniques (ART) [1]. (Respiratory Distress Syndrome – RDS, Wet Lung Syndrome, use This increase was also associated with a parallel increase in of surfactant, Mechanical Ventilation – MV, High Frequency Oscil- the frequency of discordant twin (DT) pregnancies. Incidence of DT latory Ventilation – HFOV, Continuous Pulmonary Airway Pressure varies between 12% and 32%, based on the cut-off values chosen by – CPAP, oxygen-therapy), anemia (that needed one or more blood the authors [2,3]. transfusion), metabolic disease (hypoglycemia, hypoalbuminemia), In most studies, the cut-off value is a difference of 15–25% in jaundice (requiring phototerapy, exchange transfusion, intravenous birth weight; in fact a lower degree of birth weight discordance immunoglobulin), sepsis, necrotizing enterocolitis – NEC, patent can be considered physiological. The definition of discordance that ductus arteriosus – PDA (treated with medical or surgical therapy), is widely used in the literature, is a weight difference between the neurological disease (intraventricular hemorrhage – IVH, apnea), twins greater than 20% [4]. malformations. Neonatal mortality has been defined as death in the Risk factors that increase DT incidence are of maternal, fetal, and first 28 days of life. placental origin. The role of most of these factors is controversial. Statistical analysis were performed, normally distributed data The maternal risk factors are: the recurrence to ART, high maternal are presented as mean ± standard deviation (SD), and Student’s t age, multiparity, and eclampsia. Monochorionicity, different sex test has been applied to study differences between DT and CT. The between the fetuses, and CMV congenital infection are considered chi square test was used to compare categorical variables. Statistical fetal risk factor whereas velamentous insertion of the umbilical analysis was performed using Graphpad Prism 4 software. cord is the most important placental factor [3,5,6]. Many studies have already shown as DT newborns are more 3. Results likely to present adverse outcomes at the admission to the NICU [7,8]. However only a few studies have analyzed systematically A total of 91 sets of twins (182 infants) were included in the risk factors and neonatal outcomes. Therefore the aim of this study. Twins were divided into the DT group, which included 35 observational cohort study is to evaluate DT incidence, mortality sets of twins (70 infants), and the CT group, which included 56 and morbidity rates, risk factors, and neonatal complications of DT sets of twins (130 infants). The incidence of discordant twins in and concordant twin (CT) pregnancies in a neonatal population of a the whole bigemine population of the Agostino Gemelli University tertiary center. Hospital is 37.8%. The incidence of DT in the population considered, admitted in NICU, in this study was 38.5%. The percent difference in 2. Material and methods birth weight for CT was 9.2% ± 5.3%, while DT differed from each other by 31.9% ± 10.3% (p < 0.001). Observational cohort study on newborns born to twin pregnan- As for perinatal and demographic characteristics (Table 1) birth cies admitted to the NICU of the A. Gemelli University Hospital from weight in the DT group was significantly lower than that in the CT January 2011 to May 2013. The birth weight discordance was evalu- group (1549 ± 579 g vs 1860 ± 384 g; p < 0.0001). Moreover, the ated for each pair of twins according to the formula 100 × (X − Y)/X, duration of hospitalization in the DT group was significantly longer where X is the weight of the heavier twin, Y of the lighter one. The than that in the CT group (24 ± 22 days vs 16 ± 14 days; p = 0.004). cut-off we used to define discordance is a birth weight difference The incidence of SGA in the DT group was also significantly higher ≥20% [3,4]. Following this criteria we divided the twins into two than in the CT group (37.1% vs 8%; p < 0.0001). No significant groups: DT (≥20% weight difference) and CT (<20% weight differ- differences were found in other perinatal characteristics. ence). Clinical information about mother’s obstetric story have been As regards to neonatal clinical outcomes (Table 2), the neonatal pathology frequencies are always higher in the DT group. This difference was significant for anemia, RDS (in particular as regards * Corresponding author. to the need of Surfactant therapy, CPAP, duration of MV, HFOV,

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Table 1 This study found that, in our population, use of ART, pregnancy- General features. related pathologies and monochorionicity were not significant risk CT, n =56 DT, n =35 p-value factors for the occurrence of DT. These data differs from previous (61.5%) (38.5%) reports [6]. Gender (M) 54 (48.2%) 34 (48.6%) NS The incidence of mortality and of the most common neonatal Cesarean delivery 54 (96.4%) 32 (91.4%) NS complications of DT was higher than CT; particularly as regards ± ± Mean gestational age (weeks) 33.1 2.2 32.3 3.1 NS anemia, respiratory disease, sepsis and PDA [5,6]. SGAv 9 (8.0%) 26 (37.1%) <0.0001 As previously reported the worst outcomes of DT twins can be Mean birth weight(g) 1860.2 ± 384.3 1541.7 ± 579.6 <0.0001 Mean length (cm) 42.8 ± 3.0 40.6 ± 4.1 NS related to the lower birth weight and more frequent intrauterine Mean HC (cm) 30.7 ± 1.9 29.6 ± 2.5 NS growth retardation, as confirmed by the results of this work [8]. Mean stay duration (days) 16.3 ± 14.1 24.0 ± 22.0 0.0045 A multivariate analysis and a wider population in a multicentric ± ± Mean maternal age (years) 33.1 3.8 34.5 4.1 NS study could help strengthen and confirm these results. ART (FIVET) 12 (21.4%) 4 (11.4%) NS ART (ICSI) 10 (17.8%) 6 (17.1%) NS Data available in the literature and from our study strongly Monochorionic pregnancy 12 (21.4%) 4 (11.4%) NS support the adoption of protocols aimed at reducing or eliminat- Pregnancy-induced hypertension 5 (8.9%) 4 (11.4%) NS ing risk factors for discordance, through careful control prenatal Gestational diabetes mellitus 8 (14.3%) 3 (8.6%) NS sonographic evaluation of fetal growth and aimed at the timing of Opposite sex 15 (26.8%) 10 (28.6%) NS the delivery. Moreover, referral to tertiary level centers should be CT, concordant twins; DT, discordant twins. Values are expressed as n (%). considered for pregnancies at risk of discordance. Therefore it is essential to reduce mortality and sequelae of Table 2 DT, careful monitoring and timely treatment of the common Neonatal outcomes. complications that arise during hospitalization. CT, n = 56 (112) DT, n =35(70) p-value (61.5%) (38.5%) Conflict of interest Anemia 5 (4.5%) 15 (21.4%) 0.0004 RDS 22 (19.6%) 22 (31.4%) NS The authors have no conflict of interest to declare. Wet lung syndrome 16 (14.3%) 8 (11.4%) NS Apnoea 22 (19.6%) 21 (30%) NS References Surfactant 13 (11.6%) 20 (28.6%) 0.0039 Mechanical ventilation 10 (8.9%) 12 (17.1%) NS [1] Lee YM, Cleary-Goldman J, D’Alton ME. The impact of multiple gestations on Mean duration (hours) 13.4 ± 16.3 72.9 ± 147.1 <0.0001 late preterm (near-term) births. Clin Perinatol 2006;33(4):777–92. HFOV 3 (2.7%) 5 (7.1%) NS [2] Blickstein I. Growth aberration in multiple pregnancy. Obstet Gynecol Clin Mean duration (hours) 70.3 ± 54.1 296.7 ± 502 <0.0001 North Am 2005;32(1):39–54. CPAP 20 (17.9%) 25 (35.7%) 0.006 [3] Miller J, Chauhan SP, Abuhamad AZ. Discordant twins: diagnosis, evaluation Mean duration (hours) 83.4 ± 80.8 136.9 ± 132.7 0.0009 and management. Am J Obstet Gynecol 2012;206(1):10–20. Oxigen therapy 36 (32.1%) 28 (40%) NS [4] American College of Obstetricians and Gynecologists Committee on Practice Mean duration (hours) 59.1 ± 90.2 190.4 ± 392.6 0.0008 Bulletins-Obstetrics; Society for Maternal-Fetal Medicine; ACOG Joint Editorial Hypoglycemia 4 (3.6%) 7 (10%) NS Committee. ACOG Practice Bulletin #56: Multiple gestation: complicated twin, Hypoalbuminemia 5 (4.5%) 4 (5.7%) NS triplet, and high-order multifetal pregnancy. Obstet Gynecol 2004;104(4):869– Pathological jaundice 51 (45.5%) 34 (48.6%) NS 83. Sepsis 10 (8.9%) 13 (18.6%) <0.05 [5] Mazher SB, Kanwal S. Twin birth weight discordance: associated factors and NEC 1 (0.9%) – (–) / outcome. J Coll Physicians Surg Pak 2010;20(6):391–4. IVH 2 (1.8%) 4 (5.7%) NS [6] Zhang XR, Liu J, Zeng CM. Perinatal risk factors and neonatal complications PDA 8 (7.2%) 12 (17.1%) 0.03 in discordant twins admitted to the neonatal intensive care unit. Chin Med J Malformations 4 (3.6%) 5 (7.1%) NS (Engl) 2013;126(5):845–9. CT, concordant twins; DT, discordant twins. Values are expressed as n (%). [7] Alam Machado Rde C, Brizot Mde L, Liao AW, Krebs VL, Zugaib M. Early neonatal morbidity and mortality in growth-discordant twins. Acta Obstet Gynecol Scand 2008;88(2):167–71. [8] Frezza S, Gallini F, Puopolo M, De Carolis MP, D’Andrea V, Guidone PI, Luciano CPAP and oxygen-therapy), sepsis and PDA. Neonatal mortality was R, Zuppa AA, Romagnoli C. Is growth-discordance in twins a substantial risk observed in the DT group only and accounted for 8.5% of the factor in adverse neonatal outcomes? Twin Res Hum Genet 2011;14(5):463–7. population.

4. Discussion

The DT incidence in the our population (37.8%) is higher than literature [2,3], because the Agostino Gemelli University Hospital is a tertiary level centers, where there are high-risk pregnancies. Early Human Development 89S4 (2013) S64–S65

Newborn from mother with disorders of glucose homeostasis

Enrico Bertino *, Melissa Raia, Francesco Cresi, Elena Maggiora, Alessandra Coscia, Giulio Gilli

Neonatal Unit, Department of Public and Pediatric Health Science, University of Turin, Turin, Italy

1. Introduction binemia, and need for intensive neonatal care) [3]. However no obvious thresholds at which risks increased more sharply were Normal pregnancy is a state of insulin resistance. To spare identified. glucose for the developing fetus, the placenta produces several Depending on these different diagnostic criteria, reported fre- hormones, that antagonize insulin and shift the main energy source quencies of GDM vary widely, between 1% and 14% of pregnancies from glucose to ketones and free fatty acids. In normal pregnancy, around the world [2]. the increased insulin resistance leads to an increase glucose supply U.S. studies of the racial/ethnic distribution of GDM have shown to the fetus, thereby satisfying the nutrient requirements for significant variation in its prevalence, with higher rates among fetal growth development [1]. Gestational diabetes mellitus (GDM) Asian, Hispanic, Native American, and African American women, results when the insulin secretion does not adequately counteract compared with non-Hispanic white women. Variations in the thedegreeofinsulinresistance[2]. incidence of GDM, as well as perinatal outcomes, by race/ethnicity The most important alteration of glucose homeostasis during may be related to genetic factors that affect insulin resistance, pregnancy is represented by diabetes mellitus (DM). This disorder diet, lifestyle, sociocultural factors, healthcare access/use, or even is classified in “pregestational or overt diabetes”, type 1 and provider discrimination [6]. type 2 diabetes mellitus (PGDM), and gestational diabetes mellitus (GDM). 2. Effects on fetus and newborn In 2010, the International Workshop-Conferences on GDM have defined the condition as “any degree of glucose intolerance with In 1952, Pedersen documented increased body weight in infants onset, or first recognition, during pregnancy”, (whether or not of diabetic mothers compared with control subjects. He explained insulin is used for treatment and whether or not hyperglycemia the large deposition of body fat in this “diabetic fetopathy” as a con- persists after pregnancy) [3]. This definition has some limitations: sequence of the fetal hyperinsulinemia due to the hyperglycemia of in fact, many pregnant women with previously unrecognized type the mother transmitted to the fetus [1]. 2 diabetes may be mistakenly diagnosed as having GDM [4]. The Today, 60 years later, it is well known that fetal hyperglycemia, debated issue of identification of pregnant women with likely, but hyperinsulinemia, or the combinationofbothleadstothepatho- not previously diagnosed, DM is of utmost importance because the logic conditions seen in the late gestation fetus and in the neonate. increased risk of complications in the mother (like nephropathy Even if perinatal care has improved in the last decades, the risk of and retinopathy) and increased risk of anomalies in the offspring perinatal mortality and morbidity still exists [8]. [2]. The Italian guidelines, revised in 2011, pay particular attention Babies of women with GDM are also at higher risk of having to the differentiation between overt diabetes diagnosed for the first complications other than macrosomia, such as respiratory dis- time during pregnancy and classic GDM [5]. tress syndrome, hypoglycemia, hyperbilirubinemia, cardiomyopa- Although the impact of GDM on maternal and fetal health thy, hypocalcemia, hypomagnesemia, polycythemia, hyperviscosity. has been since long recognized, universal consensus on screening, Macrosomic and LGA infants are at increased risk of injury diagnostic methods, and thresholds for GDM is still lacking. These during birth, such as shoulder dystocia, asphyxia, bone fractures, disagreements are also the results of the uncertainties about the and nerve palsies [2]. effects of maternal blood glucose levels on the fetus and the Maternal serum glucose, which is the main excess nutrient newborn. in these circumstances, freely crosses the placenta, while maternal The recent HAPO study was designed to clarify risks of adverse insulin does not. As a result of the thus induced fetal hyperglycemia, outcome associated with different degrees of maternal glucose the fetal pancreas increases levels of insulin, which acts as a growth intolerance less severe than those with overt diabetes during hormone and promotes growth and adiposity in the fetus [8]. pregnancy. This study demonstrated a continuous association of A systematic review and meta-analysis of randomized clinical maternal glucose levels with primary outcomes (e.g., birth weight trials (RCT) concluded that specific treatment for GDM, mostly >90th centile, neonatal hypoglycemia) and secondary outcomes consisting of treatment to lower blood glucose concentration, (e.g., preterm delivery, shoulder dystocia/birth injury, hyperbiliru- alone or with special obstetric care, seems to lower the risk of macrosomia, LGA and shoulder dystocia [9]. Also the risk of SGA neonates is increased in infants of diabetic * Corresponding author. mothers, especially in case of type 1 diabetes: a good metabolic

0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. E. Bertino et al. / Early Human Development 89S4 (2013) S64–S65 S65 control of diabetes during pregnancy reduces this risk [10]. As determine: (1) cost-effective therapeutic strategies for treatment; compared to studies published in the ’90s, the most recent Italian (2) optimal glycemic treatment targets; (3) appropriate follow-up anthropometric charts (INeS charts) [11], show a narrowing of birth of mothers to determine risks for later development of diabetes, weight distribution of term infants, which could be partly explained other metabolic disorders, or CVD risk factors; and (4) follow-up of by a better management of diabetes. children to assess potential associations of maternal glycemia with The risk of major congenital malformations (MCM) is increased long-term risks of obesity, altered glucose metabolism, and CVD in women with undiagnosed PGDM probably due to unrecognized risk factors [2]. maternal hyperglycemia during the time of organogenesis. Hyper- Among the preventive interventions, should be considered pos- glycemia is a known teratogen with detrimental effects on the fetal sible dietary and lifestyle interventions on modifiable risk factors heart, kidney, musculoskeletal system and SNC. Pre-pregnancy care that include overweight or obesity, physical inactivity or sedentary for women with PGDM type 1 or type 2 is effective in lowering lifestyle, excessive weight gain during pregnancy, low fibre and incidence of MCM, and perinatal mortality, and in reducing mater- high glycemic load diet [2], that constitute a priority action to nal HbA1C in the first trimester of pregnancy. Whether such risk is improve short and long term neonatal outcomes. increased in GDM is still debated. A recent meta-analysis showed that the risk of MCM is slightly higher also in women with GDM, Conflict of interest but much lower than in women with PGDM [12]. Maternal obesity is a well known risk factor for GDM, preterm The authors have no conflict of interest to declare. delivery, and adverse neonatal outcomes (macrosomia, birth de- fects, stillbirth). Both maternal GDM and obesity are independently References associated with adverse pregnancy outcomes. Their combination has a greater impact than either one alone. Concerted efforts are [1] Barthell JE, Georgieff MK. Infants of Diabetic Mothers. In: Buonocore G, needed to provide prenatal counseling for obese women, encourag- Bracci R, Weindling M (eds), Neonatology. A Practical Approach to Neonatal ing them to aim for a reasonable weight loss before pregnancy [13]. Diseases. Italy: Springer-Verlag; 2011;379–86. Also, antenatal lifestyle interventions are associated to a reduced [2] Han S, Middleton P, Crowther CA. Exercise for pregnant women for preventing gestational diabetes mellitus. Cochrane Database Syst Rev 2012(7). prevalence of GDM in the overweight and obese pregnant woman [3] International Association of Diabetes and Pregnancy Study Groups. Interna- [14]. tional Association of Diabetes and Pregnancy Study Groups recommendations on the Diagnosis and Classification of Hyperglycemia in Pregnancy. Diabetes 3. Long-term outcomes Care 2010;33:676–82. [4] Reece EA, Leguizamón G, Wiznitzer A. Gestational diabetes: the need for a common ground. Lancet 2009;373:1789–97. Infants born LGA have a higher risk of developing the metabolic [5] Linea Guida: Gravidanza Fisiologica (aggiornamento 2011). http://www.snlg- syndrome in childhood, adolescence and adulthood. Development iss.it/cms/files/LG_Gravidanza.pdf of the metabolic syndrome during childhood predicts adulthood [6] Nguyen BT, Cheng YW, Snowden JM, Esakoff TF, Frias AE, Caughey AB. The type 2 DM at 25 to 30 years of age. These health problems may effect of race/ethnicity on adverse perinatal outcomes among patients with gestational diabetes mellitus. Am J Obstet Gynecol 2012;207:322e1–6. repeat across generations [2]. [7] HAPO Study Cooperative Research Group. Hyperglycemia and Adverse Preg- This increased risk has certainly a genetic component, well nancy Outcome (HAPO) Study: associations with neonatal anthropometrics. known in the case of DM type 2, however, emerging evidence Diabetes 2009;58(2):453–9. shows that prenatal exposure to a diabetic intrauterine environ- [8] Vrachnis N, Antonakopoulos N, Iliodromiti Z, Dafopoulos K, Siristatidis C, ment contributes to the development of morbidity in adolescence Pappa KI, et al. Impact of maternal diabetes on epigenetic modifications leading to diseases in the offspring. Exp Diabetes Res 2012; 2012:1–6. and adulthood through epigenetic modifications. It must also be [9] Horvath K, Koch K, Jeitler K, Matyas E, Bender R, Bastian H, et al. Effects considered the protective effect of breast feeding against the of treatment in women with gestational diabetes mellitus: systematic review development of diabetes in the offspring of diabetic mothers [8]. and meta-analysis. BMJ 2010;340:1–18. [10] El-Masry SA, El-Ganzoury MM, El-Farrash RA, Anwar M, Abd Ellatife RZ. Size at birth and insulin-like growth factor-I and its binding protein-1 among 4. Conclusions infants of diabetic mothers. J Matern Fetal Neonatal Med 2013;26(1):5–9. [11] Bertino E, Spada E, Occhi L, Coscia A, Giuliani F, Gagliardi L, et al. Neonatal According to the DALI Core Investigator Group, a Europe-wide anthropometric charts: the Italian neonatal study compared with other agreement on screening approaches and diagnostic standards for European studies. J Pediatr Gastroenterol Nutr 2010;51(3):353–61. GDM could lead to a better detection and treatment, improved out- [12] Balsells M, García-Patterson A, Gich I, Corcoy R. Major congenital malforma- tions in women with gestational diabetes mellitus: a systematic review and comes for women and children, and a strengthened evidence base. meta-analysis. Diabetes Metab Res Rev 2012;28(3):252–7. There is an urgent need for well-designed research that can inform [13] Catalano PM, McIntyre HD, Cruickshank JK, McCance DR, Dyer AR, Metzger BE, decisions on best practice in GDM screening and diagnosis [7]. et al. The hyperglycemia and adverse pregnancy outcome study: associations Close monitoring and treatment of gestational diabetes are effec- of GDM and obesity with pregnancy outcomes. Diabetes Care 2012;35(4):780– 6. tive in improving pregnancy and neonatal outcomes [9]. However, [14] Oteng-Ntim E, Varma R, Croker H, Poston L, Doyle P. Lifestyle interventions according a Consensus Panel of the IADPSG it is likely that addi- for overweight and obese pregnant women to improve pregnancy outcome: tional well-designed RCT and other clinical studies will be needed to systematic review and meta-analysis. BMC Med 2012;10:1–15. Early Human Development 89S4 (2013) S66–S67

Babies born to mothers with thyroid disease

Paolo Ghirri *, Francesca Dini, Antonio Boldrini

Division of Neonatology and Neonatal Intensive Care Unit, University of Pisa, Pida, Italy

Thyroid dysfunctions are the second most common endocrine days of life should suffice. However babies born to mothers with disorders complicating pregnancy after diabetes mellitus. Mater- autoimmune thyroiditis may develop persistent hyperthyrotropine- nal thyroid dysfunctions are associated with miscarriage, pre- mia requiring thyroid hormone replacement therapy even if no eclampsia, eclampsia, placental abruption and preterm delivery. As TRab are detectable and TSH levels are normal at 3–4 days of life; in maternal thyroxine is essential for fetal neurodevelopment, until these cases a retesting of TSH levels on filter paper at 3–4 weeks of the foetal thyroid gland starts to produce thyroid hormones in the life is indicated. If maternal hypothyroidism is due to pre-pregnancy second trimester of gestation, reduced availability of maternal thy- treatment for Graves’ disease (radioiodine, surgery) the newborn is roid hormones may impair neurogical development of the foetus. at risk of neonatal thyrotoxicosis if maternal TRab are present. It has been reported decreased IQ in infants born to mothers with Overt maternal hyperthyroidism occurs in approximately 0.2– hypothyroidism or hypothyroxinemia. 0.4% of pregnancies and is defined as a serum TSH level below Maternal hypothyroidism, defined as an elevated TSH level with the trimester-specific reference range with elevated levels of free a decreased (overt) or normal (subclinical) levels of circulating free T4 and T3. As untreated overt hyperthyroidism during pregnancy T4, is common during pregnancy with a prevalence ranging from has been shown to be associated with miscarriage, pre-eclampsia, 0.5% (overt) to 2.5% (subclinical). Serum TSH levels, using trimester- preterm birth, fetal growth restriction and increased perinatal mor- specific reference ranges (first trimester <2.5 mIU/ml, second and bidity and mortality, treatment during pregnancy is mandatory. third trimester <3 mIU/ml), is a reliable test of maternal thyroid Subclinical maternal hyperthyroidism (reduced TSH levels with function in pregnancy. As untreated overt hypothyroidism during normal levels of free T4 and T3) is not associated with an in- pregnancy has been shown to be associated with an increased creased risk of adverse events in the mother and the fetus, and risk of miscarriage, preterm birth, low birth weight and impaired treatment during pregnancy is not recommended. The most com- fetal neurocognitive development, treatment during pregnancy is mon etiology is Graves’ disease; other causes include gestational mandatory. Treatment of subclinical hypothyroidism during preg- transient thyrotoxicosis, toxic adenoma, thyroiditis or excessive nancy is not universally recommended however a recent paper by hormone intake. Neonatal Thyrotoxicosis due to maternal Grave’s Negro et al. has shown that treatment reduces the occurrence of disease is caused by the transplacental passage of thyroid stim- adverse outcomes in the mother and fetus. The most common eti- ulating antibody (TRab) present in mothers with Graves’ disease. ology of maternal hypothyroidism is Hashimoto’s thyroiditis; other Consequentely in babies born to mothers with active or inactive causes include prior treatment for hyperthyroidism (radioactive hyperthyroidism or family history of activating mutations of TSH iodine or thyroidectomy) and iodine deficiency. The mother with receptor (rare), FT4, TSH and TRab levels should be evaluated on Hashimoto’s thyroiditis may have TSH receptor blocking or rarely cord blood at birth; a physical examination for signs of thyrotox- stimulating antibodies (TRab) causing transient neonatal hypo or icosis and presence of goitre should also be performed. Newborns hyperthyroidism. Maternal high TRab titres are associated to an are at high risk of neonatal thyrotoxicosis if the mother has clini- higher risk of hypo /or hyperthyroidism but the antibody titre does cal thyrotoxicosis requiring thionamide in the third trimester, has not discriminate blocking from stimulating antibodies that may also raised TRab during pregnancy, not assessed TRab, family history be present at the same time. If maternal TRab titre is elevated or of TSH receptor mutation or evidence of fetal thyrotoxicosis. High unknown cord blood should be evaluated at birth for TRab, FT4 risk newborns should be kept in hospital and observed checking and TSH levels. A physical examination (heart rate and presence of again FT4 and TSH levels at 2–3 days of life; if the baby if well goitre) should always be performed. In case of elevated TRab titre, without signs of thyrotoxicosis he/she can be discharged even with the newborn must be checked at 10–14 days of age for clinical pending results. Repeat the physical examination checking again signs of hypo or hyperthyroidism and TSH and FT4 levels should be FT4 and TSH at 10–14 days of life. If a neonatal hyperthyroidism is measured again; a treatment with tiroxine (10 mcg/kg/day) should present treatment with metimazole (0.5–1 mg/kg/day) given every be considered in case of elevated TSH and reduced FT4 levels. 8 hours, should be started. As thionamides may take 24–48 hours If no TRab are detectable on maternal blood or if the maternal to have effect, release of thyroid hormones could be blocked with hypothyroidism is due to a congenital cause (aplasia or hypoplasia iodine (lugol solution 5% Kl) 1 drop (8 mg iodide) every 8 hour. of the thyroid gland) the evaluation of TSH on filter paper at 3–4 Cardiovascular symptoms (severe tachycardia and arrhythmia) may require the use of propranolol. Initial hypo- or euthyroidism may be followed by thyrotoxicosis if the mother is taking thionamides * Corresponding author. at the time of delivery or if blocking and stimulating antibodies

0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. P. Ghirri et al. / Early Human Development 89S4 (2013) S66–S67 S67 co-exist. Elevated FT4 levels during fetal life may suppress the fe- [4] Ogilvy-Stuart A, Midgley P. Investigation and management of babies of tal hypothalamic–pituitary–thyroid axis causing a transient central mothers with thyroid disease. In: Ogilvy-Stuart A, Midgley P (eds), Practical hypothyroidism (low TSH, low FT4). Neonatal Endocrinology. Cambridge University Press, 2006; pp 143–5 [5] Rovelli R, Vigone MC, Giovanettoni C, et al. Newborns of mothers affected As maternal thyroxine is essential for fetal neurodevelopment by autoimmune thyroiditis: the importance of thyroid function monitoring in mainly during the first months of pregnancy, until the fetal thyroid the first months of life. Ital J Pediatr 2010;36:24. gland starts to produce thyroid hormones in the second trimester of [6] Brown RS, Bellisario RL, Botero D, et al. Incidence of transient congenital gestation, an universal maternal TSH screening has been proposed. hypothyroidism due to maternal thyrotrophin receptor-blocking antibodies in over one million babies. J Clin Endocrinol Metab 1996;81:1147–51. This should be ideally performed in the preconceptional period or [7] Chang DLF, Pearce EN. Screening for maternal thyroid dysfunction in preg- as soon as the pregnancy is recognised. Recent studies support nancy: a review of the clinical evidence and current guidelines. J Thyroid Res universal screening of pregnant women as a cost-effective measure 2013;2013:851326. compared to screening of high-risk women or not screening at all. [8] Negro R, Schwartz A., Gismondi R, et al. Universal screening versus case finding for detection and treatment of thyroid hormonal dysfunction during pregnancy. J Clin Endocrinol Metab 2010;95(4):1699–1707. Conflict of interest [9] Alexander EK, Marqusee E, Lawrence J et al. Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with The authors have no conflict of interest to declare. hypothyroidism. N Engl J Med 2004;351(3):241–9. [10] Feingold SB, Brown RS. Neonatal thyroid function. NeoReviews 2010;11(11): e640–6. References [11] Stagnaro-Green A. Maternal thyroid disease and preterm delivery. J Clin Endocrinol Metabol 2009;94(1):21–5. [1] De Groot L, Abalovich M, Alexander EK, et al. Management of thyroid [12] Medici M, de Rijke YB, Peeters RP, et al. Maternal thyroid hormone parame- dysfunctions during pregnancy and postpartum: an endocrine society clinical ters during early pregnancy and newborn thyroid hormone parameters: the practice guideline. J Clin Endocrinol Metabol, 2012;97(8):2543–65. generation R study. J Clin Endocrinol Metab 2012;97(2):646–52. [2] Haddow JE, Palomaki GE, Allan WC, et al. Maternal thyroid deficiency during [13] Vaidya B, Anthony S, Bilous M, et al. Brief report: detection of thyroid pregnancy and subsequent neuropsychological development of the child. N dysfunction in early pregnancy: universal screening or targeted high-risk case Engl J Med 1999;341(8):549–55. finding? J Clin Endocrinol Metab 2007;92(1):203–7. [3] Pop VJ, deVries E, van Baar AL, et al. Low maternal free thyroxine concen- [14] Dosiou C, Barnes J, Schwartz A, et al. Cost-effectiveness of universal and trations during early pregnancy are associated with impaired psychomotor risk-based screening for autoimmune thyroid disease in pregnant women, J development in infancy. Clin Endocrinol 1999;50(2):147–55. Clin Endocrinol Metab 2012;97(5):1536–46. Early Human Development 89S4 (2013) S68–S69

Newborn of mother with syphilis in pregnancy

P. Valentini

Pediatrics, University of the Sacred Heart, Rome, Italy

Syphilis infection during pregnancy still represents a worldwide five years preceding the pregnancy. On average, pooled estimates public health problem. of fetal loss or stillbirth, neonatal death and prematurity or low In 2008, the World Health Organization (WHO) estimated that birth weight showed significantly higher rates among the offspring 1.86 million cases of syphilis occur globally among pregnant women of women with syphilis than among the offspring of women each year and that a large proportion of them are untreated or without syphilis. The absolute differences were 21% for fetal loss inadequately treated. Between 1990 and 2009, 1,001 cases of or stillbirth, 9% for neonatal death and 6% for prematurity or congenital syphilis have been reported from 24 countries, but low birth weight. Signs and symptoms of syphilis were found in only three countries have provided data on congenital syphilis for 15% of the infants born to untreated women with syphilis. The that period (Czech Republic, Latvia and United Kingdom), while a frequency of any adverse pregnancy outcomes was 52% higher variable number of countries have provided data on 2006–2009: among women with syphilis than among women without syphilis. in this last period the majority of the cases were reported by Another study has estimated that, in the absence of effective Bulgaria, Portugal and Spain. In 2009, 18,279 syphilis cases have treatment, 25% of pregnancies will result in a 2nd trimester been reported from 28 European Union/European Economic Area miscarriage or stillbirth, 11% of pregnancies in a neonatal death at (EU/EEA) Member States with an overall rate of 4.5 per 100,000 term, 13% in a preterm or low birth weight infant and an additional population and the majority of cases of congenital syphilis was 20% with clinical signs of congenital syphilis Hence, of the 75% reported from Bulgaria (30 cases), Portugal (13), Italy (12), Spain of the pregnancies resulting in a liveborn infant, 15% would be (11) and Romania (7 cases): the overall rate was 3.5 per 100,000 expected to result in a neonatal death at term and 17% in a preterm live births, with the highest rates observed in Bulgaria (37.1 per or low birth weight infant, with a further 27% of babies who 100,000), Portugal (13.1), Lithuania (10.9) and Latvia (9.2). In a survive to 28 days developing clinical signs of congenital syphilis. recent Italian study a much higher (83%) seroprevalence of syphilis Prevention of congenital syphilis begins with an accurate screening in foreign-born pregnant women, mostly from Eastern Europe, of the pregnant women: the American College of Obstetricians and was found, but there were significant differences (p < 0.04) among Gynecologists and the American Academy of Pediatrics recommend Italian and foreign-born women regarding antenatal care status prenatal syphilis screening at the first prenatal visit and again at because 25% of Italian mothers had no antenatal syphilis screening 32–36 weeks, if the woman is at risk for syphilis. CDC recommends versus 12% of immigrant women, probably in according to an that all women should be screened serologically for syphilis at increasing use of national health services by immigrants; thus, the first prenatal visit and, for patients at high risk, during the although the seroprevalence of syphilis in pregnancy was much third trimester and at delivery. Moreover, any woman who delivers higher in foreign-born mothers, the risk of having an infected baby a stillborn infant after 20 weeks’ gestation should be tested for was the same in Italian and immigrant women. syphilis. The Italian Guidelines of Istituto Superiore di Sanità for The spectrum of perinatal syphilis is similar to that of other Physiological Pregnancy (2011) stated that serological screening for infections in which infecting organism spreads hematogenously syphilis should be offered to all pregnant women during the first from the mother to involve placenta and infect the fetus. Damage and the third trimester of pregnancy. to the fetus presumably depends on the stage of development at Congenital syphilis has traditionally been divided into early and which infection has taken place and the time that has elapsed before late stages. Clinical manifestations appearing within the first 2 years treatment. Primary, secondary, early latent, and in some cases late of life are designated early. The diagnosis of early congenital syphilis latent, stage maternal syphilis infection can lead to haematogenous should be pursued in any infant who is born prematurely if another spread to the foetus, resulting in a systemic inflammatory response. explanation of prematurity is not forthcoming or if unexplained Although spirochetes can cross the placenta to the foetus from early hydrops fetalis or an enlarged placenta is present. 70–100% of all pregnancy, foetal immune systems are not mature enough to mount pregnant women with untreated primary syphilis, 90% of women a consistent immune response until about 18 to 22 weeks gestation. with secondary syphilis and approximately 30% of women with After this time the characteristic features of congenital syphilis may latent syphilis may transmit the infection to their fetuses. The be seen. In addition, placental infiltration with reduced blood flow correct approach to infants born to mothers with reactive serologic to the foetus can lead to growth restriction which, if severe, may tests for syphilis relies on three critical stages: result in foetal death. Foetal involvement occurs most consistently in pregnant women with ‘active’ infections (i.e. RPR titer >1:4), 1. Evaluation of specific and general maternal background that that have inadequately or not treated infections acquired in the can be resumed in some questions:

0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. P. Valentini / Early Human Development 89S4 (2013) S68–S69 S69

– Is maternal diagnosis of syphilis definite? if neonatal nontreponemal test is the same or less than fourfold Diagnosis of syphilis is possible using nontreponemal and tre- the mother one and physical examination is abnormal or ma- ponemal serologic test: nontreponemal tests may be falsely ternal treatment in pregnancy is inadequate; in the latter case, negative on serum containing high concentrations of antibodies some experts consider treatment with Benzathine penicillin G, against T. pallidum (prozone phenomenon) and treponemal tests 50,000 U/kg, IM, in single dose. Anyway, even though maternal remain positive long after syphilis treatment and can be falsely treatment is considered adequate, but any clinical or laboratory positive also when other spirochetal diseases occur. feature of the newborn is abnormal, penicillin treatment is – Was the seroreactive mother adequately treated? indicated; Women with seroreactive tests for syphilis in pregnancy should – Cerebrospinal fluid (CSF) analysis, inclusive of both cells and be always treated with penicillin before the last month of proteins evaluation and Venereal Disease Research Laboratory pregnancy; Penicillin G is the preferred compound, according (VDRL) test; to the stage of syphilis (Penicillin G benzathine, 2,400,000 U, – Long bones roentgenography; IM, in a single dose in primary, secondary and early latent – Complete blood cell count; syphilis; Penicillin G benzathine, 2,400,000 U/week, IM, for – Liver function tests; three consecutive weeks, in late latent syphilis or syphilis of – Ophthalmic examination; unknown duration; Aqueous crystalline penicillin G, 3–4 million – Auditory brain stem response. U, IV, every 4 h for 10–14 days in neurosyphilis). Women with a history of penicillin allergy should be equally treated 3. A careful follow-up evaluation: All infants should be subjected with penicillin after desensitization; parenteral Ceftriaxone has to serial tests to correctly evaluate serologic status, keeping in mind been used to treat syphilis in penicillin-allergic patients, but that passive transfer of maternal antibodies makes reactive syphilis as no controlled studies among pregnant women have assessed tests, even though the newborns have not disease, till 2–3 and its efficacy in treating the foetus, this is not recommended in more months of age, while, if infection was transmitted at delivery pregnancy. or near to the time of delivery, they are well clinically, maternal – How was the maternal response to penicillin therapy? antibodies are progressively eliminated in a few weeks and the Maternal response is adequate if the maternal antibody titer infants begin to produce antibodies at about 3–4 weeks of age. of a nontreponemal test at delivery is fourfold lower than Because of IgM class antibodies do not cross placenta, the detection the pretreatment titer or the response to treatment is not of this kind of antibody in newborn peripheral blood by Fluorescent documented. Treponemal antibody Absorption (FTA-ABS) or more recent enzyme – Has the mother any additional risk factor? immunoassay is a strong evidence of active congenital disease. Any situation as HIV infection, adolescent or unmarried status, substance abuse, inadequate or absent prenatal care, prostitution Syphilis continues to be a major public health problem causing or promiscuity, treatment of nonsyphilitic venereal diseases a preventable burden on mothers, families and health systems: should be carefully considered. further efforts are needed to earlyidentifyandadequatelytreat women with reactive syphilis tests, reducing neonatal diagnostic 2. A complete medical evaluation of the newborn included: problems and the length of hospital stay of the newborn infant. – A thorough physical examination (the abnormal physical and laboratory findings in early congenital syphilis are listed in Conflict of interest Table 1); – Nontreponemal serologic test for syphilis: serologic tests in The author has no conflict of interest to declare. newborn reflect the mother’s ones, because maternal IgG class antibodies cross placenta. A neonatal nontreponemal test Selected bibliography (VDRL/RPR) at least fourfold greater than maternal VDRL/RPR titer require treatment (Aqueous penicillin G, 50,000 U/kg, IV, [1] Ingall D, Sanchez P, Musher DM. “Syphilis”. In: Remington JS, Klein JO (eds), every 12 hours, in the first week of life, or every 8 hours, after Infectious Diseases of the Fetus and Newborn Infant, 4th ed. Philadelphia, PA: 1st week, for 10 days); likewise, penicillin treatment is indicated WB Saunders, 1995; pp 529–64. [2] Gutman LT. “Syphilis”. In: Feigin RD, Cherry JD (eds), Textbook of Pediatric Infectious Diseases, 4th ed. Philadelphia, PA: WB Saunders, 1998; pp 1543–56. Table 1 [3] De Santis M, De Luca C, Mappa I, Spagnuolo T, Licameli A, Straface G, Scambia Clues suggesting early congenital syphilis G. Syphilis infection during pregnancy: fetal risks and clinical management. Infect Dis Obstet Gynecol 2012;2012:430585. doi: 10.1155/2012/430585 [Epub • Osteochondritis, periostitis 2012 Jul 4]. • Snuffles, nasal hemorrhagic discharge [4] Gomez GB, Kamb ML, Newman LM, Mark J, Broutet N, Hawkes SJ. Untreated • Condylomata maternal syphilis and adverse outcomes of pregnancy: a systematic review and • Bullous lesions, palmar/plantar rash meta-analysis. Bull World Health Organ 2013;91:217–26. • Fissures and mucous patches [5] Blencowe H, Cousens S, Kamb M, Berman S, Lawn JE. Lives saved tool • Hepatomegaly, splenomegaly supplement detection and treatment of syphilis in pregnancy to reduce syphilis • Jaundice related stillbirths and neonatal mortality. BMC Public Health 2011;11(Suppl • Nonimmune hydrops fetalis 3):S9. • Generalized lymphadenopathy [6] Tridapalli E, Capretti MG, Bacchi Reggiani ML, Stronati M, Faldella G; The • Cerebrospinal fluid abnormalities (>25 cells/mm3,protein>150/dl) Italian Neonatal Task Force of Congenital Syphilis for The Italian Society of • Hemolytic anemia, diffuse intravascular coagulation, thrombocytopenia, Neonatology – Collaborative Group. Congenital syphilis in Italy: a multicentre hypoglobulinemia study. Arch Dis Child Fetal Neonatal Ed 2012;97(3):F211–3. • Pneumonitis [7] Congenital syphilis. In: European Centre for Disease Prevention and Control. • Nephritis, nephrotic syndrome Sexually Transmitted Infections in Europe, 1990–2009. Stockholm: ECDC, 2011; • Placental villitis or vasculitis pp 69–74. • Intrauterine growth retardation, failure to thrive [8] American Academy of Pediatrics. Syphilis. In: Pickering LK (ed), Red Book: 2012 • Pancreatitis Report of the Committee on Infectious Diseases. 29th ed. Elk Grove Village, IL: • Chorioretinitis American Academy of Pediatrics, 2012; pp 690–703. Early Human Development 89S4 (2013) S70–S71

Congenital toxoplasmosis

Lina Bollani *, Luisa Strocchio, Mauro Stronati

Department of Maternal and Child Heart, Neonatal Intensive Care Unit, Fondazione IRCCS-Policlinico San Matteo, Pavia, Italy

ARTICLE INFO ABSTRACT

Keywords: Toxoplasmosis is a worldwide parasitic disease, the congenital infection being the most severe manifesta- Newborn tion and occurs in the offspring of woman who acquire Toxoplasma gondii infection for the first time during Congenital toxoplasmosis pregnancy. Retinochorioiditis The incidence and severity of congenital infection depend on when in pregnancy the mother acquires the Follow-up infection. The risk of vertical transmission of the parasite rises steeply with gestational age (GA) at maternal infection. Although about 85% of infected infants are completely asymptomatic at birth, congenital toxoplasmosis may manifest at birth or in the first months of life, with extreme heterogeneity in disease severity and organ involvement. Ophthalmologic manifestations represent the main sequelae of congenital toxoplasmosis, with retinochoroiditis being the most common expression The combination of pyrimethamine with sulfadiazine currently represents the gold standard therapeutic. Associated eye pathologies may occur later in life, An adequate follow-up programme of patients with congenital toxoplasmosis should include ophthalmologic, neurological, audiometric and serologic evaluations. © 2013 Elsevier Ireland Ltd. All rights reserved.

