Intraamniotic / or Sarah Belensky, MD High Risk OB Fellow at Swedish First Hill Medical Center My passions

 Rural and international communities  Outdoors and exercising  Healthy living and wholeness Objectives

 Define and characterize IAI  Discuss options in treatment  Discuss care for newborns of with IAI Your patient

 23 year old G1 originally from Mexico at 40 weeks and 5 days with PROM ->  Pitocin ->  Complete + 45 minutes of pushing ->  Fever of 102.2 + FHR of 170bpm ->  Unasyn and Tylenol ->  Two more hours of pushing -> SVD of well-appearing male .  ROM to delivery = 30hrs Name Controversy

 Triple I  IAI = Intraamniotic Infection/Inflammation  Chorioamnionitis Maternal fever

 Per ACOG’s March 2016 workshop summary - Evaluation and management of women and newborns with a maternal diagnosis of chorioamnionitis  Isolated maternal fever  >39°C = 102.2°F once  >38°C = 100.4°F twice Maternal fever

 Consider alternative causes:  epidural  dehydration  hyperthyroidism  elevated ambient temperature  use of for induction Suspected IAI

 Fever without a source +  Wbc >15,000 (w/o steroids)  Fetal >160bpm  Purulent fluid from os Confirmed IAI

 Suspected triple I +  Gram stain + for or high wbc (>30cells/mm^3)  Pathology confirmation in , or cord Mechanism

 Migration of bacteria in and cervix through ruptured membranes Diagnosis

 Gold standard = amniotic fluid culture (takes 24-48hrs)  Markers of infection  IL-6 specificity 83%  MMP-8 60%  MMP-9 100%  MMP-9 + IL-6 100% Organisms involved

 Genital  ureaplasma, hominis  GBS  E coli  Anaerobes Prevalence

 Clinical vs histologic (2014 Cochrane)  Clinical: 1-2% term 5-10% preterm  Histologic: 20% term 50% preterm Maternal morbidity

 C/S 2-3x  Infection  endomyometritis  pelvic  wound infection  bacteremia 3-4x (18% of maternal associated with IAI)  PPH 3-4x Risk Factors

 <18 years  non-Caucasian  primiparous  singleton  induction  prolonged or premature ROM Risk Factors

 1995 retrospective case-control study of 3109 patients published in ACOG  epidural  prolonged ROM (>24hrs)  long duration of labor (latent phase >8hrs)  Are cervical exams introducing vaginal flora into upper genital tract? Cervical Exams?

 7.2% developed intrapartum fever  Number of exams not associated Even subanalyzing for and labor type  Previous studies with high risk PROM pts  Increased duration of labor is likely underlying the association found in previous studies Epidural Use

 8% of patients with epidural developed IAI, 1% without  Epidural use was statistically associated with increased risk of IAI  Increased labor duration was highly associated with epidural use (OR 23) for chorio?

 Insufficient evidence based on August 2016 Cochrane Database Systematic Review  One small trial with 34 participants compared women already receiving .  No decreased or postpartum Chorio an indication for C/S?

 C/S does not routinely improve clinical outcomes in IAI treatment

 Goal = cover for anaerobes and beta-lactamase-producing aerobes  +  Ampicillin + gentamicin +  Ampicillin/sulfabactam  or (2nd gen)  Add clinda for C/S to cover anerobes

Duration of

 24hrs afebrile?  One postpartum dose?  No postpartum doses?  Continue on oral antibiotics? Quench the fire?

