In the Name of God Neonatal Respiratory Distres Syndreme Introduction &Prevntion Yadollah Zahed Pasha (MD)

Professor of Pediatrics & Neonatology, Non-Communicable Pediatric Diseases Research Center, Babol University of Medical Sciences, Babol, Iran.1399(Babol

INTRODUCTION

 Respiratory distress is one of the most common reasons an infant is admitted to the NICU.

 Edwards MO, Kotecha SJ, Kotecha S. Respiratory distress of the  term newborn infant. Paediatr Respir Rev. 2013;14(1):29–36 INTRODUCTION….

 NRDS is the ultimate substantial chief reason for morbidity and mortality in premature newborns .  Murphy KE, Willan AR, Hannah ME, Ohlsson A, Kelly EN, Matthews SG, et al. Effect of antenatal on fetal growth and gestational age at birth. Obstet Gynecol 2012; 119(5):917-23. McEvoy C, Schilling D, Peters D, Tillotson C, Spitale P, Wallen L, et al. Respiratory compliance in preterm infants after a single rescue course of antenatal steroids: a randomized controlled trial. Am J Obstet Gynecol 2010; 202(6):544.e1-9.  Wilms FF, Vis JY, Pattinaja DA, Kuin RA, Stam MC, Reuvers JM, et al. Relationship between the time interval from antenatal administration until and the occurrence of respiratory morbidity. Am J Obstet Gynecol 2011; 205(1):49.e1-7. INTRODUCTION….

 The basic abnormality of RDS is surfactant deficiency, hence it is also known as HMD .

Holme N, Chetcuti P. The pathophysiology of respiratory distress syndrome in neonates. Paediatr Child Health 2012; 22(12):507-12. INTRODUCTION….

Deficiency of pulmonary surfactant is due to the catastrophe to reach a sufficient FRC and the tend to collapse due to increased surface tension.

Monica,et al, Recent Understanding of Pathophysiology, Risk Factors and Treatments of Neonatal Respiratory Distress Syndrome: A review, An International Tri annually Journal,Sci Lett 2017; 5(1):70-78

INTRODUCTION….

 These infants typically have the progress of warning signs and need supplementary oxygen support.

Monica,et al, Recent Understanding of Pathophysiology, Risk Factors and Treatments of Neonatal Respiratory Distress Syndrome: A review, An International Tri annually Journal,Sci Lett 2017; 5(1):70-78 Increased Risk Decreased Risk

 Prematurity PROM  Male sex Intrauterine infection  Familial predisposition Female sex  Cesarean delivery without labor  Perinatal asphyxia Narcotic & cocaine use  Multiple gestation Corticosteroids  Maternal diabetes Thyroid hormone  European descent Tocolytic agents  Mutation in single ABCA3 gene African Risk Factors… Maternal Diabetes because of lack of maturity in spite of macrosomia, RDS has been shown 6 times greater incidence in the mothers with gestational diabetes .

Wight NE. Hypoglycemia in breastfed neonates. Breastfeed Med 2006; 1(4):253-62. Maternal risk factors for RDS Advanced maternal age Gestational diabetes Multiple Gestational hypertension Intrahepatic cholestasis of pregnancy

. Monica,et al, Recent Understanding of Pathophysiology, Risk Factors and Treatments of Neonatal Respiratory Distress Syndrome: A review, An International Tri annually Journal,Sci Lett 2017; 5(1):70-78

Maternal risk factors

Advanced maternal age. due to a greater incidence of 1) pregnancy-induced hypertension, 2) gestational diabetes, 3) abruption placenta and placenta previa in elder women.

Rubaltelli FF, Dani C, Reali MF, Bertini G, Wiechmann L, Tangucci M, et al. Acute neonatal respiratory distress in Italy: a one-year prospective study. Italian Group of Neonatal Pneumology. Acta paediatrica 1998; 87(12):1261-8. Risk Factors…

 The risk of RDS increases in CS possibly due to delay in exclusion of the lung fluid and deficiency of reaction related to selective cesarean section and normal labor ominously .

Zanardo V, Simbi AK, Franzoi M, Solda G, Salvadori A, Trevisanuto D. Neonatal respiratory morbidity risk and mode of delivery at term: influence of timing of elective caesarean delivery. Acta Paediatr 2004; 93(5):643-7. Infant risk factors for RDS Prematurity Male gender Caucasian ethnicity Familial inheritance Birth asphyxia Lung infections

Meconium aspiration syndrome. Monica,et al, Recent Understanding of Pathophysiology, Risk Factors and Treatments of Neonatal Respiratory Distress Syndrome: A review, An International Tri annually Journal,Sci Lett 2017; 5(1):70-78

Risk Factors…

RDS is more often in male babies [9]

Ingemarsson I. Gender aspects of preterm birth. BJOG 2003; 110 Suppl 20:34-8.  The male infants have a higher predominance of RDS than female infants  (male-to-female ratio ∼1.3:1).  The surfactant synthesis is possibly delayed due to the action of androgens on type II pneumocytes .