Toxoplasmosis is a worldwide parasitic disease, but is prevalent Results from a meta-analysis conducted by Systemic Review in Europe, South America and Africa. on Congenital Toxoplasmosis study group (SYROCOT) revealed that Congenital infection is the most severe manifestation and occurs 19% of the subjects had one or more clinical manifestation during in the offspring of woman who acquired Toxoplasma gondii infection the first year of life, with ocular and intracranial lesions being for the first time during pregnancy. The 90% of expectant infected present in 14% and 9% of cases, respectively [1]. women, do not experience any symptoms, but maternal diagnosis Three major T. gondii genotypes differ in the expression of of toxoplasmosis during pregnancy is primarily made by serological virulence and geographical distribution, type II is the most prevalent screening for T. gondii or on the basis of abnormal fetal ultrasound in Europe. examination. About 85% of infected infants are completely asymptomatic The incidence rate for infection during pregnancy is 1–6 per at birth, but congenital toxoplasmosis may manifest in the first 1000 pregnancies, while the occurrence of congenital toxoplasmo- months of life, or become apparent with long-term ocular and sis was found to be 0.5–3/1000 births in Europe and 0.1–1/1000 in neurologic sequelae to children and adults. The classic triad of the USA. The overall maternal–fetal transmission rate in immuno- hydrocephalus, retinochorioiditis, and intracranial calcification is competent women who acquires primary Toxoplasma infection rather rare. Clinical manifestation of congenital toxoplasmosis vary during pregnancy is near 29% [1]. widely are nonspecific and may mimic other congenital infections, The incidence and severity of congenital infection depend on including cytomegalovirus, herpes simplex virus, rubella, syphilis when in pregnancy the mother acquires the infection. The risk of or by a generalized infection [2]. Nearly two-thirds of clinical vertical transmission of the parasite rises steeply with gestational manifestations involve CNS and the eye. age (GA) at maternal infection, with a probability of 15% at 13 Ophthalmologic manifestations are the main sequelae of congen- weeks GA, 44% at 26 weeks GA, 71% at 36 weeks GA, rising to 90% ital toxoplasmosis, retinochoroiditis is the most common expression during the last weeks of pregnancy [1]. with an estimated incidence from 9 to 31%. Late onset retinal le- By contrast, the severity of embryo-fetal damage inversely sions and relapse can appear many years after birth, but the overall correlates with gestational age at maternal seroconversion, since ocular prognosis is satisfactory when infection is identified and severe disease is associated with infection in early gestation, while treated accordingly [3]. it can be subclinical in newborn from mothers who acquire the Other possible ocular manifestations, which can lead to visual infection later in pregnancy. impairment include: strabismus, microphtalmia, cataract, retinal detachment, optic atrophy, iridocyclitis, nystagm, glaucoma. Some of these features appear to occur most commonly as a consequence * Corresponding author. of a retinochoroiditis process, and represent an indirect marker

0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. L. Bollani et al / Early Human Development 89S4 (2013) S70–S71 S71 of ocular toxoplasmosis severity, in particular when involving the Wallon et al. first reported on the clinical evolution of ocular macula. lesions and final visual function in a prospective cohort of congeni- Brain ultrasonography can play a relevant role in detecting tally infected treated children, describing the occurrence of at least cerebral calcifications, ventricular dilatation, and extremely rare 1 retinochoroidal lesion in 24% of children, after a median follow-up porencephaly; when clinical manifestations suggest involvement of of 6 years, with a time between involvement of the first and the the brain, neuroimaging studies such as MRI is mandatory. second eye ranging from 1.5 to 10 years [7]. Neonatal subclinical infection refers to an asymptomatic in- There is general agreement that adequate monitoring requires fection, with prenatal or postnatal serological evidence of tox- a regular follow-up with indirect ophthalmoscopy of fundus oculi oplasmosis. Therefore, in absence of prenatal diagnosis, physical every 3 months within the first year of life, every 6 months within examination exceptionally leads to clinical suspicion that is almost the second year of life, and then annually. Parents need to be always raised by maternal serological history during pregnancy. informed of the risk of retinochoroiditis, as well as of associated Specific IgG crosses the placenta and their presence is not a eye pathologies and their consequences. marker of congenital infection. For this reason tests for IgM and In a recent study, Peyron et al. report little effect on long-term IgA antibodies together, are commonly employed for the diagnosis quality of life and visual function, with no evidence of limited of infection in the newborn. Nearly 15–55% of congenital infected cognitive function being the educational level comparable with or newborn do not have detectable specific IgM at birth or early even higher than that of the general population [8]. months. When congenital toxoplasmosis cannot be ruled out at Few data are reported on long-term evaluations of neurologic, birth, follow-up serologic testing is indicated to attempt to establish cognitive and motor functioning of children with congenital tox- the diagnosis. Maternal IgG will disappear within 6 to 12 months. oplasmosis, mainly due to difficulties in conducting a long-term When congenital toxoplasmosis is confirmed, appropriate ther- neurologic follow-up. apy should be undertaken in the hope of preventing significant Gestational age at maternal seroconversion, prenatal treatment, sequelae described among untreated patients, and to reduce the and the presence of retinochoroiditis or clinical signs at birth were risk of activation of infection later in life. found to be correlated with the occurrence of serious neurological The combination of pyrimethamine with sulfadiazine and folinic sequelae. acid, currently represents the gold standard therapeutic option for The immediate initiation of an appropriate treatment of new- congenital toxoplasmosis. In case of active retinochoroiditis, oral borns presenting neurologic signs (hydrocephalus, seizures, abnor- prednisolone should be administered and gradually tapered at the mal muscle tone) appear to be relevant to prognosis and neurologic resolution of inflammation signs [4]. outcome [9,10]. Roisen et al. observed significantly better neu- A remarkable synergistic activity of pyrimethamine adminis- rologic and developmental outcomes in children with congenital tered together with sulfadiazine was observed against T. gondii toxoplasmosis treated with pyrimethamine and sulfadiazine for and the combination of these drugs acts with an activity eighfold only 1 month in comparison to untreated children. Although the stronger than the two drugs individually administered [4]. level of cognitive function for treated children was less than for Side effects associated with folate deficiency and related to their uninfected siblings, the Authors reported no significant deteri- a possible though reversible bone marrow depression, including oration in neurologic and cognitive function of the treated children neutropenia and, less commonly, anemia and thrombocytopenia are [9]. No sensorineural hearing loss was reported in the National prevented by concomitant administration and/or intake of folinic Collaborative Chicago-Based Congenital Toxoplasmosis Study in acid. Both drugs have shown a good tolerability profile without treated infants with moderate or severe neurologic disease at birth significant toxicity, hematologic toxicity or late malignancies even [10]. after long term treatments [5]. Regular complete blood counts should be performed every Conflict of interest 7–15 days or every 15–30 days, as well as analysis of urine for crystalluria, due to poor sulfadiazine solubility, prevented by The authors have no conflict of interest to declare. hyperhydratation. Fansidar®, a combination of pyrimethamine with sulfadiazine, References widely used in France, shows a 90% plasma protein binding and a plasma half-life of approximately 120–195 hours, which allows [1] The SYROCOT (Systemic Review on Congenital Toxoplasmosis) Study Group. Effectiveness of prenatal treatment for congenital toxoplasmosis: a meta- for administration only once every 10–14 days, with improved analysis of individual patient’s data. Lancet 2007;369:115–22. medication compliance. [2] Montoya JG, Liesenfeld J. Toxoplasmosis. Lancet 2004;363(9425):1965–76. Severe complications associated with the administration of [3]WallonM,KodjikianL,BinquetC,GarwegJ,FleuryJ,QuantinC,PeyronF. Fansidar® have occurred due to long-acting reactions, including Long term ocular prognosis in 327 children with congenital toxoplasmosis. skin rash, toxic epidermal necrolysis, Lyell syndrome, that require Pediatrics 2004;113(6):1567–72. [4] Remington JS. Toxoplasmosis. In: Remington JS, Klein J, Wilson CB, Nizet CB, stop therapy [6]. Nizet V, Maldonado Y. (eds), Infectious Diseases of the Fetus and Newborn To date, less data are available that concerns pharmacokinetics of Infant, 7th edn. Philadelphia PA: WB Saunders, 2011; pp 918–1054. azithromycin, nor of atovaquone that apparently show good tissue [5]SchmidtDR,HoghB,AndersenO,HansenSH,DalhoffK,PetersenE.Treatment and intracellular concentrations, with adequate activity against T. of infants with congenital toxoplasmosis: tolerability and plasma concentra- tions of sulfadiazine and pyrimetamine. Eur J Pediatr 2006;165:19–25. gondii but that is not actually approved for pregnancy and neonatal [6] Petersen E, Schmitdt DR. Sulfadiazine and pyrimethamine in postnatal treat- period [6]. There is no consensus about the optimal duration of the ment of congenital toxoplasmosis: what are the options? Expert Rev Anti- therapy, in Denmark treatment is administered for 3 months, in infet Ther 2008;1(1):175–83. our and other Unit for 12 months The efficacy of treatment has not [7] M.Wallon M, Kieffer F, Binquet C, Thulliez P, Garcia-Meric P, Dureau P, Franck J, Peyron F, Bonnin A, Villena I, Bonithon-Kopp C, Gouyon JB, Masson S, Félin been demonstrated by appropriate studies, but some reports favour A, Cornu C. Toxoplasmose congènitale: comparison randomisée de stratégies a beneficial effect, especially in cases of severe infections. de prevention des rétinochoroidites. Thérapie 66(6):473–80. A long follow-up is necessary to assess the long-term outcome [8]PeyronF,GarwegJ,WallonM,DesclouxE,RollandM,BarthJ.Long-term of children and young adults with congenital toxoplasmosis, that impact of treated congenital toxoplasmosis on quality of life and visual performance. Pediatr Infect Dis J 2011;30(7):597–600. for the majority is favourable An adequate follow-up should [9]RoizenN,SwisherCN,SteinMA,HopkinsJ,BoyerKM,HolfelsE,MetsMB, include ophthalmologic, neurological, audiometric and serologic Stein L, Patel D, Meier P. Neurologic and developmental outcome in treated evaluations. congenital toxoplasmosis. Pediatrics 1995;95(1):11–20. S72 L. Bollani et al / Early Human Development 89S4 (2013) S70–S71

[10] McLeod R., Boyer K, Karrison T, Kasza K, Swisher C, Roizen n, Jalbrzikowwki for congenital toxoplasmosis 1981–2004: The National Collaborative Chicago- J, Remington J, Heydemann P, Noble AG, Mets M, Holfels E, Withers S, Based, Congenital Toxoplasmosis Study. Clin Infect Dis. 2006;15;42(10):1383– Latkany P, Meier P. for the Toxoplasmosis Study Group. Outcome of treatment 94. Early Human Development 89S4 (2013) S73–S75

Neonatal herpes simplex infection

Fabio Natale *, Bianca Bizzarri, Antonella Castronovo, Assunta Russo, Monica Bartolucci, Roberto Pedicino, Mario De Curtis

Department of Pediatrics and Child Neuropsychiatry, “Sapienza” University of Rome, Rome, Italy

ARTICLE INFO ABSTRACT

Keywords: Neonatal HSV infections are severe events. Due to the presence of non-specific findings, the diagnosis requires Herpes simplex virus a high index of suspicion; in fact, a prompt institution of Acyclovir therapy is fundamental to reduce the Neonatal burden of mortality and neurological morbidity frequently associated with this disease. Here, we review the Infection most recent evidence in the management of neonatal HSV infections. © 2013 Elsevier Ireland Ltd. All rights reserved.

1. Introduction laboratory criteria and independent of clinical signs; in fact, genital herpes infections, whether primary or not, may occur without any Herpes simplex virus (HSV)-1 and -2 are double-stranded, of the clinical manifestations classically described (more than 50% enveloped DNA viruses, belonging to the herpes virus family are asymptomatic or, due to the low specificity of symptoms, go (subgroup alphaherpesviridae). Once the infection in humans is unnoticed) [2]. established, HSVs have the ability to alternate latency (in the nu- The risk for neonatal infection has been demonstrated to be 57% clei of sensory ganglia) and reactivation all through the patient’s for primary, 30% for non-primary, and 2% for recurrent infections life. Neonatal HSV infections are mainly due to vertical transmis- [2]. Primary infections, whether symptomatic or not, are associated sion through contact with infected genital secretions during the with more abundant and prolonged viral excretion compared to peripartum period (∼85%). In utero (∼5%) or postnatal horizontal recurrent genital infections. Moreover, maternal primary infection transmission (∼10%) through infected people (almost always due late in gestation may not result in a significant passage of ma- to HSV-1) rarely occur. Genital HSV infections, despite the classic ternal antibodies across the placenta to the fetus. Transplacental separation in “above the belt” and “under the belt” infections acquisition of neutralizing and antibody-dependent cell-mediated (caused by HSV-1 and HSV 2 respectively), are produced by both cytotoxic antibodies seem to have a protective effect against in- viruses [1]. The type of maternal genital infection at the time of fection in infants exposed to genital HSV infected secretions, and delivery is the main risk factor for neonatal acquisition of infection. probably affects the clinical course of neonatal herpes [1]. In fact, A first-episode primary infection is a newly acquired HSV-1 or although newly acquired genital HSV-1 or -2 infections are infre- -2infectioninawomanwithoutpreformed antibodies against quent in late pregnancy, they account for 50–80% of all neonatal both HSVs. A first-episode non-primary infection refers to a new HSV infections [4]. A rupture of the membrane lasting more than acquisition of HSV-1 infection in an individual already infected six hours (ascending infection from the cervix), and the use of fetal with HSV-2, or vice versa. A recurrent infection is the isolation scalp monitors (viral entry through damaged skin) are reported to of HSV-1 or -2 from a lesion in an individual with preformed be additional risk factors. immunity against it [2]. Recent evidence has demonstrated that HSV-2 reactivations are very frequent in women (∼ every 10 days) 2. Neonatal HSV infections and are associated with rapid expansion and containment of the virus; resident dendritic cells and memory HSV-2 specific T cells, Neonatal HSV infection is an infrequent but quite severe event. in conjunction with prompt innate recognition of infected cells, Mortality and neurological morbiditywerehugebeforetheintro- lead to rapid containment of the infected cells [3]. The classifica- duction of antiviral therapy. The reported incidence ranges from tion of the different types of maternal infections is dependent on 1 every 3000 to 1 per 20.000 live births [5] and is higher in the United States than in Europe. The type and severity of the Abbreviations: HSV, herpes simplex virus; SEM, skin, eye, mouth; CNS, central clinical manifestations of neonatal HSV deal with the relatively nervous system; PCR, polymerase chain reaction; CSF, cerebrospinal fluid; ALT, impaired immune response of the newborn (lack of protection by alanine aminotransferase; ACV, Acyclovir. transplacental antibodies, an immature innate immune response, * Corresponding author: Fabio Natale, MD, Neonatal Intensive Care Unit, Depart- and a delayed acquisition of adaptive immunity) and the ability of ment of Pediatrics and Child Neuropsychiatry “Sapienza” University of Rome, V. le Regina Elena 324, 00161 Rome, Italy. Tel.: +39 064469868; fax +39 0649970668. HSV to evade host immune response [1]. E-mail address: [email protected](F. Natale).

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2.1. Intrauterine infection or Enzyme Immuno Assay (EIA) of HSV antigens)] are also available. Due to the transplacental passage of maternal antibodies and the This is a rare (∼5%) but invariably severe event diagnosed low reliability of IgM assays, serologic assays are rarely helpful and within the first 48 hours of life. It may occur at any time during not currently recommended for diagnostic purposes [1,2]. gestation and is mostly characterized by a triad of cutaneous (skin The diagnostic work-up consists of: (1) surface cultures (mouth, vesicles or scarring, rash, aplasia cutis, and cutaneous hypo/hy- nasopharynx, conjunctivae, and anus) obtained 12–24 hours after perpigmentation), ocular (chorioretinitis, keratoconjunctivitis, and birth to differentiate infection from colonization. A single swab optic atrophy), and neurological findings (intracranial calcifications, may be used, ending with the anal swab; (2) Cerebrospinal Fluid encephalomalacia, microcephaly or hydranencephaly). Hydrops fe- (CSF) (if positive, to be repeated at the end of therapy) and skin talis has also been described [1,2,6]. vesicle sampling for culture and PCR, and (3) whole blood sample for HSV PCR and alanine aminotransferase (ALT) (elevated ALT 2.2. Disseminated disease in HSV hepatitis). Radiographs may be useful in diagnosing HSV pneumonitis [2,5]. Disseminated infection (∼25% of perinatal infections) has the The American Academy of Pediatrics has recently edited some worst prognosis. It typically occurs in the second week of life, evidence-based recommendations on the management of asymp- but the initial symptoms may be present some days earlier. tomatic neonates born to women with active genital herpes lesions A hematogenous dissemination precedes multiorgan involvement. (freely available at: http://pediatrics.aappublications.org/content/ Liver and adrenals are mostly affected but nearly every organ may 131/2/e635.full.html) [7]. The need for a ready access to PCR fa- be involved. A vesicular rush, albeit frequent (∼80%), is usually ab- cilities and laboratory results may limit the diffusion of these sent at the beginning of the disease. Encephalitis occurs in 60–75% guidelines. The management of neonates from women with asymp- of infants, presenting with multiple areas of cortical hemorrhagic tomatic shedding continues to be an issue. necrosis. Nonspecific clinical signs (irritability, seizures, respiratory distress, jaundice, bleeding diatheses, and shock) mimicking bac- 4. Treatment terial sepsis make the diagnosis difficult. Mortality (∼30% with antiviral therapy) is most often due to HSV pneumonitis or dis- Acyclovir (ACV) has deeply reduced the incidence of mortality seminated intravascular coagulopathy. Psychomotor delay is seen and neurological morbidity due to HSV in infants, and is currently in ∼20% of survivors [1,2,6]. the treatment of choice in neonatal HSV infection. Current recom- mendations state that parenteral ACV should be administered at 2.3. Encephalitis (CSN disease) a dosage of 60 mg/kg divided into three daily doses for 14 days in case of SEM disease, or for a minimum of 21 days in case of Encephalitis (∼30%) occurs between the second and third week disseminated and CNS disease; more prolonged therapy is advisable of life and is probably the result of a retrograde axonal transport of in case of persistent HSV CSF positivity. Resistance to acyclovir HSV to the brain [6]. Clinical manifestations include seizures (focal treatment has been rarely reported during neonatal HSV infection. and generalized), fever, lethargy, irritability, tremors, poor feeding, Oral ACV (300 mg/m2/dose for 3 times a day) for six months temperature instability, and bulging fontanelle. Skin vesicles may following parenteral therapy has been recently demonstrated to appear later, particularly in untreated infants. Death rarely occurs improve neurodevelopmental outcome and to reduce the incidence if therapy is timely administered (4%), but a severe neurologic of cutaneous recurrences (∼50% without suppressive therapy) [8]. impairment is frequent (∼70%) [1,2,6]. Periodic assessment of absolute neutrophil count is recommended due to possible occurrence of neutropenia with Acyclovir therapy. If 2.4. Skin, eye, and mouth (SEM) disease ocular lesions are present, a topical treatment should be added (1% trifluridine, 0,1% iododeoxyuridine, or 3% vidarabine) [2,5]. SEM disease (∼45%) occurs in the second week of life. Vesicles Valaciclovir – a prodrug of ACV that enhances the bioavailability are the hallmark of this type of infection (>80%) which, in the of ACV by 3 to 5-fold compared to oral ACV, and Famciclovir – a absence of therapy, may progress to a generalized form. Ocular more stable and bioavailable compound than ACV, are currently not (keratoconjunctivitis, chorioretinitis, cataracts, and retinal detach- licensed for use in neonates [9]. Newer therapies (i.e. monoclonal ment) and oropharyngeal involvement are variably associated. SEM antibodies), aimed at inhibiting HSV cell to cell spread (a key mech- disease, adequately treated, is not associated with death, and a anism by which HSV-1/2 escapes humoral immune surveillance), moderate neurologic impairment is occasionally reported [1,2,6]. are currently ongoing [10].

3. Diagnosis 5. Prevention of neonatal herpes

Due to non-specific findings (skin vesicles are often absent at Cesarean section for women with active lesions during labor, onset), the diagnosis of neonatal HSV infection requires a high maternal antiviral suppressive therapy since the 36th week of index of suspicion. Viral (particularly enteroviral) and bacterial gestation, and strategies to prevent maternal HSV infection during (gram+ and gram−) sepsis, impetigo, respiratory distress syndrome, pregnancy, have variably shown to prevent neonatal HSV infection. intraventricular hemorrhage, necrotizing enterocolitis, and ocular To date, no vaccine has proven to be effective in preventing HSV or cutaneous diseases, are all involved in the differential diagnosis. infections [2]. Moreover, HSV infections may occur in association with other bacterial infections [1,2]. 6. Isolation of the hospitalized infant HSV isolation is fundamental for the diagnosis. Viral culture and, particularly for central nervous system (CNS) HSV infection, Infected infants should be managed with contact precautions Polymerase Chain Reaction (PCR) techniques are the mainstay for (isolation in single room, non-sterile clean gloves, hand hygiene the diagnosis of HSV infection. Both methods require accurate after glove removal, and the use of a gown during direct contact collection, storage and transport procedures. PCR on CSF has with the neonate) during the incubation period. Contact precautions demonstrated sensibility and specificity ranging from 70 to 100%. should be applied also to infants born to women with active HSV Rapid diagnostic tests [Direct Fluorescent Antibody (DFA) staining lesions; according to some experts, this practice is not necessary if a F. Natale et al / Early Human Development 89S4 (2013) S73–S75 S75 cesarean section (with membranes rupture <4 hours) is performed [4] Corey L, Wald A. Maternal and neonatal herpes simplex virus infections. N [5]. Engl J Med 2009;361:1376–85. [5] Pickering L, Baker C, Kimberlin D, et al. Herpes simplex. In: Pickering L (ed), Red Book. Report of the Committee in Infectious Diseases. 29th edition. Elk Conflict of interest Grove Village, IL: American Academy of Pediatrics, 2012; pp 398–408. [6] Whitley R. Herpes simplex viruses. In Fields BN, Knipe DM (eds), Fields’ None of the authors has any conflict of interest or financial Virology, 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2001; pp relationship to disclose in relation to this article. 3723–99. [7] Kimberlin DW, Baley J; Committee on Infectious Diseases and Committee on Fetus and Newborn. Guidance on management of asymptomatic neonates References born to women with active genital herpes lesions. Pediatrics 2013;131:e635– 46. [1] Gutierrez KM, Whitley RJ, Arvin AM. Herpes simplex virus infections. In: [8] Kimberlin DW, Whitley RJ, Wan W, et al. Oral acyclovir suppression and Remington JS, Klein JO, Wilson CB, Nizet V, Maldonado YA (eds), Infectious neurodevelopment after neonatal herpes. N Engl J Med. 2011;365(14):1284– Diseases of the Fetus and Newborn Infant, 7th ed. Philadelphia, PA: Elsevier 92. Saunders; 2011:813–33. [9] Antoine TE, Park PJ, Shukla D. Glycoprotein targeted therapeutics: a new era [2] Pinninti SW, Kimberlin DW. Neonatal herpes simplex virus infections. Pediatr of anti-herpes simplex virus-1 therapeutics. Rev Med Virol 2013;23:194–208. Clin North Am 2013;60:351–65. [10] Krawczyk A, Arndt MA, Grosse-Hovest L, et al. Overcoming drug-resistant [3] Schiffer JT, Corey L. Rapid host immune response and viral dynamics in herpes simplex virus (HSV) infection by a humanized antibody. Proc Natl herpes simplex virus-2 infection. Nat Med 2013;19(3):280–90. Acad Sci U S A 2013;110:6760–5. Early Human Development 89S4 (2013) S76–S78

The infant born to a mother with infectious disease risk

Maria Grazia Capretti *, Giacomo Faldella

UO Neonatologia, Azienda Ospedaliero-Universitaria S. Orsola-Malpighi, Bologna, Italy

1. Introduction HCV vertical transmission may occur in utero and/or during intrapartum period and currently there are no interventions to Perinatal infections remain a significant cause of neonatal mor- prevent MTCT. bidity and mortality. Mother-to-child transmission (MTCT) can Transmission rate is 4–7% when the mother is viremic, with a occur in utero (rubella, CMV, syphilis, Toxoplasma), intrapartum higher probability when HCV-RNA is >106 copies/ml and when the (HBV, HIV, group B streptococci, enteric gram-negative organisms, mother presents HIV-coinfection (transmission rate: 40–60%). gonococci, chlamydiae) or during post-natal period (TBC, HIV, CMV) Vaginal delivery and breastfeeding do not increase the risk of The microorganism type and the timing of infection influ- infection. ence the outcome that includes spontaneous abortion, intrauterine Congenital HCV infection is confirmed when HCV-RNA is de- growth restriction, premature birth, stillbirth, congenital malforma- tected in two subsequent serum samples of infant at least 3 months tion and symptomatic or asymptomatic neonatal infection. after birth or when anti-HCV IgG are positive at 18 months of life. Spontaneous clearance of HCV infection are reported in 30% of 2. Hepatitis B virus vertically infected infants. The remaining 70% of infected infants remains asymptomatic or As a conseguence of the universal immunization program started with mild hepatitis during childhood but a small number of them in 1990, currently in Italy the prevalence of women HBsAg-positive can develop progressive liver disease. at delivery is 0.86%, with a significant difference between native and immigrant women (0.4% vs 2.5%). HBV vertical transmission 4. HIV occurs almost exclusively during the perinatal period. According to the Italian Health Ministry [1]. the serological screening for The Italian Health Ministry recommends HIV screening for all hepatitis B is mandatory and free of charge in pregnancy during the pregnant women in the first and third trimester of gestation, third trimester of pregnancy irrespective of risk factors, to ensure adequate management of Women who haven’t been screened for HBV during pregnancy, pregnant infected women [1]. must undergo the test urgently at delivery. Newborns of HBsAg- Without any intervention, the vertical transmission rate is 15– positive women must receive HB Immunoglobulins and HepB 30%. In Italy, after implementation of prevention measures, the vaccine within 12–24 hours of life, a second dose of HepB vaccine overal transmission rate was 5.1% during 1996–1999, 2.2% during after 4 weeks and additional doses at 3 and 11 months of life. 2000–2005 and 1.0% during 2005–2010. In the same periods the Serologic tests (HBsAg and anti-HBs) are recommended 1–2 months proportion of immigrant woman among all the pregnant infected after the vaccine protocol is completed to determine appropriate woman was 10%, 25.5% and 43.3%, respectively [2]. Thus, being born follow up. to an immigrant woman is a risk factor for perinatal HIV infection. Hepatitis B vaccination prevents 85–95% of perinatal infections, Other major risk factors for MTCT are high maternal viral load, CD4+ while mothers with HBV replication have a high risk of MTCT: count <200 cells/mm3,symptomsofAIDSandacuteHIV-infection 10–32% of infants born to mothers with HBV DNA >108 copies/ml during pregnancy. or HBeAg-positive are infected, despite neonatal active and passive At present, according to CDC and AGOG recommendations: (A) immunizations. Intravenous zidovudine is not longer recommended for mothers Breastfeeding does not increase the risk of infection in the receiving antiretroviral drugs combination and who have HIV-RNA infants if active and passive immunizations have been correctly <400 copies/ml near delivery; (B) elective caesarean delivery is provided. recommended only when maternal HIV-1 RNA level is >1000 copies/ml or it is unknown near delivery; (C) prophylaxis for 6 3. Hepatitis C virus weeks with oral zidovudine (dosage appropriate for gestational age – GA – and birth weight) and proscription of breastfeeding Serological screening for HCV is recommended, free of charge, are recommended for newborn; (D) for infants born to mothers during the last trimester of pregnancy, only for pregnant women at with unknown HIV-status a rapid maternal testing after birth is risk [1]. recommended; if the test is positive the infant must promptly start prophylaxis with zidovudine and three doses of nevirapine * Corresponding author. [3].

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The guidelines (last updates July 2012) of US Antiretroviral seroprevalence in pregnant women was 0.44% but it was 4.3% in Pregnancy Register are available from AIDSinfo website (http:// women from Eastern Europe and 5.8% in women from Central- aidsinfo.nih.gov). South America. The rate of congenital disease among exposed Neonatal testing (HIV-1-DNA PCR) at birth is recommended only infants was 10.5% [6]. if the mother has not received antiviral drugs during pregnancy. MTCT can occur at any GA. The stage of maternal disease is the All HIV-exposed infants should undergo tests at 14–21 days of age most important risk factor for congenital syphilis. Untreated mother and, if negative, tests should be repeatead at 1–2 and 4–6 months. with primary or secondary stage has a transmission risk of 100%, Any positive test should be twice repeated for confirmation and the early latent stage has a transmission risk of 40–83% and late latent infant should be promptly referred to a pediatric HIV specialist for stage of 2.5–10%. Maternal treatment with Penicillin >4 weeks antiretroviral treatment. The absence of HIV infection is confirmed before delivery set to zero the probability of neonatal infection. by negative HIV-IgG test at 12–18 months of life. 8. Congenital cytomegalovirus infection 5. Congenital rubella syndrome Screening for cytomegalovirus during pregnancy is not recom- Serological screening for rubella is recommended and free of mended [1], given the lack of interventions to reduce MTCT. charge in the first trimester of pregnancy and, if negative, it should The rate of congenital CMV infection is 0.3–2% of all liveborn be repeated at 14–18 weeks of GA [1]. newborns. Transmission rate during primary infection in precon- In Italy the prevalence of rubella in 2005–2009 ranged from 1.8 ceptional period is 0–16.7%, in periconception period is 4.6–38.5%, to 83.3 per 1,000,000 population (vs the recommend 2015 target of in the first trimester is 30.1–42.2%, in the second trimester is <1 case/1,000,000 population) [4,5]; no cases of Congenital rubella 35.9–43.5% in the third trimester is 42.9–72.2%. syndrome (CRS) occurred in 2005–2008, but 6 were reported in The rate of symptomatic infection among infants born to moth- 2009. ers with primary infection during the first trimester of gestation Rubella infection during pregnancy can be symptomatic or inap- is 36%, during the second trimester is 17%, and no symptoms are parent. Suspicion of rubella during pregnancy requires confirmation present if the mother became infected in the last trimester of testing (IgG/IgM test, IgG avidity test, RT-PCR of blood or other gestation [7]. biologic fluid). When maternal infection occurs in the first 10 weeks MTCT of CMV is more frequent during primary than secondary of gestation the rate of infection is 90%; afterwards it is 67% at maternal infection (30–40% vs 1–3%). 11–14 weeks, 40% at 15–30 weeks, 60% at 31–36 weeks and 100% Management of women with Toxoplasma/syphilis/CMV infection near term. The rate of fetal damage is 90% in the first 10 weeks, 33% during pregnancy and their infants are available from SIN website- at 11–12 weeks, 10% at 13–18 weeks; after 18 weeks of GA only guidelines section (http://www.neonatologia.it). sporadic hearing defects have been reported. Fetal infection can result in miscarriage, stillbirth and CRS 9. Congenital varicella and neonatal chickenpox (VZV) Congenital infection is confirmed by positive RT-PCR or virus isolation in pharyngeal swab, urine, blood and cerebrospinal liquor In 1996–2003 in Italy the reported rate of VZV-seronegativity and/or positive IgM in the first month of life, and/or IgG persistence; among women of childbearing age was 12.6%. VZV infection during the disappearance of IgG after 6 months of life confirm the pregnancy can cause abortion, premature labor, and congenital absence of congenital infection. In Italy CRS notification is statutory varicella syndrome (CVS) that include skin scars, limb defects, since2005.Pregnantwomenfoundtobesusceptibleshouldbe chorioretinitis, cataracts, microcephaly, cerebral atrophy, mental vaccinated after delivery. retardation. CSV incidence rate is 0.4% when maternal infection occurs between 0 and 12 weeks of GA and 2% if infection occurs 6. Congenital toxoplasmosis between 13 and 20 weeks; the risk of birth defects is neglectable after 20 weeks of GA, but asymptomatic congenital disease occurs Serological screening for Toxoplasma gondii (Tg) is recommended in 10–25% and infantile zooster in 0.8–1.7% of cases. and free of charge in the first trimester of pregnancy and, if Congenital infection is confirmed by positive VZV-PCR or virus negative, it should be repeated every 4–6 weeks until delivery [1]. isolation in blood and/or cerebrospinal liquor and/or positive IgM Primary infection is mostly asymptomatic in pregnant women, in the first month of life, and/or IgG positivity after 6 months of life. but can cause a wide spectrum of fetal/neonatal damage. When maternal rash appears between 21 and 6 days before In our experience, the prenatal screening during the 2009–2011 delivery, a mild form of neonatal chickenpox may develop (20–50% period showed a seroprevalence rate of 22.3%, with a significantly of exposed newborns, no mortality). higher rate among non-native women than among native women When maternal rash appears in the peripartum period (5 days (32.8% vs 19.1%). The rate of primary Tg-infection during pregnancy before and 2 days after delivery) a severe form of neonatal was 0.77%; immigrant women were more likely to be infected chickenpox including hemorrhagic disease, pneumonia, menin- during pregnancy than Italian women. The rate of congenital goencephalitis may develop (20–50% of exposed newborns, 3–20% disease was 0.06%. mortality). Transmission rate is <2% in the first 10 weeks of gestation, It is recommended to administer VZ immunoglobulins to new- and progressively increases thereafter to 50% at 22–29 weeks and born when maternal rash occurs in the peripartum period. Acyclovir 60–80% at 31–38 weeks of GA. The risk of neonatal symptomatic treatment is recommended when newborn develops chickenpox. disease is 80% when the maternal infection occurs in the first trimester, and after decreases to 20% at 30 weeks and 6% near term. 10. Early onset sepsis (EOS)

7. Congenital syphilis EOS are associated with intrapartum exposure to the pathogens organisms, acquired in utero or during labor or delivery. Risk factors Serological screening for Treponema pallidum (TPHA and VDRL for EOS include prematurity, prolonged rupture of membranes or RPR) is recommended and free of charge during the first and the >18 h (PROM), maternal colonization with group B Streptococcus third trimester of pregnancy [1]. (GBS) and maternal chorioamnionitis. This latter condition can In our experience (2000–2006 period), the overall syphilis remain clinically silent in the mother and can be diagnosed by S78 M.G. Capretti, G. Faldella / Early Human Development 89S4 (2013) S76–S78 histological abnormalities of the placenta; severe but rare cases [2] Chiappini E, Galli L, Giacquinto C et al.: Risk of Perinatal HIV infection in infant of chorioamnionitis may be symptomatic (maternal fever >38°C, born in Italy from immigrant mothers. CID, 2011:53(3): 310–313. maternal tachycardia, leukocytosis, elevated C-reactive protein – [3] Nielsen-Saines K, Watts H., Veloso VG et al.: Three postpartum antiretroviral regimens to prevent intrapartum HIV infection. N Engl J Med 2012; 366:2368– CRP, uterine fundal tenderness, vaginal discharge, fetal tachycardia). 79. According to the 2012 statement of the AAP Committee on Fetus [4] World Health Organization Regional Office for Europe. Surveillance Guidelines and Newborn, asymptomatic at term neonates with suspected sep- for Measles, Rubella and Congenital Rubella Syndrome in the WHO European sis or inadequate intrapartum antibiotic prophylaxis should receive region. Update December 2012 [5] Center for Disease Control and Prevention: Manual for the Surveillance of CRP and WBC count evaluation and, if abnormal, blood culture and Vaccine-Preventable Diseases (5th edition 2012); chapter 15: congenital rubella broad spectrum antibiotics (ampicillin and aminoglycoside). Then, syndrome. Available on the internet at: http://www.cdc.gov/vaccines/pubs/ if the newborn remains well and the blood culture is negative, he surv-manual/. can be discharged at 48 hours [8]. This approach has several critical [6] Tridapalli E, Capretti MG, Sambri V et al: Prenatal syphilis infection is a points as it increases the number of newborns undergoing diagnos- possibile cause of preterm delivery among immigrant women from eastern Europe. Sex Transm Infect 2007; 83(2): 102–5. tic tests and admitted to the Neonatology ward to receive broad [7] Enders G, Daiminger A, Bader U et al: Intrauterine transmission and clinical spectrum antibiotics with potential risk of selection of antibiotic- outcome of 248 pregnancies with primary cytomegalovirus infection in relation resistant organisms. to gestational age. J Clin Virol 2011;53(3):244–6. [8] Polin RA and the Committee on Fetus and Newborn: Management of neonates with suspected or proven early-onset bacterial sepsis. Pediatrics 2012; 129(5): Conflict of interest 1006–15.

