UOG Journal Club: September 2012

1. UOG Journal Club: September 2012 Perinatal outcome in women treated with progesterone for the prevention of preterm birth: a meta-analysis Sotiriadis A, Papatheodorou S, Makrydimas G Volume 40, Issue 3, Date: September 2012, pages 257–266 Journal Club slides prepared by Dr Aly Youssef (UOG Editor for Trainees)

2. Preterm birth (PTB) is the leading cause of neonatal mortality and the most common reason for antenatal hospitalization • Screening for PTB based on obstetric history and cervical length can identify more than 50% of those who will deliver <34 weeks • Progesterone prophylaxis clearly reduces the risk of preterm birth in women at risk • Nevertheless, its effects on the actual perinatal and long-term consequences of prematurity are more difficult to assess Centre for Maternal and Child Enquiries (CMACE) Perinatal Mortality 2009:UK Martin JA et al., Natl Vital Stat Rep 2010

3. Perinatal outcome in women treated with progesterone for the prevention of preterm birth: a meta-analysis Sotiriadis et al., UOG 2012 The aim of this meta-analysis was to systematically review published evidence and pool data on the perinatal outcome in women treated with progesterone for the prevention of preterm birth

4. Perinatal outcome in women treated with progesterone for the prevention of preterm birth: a meta-analysis Sotiriadis et al., UOG 2012 Methods Search of the literature (last update December 2011) for clinical trials in which progesterone was given for the prevention of PTB in pregnant women at risk compared to placebo • Exclusion criteria • No adequate randomization • No placebo group • Women with symptoms of PTB, bleeding or rupture of membranes • Studies that did not provide data on neonatal outcomes • Inclusion criteria • Randomized controlled trials (RCTs) • Intervention:progesterone vs. placebo • Type of participants: singleton pregnancy at risk for preterm birth due to previous history or short cervix during the second trimester ormultiple pregnancies

5. Perinatal outcome in women treated with progesterone for the prevention of preterm birth: a meta-analysis Sotiriadis et al., UOG 2012 Primary outcome: - neonatal mortality number of deaths from birth to less than 28 days of age Secondary outcomes: - perinatal complications respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, sepsis, retinopathy and NICU admission - composite adverse outcome

6. Perinatal outcome in women treated with progesterone for the prevention of preterm birth: a meta-analysis Sotiriadis et al., UOG 2012 Results MEDLINE, SCOPUS, EMBASE search 628 articles 458 articles: excluded based on title and abstract 170 articles Reviews: 79 Letters, Editorials, Notes, Guidelines: 18 No placebo group or other outcomes: 39 Symptomatic women: 6 Overlapping: 3 No neonatal outcomes: 8 No separate data on twins and singleton: 1 16 studies included in the meta-analysis

7. Results: singletonpregnancies, all indications, all progestogens(6 RCTs) RR 95% CI NNT Neonatal death † 0.487 0.290–0.818 57 Composite adverse outcome 0.576 0.373–0.891 17 RDS 0.677 0.490–0.935 26 NICU admission 0.410 0.204–0.823 4 Perinatal outcome in women treated with progesterone for the prevention of preterm birth: a meta-analysis Sotiriadis et al., UOG 2012 Outcome Birth <34 weeks 0.577 0.427–0.779 6 No significant difference was found in the rates of perinatal death, grade III-IV intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), retinopathy and sepsis. †Primary study outcome. NICU, neonatal intensive care unit; NNT, number needed to treat; RDS, repiratory distress syndrome.

8. I. Singletonpregnancies with history of PTBtreated with systemic progesterone (3 RCTs) II. Singleton pregnancies with a short cervix in the second trimester treated with local (vaginal) progesterone (3 RCTs) RR RR 95% CI 95% CI NNT NNT Composite adverse outcome Neonatal death † 0.576 0.412 0.373–0.891 0.201–0.842 17 24 NICU admission RDS 0.277 0.464 0.160–0.479 0.275–0.786 3 15 Perinatal outcome in women treated with progesterone for the prevention of preterm birth: a meta-analysis Sotiriadis et al., UOG 2012 Results: singleton pregnancies subgroup analysis The available data allowed only two subgroup analyses Outcome Outcome †Primary study outcome

9. Results: twin pregnancies, all progestogens (7 RCTs) RR 95% CI NNH† Composite adverse outcome 1.211 1.029–1.425 31 Perinatal death 1.551 1.014–2.372 71 RDS 1.218 1.038–1.428 39 Perinatal outcome in women treated with progesterone for the prevention of preterm birth: a meta-analysis Sotiriadis et al., UOG 2012 Outcome* Progesterone administration did not significantly affect the rates of neonatal death, grade III-IV IVH, NEC, retinopathy, sepsis and NICU admission. Triplet pregnancies: The pooled data of 2 RCTs did not show significant differences in the rates of composite adverse outcome, neonatal death, RDS, grade III-IV IVH, NEC and sepsis †NNH, number needed to harm.

10. Perinatal outcome in women treated with progesterone for the prevention of preterm birth: a meta-analysis Sotiriadis et al., UOG 2012 Discussion • The present meta-analysis focused on the effects of progesterone on the actual perinatal outcomes of treated pregnancies • Prophylactic progesterone administration in singleton pregnancies at risk succeeds in reducing the rates of neonatal mortality, RDS, admission to the NICU and composite adverse outcome • Whether local or systemic progesterone is better for women with a short cervix remains to be answered • In multiple pregnancies, no beneficial effect of progesterone was demonstrated and in fact the rates of perinatal death, RDS and composite adverse outcome may even be increased

11. Perinatal outcome in women treated with progesterone for the prevention of preterm birth: a meta-analysis Sotiriadis et al., UOG 2012 Limitations • Pooled studies cannot have identical inclusion criteria, treatment and reporting protocols. However, in the present meta-analysis there was marked consistency in the results across studies for most outcomes • The relatively small number of triplets prevented reaching statistically significant results in this group Future perspectives • The next step after testing the effects of progesterone treatment on the rates of preterm birth and immediate perinatal complications is to examine its impact on the longer-term neurodevelopment of treated children

12. Perinatal outcome in women treated with progesterone for the prevention of preterm birth: a meta-analysis Sotiriadis et al., UOG 2012 Discussion points • Should a policy of universal screening of pregnant women for PTB and progesterone prophylaxis be implemented? • What level of cut-off for cervical length should be used to define a woman with a singleton pregnancy as “high-risk” for PTB? • In women with short cervices, which progesterone (local/systemic) should be used? • Are there any beneficial measures for the prevention of PTB in twin pregnancies? • Does the available data support the application of preventative measures of PTB in multiple pregnancies?