This Journal Club presentation provides a summary and discussion of the following free access article published in UOG: Perinatal outcome in women treated with progesterone for the prevention of preterm birth: a meta-analysis A. Sotiriadis, S. Papatheodrou, G. Makrydimas Volume 40, Issue 3, Date: September 2012, pages 257-266 It can be accessed here: http://onlinelibrary.wiley.com/doi/10.1002/uog.11178/abstract

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
Inclusion criteria Exclusion criteria
1) Randomized controlled trials (RCTs) 1) No adequate randomization
2) Intervention: progesterone vs.
2) No placebo group
placebo
3) Type of participants: singleton 3) Women with symptoms of PTB,
pregnancy at risk for preterm birth bleeding or rupture of membranes
due to previous history or short cervix
during the second trimester or 4) Studies that did not provide data on
multiple pregnancies neonatal outcomes

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. Perinatal outcome in women treated with progesterone for
the prevention of preterm birth: a meta-analysis
Sotiriadis et al., UOG 2012
Results: singleton pregnancies,
all indications, all progestogens (6 RCTs)
Outcome 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
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. 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
I. Singleton pregnancies with history of PTB treated with systemic
progesterone (3 RCTs)
Outcome RR 95% CI NNT
Neonatal death † 0.412 0.201–0.842 24
NICU admission 0.277 0.160–0.479 3
II. Singleton pregnancies with a short cervix in the second trimester treated
with local (vaginal) progesterone (3 RCTs)
Outcome RR 95% CI NNT
Composite adverse outcome 0.576 0.373–0.891 17
†Primary
RDS 0.464 0.275–0.786 15 study
outcome

9. Perinatal outcome in women treated with progesterone for
the prevention of preterm birth: a meta-analysis
Sotiriadis et al., UOG 2012
Results: twin pregnancies, all progestogens (7 RCTs)
Outcome* 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
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?