The authors have no conflict of interest to declare.

References

[1] Ministero della Salute, Istituto Superiore di Sanità, CeVEAS: Sistema Nazionale per le Linee Guida: Gravidanza fisiologica aggiornamento 2011, http://www. snlg-iss.it Early Human Development 89S4 (2013) S79–S81

The floppy newborn

S. Orcesi

Child Neurology and Psychiatry Unit, C. Mondino National Institute of Neurology Foundation, IRCCS, Pavia, Italy

1. Introduction The components of the reflex arc (alpha and gamma motor neurons in particular) are also subject to supraspinal control which Hypotonia is frequent in neonates and has many different causes modulatesmuscletone(Fig.1). (congenital, acquired, transitory), which can be linked to peripheral Hypotonia may be due to: a peripheral nervous system disorder, or central nervous system (CNS) impairment. Muscle tone varies at any level of the reflex arc, an acute or sub-acute CNS disorder greatly between individuals and hypotonia is an aspecific symptom (in which the hypertonia gradually becomes established during the that,innewborns,canalsobeacomponentofdisordersnot first year of life), a cerebellar disorder, or less specific causes, such involving the nervous system. The identification of a specific as genetic or metabolic syndromes. etiology is a clinical challenge. Muscle tone is assessed by observing posture and evaluating The tone of a muscle is its degree of resistance to passive the resistance offered by different body segments to passive stretching. Even at rest muscles are in a state of basal contraction, movements. In newborns too, the first aspect to assess is posture determined by the activity of the gamma motor neurons, necessary (flexed in a healthy newborn and very different in a hypotonic to maintain posture and overcome the force of gravity. infant) followed by muscle tone proper, using manoeuvres specific The tonic stretch reflex is the basis of muscle tone (Fig. 1): a to the neonatal neurological examination [2]: recoil of the limbs, disease that interrupts the reflex arc at any level will result in scarf sign, adductors, popliteal and leg-foot angles, ventral and reduced muscle tone. dorsal incurvation of the axis.

Fig. 1. The reflex arc and superior control of muscle tone (from Prasad and Prasad [1], modified). The superior system essentially exerts inhibitory control (–)overthe gamma and alpha motor neurons: in the presence of a central lesion, absence of this inhibition means that muscle tone, in most cases, tends to increase. However, what is initially observed, in the acute phase, is usually hypotonia, as the hypertonia is established gradually over time. Cerebellar influences instead have a facilitatory (+) effect on muscle tone. Consequently, cerebellar disease or damage, interfering with this role, result in hypotonia, and not hypertonia.

0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. S80 S. Orcesi / Early Human Development 89S4 (2013) S79–S81

2. Causes of neonatal hypotonia and general clinical 4. General and neurological examination considerations It is crucial to perform a detailed general and neurological exam- In very early life, central causes of hypotonia are the most ination, looking for signs and symptoms assicated with hypotonia: frequent (60–80% of cases), while peripheral causes are found in 15–30%. 4.1. Posture Paro-Panjan [3], in 138 hypotonic newborns, found hypoxic- ischemic encephalopathy to be the most frequent cause, followed Neonatal hypotonia confers an abnormal posture, very different by syndromic and genetic diseases and then metabolic diseases; from the flexed posture typical of the healthy newborn. There may in only 10% was the cause peripheral. The causes reported in the be other associated signs, such as arthrogryposis (multiple joint literature are increasing progressively as diagnostic possibilities in- contractures), which, indicating hypomotility in utero,ishighly crease: refined diagnostic techniques, both instrumental (magnetic suggestive of neuromuscular disease [6]. A marked “frog-like” resonance, spectroscopy) and genetic (CGH microarray, next gener- posture in which the externally rotated limbs lie on the bed is ation sequencing) have increased the scope for differential diagnosis seen in neonatal forms of spinal muscular atrophy (SMA) type I, and led to the development of complex diagnostic algorithms that, associated with a bell-shaped chest (narrow at the top and wider at however, are often impracticable in clinical routine. the bottom) due to paralysis of the intercostal muscles with sparing Establishing the causes of hypotonia in newborns and infants of the diaphragm. thus remains difficult, making it fundamental to obtain clinical “clues” to follow. 4.2. Spontaneous movement Every effort should be made to guide and target the diagnostic Spontaneous movements must be evaluated quantitatively and work-up, also with a view to: qualitatively. The crucial “clue”, according to Dubowitz [4], is • sparing the child invasive diagnostic tests (e.g. muscle biopsy) whether or not hypotonia is associated with muscle weakness: when these are not necessary; the presence of antigravity movements, indicating that strength • ensuring, when possible a timely genetic diagnosis, and there- is preserved or at least not severely impaired points to a cen- fore adeqaute counselling for couples planning future pregnan- tral or metabolic disorder, or to a syndrome. Instead, absence of cies; movements, especially during wakefulness and even during crying, • avoiding 360° diagnostic testing, which can be a waste of energy means that the hypotonia is associated with severe weakness and and resources. is probably of peripheral origin. When antigravity movements are Repeated assessments are crucial in newborns. Indeed, hypotonia present ruling out severe weakness spontaneous general move- in the early life can be due to nonneurological causes, and repeated ments [7] should be assessed qualitatively: in the presence of assessments are important: CNS impairment these movements lose their complex and variable –todistinguish non-specific transient hypotonia (child’s general character and become monotonous and poor. conditions, metabolic problems, maternal sedation ...) from sta- ble hypotonia (probably due to a specific neurological problem); 4.3. Vigilance and responsiveness –toestablish, once the problem is known to be neurological, whether the picture was stable from birth (cause probably oc- These parameters provide information on the state of the CNS curred in utero) or whether there were changes in the symptoms and the integrity of the “higher functions”. Good responsiveness in the first days of life (indicating that the brain injury is recent and interaction, adequate fixation and visual pursuit, and effective and evolving). sucking indicate absence of CNS depression. The association of Dubowitz in 1980 [4] emphasised that the priority when evalu- severe hypotonia and reduced muscle strength with good vigilance ating a floppy infant is to determine whether the cause is central or and responsiveness suggests a peripheral disorder. Conversely, hy- peripheral, starting from the awareness that central causes are far potonia and abnormal responsiveness (lethargy or hyperexcitability more frequent than peripheral ones, and that both can sometimes to the point of seizures) may mean a CNS disorder, such as be present [5]. hypoxic–ischaemic encephalopathy. The cornerstones of the diagnostic work-up are: (1) athorough In a floppy lethargic infant with no history of hypoxic–ischaemic history,and(2)a targeted neurological examination. encephalopathy the possibility of congenital myotonic dystrophy or Prader-Willi syndrome (PWS) should be entertained, as the prompt 3. History identification of other clinical signs of these diseases (myotonia in the mother or typical dysmorphisms in PWS) will allow a more It is important to investigate the pregnancy and delivery history, targeted diagnostic work-up, avoiding unnecessary and invasive noting any complications (e.g. abnormal presentation, difficult de- examinations. livery, Caesarian section) including neonatal ones (need for assisted ventilation, presence of neonatal asphyxia, hypoglycaemia, hyper- 4.4. Head circumference bilirubinaemia, heart disease, etc.) to note the presence of parental consanguinity (many neuromuscular or syndromic diseases are au- Neonatal head circumference provides a measure of the quality tosomal recessive) and any family history of neonatal deaths and of prenatal brain growth. Microcephaly associated with hypotonia neurological disorders remembering that some disorders (e.g. Stein- may indicate prenatal brain impairment, a malformation or a syn- ert myotonic dystrophy or myasthenia) can remain unrecognised in dromic picture, while macrocephaly can point to hydrocephalus, the mother until the birth of a sick child. It is also necessary to Sotos syndrome, or certain peripheral disorders (e.g. the centronu- establish the presence of any hypotonia and ligamentous laxity in clear myopathies). the family, and the age at which the parents and siblings walked. The prenatal history may include reduced foetal movements 4.5. Facies or the presence of polyhydramnios, a possible sign of impaired fœtal swallowing. Olighydramnios may instead indicate chronic The facial appearance of the newborn can provide other “clues”: fetal distress or disease in the mother, which should be investigated the SMAs, for example, are characterised by conservation of facial together with any maternal medication or drug intake. movements associated with absence of limb movements. S. Orcesi / Early Human Development 89S4 (2013) S79–S81 S81

The most evident signs of hypomimia in newborns may be 5. Deep tendon reflexes ptosis, lagophthalmos (incomplete eyelid closure during sleep) or a distinctive “inverted V” shape of the mouth, which indicates the Deep tendon reflexes are, in newborns too, an important ele- presence of facial diplegia and suggests a peripheral disorder, such ment for distinguishing a central disease, in which they are present, as congenital myopathy (especially nemaline or centronuclear) or often brisk and polykinetic, from a peripheral disease, in which they congenital myotonic dystrophy. In the latter, the facial appearance are very weak, or, as in SMA, absent. in newborns may be meaningful if considered together with that of the mother. Typical facial traits, together with hypotonia, can 6. Organomegaly/dysmorphisms be suggestive of syndromes like Down’s syndrome or PWS (high forehead, thin upper lip, and downturned corners of the mouth). Finally, it is important to look for possible organomegaly, es- It is also important to examine the tongue – this can present pecially in metabolic disorders (peroxisomal, lysosomal, energy fasciculations in motor neuron disease or be enlarged (e.g. in Pompe metabolism and storage disorders) or characteristic dysmorphic disease) – and the shape of the palate. features (e.g. inverted nipples or abnormal distribution of subcuta- neous fat in CDG IA syndrome). 4.6. Breathing pattern In conclusion, it is crucial, when faced with a floppy infant, to establish the most appropriate “line of investigation”. Clinical and Hypotonic infants can also have breathing difficulties, and neurological examination remain the essential starting point and may even need assisted ventilation. The shape of the chest, as men- can point us in the direction of a peripheral or central disorder. tioned, may indicate SMA, in which the characteristic breathing pat- tern is diaphragmatic, as the diaphragm as the only muscle spared. Conflict of interest Some neuromuscular diseases (congenital muscular dystrophies, some congenital myopathies) are, instead, characterised by di- The author has no conflict of interest to declare. aphragmatic weakness and a paradoxical breathing pattern. This also applies to SMARD (spinal muscular atrophy with respiratory References distress), an unusual form of SMA with contractures already present at birth. In SMARD the muscle weakness is mostly distal and not [1] Prasad AN, Prasad C. Genetic evaluation of the floppy infant. Semin Fetal proximal, often associated with foot deformities and limb contrac- Neonatal Med 2011;16(2):99–108. [2] Amiel-Tison C. Update of the Amiel-Tison neurologic assessment for the term tures and affects the diaphragm selectively. The disease is inherited neonate or at 40 weeks corrected age Pediatr Neurol. 2002; 27(3):196–212. as an autosomal recessive trait, although the gene responsible [3] Paro-Panjan D, Neubauer D. Congenital hypotonia: is there an algorithm? J (IGHMBP2) is not the same as in the classic SMAs. Child Neurol 2004;19(6):439–42. Apnoeas or hypopnoeas may also be present: once seizures [4] Dubowitz V. The Floppy Infant, 2nd Edition. London: Spastics International Medical Pubblications, 1980. have been ruled out, the presence of neonatal apnoeas associated [5] Bodensteiner JB. The evaluation of the hypotonic infant. Semin Pediatr Neurol with hypotonia and a peculiar facial appearance may indicate 2008; 15(1):10–20 Joubert syndrome, a disease characterised by a malformation of the [6] Vasta I, Kinali M, Messina S, et al. Can clinical signs identify newborns with midbrain and cerebellar vermis with the characteristic “molar tooth neuromuscular disorders? J Pediatr 2005;146(1):73–9. sign” on MRI. [7] Einspieler C, Prechtl HFR. Prechtl’s assessment of general movements: a diagnostic tool for the functional assessment of the young nervous system. Ment Retard Dev Disabil Res Rev 2005; 11: 61–7. Early Human Development 89S4 (2013) S82–S84

Obstetrical brachial plexus injury

Luigi Memo a,*, Stefania Caminiti a,AndreaMemob, Debora Garozzo c, Stefano Ferraresi c aPediatric Unit, Ospedale San Martino, Belluno, Italy bUniversity of Ferrara, Ferrara, Italy cDepartment of Neurosurgery, Ospedale Santa Maria della Misericordia, Rovigo, Italy

ARTICLE INFO ABSTRACT

Keywords: Obstetric brachial plexus palsy (OBPP) is a potentially devastating form of cervical nerve injury that frequently Brachial plexus leads to significant physical disability and occurs in 0.38 to 2.6 births per thousand. The overall incidence of Peripheral nerve injury birth injuries has declined with improvements in obstetrical care and prenatal diagnosis, although a hard- Obstetrical brachial plexus injury core of 1/1000 birth still is considered inevitable. Brachial plexus injuries at birth can be caused by various Root avulsive injuries mechanisms, due to fetopelvic disproportion, causing shoulder dystocia. The use of obstetrical instrumenta- Shoulder dystocia tion during delivery is the consequence of such an event and should not be regarded as the cause of OBPP, Breech delivery especially in medico-legal issues. Often the diagnosis is delayed or ignored and the management of these le- sions has been historically conservative, with observation and physical therapy as the primary modalities of treatment. However, more direct and invasive approaches are often desirable, and consist in primary surgery (nerve microreconstruction) and/or bone, tendon and muscle secondary procedures. © 2013 Elsevier Ireland Ltd. All rights reserved.

1. Introduction of contradicting recommendations regarding the ideal surgical management of obstetrical brachial plexus injuries. The incidence of obstetrical brachial plexus lesions is reported Kennedy and Taylor in the early 1900s became the first to to be 0.38–2.6 per 1000 term infants in United States. History has surgically repair a brachial plexus lesion in the newborn. shown that the great majority of obstetrical brachial plexus palsies However, the high incidence of perioperative and postoperative (OBPP) do resolve without any surgery, with 92% of the recovery morbidity and mortality lead to much controversy regarding the taking place during the first 3 months. Nevertheless, many patients ideal surgical management of these patients in the following years. are left with some sequelae at shoulder, elbow or forearm level. It was not until the advent of microsurgery in the 1960s that According to our experience, gained with a follow-up of more than surgical intervention of brachial plexus lesions truly became a 400 newborns, only those who recover spontaneously a full range mainstay of therapy. Developments and advances by Millesi in of movements within the first month of age make an effective 1964 and Narakas in 1966 furthered the concept of primary nerve normal recovery. grafting and neurorrhaphy, revealing that surgical intervention Brachial plexopathy has been traced back to the early begin- afforded patients better long-term recovery and function of their nings of civilized man. Galen masterfully associated and treated a disabling injuries [1]. temporary paralysis and hypoesthesia of the upper extremity to a lateral traction injury of the neck and elucidated the existence of 2. Etiology somatomotor and somatosensory units within the nerve structure. Following these masterful findings, the true classification of obstet- Thebrachialplexusisanetworkofnervefusionsanddivisions rical brachial plexus palsy then took inception from Smellie in 1746, that originate from cervical and upper thoracic nerve roots and with his description of transient arm palsy in a newborn. Duchenne, terminate as named nerves that innervate muscles and skin of the Erb, Klumpke, and Seeligmuller followed suit by isolating cervical shoulder and arm. nerve roots injuries associated with specific muscle groups in the Birth injury is defined as an impairment of the neonate’s upper extremity. body function or structure due to an adverse event that occurred Following the establishment of the diagnosis and classification at birth. The overall incidence of birth injuries has declined of these injuries, history then became entangled in a quagmire with improvements in obstetrical care and prenatal diagnosis. In particular, in our Country presently the breech presentation is regularly addressed to cesarean section. In the last few years breech delivery has almost disappeared in Italy as a leading cause of OBPP, * Corresponding author: Luigi Memo, U.O.C. di Pediatria e Neonatologia, Ospedale leaving the pace to shoulder dystocia. San Martino Azienda ULSS n°1 Belluno, Viale Europa, 22, 32100 Belluno, Italy. Tel.: +39 0437 516231; fax: +39 0437 516364. Risk factors that increase the risk of birth injuries may be due to E-mail address: [email protected] (L. Memo). fetus (e.g. fetal size and presentation), the mother (e.g. maternal size

0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. L. Memo et al. / Early Human Development 89S4 (2013) S82–S84 S83 and the presence of pelvic abnormalities), and especially in those Ultrasound are also used to image the brachial plexus, ad may severe cases where obstetrical instrumentation is applied [2,3]. be able to suggest noninvasively [6] if an injury is preganglionic Traction, or better, a sudden acceleration during traction, is or postganglionic (the finding of a neuroma in continuity suggest the predominant force creating these devastating injuries. The postganglionic). pathogenesis of injury, as explained by Server and Taylor, is The differential diagnosis of OBPP include decreased arm move- excessive lateral traction on the head of the infant away from the ments due to pain consequent to clavicular or humeral fracture, shoulder during labor. weakness caused by a damage in the epiphyseal cartilage of the In the great majority of lesions, lateral traction during birth is humerus or the extremely rare cases of septic arthritis of the the culprit. These beliefs are further supported by a myriad of other shoulder joint (one case in our series). Among the others, a lesion compounding factors that have been associated with increased risks of the nervous system outside the brachial plexus, or a lesion in the of sustaining obstetrical brachial plexus lesions. brachial plexus due to non-obstetrical causes [7]. Studies performed by Server determined that prolonged labor, forceps delivery, and shoulder dystocia were compounding risk fac- 4. Treatment tors in obstetrical brachial palsy injuries. Factors such as gestational diabetes, forceps delivery, vacuum extraction, and shoulder dystocia After the paper by Gilbert and Tassin in the early 80s, the lack all correlated highly with brachial plexus lesion. In addition, other of recovery of the biceps muscle function at three months of age investigators have found breech delivery, multiparity, macrosomia, was considered the key point leading to nerve microsurgery versus and history of a previous child with brachial plexus injury to be a conservative attitude. Actually we can now count on a world independent risk factors for injury [1]. wide experience of many cases through many observers and some criteria have been slightly modified. 3. Diagnosis Our own experience regards more than 400 OBPP cases and our recommendations are the following: The pathologic basis and histologic changes seen with OBPP Group 4 must be operated as soon as possible because a vary. They include nerve compression, rupture with neuroma in spontaneous recovery is virtually impossible and those babies, if continuity, and multiple root avulsions. Differently from what untreated, are left severely disabled. happens in adult injuries, we have never seen an avulsion of the Groups 1 and 2 are treated by nerve reconstruction if no re- nerve from the muscle and a 5-root avulsive injury is considered an covery in biceps function and/or shoulder elevation is visible at exceptional finding. 4,5 months of age. A mini invasive selective reinnervation of the The initial presentation can range from the classic Erb’s palsy suprascapular nerve can also be decided with the aim of reinner- (OBPP type 1) posture consistent with C5–C6 injury (internal vating the sole shoulder and this is a quick and straightforward rotation and adduction of the shoulder, elbow extension, forearm procedure done through a very small linear incision above the pronation, and wrist flexion), to the modified Erb palsy involving clavicle (see www.plexus.it in the section dedicated to OBPP). C5–C7 also called OBPP type 2 (lacking wrist and finger extensions Although, in type 1 and 2 (under the abovementioned condi- in variable degree), to the complete palsy C5–T1 type without root tions) some degree of recovery is also possible lately without any avulsion (OBPP type 3) or the severely affected flail limb with surgery, the outcome after microreconstruction is by far superior Horner syndrome due to multiple cervical root avulsive injury with among the operated group in terms of quality of function and less or without a phrenic nerve palsy (OBPP type 4). sequelae of deformity. Patients undergo a meticulous history and physical examination The OBPP type 3 is particular. Inasmuch the reconstruction paying particular attention to the perinatal period and the use should include the whole plexus, we prefer in these cases defer of any instrumentation during delivery, presence of clavicular surgery until about 5–6 months of age. The major concern in these or humeral bone fractures, phrenic, recurrent laryngeal, or facial patients regards the treatment of the hand. nerve paralysis and Horner syndrome. A very detailed physical and If in the group 4 the finding of avulsed C8 and T1 prompts neurologic examination must be performed, attempting to grade to reconstruct without hesitations, in the group 3, the lack of and document the affected upper extremity function. interruption of these roots poses hard questions of opportunity. The Concomitant injuries such as Horner syndrome, facial nerve risk is to graft a potentially regenerating lower root, with a late palsy, hoarseness, and contralateral arm function have to be also result which is largely inferior to the spontaneous recovery. documented. Waiting 6 months allows a safer surgery because the electrical The classification system of Mallet is the most famous and monitoring, by that time, can help much in this decision. widespread but is only used to grade muscle function for the Secondary procedures (tendon, muscle and bone surgery) are shoulder in older patients and in those with residual secondary done to overcome the sequelae no longer amenable to correction deformities. with physiotherapy. Photographing and videotaping of the upper extremity may They too are a mainstay of the surgical therapy of OBPP and in also be performed to evaluate and record functionality at time of some cases represent an invaluable armamentarium to improve the presentation. Patients are recorded attempting to use the affected final result of these patients. Subscapularis release and latissimus extremities while placed through several exercises [1] (e.g. the dorsi transfer are the most popular procedures in pure C5–C6 cookie and the handkerchief test). injuries, while derotational osteotomy of the radius and tendon Needle electromyography is no longer considered useful nor transfers at the forearm and hand level are added to them in the predictive of the evolution of the picture. We use it only in those total palsies. rare cases where a different diagnosis is suspected (congenital anomalies do not show degeneration–regeneration patterns). Conflict of interest Magnetic resonance neurography is a specialized procedure that can visualize individual roots, segments of the plexus and The authors have no conflict of interest to declare. peripheral nerves. It is more sensitive than conventional MRI for plexus lesions, and can identify local factors relevant to possible References demyelination and/or compression [4,5] and especially avulsive root injuries. [1] Shenaq SM, Armenta AH, Roth FS, Lee RT, Laurent JP. Current management of S84 L. Memo et al. / Early Human Development 89S4 (2013) S82–S84

obstetrical brachial plexus injuries at Texas Children’s Hospital Brachial Plexus [5] Moore K. MR imaging of peripheral nerve. In: Bromberg M, Smith A (eds), Center and Baylor College of Medicine. Semin Plast Surg 2005;19:42–55. Handbook of Peripheral Neuropathy, 1st ed. Boca Raton: Taylor & Francis [2] Alexander JM, Leveno KJ, Hauth J, Landon MB, Thom E, Spong CY, Varner Group, 2005; p 91. MW, Moawad AH, Caritis SN, Harper M, Wapner RJ, Sorokin Y, Miodovnik [6] Tagliafico A, Succio G, Serafini G, Martinoli C. Diagnostic performance of M, O’Sullivan MJ, Sibai BM, Langer O, Gabbe SG. Fetal injury associated with ultrasound in patients with suspected brachial plexus lesions in adults: a cesarean delivery. Obstet Gynecol 2006;108:885–90. multicenter retrospective study with MRI, surgical findings and clinical follow- [3] Demissie K, Rhoads GG, Smulian JC, Balasubramanian BA, Gandhi K, Joseph up as reference standard. Skeletal Radiol 2013;42:371–6. KS, Kramer M. Operative vaginal delivery and neonatal and infant adverse [7] Alfonso I, Papazian O, Grossman JA. Clinical presentations, differential diagnosis outcomes: population based retrospective analysis. BMJ 2004;329:24–9. and management of obstetric brachial palsy. Rev Neurol 1998;27:258–63. [4] Zhou L, Yousem DM, Chaudhry V. Role of magnetic resonance neurography in brachial plexus lesions. Muscle Nerve 2004;30:305–9. Early Human Development 89S4 (2013) S85–S87

Neonatal abstinence syndrome

Iliana Bersani, Mirta Corsello, Marianna Mastandrea, Vanessa Patacchiola, Silvia Foligno, Virginia Garofalo, Andrea Dotta *

Neonatal Intensive Care Unit, Department of Medical and Surgical Neonatology, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

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Keywords: Substance abuse Neonatal abstinence syndrome Neonate Withdrawal Methadone

1. Drug abuse during pregnancy troschisis, heart defects, cleft lip and palate), neonatal abstinence syndrome (NAS), sudden infant death syndrome, increased inci- Substance abuse during pregnancy is a serious health problem dence of respiratory, ear, and sinus infections, as well as neurologic able to affect either maternal or neonatal clinical status and and behavioural disorders [1,3]. Since pregnant women are often wellbeing [1]. Despite the increasing knowledge on the possible side unaware about the possible consequences of drug abuse during effects related to drug abuse and the attempt to raise awareness pregnancy, assessment of intrauterine exposure to abused drugs, by health caregivers, the use of substances of abuse in pregnancy implementation of toxicology screening and medical issues, proper remained relatively high during the last decades [2,3], with a education about the possible long-lasting stay in a neonatal unit prevalence of about 4.4% among 15 and 44 year old pregnant and the possible need for specific treatment, and periodic follow-up women [3]. However, the exact prevalence of drug abuse during of both the mother and the neonate result of primary importance pregnancy is highly variable and not clearly determinable. Self- [2]. NAS may develop in the early life period after prenatal expo- report is essential to the identification of drug users and, therefore, sure to drugs such as morphine, methadone, codeine, oxycodone, of neonates at risk of complications, but is also limited by the or heroin. Physical dependence on these substances may lead to unsure accuracy and truthfulness of the information. The analysis withdrawal symptoms already early after birth. The main symp- of biological specimens belonging to the mother or the neonate are toms of the NAS include central nervous system hyperirritability helpful to identify the exact prevalence of drug abuse throughout (high-pitched cry, increased muscle tone, tremors, restlessness, con- pregnancy. vulsions), gastrointestinal dysfunctions (poor feeding, weak suction A series of medications, including benzodiazepines, opioids, reflex, regurgitation, vomit, loose or watery stools), fever, sweating, mood-stabilizing drugs, selective serotonin reuptake inhibitors, and respiratory distress, apnea. Finnegan neonatal abstinence score, fist nicotine are able to induce neonatal withdrawal symptoms [1,3–5]. described in 1975 by Finnegan et al. And then modified during the Such drugs are metabolized by the placenta and their metabolites following years [7], is widely used in neonatal units to initiate and cross placental barrier by passive diffusion process, facilitated guide the proper treatment of neonates born to mothers with opi- diffusion, active transport, or, less frequently, pynocitosis [1,6]. oid abuse, although some modifications of the original score have A large number of pregnancy complications often associated been performed throughout the years (Table 1). Score monitoring to substance abuse has been widely described, such as miscar- should begin upon suspicion of NAS in order to allow a systematic riage, preterm labor, placental abruption, premature rupture of and periodic evaluation of the neonate and to design the most membranes, postpartum hemorrhage, malnutrition, anemia, and appropriate therapeutic approach. Finnegan score >8 is currently infections (urinary tract infections or infections often associated considered suggestive of neonatal withdrawal (Table 1). Initially, to drug abuse such as sexually transmitted infections, hepatitis, the duration of score monitoring should be programmed according HIV). Concerning the fetus, possible complications developing after to the half life of the suspected abuse drug. For example, exposure in utero exposure to abused drugs include intrauterine growth to short-acting opioids prompts score monitoring for 48–72 hours restriction, preterm birth, low birth weight, malformations (gas- while in case of methadone exposure score monitoring should be prolonged up to at least 120 hours, since the beginning of withdrawal symptoms may appear belatedly [2]. * Corresponding author: Dr. Andrea Dotta, Bambino Gesù Children’s Hospital, IRCCS, Piazza Sant’Onofrio 4, Rome, Italy. Diagnosis of NAS is first made according to maternal self-report E-mail address: [email protected] (A. Dotta). or medical clinical suspicion. The analysis of biological specimens

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Table 1 Neonatal Abstinence Scoring System [7].

belonging to the mother or the neonate, more commonly urine, of breastfeeding. No safety concerns have been reported also con- meconium, and hair, is a useful diagnostic tool to establish drug cerning breastfeeding in case of mothers receiving buprenorphine exposure during prenatal period [3], although none of these tests is [8]. widely accepted as “gold standard”. Urine testing identifies recent Methadone is the treatment of choice for opioid dependent exposure to maternal drugs. The neonate’s first urine represents the pregnant women, although buprenorphine is a valid and effective best sample. However, the drugs remain only for very short time in alternative to methadone [2]. However, proper prenatal medical the urine, and negative results do not exclude prenatal exposure. care and psychosocial support are recommended [2]. On the other Meconium and hair testing are useful to identify fetal exposure to hand opioid replacement treatment represents the main phar- abused drugs in the second trimester. As for urine, the neonate’s macologic approach also to neonates with withdrawal symptoms first meconium is the most appropriate sample. Further specimens [9,10], but extreme heterogeneity still exists concerning the drug include cord blood and tissue, amniotic fluid, breast milk, oral fluids, of choice and the most appropriate posologic regimens. Mor- blood, sweat, or placental tissue, although these samples are not phine is the most commonly used opioid for replacement therapy, routinely used in clinical practice [1]. Moreover, even the analysis followed by methadone. Further drugs for NAS include buprenor- of biologic samples may provide incomplete results due to the phine, phenobarbital, or clonidine, but fewer investigations about use of different sampling methods or drug-detection methods, to their exact effectiveness and safety have been performed in the the intrinsic sociodemographic variables depending on the different neonatal period. The current posology of these drugs has already settings, or to the test timing during pregnancy or early neonatal been discussed elsewhere [8]. Once the infant is eligible for dis- life [3]. charge, primary health caregivers and community support should Treatment of NAS often requires prolonged hospitalization in be provided. neonatal subintensive/intensive care units. In the presence of neonate’s withdrawal symptoms, minimization of external stim- 2. Nursing monitoring ulation should be guaranteed. Breastfeeding is recommended. In particular, although the absolute amount of methadone in breast Nursing care measures can be divided in: milk is low (<0.2 mg/day) and does not modify neonatal serum Monitoring phase: concentration, a pharmacodynamic effect is suggested, being breast- • Finnegan’s scale fed neonates characterized by less severe NAS and lower need for • Body temperature monitoring; pharmacologic treatment [8]. However it is not clear yet if these ef- • Monitoring of heart and respiratory rate every 15 minutes, if the fects are secondary to the drug itself or rather to the calming effect infant is stable; I. Bersani et al. / Early Human Development 89S4 (2013) S85–S87 S87

• Frequent administration of small amounts of milk to avoid de- neonate. Concerning the pharmacologic therapy, uncertainty still hydration, especially if the infant has vomiting and/or diarrhea. exists about the best drug and posology to be used, and further Practice relief: investigations are required to identify the most appropriate phar- • Place the infant in “Semi-Fowler position” to avoid inhalation of macologic approach. Both medical and nursing care are of primary vomit or secretions; importance for the proper assistance to neonates with NAS. • In case of vomiting or diarrhea, weigh the baby every 8 hours; • In case of motor agitation, protect the face and extremities from Conflict of interest excoriations with gloves and soft sheets; • Prefer a quiet environment with soft lighting. The authors have no conflict of interest to declare. To ensure the proper use of the Finnegan’s scale, it is essential that the nurse knows how to use it properly. A new score sheet References should be initiated at the beginning of each day. The first score should be assigned to the infant immediately after birth or shortly [1] Narkowicz S, Płotka J, Polkowska Z,˙ Biziuk M, Namie´snik J. Prenatal exposure after therapy discontinuation. The first assessment of the newborn to substance of abuse: a worldwide problem. Environ Int 2013;54:141–63. [2] Dow K, Ordean A, Murphy-Oikonen J, Pereira J, Koren G, Roukema H, allows the assignment of a “base score” on which will depend the et al.; Neonatal Abstinence Syndrome Work Group. Neonatal abstinence further evaluations for the entire monitoring period. The Finnegan’s syndrome clinical practice guidelines for Ontario. J Popul Ther Clin Pharmacol score is divided into columns and rows allowing an assessment that 2012;19(3):e488–506. starts from a minimum of 2 hours up to a maximum of 4 hours. [3] Behnke M, Smith VC. Committee on Substance Abuse; Committee on Fetus and Newborn. Prenatal substance abuse: short- and long-term effects on the If the patient has a score >8, the evaluation should be carried out < exposed fetus. Pediatrics 2013;131(3):e1009–24. every 2 hours for a minimum of 24 hours; if the score is 8during [4] Swortfiguer D, Cissoko H, Giraudeau B, Jonville-Béra AP, Bensouda L, Autret- 1 day, the patient can be re-evaluated every 4 hours. However, if Leca E. Neonatal consequences of benzodiazepines used during the last month the infant has a value <8 at the first base assessment, an evaluation of pregnancy. Arch Pediatr 2005;12(9):1327–31. performed every 4 hours we should be performed. It is important [5] ACOG Committee on Practice Bulletins–Obstetrics. ACOG Practice Bulletin: clinical management guidelines for obstetrician-gynecologists number 92, to note that if after discontinuation of drug therapy the score is less April 2008. Use of psychiatric medications during pregnancy and lactation. than 8 for the next 3 days, scoring can be stopped. Obstet Gynecol 2008;111(4):1001–20. Otherwise, if after discontinuation of drug therapy the scores is [6] Minnes S, Lang A, Singer L. Prenatal tobacco, marijuana, stimulant, and ≥8, the assessment should be continued at least for the following 4 opiate exposure: outcomes and practice implications. Addict Sci Clin Pract 2011;6(1):57–70. Review. days to avoid the development of late-onset abstinence symptoms. [7] Finnegan LP. Neonatal abstinence syndrome: assessment and pharmacother- apy. In: Nelson N (ed), Current Therapy in Neonatal-Perinatal Medicine, 2nd 3. Conclusions ed. Ontario: BC Decker, 1990. [8] Kraft WK, van den Anker JN. Pharmacologic management of the opioid In conclusion, prenatal exposure to substances of abuse still neonatal abstinence syndrome. Pediatr Clin North Am 2012;59(5):1147–65. [9] Osborn DA, Jeffery HE, Cole MJ. Opiate treatment for opiate withdrawal in represents a serious health problem leading to maternal and neona- newborn infants. Cochrane Database Syst Rev. 2010;6;(10):CD002059. Review. tal complications. Non-pharmacologic as well as pharmacologic [10] Osborn DA, Jeffery HE, Cole MJ. Sedatives for opiate withdrawal in newborn treatments are recommended for both the mother and thelinebreak infants. Cochrane Database Syst Rev. 2010;6;(10):CD002053. Review. Early Human Development 89S4 (2013) S88–S90

Risk factors of hospitalization for lower respiratory tract infections in infants with 33 weeks of gestational age or more: a prospective Italian cohort study on 2210 newborns

Marcello Lanari a, Federica Prinelli b,c,FulvioAdornib,SimonaDiSantod, Massimo Musicco b,d,* and the “Italian Study Group on Risk Factors for RSV Hospitalization” ✩ aPediatrics and Neonatology Unit, Imola Hospital, Imola, Italy bInstitute of Biomedical Technologies, National Research Council Milan, Italy cDepartment of Food, Environmental and Nutritional Sciences, University of Milan, Italy d Foundation IRCCS Santa Lucia, Rome, Italy