Rocha G, Rodrigues M, Guimarães H. Respiratory distress syndrome of the preterm neonate - placenta and necropsy as witnesses. J Matern Fetal Neonatal Med 2011; 24(1):148-51. Estrogen, which stimulates ; 1)the production of pulmonary surfactant, 2) surfactant proteins A and B together with phospholipids, lecithin, as well expands lung maturity of 3) by means of enhancing the amount of type II pneumocytes .

Nielsen HC, Torday JS. Sex differences in avian embryo pulmonary surfactant production: evidence for sex chromosome involvement. Endocrinology 1985; 117(1):31-7. Bouhaddioui W, Provost PR, Tremblay Y. Expression profile of androgen-modulated microRNAs in the fetal murine lung. Biol Sex Differ 2016; 7:20. Risk Factors… The greatest risk factors; 1) young GAand LBW 2) late preterm delivery (35-36 weeks), 3) elective delivery in the absence of labor . Anadkat JS, Kuzniewicz MW, Chaudhari BP, et al. Increased risk for respiratory distress among white, male, late preterm and term infants. J Perinatol. 2012;32:780–785. Mahoney AD, Jain L. Respiratory disorders in moderately preterm, late preterm, and early term infants. Clin Perinatol. 2013;40:665–678. Zanardo V, Simbi AK, Franzoi M, et al. Neonatal respiratory morbidity risk and mode of delivery at term: influence of timing of elective caesarean delivery. Acta Paediatr. 2004;93:643–647. Risk Factors… Pathogenic mutations in genes encoding ;  surfactant protein-B (SP-B, SFTPB),  surfactant protein-C (SP-C, SFTPC),  the ATP binding cassette subfamily A,  member 3 (ABCA3,),  and the thyroid transcription factor (TTF-1, NKX2-1) represent rare monogenic causes of RDS. Hamvas A, Deterding RR, Wert SE, et al. Heterogeneous pulmonary phenotypes associated with mutations in the thyroid transcription factor gene NKX2-1. Chest. 2013;144:794–804. Nogee LM, de Mello DE, Dehner LP, Colten HR. Brief report:deficiency of pulmonary surfactant protein B in congenital alveolar proteinosis. N Engl J Med. 1993;328:406–410. Nogee LM, Dunbar AE 3rd, Wert SE, et al. A mutation in the surfactant protein C gene associated with familial interstitial lung disease. N Engl J Med. 2001;344:573–579. Shulenin S, Nogee LM, Annilo T, et al. ABCA3 gene mutations in newborns with fatal surfactant deficiency. N Engl J Med. 2004;350:1296–1303. Risk Factors…

 Inherited SP-B deficiency is a recessive disorder that presents as severe respiratory failure in the immediate newborn period and is unresponsive to standard neonatal intensive care interventions. Risk Factors…

 With a disease frequency of approximately 1 per million live births, the absence of SP-B, the presence of an incompletely processed proSP-C, and a generalized disruption of surfactant metabolism cause surfactant dysfunction and the clinical syndrome.  A triad of neurologic disease, characterized by ;  hypotonia, developmental delay and movement disorders,  congenital hypothyroidism,  RDS has been termed the  brain-thyroid-lung syndrome, but any single organ presentation or combination there of may be the initial and only manifestation of the syndrome.

Hamvas A, Deterding RR, Wert SE, et al. Heterogeneous pulmonary phenotypes associated with mutations in the thyroid transcription factor gene NKX2-1. Chest. 2013;144:794–804. Risk Factors ….  Suppression of surfactant production is associated with ;  cold stress,  asphyxia,  hypoxemia,  hypovolemia  and pulmonary ischemia. In addition to short gestation. Fraser J, Walls M, McGuire W. Respiratory complications of preterm birth. British Med J 2004; 329(7472):962-5. Incidenc the RDS was ;  42% in 501-1500g,  71% in 501-750g,  54% in 751-1000g,  36% in 1001-1250g,  22% in 1251-1500g according to NICHD .

 Hintz SR, Van Meurs KP, Perritt R, Poole WK, Das A, Stevenson DK, et al. Neurodevelopmental outcomes of premature infants with severe respiratory failure enrolled in a randomized controlled trial of inhaled nitric oxide. J Pediat 2007; 151(1):16-22, .e1-3. Incidence….

 The incidence of RDS is reciprocal to advancing gestational age, declines gradually  from 60–80% in between 26–28 weeks GA  15–30% between 32–36 weeks GA.