 Maternal fever + cord -> increased risk of encephalopathy  Tylenol Preterm neonates

 IAI associated with 50% of preterm deliveries  Accounts for 70% of perinatal deaths, 50% neurologic morbidity  Higher neonatal mortality - 1.4/1000 of with chorio vs 0.8/1000  Inflammation-induced white matter injury Neonatal infection

 Early onset sepsis = a leading cause of death  EOS incidence = ~1 in 1000 (0.061% vs 0.077% vs 0.098%)  A 2010 RCS showed EOS risk in IAI of 4 in 1000  IAI = 8.7 fold higher risk  IAI is associated with 40% of EOS  E coli and GBS Neonatal mortality

 2008 analysis of 2.28 million births at 37-42 weeks in US from birth and death certificate files revealed…  IAI prevalence was 0.97%.  In other studies rates up to 5%  Neonatal mortality rate for exposed infants was 0.14%  (vs 0.081% w/o chorio) Mechanism

 Mechanisms: altered BBB, endothelial damage, etc.  Infection exposure in utero stimulates fetal inflammatory response  Bronchopulmonary dysplasia  Periventricular leukomalasia  IVH

CDC+AAP+NIH Guidelines

 From: “Prevention of perinatal group B streptococcal disease: revised guidelines from CDC 2010” in the Morbidity and Mortality Weekly Report (MMWR)  Empiric broad spectrum antibiotics +  Labs  cx  cbc with differential  +/- crp Impact of maternal antibiotics

 Start upon diagnosis!  2011 study including 400,000 infants: Intrapartum abx to women with chorio reduced risk of EOS by 82%.  In 1980s, EOS rate in IAI was 80-200/1000  Now 1-5/1000  Widespread GBS screening Maternal and infant characteristics based on clinical chorioamnionitis status Characteristics No CAM CAM[a] p Value 29,869 1,243 Gestational age in wks, 38.9 (1.35) 39.3 (1.27) < 0.001 mean (SD) Highest temperature, °F, 98.8 (95.5, 105.0) 101.2 (96.8, 105.1) < 0.001 median (range)

Maternal vaginal GBS GBS test not done 3,468 (11.6) 52 (4.2) < 0.001 GBS test done 26,401 (88.4) 1,191 (95.8) < 0.001 Test positive 4,879 (16.3) 167 (13.4) 0.007 Intrapartum antibiotics Overall 13,768 (46.1) 1,229 (98.9) < 0.001 GBS-positive mothers 4,306 (88.3) 165 (98.8) < 0.001

Neonatal infection and antibiotic treatment Culture positive 14 (0.05) 5 (0.4) < 0.001 Mother received 6 (42.9) 5 (100) intrapartum antibiotics

Culture negative, 211 (0.7) 42 (3.4) < 0.001 antibiotics ≥ 5 days Mother received 133 (63.0) 42 (100) intrapartum antibiotics

Culture negative, 1,043 (3.5) 318 (25.6) < 0.001 antibiotics < 5 days Mother received 723 (69.3) 316 (99.4) intrapartum antibiotics Serial Physical Exams

 World Journal of : Multicenter retrospective cohort study over 4 months evaluated 2092 neonates >35 wks with 216 initially managed with SPEs  32 of the neonates were intrapartum fever/chorio-exposed  21.8% had signs of illness  62.5% had sepsis w/u  21.9% were given empirical antibiotics Serial Physical Exams in IAI

 All had a normal outcome and none had culture-proven sepsis  Standard intervals – 3/6/12/18/36/48 hrs  Standard forms: clinical appearance  However, 22% of term infants with EOS born to chorio mothers are asymptomatic at 72hrs of life  None of these infants died  According to an RCS of 400,000 infants with 81 cases of EOS in term infants, 22% had no clinical symptoms at 72 hours Neonatal clinical signs of illness

 Temp out side range 36.5-37.5 (rectal)  Pallor  Cyanosis  Lethargy  Irritability  Respiratory distress   Concerning rash  Hypoglycemia Physical exam + risk calculator

 2015 Academy of Pediatrics: 698 well-appearing newborns >34 weeks born to chorio mothers.  One had culture positive EOS.  65% received lab tests+abx therapy  But EOS calculator and clinical appearance would lower lab tests+abx therapy to 12% without missing any cases. Newborn Sepsis Calculator

 http://newbornsepsiscalculator.org/  Prevalence of culture-positive sepsis was 0.058% Concerns