1. Introduction environmental conditions in determining the risk of hospitalization for LRTI in a large cohort of preterm and full term newborns. Lower respiratory tract infections (LRTI) caused by the Respira- tory Syncytial Virus (RSV) represent the major cause of hospitaliza- 2. Subjects and methods tion among young children, especially infants under 12 months of age [1]. 2.1. Study population Children at high risk of hospitalization for RSV-LRTI include preterm infants [2] and infants who are affected by chronic lung dis- This was a longitudinal multicenter cohort study promoted by ease (CLD), congenital heart disease (CHD), immunodeficiency and the Italian Society of Neonatology with the Italian National Research neuromuscular disorders [3]. For these high-risk infants, RSV pro- Council and including thirty neonatology units. Exclusion criteria phylaxis with humanized RSV monoclonal antibodies (palivizumab) for recruitment of newborns were life expectancy shorter than six is effective in reducing the risk of developing severe RSV infections months, CHD and CLD, participation in clinical studies on pharma- and hospitalization [4]. cological or surgical interventions, prophylaxis with palivizumab. Several epidemiological studies have found other determinants The study recruited an equal number of consecutive newborns of of severe RSV infections [5] but results show variability, probably 33+0d–34+6d,35+0d–37+6d and 38+0d or more weeks of gestational because performed in different countries or with alternation in the age (wGA). For each 33+0d–34+6d newborn enrolled, one of 35+0d– RSV epidemic season, and even for the different methodologies 37+6d and one of 38+0d or more wGA newborn of the same gender adopted. Several potential risk conditions are identified to be age and with the closest date of birth were enrolled. At each partici- at the time of RSV infection or birth early during the RSV season, pating hospital unit information was collected by the coordinating younger age, male gender, day care attendance, presence of siblings, investigator. Data collected on prenatal conditions included: pres- household crowding, exposure to tobacco smoke or to air pollution, ence of maternal diseases that could influence neonatal outcome, and lack of breastfeeding [6–9]. history of parents’ respiratory diseases, any assisted reproductive Despite several epidemiological studies have identified some technology, use of corticosteroid therapy for lung maturation, pres- risk factors for RSV infection in preterm babies, only few epidemio- ence of foetal growth restriction, and smoking habits of the mother logical data in healthy and at term infants are available. Aim of this and of the persons living with her. At birth the newborn Apgar study was to evaluate the role of prenatal, perinatal and postnatal/ scores and weight were registered. The perinatal factors investi- gated were: birth from C-section, resuscitation after delivery, use of oxygen and respiratory devices (CPAP), administration of surfactant, ✩ Co-authors of the “Italian Study Group on Risk Factors for RSV Hospitalization”: use of antibiotics, occurrence of disorders after delivery requiring Corsello G, Gabriele B, La Forgia N, Loprieno S, Boldrini A, Vuerich M, Del hospitalization. After discharge, the child’s parents participated to Vecchio A, Bertino E, Gaudino M, Coscia A, Faldella G, Spinelli M, Vandini S, two follow-up phone interviews consisting in a semi-structured Fanos V, Puddu M, Gargano G, Braibanti S, Corso G, Orfeo L, De Luca MG, questionnaire administered by the same trained interviewers. The Paolillo P, Fabiano A, Barberi I, Arco A, Barboni G, Molinari L, Bonomi A, Ladetto L, Carlucci A, Zorzi G, Dall’Agnola A, Girardi E, De Curtis M, Natale F, Di Fabio S, first interview took place at the end of the RSV epidemic season Faccia P, Bottau P, Macagno F, Ellero S, Magaldi R, Rinaldi M, Memo L, Nicolini G, and the second interview at the twelfth month after birth. The Ngalikpima CJ, Nosari N, Sarnelli P, Parmigiani S, Agosti M, Negri C, Corona MF, interviews enquired on environmental conditions of risk, such as PianoF, Scarcella A, Umbaldo A, Aurilia C, Romagnoli C. household health conditions, daily frequentation of other children, * Correspondence to: Massimo Musicco, Institute of Biomedical Technologies, persons smoking in the child’s living environment, and possible National Research, Council Via Fratelli Cervi 93, 20090 Segrate (MI), Italy. Tel.: +39 02 26422629. presence of atmospheric pollution defined as living in an area with E-mail address: [email protected] (M. Musicco). intense vehicular traffic. A further risk condition considered in this

0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. / Early Human Development 89S4 (2013) S88–S90 S89 study was the exposure to the RSV epidemic season. We considered 3. Results children as having been exposed those who lived for at least one month of their first three months of life from November to April. Overall, the children enrolled in the study from birth to the 1- Presence and length of the breastfeeding was recorded. During the year follow up were 2,210 of which 120 (5.4%) were hospitalized for interview, parents were asked about hospitalizations of the child: bronchiolitis (Table 1). Male gender and low GA at birth were asso- in case the child had been admitted to hospital, the interviewer ciated with an increased risk of hospitalization for bronchiolitis. At transmitted the information to the enrolling physician who then multivariable analysis GA lost statistical significance whereas males searched the hospital records and retrieved data on the causes, had a significant 60% risk increase compared to females. Among treatments, and outcome of the disease. prenatal conditions, only corticosteroid therapy during pregnancy The main outcome of this study was hospitalization and/or and exposure of the mother to active or passive cigarette smoke death for bronchiolitis during the first year of life as classified by were found to increase the risk of the outcome in multivariable the ICD-9 codes (466.1, 466.11 and 466.19). Patients admitted for analysis. Compared to singleton delivery, twin delivery appeared to bronchiolitis underwent RSV laboratory confirmatory test whenever be protective on the occurrence of hospitalization for bronchiolitis, the test was foreseen as part of the routine diagnostic work-up with no substantial variation of the adjusted hazard from the crude (approximately 30% of the hospitals participating to this study). estimate. Administration of oxygen after delivery for resuscitation purposes (that was of border-line statistical significance in the anal- 2.2. Analysis ysis adjusted for gender and GA lost significance in multivariable analysis. Respiratory diseases requiring neonatal hospitalization The time-dependent risk of hospitalization for bronchiolitis was and surfactant therapy were associated with a significant increase estimated with survival analysis. The relative risks of exposed of risk. The latter resulted independent from the other variables versus non-exposed children were estimated as hazard ratios (HR) considered at multivariable analysis. Children breastfed had nearly with Cox’ proportional hazard method. Firstly, we evaluated the a 50% reduction in the occurrence of hospitalization for bronchi- HR of each considered variable within prenatal, perinatal, and olitis. Among postnatal/environmental conditions, living with other postnatal groups of conditions, adjusting for GA at birth and for persons in a crowded and/or unhealthy home and having siblings sex; then a multivariable analysis was carried out considering aged less than 10 years old were associated with higher rates of only the variables significantly associated with the outcome. The hospitalization. Finally, children younger than three months of age significant variables within each group of conditions at this second during the RSV epidemic season had a two-fold risk increase of step analysis were finally entered in a final multivariable model. being admitted to hospital for this disease.

Table 1 Relative risks estimates (hazard ratios) according to prenatal, neonatal/perinatal and postnatal/environmental conditions for hospitalization.

Exposures Bronchiolitis hospitalization +/– (%) Multivariable HR a (95% CI b) Exposed No Yes [HR c, 95% CI] Gender – male 44/1060 (4.2) 76/1150 (6.6) [1.6, 1.1–2.3] 1.6 (1.1–2.4) Week of gestational age 33–34 vs ≥38 25/706 (3.5) 54/737 (7.3) [2.1, 1.3–3.4] 35–37 vs ≥38 25/706 (3.5) 41/767 (5.3) [1.5, 0.9–2.5] Prenatal Mother’s history of BPCO 117/2184 (5.4) 3/26 (11.5) [2.2, 0.7–6.9] Mother’s history of eczema 113/2123 (5.3) 7/87 (8.0) [1.6, 0.7–3.4] Father’s history of BPCO 115/2180 (5.3) 5/30 (16.7) [3.6, 1.5–8.9] Assisted reproductive technology 115/1959 (5.9) 5/251 (2.0) [0.3, 0.1–0.6] Treatment with corticosteroids 75/1645 (4.6) 45/565 (8.0) [1.4, 0.9–2.2] 1.6 (1.1–2.4) Mother’s pregnancy pathologies 78/1623 (4.8) 42/587 (7.2) [1.4, 0.9–2.0] Cigarette smoke exposure 58/1358 (4.3) 62/852 (7.3) [1.8, 1.2–2.5] 1.6 (1.1–2.3) Neonatal-perinatal Delivery Singleton 23/537 (4.3) 97/1673 (5.8) [1.9, 1.2–3.0] 1.8 (1.1–2.9)

Resuscitation with O2 95/1911 (5.0) 25/299 (8.4) [1.4, 0.9–2.3)] Perinatal Respiratory diseases 83/1770 (4.7) 37/440 (8.4) [1.5, 1.0–2.2] 1.6 (1.0–2.5) Surfactant therapy 109/2150 (5.1) 11/60 (18.3) [3.8, 1.6–5.8] 2.0 (1.1–3.8) Lack of breastfeeding 78/1728 (4.5) 42/482 (8.7) [1.8, 1.2–2.6] 1.8 (1.2–2.6) Postnatal (environmental) Having sibilings <10 years 40/1310 (3.1) 73/792 (9.2) [3.3, 2.2–4.8] 3.0 (2.0–4.5) ≥10 years 40/1310 (3.1) 7/108 (6.5) [2.2, 1.0–5.0] 1.9 (0.9–4.4) Environmental (home) conditions Crowding 93/1983 (4.7) 27/227 (11.9) [2.6, 1.7–3.9] 2.4 (1.5–3.7) Humidity (Moulds) 101/1988 (5.1) 19/222 (8.6) [1.7, 1.0–2.8] 1.6 (1.0–2.6) Heating system generating smoke 90/1742 (5.2) 30/468 (6.4) [1.2, 0.8–1.8] Residence in the proximity of intense vehicular traffic roads 100/1926 (5.2) 20/284 (7.0) [1.4, 0.9–2.3] Sibilings 63/1414 (4.5) 57/796 (7.2) [1.6, 1.1–2.3] Passive cigarette smoke exposure 112/2102 (5.3) 8/108 (7.4) [1.5, 0.7–3.1] Exposed to epidemic RSV season 31/887 (3.5) 89/1323 (6.7) [2.0, 1.3–3.0] 1.9 (1.3–2.9) a Estimates from a model including all significant variables at gender and weeks of gestational age adjusted analysis. b 95% confidence interval. c Hazard ratios estimates adjusted for gender and weeks of gestational age. S90 / Early Human Development 89S4 (2013) S88–S90

4. Discussion lower respiratory infections in young children in 2010: a systematic analysis. Lancet 2013;381(9875):1380–90. The present study provides a portrait on hospitalizations for [2] Park HW, Lee BS, Kim AR, Yoon HS, Kim BI, Song ES, Kim WT, Lim J, Kim S, Jin HS, Byun S, Chee DH, Kim KS. Epidemiology of respiratory syncytial bronchiolitis within an Italian network of thirty paediatric and virusinfectionininfantsbornatlessthan thirty-five weeks of gestational age. neonatology units. According to our findings, also late preterm and Pediatr Infect Dis 2012;31(8)::99–104. at term babies who do not feature conditions known to increase the [3] Thorburn K. Pre-existing disease is associated with a significantly higher risk for RSV bronchiolitis hospitalization may present other relevant risk of death in severe respiratory syncytial virus infection. Arch Dis Child 2009;94(2):99–103. risk factors. This seems particularly relevant since a large part of [4] Feltes TF, Cabalka AK, Meissner C, Piazza FM, Carlin DA, Top FH jr, Connor EM, RSV infections are observed in children not presenting any relevant Sondheimer HM; Cardiac Synagis Study Group. Palivizumab prophylaxis re- risk conditions. It is worth noting also that in this cohort of preterm duces hospitalization due to respiratory syncytial virus in young children with and at term babies, GA was no longer a determinant of hospitaliza- hemodynamically significant congenital heart disease. J Pediatr 2003;143:532– tion for bronchiolitis when other variables were accounted for: thus 40. [5] Sommer C, Resch B, Simões EAF. Risk Factors for Severe Respiratory Syncytial finding additional criteria could help define a target population of Virus Lower Respiratory Tract Infection. Open Microbiol J 2011;5(Suppl 2- those who would most benefit from RSV prophylaxis. Finally, our M4):144–54. results confirm the importance of environmental factors as relevant [6] Rossi GA, Medici MC, Arcangeletti MC, et al. for Osservatorio RSV Study Group. determinants of LRTI hospitalization (caused or not by RSV). In par- Risk factors for severe RSV-induced lower respiratory tract infection over four consecutive epidemics. Eur J Pediatr 2007;166(12):1267–72. ticular we found that factors enhancing the possibility of contacts [7] Lanari M, Giovannini M, Giuffré L, Marini A, Rondini G, Rossi GA, Merolla with RSV such as living with older siblings, household crowding, R, Zuccotti GV, Salvioli GP, and the Investigators R.A.DA.R. Study Group. exposure to epidemic season were strong and independent factors Prevalence of respiratory syncytial virus infection in Italian infants hospitalized favouring the infection severe enough to require hospitalization. for acute lower respiratory tract infections, and association between respiratory syncytial virus infection risk factors and disease severity. Pediatr Pulmonol 2002;33:458–65. Conflict of interest [8] Karr CJ, Demers PA, Koehoorn MW, Lencar CC, Tamburic L, Brauer M. Influence of ambient air pollutant sources on clinical encounters for infant bronchiolitis. MM is responsible for a research agreement between his institu- Am J Respir Care Med 2009;180,995–1001. tion (CNR) and Abbvie SpA Italy that partially covered the expenses [9] Lanari M, Prinelli F, Adorni F, Di Santo S, Faldella G, Silvestri M, Musicco M on behalf of the “Italian Neonatology Society Study Group of RSV Infections”. for this study. ML, FP, SDS, FA and MS have no conflict of interest Maternal milk protects infants against bronchiolitis during the first year of with the contents and results of this study. life. Results from an Italian cohort of newborns. Early Hum Dev 2013;89(Suppl 1):S51–7. doi: 10.1016/S0378-3782(13)70016-1. References

[1] Nair H, Simões EA and the Severe Acute Lower Respiratory Infections Working Group. Global and regional burden of hospital admissions for severe acute Early Human Development 89S4 (2013) S91–S93

TheguidelinesfortheprophylaxisofRSV:theneedtoupgrade

Alberto Dall’Agnola a,*, Elisa Girardi a,RenzoBeghinib aDepartment of Maternal and Child Health “Silvio Orlandi” Hospital, Bussolengo, Verona, Italy bNeonatal Intensive Care Unit (NICU), “Giambattista Rossi” Hospital Borgo Roma, Verona, Italy

ARTICLE INFO ABSTRACT

Keywords: Respiratory syncytial virus (RSV) is one of the leading causes of severe respiratory illness in infants and young Respiratory syncitial virus children. Prematurity, the presence of congenital heart diseases (CHD) especially if haemodynamically un- Late preterm stable, chronic lung disease, neuromuscular disorders, immunodeficiency, and Down syndrome are all well Premature accepted as placing patients at high risk. Late preterm, is an important risk group for RSV infections to lead to Palivizumab severe bronchiolitis with resource utilization. The findings add support to the theory that RSV infection is an important cause of recurrent wheezing in premature babies. © 2013 Elsevier Ireland Ltd. All rights reserved.

1. Introduction • Infants and children younger than 2 years of age with hemodynamically significant CHD, particularly patients with Premature infants of all gestational ages are at increased risk for pulmonary hypertension or cyanotic heart disease, and those severe Respiratory Syncitial Virus (RSV) disease requiring hospital- who require medication for congestive heart failure. ization and infants younger than two years of age with pre-existing • Infantsbornatlessthan28weeks’gestationandyounger conditions, such as chromosomal abnormalities, neuromuscular, than 12 months before the beginning of the season. Infants cardiac or chronic lung disease (CLD), experience significant com- born at 29 through 31 weeks’ gestation and younger than plications following hospitalization, with a mortality rate ranging 6/12 months before the beginning of the season. from 1% to 4% [1] Extremely low-birth-weight premature in- • Infants born at 32 through 34/35 weeks’ gestation and fants with CLD who acquire RSV infection have an incidence of younger than 3/6 months before the beginning of the season RSV-associated hospitalization of 12.8% to 13.5%, a rate that is who have at least 2 risk factors. approximately 10-fold higher than children without CLD, even up Several studies have established that the following are major to three years of age. The risk of ICU admission and mechanical risk factors: age less than three months at the beginning of the RSV ventilation is almost three- and five-fold higher, respectively, than season, low birthweight and gestational age, siblings and crowded for healthy infants [2]. The direct costs of RSV hospitalization are living conditions, daycare attendance, and exposure to tobacco significant, involving health care resources both in hospital and smoke (passive and during pregnancy) [4]. following discharge. In a prospective, multicentre, population-based In multivariate analyses of several cohort studies [4], sex, age, study [3], the annual economic burden in Germany due to LRTI was birth weight, birth in the first one-half of the RSV season, crowding € 66 million, of which the highest cost per hospitalized RSV case in the household, subject or siblings attending daycare, preschool- was € 2,772. age siblings, passive smoke exposure, breastfeeding and family Immunoprophylaxis with palivizumab, resulting in inhibition history of atopy are evidence-rated variables influencing the risk of RSV replication. is the only available agent for replication of hospitalization. In late preterm risk factors have been used to prevention of RSV infection in high-risk infants reducing the rate of develop robust predictive models both in Canada and Europe to hospitalization and the severity of illness determine which infants are at greatest risk for RSV hospitalization The guidelines specify that immunoprophylaxis should be consid- [5] (Table 1). ered for: • Infants and children younger than 2 years of age who have 2. Why should the guidelines be updated? required medical therapy for CLD within the 6 months prior to the start of RSV season; patients with severe CLD may 1. Several groups of infants and children are documented as having benefit from prophylaxis with palivizumab through 2 RSV an increased risk of severe RSV infection and hospitalization; seasons. however, not all of these special populations are included in the current official prophylaxis recommendations.

* Corresponding author: Alberto Dall’Agnola, Department of Maternal and Child Health “Silvio Orlandi” Hospital, Via Ospedale 1 Bussolengo (Vr), Italy. E-mail address: [email protected] (A. Dall’Agnola).

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Table 1 They have been considered a “major forgotten population” but Risk scoring tool for infants born at 33 to 35 completed weeks’ gestational age in have a threefold higher mortality rate than the healthy term Canada. neonates and are up to five-fold more often Hospitalizated then Risk factor Yes No term infant with RSV-bronchilitis in particular in the first years of Birth month November, December or January 25 0 live. In the Canadian PICNIC prospective cohort study, which en- Subject or siblings attend daycare 17 0 rolled 1205 moderately premature infants, RSV admissions ranged > 5 individuals in the home, including the subject 13 0 from 5.0/1000 to 16.9/1000 infants for those younger than 33 SGA (birth weight <10% for gestational age) 12 0 weeks’ GA; 9.7/1000 to 25.3/1000 for infants between 33 and 36 Family history without eczema 12 0 Male sex 11 0 weeks’ GA, and 1.6/1000 to 3.5/1000 for infants older than 36 >1 smoker in the household 10 0 weeks’ GA. These infants were also more likely to require ICU Total score*/100 admissions and ventilation. Low birth weight is considered to be Eligible to receive palivizumab if total risk score is from 49 to 100,basedon an important predictor of mortality; infants with RSV bronchiolitis provincial guidelines and expert panels (96): low risk (0 to 48), moderate risk (49 weighing less than 1500 g, and 1500 g to 2499 g compared with to 64) and high risk (65 to 100). SGA Small for gestational age. Adapted from Paes those weighing more than 2500 g have an OR of 13.9 (95% CI 5.2 et al. [5]. to 37.0) and OR of 3.0 (95% CI 1.7 to 5.3) for death, respectively. An Italian network of paediatric and neonatology unit, show that 2.1. Special populations not yet included in the current official it is possible to individuate some relevant risk factors that may prophylaxis recommendations increase the risk of this outcome also in those preterm and at term babies without conditions widely recognized to increase the risk for Neuromuscular disease RSV bronchiolitis hospitalization. In this cohort of preterm and at In a prospective RSV surveillance study of 1541 patients across term babies, GA was no more a determinant of hospitalization for 14 pediatric hospitals in Germany children with neuromuscular bronchiolitis but other variables were accounted for. In particular impairments were hospitalized at a median age of 14 months we found that factors enhancing the possibility of contacts with RSV and had a nine-fold increased risk of seizures with a five-fold as living with older brothers or sisters, crowding in the house and increased risk for ventilation compared with the control group. exposure to epidemic season were strong and independent factors The attributable mortality was significantly higher in children with favouring the infection severe enough to require hospitalization neuromuscular disease than controls (5.5% versus 0.2%). Similarly, [9]. an observational study confirmed that infants between 29 and 32 weeks’ GA with neurological disease were twice as likely to require 3. Primary prevention will prevent recurrent wheeze of RSV bron- re-hospitalization with RSV than were preterm infants without chiolitis? impairment [6]. The relationship between RSV infection in infancy, and wheezing Down syndrome and asthma later in life has been the subject of intense debate. Down syndrome have several risk factors that increase their In a prospective observational study of children 35 weeks’ GA or propensity to do poorly if infected with RSV. Bloemers et al. re- younger who had or had not received palivizumab, those receiv- ported an increased incidence of RSV LRTI associated hospitalization ing prophylaxis had a significantly lower incidence of recurrent among children with Down syndrome(DS); namely 9.9% vs 0.7% in wheezing. Two major prospective studies of infants with RSV LRTI siblings with RSV or 0.5–2% among the general paediatric popula- conducted in Sweden and Tucson (Arizona, US) demonstrated that tion, and found DS to be a novel independent risk factor for severe the risk for significant wheeze and asthma symptoms persisted at RSV-bronchilitis [7]. 13 and 11 years of age, respectively, in children who experienced RSV low respiratory trait infection (LRTI) in infancy compared Cystic fibrosis with those without LRTI. In a systematic review of 12 longitudi- Patients with cystic fibrosis (CF) develop recurring exacerbations nal studies, an association of RSV infection with different asthma of pulmonary inflammation and infection with a striking propen- phenotypes was noted, with progressive disappearance of this as- sity for airway colonization with Pseudomonas species. Van Ewijk sociation with increasing age. In a randomized, double-blind trial, et al. demonstrated a 1.2-fold to 8.2-fold increased adherence of Louis Bont and colleagues demonstrated as in healthy infants born Pseudomonas species to epithelial cells in vitro with previous RSV at 33 to 35 weeks of gestation receiving palivizumab injections had infection, and a 1.7-fold to 16-fold increased adherence with con- 61% fewer days of wheezing during their first year of life compared current addition of RSV to cell monolayers. The authors’ hypothesis with those treated with placebo (95% CI 56% to 65%) [10]. was that RSV promotes Pseudomonas attachment to RSV glyco- protein G. Most respondents to a national questionnaire survey 3. Conclusions conducted in the UK in 2007 considered RSV infection important in CF lung pathogenesis and would prescribe palivizumab if funding Prophylaxis with palivizumab is important in high-risk cate- was not an issue; however, only 3 out of 34 centres surveyed gories as Infants born at less than 32 weeks’ gestation, neonate with prescribed palivizumab [8]. congenital heart disease, especially if haemodynamically unstable, chronic lung disease and for special population. Neuromuscular Immunodeficiency disorders, immunodeficiency, Down syndrome, Cystic Fibrosis are Immunocompromised children, particularly those with cell- all well accepted as placing patients at high risk. More attention mediated immune defects, have difficulty clearing RSV infection and should be given to risk factors in late preterm-subgroup. Evidence demonstrate prolonged viral shedding, increased illness severity, exists that infant respiratory RSV infections, further contribute to prolonged hospital stays, and morbidity and mortality rates ranging long-term airway disease, although further trials is necessary. from 1.7% to 40% [6]. Conflict of interest 2. Infants between 33 and 35 completed weeks’ gestational age (GA) have been identified as “late preterm a risk group”forRSV The authors have no conflict of interest to declare. infection. A. Dall’Agnola et al. / Early Human Development 89S4 (2013) S91–S93 S93

References virus prophylaxis in premature infants born at 33–35 completed weeks’ gestational age in Canada. Curr Med Res Opin 2009;25:1585–91. [1] Thorburn K. Pre-existing disease is associated with a significantly higher [6] Resch B, Manzoni P, Lanari M. Severe respiratory syncytial virus (RSV) risk of death in severe respiratory syncytial virus infection. Arch Dis Child infection in infants with neuromuscular diseases and immune deficiency 2009;94:99–103. syndromes. Paediatr Respir Rev 2009;10:148–53. [2] Boyce TG, Mellen BG, Mitchel EF Jr, Wright PF, Griffin MR. Rates of hospital- [7] Bloemers BL, van Furth AM, Weijerman ME, Gemke RJ, Broers CJ, van den ization for respiratory syncytial virus infection among children in medicaid. J Ende K, et al. Down syndrome: a novel risk factor for respiratory syncytial Pediatr 2000;137:865–70. virus bronchiolitis: a prospective birth-cohort study. Pediatrics 2007;120: [3] Ehlken B, Ihorst G, Lippert B, et al.; PRIDE Study Group. Economic impact e1076–81 of community-acquired and nosocomial lower respiratory tract infections in [8] McCormick J, Southern KW. A survey of palivizumab for infants with cystic young children in Germany. Eur J Pediatr 2005;164:607–15. fibrosis in the UK. Arch Dis Child 2007;92:87–8. [4] Carbonell-Estrany X, Figueras-Aloy J, Law BJ, and the Infeccíon Respiratoria [9] Lanari M, Prinelli F Adorni F, et al. and the Italian Neonatology Society Study Infantil por Virus Respiratorio Sincitial Study Group and the Pediatric Investi- Group of RSV Infections. Risk factors of hospitalization for lower respiratory gators Collaborative Network on Infections in Canada Study Group. Identifying tract infections in infants with 33 weeks of gestaional age or more: a risk factors for severe respiratory syncytial virus among infants born after prospective Italian Cohort Study on 2210 newborns. Early Hum Dev 2013; 33 through 35 completed weeks of gestation: different methodologies yield this issue. consistent findings. Pediatr Infect Dis J 2004;23(11 Suppl):S193–201. [10] Blanken M, et al. Respiratory syncytial virus and recurrent wheeze in healthy [5] Paes B, Steele S, Janes M, Pinelli J. Risk-Scoring Tool for respiratory syncytial preterm infants. New Engl J Med 2013;368:1791–9. Early Human Development 89S4 (2013) S94–S95

Bronchiolitis: update on the management

Eugenio Baraldi *, Dania El Mazloum, Michela Maretti, Francesca Tirelli, Laura Moschino

Women’s and Child’s Health Department, Pediatric Respiratory Medicine and Allergy Unit, University of Padova, Italy

ARTICLE INFO ABSTRACT

Keywords: Bronchiolitis is the main cause of lower respiratory tract infection and hospitalization during the first year of Bronchiolitis life. It may occasionally lead to respiratory failure requiring admission to an intensive care unit. Until now, RSV supportive therapy with O2 and hydration has been the main approach recommended by the international Nebulized hypertonic saline guidelines, while the role of pharmacological treatment is still debated. Novel therapeutic strategies, such as High-flow nasal cannula (HFNC) oxygen nebulized hypertonic saline and high-flow oxygen therapy, have been proposed in recent years. The lack of therapy effective treatments for bronchiolitis makes prevention particularly important in reducing the impact of this disease, especially in subjects at risk (i.e. preterm infants with BPD, congenital heart disease, or immunodefi- ciency). © 2013 Elsevier Ireland Ltd. All rights reserved.

Acute bronchiolitis is the most common infection of the lower There are still many controversies regarding the best therapeutic respiratory tract in infants and the leading cause of hospital ad- approach to bronchiolitis. As drug therapies used in the past have mission within the first year of life (affecting 2–4% of all children), proved scarcely effective, supportive treatment is still the only occasionally even requiring admission to an intensive care unit. approach recommended today in the guidelines of the American Children under 6 months old or with pre-existing risk factors, such Academy of Pediatrics [1] (AAP). New therapeutic options have as prematurity, bronchopulmonary dysplasia, cystic fibrosis, con- recently been emerging, however [2]. Supportive therapy relies genital heart disease, structural or functional airway abnormalities, mainly on oxygen therapy, hydration, and nebulized hypertonic Down syndrome, neuromuscular syndromes or immunodeficien- saline. cies, are at greater risk of more severe bronchiolitis, hospitalization The AAP [1] guidelines recommend administering supplemental and mortality. The most frequently involved pathogen is respira- O2 for SaO2 <90% in ambient air. The humidified oxygen can be tory syncytial virus (RSV), but other respiratory viruses such as administered using a nasal cannula or a mask. In clinical practice, rhinovirus (RV) and metapneumovirus (MPV) have been implicated high-flow oxygen therapy with warmed and humidified oxygen too, often as a co-infection. (high-flow nasal cannula [HFNC]) is an increasingly popular form The diagnosis focuses on two main aspects: (1) clinical findings of non-invasive ventilatory support applicable even outside the on physical examination (runny nose, cough, bronchospasm, rales, intensive care setting [3]. HFNC generates a positive pressure in dyspnea, tachypnea, feeding difficulties, apnea, lethargy) and the the pharynx and reduces the workload of the respiratory muscles. patient’s medical history; and (2) etiology, which is important The flow of warmed and humidified O2 at 2L/kg/min (up to a to avoid any pointless use of antibiotics and reduce the risk of maximum of 10L/min) leads to a rapid improvement in infants’ nosocomial transmission. The methods generally used to isolate the SaO2 with a reduction in their CO2. By providing a continuous virus(es) are Antigen or Genome Detection tests (PCR). positive airway pressure, HFNC helps to keep the alveoli open and Hospitalization is recommended for children under 3 months to prevent micro-atelectasis. Studies on bronchiolitis are currently old, also because of the risk of central apneas – when O2 therapy assessing the impact of HFNC, particularly as regards important (SaO2 <90%) or ventilatory support become necessary – and in outcomes such as length of hospital stay and need for admission to caseswithaninadequatesupplyofliquids.Intheabsenceof the intensive care unit. immediate indications for hospitalization, or in cases with pre- Nutrition and hydration are key interventions in the course existing risk factors, intensive short-stay observation should be of bronchiolitis, as they may be hindered by fever, tachypnea, considered. Respiratory failure requiring mechanical ventilation the greater effort of breathing, and upper airway obstruction. and apnea or impaired general conditions warrant admission to the Rehydration can be provided intravenously or via a nasogastric intensive care unit. tube: these two approaches coincide with no significant differences in terms of the length of hospital stay or transfers to intensive care, but the nasogastric tube is easier to insert. * Corresponding author: Eugenio Baraldi, MD, FCCP, Unit of Pediatric Respiratory The use of nebulized hypertonic saline has been amply sup- Medicine and Allergy, Women’s and Children’s Health Department, University of Padova, Via Giustiniani 3, 35128 Padova, Italy. Tel.: +39 049 8213560. ported by many studies in recent years. This therapy is inexpensive, E-mail address: [email protected] (E. Baraldi). well tolerated and effective in reducing patients’ hospital stay [4].

0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. E. Baraldi et al. / Early Human Development 89S4 (2013) S94–S95 S95

Table 1 The monoclonal antibody Palivizumab has proved effective in < Clinical implication reducing hospital admissions and hospital stays in 6-month-old preterm babies and <2-year-old preterm babies with BPD, respec- Supportive therapy tively. It is generally agreed that preterm newborn <32 weeks of Oxygen Mainstay of therapy in patients with SaO2 <90–92% gestation should be treated with palivizumab, while debate still Nebulized hypertonic solution Safe and apparently effective rages on this treatment for infants born after >33 weeks of ges- Chest physiotherapy Not effective tation. There is also evidence to support treating with Palivizumab Pharmacological therapy children with significant congenital heart diseases featuring hemo- Nebulized beta2-agonists Not effective dynamic alterations (heart disease with a significantly increased Nebulized adrenaline Effective in reducing hospital admissions 24 hours after assessment at A&E services pulmonary blood flow, pulmonary venous congestion, or primary or Systemic and inhaled steroids Not effective secondary pulmonary hypertension, or after heart transplantation). Antibiotics Only in selected cases, i.e. those with Children with cystic fibrosis and immunodeficiencies should also be bacterial co-infection or for severe disease considered for this treatment. in children with underlying conditions In recent years, vitamin D has been proved to have a role in the Ribavirin Only in selected cases Montelukast Not effective risk of developing viral respiratory diseases. Preliminary data have Nebulized deoxyribonuclease Not effective revealed a significant correlation between vitamin D deficiency and a higher risk of RSV infection during the first year of life, suggesting that vitamin D supplementation in pregnant women and There is little evidence of any drug therapy being effective the newborn might help to prevent infectious and RSV-associated in the course of bronchiolitis. Two recent systematic reviews bronchiolitis. [5,6] confirmed that inhaled beta2-agonists are not useful in the In conclusion, traditional supportive therapies are still the treatment of bronchiolitis, thus supporting the AAP [1] and SIGN most effective options for the treatment of bronchiolitis, although [7] guidelines. Systemic and inhaled steroids have been extensively promising novel non-invasive approaches such as HFNC are coming assessed over time and found to offer no benefit in terms of to light. Since pharmacological approaches are the object of much reducing the hospitalization rates or hospital stays, or as regards debate, prophylaxis and prevention seem to be fundamental to patients’ short- and long-term prognosis. reducing the burden of this disease in terms of its impact on Recent studies indicate that nebulized adrenaline can be effec- children, families and healthcare systems. tive in reducing the hospitalization rate among children presenting to Emergency Department, but it affords no benefit in terms of Conflict of interest reducing a patient’s hospital stay. Antibiotics are still widely used in the treatment of bronchiolitis, The authors have no conflict of interest to declare. but their routine administration should be avoided due to the related risk of side effects, high costs and potential for inducing an- References tibiotic resistance. The AAP guidelines [1] consequently recommend administering antibiotics only in the event of bronchiolitis with a [1] American Academy of Pediatrics Subcommittee on Diagnosis and Manage- ment of Bronchiolitis. Diagnosis and management of bronchiolitis. Pediatrics bacterial co-infection. 2006;118(4):1774–93. According to the AAP [1] and SIGN [7] guidelines, it is reasonable [2] Da Dalt L, Bressan S, Martinolli F, Perilongo G, Baraldi E. Treatment of to consider using antiviral drugs like ribavirin in cases of severe bronchiolitis: state of the art. Early Hum Dev 2013;89(Suppl 1):S31–6. bronchiolitis or its association with other pre-existing risk factors. [3] Bressan S, Balzani M, Krauss B, Pettenazzo A, Zanconato S, Baraldi E. High-flow nasal cannula oxygen for bronchiolitis in a pediatric ward: a pilot study. Eur J The most recently published data failed to support the efficacy Pediatr 2013 Jul 31 [Epub ahead of print]. of alternatives such as montelukast, inhaled DNase or nebulized [4] Zhang L, Mendoza-Sassi RA, Wainwright C, Klassen TP. Nebulised hypertonic furosemide. saline solution for acute bronchiolitis in infants. Cochrane Database Syst Rev Since there is no specific and effective treatment for bronchi- 2013. olitis, prophylaxis and prevention have an important part to play. [5] Gadomski AM, Brower M. Bronchodilators for bronchiolitis. Cochrane Database Syst Rev 2010;(12):CD001266. Environmental prophylaxis is essential to contain the diffusion of [6]HartlingL,FernandesRM,BialyL,MilneA,JohnsonD,PlintA,etal.Steroids the virus in hospital and at home. The guidelines recommend and bronchodilators for acute bronchiolitis in the first two years of life: frequently washing hands and stethoscopes, and decontamination systematic review and meta-analysis. BMJ 2011;342:d1714. with alcoholic solutions, cleaning firm surfaces with water and [7] Scottish Intercollegiate Guidelines Network (SIGN). Bronchiolitis in children. disinfectant, and avoiding any sharing of contaminated objects. It is NHS Quality improvement Scotland. Available at www.sign.ac.uk. [8]PlintAC,JohnsonDW,PatelH,WiebeN,CorrellR,BrantR,etal.;Pedi- also important to minimize any contact between infected individu- atric Emergency Research Canada (PERC). Epinephrine and dexamethasone in als and young children or other groups at risk during the epidemic children with bronchiolitis. N Engl J Med 2009;360:2079–89. period. Early Human Development 89S4 (2013) S96–S98

Management of acute lung injury and acute respiratory distress syndrome in infants

C. Moretti *, P. Papoff, C.S. Barbàra, E. Caresta, C. Liberati, F. Midulla

Department of Paediatrics, Paediatric Emergency and Intensive Care, Sapienza University of Rome, Rome, Italy