Stoelhorst GM, Rijken M, Martens SE, Brand R, den Ouden AL, Wit JM, et al. Changes in neonatology: comparison of two cohorts of very preterm infants (gestational age <32 weeks): the project on preterm and small for gestational age infants 1983 and the leiden follow-up project on prematurity 1996-1997. Pediatrics 2005; 115(2):396-405. Ventolini G, Neiger R, Mathews L, Adragna N, Belcastro M. Incidence of respiratory disorders in neonates born between 34 and 36 weeks of gestation following exposure to antenatal corticosteroids between 24 and 34 weeks of gestation. Am J Perinatol 2008; 25(2):79-83. Incidence….  The overall incidence is 10-15%,  high as 80% in neonates less than 28 weeks. It is most frequently seen in babies born at  less than 28 weeks GA  and 1/3 of babies at 28 to 34 weeks GA  but less than 5% after 34 weeks GA .  Hermansen CL, Lorah KN. Respiratory distress in the newborn. Am Fam Physician 2007; 76(7):987-94. Incidence….  The incidence of RDS is inversely proportional to gestational age:  nearly all infants born at 22-24 weeks‟ gestation have RDS,100  decreasing to approximately 25% in infants with birth weights between 1251 and 1500 g. Fanaroff AA, Stoll BJ, Wright LL, et al; NICHD Neonatal Research Network. Trends in neonatal morbidity and mortality for very low birthweight infants. Am J Obstet Gynecol. 2007;196:147, e e8 Stoll BJ, Hansen NI, Bell EF, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics. 2010;126:443–456. Incidence….  15 percent of term infants and  29% of LPIs admitted to the NICU develop significant respiratory morbidity;  this is even higher for infants born  before 34 weeks‟ gestation.  Hibbard JU, Wilkins I, Sun L, et al; Consortium on Safe Labor. Respiratory morbidity in late preterm births. JAMA. 2010;304 (4):419–425 Pathophysiology

Preterm babies born <37weeks GA are most likely to develop RDS, as the most pulmonary surfactant is synthesized usually after 30-32 weeks gestation.

Monica,et al, Recent Understanding of Pathophysiology, Risk Factors and Treatments of Neonatal Respiratory Distress Syndrome: A review, An International Tri annually Journal,Sci Lett 2017; 5(1):70-78

Pathophysiology…

Deficiency of pulmonary surfactant is due to the catastrophe to reach a sufficient forced residual capacity (FRC) and the lungs tend to collapse due to increased surface tension.

Monica,et al, Recent Understanding of Pathophysiology, Risk Factors and Treatments of Neonatal Respiratory Distress Syndrome: A review, An International Tri annually Journal,Sci Lett 2017; 5(1):70-78

Laplaces law

P = 2ST/r

where: P = pressure ST = surface tension r = radius of the bubble

Clinical Features RDS presents with; Tachypnea  grunting,  nasal flaring,  chest wall retractions,

 and increased the effort of inhalation at birth, or in a while subsequently.  These infants typically have the progress of warning signs and need supplementary oxygen support. Clinical Features…

Most infants present with signs and symptoms either ;

1) in the delivery room

2) or within the first 6 hours after birth. Clinical Features….. classic clinical presentation; 1) Tachypnea 2) retractions, 3) nasal flaring, 4) cyanosis, 5) grunting (characteristic) 6) Apneic 7) increased oxygen requirement, 8) together with diagnostic CXR findings and onset of symptoms shortly after birth. Clinical Features… The presence of apneic episodes at this early stage is an ominous sign that could reflect; 1) thermal instability 2) sepsis 3) more often hypoxemia 4) respiratory failure. Diagnosis…. 1) History Diagnosis..

2) Laboratory findings of the ABG analysis are characterized initially by ;  Hypoxemia  Hypercapnia  variable metabolic and respiratory acidosis. Diagnosis…. 3)The chest radiograph illustrates;  Air bronchograms  Ground-glass opacification in bilateral lung  Decreased lung volume.  A whole “white-out” of the lung fields is frequently seen in more severely affected infants.  Avery ME, Mead J. Surface properties in relation to atelectasis and hyaline membrane disease. AMA J Dis Child 1959; 97(5, Part 1):517-23.

Diagnosis….  Based on chest x-ray features, RDS is categorized into grades:  (1) light, slight ground glass opacification  (2) moderate, decreased lung volume and air bronchograms;  (3) severe, indistinct cardiac marginsor white lung .

Couchard M, Polge J, Bomsel F. Hyaline membrane disease: diagnosis, radiologic surveillance, treatment and complications. Annales de radiologie 1974; 17(7):669-83. Diagnosis….  The diagnostic criteria conferring to the 2013 European Consensus Guidelines are:  (1) Arterial oxygen pressure (PaO2) <50 mm Hg or cyanotic or a need for supplemental oxygen to sustain the level of oxygen saturation SpO2 >85% within one day of birth and  (2) a chest x-ray demonstrates air bronchograms and reticular granularity of parenchyma .