 Labs  15% with abnormal I/T  22% with abnormal crp  0.7% with positive  21.6% underwent lumbar puncture  = Large numbers of chorio-exposed infants were treated with prolonged abx therapy due to abnormal labs alone. Concerns

 Most studies included in CDC guidelines were before widespread GBS screening  Neonatal risks with antibiotics:  exposure to MDR bacteria  attachment and issues  altered gut flora Concerns

 How many newborns would need labs and antibiotics to detect an infant with EOS?  NNT = 60-1400  To prevent death -> NNT = 1785  Treating all infants for 48hrs with abx in NICU = $$$

Back to your patient…  23 year old G1 from Mexico at 40 weeks 5 days with PROM ->  Pitocin ->  Complete + 45 minutes of pushing ->  Fever of 102.2 + FHR of 170bpm ->  Unasyn and Tylenol ->  Two more hours of pushing -> SVD  ROM to delivery = 30hrs  What should we do with baby? The bottom line for babies

 Early onset sepsis rate is 0.5 to 1 in 1000  IAI increases this risk by 4-8 times  Neonatal morbidity is about 8 in 10,000  IAI doubles this risk  Labs, 48hr NICU stay and antibiotics are standard of care  Clinicians worldwide are questioning if a kinder, gentler approach is reasonable  Utilizing the sepsis calculator, serial physical exams and limited work up is one possible solution Discussion with patient

 Use calculator  Consider staff capabilities, ease of transfer  Discuss risks vs benefits of standard Abx+labs+NICU stay Take home points for IAI care

 Correctly establish diagnosis  Start antibiotics once diagnosis established  Provide optimum care for newborns of mothers diagnosed with IAI References

 Herbst A, Wølner-Hanssen P, Ingemarsson I. Risk factors for fever in labor. Obstet Gynecol 1995; 86 (5) 790-794  Alison G. Cahill, MD, MSCI, Cassandra R. Duffy, MD, MPH, Anthony O. Odibo, MD, MSCE, Kimberly A. Roehl, MPH, Qiuhong Zhao, MS, and George A. Macones, MD, MSCE. Number of Cervical Examinations and Risk of Intrapartum Maternal Fever. ACOG VOL. 119, NO. 6, JUNE 2012.  Fishman SG, Gelber SE. Chorioamnionitis. Seminars in Fetal and Neonatal Medicine. 2012; 17 (1) 46-50.  Safe Prevention of the Primary Cesarean Delivery. ACOG Obstetric Care Consensus March 2014  Adi Abramovici, Jeff Szychowski, Joseph Biggio, Yasser Sakawi, William Andrews, Alan TN Tita. Epidural Use and Clinical Chorioamnionitis among Women Who Delivered Vaginally. Amer J Perinatol 2014; 31(11): 1009-1014  Gibbs RS1, Duff P. Progress in pathogenesis and management of clinical intraamniotic infection. Am J Obstet Gynecol. 1991 May;164(5 Pt 1):1317-26.  Hofmeyr GJ1, Kiiza JA. Cochrane Database Syst Rev. Amnioinfusion for chorioamnionitis. 2016 Aug 24;(8):CD011622. doi: 10.1002/14651858.CD011622.pub2.  Chapman E1, Reveiz L, Illanes E, Bonfill Cosp X. Cochrane Database Syst Rev. Antibiotic regimens for management of intra-amniotic infection. 2014 Dec 19;(12):CD010976. doi: 10.1002/14651858.CD010976.pub2.  Impey LW, Greenwood CE, Black RS, Yeh PS, Sheil O, Doyle P. The relationship between intrapartum maternal fever and neonatal acidosis as risk factors for neonatal encephalopathy. Am J Obstet Gynecol. 2008;198(1):49.e1.  Soraisham, Amuchou; Singhal, Nalini; McMilan, Doug; Sauve, Reg; Lee, Shoo. A Multicenter Study on the Clinical Outcome of Chorioamnionitis in Preterm Infants. AJOG. Volume 200, Issue 4, pgs 372 e1-372.e6  Boardman. Association between injury and exposure to chorioamnionitis during fetal life. References