ARTICLE INFO

Keywords: Infants Acute lung injury Respiratory distress

1. Introduction significantly affect long term patient outcomes reducing the impact and effectiveness of pulmonary-based therapies. Acute lung injury and acute respiratory distress (ALI/ARDS) is a clinical syndrome caused primarily by increased permeability 2. Pathophysiology of ALI/ARDS to proteins across the endothelial and epithelial barriers of the lungs. It is characterized as restrictive disease with reduced lung ALI is characterized by an initial injury which triggers cell- compliance caused by loss of surfactant function, atelectatic lung mediated mechanisms releasing a cascade of a variety of mediators regions and accumulation of interstitial/alveolar plasma leakage. that disturb the integrity and function of the cellular linings of Patients usually develop acute respiratory failure rapidly because the alveolar-capillary unit [3]. Hyaline membranes, flooded alveoli of arterial hypoxemia as well as impaired carbon dioxide excretion with protein-rich oedema fluid, infiltrates of polymorphnuclear and elevated work of breathing. The American–European Consensus neutrophils, macrophages and erythrocytes are the leading his- Conference (AECC) in 1994 defined ARDS as respiratory failure of tological hallmarks of ALI. The degree of inflammation depends acute onset with a PaO2/FiO2 ratio ≤200 mm Hg (regardless of on the biological activity and the imbalance between pro- and the level of positive end expiratory pressure, PEEP) and bilateral anti-inflammatory cytokines and, similar to bacterial sepsis, a close infiltrates on a frontal chest radiograph. ALI is defined identically interrelationship exists between inflammatory mediators and the except for a higher PaO2/FiO2 limit of <300 mm Hg. A large coagulation cascade. Activation of pro-coagulative factors (tissue prospective trial from Spain demonstrated that 1.4% of all patients factor) and inhibition of fibrinolysis (plasminogen activator in- admitted to the paediatric intensive care unit and 8.3% of all those hibitor) have been identified to produce platelet–fibrin thrombi in mechanically ventilated met ARDS criteria [1]. Overall mortality small pulmonary vessels. This interplay occurs both in the alveolar in children suffering from ALI/ARDS ranges from 18 to 27%, but compartment and in intra- and extravascular space: unresolved fib- increases to 29–50% when considering only the ARDS group and rin depositions and alveolar hyaline membranes are the net result. is only 3–11% in those who do not develop ARDS [2]. It is Surfactant function is inactivated by leakage of plasma proteins essential, however, to distinguish between ALI/ARDS associated and its production is further diminished by damage to type II with direct pulmonary causes compared to systemic (indirect, pneumocytes. extra-pulmonary) causes. In infants, as well as in children and adults, the most frequent direct cause of either ALI or ARDS is 3. Mechanical ventilation: treatment strategies viral or bacterial pneumonia, followed by aspiration (e.g., gastric aspiration, meconium aspiration in newborns) and, less frequently, Positive pressure mechanical ventilation (MV) with supplemen- near-drowning and inhalation of toxicants. Indirect (systemic) tal oxygen is the cornerstone of therapy of severe hypoxemia, causes of ALI/ARDS are primarily systemic infections followed but careful attention must be given also to nutrition, sedation, by burn injury, hypovolemic shock, generalized trauma, multiple analgesia, cardiopulmonary interactions and fluid balance. Over transfusions and other primary extra-pulmonary injuries. Indirect the past decades patho-anatomical and computerized tomographic forms of ALI/ARDS have substantial multi-organ pathologies that studies have demonstrated the uneven distribution of aerated areas and dense consolidated regions of the lung affected by ALI/ARDS: the remaining alveolar surface for gas exchange was found to be * Corresponding author: Prof. Corrado Moretti. Tel. +39 06 49979382. largely reduced in adult patients and Gattinoni [4] introduced the E-mail address: [email protected] (C. Moretti). term “baby lung” to represent this condition. The use of large

0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. C. Moretti et al. / Early Human Development 89S4 (2013) S96–S98 S97 tidal volumes (10 ml/kg) may cause a remarkable overdistention randomized controlled trials suggested that the use of surfactant of the “baby lung” resulting in loss of compliance. Based on these for critically ill infants and children with bronchiolitis may decrease observations the concept of ventilator induced lung injury (VILI) the duration of MV and PICU stay and also showed favourable evolved during the 1990s and VILI is now considered to initiate effects on oxygenation and CO2 elimination [8]. These data suggest and to sustain lung injury (secondary lung injury) following a a beneficial role for exogenous surfactant in the treatment of viral similar histo-morphological and inflammatory pattern to that of respiratory infection, however the small number of methodologi- the original ALI. Current opinion is that secondary lung injury may cally flawed trials is the main limitation of this review. be reduced using a “lung protective” or “open-lung” strategy [3] characterized by: 6. Inhaled nitric oxide (a) low tidal volumes (≤6 ml/kg) in order to avoid overdisten- sion (volutrauma); Hypoxemia in ALI/ARDS is mainly caused by ventila- (b) sufficient PEEP in order to maintain functional residual tion/perfusion mismatch with increased intrapulmonary shunting capacity (FRC) above closing volumes and to minimize and pulmonary hypertension. Inhaled nitric oxide (iNO) has been repeated alveolar collapse and re-expansion (atelectrauma). shown to be an ideal selective pulmonary vasodilator improving It is likely that individual patients respond differently to oxygenation and decreasing pulmonary artery pressure. In a mul- different PEEP levels: infants with recruitable lung may ticenter RCT, iNO improved oxygenation at 12 and 24 h, however benefit from a more aggressive PEEP strategy whereas in by 72 h there was no difference between the treatment and the patients with non-recruitable lung a more aggressive PEEP placebo group [9]. Subgroup analysis suggests that iNO was more strategy might worsen outcomes. Lung recruitability may be efficacious than placebo in patients with severe hypoxemia, but determined by assessing whether oxygenation, pulmonary despite these effects mortality was not reduced. These data suggest compliance and/or dead space improves with increased that iNO may be effective in specific clinical conditions and perhaps PEEP; this is the reason why its use persists despite no clear evidence of (c) plateau pressure limited to 30 cm H2O or less. efficacy. If achievement of a normal pH and normal PaCO2 requires respiratory support strategies that are potentially damaging to the 7. Prone position lung, lower pH and higher PaCO2, compared to normal levels, should be tolerated. Adult data have demonstrated significant When the patient is in prone position, dependent lung re- improvement in mortality with this approach, which has also gions are recruited under the influence of gravity. Promising gained widespread acceptance in the paediatric field, although no clinical observations in adult ALI/ARDS patients demonstrated that large-scale RCTs have been performed to date. prone position improves oxygenation. Possible mechanisms are in- creased FRC, improved compliance and ventilation, better bronchial 4. High frequency oscillatory ventilation drainage and enhanced perfusion and V/Q matching. A recent meta- analysis concluded that in hospitalized infants and children affected With high frequency oscillatory ventilation (HFOV), it is pos- by acute respiratory distress the prone position is significantly sible to ventilate the patients in the so-called “safe zone of the superior to the supine position in terms of oxygenation [10]. In pressure/volume curve” preventing volutrauma and atelectrauma: summary, currently there is not enough evidence to recommend consequently, with HFOV, the main goals of lung protective venti- prone position for routine use, but “turning the child over” must be lation may be theoretically achieved. For pediatric ALI/ARDS, only considered in infants affected by severe ARDS. one prospective RCT on HFOV has been conducted: it was found that physiological parameters, oxygenation and lung recruitment, Conflict of interest improved, but the duration of MV and 30-day mortality did not differ between the HFOV and the control group [5]. Moreover in The authors have no conflict of interest to declare. theconventionalgrouplargetidalvolumeswereemployedandthis factor could have favored the HFOV group. A recent multicenter References RCT compared the outcomes of adult patients affected by ARDS and treated with the open-lung approach or HFOV [6]. The trial [1] López-Fernández Y, Azagra AM, de la Oliva P, Modesto V, Sánchez JI, Parrilla demonstrated that early application of HFOV does not reduce, J, et al. Pediatric acute lung injury epidemiology and natural history study: and may increase, in-hospital mortality. Thus the use of HFOV in incidence and outcome of the acute respiratory distress syndrome in children. Crit Care Med 2012;40:3238–45. paediatric patients should be carefully considered on an individual [2] Bindl L, Dresbach K, Lentze MJ. Incidence of acute respiratory distress basis. syndrome in German children and adolescents: a population-based study. Crit Care Med 2005;33:209–312. 5. Surfactant replacement therapy [3] Dahlem P, van Aalderen WMC, Bos AP. Pediatric acute lung injury. Paediatr Respir Rev 2007;8:348–62. [4] Gattinoni L, Pesenti A. The concept of “baby lung”. Intensive Care Med There are few studies that have analysed the efficacy of surfac- 2005;31:776–84. tant in paediatric lung injury. Several authors suggest that studies [5] Arnold JH, Hanson JH, Toro-Figuero LO, Gutiérrez J, Berens RJ, Anglin DL. are hampered by the lack of appropriate surfactant preparations Prospective, randomized comparison of high-frequency oscillatory ventilation able to resist local inactivation. A systematic review including six and conventional mechanical ventilation in pediatric respiratory failure. Crit prospective, randomized, controlled trials of surfactant in intubated Care Med 1994;22:1530–9. [6]FergusonND,CookDJ,GuyattGH,MehtaS,HandL,AustinP,etal.High- and mechanically ventilated children with acute respiratory failure frequency oscillation in early acute respiratory distresssyndrome.NEnglJ (trials enrolling neonates or patients with asthma were excluded), Med 2013;368:795–805. showed that surfactant was associated with significantly lower [7]DuffettM,ChoongK,NgV,RandolphA,CookDJ.Surfactanttherapyforacute mortality and that there were positive effects on several other respiratory failure in children: a systematic review and meta-analysis. Crit secondary outcome measures, such as more ventilator-free days Care 2007;11:R66. [8] Jat KR, Chawla D. Surfactant therapy for bronchiolitis in critically ill infants to day 28, significantly shorter duration of mechanical ventilation, (Review). Cochrane Database Syst Rev. 2012;9:CD009194. shortened duration of PICU stay and lower use of rescue therapy [9] Dobyns EL, Cornfield DN, Anas NG, Fortenberry JD, Tasker RC, Lynch A, et [7]. Moreover, a recent meta-analysis which included three small al. Multicenter randomized controlled trial of the effects of inhaled nitric S98 C. Moretti et al. / Early Human Development 89S4 (2013) S96–S98

oxide therapy on gas exchange in children with acute hypoxemic respiratory in hospitalized infants and children (Review). Cochrane Database Syst Rev failure. J Pediatr 1999;134:406–12. 2012;7:CD003645. [10] Gillies D, Wells D, Bhandari AP. Positioning for acute respiratory distress Early Human Development 89S4 (2013) S99–S101

Cerebral ultrasound in full term neonates: why and when?

L. Bartalena *, M. Giampietri, M. Bernardini, P. Biver, F. De Cesaris, E. Fiorentini, V. Madrigali, A. Boldrini

Department of Maternal and Child Health, Division of Neonatology and Neonatal Intensive Care Unit, S. Chiara Hospital, University of Pisa, Italy

1. Introduction Santa Chiara Hospital of Pisa between July 2006 and June 2013. During that period of time all of the examinations were performed Cranial ultrasonography (cUS) is an useful modality to image the and reported by the same well trained attending neonatologists. neonatal brain and it is an essential part of the routine standard of In addition the same ultrasound system (Acuson, Siemens Medical care in high-risk neonates [1]. The advantages of cUS are numerous: Solutions USA, Inc) with the same transducer probe (Acuson 7V3C it can be performed at the bedside with little disturbance to ultrasound probe, Siemens Medical Solutions USA, Inc) was used the infant, it is relatively safe and can be repeated whenever to perform cranial ultrasonography. The setting and the scanning needed. The brain of the full-term infant is slightly more difficult procedures including at least six coronary and seven sagittal views to visualize with cUS than the preterm because the head is larger, were all kept consistent. The criteria for enrollment of subjects most brain structures are further away from the transducer and were defined as follows: (1) small gestational age neonates, (2) the fontanels may be small [2]. The standard acoustic window used asphyxiated full term infants, (3) neonatal seizures, (4) neona- for imaging the neonatal brain is the anterior fontanelle. However tal dysmorphisms, (5) obstetric ultrasound indications, (6) TORCH the cerebellum, brainsteam and posterior subcortical white matter infections, (7) potential sick neonates, and (8) miscellaneous. may be poorly visualized using this approach. The detection of cerebellar abnormality via the anterior fontanelle is complicated by 3. Results the echogenic appearance of the tentorium and cerebellar vermis [3]. Scanning through the posterior or mastoid fontanelle can help During the study period 1240 neonates with gestational age to detect lesions and structural malformations in these areas [4]. of 39±2 (range 37–42 weeks), underwent cranial ultrasonographic With cUS in sick full-term infants it can be possible assess injuries screening testing (Table 1). or congenital abnormalities. Hypoxic–ischemic lesions are the most common injuries in full term infants and several patterns can be 3.1. Small gestational age infants distinguished: predominant injury to the deep grey matter after a severe hypoxic–ischemic event, predominant injury to the cortex This group included 245 neonates. There was no significant and subcortical white matter (watershed pattern) after longer difference between male and female infants. The most common lasting or repetitive hypoxic periods or global brain injury in finding was normal ultrasonographic test and in 42% of neonates very severe cases including the deep grey matter, cortical grey mild periventricular echogenicity; 5% of neonates presented cystic matter and white matter. Hemorrhages (subdural, subarachnoid, lesions of choroid plexus. intraventricular or intraparenchymal) in full term infants are rare. Instead cUS may show many patterns in case of brain infections 3.2. Asphyxiated infants like increased echogenicity in the periventricular and/or subcortical white matter, hydrocephalus and other abnormalities such as This group included 66 infants. Infants with mild asphyxia calcifications and lenticulostriate vasculopathy [5]. In the case presented with normal findings instead infants with moderate to of neonatal seizures strokes are very common causes and the severe hypoxic ischemic encephalopathy presented with periven- ultrasound pattern is characterized by asymmetrical parenchymal tricular echogenicity and increasing echogenicity of basal ganglia echogenicity (i.e. wedge shaped echogenic). cUS is also a valuable and thalami. Basal ganglia and thalamic echogenicity was usually tool for imaging of congenital anomalies [6]. Mega cisterna magna, bilateral. Sometimes widespread injuries were found. arachnoid cyst, cerebellar vermis agenesis or hypoplasia and Dandy Walker malformation or variants can be detected in posterior fossa 3.3. Neonatal seizures especially by mastoid fontanels [7]. This group included 13 infants. All of them were subjected 2. Methods to cUS testing at 2–7 days and 2 weeks after the onset of seizures. We found a stroke with a wedge shaped echogenic area We retrospectively reviewed all cranial ultrasonographic screen- suggestive of middle or posterior cerebral artery infarction in 6 ing tests in full term neonates who were born or transferred to infants, cortical dysplasia in 2 neonates, hemimegalencephaly in 1 infant and in the others cUS remained normal. In all infants with * Corresponding author. seizures a neonatal MRI examination was performed and lesion size

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Table 1 3.6. TORCH infections Total Percentage of total cases This group included 84 infants. They were all born to moth- Small gestational age 245 19.7% ers with probable infections and they were at risk for congenital Normal 114 46.5% lesions. cUS might show a range of changes including increased Mild periventricular echogenicity 103 42% echogenicity in the periventricular and or subcortical white mat- Choroid plexus cyst 13 5% ter, smaller echogenic lesions within the parenchyma, ventricular Other normal variation 15 6.5% dilatation. In 64.3% of the infants cUS scans were normal, in 13% Asphyxiated infants 66 5.3% a mild periventricular echogenicity was found. In 1.1% (one baby) Normal 9 13.6% Mild periventricular echogenicity 40 60.8% we found echogenic parenchymal lesions caused by herpes simplex Increasing echogenicity of basal ganglia and thalami 17 25.6% virus 1 infection. In the remaining 21.2% we found lenticulostriate Neonatal seizures 13 1% vasculopathy, germinolytic or choroid plexus cysts. Normal 1 7.7% Cerebral stroke 6 46.2% 3.7. Potential sick neonates Hemimegalencephaly 1 7.7% Cortical dysplasia 2 15.4% This group included 283 infants and we performed cUS for Mild periventricular echogenicity 3 23% respiratory distress, hypoglycemia, apneas or suspected ALTE. About Neonatal dysmorphisms 92 7.5% 40% of them had normal scans while about 50% showed a mild Normal 50 54.4% Mild periventricular echogenicity 18 19.5% periventricular echogenicity. In the remaining 10% we found other Cortical dysplasia 2 2.2% normal variations like mild ventricular dilatation, prominence of Minor anomalies 12 13% cisterna magna or frontal horn prominence. Other normal variations 10 10.9% Obstetric ultrasound indications 80 6.5% 3.8. Miscellaneous Normal 41 51% Mild periventricular echogenicity 5 6.3% Choroid plexus cyst 7 9% This group included 377 infants. All infants with single umbilical Corpus callosum agenesis 4 5% artery as cUS indication had normal scan or minor anomalies Hydrocephalus 4 5% (i.e. choroid plexus cyst). In the other cases infants had maternal Cerebellar hypoplasia 1 1.2% diabetes or maternal autoimmune disease as scan indication and Other normal variations 18 22.5% they presented with normal findings in 60% of them and in the TORCH infections 84 6.7% other 40% presented with mild periventricular echogenicity. Normal 54 64.3% Mild periventricular echogenicity 11 13% Lenticulostriate vasculopathy 10 12% 4. Discussion Echogenic lesions 1 1.1% Germinolytic/choroid plexus cyst 8 9.6% Pregnant women received regular obstetric ultrasound follow up Potential sick neonates 283 22.8% before delivery so that most major lesions could be detected during Normal 108 38.1% pregnancy. Any neonates known to have any concern of significant Mild periventricular echogenicity 139 49.2% intracranial anomalies was examined soon after birth. Fortunately Other normal variations 36 12.7% the majority of infants presented with normal scan, normal cranial Miscellaneous 377 30.5% Normal 223 59.1% variations (i.e. cavum septum pellucidum, cavum vergae, ventricu- Mild periventricular echogenicity 154 40.9% lar variation, mild periventricular echogenicity) or minor anomalies (i.e. choroid plexus cyst, germinal matrix hemorrhage, choroid plexus hemorrhage, mild ventricular dilatation) [2]. In the present study all small gestational age neonates or infant who underwent and location were better defined on MRI allowing more precise cUS for single umbilical artery presented normal findings, normal prognosis. variations or minor anomalies. Most major anomalies found before delivery were confirmed after birth and controlled in subsequent 3.4. Neonatal dysmorphisms follow up. In regard to cerebral malformations ultrasound is a valuable tool to confirm diagnosis of hydrocephalus, agenesis of the This group included 92 infants. They presented at birth with corpus callosum or cerebellar hypoplasia while ultrasound diagnosis facial dysmorphisms (i.e. hypo-hypertelorism, frontal bossing, mi- of cortical dysplasia is very difficult and in all our cases has always crognathia), body disproportions or other defects. In 54.4% of these needed confirmation by MRI. Other worst injuries were those from infants we found normal scans, in only 19.5% an increased periven- hypoxic–ischemic encephalopathy obviously only found in postna- tricular echogenicity and in 2.2% cortical dysplasia. In the remaining tal ultrasound because the damage in the majority of cases occurred 23.9% we found other normal variations (i.e. cavum septum pel- peri-partum [5]. Term infants with early neonatal seizures who had lucidum, frontal horn prominences, corpus callosum variations) or normal Apgar scores and were not acidotic at birth are most minor anomalies (i.e. mild ventricular dilatation or choroid plexus likely to have had neonatal stroke. We found that cUS in all our cyst). cases of stoke showed abnormalities (i.e. asymmetrical parenchy- mal echogenicity, a wedge shaped echogenic area or rounded very 3.5. Obstetric ultrasound indications echogenic lesions). For these infants a neonatal MRI examination was performed to better define lesion size, location and prognosis. This group included 80 infants in whom we performed cUs In other three infants with seizures we found two cortical dys- for abnormal fetal findings. We found normal scan in 51% of plasias and one hemimegalencephaly. We found two other cases of the infants, increased periventricular echogenicity in 6.3%, choroid cortical dysplasia among infants with facial dysmorphisms. Regard- plexus cysts in 9%, corpus callosum agenesis in 5%, hydrocephalus ing newborns of mothers with suspected infection many have had in 5%, cerebellar hypoplasia in 1.2% and other normal variations in normal brain scans, some lenticulostriate vasculopathy and only 22.5%. one echogenic parenchymal lesions by herpes simplex virus. L. Bartalena et al. / Early Human Development 89S4 (2013) S99–S101 S101

In conclusion there have been significant advances in the [2] Hsu CL, Lee KL, Jeng MJ, Chang KP, Yang CF, Tsao PC, Lee YS, Chen SJ, Soong technology of medical ultrasonography in recent years. In cranial WJ, Tang RB. Cranial ultrasonographic findings in healthy full-term neonates: ultrasonography it is not difficult to examine the brain and even a retrospective review. J Chin Med Assoc 2012;75(8):389–95. doi: 10.1016/ j.jcma.2012.06.007 [Epub2012 Jul 25]. the changes in cerebral blood flow and parenchymal perfusion. [3] Govaert P, de Vries LS. An Atlas of Neonatal Brain Sonography. Mac Keith Although cranial ultrasonography is a convenient technology it has Press, 2010. some limitations especially in minimal parenchymal abnormalities [4] Steggerda SJ, Leijser LM, Walther FJ, van Wezel-Meijler G. Neonatal cra- or anomalies of neonatal cortex. However cUS facilitates early nial ultrasonography: how to optimize its performance. Early Hum Dev 2009;85(2):93–9. doi: 10.1016/j.earlhumdev.2008.11.008 [Epub2009 Jan 13]. bedside diagnosis in a way that is relatively easy and not disturbing [5] Van Wezel-Meijler G, Steggerda SJ, Leijser LM. Cranial ultrasonography in the newborn infant. neonates: role and limitations. Semin Perinatol 2010;34(1):2838. doi: 10.1053/ j.semperi.2009.10.002. Conflict of interest [6] Yikilmaz A, Taylor GA. Cranial sonography in term and near-term infants. Pediatr Radiol 2008;38(6):605–16; qiuz 718–9. doi:10.1007/s00247-007-0692-x [Epub 2008 Jan 9]. The authors have no conflict of interest to declare. [7] Steggerda SJ, de Bruïne FT, Smits-Wintjens VE, Walther FJ, van Wezel-Meijler G. Ultrasound detection of posterior fossa abnormalities in full-term neonates. References Early Hum Dev 2012;88(4):233–9. doi: 10.1016/j.earlhumdev.2011.08.011 [Epub 2011 Sep 15]. [1] Leijser LM, de Vries LS, Cowan FM. Using cerebral ultrasound effectively in the newborn infant. Early Hum Dev 2006;82(12):827–35 [Epub 2006 Oct 30]. Early Human Development 89S4 (2013) S102–S103

Developmental dysplasia of the hip: to screen or not to screen with ultrasound

Alberto Chiara a,*, Maurizio De Pellegrin b,* aPaediatrics Department, Azienda Ospedaliera della Provincia di Pavia, Voghera and Broni-Stradella Hospitals, Italy bPaediatric Orthopaedics Unit, Vita Salute University, IRCCS San Raffaele Hospital, Milan, Italy

ABSTRACT

Early diagnosis is critical for the prompt implementation of treatment and to ensure the best results in de- velopmental dysplasia of the hip (DDH). Clinical DDH screening with a search for Ortolani’s sign does not detect all cases affected by DDH. Universal ultrasound screening is currently the most viable strategy to iden- tify dysplastic hips including subjects with negative results at clinical examination and in the absence of risk factors. © 2013 Elsevier Ireland Ltd. All rights reserved.

Early DDH diagnosis not only facilitates early treatment, but for cases presenting risk factors for DDH. For many years, early it also reduces the likelihood of avascular necrosis of the femoral screening for DDH was conducted throughout the world using head and early osteoarthritis of the hip and leads to the best results Ortolani and Barlow manoeuvres. However in recent years, there [1]. The Norwegian Arthroplasty Register reports that of the 163 have been numerous publications reporting on the failure of this dysplastic hips treated with total hip replacement in young adults type of screening, which is based on the indirect identification of a between 1987 and 2007, 82% were female and 18% were male, and functional sign, and is not an actual morphological evaluation of the the mean age at diagnosis was 4.4 years in the first and 22 in the pathological anatomy that is the basis of DDH. While it is true that second [2]. Also the Register of Orthopaedic Prosthetic Implants of in the presence of a positive Ortolani sign (already described in the the Emilia Romagna Region, home of Ortolani, reports that in the literature as a “click”, after exclusion of other articular noises) the years 2000–2011, with 10% of total hip prostheses fitted, hip dyspla- X-ray or ultrasound have always documented the presence of DDH, sia was the second most frequent cause for intervention, reaching it is equally true that the absence of Ortolani’s sign does not verify first place with 31.1% in patients under the age of 40 [3]. Even the absence of DDH [6]. Moreover, the disappearance of Ortolani’s though both Norway and the Italian region mentioned above have sign, if initially present, does not confirm the normalization of an always given attention to DDH screening, these clinical data have unstable hip, rather it is an indication of the worsening of the not guaranteed a precocious clinical diagnosis and early treatment. morphology. Femoral head necrosis is the most alarming complication in the We report on these two aspects, namely the reliability of treatment of congenital hip dislocation as it is the cause of early Ortolani’s sign and that of identifying risk factors in early detection osteoarthritis of the hip. Its incidence is on average 20% in late of DDH. The results of a large scale study we conducted over an 11- diagnosis [4]. If treatment is started before three months of age the year period at our hospital are as follows: of the 21,709 newborns probability of cephalic necrosis is zero [1] Any residual alteration (43,418 hips) examined by ultrasound, 431 (356 females, 75 males) of the acetabulum, albeit minimal, in adulthood leads to premature displayed 574 (1.32%) hips with severe dysplasia according to Graf’s osteoarthritis of the hip. classification (Types D, III and IV). Regarding the affected side, in In light of the above mentioned data, it appears that early 183 cases it involved the right hip, in 193 cases it involved the detection is the key, but how we should go about implementing it left hip and in 99 cases the hips were bilaterally involved. Of the remains unclear. 431 patients, 315 (73.09%) did not have any known, identifiable It is necessary to screen for this condition and it has been risk factor for DDH; 80 (18.56%) had a positive family history recently reported by a careful study of decision analysis that is for DDH; 24 (5.57%) had a breech position during delivery, or wrong not to do so [5]. The authors of the report recommend global adopted a breech position for the majority of the pregnancy; 12 screening and selective clinical ultrasound should be reserved (2.78%) had both risk factors. The correlations between Ortolani’s sign and DDH at the clinical and ultrasound examination and the * Corresponding authors: Alberto Chiara, Paediatric Department, Azienda Os- correlation between risk factors and DDH are reported in Tables 1 pedaliera della Provincia di Pavia, Voghera and Broni-Stradella Hospitals, Italy. Tel. and 2, respectively. In this large series, the Ortolani maneuver was +39 0383695770. positive in 61 hips (10.63%), while it was negative in the remaining E-mail address: [email protected] (A. Chiara). hips (89.37%). Maurizio De Pellegrin Paediatric Orthopaedics Unit, Vita-Salute University, IRCCS San Raffaele Hospital, Milan, Italy. Tel +39 0226432346. It is therefore not possible to affirm that hip dysplasia will E-mail address: [email protected] (M. De Pellegrin). always be associated with clinical signs, and a negative clinical

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Table 1 In Italy, in surgical referral centers for this disease, cases with a Correlation between Ortolani’s sign and DDH with age at clinical and ultrasound missed or delayed DDH diagnosis are also on the rise, since some evaluation. regions have adopted the U.S. guidelines for screening clinical DDH Hip types (according Number Number of hips with positive Mean age proposed in 2000 and 2006 [7]. to Graf) of hips Ortolani’s sign (%) (days) Finally, if the female sex is considered a risk factor, and all D 298 1 (0.34) 43.47 male infants are excluded apriorifrom ultrasound screening this IIIa 252 48 (18.65) 35.39 assumption does not support the data reported in the literature IIIb 4 1 (25) 124.75 [2,8]. In both studies, in fact, the DDH percentage reported in males IV 20 11 (55) 36.15 was 18% and 17.4%. In light of the above, the most effective strategy for early Table 2 diagnosis and treatment of DDH is the following: Correlation between risk factors and DDH (classification according to Graf) with • clinical screening for all newborns (to immediately check for age at clinical and ultrasound evaluation. signs of hip instability, such as the Ortolani or Barlow sign); Number of Risk Mean age at Type D Type IIIa Type IIIb Type IV • ultrasound examination at birth: in the presence of positive patients factors a US and clinical examination clinical signs (Ortolani, Barlow) or in doubt, in the presence of (days) universally recognized risk factors (family history and breech 315 45.44 154 141 4 16 presentation without distinction of sex). 80 F 34.09 44 36 Ultrasound screening for all newborns between the fourth and 24 B 32.96 17 6 1 sixth week of life (because in the absence of clinical signs and risk 12 F, B 33.67 3 9 factors, dysplasia may be present, because at this age, ultrasound a F = positive family history, B = breech presentation. US, ultrasound. control exams and unnecessary treatments are reduced, because in the case of severe dysplasia it is still possible to implement early treatment, at an age in which the healing potential of the hip is still examination and negative medical history (risk factors) do not ex- very high) clude the presence of dysplasia. In our opinion, the implementation of DDH screening on a selective basis based only on risk factors or Conflict of interest relying solely on the Ortolani maneuver is an inevitable source of delayed diagnosis. None of the authors has any conflicts of interest to declare. However, according to other authors [6,7], the attention of the medical examiner should be focused on identifying those clinical signs that will help make a diagnosis or at least raise the suspicion References of a pathological situation. In this case, distinguishing a “click” from a “clunk” is fundamental because this distinction will be [1] Senaran H, Bowen JR, Harcke HT. Avascular necrosis rate in early reduction critical for the prognosis of the newborn. In fact, a “click” will after failed Pavlik harness treatment of developmental dysplasia of the hip. J not necessitate any additional exams, while the presence of a Pediatr Orthop 2007;27(2):192–7. “clunk” will require further in-depth examination by a specialist [2] Engesæter IØ, Lehmann T, Laborie LB, Lie SA, Rosendahl K, Engesæter LB. Total hip replacement in young adults with hip dysplasia: age at diagnosis, (orthopaedic) or instrumental examination (X-ray or ultrasound). previous treatment, quality of life, and validation of diagnoses reported to In our opinion, to entrust the future of a hip and a baby to the the Norwegian Arthroplasty Register between 1987 and 2007. Acta Orthop difficult distinction between different “joint sounds” is very risky. 2011;82(2):149–54. The authors themselves admit that distinguishing between a slight [3] Register of the Orthopedic Prosthetic Implants. R.I.P.O. Regione Emilia- Romagna 2000 – 2011. http://ripo.cineca.it. laxity on clinical examination and a real instability requires a lot of [4] Gulati V, Eseonu K, Sayani J, Ismail N, Uzoigwe C, Choudhury MZ, Gulati P, experience and skill [6]. Aqil A, Tibrewal S. Developmental dysplasia of the hip in the newborn: A The same authors report that a child with a negative clinical systematic review. World J Orthop 2013;4(2):32–41. examination at birth may develop a dislocation over time. This leads [5] Mahan ST, Katz JN, Kim YJ. To screen or not to screen? A decision analysis of to the question of whether a morphologically normal/healthy hip the utility of screening for developmental dysplasia of the hip. J Bone Joint Surg Am 2009;91(7):1705–19. may develop DDH or whether the initial clinical examination was [6] Nemeth BA, Narotam V. Developmental dysplasia of the hip. Pediatr Rev false negative. Both possibilities are disturbing, and in the light of 2012;33(12):553–61. the above data [2,8], this further underlines that a negative clinical [7] Shipman S, Helfand M, Nygren P, Bougatsos C. Screening for Developmental examination does not exclude the presence of a dysplastic hip. Late Dysplasia of the Hip. Rockville, MD: Agency for Healthcare Research and Quality (US), 2006. diagnoses inevitably lead to an increase in surgical procedures and [8] De Pellegrin M, Moharamzadeh D, Fraschini G. Early diagnosis and treatment a worse outcome [6]. Instead, it is reported that global ultrasound of DDH: a sonographic approach. Hip Int 2007;17(Suppl 5):S15–21. screening reduces the rate of surgical procedures for DDH [9]. [9]VonKriesR,IhmeN,AltenhofenL,NiethardFU,KrauspeR,RückingerS. Lawsuits for failure to diagnose DDH are on the rise in the UK General ultrasound screening reduces therateoffirstoperativeprocedures and the U.S.; in the first they are the third most frequent cause for developmental dysplasia of the hip: a case-control study. J Pediatr 2012; 160(2):271–5. of litigation in orthopaedics [10]. Even in Italy, lawsuits related to [10]ClarkeNM,ReadingIC,CorbinC,TaylorCC,BochmannT.Twentyyearsexpe- misdiagnosis or delayed diagnosis of DDH are increasing. In these rience of selective secondary ultrasound screening for congenital dislocation disputes, the question that is inevitably asked is whether there were of the hip. Arch Dis Child 2012;97(5):423–9. other instruments available, in addition to clinical examination, to assess the early presence of DDH? The answer is obviously yes. Early Human Development 89S4 (2013) S104–S108

How has research changed our clinical practice in the last years?

Fabio Mosca a,*, Mariarosa Colnaghi a, Lorella Giannì a, Paola Roggero a, Ida Sirgiovanni a, Massimo Agosti b, Monica Fumagalli a aNeonatal Intensive Care Unit, Department of Clinical Science and Comunity Health, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy bMaternal and Child Health Department, Del Ponte Hospital, A.O. Di Circolo Fondazione Macchi, Varese, Italy

ARTICLE INFO ABSTRACT

Keywords: Research plays an important role in influencing clinical decisions and building up a safe clinical practice Research although it must be taken into consideration that the practice of the evidence based medicine derives from Clinical practice the integration of the best available external clinical evidence from systematic research with own individual Newborn clinical expertise. The practice of neonatology aims to provide the optimal individualized care for the mother and her baby. In this paper we will address some of the main research findings that have brought recent changes in neonatal clinical practice although frequently raising new questions and therefore making research pathways still incomplete. © 2013 Elsevier Ireland Ltd. All rights reserved.

1. Introduction that were analyzed by means of bacterial inhibition assays ac- cording to Guthrie’s method in order to detect individuals affected Research plays an important role in influencing clinical decisions by phenylketonuria. In the following years screening programs and building up a safe clinical practice. Indeed, it provides the have been extended to other conditions (i.e. congenital hypothy- best external evidence that helps doctors in answering their clinical roidism, cystic fibrosis). The availability of advanced technologies questions (i.e. the accuracy of a diagnostic test, the prognosis (i.e. tandem mass spectrometry), characterized by high analytical of diseases, the best treatment options). It must be taken into specificity and accuracy, has made feasible the assessment of a consideration, however, that the practice of the evidence based greatly increased number of metabolites. Consequently, some 12 medicine derives from the integration of own individual clinical years ago, scientists began to evaluate whether a greater range of expertise with the best available external clinical evidence from metabolic conditions could be successfully included in a screening systematic research. program using a single test. This led to the advent of the so called The practice of neonatology aims to provide the optimal individ- “expanded” newborn screening. However, the “expanded” newborn ualized care to meet the needs of a mother and her baby following screening is so far characterized by a noticeable national, or even childbirth. In this paper we will address some of the main research interregional, variety of practice [1]. Indeed, the introduction of findings that have brought recent changes in neonatal clinical the expanded screening has posed new therapeutic challenges as practice although frequently raising new questions and therefore it may detect affected individuals with attenuated phenotypes that making research pathways still incomplete. can remain asymptomatic for many years or even for life. Disorders with little or no clinical significance could also be detected [2]. 2. “Expanded” newborn screening The assessment of the outcomes related to the expanded newborn programs is also of extreme importance. Wilcken et al. [3] com- Newborn screening represents a composite scientific and med- pared the outcomes at 6 years of age of two cohorts of children: ical field. Indeed, the early detection of severe disorders or po- one including newborns from 1994 to 1998 that were not screened tentially fatal conditions (i.e. genetic, endocrine and metabolic and one including newborns from 1998 to 2002 that were either diseases), that are not symptomatic at birth, leads to well screened or not screened depending on where they were born. known benefits both for the affected individuals and the soci- The authors found that patients that had undergone the “expanded” ety. Population-based newborn screening started in the 1960s with newborn screening had fewer deaths and fewer clinically significant the introduction of the collection of blood spots on filter paper disabilities than unscreened patients. Heringer et al. [4] followed up to 10 years of age 52 subjects identified by newborn screening affected by glutaric aciduria type 1. The authors found that 35 out * Corresponding author: Fabio Mosca, Neonatal Intensive Care Unit, Fondazione of 37 patients treated according to the treatment recommenda- IRCCS “Cà Granda” Ospedale Maggiore Policlinico, University of Milan, Via Com- menda 12, 20122 Milan, Italy. tions remained asymptomatic whereas two patients presented mild E-mail address: [email protected] (F. Mosca). dystonia.