Sweet DG, Carnielli V, Greisen G, Hallman M, Ozek E, Plavka R, et al. European Consensus Guidelines on the Management of Respiratory Distress Syndrome - 2016 Update. Neonatology 2016; 111(2):107-25.

D.D

 The term respiratory insufficiency of prematurity had been used in some centers for infants who require oxygen and ventilator support in the absence of typical radiographic evidence of RDS. D.D…

 More recently, the term respiratory instability of prematurity has been proposed to describe VLBW infants who require some respiratory support but may have additional contributing factors such as inconsistent central respiratory drive or poor inspiratory effort. Bancalari EH, Jobe AH. The respiratory course of extremely preterm infants: a dilemma for diagnosis and terminology. JPediatr. 2012;161:585–588. D.D…

1) Infection 2) CHD 3)…….. The major complications of RDS are;  air leaks (PTX and PIE),  BPD,  death.

 Schwartz RM, Luby AM, Scanlon JW, Kellog RJ. Effect of surfactants o morbidity, mortality and resource use in new-born infants weighing 500 to 1500g. New Eng J Med 2009:330(21):1476–80. Management

The essential treatment goals are ;  temperature control,  Nutrition  Respirtaory  cardiovascular maintenance  management of early neonatal sepsis.  the chief respiratory support of RDS infants is;  Surfactant .  CPAP .  MV.  In infants after 36 weeks or at term gestation, RDS may be exist, but is occasional and further diagnostic evaluation must be deliberated [4].

 Holme N, Chetcuti P. The pathophysiology of respiratory distress syndrome in neonates. Paediatr Child Health 2012; 22(12):507-12.

StagDevelopmen tes of Lung

Period Stage Postconceptual Characteristics age Embryonic Embryonic 3 - 7 weeks lung organogenesis begins, lung budding, formation of rudimentary bronchopulmonary segments

Fetal Pseudoglandular 5 - 16 weeks division of conducting airways completed, terminal bronchioles, beginning of airway cell differentiation, cartilage and smooth muscle appear

Canalicular 16 - 27 weeks branching of the respiratory tree, acinar formation, capillarization, Clara cells, Type I and Type II alveolar cells, lamellar bodies (?surfactant)

Saccular 24 - 36 weeks thining of respiratory epithelial cells (type I and type II), terminal saccular formation, surfactant

Postnatal Alveolar > 36 weeks appearance of true alveoli, alveolar septation, (eventual remodeling of interalveolar septa, restructuring and maturation of capillary bed) Fetal lung development

 can be divided into five stages:  embryonic,  Pseudoglandular

 canalicular  terminal sac  and alveolar. Canalicular Stage The three major events during this stage are the appearance of the;  acinus  development of the potential air-blood barrier,  start of surfactant synthesis within recognizable typeII cells.  Burri PH. Structural aspects of prenatal and postnatal development and growth of the lung. In: McDonald JA, ed. Lung growth and development. New York: Marcel Dekker; 1997. Fetal lung development Canalicular Stage… Fetal lung development... Fetal lung development... Fetal lung development...

 The lung first appears as an outgrowth of the primitive foregut at 22 to 26 days after conception.  By 34 days, the outgrowth has divided into left and right sides and further to form the major units of the lung. Fetal lung development...

 lung. Mature lungs contain more than 40 different cell types derived from this early tissue.

 From eight to 16 weeks‟ gestation, the major bronchial airways and associated respiratory units of the lung are progressively formed.  At this time the lung blood vessels also begin to grow in parallel. Fetal lung development...

 At birth there are an average of 150 million alveoli (half the expected adult number).

 Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth (Review) 8 Copyright © 2017 The Cochran Collaboration. Published by JohnWiley & Sons, Ltd. Preventions  prevention of prematurity,

 avoiding unnecessary c-s deliveries,  addiction of narcotics,  smoking,  cold stress,  asphyxia,  alcohol by mothers.  the proper control of high-risk perinatal period and labor,(PNC).  and estimation of lung immaturity with likely in utero quickening of development  Corticosteroids. Curet LB, Rao AV, Zachman RD, Morrison J, Burkett G, Poole WK. Maternal smoking and respiratory distress syndrome. Am J Obstet Gynecol 1983; 147(4):446-50. Ioffe S, Chernick V. Maternal alcohol ingestion and the incidence of respiratory distress syndrome. Am J Obstet Gynecol 1987; 156(5):1231-5. Preventions….

 While researching the effects of the steroid on premature parturition in fetal sheep in 1969, Liggins found that there was some inflation of the lungs of lambs born at gestations at which the lungs would be expected to be airless (Liggins 1969). Preventions….

