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Antenatal corticosteroids (ANS)

This review examines the efficacy of antenatal corticosteroids (ANS) in improving neonatal outcomes for preterm infants, analyzing data from over 8,000 babies. Key findings indicate that ANS significantly reduce neonatal mortality (31%), respiratory distress syndrome (34%), and the need for mechanical ventilation (32%) in high-income settings. However, optimal administration timing is critical, with maximum benefits observed when ANS are given 24-48 hours before delivery. The practice of administering ANS varies across hospitals and countries, raising concerns regarding adherence to evidence-based practices in neonatal care.

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Antenatal corticosteroids (ANS)

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  1. Liggins & Howie1972 • >8,000 babies included inRCTs Antenatal corticosteroids(ANS)

  2. Liggins & Howie1972 >8,000 babiesrandomized Antenatal corticosteroids(ANS) ANS decreases (in high-income settings): • Neonatal mortality(31%) • RDS(34%) • Need for mechanical ventilation(32%) • IVH(45%) • NEC(50%) • Systemic infections <48h(40%) Roberts D, Brown J, Medley N, Dalziel SR. Cochrane Database of Systematic Reviews2017;3:CD004454

  3. VON; Green dots Turku Univ HospFinland

  4. 65-100% of pregnant women delivering at 24-32 weeks of GA receivesANS • Practicevaries: • overtime • between hospitals, regions andcountries • by gestationalage Are ANSused?

  5. Only about 100 deliveries <28 wks GA included in the >20 RCTs onANS Jobe A, PAS2017 ANS for extremely preterminfants

  6. Only about 100 deliveries <28 wks GA included in the >20 RCTs onANS Jobe A, PAS2017 Previous meta-analysis: no reductions of mortality & morbidity prior to 26wks Onland W et al, Am J Perinatol2011 ANS for extremely preterminfants

  7. Only about 100 deliveries <28 wks GA included in the >20 RCTs onANS Previous meta-analysis: no reductions of mortality & morbidity prior to 26wks Onland W et al, Am J Perinatol2011 ANS for extremely preterminfants More recent studies: indicate similar or even more pronounced benefits from ANS for extremely pretermbirths Carlo WA et al, JAMA 2011; Mori R et al, J Pediatr 2011; Melamed N et al, Obstet Gynecol2015

  8. VON 2012-2015, survival rates by GA andANS Ehret D, PAS abstract2017

  9. Observational data indicate that ANS may be effective also for extremely pretermbirth Do they work in extermely preterminfants?

  10. Maximized benefits -> ANS administered 24-48 hours to 7 days beforedelivery • Cochrane2006,AJOG 2004,2005,2007,2011&2015,Obstet&Gynecol2001& 2013 Concepts abouttiming

  11. Neonatal benefits maximized when ANS are administered24-48 hours up to 7 days beforedelivery Cochrane2006,AJOG 2004,2005,2007,2011&2015,Obstet& Gynecol2001& 2013 Concepts abouttiming • Administration-to-birth intervals <24 (-48) hours described and considered as incomplete, suboptimal orpartial • AJOG 2004, J Maternal-Fetal & Neonatal Medicine 2009, Obstet & Gynecol2015

  12. 1.0 Neonatal survivala in EXPRESS by ANS administration-to-birthintervals (n=707, GA 22-26 wks, 84% exposed toANS) Cumulative neonatalsurvival ANS 24-47 hours beforebirth 0.9 ANS 48h – 7 days beforebirth 0.8 ANS >7 days before birth ANS but no info on timing ANS 1-23 hours beforebirth 0.7 0.6 NoANS 0.5 0 7 14 21 28 Age,days a Adjusted for maternal smoking, maternal HT/PE, placenta previa, placental abruption, PPROM, regionalization of care, gestational age, small for gestational age, infant gender and surfactant <2h afterbirth Hanna Norberg, BJOG2016

  13. Timely prediction of preterm deliveryunresolved • most women deliver outside the “optimal”interval • many deliver before 24 (-48) hours have passed from admin ofANS • BMJ2016 Theproblem

  14. Researchquestion What is the shortest administration-to-birth interval of antenatal corticosteroids to promote survival in very preterminfants?

  15. EPICE COHORT Effective Perinatal Intensive Care inEurope • Overall aim: to study implementation of evidence based practices in perinatal and neonatalmedicine • 19 regions from 11 Europeancountries • GA<32weeks • All deliveries in2011-2012

  16. All very pretermbirths (<32 gestationalweeks) n= 10329 Terminations of pregnancy and stillbirths (n=2429) Severe malformations (n=126) Births <24 weeksof gestation(n=300) Multiples (n=2336) Unknown timing of antenatal corticosteroids(n=362) Repeat courses of antenatal corticosteroids(n=182) 4 594 infantsincluded

  17. Design Exposure: ANS administration-to-birth interval inhours Outcomes: In-hospitalmortality Mortality or severe neonatal morbidity (IVH ≥3, cPVL, NECor ROP stage ≥3) Severe neonatal brain injury ((IVH ≥3 orcPVL) Co-variates: maternalage parity pregnancy complications GA small for gestationalage infantsex delivery on day of admission mode ofdelivery delivery in level IIIunit

  18. % 100 100 90 80 70 60 50 40 30 20 10 0 18,2 90 Results 80 >14d 8d-14d 5d-7d 2d-4d 25h-48h 13h-24h 6h-12h 3h-5h <3h NoANS >7 days 24 hours -7days <24hours NoANS 70 39,2 60 50 40 30 27,3 20 15,3 10 0 4categories 10categories