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On the basis of the available data it appears that properly Improved information, active surveillance as well as write organized screening programs, in addition to the establishment of evidence-based guidelines on risk factors and postnatal surveillance agreed case definitions and treatment protocols, could represent even in infants considered healthy at birth are suggested. a useful tool in optimizing the use of mass spectrometry based programs [1]. 5. Breastfed term newborn weight loss

3.Delayedcordclamping The breastfed term newborn weight loss represents a complex event influenced by several factors. In a systematic review 11 A delayed cord clamping (DCC) is generally defined as umbilical studies reported a mean loss of about 6% with a standard deviation clamping performed 30–60 seconds after birth. Systematic reviews of about 2. The timing of the weight loss nadir, that is the point have suggested that clamping the umbilical cord in all births should of lowest weight, has been reported to occur on the third day be delayed for at least 30–60 seconds, with the infant maintained [12]. According to the American Academy of Pediatrics 7% weight at or below the level of the placenta because of the associated loss is considerable acceptable for breastfed newborns regardless of neonatal benefits, including increased blood volume, reduced need mode of delivery. When weight loss exceeds 7% of birth weight, for blood transfusion, decreased incidence of intracranial hemor- the presence of breastfeeding problems and/or the establishment rhage in preterm infants, and lower frequency of iron deficiency of interventions to enhance milk production should be evaluated. anemia in term infants. A longer duration of placental transfusion Excess weight loss (≥10%) is associated with morbidities such as after birth may be beneficial also because this blood is enriched hypernatremic dehydration and hyperbilirubinemia, that can cause with immunoglobulins and stem cells [5,6]. The belief that DCC long term adverse outcomes or even death. causes hyperbilirubinemia or symptomatic polycythemia is unsup- Research has focused the attention in understanding the compo- ported by the available research. Placental transfusion facilitates an sition of losses that accompanies physiological weight loss during increase in the circulatory bed at the same time that the infant’s the initial hours of life in healthy breastfed term newborns. Data various organs assume the many functions maintained by the pla- indicate that during weight loss in breastfed term newborns, body centa during fetal life. This additional blood volume may reduce composition modifications are produced both by a decrease in fat the vulnerability of infants to inflammatory processes and provide free mass and fat mass, being the decrease in fat mass greater protection against infection. than that in fat free mass [13,14]. The significant decrease in the Cord milking is a safe alternative to DCC when the clinical percentage of fat mass may be partly explained by the fact that the situation requires to clamp and cut the umbilical cord quickly. It human milk supply in the first days of life is relatively insufficient consists of stripping the cord from the placenta toward the infant to cover the high metabolic needs of the newborns leading, as a several times; the available studies on term infants conclude that consequence, to a catabolic status. In full-term, breast fed neonates, cord milking significantly improves hematocrit and hemoglobin however, the catabolic period lasts only a few days as human milk levels in the first few days of life when compared with immediate supplied by the mother beyond the first postnatal days remarkably cord clamping, with no associated harm [7]. increases. However, when evaluating the breastfed term newborn weight loss, it must be taken into consideration that iatrogenic 4. Postnatal collapse factors can affect the newborn weight loss and, hence, its composi- tion. Indeed, it has been reported that newborns born to mothers Sudden unexpected postnatal collapse (SUPC) in the first hours that have received a high amount of intravenous fluids show a after birth of apparently healthy term infants is a rare event, which greater newborn weight loss than infants born to mothers that have carries a high risk of mortality and significant neurodisability in received lower amounts of intravenous fluids [15]. These findings survivor. A recent definition of a SUPC event included infants born underline the importance of considering the amount of volumes of >35 weeks gestational age, with 10 min Apgar of >7, considered intravenous fluids infused to the mothers intrapartum as a factor healthy who collapsed suddenly and unexpectedly within the first that may increase the newborn weight loss with regard to the fat postnatal week [8]. The incidence of SUPC has been estimated to free mass component of body composition. range between 2.6–5/100,000 live births. The SUPC may be the first The available evidence underline the need for paying attention presentation of an underlying previously unrecognized congenital to the potential additional risk posed to infants lacking energy anomaly of the cardio respiratory systems or neural control systems stores at birth (i.e. preterm or intrauterine growth restricted) in or an underlying metabolic disorder. An underlying condition can order to optimize their early nutritional management. be found in 60% of cases who undergo detailed postmortem but in most cases no underlying explanation is identified or situational 6. Baby friendly hospital initiative factors that led to a diagnosis of presumed accidental suffocation have been present [9]. Some studies concur in recognizing the Breastfeeding is recommended as as the normal and unequalled association between unexpected postnatal collapse on the first day method for infants’ nutrition as it provides many health advantages and primiparous mothers, skin-to-skin contact and the prone or for infants, mothers, families and society. In 1989 WHO and UNICEF side position of the baby; unlike other unexpected infant deaths, developed the “Ten Steps to Successful Breastfeeding” aimed to there is no excess of male infants or night-time occurrence. The risk promote the initiation and continuation of breastfeeding. The Baby of unexpected postnatal collapse should not be seen as a reason Friendly Hospital Initiative (BHFI) was launched in 1991 on the to reduce or avoid the skin-to skin practice, but it is important to basis of the Ten Steps to Successful Breastfeeding, the Innocenti ensure that infants are not left under the covers unobserved by Declaration and the WHO International Code of Marketing of Breast- staff and that the infant’s position is safe and the nose and mouth milk Substitutes with the aim of making all hospitals with maternity are not occluded [10]. The fact that mothers rarely recognized wards protecting, promoting and supporting breastfeeding. The their infant’s deterioration suggests that inexperience and a lack BFHI has led to increased rates of exclusive breastfeeding [16] and of knowledge of the signs of wellness are important factors. Such positively affected breastfeeding practices with regard to both term delay in recognition may contribute to the poor outcomes observed. and preterm infants [17,18]. Although the growing evidence of Vital signs such as color or respiratory effort may also be more the beneficial impact of BFHI on rates of breastfeeding initiation, difficult to observe if maternal mobility is impaired due to pain, exclusivity and duration, the degree of implementation of the postoperative status or spinal anaesthesia [11]. BFHI differs widely across communities and countries but remains S106 F. Mosca et al. / Early Human Development 89S4 (2013) S104–S108 worldwide well below target. A wide range of barriers and potential 8. “Early protein hypothesis” solutions to BFHI implementation, with regard to the sociopolitical, organizational, and individual settings, has been recently identified A recent systematic review has found that formula-fed infants [19]. Given the available evidence related to the advantages of assume a 1.2 to 9.5-fold greater energy intake and a 1.2 to 4.8-fold breastfeeding, the BFHI implementation is of extreme importance, greater protein intake in the first two weeks of life than breastfed being it also part of the global strategy for infant and young child ones. From the 14th day of life up to the 6th month of life feeding. energy and protein intakes of formula fed infants persists much higher than those of breastfed infants [28]. Indeed, the energy 7. Influence of early nutrition on growth and body composition and protein content of formula is higher than that of breast milk. development In addition, the volumes of milk that formula fed infants assume are greater than those assumed by breastfed infants, probably It is widely acknowledged that growth of breastfed infants sig- contributing to the greater weight gain that characterize formula nificantly differs from that of formula fed infants. The differences fed infants during early infancy. Fast early postnatal weight gain in growth between breastfed and formula fed infants become ap- has been demonstrated to be associated with an increased risk of parent since the first days after delivery. There is evidence that developing the metabolic syndrome. According to the “Early Protein exclusive formula feeding is associated with a much lower newborn Hypothesis”, a high protein intake assumed early in life determines weight loss than breastfeeding [20] even though the weight loss an increased insulin and IGF-1 secretion, promoting early weight nadir occurs irrespectively of mode of feeding [21]. Furthermore, it gain and obesity in young adulthood. The Early Protein Hypothesis has been demonstrated that formula fed infants show an increased has been tested in a large randomized multicenter clinical trial rate of accretion, with regard both to weight and length, from [29]. 1138 healthy, term, exclusively formula fed infants born from the 3rd up to the 12th month of life as compared to breastfed uncomplicated, singleton pregnancies were randomized within the infants [22,23]. On the basis of this evidence, new World Health 8th week of age to receive either a low protein (1.8 g protein/100 Organization growth standards has been developed. The interna- kcal) or a high protein (2.9 g protein/100 kcal) formula up to the tional sample used for obtaining the new charts comprised healthy 5th month of age. Infants belonging to the high protein group breastfed infants grown in environments free from conditions that showed a higher weight and weight-for-length from the 6th month could negatively affect growth [24]. of age throughout the study (up to 24 months).With regard to Assessment of the quality gain in addition to the quantity the endocrine indexes, the serum concentrations of total IGF-I and of growth is of great importance. The dynamic changes of body free IGF-I were 40% higher in the high protein group than in the composition in exclusively breast fed infants (n = 220) during the low protein group. Infants belonging to the high protein group first six months of life have been evaluatedinanobservational, showed an enhanced insulin secretion too [30]. The results from multicenter, prospective study by means of a pediatric air displace- this randomized intervention trial demonstrates the effectiveness of ment plethysmography [25,26]. Three US and one Italian centers reducing protein supply in healthy term infant on the modulation participated into the study. Percentage of fat mass increased over of infants growth and metabolism. the first 4 months of age, from values ranging from 8.69% to 13.19% at birth up to values ranging from 25.29% to 28.28% at four months. 9. Influence of mode of delivery and feeding on the These data, taken all together, demonstrate that a rapid deposition development of gastrointestinal microbiota of fat mass takes place within the first two months of life followed by a gradual rate thereafter. Increasing evidence indicates that gastrointestinal (GI) micro- A systematic meta-analysis of 15 studies has recently been biota plays an important role in human health. Indeed, it promotes performed in order to elucidate the body composition changes in intestinal homeostasis, stimulates immune development, protects healthy term infants according to mode of feeding [27]. The authors against pathogens and affects nutrient utilization. Several factors reported that formula fed infants show higher fat-free mass values are known to influence the postnatal development of GI micro- (kg) during the first year of life than breastfed infants, particularly biota. As Caesarian section prevents exposure to maternal microbes, at 3–4 months (+0.13; 95% CI: 0.03, 0.23, p = 0.01), at 8–9 months infants born by caesarean section have been reported to show a (+0.29; 95% CI: 0.09, 0.49, p = 0.005) and at 12 months (+0.30; 95% different microbiota composition, in terms of a more frequent colo- C:I 0.13, 0.48, p = 0.0008). On the contrary, formula fed infants have nization with Clostridia and Bacteroides and less with Bifidobacteria significantly lower fat mass values than breastfed infants at 3–4 and Lactobacilli as compared with infants born by vaginal delivery months of age (−0.09 kg; 95% CI: −0.18, −0.01, p = 0.04; −1.46%; 95% [31]. Although the biological significance of these modifications CI: −2.75, −0.17, p = 0.03) and at 6 months of age (−0.18 kg; 95% CI: have not been elucidated yet, it can be speculated that the post- −0.34, −0.01, p = 0.03; −1.71%; 95% CI: −3.14, −0.29 p =0.02). natal immune system may develop differently according to the The biological and clinical implications of these results needs mode of delivery. Indeed, an increased risk for atopic diseases has to be further investigated. These data could indicate that the fat been found in children born by caesarean section as compared to stores developed by formula fed infants in the pre-weaning period children born by vaginal delivery [32]. are inadequate, reflecting an abnormal pattern of adipose tissue Compelling evidence indicate that infant mode of feeding development. On the other hand, the rapid increase of fat mass strongly affects infant’s gut colonization. Breastfeeding influences in early life shown by the breastfed infants may represent an the development of a “healthy” gut by providing the substrates evolutionary mechanism to provide the infant with fat stores that for the proliferation and function of beneficial bacteria. Breastfed can be promptly utilized in the case of occurrence of unfavor- newborns have been found to have a more stable and uniform able environmental conditions or during the precarious weaning microbiota spectrum, with L. rhamnosus and Staphylococci being period. the most prevalent, when compared to the formula-fed ones. On The quantity and quality of human milk compounds, especially the other hand, facultative anaerobes such as Bacteroides and proteins and amino acids composition, have been advocated as Clostridium, followed by Staphylococcus, Streptococcus and En- one of the major contributors in determining the differences in terobacteriaceae, characterize formula fed GI microbiota whereas growth and body composition between breastfed and formula fed colonization by bifidobacteria is delayed [33]. infants. On the basis of the available evidence, the potential long-term F. Mosca et al. / Early Human Development 89S4 (2013) S104–S108 S107 consequences of decisions regarding mode of delivery and infant brain lesions which is lower than more premature babies but diet have to be taken into consideration. higher than term newborns and they can be affected by brain lesions common to both preterm and term infants. Some lesions 10. The newborn of the pregnant mother with cancer have a clinical presentation, others are clinically subtle or silent, supporting the possible role of cranial ultrasound screening. Our Cancer in pregnancy is an increasing phenomenon due to preliminary data suggest that lower gestational age, within the late delayed childbearing and increased rates of malignancies related preterm period, and early neonatal morbidities, mainly respiratory to maternal age and it now affects about 0.05–0.1% of pregnancies distress syndrome, can provide an indication at birth to undergo a [34]. Cancer treatment in a pregnant woman is still debated, cranial ultrasound scan as they are associated with a higher risk to as life-saving therapies for the mother arise concerns about the develop brain abnormalities. potential detrimental effects for the developing fetus. However, rapid advances in diagnostic procedures and treatment techniques 12. Conclusions as well as research and clinical experience have allowed new insights into the understanding of the management of cancer When considering the main research findings regarding the during pregnancy. Initial limited but promising evidence-based full term newborn, it must be taken into consideration that data have been provided to support the effectiveness of treatment research efforts have been primarily focused on promoting an of cancer during pregnancy preserving both maternal prognosis and optimal individualized care for the mother-newborn dyad rather fetal well-being. than on evaluating the efficacy of diagnostic procedures and/or Based on this experience, updated oncological and obstetrical the safety of specific therapies as in the case of the preterm guidelines have been published to optimize maternal treatment and newborn. Indeed, being the full term newborn the physiological preserve fetal safety when administering potentially teratogenic reference, understanding the biological processes that take place medications. According to published data chemotherapy after the during the switch from the intrauterine to the extrauterine life first trimester is safe [35–38] and does not increase the rates of and the procedures to undertake in order to optimize the postnatal birth defects (3%) [34,36–38] although intrauterine growth restric- care for the mother and her baby is of extreme importance and tion (IUGR) and transient myelosuppression have been reported represents the first step to address research on newborns affected rarely [39].These advances in maternal management have allowed by pathological conditions. changes in current management of pregnancy and improvement in neonatal outcomes, in particular due to an optimal definition of the Conflict of interest timing of delivery. From a neonatologist perspective prematurity was indeed the commonest neonatal outcome reported in neonates The authors have no conflict of interest to declare. born to pregnant cancer patients, directly associated with potential adverse long term outcomes in childhood [34,40]. The recently References proposed treatment protocols encourage to avoid preterm birth (in particular at gestational ages <34 weeks) by optimizing maternal [1] Wilcken B. Expanded newborn screening: reducing harm, assessing benefit. J treatment during pregnancy, in order to reduce neonatal morbidi- Inherit Metab Dis 2010;33(Suppl 2):S205–10. [2] Dhondt JL. Expanded newborn screening: social and ethical issues. J Inherit ties [41,42]. The delivery planning should aim to term birth unless Metab Dis 2010;33(Suppl 2):S211–7. deterioration of maternal condition or specific therapeutic needs [3] Wilcken B, Haas M, Joy P, Wiley V, Bowling F, Carpenter K, Christodoulou J, to preserve maternal prognosis. Nowadays late preterm infants CowleyD,EllawayC,FletcherJ,KirkEP,LewisB,McGillJ,PetersH,PittJ, are the most represented babies in this population. We assessed Ranieri E, Yaplito-Lee J, Boneh A. Expanded newborn screening: outcome in twenty-seven neonates in utero exposed to chemotherapy for ma- screened and unscreened patients at age 6 years. Pediatrics 2009;124:e241–8. [4] Heringer J, Boy SP, Ensenauer R, Assmann B, Zschocke J, Harting I, Lücke T, ternal breast cancer (unpublished data) who were born at a median Maier EM, Mühlhausen C, Haege G, Hoffmann GF, Burgard P, Kölker S. Use of gestational age of 34 weeks (range 25–39); only 22% (6/27) were guidelines improves the neurological outcome in glutaric aciduria type I. Ann born very preterm (between 25 and 33 weeks of gestation), 70.5% Neurol 2010;68:743–52. (19/27) late preterm and 7.5% (2/27) at term. Neither major mal- [5] Committee on Obstetric Practice, American College of Obstetricians and formations nor IUGR were observed and early neonatal morbidities Gynecologists. Timing of umbilical cord clamping after birth. Obstet Gynecol 2012;120:1522–6. were related to prematurity. No cardiac complications were noticed. [6] McDonald SJ, Middleton P, Dowswell T, Morris PS. Effect of timing of umbilical A multidisciplinary team is necessary to counsel the mother and cord clamping of term infants on maternal and neonatal outcomes. Cochrane the family during pregnancy and to provide advanced oncological, Database Syst Rev 2013;7:CD004074. obstetrical and neonatal care. The management of pregnancy has to [7] Mercer JS, Erickson-Owens DA. Rethinking Placental Transfusion and Cord Clamping Issues. J Perinat Neonat Nurs 2012;26:202–17. be focused on the concept of optimal maternal treatment, trying to [8] Wellchild. 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Unexpected collapse in apparently healthynewborns – a prospective national study of a missing cohort of the early neonatal period, compared to term babies. More recently, neonatal deaths and near-death events. Arch Dis Child Fetal Neonatal Ed advances in neuroimaging techniques have highlighted a higher 2012;97:F30–4. brain vulnerability: at 34 weeks gestation the developing brain [12] Noel-Weiss J, Courant G, Woodend AK. Physiological weight loss in the weights only 65% of the term brain, the cortical volume is only breastfed neonate: a systematic review. Open Med 2008;2:e99–110. [13] Rodríguez G, Ventura P, Samper MP, Moreno L, Sarría A, Pérez-González JM. 53% of the term volume [45] and a five-fold increase in white Changes in body composition during the initial hours of life in breast-fed matter volume occurs between 35 and 41 weeks of gestation healthy term newborns. Biol Neonate 2000;77:12–6. [46]. 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Preventing errors in neonatology

Nicola A. Romeo *, Elisabetta Muccioli

Integrated Operational Unit of Paediatrics, Republic of San Marino Hospital, San Marino

Clinical risk management – where clinical risk is defined as For a long time medical errors, defined as “failure to administer potential patient harm due to medical error – is one of the principal care or administration of improper care, leading to a clinically elements of clinical governance, defined as a systematic approach to significant adverse effect which could have been avoided” have been healthcare complexity that aims to improve the quality of the ser- attributed to individual healthcare workers, who thus take the vices offered to the citizens/users of the national healthcare system. blame. This has made it difficult for professionals to fully accept Over the past two decades, healthcare organisations and admin- the logic inherent in the new “culture” of learning from mistakes, istrators have shown major interest in the issue of clinical risk. The which calls for an accurate reporting of adverse events or near reason for this interest can be found, in particular, in the literature, misses. which shows a marked incidence of errors within the scope of However, knowing the epidemiology of the errors in one’s field patient diagnostics and therapy. These errors negatively impact of work is the first indispensable stage of clinical risk management, patients’ health and entail higher social costs, not only in terms of followed by the analysis and treatment of the error itself. For this monetary expenditure. reason we must understand that today an error must be seen Beginning with the historical study carried out over 20 years ago as “the final event in a chain of factors where the error of the by the Harvard Medical Practice [1], the available epidemiological individual worker is only the final link and not necessarily the main data show an extremely variable incidence of medical errors from culprit.” one country to another and from one centre to another (Table 1), as Errors in the medical field are divided into three cause-based well as from one medical discipline to another [2,3]. categories: Especially within the scope of Intensive Neonatal Care (INC) • latent errors, due to organisational and management issues units, paediatrics and neonatology are recognised as being exposed within a company; to a greater risk of medical error, impacting an estimated 1–3% • active errors, due to errors by individual healthcare workers; of admitted newborns [4,5]; however, these data refer exclusively • errors due to failure of control mechanisms intended to prevent to therapeutic errors committed in INC units, with an average of the occurrence of adverse events or incidents. 25 errors per 1000 patients. Understandably, the category most A not-so-recent dossier [6] focussing on error assessment in exposed to medical error is that of low birth-weight and low hospitals has shown that medical errors are most often due to or- gestational age newborns. ganisational issues (41.3%), whereas errors attributed to healthcare The actual incidence of medical errors has likely been under- professionals are less frequent (16.7%). estimated for a number of reasons, the main one being biased As part of the Risk Management in Healthcare Facilities pro- reports by health workers. As we know, incident reporting – by gramme, the Italian Region of Emilia-Romagna [7] carried out an far the most common data measurement tool in literature – is not incident-report based investigation into incidents concerning moth- suitable for drawing epidemiological conclusions, given also that ers and newborns during the stages of labour and delivery. The many healthcare workers still fear that an incident report may lead investigation involved around 53% of the region’s birth centres (15 to penalties or even medical legal charges. Departments of Obstetrics and Gynaecology) and was intended

Table 1 WHO 2005 data.

Study Site and year Admissions A.E. % USA (New York State) (Harvard Medical Practice Study) Hospital (1984) 30,195 1,133 3.8% USA (Utah–Colorado Study) (UTCOS) Hospital (1992) 14,565 475 3.2% USA (UTCOS) Hospital (1992) 14,565 787 5.4% Australia (Quality in Australian Health Care Study) (QAHCS) Hospital (1,992) 14,179 2,353 16.6% Australia (QAHCS) 2 Hospital (1992) 14,179 1,499 10.6% United Kingdom Hospital (1999–2000) 1,014 119 11.7% Denmark Hospital (1998) 1,097 176 9.0% New Zealand Hospital (1998) 6,579 849 12.9% Canada Hospital and health districts (2001) 3,720 279 7.5%

* Corresponding author.

0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. S110 N.A. Romeo, E. Muccioli / Early Human Development 89S4 (2013) S109–S110 to raise awareness among healthcare workers of the risks inherent analysis and treatment of clinical risk and medical error prevention. in their jobs; furthermore, it aimed to create a database for use Risk management in neonatology – currently limited to therapy within companies and the entire region that could help to pinpoint error prevention experiences – must be expanded to include critical areas requiring intervention. diagnostic error awareness and prevention, as well as assistance 171 reports were recorded between 2005 and March 1st, to healthy newborns, particularly when these newborns are being 2007; in 52.6% of cases they were filed by obstetricians. Of these prepared to be discharged from birth centres and entrusted to the reports, 25 (14.6%) involved a minor/moderate outcome, 10 (5.8%) a local healthcare services. significant/severe outcome, and the remaining 136 reports (79.5%) Furthermore, efforts must be made to single out latent errors. concerned near misses and harmless events. These errors are dangerous because they are so hard to pinpoint, The causes of the reported events can be broken down as as they are mostly ensconced in the thick management and follows: human error in 118 cases (40.9%), organisational error in organisational mesh that is typical of our healthcare companies. 117 cases (40.6%), patient issues in 21 cases (7.3%), environments Certain tools, such as Root Cause Analysis (RCA) and FMEA/ and technology in 32 cases (11.1%). FMECA are effective in systemically approaching errors and discov- During the same period the Italian Ministry of Health, which was ering their roots. The FMEA/FMECA method in particular deserves carrying out a number of initiatives aimed at promoting clinical risk to be implemented, since it involves healthcare professionals in management, activated an experimental protocol for monitoring the planning and revising of the main healthcare services, whose sentinel events [8], defined as “particularly severe and potentially individual stages theey may also be in charge of. Shared analysis avoidable adverse events, which may cause severe harm to patients of these processes makes it easier to single out critical patient and lead citizens to lose confidence in the national healthcare system.” and/or healthcare worker safety areas and to plan corrective actions Of the ten monitored sentinel events, one concerned the death of or improvements. Involving the entire healthcare staff ensures a a mother or a severe labour/delivery-related condition and another series of advantages that goes beyond clinical risk prevention and concerned the death or permanent disability of a healthy newborn enhances the overall quality of healthcare services – a goal shared with birth-weight exceeding 2500 grams and with no correlated by the various stakeholders and consistent with the definition of congenital conditions. 17% of these sentinel events occurred in clinical governance. Obstetrics and Gynaecology departments and 2% in INC units; the most common sites of these events were hospital rooms (37%), Conflict of interest followed by delivery rooms (14%) and INC units (2%). The data emerging from the analysis of sentinel event causes and factors The authors have no conflict of interest to declare. (Table 2) are especially interesting, since they show that the most common cause is the lack or inobservance of procedures and References guidelines within healthcare facilities. These experiences show the urgency for a system as complex as [1] Brennan TA. Incidence of adverse events and neglicence in hospitalised pa- tients. Result of the Harvard Medical Practice Study. N Engl J Med 1991;324(6): a healthcare company to implement a systematic approach to the 370–76. [2] Wilson RM. The quality in Australian Health Care Study. Med J Aust 1995;163:458–71. Table 2 [3] Vincent C. Adverse event in British hospitals: preliminary retrospective record Monitoring sentinel events – Italian Ministry of Health, 2007. review. BMJ 2001;322:517–19. [4] Otero P. Medication error in Pediatric in-patients: prevalence and results of a Breakdown of causes and contributing factors n % prevention program. Pediatrics 2008;122:757–63. Procedures and guidelines 23 24% [5] Ferranti J. Reevaluating the safety profile of pediatrics: a comparison of Patient assessment 18 19% computerized adverse drug event surveillance and voluntary reporting in the Communication 16 17% pediatric environment. Pediatrics 2008;121:1201–7. Staff training and skills 11 12% [6] Novaco F. Gestione del rischio clinico. In: Plebani M, Trenti T, Praticare il Information 11 12% Governo Clinico: qualità, efficacia e professionalità in Medicina. Turin: Centro Safety systems/Patient protection devices 9 9% Scientifico Editore, 2002; pp 131–46. Tools/equipment 7 7% [7] Dossier No. 146/2007. Agenzia Sanitaria Regione Emilia Romagna, April 2007. [8] Italian Ministry of Health. Protocollo sperimentale di Monitoraggio degli eventi Total causes and contributing factors 95 100% sentinella: I rapporto (Settembre 2005–Febbraio 2007). April 2007. Early Human Development 89S4 (2013) S111–S112

Synthetic surfactant: primary data

Tore Curstedt

Section of Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet at Karolinska University Hospital, Stockholm,Sweden

ABSTRACT

Treatment of premature newborn rabbits with synthetic surfactants containing both an SP-B and an SP-C analogue in a simple phospholipid mixture has similar tidal volumes as those treated with animal-derived surfactant preparations and will also to some extent prevent the alveoli to collapse at end expiration, even if no positive end-expiratory pressure is applied. The stabilising effect seems to depend on the structure of the peptides as well as the phospholipid composition. Thus, optimal synthetic surfactants containing two peptides combined with a complex phospholipid composition seem to be ideal to replace natural surfactants within a near future. © 2013 Elsevier Ireland Ltd. All rights reserved.

1. Introduction 2. Activity of synthetic surfactants

Animal-derived surfactant preparations are very effective in A good surface activity in vitro does not mean that the prepara- treatment of premature infants with respiratory distress syndrome tion will have optimal effects in vivo. In experiments on premature but they are expensive to produce and supplies are limited. In order rabbits treated with exogenous surfactant both tidal volumes and to widen the indications for surfactant treatment there is a need for functional residual capacity, determined as lung gas volumes at end synthetic preparations, which can be produced in large quantities expiration, should be measured since the quality of the surfactant and at a reasonable cost. However, the development of clinically is crucial for stabilising the lung at end expiration [4] especially in active synthetic surfactants has turned out to be very complicated experiments without positive end-expiratory pressure (PEEP). since the composition of pulmonary surfactant is complex. PEEP greatly facilitates aeration of the distal airways and Natural surfactant contains at least fifty different phospho- prevents distal airway collapse at end expiration in very preterm lipids [1] and four specific proteins SP-A, SP-B, SP-C and SP-D rabbits mechanically ventilated from birth [5]. [2]. Essential components for optimal surface activity seem to Premature rabbits treated with synthetic surfactants based be the surface-active phospholipid dipalmitoylphosphatidylcholine on a simple phospholipid mixture and only one peptide have and the hydrophobic proteins SP-B and SP-C. However, the com- adequate tidal volumes but the lungs seem to collapse at end plexity of the phospholipid composition and the difficulties to expiration in experiments without PEEP [6]. In contrast, treatment produce synthetic SP-B and SP-C or analogues thereof have delayed with a synthetic surfactant preparation containing phospholipids the development of synthetic surfactant suitable for treatment of and both SP-B and SP-C or their analogues in the same model patients. without PEEP also increases alveolar stability at end expiration [4]. In a recently published review [3] we have discussed the However, both tidal volumes and lung gas volumes are functions effects of synthetic surfactants containing different compositions of of the phospholipid composition as well as the peptides. Since phospholipids and synthetic peptides. Increased understanding of the correlation between tidal volumes and lung gas volumes in the molecular mechanism involved in formation and preservation surfactant-treated animals is poor, the two parameters seem to of the surfactant film at the alveolar surface has lead to the measure different surfactant functions. development of stable and rather simple peptides to replace native SP-B and SP-C but incomplete knowledge of the function of some 3. Clinical trials surfactant phospholipids has resulted in the use of very simple phospholipid mixtures. Clinical trials using synthetic surfactant preparations have been published [7,8]. Venticute [7], which contains a recombinant SP-C analogue, has only been used in clinical trials on patients with acute respiratory distress syndrome. However, these results were of no clinical benefit to the patients [7]. Surfaxin, containing a simple lipid * Correspondence to: Tore Curstedt, Section of Clinical Chemistry, Department mixture and sinapultide (KL ), was given as prophylactic treatment of Molecular Medicine and Surgery, Karolinska Institutet at Karolinska University 4 Hospital, S-171 76 Stockholm, Sweden. to premature infants in randomized clinical trials [8]. Surfaxin E-mail address: [email protected] (T. Curstedt). was approved by FDA in the beginning of 2012 for prevention of

0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. S112 T. Curstedt / Early Human Development 89S4 (2013) S111–S112 respiratory distress syndrome in preterm babies but is still not Acknowledgements commercially available on the US market. In contrast to the above-mentioned synthetic surfactants with This work was supported by the Swedish Heart-Lung Foundation only one peptide a synthetic surfactant containing both an SP-B and and Chiesi Farmaceutici. an SP-C analogue in a phospholipid mixture of dipalmitoylphos- phatidylcholine:palmitoyloleoylphosphatidylglycerol 1:1 (w/w) Conflict of interest have been studied in preterm lambs [9,10]. In one study the results showed that the synthetic surfactant was as effective as The author have no conflict of interest to declare. Survanta in treatment of extremely immature newborn lambs with surfactant deficiency under the study period of five hours [9]. In the References other study the synthetic surfactant and Curosurf were compared regarding inactivation in preterm lambs treated with a combination [1] Berggren P, Curstedt T, Grossmann G, Nilsson R, Robertson B. Physiological ac- of albumin and surfactant [10]. The survival rate after 48 hours of tivity of pulmonary surfactant with low protein content: effect of enrichment with synthetic phospholipids. Exp Lung Res 1985;8:29–51. ventilation was significantly higher after treatment with the syn- [2] Johansson J, Curstedt T. Molecular structures and interactions of pulmonary thetic surfactant than after treatment with Curosurf. Clinical trials surfactant components. Eur J Biochem 1997;244:675–93. on premature newborn babies with respiratory distress syndrome [3] Curstedt T, Andrea Calkovska, Johansson J. New generation synthetic surfac- are ongoing. tants. Neonatology 2013;103:327–30. [4] Almlén A, Stichtenoth G, Linderholm B, Haegerstrand-Björkman M, Robertson B, Johansson J, Curstedt T. Surfactant proteins B and C are both necessary 4. Further development for alveolar stability at end expiration in premature rabbits with respiratory distress syndrome. J Appl Physiol 2008;104:1101–8. During the development of synthetic surfactants most efforts [5] Siew ML, te Pas AB, Wallace MJ, Kitchen MJ, Lewis RA, Fouras A, Morley have involved the hydrophobic proteins SP-B and SP-C. Because of CJ, Davis PG, Yagi N, Uesugi K, Hooper SB. Positive end-expiratory pressure the difficulties to obtain the endogenous proteins with the right enhances development of a functional residual capacity in preterm rabbits ventilated from birth. J Appl Physiol 2009;106:1487–93. configuration different analogues have been developed as well as [6] Johansson J, Some M, Linderholm BM, Almlén A, Curstedt T, Robertson B. other simple peptides. Even if the phospholipid composition in A synthetic surfactant based on a poly-Leu SP-C analog and phospholipids: endogenous surfactant has been studied in detail only simple phos- effects on tidal volumes and lung gas volumes in ventilated immature pholipid mixtures have been used for development of synthetic newborn rabbits. J Appl Physiol 2003;95:2055–63. [7] Spragg RG, Taut FJH, Lewis JF, Schenk P, Ruppert C, Dean N, Krell K, Karabinis surfactants. By using a more complicated phospholipid composition A, Günther A. Recombinant surfactant protein C-based surfactant for patients mixed with both an SP-B and an SP-C analogue an optimal surfac- with severe direct lung injury. Am J Respir Crit Care Med 2011;183:1055–61. tant preparation which is as effective as Curosurf in stabilising the [8] Sinha SK, Lacaze-Masmonteil T, Valls-i-Soler A, Wiswell TE, Gadzinowski alveoli at end expiration may be developed. However, further ex- J, Hajdu J, Bernstein G, Sanchez-Luna M, Segal R, Schaber CJ, Massaro J, periments are needed in order to determine the exact composition d’Agostino R for the Surfaxin Therapy Against Respiratory Distress Syndrome Collaborative Group. A multicenter, randomized, controlled trial of lucinac- for an optimal synthetic surfactant. tant versus poractant alfa among very premature infants at high risk for respiratory distress syndrome. Pediatrics 2005;115:1030–8. Ethics [9] Sato A, Ikegami M. SP-B and SP-C containing new synthetic surfactant for treatment of extremely immature lamb lung. PLoS ONE 2012;7(7):e39392. [10] Seehase M, Collins JJ, Kuypers E, Jellema RK, Ophelders DRMG, Ospina OL, The animal experiments were approved by the local ethical Perez-Gil J, Bianco F, Garzia R, Razzetti R, Kramer BW. New surfactant with committee for animal research, Stockholms norra djurförsöksetiska SP-B and C analogs gives survival benefit after inactivation in preterm lambs. nämnd (N192/12). PloS ONE 2012;7 (10):e47631. Early Human Development 89S4 (2013) S113–S114

Surfactant therapies to treat pulmonary disorders in young infants

P. Biban, S. Spaggiari, L. Andaloro, F. Sacco, D. Silvagni, M. Gaffuri, P. Bonetti

Paediatric and Neonatal Intensive Care Unit, Department of Paediatrics, Azienda Ospedaliera Universitaria Integrata Verona, Italy

ARTICLE INFO ABSTRACT

Keywords: The therapeutic role of surfactant in children suffering acute respiratory failure of different aetiology is still Acute respiratory distress syndrome unclear. Actually, surfactant dysfunction appears to be an important contributor in paediatric pulmonary Acute lung injury diseases causing acute hypoxemic respiratory failure, such as ARDS and bronchiolitis. Thus, surfactant ad- Bronchiolitis ministration might be a valid therapeutic option in these critically ill patients. Despite several studies have Surfactant shown positive effects of exogenous surfactant, improving important outcomes such as oxygenation, dura- Child tion of mechanical ventilation, length of intensive care unit stay, as well as mortality, some other trials have Infant not confirmed such beneficial effects. Larger randomized trials are still needed to clarify the role of surfactant in paediatric patients with severe acute respiratory failure. © 2013 Elsevier Ireland Ltd. All rights reserved.

1. Introduction 2. Exogenous surfactant in paediatric acute respiratory distress syndrome Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) may lead to severe hypoxemia and respiratory failure, still Randomized trials of surfactant treatment in children with ARDS being associated with significant morbidity and mortality, both in have shown more encouraging results than those observed in adults and children. Even though ARDS occurs with less frequency adults. In a multi-institutional, prospective, randomized, controlled, in children than in adults, its pathophysiology and risk factors are unblinded trial, Willson et al. investigated the effect of calf lung sur- somewhat similar. Regardless the aetiology, acute lung injury is factant extract (Infasurf) in 42 patients affected by ALI/ARDS, with a associated with surfactant dysfunction, which is caused by several quite variable age (1 month–16 years). In those patients receiving mechanisms including inhibition of surfactant biophysical function, surfactant they observed a significant and rapid improvement of alterations in alveolar surfactant aggregates, alterations of synthe- oxygenation, an earlier extubation and a shorter stay in paediatric sis, secretion and composition of surfactant by the alveolar type II intensive care when compared to the control group [4]. pneumocytes, the primary cells involved with its metabolism [1]. Few years later, they performed a larger randomized, multicen- However, early trials of surfactant replacement therapy in adults tre blinded trial of endotracheal calfactant instillation compared with severe respiratory failure did not show positive effects on with placebo (153 patients) in infants, children and adolescents major outcomes [2]. with acute lung injury. Surfactant not only improved oxygenation In neonatal and paediatric patients, surfactant deficiency or but, for the first time, it was also associated with a significant dysfunction is usually the result of different pathologic conditions, reduction of mortality. Notably, other important outcomes, such as such as extreme prematurity of the newborn, meconium aspiration duration of mechanical ventilation, PICU or hospital stay were not syndrome, sepsis, pneumonia or ARDS, which may all severely different in the two groups [5]. affect the endogenous surfactant pool. In preterm newborns with Recently, in a masked, randomized, placebo-controlled interna- respiratory distress syndrome (RDS), surfactant therapy is one of the tional trial in 24 children’s hospitals, Willson et al. evaluated the few treatments that has significantly decreased overall mortality, efficacy of a natural exogenous surfactant (calfactant) administra- changing our clinical practice in neonatology. European consensus tion in children up to 18 years of age, suffering acute respiratory guidelines have recently confirmed the effectiveness of surfactant distress syndrome due to direct lung injury. Differently from pre- in RDS and refined its clinical indications [3]. vious results observed by the same authors, in this trial surfactant Differently, the therapeutic role of surfactant in older infants, did not improve mortality at 90 days, ventilator-free days at 28 i.e. beyond the neonatal age, suffering acute respiratory failure of days, durations of ICU and hospital stay, and oxygenation after different aetiology is still unclear. the study intervention, when compared with placebo. As possible explanations for such unexpected negative results, compared with those of previous studies, the authors proposed some differences in * Corresponding author: Dott. Paolo Biban. Tel.: +39 0458122041; fax: +39 0458123373. surfactant concentration, lack of recruitment manoeuvres and less E-mail address: [email protected] (P. Biban). patient positioning changes during surfactant administration [6].