 In 1972, Liggins and Howie were the first to show that glucocorticoid administration to pregnant mothers accelerates lung maturation and reduces the incidence of RDS in premature babies delivered within 7 days of corticosteroid therapy .  Liggins GC, Howie RN (1972) A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratorydistress  syndrome in premature infants. Pediatrics 50:515–525 Liggins and Howie first reported a decreased incidence in RDS with maternal corticosteroid treatments in 1972.

 Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics. 1972;50:515–525. Preventions…. Corticosteroids;

 increase protein production,

 increase bio-synthesis of phospholipids increase surfactant in fetal lungs. Preventions….  The recommended regimen of steroid therapy according to National Institutes of Health Consensus is either of these:  two doses of 12 mg given intramuscularly 24 hours apart

 or four doses of 6 mg dexamethasone given intramuscularly 12 hours apart between 24 and 34 weeks of gestation in at risk for preterm delivery.  Wang K, Chen CY, Chen CP. Effects of Antenatal Corticosteroids in Preterm Delivery. Taiwan J Obstet Gynaecol 2004;43(4):193–8.  Mwansa-Kambafwile J, Cousens S, Hansen T, Lawn JE. Antenatal steroids in preterm labour for the prevention of neonatal deaths due to complications of preterm birth. Int J Epidemiol 2010;39(Suppl 1):i122–33.  The ACS regime practiced in KK Women & Children‟s Hospital (KKH) in Singapore involves  administration of IM Dexamethasone 12 mg every 12 h for two doses to women at risk of preterm delivery from 23+ 5 (48 h before viable gestation) up to 35+ 6 weeks‟ gestation.  Conclusion The results of this study support the current practice among obstetricians to aim to administer ACS within 7 days of delivery.

 Hester C. Q. Lau1 etal. Timing of antenatal steroids exposure and its effects on neonates, Arch Gynecol Obstet (2017) 296:1091–1096 DOI 10.1007/s00404-017-4543-1  Steroid therapy decreases the risk of  hyaline lung disease in 50% cases

 and mortality risk of a premature by almost 40%.

Bonanno C, Wapner RJ. Antenatal Corticosteroids in the Management of Preterm Birth: Are we back where we started?Obstet Gynecol Clin North Am. 2012 March; 39(1):47–63. Chien LY, Ohlsson A, Seshia MM, Boulton J, Sankaran K, Le SK. Variations in Antenatal Corticosteroid Therapy: A Persistent Problem Despite 30 Years of Evidence. Obstet Gynaecol 2002;99(3):401–8. Preventions….

 The most recent Cochrane review on ACS [4] showed that a single course of ACS significantly reduced the Incidence of RDS of average 34%  (risk ratio (RR) 0.66, 95% confidence interval 0.56– 0.77; 28 studies, 7764 participants). 

 Roberts D, Brown J, Medley N, Dalziel SR (2017) Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 3:CD004454. doi:10.1002/14651858.CD004454.pub3 Preventions….

A rescue dose of 12 mg betamethasone is considered when the gestational age is below 28+0/7 and more than seven days have passed since the initial ACS course.

JULIA FRANDBERet al,Antenatal corticosteroids: a retrospective cohort study on timing, indications and neonatal outcome, 2018 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 97 (2018) 591–597 Preventions….

 A single course of prenatal corticosteroids given to mothers with anticipated preterm delivery improves ;  survival,  reduces RDS, NEC and IVH  and does not appear to be associated with any significant maternal or short-term fetal adverse effects .  Roberts D, Brown J, Medley N, Dalziel SR. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2017 Mar; 3:CD004454. Preventions….

 The optimal treatment–delivery interval for administration of ACS proposed by the Royal College of Obstetrics and Gynaecology (RCOG) is more than 24 h and before 7 days after the completion of a course of ACS. Preventions….  There are current studies that showed that infants delivering more than 7 days after initial ACS exposure have a higher frequency of RDS han those who were delivered within a week .  Waters TP, Mercer B (2009) Impact of timing of antenatal corticosteroid exposure on neonatal outcomes. J Matern Fetal Neonatal Med 22:311–314  Vis JY, Wilms FF, Kuin RA, Reuvers JM, Stam MC, Pattinaja DAPM et al (2011) Time to delivery after the first course of antenatal corticosteroids: a cohort study. Am J Perinatol 28:683–688  Boesveld M, Heida KY, Oudijk MA, Brouwers HAA, Koenan SV, Kwee A (2014) Evaluation of antenatal corticosteroid prescribing patterns among 984 women at risk for preterm delivery. J Matern Fetal Neonatal Med 27(5):516–519  Ring AM, Garland JS, Stafeil BR, Carr MH, Peckman GS, Pircon RA (2007) The effect of a prolonged time interval betwean ntenatal corticosteroid administration and delivery on outcomes  in preterm neonates: a cohort study. Am J Obstet Gynecol 196:457 Preventions….

