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)

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

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

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 Perinatal outcome in women treated with progesterone for the prevention of preterm birth: a meta-analysis Sotiriadis et al., UOG 2012 Inclusion criteria 1)Randomized controlled trials (RCTs) 2)Intervention: progesterone vs. placebo 3)Type of participants: singleton pregnancy at risk for preterm birth due to previous history or short cervix during the second trimester or multiple pregnancies Exclusion criteria 1)No adequate randomization 2)No placebo group 3)Women with symptoms of PTB, bleeding or rupture of membranes 4)Studies that did not provide data on neonatal outcomes Methods

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

Results MEDLINE, SCOPUS, EMBASE search 628 articles 170 articles 458 articles: excluded based on title and abstract 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 Perinatal outcome in women treated with progesterone for the prevention of preterm birth: a meta-analysis Sotiriadis et al., UOG 2012

Perinatal outcome in women treated with progesterone for the prevention of preterm birth: a meta-analysis Sotiriadis et al., UOG 2012 †Primary study outcome. NICU, neonatal intensive care unit; NNT, number needed to treat; RDS, repiratory distress syndrome. Results: singleton pregnancies, all indications, all progestogens (6 RCTs) RR95% CINNT RDS NICU admission Composite adverse outcome – – – –0.818 Neonatal death † Birth <34 weeks – Outcome No significant difference was found in the rates of perinatal death, grade III-IV intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), retinopathy and sepsis.

Perinatal outcome in women treated with progesterone for the prevention of preterm birth: a meta-analysis Sotiriadis et al., UOG 2012 †Primary study outcome I. Singleton pregnancies with history of PTB treated with systemic progesterone (3 RCTs) RR95% CINNT NICU admission – –0.842 Neonatal death † Outcome II. Singleton pregnancies with a short cervix in the second trimester treated with local (vaginal) progesterone (3 RCTs) RR95% CINNT RDS – –0.891 Composite adverse outcome Outcome Results: singleton pregnancies subgroup analysis The available data allowed only two subgroup analyses

Perinatal outcome in women treated with progesterone for the prevention of preterm birth: a meta-analysis Sotiriadis et al., UOG 2012 †NNH, number needed to harm. Results: twin pregnancies, all progestogens (7 RCTs) RR95% CINNH† RDS Perinatal death – – –1.425 Composite adverse 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 Outcome*

Perinatal outcome in women treated with progesterone for the prevention of preterm birth: a meta-analysis Sotiriadis et al., UOG 2012 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 Discussion

Perinatal outcome in women treated with progesterone for the prevention of preterm birth: a meta-analysis Sotiriadis et al., UOG 2012 Limitations 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 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

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?