  19. Mainfinding Infant mortality by ANSadministration- to-birthintervals RR adjusted for patient case-mix (maternal age; parity; pregnancy complications including preeclampsia, eclampsia and HELLP-syndrome and PPROM; GA; small forgestational age and infant sex) and factors related to management (delivery on day of admission, mode of delivery, delivery in hospital with level III neonatalunit) Norman M et al, JAMA Peds2017

  20. Summary 77% of women did not receive ANS or received ANS outside of the desired administration-to-birth interval, i.e., 2 to 4days

  21. Summary 77% of women did not receive ANS or received ANS outside of thedesired administration-to-birth interval, i.e., 2 to 4days ANS associated with immediate and rapid decline inmortality

  22. 77% of women did not receive ANS or received ANS outside of thedesired administration-to-birth interval, i.e., 2 to 4days ANS associated with immediate and rapid decline inmortality Summary Under the assumption of a causal relationship, a simulation of ANS given 3 hours before delivery to infants who did not receiveANS -> their estimated decline in mortality would be26%

  23. 77% of women did not receive ANS or received ANS outside of thedesired administration-to-birth interval, i.e., 2 to 4days ANS associated with immediate and rapid decline inmortality Under the assumption of a causal relationship, a simulation of ANS given 3 hours before delivery to infants who did not receiveANS -> their estimated decline in mortality would be26% Summary Infants with an ANS administration-to-birth interval >7 days (19% of all infants in our study) exhibited 40% higher mortality than those with ANS given 1-7 days beforebirth

  24. ANS may be effective even if given only hours beforedelivery meaning Infants of pregnant women at risk of imminent/immediate very preterm delivery may benefit from itsuse Conclusion

  25. OBSTETRICS CrossMark AugustoF..Schmidt,MD,PhD;MatthewW.Kemp,PhD;JudithRittenschober-Böhm,MO;ParanthamanS.Kannan,PhD; Haruo Usuda, MD; Masatoshi Saito, MD; Lucy Furtaro, BSc; Shimpei Watanabe, MD; Sarah Stock, PhD,MBChB; BorisW.Kramer,MD,PhD;JohnP.Newnham,MD;SuhasG.Kallapur.,MD;AlanH.J1obe,MD,PhD Low-dose betamethasone-acetate for fetal lung maturation in pretermsheep S _DY DESIGN: Gmups o ·1Dsing, leon-pregnan e es rece,ived ·1or 2 intramusculardoses24hoursaparto·0.25img/kg(dose·o ·o be,t,ame,tllasone,-phospha,te+be,t,ame,hasone,-ace,taehestandard care, dose) or 1 in ramulScular dose, of 0.5mg/kg, 0.25imgfkg,or o.·125i ·.,eth.,1a':sJoIn'e-'e,r:e'a,'ft.e.I'r g(k'.goIfb..ea.m.a1ceIt,a.'t'eI.FeI'tulse,s:.d..e'I1ve're.d.l.4·.·8''h1Iour'.s:. m.. CONCLU,S O1 : A sing, le dose o b, etam, et111aso, ne-a,ceta, e resul s in similar,eallungmaturationas,he2-dlose,clinicalformulaonof e.:, b· e a·m··e,4h1a·s01ne-,-ace a· e, 1'.11!,h,1.-1,1ecn·e,a· ·s-·e.-1,1fe,a·I be.:,.a.-·'m··e.:,.hIl1la.·'s_:.10-.1ne.:,-p·_hIlir0..5:._:.p·hI[Il,a·' U [I IJ . :. . . : .' r _: • . : U . : _r' 1 • 1 • : . r -' . : . U ll .' _:.-. . : _r ' . . . : . r -' . : 1 exposu, re to be,tame,thasone,.Alo er dose o· be,tame,thasone,-ace,t,a emay be,ane, ecti,ve al e,m1a iveto1ndu,ce· e,ta lung maturation 18' fe,LIS. ithlessrisko

  26. JAMA I Originallnvestigation Association Between Year of Birth and 1-YearSurvival Among Extremely Preterm lnfants inSweden During 2004-2007 and2014-2016 MikaelNorman,MD,PhD;BoubouHallberg,MD,PhD;ThomasAbrahamsson,MD,PhD; LarsJ.Björklund,MD,PhD;MagnusDomellöf,MD,PhD;AijazFarooqi,MD,PhD;CathrineFoynBruun,MD,PhD; ChristianGadsb0II,MD;LenaHellström-Westas,MD,PhD;Fredriklngemansson,MD:Karinl<ällen,PhD; DavidLey,MD,PhD;l<arelMarsal.MD,PhD;ErikNormann,MD,PhD;FredrikSerenius,MD,PhD; OlofStephansson,MD.PhD;LennartStigson,MD;PetraUm-Bergström,MD:StellanHåkansson,MD,PhD

  27. START AKTUELLT KLINIK&VETENSKAPOPI AKTUELLT-START NYHETER PATIENTSÄKERHET KULTUR MÄNNISKOR &MÖTEN Läkartidningen SENASTE »Vårdpersonalbehövermerkunskapomalternativmedicin« KONTAKT SKRIV V NYHETER Flerextremttidigtföddaöverlever överlevnadenhosextremttidigtföddabarnharökatiSverigepåsenareår,enligten färsk studie i JAMA. Och det har inte skett till priset av fierkomplikationer. IKatrin Trysell - Vi ser förbätt ringar på alla plan. Det är färre andel dödfödda, färre barn som dör direkt i förlossningsrummet och färre barn som dör under neonatalvård, säger Mikael Norman, professor i pediatrikvidKarolinskainstitutetochenavforskarnabakomdenyafynden.

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