0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. S114 P. Biban et al. / Early Human Development 89S4 (2013) S113–S114

Finally, in a multicentre international trial for the PALISI net- some methodological flaws of the studies and the small sample of work, the same authors evaluated the safety and the effects on enrolled patients, the authors concluded that available data were clinical outcomes of intratracheal lucinactant, a synthetic, peptide- notsufficienttoconfirmorrefutethe effectiveness of surfactant containing surfactant, in young infants with acute hypoxemic res- therapy for severe bronchiolitis requiring mechanical ventilation, piratory failure (1 day–2 years of age). Of the 165 enrolled patients, calling for larger and better designed controlled trials [10]. 67% were from Chile and 33% from U.S. centres [7]. No differences were observed in terms of duration of mechanical ventilation or 4. Conclusions duration of PICU stay. Of note, peri-dosing complications, such as transient oxygen desaturation and bradycardia, were associated Surfactant dysfunction appears to be an important contributor in more frequently with instillation in the lucinactant-treated group paediatric pulmonary diseases causing acute hypoxemic respiratory [7]. failure, such as ARDS and bronchiolitis. Thus, exogenous surfactant administration might be a valid therapeutic option in these critically 3. Exogenous surfactant in acute bronchiolitis ill patients. Indeed, several studies have shown positive effects of various Viral bronchiolitis is one of the commonest causes of acute types of surfactant, mostly of natural origin, improving important respiratory failure in young children, particularly in the first few outcomes such as oxygenation, duration of mechanical ventilation, months of life. Interestingly, an impaired surfactant functional length of intensive care unit and hospital stay, as well as mortality. activity during acute viral bronchiolitis has been observed in However, some other trials have not confirmed these positive humans, which resolves by clinical recovery of the disease. Thus, at findings, in fact showing some unexpected adverse effects on least in theory, exogenous surfactant administration might appear outcomes. At present, such discrepancy of available data does not to be a promising therapy for severe bronchiolitis. allow firm recommendations about the use of surfactant in ARDS In fact, early studies were showing some ameliorating effects, and bronchiolitis. Large randomized controlled trials are still needed particularly in infants with severe bronchiolitis [8,9]. to better clarify the role of surfactant in treating paediatric patients In a small randomized, controlled pilot study Tibby et al. with severe respiratory failure. Furthermore, future trials will have assessed the effects of exogenous surfactant in young infants (mean to elucidate the cost-effectiveness of exogenous surfactant therapy age of 9 weeks) mechanically ventilated for severe RSV-bronchiolitis in this critically ill paediatric population. [8]. Nineteen infants received either two doses of bovine surfactant (Survanta, 100 mg/kg) within 24 and 48 h of mechanical ventilation Conflict of interest or air placebo. Ventilation index (VI) and oxygenation index (OI) significantly improved at 60 h in the surfactant group, whilst The authors have no conflict of interest to declare. static lung compliance and resistance became progressively worse in infants in the placebo, but not in the surfactant-treated group. References However, mean ventilation time and mean length of stay in PICU did not differ between the intervention and the control group, even [1] Willson DF, Notter RH. The future of exogenous surfactant therapy. Respir though the study did not have sufficient power to detect clinically Care 2011;56:1369–86. significant changes in such outcomes [8]. [2] Zhang LN, Sun JP, Xue XY, Wang JX. Exogenous pulmonary surfactant for acute respiratory distress syndrome in adults: A systematic review and In a multicentre, randomized, controlled study, Luchetti et al. meta-analysis. Exp Ther Med 2013;5:237–42. evaluated the effectiveness of exogenous surfactant (Curosurf) in [3] Sweet DG, Carnielli V, Greisen G, et al. European consensus guidelines on the infants with RSV disease with severe acute respiratory failure, management of neonatal respiratory distress syndrome in preterm infants – requiring mechanical ventilation [9]. In 20 infants treated with 2013 update. Neonatology 2013;103:353–68. porcine surfactant, the authors reported a significant improvement [4] Willson DF, Bauman LA, Zaritsky A, et al. Instillation of calf lung surfactant extract (calfactant) is beneficial in pediatric acute hypoxemic respiratory of gas exchange and respiratory mechanics, as well as a shorter failure. Crit Care Med 1999;27:188–95. duration of conventional mechanical ventilation and intensive care [5] Willson DF, Thomas NJ, Markovitz BP, et al. Effect of exogenous surfactant unit stay, when compared with a control group of 20 patients [9]. (calfactant) in pediatric acute lung injury: A randomized controlled trial. Nonetheless, recent systematic reviews performed on this sub- JAMA 2005;293:470–6. [6] Willson DF, Thomas NJ, Tamburro R, et al. for the Pediatric Acute Lung and ject have not clearly confirmed the effective role of surfactant Sepsis Investigators Network. Pediatric calfactant in acute respiratory distress in these patients. In their recent meta-analysis, Jat and Chawla syndrome trial. Pediatr Crit Care Med 2013; in press. incorporated three relatively small randomized studies, including [7] Thomas NJ, Guardia CG, Moya FR, et al. A pilot, randomized, controlled clinical 79 subjects, either treated with natural surfactant (porcine or trial of lucinactant, a peptide-containing synthetic surfactant, in infants with bovine) or with nothing/placebo (air) [10]. Among major outcomes, acute hypoxemic respiratory failure. Pediatr Crit Care Med 2012;13:646–53. [8] Tibby SM, Hatherill M, Wright SM, et al. Exogenous surfactant supplementa- duration of mechanical ventilation was not different between the tion in infants with respiratory syncytial virus bronchiolitis. Am J Respir Crit groups, even though there was an obvious trend favouring the Care Med 2000;162:1251–6. intervention group. Interestingly, other outcomes such as duration [9] Luchetti M, Ferrero F, Gallini C, et al. Multicenter, randomized, controlled study of porcine surfactant in severe respiratory syncytial virus induced of intensive care unit (ICU) stay, PO2/FiO2 ratio and CO2 elimination respiratory failure. Pediatr Crit Care Med 2002;3:261–8. at 12 and 24 hours, were all supporting a favourable effects of [10] Jat KR, Chawla D. Surfactant therapy for bronchiolitis in critically ill in- surfactant use. Of note, no adverse effects or complications were fants. Cochrane Database Syst Revi 2012;9:CD009194. doi: 0.1002/14651858. reported in the group treated with surfactant. However, due to CD009194.pub2. Early Human Development 89S4 (2013) S115–S116

Sustained lung inflation to manage preterm infants (25–29 weeks’ gestation) in the delivery room: the Italian SLI study

Gianluca Lista a,*, Carlo Dani b,LucaBonic, Francesco Cavigioli a,SimonePratesib, Massimo Agosti d, Massimo Bellettato e,PaoloBibanf, Antonio Del Vecchio g, Diego Gazzolo h, Camilla Gizzi i,RosarioMagaldij, Hubert Messner k,FabioMoscal, Fabrizio Sandri m, Fabio Scopesi n, Daniele Trevisanuto o, Giovanni Vento p, Antonio Boldrin q aNeonatal Intensive Care Unit, “V. Buzzi” Children Hospital of Milan, Italy bDepartment of Surgical and Medical Critical Care, Section of Neonatology, Careggi University Hospital of Florence, Italy cClinical Trials Coordinating Center, Istituto Toscano Tumori, Florence; Department of Human Pathology and Oncology, University of Florence, Italy d Maternal and Child Health Department, Del Ponte Hospital, A.O. Di Circolo Fondazione Macchi, Varese, Italy eDivision of Neonatology, Ospedale San Bortolo, Vicenza, Italy fDepartment of Pediatrics, Pediatric and Neonatal intensive Care Unit,University of Verona, Italy g Neonatal Intensive Care Unit, Di Venere Hospital, Bari, Italy hDepartment of Maternal Fetal and Neonatal Medicine C. Arrigo Children’s Hospital, Alessandria, Italy i Division of Neonatology, S. Giovanni Calibita Hospital Fatebenefratelli, Isola Tiberina, Rome, Italy jNeonatal Intensive Care Unit, Ospedali Riuniti, Azienda Ospedaliero-Universitaria, Foggia, Italy kNeonatal Intensive Care Unit, Ospedale Regionale, Bolzano, Italy l Neonatal Intensive Care Unit, Department of Mother and Infant Science, Fondazione IRCCS “Cà Granda” Ospedale Maggiore Policlinico, University of Milan, Milan, Italy mMaternal and Pediatrics Department, Maggiore Hospital, Bologna, Italy nDepartment of Neonatology Obstetrics and Neuroscience, G. Gaslini Children’s University Hospital, Genoa, Italy o Department of Pediatrics, Padua, Italy pDivision of Neonatology, Catholic University of Rome, Italy qDivision of Neonatology, University of Pisa, Italy

ABSTRACT

There is not a conclusive role of Sustained Lung Inflation (SLI) in the management of preterm infants at risk for RDS in the delivery room. This strategy would permit lung recruitment immediately after birth through delivery of brief peak pressure to the infant airways via a nasopharyngeal tube or mask allowing preterm in- fants to achieve FRC and reduce need of mechanical ventilation. We planned in Italy a randomized controlled trial (RCT) to confirm or refute these findings. © 2013 Elsevier Ireland Ltd. All rights reserved.

1. Background for respiratory support [4]. We planned in Italy a randomized controlled trial (RCT) to confirm or refute these findings (Trial Recently, some studies have investigated the effectiveness of the registration: ClinicalTrials.gov Identifier: NCT01440868). early sustained lung inflation (SLI) procedure in preterm infants for prevention of mechanical ventilation (MV), with interesting 2. Aim of the study results but without definite conclusions in term of reduction of MV and capacity to improve respiratory outcomes [1–3]. This To verify if a SLI (by mask) in the DR can reduce the need of strategy would permit lung recruitment immediately after birth MV in the first 72 hrs of life in preterm infants at high risk for RDS through delivery of brief peak pressure to the infant airways (primary end-point). via a nasopharyngeal tube or mask allowing preterm infants to achieve FRC. To avoid lung collapse at the end of the expiration, 3. Study design the effect of PEEP is crucial. SLI and PEEP seem to have an additive effect on adequate FRC formation by permitting optimal Multicenter RCT (Italy, 16 NICUS; study period: October 2012– gas exchange, improving lung mechanics and reducing the need January 2013) approved by local ethical committee. All inborn infants delivered at 25+0–28+6 weeks’ gestation at high risk of respiratory distress syndrome (RDS) were considered eligible and * Corresponding author: Gianluca Lista, MD, Division of Neonatology, “V. Buzzi” Children Hospital, Via Castelvetro, 32-20154 Milan, Italy. Tel./fax: +39 02 57995346. after parental consent were randomized to receive the SLI maneu- E-mail address: [email protected] (G. Lista). ver (peak pressure = 25 cm H2O for 15 seconds; 1 or 2 times

0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. S116 G. Lista et al. / Early Human Development 89S4 (2013) S115–S116 according to cardiorespiratory response) followed by nasal contin- References uous positive airway pressure – NCPAP (5 cm H2O) (SLI group) [1] Lindner W, Högel J, Pohlandt F. Sustained pressure-controlled inflation or or NCPAP alone (5 cm H2O) (control group) in the delivery room. SLI and NCPAP will be delivered using a neonatal face mask and intermittent mandatory ventilation in preterm infants in the delivery room? A ® randomized, controlled trial on initial respiratory support via nasopharyngeal a T-piece ventilator (Fisher and Paykel ). We calculated that 138 tube. Acta Paediatr 2005;94:303–9. newborns must be enrolled in each group to detect this difference [2] te Pas AB, Walther FJ. A randomized, controlled trial of delivery-room respira- as statistically significant with 80% power at a level of 0.05. tory management in very preterm infants. Pediatrics 2007;120:322–9. [3] Lista G, Fontana P, Castoldi F, Cavigioli F, Dani C. Does sustained lung inflation at birth improve outcome of preterm infants at risk for respiratory distress 4. Results syndrome? Neonatology 2011;99:45–50. [4]tePasAB,SiewM,WallaceMJ,KitchenMJ,FourasA,LewisRA,YagiN,Uesugi We are completing the collection of the Case Report Forms K,Donath S, Davis PG, Morley CJ, Hooper SB. Effect of sustained inflation length (CRFs) of the 291 infants studied at the end of study period to on establishing functional residual capacity at birth in ventilated premature perform the statistical analysis of the data. rabbits. Pediatr Res 2009;66:295–300.

Conflict of interest

The authors have no conflict of interest to declare. Early Human Development 89S4 (2013) S117–S118

Chemical contaminants in breast milk

Simonetta Picone *, Piermichele Paolillo

Neonatal Intensive Care, Policlinico Casilino, General Hospital, Rome, Italy

ARTICLE INFO ABSTRACT

Keywords: Even if breast milk is the natural and optimal food for infants, toxic pollutants of the environment can be Breastfeeding transferred from mothers to neonates through breastfeeding. Among chemical contaminants, phthalates are Phthalates ubiquitous and in animals studies produce developmental and/or reproductive toxicity in a wide range of Male reproductive development mammalian species with a period of susceptibility extending from fetal to pubertal stage of life. Preliminary studies support the hypothesis that prenatal exposure at environmental levels can adversely affect male re- productive development in humans. Further studies are needed to evaluate possible risks for infants due to this contaminants. © 2013 Elsevier Ireland Ltd. All rights reserved.

1. Introduction 2. Exposures and pharmacokinetic

Human milk is the best source of nutrition for infants with Environmental chemicals can be absorbed into the bloodstream several immunological, developmental and practical advantages ex- by three routes: ingestion, inhalation and dermal contact. They tending throughout childhood into adulthood. The World Health circulate in the bloodstream either in their free or bound form to Organization strongly support breastfeeding for 6 months as a albumin and lipoproteins and are deposited into adipose tissue. global public health recommendation and to provide safe and Chemicals with high lipid solubility concentrate in tissue with appropriate complementary foods, suggests to continued breast- higher fat content, such as adipose tissue in the brain, liver, kidney feeding for up to 2 years of age or beyond. However, human milk and in lactating women in the mammary gland. Maternal factors nowadays is not always pure. Contamination of human milk is can effect transfer of chemicals through BM are: the degree of widespread and it is the consequence of decades of inadeguately maternal exposure, maternal age (older women have a greater controlled pollution of the environment by toxic chemicals. As milk opportunity for high level exposures), number of pregnancies and fat content is relatively high, breastfeeding potentially causes high duration of lactation. Chemicals with a slower rate have a long dose exposure of lipid-soluble pollutants. half-life, allowing for more time in the body and hence more The most common toxic chemicals found in breast milk time for bioaccumulation in BM. For exemple many halogenated (BM) are: parabens, octylphenols, bisphenols, dioxins, fu- compounds, including insecticides, for their resistance to oxidative rans, dichlorophenylcloroethane (DDT), organochlorine cyclodienes, degradation have long biological half-lives, up to 15 years. Phtha- semi-volatile organohalogens, heavy metals, pesticides, volatile and lates are metabolized and excreted with an elimination half-life other organic compounds including the phthalates [1]. Phthalates of 8–10 hours in adults. The half-life of phthalates in children or are plasticizers that are added to polyvinyl chloride (PVC) products; lactating women is unknown. The major source of human expo- diethylhexyl phthalate (DEHP) and diisononyl phthalate (DINP), sure to phthalates is food contaminated during growth, production, toxic phthalate metabolites, are often found in children’s toys, in processing and packaging. Food with the highest levels in fatty medical devices and in food packaging, clothing, oils, detergents, foods such as dairy (including infant formulas), fish, meat and oils cosmetics, wood finishes, etc. Phthalates are not covalently bound were identified with highest levels of DEHP. Paper and cardboard to the plastic matrix and leach out of PVC when they come in packaging made from recycled fibers are another important source contact with lipophilic substances, and variables concentrations of contamination. The highest concentrations of DEHP reported can be found in serum, urine, saliva and milk of lactating women were detected in food of high fat content stored in glass jars. For [2]. Phthalate monoesters can also cross the placental barrier after infants nourished with formula, phthalate intake is of the same maternal exposure do DEHP, as demonstrated by Silva et al. [3] magnitude than for exclusively breast-fed infants. In addition to with a study on 54 amniotic fluid samples obtained during routine ingestion, the second highest source of exposure of phthalates is amniocentesis. indoor air, where DEHP adheres strongly to aerosol particles. Non dietary ingestion of phthalates can occur when children mouth, suck or chew on phthalate-containing toys. Neonates can have high exposures to DEHP and its toxic metabolite, monoethylhexyl * Corresponding author. phthalate (MEHP), when undergoing replacement of blood prod-

0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. S118 S. Picone, P. Paolillo / Early Human Development 89S4 (2013) S117–S118 ucts, exchange transfusion, extracorporeal membrane oxygenation thepituitaryglandtoproduceACTHwhichinturnactivates (ECMO) and other life-saving procedures in which is used material adrenocortical steroidogenesis. Adrenocortical cells isolated from in PVC. DEHP is the only plasticizer approved by US Food and Drug such rats exhibited an enhanced capacity to produce corticosterone Administration for medical uses. DEHP can be present in flexible in response to ACTH, an hormonal response similar to any stressor tubing used for parenteral solutions, umbilical catheters, nasogastric factor. and enteral feeding tubes, respiratory masks, endotracheal tubes, Phthalates have some effects also in female reproductive sys- chest tubes for pneumothorax [4]. Cafalat et al. [5] in 6 premature tem. Exposure of adult rats to DEHP results in hypoestrogenic infants who underwent intensive therapeutic interventions found a anovulatory cycle and polycystic ovaries. Svechnikova et al. [10] concentration of metabolites of DEHP several fold higher than in have demonstrated that the treatment of prepubertal female rats the US general population. More research is needed to determine with DEHP lowers their serum levels of progesterone and estradiol, whether infants who undergo intensive therapeutic interventions but DEHP is also able to enhances GnRH-stimulated production using DEHP-containing devices are at higher risk for altered health of LH by pituitary cells: therefore DEHP exerts a dual effect on outcomes than infants not exposed to DEHP. When DEHP is admin- the pituitary–ovary axis, both stimulating production of LH by the istered orally it is rapidly metabolized by pancreatic lipases in the pituitary and inhibiting steroidogenesis in granulose cells. lumen of the gut to the toxic metabolite MEHP, which is absorbed across the intestine. The metabolites are excreted in the urine and 4. Conclusions feces, either in their free form or as conjugates, primarily glu- curonides. In infants pancreatic lipase system are not fully mature Breastfeeding potentially causes high dose exposure of chemical until 6 to 12 month of age, suggesting a possible protective effect pollutants. Levels of environmental chemicals are influenced by of immaturity by decreasing the creation and absorption of MEHP. global and local use patterns of chemical and furthermore by diet, Breast milk, salivary and gastric lipases may, however compensate maternal age, parity and duration of lactation. Infants and children and allow conversion of DEHP in MEHP. may exhibit unique susceptibilities to the toxic effects of chemicals because they are undergoing rapid tissue growth and development 3. Toxicity of phthalates and due to the early exposure. The benefits of breastfeeding outweigh any potential risk associated with this practice, but close Many of environmental pollutants have estrogen-like activities surveillance is needed to keep it as contaminant free as possible. and are referred to as “xenoestrogens”, as they are produced outside the body. Reproductive toxicity and hepatocarcinogenecity Conflict of interest exerted by DEHP in rodents have been showed and suggested to be caused by its metabolite MEHP. In rodent pups DEHP causes The authors declare absence of any conflict of interest. skeletal, cardiovascular and eye abnormalities, neural tube defects, intrauterine death, intrauterine retard growth. But the most sen- References sitive system is the reproductive tract of immature rodent males: exposure of rodent dams to DEHP in utero pups causes pathologic [1] Massart F, Harell JC, Federico G, Saggese G. State of art. Human breast milk and xenoestrogen exposure: a possible impact on human health. J Perinatol changes in the testes, decreased sperm numbers, vacuolization 2005;25:282–8. of Sertoli cells, atrophy of the seminiferous tubules and shortens [2] Latini G, Wittassek M, Del Vecchio A, et al. Lactational exposure to phthalates ano-genital distance (AGD). In humans, a study on 134 boys (2– in southern Italy. Environ Int 2009;35:236–9. 36 months of age)demonstrated a phthalate-related syndrome of [3] Silva MJ, Reidy JA, Herbert AR, et al. Detection of phthalate metabolites in human amniotic fluid. Bull Environ Contam Toxixol 2004;72:1226–31. incomplete virilization with the AGD decreased significantly and [4] Shea KM and Committee on Environmental Health. Pediatric exposure and increase the incomplete testicular descent or small and indistinct potential toxicity of phthalate plasticizers. Pediatrics 2003;111:1467. scrotum [6]. Masculinization of external male genitalia is controlled [5] Cafalat AM, Needham LL, Silva MJ, et al. Exposure to di-2-ethylhexyl phthalate by dihydrotestosterone, which is markedly decreased by prenatal among premature neonates in a neonatal intensive care unit. Pediatrics administration of phthalate monoesters that acts as antiandrogens. 2004;113:e429. [6] Swan SH, Main KM, Liu F, et al. Decrease in anogenital distance among Main et al. [7] investigated 130 boys at 3 months of age and male infants with prenatal phthalate exposure. Environ Health Perspect analyzed their serum gonadotropins, sex-hormone binding globulin 2005;113:1056–61. (SHBG), testosterone and inhibin B. Higher phthalate monoester [7] Main KM, Montersen GK, Kaleva MM, et al. Human Breast milk contamination concentrations in mother’s milk were linked with higher SHBG with phthalates and alterations of endogenous reproductive hormones in infants three months of age. Environ Health Perspect 2006;114:270–6. levels, elevated LH level and with decreased free-testosterone and [8] Parks LG, Ostby JS, Lambright CR et al. The plasticizer diethylhexyl phthalate elevated LH/free-testosterone ratio; these findings are consistent induces malformations by decreasing fetal testosterone synthesis during with an adverse effect on Leydig cell function leading to a reduced sexual differentiation in male rat. Toxicol Sci 2000;58:339–49. biologic androgen effect [8]. [9] Supornsilchai V, Soder O, Svechnikov K. Stimulation of the pituitary-adrenal DEHP can influence the pituitary–adrenocortical axis in vivo and axis and of adrenocortical steroidogenesis ex vivo by administration of di-2- ethylhexyl phthalate to prepubertal male rats. J Endocrinol 2007;192:33–9. adenocortical steroidogenesis in vitro. In an experimental study [10] Svechnikova I, Svechnikov K, Soder O. The influence of di-2ethylhexyl phtha- on rats to which were administered DEHP orally, Supornsilchai et late on steroidogenesis by the ovarian granulosa cells of immature female al. [9] observed that DEHP in young rats increased their plasma rats. J Endocrinol 2007;194:603–9. concentration of ACTH and level of corticosterone. DEHP stimulates Early Human Development 89S4 (2013) S119–S120

Human milk in the neonatal intensive care unit: good practices

S. Di Fabio *, C. Di Natale, L. Di Ventura

Division of Neonatology, S. Salvatore Hospital, L’Aquila, Italy

1. Introduction was significantly reduced in human-milk fed infants compared with exclusively formula-fed infants [4]. The beneficial effects of human milk (HM), well recognized for the term infant, extend to the feeding of premature infants, 3. Effects of HM on developmental outcome because their nutrition support must be designed to compensate for metabolic and gastrointestinal immaturity, immunologic compro- There are increasing reports that the diet in the NICU might af- mise, and maternal psycosocial conditions. Significant benefits to fect long-term neurodevelopmental outcomes in premature infants. infant host defense, gastrointestinal maturation, neurodevelopment, Improved neurodevelopment has been related to the presence of and some aspects of nutritional status are observed when prema- long-chain polyunsatured fatty acids (LC-PUFA, arachidonic and ture infants are fed HM. In the past, this vulnerable population docosahexaenoic), wich are found in HM but not bovine milk. of high-risk neonates has limited exposure to breast milk in the Premature infants are immunologically immature at birth and may neonatal intensive care unit (NICU). However, in 1997 and 2005, have deficiencies of LC-PUFA because accretion occurs in the third the American Academy of Pediatrics published position statements trimester. Extremely low birth weight (ELBW) infants are at in- recommending breast milk for premature and other high-risk in- creased risk for developmental delays, neurosensory impairments, fants by breast-feeding and/or using the mothers’s own expressed and neurodevelopmental disability. The 12 to 14 weeks before term milk. Although the use of HM in NICU is increased, a recent study may be an important window of opportunity for this vulnera- shows that only one-third of these units are routinely providing ble population of infants. Active brain development, neurogenesis, HM to most infants [1]. migration and synaptogenesis occur during this time, and brain de- velopment may be particularly responsive to “maternal nutrition”. 2. Effects of HM on host defense Studies show that HM-fed infants were more likely to have a Bayley Mental Development Index ≥85, higher mean Bayley Psychomotor The relation between diet and the incidence of infection in pre- Development Index and higher Bayley BRS percentile score for ori- mature infants shows that the feeding of mother’s milk mitigates entation/engagement, motor regulation, and total score. There were the high rate of infection common to hospitalized premature in- no differences in the rates of moderate to severe cerebral palsy or fants. Studies comparing HM from preterm mothers with that from blindness or hearing impairment between the 2 study groups [5]. term mothers suggest that these immunologic benefits may be even greater for preterm infants because secretory immunoglobulin A, 4. Effects of HM on retinopathy of prematurity (ROP) lisozyme, lactoferrin, and interferon are found in greater concen- tration in preterm HM compared with term milk [2]. Necrotizing ROP is a vascular disorder of the retina affecting infants born enterocolitis (NEC) was reduced significantly by feeding premature prematurely. The pathogenesis of ROP is incompletely understood, infants HM, either exclusively or partially supplemented with either but factors that have been implicated include exposure of the formula or pasteurized donor HM. When compared with HM feed- developing retina to abnormal oxygen levels and cytotoxic reac- ing, the receipt of formula was associated with a 2.5 fold increase tive oxygen species, the premature infants’ reduced antioxidant in NEC [3]. In many hospitals donor HM is not used, and because defenses, and decreased ability to synthesize LC-PUFA. Because it of insufficient maternal milk production, most infants who receive contains LC-PUFA and antioxidant enzyme, HM might influence the HM also receive varying amounts of formula. Studies observed a development of ROP. A recent study shows that exclusive human, lower incidence of NEC cases in premature infants who received at maternal milk feeding since birth may prevent ROP of any stage in least 50 ml/kg/day of HM throughout hospitalization. Infants who VLBW infants in the NICU [6]. received donor milk or preterm formula had a higher incidence of NEC compared to infants receiving 100% of their own mother’s 5. Early trophic feeding for very low birth weight infants milk. Other studies show that the incidence of sepsis/meningitis (VLBW)

The introduction of enteral feeds for very preterm (<32 weeks) or VLBW (<1500 g) infants is often delayed due to concern that * Corresponding author: S. Di Fabio, Division of Neonatology, S. Salvatore Hospi- tal, L’Aquila, Italy. early introduction may not be tolerated and may increase the E-mail address: [email protected] (S. Di Fabio). risk of NEC. However, prolonged enteral fasting may diminish

0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. S120 S. Di Fabio et al. / Early Human Development 89S4 (2013) S119–S120 the functional adaptation of the immature gastrointestinal tract second or third week of life, there is a significant decrease in the and extend the need for parenteral nutrition with its attendant protein content [9]. Feeding VLBW infants without supplemented infectious and metabolic risks. Trophic feeding, giving infants HM has been associated with delays in growth and nutritional very small volumes of milk to promote intestinal maturation, deficits, both during hospitalization and after discharge. Although may enhance feeding tolerance and decrease the time taken to HM is the recommended nutritional source for newborn infants reach full enteral feeding independently of parenteral nutrition. for at least the first six months of postnatal life, unfortified HM A recent review demonstrated that there is no evidence that may not meet the recommended nutritional needs of growing early trophic feeding affected feed tolerance or growth rates. preterm infants. HM must therefore be supplemented (fortified) Meta-analysis did not detect a statistically significant effect on with the nutrients in short supply. The objective of fortification theincidenceofNEC.Theavailable trial data do not provide is to increase the concentration of nutrients to such levels that evidence of important beneficial or harmful effects of early trophic at the customary feeding volumes infants receive amounts of all feeding for very preterm or VLBW infants. The applicability of these nutrients that meet their requirements. The Committee advocates findings to extremely preterm, ELBW or growth restricted infants the use of HM for preterm infants as standard practice, provided is limited. Further randomised controlled trials would be needed it is fortified with added nutrients where necessary to meet to determine how trophic feeding compared with enteral fasting requirements. The fortification of HM can be implemented in affects important outcomes in this population [7]. two different forms: standard and individualized. The “standard fortification” consists of adding fixed concentrations of fortifier 6. Use of galactogogues to maternal milk. The new concepts and recommendations for optimization of HM fortification is the “individualized fortification”, Poor breast milk production is the most frequent cause of which produces adequate growth in premature infants and satisfies breastfeeding failure. A reduced breast milk production can occur the specific nutritional requirements of these infants [10]. in many circumstances, such as preterm birth, illness of the mother or the child, mother–baby separation. Anxiety, fatigue, and emo- Conflict of interest tional stress are also powerful inhibitors of lactation. Educational programs should be offered to all breastfeed mothers to address The authors have no conflict of interest to declare. problems such as inadequate frequency and duration of breast- feeding, incorrect breast attachment. Nevertheless, many mothers References ask quite often their physician for medications or other products to increase their breast milk production. The use of galactagogues [1] Perrine CG, Scanlon KS. Prevalence of use of human milk in US Advanced should be restricted when reduced milk production from treatable Care Neonatal Units. Pediatrics 2013;131(6):1066–71. causes have been excluded and educational plans failed. Pharma- [2] American Academy of Pediatrics. Section of Breastfeeding. Breast feeding and the use of human milk. Pediatrics 2005;115:496–506. cotherapy should only be recommended for mothers who desires to [3] Schanler RJ. Evaluation of the evidence to support current recommendation breast-feed but are unable to maintain an appropriate lactation. For to meet the needs of premature infants: the role of human milk. Am J Clin the choice of the appropriate galactogogue is important to evaluate Nutr 2007;85(Suppl):625S–8S. the potential benefit and side effects, both for the mother and the [4] Sisk PM, Lovelady CA, Dillard RG, Gruber KJ, O’Shea TM. Early human milk infant. The use of natural products believed to be able of increasing feeding is associated with a lower risk of NEC in VLBW infants. J Perinatol 2007;27,428–33. milk production has a long history. The most frequently used prod- [5] Vohr BR, Poindexter BB, Dusick AM, McKinley LT, Wright LL, Langer JC, ucts include fenugreek, galega, and Silymarin. More randomized Kenneth Poole W. Beneficial effects of breast milk in the neonatal intensive controlled studies are needed for all galactogogues, in particular care unit on the developmental outcome of ELBW infants at 18 months of for herbal/natural substances to establish efficacy, standard dosages age. Pediatrics 2006;118;e115–23. [6] Manzoni P, Stolfi I, Pedicino R, Vagnarelli F, Mosca F, Pugni L, Bollani L, Pozzi and safety [8]. M, Gomez K, Tzialla C, Borghesi A, Decembrino L, Mostert M, Latino MA, Priolo C, Galletto P, Gallo E, Rizzollo S, Tavella E, Luparia M, Corona G, Barberi 7. Fortification of HM in preterm infants I, Tridapalli E, Faldella G, Vetrano G, Memo L, Saia OS, Bordignon L, Messner H, Cattani S, Casa ED, Laforgia N, Quercia M, Romeo M, Betta PM, Rinaldi M, There are no doubts about the fact that maternal milk is the Magaldi R, Maule M, Stronati M, Farina D; Italian Task Force for the Study and Prevention of Neonatal Fungal Infections, Italian Society of Neonatology. best food for all neonates. There are qualitative and quantitative Human milk feeding prevents retinopathy of prematurity (ROP) in preterm differences in the milk secreted by mothers of preterm infants VLBW neonates. Early Hum Dev 2013;89(Suppl 1):S64–8. from that of mothers who give birth to full-term infants. Preterm [7] Morgan J, Bombell S, McGuire W. Early trophic feeding versus enteral fasting milk contained significantly more fat than term milk and showed a for very preterm or VLBW infants. Cochrane Database Syst Rev 2013;3:CD 000504. further increase during lactation. Bauer et al. showed that there was [8] Zuppa AA, Sindico P, Orchi C, Carducci C, Cardiello V, Romagnoli C, Catenazzi a significant difference in milk protein levels between women de- P. Safety and efficacy of galactogogues: substances that induce, maintain and livering extremely early (<28 weeks) compared to mothers giving increase breast milk production. J Pharm Pharmaceut Sci 2010;13(2):162–74. birth at term. The modified composition of preterm milk is related [9] Bauer J, Gerss J. Longitudinal analysis of macronutrients and minerals to different nutritional needs of the preterm infant. In fact, preterm in human milk produced by mothers of preterm infants. J Clin Nutr 2011;30(2):215–20. milk contains higher protein levels (1.8–2.4 g/dl) than term human [10] Arslanoglu S, Moro GE, Ziegler EE; The Wapm Working Group on Nutrition. milk (1.6–2 g/dl). Unfortunately, these protein levels do not cover Optimization of human milk fortification for preterm infants: new concepts nutritional requirements of VLBW infants. Moreover, after the and recommendations. J Perinat Med 2010;38:233–8. Early Human Development 89S4 (2013) S121–S122

Vitamin D and fluoride: in order to prevent, not to cure

Serafina Lacerenza a,*,MauroStronatia, Piermichele Paolillo b, Costantino Romagnoli c aDepartment of Maternal and Child Health, Neonatal Intensive Care Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy bDepartment of Neonatology, Neonatal Pathology, Neonatal Intensive Care Unit, Policlinico Casilino General Hospital, Rome, Italy cDepartment of Pediatrics, Division of Neonatology, Catholic University of Sacred Heart, Rome, Italy

ARTICLE INFO ABSTRACT

Keywords: Vitamin D and fluoride are two typical examples of dietary supplements given to infants, children and ado- Vitamin D lescents. They allow to prevent specific diseases as rickets and dental caries, respectively, but questions have Fluoride been suggested about adequate dosages and risk of excess. Neonates, particularly preterm, are a special risk Dietary supplements class because of possible nutritional deficiency during hospitalization and post-discharge. Rickets © 2013 Elsevier Ireland Ltd. All rights reserved. Fluorosis

1. Introduction strictly dependent on maternal vitamin D status, have been investi- gated in order to prevent both rickets and other conditions related Vitamin D and fluoride are two typical examples of dietary to calcitriol deficiency. During pregnancy, vitamin D could influ- supplements given during infancy. Several studies have shown that ence placental, fetal and maternal health with several mechanisms they allow to prevent specific diseases as rickets and dental caries, [2]: immunomodulating properties, to establish a proper maternal respectively. However, over the years, risk of dosages excess has immune response to the placenta; key target genes regulation, to been also suggested; therefore, in this paper recommendations are guide placenta implantation; placental production of antimicrobial presented about appropriate dosage required to achieve a correct peptides, to prevent infection. The definition of maternal vitamin prevention. D status has been recently proposed, establishing as “Sufficiency” a 25(OH)D blood level at least of 50 nmol/L, or 20 ng/mL [3]. 2. Vitamin D Vitamin D deficiency is common in pregnant and lactating women, and may influence the health status of the child: it may be Vitamin D is a fat-soluble vitamin and plays an important associated not only with rickets and hypocalcemia in the newborn, role in perinatal growth and development. The term vitamin D but also with smaller size and dental malformations. Evidence refers to two forms: vitamin D2 (ergocalciferol), synthesized by suggests that a dietary reference intake of 400 UI/day of vitamin D plants, and vitamin D3 (cholecalciferol), which is produced in is necessary during pregnancy and lactation [4]. the skin of the animals through the action of UVB radiation RicketsisanextremevitaminDdeficiency,withapeakof on 7-deyhdrocholesterol [1]. The sunlight exposure is the major incidence between 3 and 18 months of age. In a review regarding influence on vitamin D status and it is influenced by skin color, United Kingdom, there were two types of presentations: the first, latitude, season, lifestyle and cultural practices [2]. characterized by symptomatic hypocalcemia and seizures, occurring Both vitamin D2 and vitamin D3 are metabolized in a similar during periods of rapid growth, long before physical and radiologi- manner, through two subsequent processes: the first, in the liver, cal findings; the second, more chronic, characterized by decreased is a 25-hydroxylation, whereas the second, in the kidney, is a bone mineralization and either normocalcemia or asymptomatic 1-hydroxylation; the primary active form of vitamin D is 1,25-di- hypocalcemia [5]. The American Academy of Pediatrics recom- hydroxycholecalciferol (calcitriol). Calcitriol circulates in the blood mends that all infants and children, including adolescents, have a bound to a vitamin D-binding protein, acting as an autocrine and minimum daily intake of 400 UI of vitamin D beginning soon after paracrine molecule on multiple cellular targets [1]. birth [6]. Most fortified milk products and vitamin D supplements The main hormonal function of calcitriol is to maintain nor- now contain vitamin D3 (cholecalciferol); vitamin D-only prepara- mal blood calcium concentrations, regulating intestinal absorption, tions are now available and particularly appropriate for breastfed renal excretion and bone deposition. Moreover, recent studies iden- infants. tified the role of vitamin D in controlling cellular growth, insulin In a recent randomized controlled trial [7] on different oral secretion, immunomodulatory activity and neuroprotection [1]. vitamin D dosages in healthy breastfed infants, all dosages used Therefore, vitamin D blood concentrations in fetus and neonate, (400, 800, 1200 and 1600 UI/day) determined an increase of 25(OH)D concentrations above 50 nmol/L in 97% of infants in all groups at 3 months, and in 98% at 12 months. Consequently, * Corresponding author. recommended dosage of 400 UI/day achieves adequate plasmatic

0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. S122 S. Lacerenza et al. / Early Human Development 89S4 (2013) S121–S122 concentrations of vitamin D with the highest degree of safety. This Table 1 dosage has been recommended as minimal also in preterm neonate, Age <0.3 ppm F 0.3–0.6 ppm F >0.6 ppm F whether they are breastfed or formula-fed; nevertheless, several Since 3rd month of pregnancy 1 mg 1 mg 0 studies reported that higher vitamin D supply could be necessary 0–6months 0.25mg 0 0 in preterm infants to increase vitamin D blood concentrations 6months–3years 0.25mg 0 0 [8]. Therefore, the European Society of Pediatric Gastroenterology, 3–6 years 0.50 mg 0.25 mg 0 Hepatology, and Nutrition Guidelines recommended a vitamin D intake of 800–1000 UI/day in preterm neonates during the first month of life, to achieve vitamin D sufficiency without risk of Conflict of interest toxicity [9]. The authors have no conflict of interest to declare. 3. Fluoride References Fluoride has two effects in controlling dental caries: topical and systemic. Topical action inhibits demineralization of enamel, [1] Murguía-Peniche T. Vitamin D, Vitamin A, maternal-perinatal considerations: enhancing remineralization of lesions already presents; moreover, old concepts, new insights, new questions. J Pediatr 2013;162:S26–30. fluoride inhibits acid production and adhesion of bacterial plaque. [2] Thorne-Lyman A, Fawzi WW. Vitamin D during pregnancy and maternal, Fluoride achieves also a systemic action because it is incorporated neonatal and infant health outcomes: a systematic review and meta-analysis. Paediatr Perinatal Epidemiol 2012;26(Suppl 1):75–90. into the tooth pre-eruptively, as in other calcified tissues [10]. [3] Insitute of Medicine, Committee to Review Dietary Reference Intakes for However, fluoride ingestion may be associated with increased risk Vitamin D and Calcium. Dietary Reference Intakes for Calcium and Vitamin D. of developing fluorosis, a characteristic type of hypomineralization Washington, DC: National Academies Press, 2011. of tooth enamel that recognize mild to severe forms. In recent [4] Vitamin D supplementation: recommendations for Canadian mothers and infants. Pediatr Child Health 2007;12(7):583–9. decades, the prevalence of enamel fluorosis apparently has in- [5] Misra M, Pacaud D, Petryk A, Collet-Solberg PF, Kappy M; Drug and Therapeu- creased in US children: this could be a consequence of an increasing tics Committee of the Lawson Wilkins Pediatric Endocrine Society. Vitamin D exposure to source of fluoride (toothpastes, dietary supplements, deficiency in children and its management: review of current knowledge and beverages, foods and professional dental products), especially in recommendations. Pediatrics 2008;122(2):398–417. those who take fluoride-deficient water [10]. [6] Wagner CL, Greer FR; American Academy of Pediatrics Section on breast- feeding; American Academy of Pediatrics Committee on Nutrition. Prevention Evidence suggests that the incidence of caries can be reduced of rickets and vitamin D deficiency in infants, children and adolescents. with fluoride supplements, both in decidual and permanent teeth Pediatrics 2008;122(5):1142–52. of children; nevertheless, studies have shown that fluoride intake [7] Gallo S, Comeau K, Vanstone C, Agellon S, Sharma A, Jones G, et al. Effect of from birth to 36 months may be associated with enamel fluorosis. different dosages of oral vitamin D supplementation on vitamin D status in healthy, breastfed infants. JAMA 2013;309(17):1785–92. Therefore, the American Dental Association recommends fluoride [8] Bathia J, Griffin I, Anderson D, Kler N, Domellöf M. Selected macro/micronutri- supplementations only for children at high risk of developing caries ent needs of the routine preterm infant. J Pediatr 2013;162(3 Suppl):S48–55. and for those who take fluoride-deficient water (<0.6 ppm) [10]. As [9] Agostoni C, Buonocore G, Carnielli VP, De Curtis M, Darmaun D, Decsi T, et al. revised in 2012, the American Academy of Pediatric Dentistry rec- Enteral nutrient supply for preterm infants: commentary from the European ommends dietary fluoride supplementation by 6 months of age [11]. Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition. J Pediatr Gastroenterol Nutr 2010;50(1):85–91. Also Italian practice guidelines recommends fluoride supple- [10] Rozier RG, Adair S, Graham F, Iafolla T, Kingman A, Kohn W, et al. Evidence- ments for children drinking fluoride-deficient water (<0.6 ppm); based clinical recommendations on the prescription of dietary fluoride sup- they suggest supplementation in the mother by the third month of plements for caries prevention: a report of the American Dental Association pregnancy, going on since lactating and neonatal period both in the Council on Scientific Affairs. J Am Dent Assoc 2010;141(12):1480–9. [11] American Academy of Pediatric Dentistry. Liaison with Other Groups Commit- mother and in the infant (Table 1) [12]. tee. Guideline on fluoride therapy. Pediatr Dent 2012;34(5):166–9. Fluoridated toothpaste with low fluoride concentration should [12] National Guidelines on the Promotion of Oral Health and Prevention of Oral be used twice daily between 3 and 6 years of age. Beyond 6 Diseases in Children and Adolescents. Italy: Ministry of Health, 2008. years of age, fluoridated toothpaste containing at least 1000 ppm F (fluoride) used twice daily can be the only fluoride supplement. Early Human Development 89S4 (2013) S123–S125

Is sucrose useful in neonatal medicine?

