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Liggins & Howie 1972 >8,000 babies included in RCTs. Antenatal corticosteroids (ANS). Liggins & Howie 1972 >8,000 babies randomized. Antenatal corticosteroids (ANS). ANS decreases (in high-income settings) :. Neonatal mortality (31%) RDS (34%)
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Liggins & Howie1972 • >8,000 babies included inRCTs Antenatal corticosteroids(ANS)
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
65-100% of pregnant women delivering at 24-32 weeks of GA receivesANS • Practicevaries: • overtime • between hospitals, regions andcountries • by gestationalage Are ANSused?
Only about 100 deliveries <28 wks GA included in the >20 RCTs onANS Jobe A, PAS2017 ANS for extremely preterminfants
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
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
VON 2012-2015, survival rates by GA andANS Ehret D, PAS abstract2017
Observational data indicate that ANS may be effective also for extremely pretermbirth Do they work in extermely preterminfants?
Maximized benefits -> ANS administered 24-48 hours to 7 days beforedelivery • Cochrane2006,AJOG 2004,2005,2007,2011&2015,Obstet&Gynecol2001& 2013 Concepts abouttiming
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
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
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
Researchquestion What is the shortest administration-to-birth interval of antenatal corticosteroids to promote survival in very preterminfants?
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
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
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
% 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
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
Summary 77% of women did not receive ANS or received ANS outside of the desired administration-to-birth interval, i.e., 2 to 4days
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
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%
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
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
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
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
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.