 These question the need for a repeated dose of ACS if delivery did not occur within 7 days of first ACS exposure.  Yet, there are concerns regarding the safety of repeated doses of ACS . Garite TJ, Kurtzman J, Maurel K, Clark R (2009) Impact of a „rescue course‟ of antenatal corticosteroids: a multicenter randomized placebo-controlled trial. Am J Obstet Gynecol 200:248. Crowther CA, Harding JE (2007) Repeat doses of prenatal corticosteroids for women at risk of preterm birth for preventing neonatal respiratory disease. Cochrane Database Syst Rev 3:CD003935. doi:10.1002/14651858.CD003935.pub2 Murphy KE, Hannah ME, Willan AR, Hewson SA, Ohlsson A, Kelly EN, MACS Collaborative Group et al (2008) Multiple courses of antenatal corticosteroids for preterm birth (MACS): a randomised controlled trial. Lancet 372:2143–2151 Preventions…. Beneficial effects of the first dose of antenatal steroid start within a few hours, so advanced dilatation should not be a reason to refrain from therapy and the same may hold for MgSO4 .   Norman M, Piedvache A, Børch K, Huusom LD, Bonamy AE, Howell EA, et al.; Effective Perinatal Intensive Care in Europe (EPICE) Research Group. Association of short antenatal corticosteroid administration-to-birth intervals with survival and morbidity among very preterm infants: results from the EPICE cohort. JAMA Pediatr. 2017 Jul; 171(7): 678– 86. Preventions….

 WHO recommends that a single repeat course of steroids may be considered if preterm birth does not occur within 7 days after the initial course and there is a high risk of preterm birth in the next 7 days .  WHO. WHO recommendations on interventions to improve preterm birth outcomes. Geneva: WHO; 2015. Preventions….

 It is unlikely that repeat courses given after 32 weeks‟ gestation improve outcome .

Asztalos, Murphy KE, Willan AR, Matthews SG, Ohlsson A, Saigal S, et al: Multiple courses of antenatal corticosteroids for preterm birth study: outcomes in children at 5 years of age (MACS-5). JAMA Pediatr 2013; 167: 1102-1110.  While antenatal, corticosteroids have routinely been administered to women at risk for preterm delivery before 34 weeks‟ gestation since the 1990s, recent data suggest that late preterm infants born at 34-36 weeks‟ gestation may also benefit.

Gyamfi-Bannerman C, Thom EA. Antenatal betamethasone for women at risk for late preterm delivery. N Engl J Med. 2016; 375:486–487. Preventions….  A workshop in 2005 recommended redirecting research to evaluate infants who are born between 34 and 36 weeks of gestation, particularly to answer the question of whether antenatal glucocorticoids are beneficial in this population.  Raju TN, Higgins RD, Stark AR, Leveno KJ. Optimizing care and outcome for late- preterm (near-term) infants: a summary of the workshop sponsored by the National Institute of Child Health and Human Development. Pediatrics 2006; 118: 1207-14. Preventions….  However, it is now clear that infants who are born during the late preterm period  (34 weeks 0 days to 36 weeks 6 days) have more neonatal and childhood complications than do newborns who are born at term (37 weeks or later).  McIntire DD, Leveno KJ. Neonatal mortality and morbidity rates in late preterm births compared with births at term. Obstet Gynecol 2008; 111: 35-41.  Yoder BA, Gordon MC, Barth WH Jr. Late-preterm birth: does the changing obstetric paradigm alter the epidemiology of respiratory complications? Obstet Gynecol 2008; 111: 814-22.  Hibbard JU, Wilkins I, Sun L, et al. Respiratory morbidity in late preterm births. JAMA 2010; 304: 419-25. Preventions….  In A randomized, multicenter trial, found that antenatal administration of betamethasone to women at risk for late preterm delivery decreased the need for substantial respiratory support during the first 72 hours after birth. C. Gyamfi-Bannerman,et al. Antenatal Betamethasone for Women at Risk for Late Preterm Delivery. The New England Journal of Medicine Downloaded from nejm.org on December 18, 2020. For personal use only. No other uses without permission. Copyright © 2016 Massachusetts Medical Society. All rights reserved Preventions….

 Betamethasone administration late preterm also resulted in reduced rates of severe respiratory complications, TTN , and BPD , along with reduced rates of; 1) Surfactant use, 2) Resuscitation,

3) prolonged stay in a special care nursery.  C. Gyamfi-Bannerman,et al. Antenatal Betamethasone for Women at Risk for Late Preterm Delivery. The New England Journal of Medicine Downloaded from nejm.org on December 18, 2020. For personal use only. No other uses without permission. Copyright © 2016 Massachusetts Medical Society. All rights reserved Preventions….  In pregnancies between 34 and 36 weeks‟(LPIs) gestation, prenatal steroids also ; 1) reduce risk of short-term respiratory morbidity 2) not mortality, 3) increased risk of hypoglycaemia .