Roberto Antonucci a,*, Luca Antonucci b aDivision of Neonatology and Pediatrics, “Nostra Signora di Bonaria” Hospital, San Gavino Monreale, Italy bMedical Student, University of Cagliari, Cagliari, Italy

ARTICLE INFO ABSTRACT

Keywords: The use of oral sucrose for procedural pain relief has been extensively studied in newborn infants. In general, Sucrose sucrose or other sweet solutions have been shown to significantly reduce pain responses to common painful Procedural pain procedures (e.g. heel lance or venipuncture) in newborn and young infants. The analgesic effect of sucrose Analgesia seems to peak at about two minutes after administration by mouth and to last for several minutes. The mech- Newborn anisms underlying sucrose-induced analgesia in human infants are not fully understood, but the endogenous opioid system seems to play a key role. The optimal dose of sucrose remains unclear, although doses from 0.012 g to 0.12 g (0.05–0.5 mL of 24% solution) have been reported to be effective. No clinically significant side effects have been observed with the use of single doses of sucrose. Currently, oral sucrose appears to be safe and effective for relieving procedural pain from single events in neonates, while more research is needed to clarify the effect of repeated sucrose administration on immediate and long-term outcomes, especially in extremely preterm, unstable, ventilated neonates. This paper provides an overview of existing evidence on sucrose-induced analgesia and its mechanisms, highlighting current knowledge gaps. © 2013 Elsevier Ireland Ltd. All rights reserved.

1. Introduction has been the most extensively investigated pain intervention in neonatal care, the first randomized controlled trials evaluating the Healthy neonates routinely experience acute pain during skin- effects of this compound in infants dating back to the late 1980s. breaking procedures such as blood sampling for metabolic screen- There is abundant evidence that small volumes of sucrose solution ing, injection of vitamin K, or hepatitis B vaccination. Preterm or significantly reduce behavioral responses and composite pain scores critically-ill term neonates admitted to a NICU undergo repeated to common painful procedures in newborns and young infants. painful procedures that are necessary for their survival (e.g., heel This paper provides an overview of existing evidence on sucrose- lance, venipuncture, and intramuscular injection). induced analgesia and its mechanisms, highlighting current knowl- Early pain experiences during a critical period of anatomical and edge gaps. physiological brain development may have profound consequences for neonates. Acute pain caused by skin-breaking procedures can 2. Sucrose analgesia in neonates determine physiological instability and behavioral distress, and it has detrimental downstream effects on subsequent pain processing, The use of oral sucrose to decrease pain in neonates undergoing stress responsivity and development [1]. painful or stressful procedures has been extensively investigated. Prevention or reduction of pain are worthy clinical goals More than 100 studies relating to sucrose-induced calming and in neonatal medicine. Avoiding non-essential painful procedures analgesia in human infants have been published. With only a few whenever possible is central to good clinical practice. If invasive exceptions, oral sucrose has been shown to reduce pain responses procedures are clinically indicated, it is necessary to reduce pain by during common painful procedures in newborns and infants up to employing non-pharmacologic measures or drug therapies. 12 months of age [2,3]. In 2004, the Cochrane review by Stevens Numerous non-pharmacologic interventions such as breastfeed- et al. [4] reported significant decreases in crying, grimacing, heart ing, non-nutritive sucking (NNS), infant massage, maternal skin to rate, and pain scores in neonates who received sucrose solution skin contact, multisensory stimulation and oral sucrose are avail- before a painful procedure. Another study found that intraoral able for prevention and/or relief of procedural pain and stress in sucrose was more effective than topical local anesthetic creams in the newborn. neonates undergoing heel prick or venipuncture. Additionally, the For many years, sweet substances have been known to have co-administration of NNS (pacifiers) and sucrose in term infants analgesic and calming effects in infants. The use of oral sucrose was shown to be more efficacious for pain from heel lance and immunization than either was on its own. Sucrose is less effective for pain relief during prolonged and/or * Corresponding author: Roberto Antonucci, MD, Chief, Division of Neonatology and Pediatrics, “Nostra Signora di Bonaria” Hospital, San Gavino Monreale, Italy. more intensely painful procedures such as circumcision or urethral E-mail address: [email protected] (R. Antonucci). catheterization. This may be due to the short-lasting effects of a

0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. S124 R. Antonucci, L. Antonucci / Early Human Development 89S4 (2013) S123–S125 single dose of sucrose administered 2 minutes before the procedure. compared to infants who received fewer doses of sucrose, infants Accordingly, administering sucrose in small aliquots throughout the receiving higher numbers of doses exhibited lower scores on duration of prolonged painful procedures can ensure a more certain components of the Neurobehavioral Assessment of the sustained analgesic effect [2]. Preterm Infant, and also higher Neurobiologic Risk Scores at 2 A recent study by Slater et al. [5] assessed brain and spinal weeks’ postnatal age but not at discharge. These findings suggest cord activity after an acute painful procedure in newborn infants possible long-term effects of sucrose, so it is advisable to limit the given sucrose. In this study, sucrose did not significantly influence number of doses in infants <31 weeks gestation. the activity in neonatal brain or spinal cord nociceptive circuits, In a randomized controlled trial, Gibbins et al. assessed the although it reduced observed pain behavior in the newborns. This efficacy and short-term safety of oral sucrose during heel lance in led the authors to question whether sucrose is really an effective 190 newborns; only minor adverse effects (eg, oxygen desaturation, analgesic or whether it only attenuates behavioral responses. choking) were observed in 3% of the study population. Other possible adverse effects of oral sucrose that have been sus- 2.1. Mechanisms of action pected include hyperglycemia and necrotizing enterocolitis (NEC), but they have not been proven in neonates. The key mechanism underlying the action of oral sucrose ap- Neurodevelopmental outcomes were investigated in a double- pears to involve endogenous opioid system. Animal studies have blind, randomized, controlled trial by Johnston et al. [8]. This study provided evidence that sweet solutions modulate pain through examined neonates born at <31 weeks’ gestation receiving orally opioid mechanisms. Opioid-mediated hypothesis is also supported either sterile water or sucrose (0.1 mL of 24%) for every invasive by the results from the human study by Blass et al. These au- procedure, during the first week of life. Greater exposure to thors demonstrated that oral sucrose was ineffective in calming sucrose (>10 doses in 24 hours) was associated with poorer motor term infants exposed to antenatal methadone, thus supporting development and attention at 36 and 40 weeks’ gestation. Potential the association among sweet taste, an intact opioid system and mechanisms underlying the effects of sucrose on development have analgesia. Other studies have suggested that the recruitment of been suggested [6]. “taste sense” could be the mechanism by which oral sucrose ac- tivates the endogenous opioid system, thus initiating analgesia. 3. Conclusions On the other hand, the results of a study investigating changes in serum β-endorphin concentrations in preterm infants treated Untreated or poorly treated pain in the neonate has well- with intraoral sucrose indicate that central mechanisms alterna- documented short-term negative consequences and potential tive to those mediated by opioid pathways may be involved. longer-term adverse effects. Therefore, the ethical responsibility In particular, mechanisms including dopamine and acetylcholine of clinicians in the care of neonates include the responsibility to have been postulated [6]. Another possible mechanism contribut- minimize pain exposure. Currently, there are a large number of ing to the beneficial effects of oral sucrose is the suppression of non-pharmacologic and pharmacologic measures for pain control. hypothalamic–pituitary–adrenal axis, which is especially activated The choice of one of these measures depends on the type of pro- in painful situations in the newborn. cedure and degree of discomfort to be experienced. Oral sucrose is safe and effective for relieving procedural pain from single painful 2.2. Clinical indications events in neonates, while the effect of repeated sucrose administra- tion on immediate and long-term outcomes needs to be clarified, Successful use of sucrose to decrease pain during heel lance especially in extremely preterm neonates [9]. and venipuncture is well documented. Other clinical indications In a recent paper by Harrison et al. [10], recommendations for for the use of oral sucrose include suctioning, orogastric or na- practice have been proposed: (a) using small volumes of sucrose sogastric tube insertion, intravenous insertion, intramuscular or exclusively for painful procedures; (b) avoiding sucrose use for subcutaneous injections, eye examinations, and dressing changes calming newborns who are not undergoing procedures; (c) giving [7]. Additionally, sucrose is an effective adjunct to pharmacologic sucrose solutions in aliquots over the duration of the procedure, pain relief measures during more invasive procedures [7]. if it is prolonged; (d) avoiding administration of >10 doses per 24 hours, particularly in the first week of life; and (e) using other 2.3. Administration and dosing regimens effective strategies for procedural pain management, whenever feasible. Solutions of 24% sucrose may be administered orally via a In conclusion, sucrose remains one of the interventions of choice syringe onto the tongue, via a syringe into the infant’s mouth for pain associated with minor invasive procedures in the neonate, followed by NNS on a pacifier, or by dipping a pacifier in sucrose although a number of knowledge gaps still exist (Table 1). solution and allowing the neonate to suck on it. The analgesic effect of sucrose seems to peak at about two minutes after administration by mouth and to last for several minutes. A sucrose dose range Table 1 for reducing procedural pain in newborns has been established as Current knowledge gaps concerning sucrose analgesia in the neonate. 0.012 to 0.12 g (0.05–0.5 mL of 24% solution) of sucrose. • Optimal dosing regimens Of note, the effect of oral sucrose seems to disappear as the • Mechanisms underlying the effects of oral sucrose infant matures. • Identification of the best indicator(s) for assessing pain in neonates • Effectiveness and safety of repeated sucrose administration in extremely 2.4. Adverse effects preterm infants and critically-ill neonates • Effectiveness on neonates exposed to prenatal methadone or receiving postnatal opiates Few studies have described adverse effects of oral sucrose in • Long-term consequences of prolonged use of oral sucrose for management the management of procedural pain in newborns. A randomized, of procedural pain double-blind, controlled trial by Johnston et al. found no differences • Use in longer duration procedures (e.g. lumbar punctures, eye in outcomes between infants less than 31 weeks gestation receiving examinations) • Combined use of sucrose and other non-pharmacologic and pharmacologic 0.1 mL of a 24% oral sucrose solution and infants receiving interventions water for invasive procedures in the first week of life. When R. Antonucci, L. Antonucci / Early Human Development 89S4 (2013) S123–S125 S125

Further studies need to address these knowledge gaps and cur- [4] Stevens B, Yamada J, Ohlsson A. Sucrose for analgesia in newborn infants un- rent controversies, in order to ensure that no newborn experiences dergoing painful procedures. Cochrane Database Syst Rev 2004;(3):CD001069. unnecessary procedural pain. [5] Slater R, Cornelissen L, Fabrizi L, Patten D, Yoxen J, Worley A, et al. Oral sucroseasananalgesicdrugforproceduralpaininnewborninfants:a randomised controlled trial. Lancet 2010;376(9748):1225–32. Conflict of interest [6] Holsti L, Grunau RE. Considerations for using sucrose to reduce procedural pain in preterm infants. Pediatrics 2010;125(5):1042–7. The authors have nothing to disclose with relation to this article. [7] Anand KJ; International Evidence-Based Group for Neonatal Pain. Consensus statement for the prevention and management of pain in the newborn. Arch Pediatr Adolesc Med 2001;155:173–80. References [8] Johnston CC, Filion F, Snider L, Majnemer A, Limperopoulos C, Walker CD, et al. Routine sucrose analgesia during the first week of life in neonates younger [1] Anand KJ. Pain, plasticity, and premature birth: A prescription for permanent than 31 weeks’ postconceptional age. Pediatrics 2002;110(3):523–8. suffering? Nat Med 2000;6:971–3. [9] Stevens B, Yamada J, Lee GY, Ohlsson A. Sucrose for analgesia in newborn [2]HarrisonD,StevensB,BuenoM,YamadaJ,Adams-WebberT,BeyeneJ,etal. infants undergoing painful procedures. Cochrane Database Syst Rev 2013 Jan Efficacy of sweet solutions for analgesia in infants between 1 and 12 months 31;1:CD001069. of age: a systematic review. Arch Dis Child 2010;95(6):406–13. [10] Harrison D, Beggs S, Stevens B. Sucrose for procedural pain management in [3] Stevens B, Yamada J, Ohlsson A. Sucrose for analgesia in newborn infants un- infants. Pediatrics 2012;130(5):918–25. dergoing painful procedures. Cochrane Database Syst Rev 2010;(1):CD001069. Early Human Development 89S4 (2013) S126–S128

The ideal formula for healthy term infants

Gaia Francescato a,FabioMoscab,CarloAgostonic, Massimo Agosti a,* aNICU, Ospedale Filippo Del Ponte, Varese, Italy bNICU, Department of Clinical Sciences and Community Health, University of Milan, IRCCS Ospedale Maggiore Policlinico, Milan, Italy cPediatrics, Department of Clinical Sciences and Community Health, University of Milan, IRCCS Ospedale Maggiore Policlinico, Milan, Italy

ABSTRACT

Ideal composition of formulas should be resulting in effects on growth pattern, biochemical markers and functional outcome comparable with those obtained with exclusive breastfeeding. In terms of composition, minimum and maximum values are based, where available, on adequate scientific data on infant require- ments and the absence of adverse effects. Whereas to special components, high beta-palmitate content and LCPUFA supplementation have shown proven benefits. Lactoferrin supplementation holds promising results in terms of growth and immune response. The use either of prebiotics and probiotics alone, or in combi- nation, is still a matter of debate. Other components such as polyamine, nucleotides and peptides are still to be proven of any benefit. Composition of infant formulas should be tailored on providing nutritional or functional benefits. © 2013 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Moreover, the International Expert Group (IEG) of ESPGHAN states that infant formulas should only contain components in The composition of the diet of infants has a major impact such amounts that serve a nutritional purpose or provide another on short and long term child health and development. Breast benefit. The inclusion of unnecessary components, or unnecessary milk represents the natural food for infants, and it is universally amounts of components, may put a burden on metabolic and other recognized as the optimal feeding choice for every infant. physiologic functions of the infant [1]. Infant formulas are originally thought to be as similar as possible to human milk of healthy, well-nourished women, approximating 2. General composition its macro and micronutrient composition. However human milk shows remarkable variations in terms of composition by means In terms of composition, energy content should be held between of daytime and feeding time. Moreover, there are considerable 60 e 70 KCal, being this amount appropriate to support physiologi- differences in the bioavailability and metabolic effects of similar cal rates of weight gain in healthy infants, and not associated with contents of many specific nutrients in human milk and formula, excessive weight gain and risk of later obesity. respectively [1]. Macronutrient “ideal” composition is shown on Table 1. Therefore, the present standard of composition of formulas Minimum and maximum values are based, where available, on should ensure the best possible nutrition, leading to optimal adequate scientific data on infant requirements and the absence of growth, development and future health. It should be resulting in adverse effects. In the absence of an adequate scientific evaluation, effects on growth pattern, biochemical markers and functional out- values are based on an established history of apparently safe use come comparable with those obtained with exclusive breastfeeding. [1]. The concept has switched from the reproduction of a food to that of Forty percent of carbohydrates (CHO) should be represented by the functional effects. lactose; no glucose should be added because of its heavy effect on Cow milk based infant formulas are the only current acceptable osmolality and because of the possible unpleasant Maillard reaction alternative among animal milk based formulas, when human milk with proteins; no fructose should be added due to the possible is not available. This is due to a lack of large RCTs on the use severe reactions in young infants affected by hereditary fructose of other animals milk based formulas. Nevertheless, cow milk has intolerance. an unbalanced fat composition and an excessive concentration of Maltose and malto-dextrins, generally produced by controlled proteins and minerals; for these reasons it represents only the hydrolysis of corn starch, are sometimes employed to improve the matrix, which must be largely modified and adapted to the needs gastro-intestinal tolerance of milk formulas. Starch may be added of human infants. to infant formulas up to 2 g/100 mL (30% of total carbohydrates) [1].

* Corresponding author.

0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. G. Francescato et al. / Early Human Development 89S4 (2013) S126–S128 S127

Table 1 LCPUFA supplementation of infant formulas improves infants’ Modified from Koletzko et al. [1]. visual acuity up to 12 months of age and it positively affects the Unit Min Max speed of processes involved in information encoding, storage, and Energy kcal/100 mL 60 70 retrieval from memory [4]. The IEG of ESPGHAN, among other scientific organizations, supports their optional addition in infant Protein Cows’milk proteins (CMP) g/100 kcal 1.8 3 formulas, specifying that the DHA content should not exceed 0.5% Soy protein isolates g/100 kcal 2.25 3 of total fat intake, that ARA content should be at least the same Hydrolyzed CMP g/100 kcal 1.8 3 concentration as DHA, and that the EPA content should not exceed Lipids the DHA content [1]. Tot g/100 kcal 4.4 6 The EU Commission Directive established the minimum and Linoleic acid g/100 kcal 0.3 1.2 maximum levels of the different fatty acids: α-linolenic acid mg/100 kcal 50 Ns • α linoleic acid (300–1200 mg/100 kcal) Ratio linoleic acid/ -linolenic acid – 5 : 1 15 : 1 • α DHA mg/100 ml 10 12 -linolenic acid (not less than 50 mg/100 kcal) • linoleic/α-linolenic acid ratio (5–15) Carbohydrates • Tot g/100 kcal 9 14 n-3 LCP (not more than 1% total fat, DHA should not exceed total n-3 LCP content) Vitamins • A μg RE/100 kcal 60 180 n-6 LCP (not more than 2% of total fat, for ARA not more than D3 μg/100 kcal 1 2.5 1% of total fat) Emgα-TE/100 kcal 0.5 5 • EPA not more than DHA. μ K g/100 kcal 4 25 Different oligosaccharides (OS) have been investigated for their Thiamin μg/100 kcal 60 300 Riboflavin μg/100 kcal 80 400 prebiotic effect in infancy, such as neutral galacto-oligosaccharides Niacin μg/100 kcal 300 1500 (GOS) and acidic GOS from pectin hydrolysis, short-and long chain B6 μg/100 kcal 35 175 fructooligosaccharides (scFOS), inulin, and combinations such as a B12 μg/100 kcal 0.1 0.5 mixture of these substances. μ Panthotenic g/100 kcal 400 2000 A recent systematic review [5] of published randomized clinical Folic acid μg/100 kcal 10 50 C μg/100 kcal 10 30 trials on the effectiveness of synbiotics (prebiotics and probiotics) Biotina μg/100 kcal 1.5 7.5 supplementation in term infants, has shown that supplemented for- Minerals and trace elements mulas do seem to significantly increase stool frequency compared Iron mg/100 kcal 0.3 1.3 to the controls, but it do not seem to change stool consistency or Calcium mg/100 kcal 50 140 affect minor – or major, for that matters – digestive problems. Phosphorus mg/100 kcal 25 90 Prebiotics alone seem to have a positive effect on stool frequency Ratio – 1 : 1 2 : 1 (higher) and consistency (softer), than controls. Magnesium mg/100 kcal 5 15 Sodium mg/100 kcal 20 60 The use of synbiotics or probiotics alone does not appear to Chloride mg/100 kcal 50 160 be correlated with better growth parameters, while the use of Manganese μg/100 kcal 1 50 prebiotics alone is related to higher length gain in the first year. μ Fluoride g/100 kcal Ns 60 Data on infections, antibiotic use and length of hospitalization Iodine μg/100 kcal 10 50 Selenium μg/100 kcal 1 9 were inconclusive for all treatment. Copper μg/100 kcal 35 80 Acidic oligosaccharides in addiction to neutral GOS have resulted Zinc mg/100 kcal 0.5 1.5 in good tolerance as ingredient in infant formulae without affecting intestinal microecology in previous findings, while they seemed promising in empowering the effect of neutral GOS on promoting 3. Special components bifidobacteria proportions in a more recent trial [6]. Overall, there is a lack of published evidence on clinical benefits Lactofferin is a glycoprotein contained in both human and bovine from long term use of probiotic containing infant formula. milk, where it shows a good structural and functional homology Thehighprevalenceofiron deficiency and iron-deficiency (70%) with its human counterpart, that can is partially digested and anemia (IDA) in infancy and the belief that iron absorption from exherts its biological activities within the gastrointestinal tract. formula feeding is reduced in comparison with breastfeeding due to In animal and in vitro studies, it exhibits several functions, different bioavailability, has led to routine iron fortification of infant including enhanced growth, antibacterial and antiviral activity, formula and foods in many countries, with different methods. fungistatic effect, binding of iron and various other metal ions, The optimal amount of iron in such products, especially infant antioxidant activity, and immunomodulation. When added to term formula, is debated. infant formula in a double-blind pilot study, it was associated In a study from Chile, infants were fed formulae with about 0.34 with better weight gain up to 6 months of age, decreased lower mg and 1.9 mg/100 kcal, respectively, from 6 to 12 months of age. respiratory tract infections, and improved hematologic parameters Even though higher amounts of iron resulted in better haematolog- [2], even though it is not clear if it enhances iron absorption ical status, there was no significant difference in prevalence of iron Waiting for larger RCTs, current recommendations could include deficiency anemia between groups. the addiction of lactoferrin to infant formulas. A recent follow-up of the same study offered a comparison of Palmitic acid (PA) constitutes 17% to 25% of the human milk fatty developmental outcome at 10 years, showing poorer developmental acids, and ≈70% is esterified in the sn-2 position of triglycerides outcomes in the “high” group [7]. (β-palmitate). Such PA is not hydrolyzed and thus is efficiently Furthermore, studies of iron absorption have shown that increas- absorbed; PA in palm oils, commonly used in infant formulas, is ing the level of iron fortification in formula does not significantly instead esterified in the sn-1 and sn-3 positions; it is so hydrolyzed increase the amount absorbed. and poorly absorbed. The IEG of ESPGHAN suggests an Iron content in infant formulas When given a high (>40%) xnβ-palmitate infant formula, healthy within the range of 0.3–1.3 mg/100 kcal, only specifying that popu- term infants show beneficial increment of Lactobacillus and bifi- lations at higher risk for IDA should be fed formulas supplemented dobacteria counts in fecal stools and enhanced bone strength [3]. with amounts closer to the maximum limit. S128 G. Francescato et al. / Early Human Development 89S4 (2013) S126–S128

Polyamines such as sputrescine, spermidine and spermine, a evidence, as from the recommendations of the last twenty years. family of nitrogenous compound that are widely distributed in Nevertheless also industrial innovation, ecologic and economic sus- biological systems, can be detected in human milk. Their content tainability and consistency with the recommendations of regulatory in cow milk and formulas is notsufficienttopromotetheir bodies (such as FDA in US and EFSA in EU) represent steps that biological functions which include: cellular growth, maturation and should be considered in order to prevent useless waist of money differentiation [8]. Studies on animal models have so far led to and safeguard infants’ optimal health. thinking that these substances may play an important role on infant health, but further studies are needed to establish the appropriate Conflict of interest dose and proportions of each of the polyamines for addition to infant formulas. The authors have no conflict of interest to declare. Biologically active peptides derived from human and bovine milk protein hydrolysates (encrypted peptides) are of particular interest References in infant nutrition, and they represent a promising field in infant formulas’ optimization. Their identification and linking to specific [1] Koletzko B, Baker S, Cleghorn G, et al Global standard for the composition of biological functions is still under investigation, although they infant formula: recommendations of an ESPGHAN coordinated international expert group. J Gastroenterol Nutr 2005;41:584–99. seem to play different physiological roles such as antihypertensive, [2] King JC Jr, Cummings GE, Guo N, Trivedi L, Readmond BX, Keane V, Feigelman antithrombotic, hypocholesterolemic, immunomodulant, cytotoxic, S, de Waard R. A double-blind, placebo-controlled, pilot study of bovine antioxidant, antimicrobial, antigenic, or opioid [9]. lactoferrin supplementation in bottle-fed infants. J Pediatr Gastroenterol Nutr Several publications have reported beneficial effects of the 2007;44(2):245–51. [3]LitmanovitzI,DavidsonK,EliakimA,RegevRH,DolfinT,ArnonS,Bar-Yoseph addition of nucleotides, but there is no sufficient data to support F, Goren A, Lifshitz Y, Nemet D. High beta-palmitate formula and bone additional benefits from increasing intakes to levels greater than strength in term infants: a randomized, double-blind, controlled trial. Calcif 5 mg/100 kcal, because an increased risk of respiratory tract Tissue Int 2013;92(1):35–41. infections has been reported for higher amounts [10]. [4] Qawasmi A, Landeros-Weisenberger A, Bloch MH. Meta-analysis of LCP- Protein hydrolysis is not recommended, nor for general preven- UFA supplementation of infant formula and visual acuity. Pediatrics 2013;131:e262–72. tion of cow milk protein allergy (CMA) [11], neither in infants [5] Rao S, Srinivasjois R, Patole S. Prebiotic supplementation in full-term at higher risk of CMA who cannot be fully breastfed, being the neonates: a systematic review of randomized controlled trials. Arch Pedi- evidence too limited to suggest any differently. atr Adolesc Med 2009;163:755–64. [6] Magne F, Hachelaf W, Suau A, Boudraa G, Bouziane-Nedjadi K, Rigottier- Gois L, Touhami M, Desjeux JF, Pochart P. Effects on faecal microbiota of 4. Safety considerations dietary and acidic oligosaccharides in children during partial formula feeding. J Pediatr Gastroenterol Nutr 2008;46(5):580–8. Powdered infant formulae are not sterile and may contain [7] Lozoff B, Castillo M, Clark KM, Smith JB. Iron-fortified vs low-iron infant pathogenic bacteria such as Enterobacter Sakazakii, responsible for formula: developmental outcome at 10 years. Arch Pediatr Adolesc Med rare outbreaks of sepsis and meningitis, particularly in the first 2012;166(3):208–15. [8] Ruiz-Cano D, Pérez-Llamas F, Zamora S. Polyamines implications for infant 2 months of life [12]. The manufacturing process accounts for health. Arch Argent Pediatr 2012;110(3):244–50. some percentage of contamination cases, since this can occur also [9] Català-Clariana S, Benavente F, Giménez E, Barbosa J, Sanz-Nebot V. Iden- during handling and preparation of feeds. Nevertheless, methods tification of bioactive peptides in hypoallergenic infant milk formulas by aimed at eliminating such contamination both from manufacturing CE-TOF-MS assisted by semiempirical model of electromigration behavior. Electrophoresis 2013;34(13):1886–94. and processing are desirable. Treatments such as ionizing radiation [10] Yau K, Huang C, Chen W, et al. Effect of nucleotides on diarrhea and and monocaprylin have been proposed in experimental settings immune responses in healthy term infants in Taiwan. J Pediatr Gastro Nutr but none is considered safe at present time. Correct heating and 2003;36:37–43. handling as indicated by WHO still seem to be the best form of [11] Marini A, Agosti M, Colombo C. Use of a Partially Hydrolyzed Formula prevention [12]. in the Dietary Prevention of Allergic Disease. Arch Pediatr Adolesc Med 2006;160(8):854–5. [12] Agostoni C, Axelsson I, Goulet O, et al. Preparation and handling of powdered 5. Final remarks infant formula: a commentary by the ESPGHAN Committee on Nutrition. J Pediatr Gastroenterol Nutr 2004;39(4):320–2. The development of new, advanced formulations for infant sub- stitutes of breast milk requires biologic plausibility and scientific Early Human Development 89S4 (2013) S129–S130

The detection of oxygen saturation in the healthy newborn

Monica Ravani *, Margherita Fornaciari 1

NeonataI Intensive Care, 1Risk Manager, Azienda Istituti Ospitalieri di Cremona, Cremona, Italy

1. Introduction A capillary education was carried out to the midwives and neonatology nurses, after the presentation of the protocol in a The birth of a physiological newborn occurs in the daily clinical plenary session in the presence of the Risk Manager and the care, but in the minds of every parent, in a comfortable environment Directors of the Obstetrics and Neonatology Units. where the adoption of behaviors are expected to respect the natural childbirth. It is preferred to minimize the interference of clinical 4. Results practices, which may in any way restrict the free expression of the triad parents/newborn. The protocol has been applied since August 2012. Tables 1 and 2 It is true that in a hospital setting, at the same time, it is show the results of the monitoring of cases in which the protocol required to guarantee the safety with respect to possible, although was applied from August 2012 to July 2013. rare, adverse events – whether related to the care practices or First it should be noted that more than 75% of infants in the health condition of the infant or the mother. evaluation period could be enlisted in monitoring because, as the

2. Methods Table 1

In our department, in a perspective of improvement, we per- Time No. of births Physiological Not recruited Recruited Alarms formed a failure mode and effects analysis (FMEA), an analysis of 2012/2013 with newborn newborns newborns newborns alive the existing process and procedures, identifying the critical points. The setting of this experience is a point level III birth-centers August 120 91 16 75 3 September 103 62 7 55 0 with about 1400 childbirths/year, staffed with a midwife designated October 115 73 22 51 2 to fund the delivery room. Nonetheless, it is not possible to November 100 84 29 55 0 guarantee the continuous presence of a pediatric nurse in the December 111 74 20 54 0 delivery room. January 88 59 18 41 0 February 83 56 19 37 0 The analysis of the process performed revealed, in the chain of March 97 87 19 68 1 events that develops in the event birth, a weak link. The critical April 96 77 25 52 0 point is given by the fact that, during the first two hours after birth, May 93 66 15 51 2 the baby is given to the new mother without a precise and specific June 92 68 24 44 0 surveillance of the same by health care professionals. July 132 125 27 98 0 Such problems could lead to adverse events, which are rare but Total 1230 922 241 681 8 they could be extremely serious. The most feared is the delated recognition of sudden alteration of the vital parameters of the Table 2 newborn. Not recruited newborns

Time Back at nursery Maternal impediment Back at nursery for No. of 3. Operational decision 2012/2013 in advance or cesarean section maternal refusal cases August 3 10 3 16 The barrier that has been identified is the ability to provide September 0 7 0 7 the infant a cardio-oximeter with alarm sound when it is possible October 10 12 0 22 to record the trend to recover a posteriori values of vital signs. November 12 16 1 29 This new task has been made possible with the cooperation of the December 1 18 1 20 January 2 16 0 18 obstetric and pediatric nurses. February 2 16 1 19 A new protocol used by all operators of Units of Obstetrics and March 2 15 2 19 Neonatology has been developed before implementing this new April 8 15 2 25 procedure. Newborns defined as physiological (Apgar score >7at May 1 14 0 15 June 6 18 0 24 5) were included in the protocol. July 8 19 0 27 Total 55 176 10 241 * Corresponding author.

0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. S130 M. Ravani, M. Fornaciari / Early Human Development 89S4 (2013) S129–S130 protocol requires, the remaining 25% were cases that met different event is actually remote. On the other hand, in the protocol, it is exclusions criteria (e.g. APGAR score <7) and did not allow the expected that the baby is given to the new mom with the oximeter baby to stay with the mother in the first two hours after birth, or at only after medical evaluation of the neonatologist, confirming the least were not considered normal births. good health status. However, although unlikely, the event is not Secondly, in 26% of eligible infants the cardio-oximeter monitor- impossible. For instance in the case of a genetic or metabolic ing was not applied for the clinical indication of the neonatologists. disease of the newborn that is not present at birth, but a sudden The main reasons to admit early the baby to the nursery were: (1) change can appear in a very short time (for example, during the safety reasons (22.8% of cases), (2) maternal issues (i.e., a caesarean two hours after birth), as a first manifestation of severe and sudden section, no family support, 73% of cases), 3) maternal rejection (i.e., illness. in the case of a woman who does not want to be named or when Certainly it is essential that the infant stays “skin to skin” the mother does not want the baby in her room for the first two with his mother as soon as possible to facilitate the succession of hours, 4.2% of cases). prodromal breastfeeding and to allow to continue that close union lasted for (symbiosis) 9 months. This union is important not only 5. Experienced the process of actors for the child but also the mom and dad need in the delicate process of joining family. The staff at the Nursery (pediatric nurses and nurses who did Therefore, taking into account the above considerations, it is not participate directly in the decision-making stage, but only concluded that the protocol designed and operationalized is a after they have shared the reasons), after the acceptance phase of safety monitoring to prevent adverse events without affecting the the additional workload (in fact linked to the data collection, not maintenance of the intimate relationship that must take place so much to the monitoring in itself) led the experience without immediately between mother and newborn. Therefore it becomes a particular difficulties. Indeed, they showed good communication routine operational procedure after the first experimental phase. with the illustration of the monitoring to the parents in the delivery room. Conflict of interest Midwives contributed constructively, but they had to overcome an initial phase of understandable fear related to the possible The authors have no conflict of interest to declare. absence of contact between the mother and the newborn. In fact many objections have been raised during the plenary presentation. Selected bibliography The neonatologists did not actually needed change its opera- [1] Buscemi A, et al. Il risk management in sanità. Gestione del rischio, errori tions. Therefore they have experienced the new protocol as innova- responsabilità professionale e aspetti psicologici. Casa editrice Franco Angeli tive with higher safety for the newborn, and therefore positive. (Prima Edizione 2009). The experience of parents was influenced by the strong moti- [2] Dawson JA, Davis PG, et al. Pulse oximetry for monitoring infants in the vation that the Nurse’s Nursery have transferred. Therefore they delivery room: a review. Arch Dis Child Fetal Neonatal Ed 2007;92:4–7 have interpreted the monitoring as a valuable additional procedure [3] Poets A, Steinfeldt R, Poets CF. Sudden deaths and severe apparent life- threatening events in term infants within 24 hours of birth. Pediatrics 2011; without disturbance. 127(4):e869–73. [4] Moccia F. Osservatorio civico sul federalismo in sanità – rapporto 2011: Il 6. Conclusions Percorso Nascita (cap. 8):132–48, Presentato a Roma 29 settembre 2011. [5] Commissione Tecnica sul Rischio Clinico (DM 5 marzo 2003) Risk management in Sanità – Il problema degli errori. Ministero della Salute, Dipartimento The 681 cases of infants monitored show that, during the imple- della Qualità, Direzione Generale della Programmazione Sanitaria, dei Livelli mentation period, no alarm was linked to a significant alteration of Essenziali di Assisenza e dei Principi Etici di Sistema – Ufficio III; marzo 2004 the baby’s vital signs (i.e., heart rate and O2 saturation). This posi- Roma. tive data, which in fact was fully expected, underlined that the