 Berardi, Alberto; Buffagni; Rossi, Cecilia; Vaccina, Eleonora; Cattelini, Chiara; Gambini, Lucia; Baccillieri, Federica; Varioli, Francesca; Ferrari, Fabrizio. Serial physical examinations, a simple and reliable tool for managing neonates at risk for early-onset sepsis. World Journal of Clinical Pediatrics. November 8, 2016. 5(4): 358-364.  Brady, Michael; Polin, Richard. Prevention and management of infants with suspected or proven neonatal sepsis. Pediatrics. Pediatrics 2013; 132;166.  Devasuda Anblagan, Rozalia Pataky, Margaret J. Evans, Emma J. Telford, Ahmed Serag, Sarah SparrowChinthika PiyasenaScott I. SempleAlastair Graham WilkinsonMark E. BastinJames P. Malloy MH. Chorioamnionitis: epidemiology of newborn management and outcome United States 2008. J Perinatol. 2014 Aug;34(8):611-5.  James A. Taylor, Douglas J. Opel. Pediatrics. Choriophobia: A 1-Act Play. August 2012, VOLUME 130 / ISSUE 2.  Higgins, Rosemary, Saade, George, Polin, Richard; Grobman, William; Buhimschi, Irina; Watterberg, Kristi; Silver, Robert; Raju, Tonse. Evaluation and Management of Women and Newborns with a Maternal Diagnosis of Chorioamnionitis. ACOG Vol 127, No 3, March 2016.  Stephanie D. Reilly, Ona M. Faye-Petersen. Chorioamnionitis and Funisitis. NeoReviews Sep 2008, 9 (9) e411- e417; DOI: 10.1542/neo.9-9-e411  Shakib J, Buchi K, Smith E, Young PC. Management of newborns born to mothers with chorioamnionitis: is it time for a kinder, gentler approach? Acad Pediatr. 2015 May-Jun;15(3):340-4. doi: 10.1016/j.acap.2014.11.007. References

 Kiser C, Nawab U, McKenna K, Aghai ZH. Role of guidelines on length of therapy in chorioamnionitis and neonatal sepsis. Pediatrics. 2014 Jun;133(6):992-8. doi: 10.1542/peds.2013-2927.  Escobar GJ, Li DK, Armstrong MA, et al. Neonatal sepsis workups in infants ./=2000 grams at birth: a population-based study. Pediatrics. 2000;106(2 pt 1):256–263  Van Dyke MK, Phares CR, Lynfield R, et al. Evaluation of universal antenatal screening for group B . N Engl J Med. 2009;360(25):2626–2636  Stoll BJ, Hansen NI, Sánchez PJ, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Early onset neonatal sepsis: the burden of group B streptococcal and E. coli disease continues. Pediatrics. 2011;127(5):817–826  Braun D, Bromberger P, Ho N, Getahun D. Low Rate of Perinatal Sepsis in Term Infants of Mothers with Chorioamnionitis. American Jounal of Perinatology 2016; 33(02): 143-150.  Wortham JM, Hansen NI, Schrag SJ, Hale E, Van Meurs K, Sánchez PJ, Cantey JB, Faix R, Poindexter B, Goldberg R, Bizzarro M, Frantz I, Das A, Benitz WE, Shane AL, Higgins R, Stoll BJ; Eunice Kennedy Shriver NICHD Neonatal Research Network. Chorioamnionitis and Culture-Confirmed, Early- Onset Neonatal . Pediatrics. 2016 Jan;137(1). doi: 10.1542/peds.2015-2323. Epub 2015 Dec 30. Image references

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