Gyamfi-Bannerman C, Thom EA, Blackwell SC, Tita AT, Reddy UM, Saade GR, et al.; NICHD Maternal–Fetal Medicine Units Network. Antenatal betamethasone for women at risk for late preterm delivery. N Engl J Med. 2016 Apr; 374(14): 1311–20. Preventions….

 Administration of betamethasone to women at risk for late preterm delivery significantly reduced the rate of neonatal respiratory complications.  Neonatal hypoglycemia was more common in the betamethasone group than in the placebo group (24.0% vs. 15.0%; RR, 1.60; 95% CI, 1.37 to 1.87; P<0.001).  C. Gyamfi-Bannerman,et al. Antenatal Betamethasone for Women at Risk for Late Preterm Delivery. The New England Journal of Medicine Downloaded from nejm.org on December 18, 2020. For personal use only. No other uses without permission. Copyright © 2016 Massachusetts Medical Society. All rights reserved. Preventions….

When ANS given before elective CS up to 39 weeks, they reduce risk of admission to NICU, although the number needed to treat is > 20 and follow-up data on term babies exposed to antenatal steroids are lacking . Sotiriadis A, Makrydimas G, Papatheodorou S, Ioannidis JP, McGoldrick E. Corticosteroids for preventing neonatal respiratory morbidity after elective caesarean section at term. Cochrane Database Syst Rev. 2018 Aug; 8:CD006614. Preventions…. In some cases when an early CS is needed, establishment of fetal lung maturity may be better than giving steroids to all women .

Besnard AE, Wirjosoekarto SA, Broeze KA, Opmeer BC, Mol BW. Lecithin/sphingomyelin ratio and for fetal lung maturity: a meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2013 Jul; 169(2): 177–83. There is little evidence that delivering preterm infants by CS rather than allowing vaginal delivery improves outcome. Preventions….

 Steroids are potent drugs with many side effects, but when given appropriately they improve outcome. If not, then side effects, such as  impaired fetal and placental growth.  apoptosis in the brain .  increased infection, may prevail. Preventions….

 Maternal steroids may induce an increase in;  total leukocyte and  immature neutrophil counts in the infant, which should be considered if neonatal sepsis is suspected.

 Barak M, Cohen A, Herschkowitz S. Total leukocyte and neutrophil count changes associated with antenatal betamethasone administration in premature infants. Acta Paediatr. 1992; 81:760–763. Preventions….

These structural changes translate into improved physiologic properties of the lung, such as ; 1) increased lung volume, 2) increased lung compliance, 3) increased response to exogenous surfactant treatment. Jobe AH, Mitchell BR, Gunkel JH. Beneficial effects of the combined use of prenatal corticosteroids and postnatal surfactant on preterm infants. Am J Obstet Gynecol. 1993;168:508–513 Preventions….

 Decreased fetal growth and poorer neurodevelopmental outcomes have been reported with exposure to multiple courses of antenatal corticosteroids in retrospective clinical studies.

Banks BA, Cnaan A, Morgan MA, et al. Multiple courses of antenatal corticosteroids and outcome of premature neonates. North American Thyrotropin-Releasing Hormone Study Group. Am J Obstet Gynecol. 1999;181:709–717. Wapner RJ, Sorokin Y, Thom EA, et al; National Institute of Child Health & Human Development Maternal Fetal Medicine Units Network. Single versus weekly courses of antenatal corticosteroids: evaluation of safety and efficacy. Am J Obstet Gynecol. 2006;195:633–642.  Use of steroids should be reduced by adequate preterm birth risk assessment and avoidance of unnecessary early E CS. Prevention 1) Lack of antenatal care increases risk of death or severe morbidity . Diguisto C, Foix L‟Helias L, Morgan AS, Ancel PY, Kayem G, Kaminski M, et al. Neonatal outcomes in extremely preterm newborns admitted to intensive care after no active antenatal management: a population-based cohort study. J Pediatr. 2018 Dec; 203: 150–5. 2) use of is associate with reduced preterm delivery rates and reduce neonatal mortality. Vintzileos AM, Visser GH. Interventions for women with mid-trimester short cervix: which ones work? [editorial]. Ultrasound Obstet Gynecol. 2017 Mar; 49(3): 295–300. Jarde A, Lutsiv O, Beyene J, McDonald SD. Vaginal progesterone, oral progesterone, 17- OHPC, cerclage, and pessary for preventing preterm birth in at-risk singleton pregnancies: an updated systematic review and network meta-analysis. BJOG. 2019 Apr; 126(5): 556-56 3) Routine cervical length measurements may be advised in populations at risk of preterm birth but not in populations with an overall low risk and/or very low incidence of short cervix . McIntosh J, Feltovich H, Berghella V, Manuck T; Society for Maternal-Fetal Medicine (SMFM). McIntosh J, Feltovich H, Berghella V, Manuck T: The role of routine cervical length screening in selected high- and lowrisk women for preterm birth prevention. Am J Obstet Gynecol. 2016; 215(3):B2–7. Prevention…

