In preterm labour 2016

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Renée Agnes Claessens
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1 In preterm labour 2016 Yves Jacquemyn Richtlijnen blijven een onmisbare bron van gestolde kennis, maar richten zich niet op de individuele patient Ned Tijdschr Geneeskd 2016; 160: D584 1

2 Sir Graham Liggins Weddell seal, Leptonychotes weddellii 2

3 Premature parturition after infusion of corticotrophin or cortisol into foetal lambs. Liggins GC. J Endocrinol Oct;42(2):

4 A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Liggins GC, Howie RN. Pediatrics Oct;50(4):

5 5

6 Introductory generalities 6

7 Tijdstip eerste i njectie 12 uur 24 uur 36 uur 48 uur 14/11/2016 Beta vs dexa 2* 24h vs 4* 6 h etc Not for today???? 7

bij stress 12 mg ~75% saturatie Na tweede dosis lichte stijging Standaarddosis = quasi maximale inductie cortico receptor

8 We lack the pharmacokinetic and dose-response data necessary to optimize dosing regimens (Kemp et al, Hum Reprod Update 2016) What we know Fysiologisch 30-40% intracytoplasmatische corticosteroidreceptoren long gevuld 12 mg ~endogene cortisol stijging bij stress 12 mg ~75% saturatie Na tweede dosis lichte stijging Standaarddosis = quasi maximale inductie cortico receptor activiteit Ballard et al. Scientific basis and therapeutic regimens for use of antenatal clucorticoids Am J O G 1995; 173:

9 One message to remember Cave treatment creeps the 2006 Cochrane review described a worrying trend towards an increased risk of death for babies who go on to deliver at full term ( RR 3,25: 0,99-10,66) It is not statistically significant but can become relevant NO PREVENTIVE CORTICOSTEROIDS just for in Ridout A, BJOG 2016 case 9

10 Harmfull effects % who receive Corticos deliver at term Then : Increased risk death and disability ( OR1,7; Asztalos JAMA Pediatr 2013) Lower academic achievement at 8-15 y ( ASTECS) Increased cortisol reactivity to acute psychosocial stress at 6-11 years ( Alexander J Clin Endocrinol Metab 2012) Quid lasting epigenetic changes? Eg postnatal regulation of gene PNMT for epinephrine ( Nguyen J Endocrinol 2015) 19 y after betamethasone POPS trial: genetic variation in glucocorticoid sensitivity ( receptor polymorphism) associated with IQ and behavior ( vaan der Voorn, J endocrinol metabo 2015) Adminstering steroids just in case is not acceptable (Vidaeff, BJOG 2016) Product en schema Betamethasone Dexamethasone Modus Sectio primair Spontaan Inductie Week/ eenlingmeerling 10

11 34-40 weken inductie weken spontane arbeid weken sectio Repeat dosis? weken inductie weken spontane arbeid weken sectio Repeat dosis? 11

12 34-40 weken inductie weken spontane arbeid weken sectio Repeat dosis? weken inductie weken spontane arbeid weken sectio Repeat dosis? 12

13 > 34 weken After immature fetal lung indices Before elective cesarean delivery general Immature fetal lung indices: amniocentesis 2 retrospective cohorts 1. MORE resp problems; hypoglycemia 2. NO difference RDs; hypoglycemia 1.Kamath-Rayne Obstet Gynecol 2012;2. Yinon AJOG

14 Immature fetal lung indices: amniocentesis Irrrelevant: We do not perform amniocentesis anymore for this in europe 1.Kamath-Rayne Obstet Gynecol 2012;2. Yinon AJOG 2012 BMJ 12 october

15 Risk RDS 15

16 Transiente tachypnee Severe rds 16

17 Neonatal hypoglycemia Summary RR: 1,61 ( 95%CI 1,16-2,12) Significance not yet clear Hypoglycemia 24% vs 15.0% ( RR 1,60; 1,37-1,87) Self limiting: hypoglycemic babies on average dsicharged 2 days EARLIER than non hypoglycemic Nadir neonatal glycemia not reported, neither treatment Explanations? Transient hyperinsulinism due to maternal hyperglycemia? Non exposed sicker and IV fluid + glucose? 17

18 conclusion Steroids reduce respiratory problems > 34 weeks Give corticosteroids if imminent delivery 34 0/7 to 36 6/7 Give corticosteroids for planned cesarean until 38 6/7 Plan a CS at >= 39 weeks!!!!! ( or give corticosteroids) Strictly defined high risk of imminent delivery PTL, intact membranes ; >= 3 cm dilation or 75 %effacement Or Spontaneous rupture of membranes 18

19 overall Adhere strictly to crietria for imminent late preterm delivery No tocolysis Until 36 6/7 After 34 0/7 : no repeat course ( ACOG 2016) Cave treatment creep Lack of long term outcome Follow glycemia 19

20 Long term follow up weeks: 50 %increase cortical brain volume; +25% volume cerebellum! ASTECS follow up 8-15 years Higher incidence in lower quarter of academic abilisty ( 17,7% betamethasone, 8,5% placebo) ( no other cognitive, behaviouural asthma etc differnces) No data on long term cardiovascular or metabolic data weken inductie doses weken spontane arbeid weken sectio Repeat dosis? 20

21 Crowther CA et al. Cochrane 2015: repeat doses of prenatal corticosteroids for women at risk of preterm birth forimproving neonatal health outcomes 10 trials 4733 women 5700 babies RDS RR 0,83; 0,75-0,91; NNT 17 Serious infant ouctome RR 0,84; 0,75-0,94 NNT 30 Adjusted birthweight for gestational age: no difference Long term? Need individual patient data meta-analysis Follow up of a 1998 study at ages 6 to 8 21

22 PPROM Repeat course does not increase chorioamnionitis risk ( Brookfiedl Am J Perinatol 2015) A single repeat course of antenatal corticosteroids should be considered in women whose prior course of antenatal corticosteroids was administered at least 7 days previously and who remain at risk of preterm birth before 34 weeks of gestation ACOG

23 34-40 weken inductie weken spontane arbeid weken sectio Repeat dosis? weken inductie DOEN weken spontane arbeid DOEN weken sectio Plan 39 weken DOEN Repeat dosis? DOEN 23

34-40 weken inductie DOEN 34-37 weken spontane arbeid DOEN Never just in 37-42 weken sectio

24 34-40 weken inductie DOEN weken spontane arbeid DOEN Never just in weken sectio case Plan 39 weken DOEN Repeat dosis? DOEN A note on twins NO RCT specific for twins 24

25 Viteri et al Obstet Gynecol 2016 Subanalysis of an rct overall 25

26 < 34 weeks conclusion No reduced incidence RDS No better neonatal outcome > 34 weken MORE NICU! Cochrane ( Roberts; 2006): insufficient evidence 26

27 BUT Retrospective cohort study AJOG october

28 Dubbele dosis? Suggested, not studied Clearance of betamethasone 39% increase twins vs singletons But: Standaarddosis = quasi maximale inductie cortico receptor activiteit Ballabh Clin Pharmacol Ther 2002 We are a far way from precision medicine to fit therapy in type and dose to the lesion, the disease and the individual and thus prevent under or over treatment 28

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