3) Routine cervical length measurements may be advised in populations at risk of preterm birth but not in populations with an overall low risk and/or very low incidence of short cervix . McIntosh J, Feltovich H, Berghella V, Manuck T; Society for Maternal-Fetal Medicine (SMFM). McIntosh J, Feltovich H, Berghella V, Manuck T: The role of routine cervical length screening in selected high- and lowrisk women for preterm birth prevention. Am J Obstet Gynecol. 2016; 215(3):B2–7. 3) Cervical cerclage may also reduce preterm birth in high- risk singleton pregnancies .

Alfirevic Z, Stampalija T, Medley N. Cervical stitch (cerclage) for preventing preterm birth n singleton pregnancy. Cochrane Database Syst Rev. 2017 Jun; 6:CD008991.

Prevention…. 4) Extremely preterm babies should, if possible, be transported in utero to tertiary center.

centres.15Marlow N, Bennett C, Draper ES, Hennessy EM, Morgan AS, Costeloe KL. Perinatal outcomes for extremely preterm babies in relation to place of birth in England: the EPICure study. Arch Dis Child Fetal Neonatal Ed. 2014 May; 99(3):F181–8. 5) In cases of prenatal PPROM, antibiotics can delay preterm delivery and reduce neonatal morbidity, co-amoxiclav should be avoided increased risk of NEC . Kenyon S, Boulvain M, Neilson JP. Antibiotics for preterm rupture of membranes. Cochrane Database Syst Rev. 2013 Dec;(12): D001058. Prevention…. MgSO4 given to women with imminent preterm delivery reduces cerebral palsy at 2 years of age by about 30% . Doyle LW, Crowther CA, Middleton P, Marret S, Rouse D. Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database Syst Rev. 2009 Jan; 1(1):CD004661. Tocolytic drugs can be used in the short-term to delay birth, permit safe transfer to a perinatal centre and allow prenatal corticosteroids time to take effect, although tocolytics have no direct beneficial effect on the fetus . Haas DM, Caldwell DM, Kirkpatrick P, Mc- Intosh JJ, Welton NJ. Tocolytic therapy for preterm delivery: systematic review and network meta-analysis. BMJ. 2012 Oct; 345 oct09 2:e6226. Representations of quality of evidence and strength of recommendations

Quality of evidence

High quality A Moderate quality B Low quality C Very low quality D Strength of recommendation Strong recommendation 1 for using intervention Weak recommendation 2 for using intervention In conclusion 1) Mothers at high risk of preterm birth < 30-32 weeks‟ gestation should be transferred to perinatal centres with experiencein management of RDS (C1). 2) Clinicians should offer a single course of prenatal corticosteroids to all women at risk of preterm delivery from when pregnancy is considered potentially viable until 34 weeks‟ gestation ideally at least 24 h before birth (A1). 3) A single repeat course of steroids may be given in threatened preterm birth before 32 weeks‟ gestation if the first course was administered at least 1–2 weeks earlier (A2). In conclusion….

4) MgSO4 should be administered to women in imminent labour before 32 weeks‟ gestation (A2). 5) In women with symptoms of preterm labour, cervical length and fibronectin measurements should be considered to prevent unnecessary use of tocolytic drugs and/or antenatal steroids (B2). 6) Clinicians should consider short-term use of tocolytic drugs in very preterm pregnancies to allow completion of a course of corticosteroids and or in utero transfer to a perinatal centre (B1). In conclusion…

 However, sonographic measurement of residual cervical length (CL) does appear to accurately identify women at risk for PTB .  (Cervical length= or les than 25 mm).

 Watson WJ, Stevens D, Welter S, Day D. Observations on the sonographic measurement of cervical length and the risk of premature birth. J Matern Fetal Med. 1999;8:17-19. In conclusion….

 The most widely used and consistently supported of these markersis cervico vaginal (fFN) 25,26  the 2 best and most widely accepted methods of identifying women at high risk of PTB in both nullipara and multipara: fFN and CL measurements. Nageotte MP, Casal D, Senyei AE. Fetal fibronectin in patients at increased risk for premature birth. Am J Obstet Gynecol. 1994;170:20-25. Goldenberg RL, Klebanoff M, Carey JC, et al. Vaginal fetal fibronectin measurements from 8 to 22 weeks‟ gestation and subsequent spontaneous preter birth. Am J Obstet Gynecol. 2000; 183:469-475. Thank You