1. UOG Journal Club: July 2011
Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial
S. S. Hassan, R. Romero, D. Vidyadhari et al. for the PREGNANT Trial
Volume 38, Issue 1, Date: July 2011, pages 18–31
Journal Club slides prepared by Dr Asma Khalil
(UOG Editor for Trainees)

2. Perinatal mortality (%)
Preterm birth 10 20 30 40 50 60 24 25 26 27 28 29 31 32 33 34
Perinatal mortality (%)
Gestation (weeks)
Leading cause of perinatal morbidity and mortality
Centre for Maternal and Child Enquiries (CMACE) Perinatal Mortality 2009:UK
Mathews TJ et al., Natl Vital Stat Rep 2000

3. Cervical length is the best predictor for preterm birth
Detection rate (FPR 10%)
Cervical length + Obstetric Hx
Cervical length
Cervical length + Obstetric Hx + Maternal characteristics
PTB 31 – 33 weeks
PTB 34 – 36 weeks
PTB 28 – 30 weeks 57 59 62 47 53 55 24 29 81
PTB < 28 weeks 76 82 35 32 23
Obstetric Hx + Maternal characteristics
For every 100,000 women screened, $12 million can be saved and 22 cases of neonatal death or long-term neurologic deficits prevented
Universal cervical length screening is cost-effective
Celik E et al., UOG 2008
Werner EF et al., UOG 2010

4. Proposed strategies to reduce the risk of preterm birth
Preterm birth prevention
Progesterone
Cerclage
Pessary
Proposed strategies to reduce the risk of preterm birth
Mechanism of action of progesterone
Not well understood
Exerts biological effects on the chorioamniotic membranes and cervix (Yellon S et al., Reprod Sci 2009)
Prevents cervical ripening (Xu H et al., AJOG 2008)
Suppresses uterine smooth muscle activity (Grazzini E et al., Nature 1998)

5. Progesterone versus placebo
Prenatal administration of progesterone for prevention of preterm birth (Cochrane Review)
Prevention of PTB
Progesterone versus placebo RR
RCTs included
95% CI
Multiple pregnancy#†
Prior threatened PTB#†
Sonographic short cervix*
Fonseca 2007
0.58
0.38 – 0.87
Hartikainen 1980; Rouse 2007 NS
Facchinetti 2007
0.29
0.12 – 0.69
0.15
Past Hx of spontaneous PTB*
da Fonseca 2003
0.04 – 0.64
250
732 60
142
Total
*Preterm birth < 34 weeks
#Preterm birth < 37 weeks
†17-alpha hydroxyprogesterone caproate
Dodd JM et al., Cochrane Review 2009

6. Vaginal progesterone reduces the rate of preterm birth
in women with a sonographic short cervix
Hassan et al., UOG 2011
Phase III, prospective, randomized, placebo-controlled, double-masked, parallel-group, multi-center, international trial.
Objective
To determine the efficacy and safety of vaginal progesterone gel in reducing
the rate of PTB < 33 weeks in asymptomatic women with a mid-trimester
sonographic short cervix.

7. Methodology Inclusion criteria Exclusion criteria
Vaginal progesterone reduces the rate of preterm birth
in women with a sonographic short cervix
Hassan et al., UOG 2011
Methodology
Inclusion criteria
Singleton
GA 19+0 – 23+6 weeks
Cervical length (TV US): – 20 mm
Asymptomatic (no symptoms or signs of preterm labor)
Exclusion criteria
Planned cerclage
Acute cervical dilation
Allergy to progesterone
Recent progestogen treatment (within 4 weeks)
Chronic medical conditions
Major fetal anomaly or chromosomal abnormality
Uterine malformations
Vaginal bleeding
Known/suspected chorioamnionitis

8. Preterm birth <33 weeks
Outcomes
Secondary outcomes
Neonatal morbidity
RDS
Bronchopulmonary dysplasia
Intraventricular hemorrhage (Grade III or IV)
Periventricular leukomalacia
Sepsis
Necrotizing enterocolitis
Perinatal mortality
PTB <28, <35, and <37 weeks
Neonatal biometry at birth
Congenital abnormalities
Primary outcome
Preterm birth <33 weeks

9. Intent-to-treat analysis Treated patient analysis
Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix
Hassan et al., UOG 2011
Analysis sets
Intent-to-treat analysis
Treated patient analysis
Compliant analysis
All patients randomized to either vaginal progesterone or placebo
Patients who took at least one dose of either placebo or progesterone
Patients who used at least 80% of study medication, no cerclage and no loss to follow-up

10. Preterm birth Neonatal morbidity
Outcome
ITT analysis Treated patient Compliant analysis
Adjusted*
Unadjusted
P value
PTB < 35 weeks
PTB < 37 weeks
PTB < 33 weeks†
0.02
0.01 NS
PTB < 28 weeks
0.04
RDS
Any morbidity/mortality
Birth weight < 1500g
0.03
Neonatal morbidity
Preterm birth
†Primary study outcome
*Adjustment for study site and risk strata

11. Preterm birth < 33 weeks (%) Preterm birth < 34 weeks (%)
Progesterone for the prevention of preterm birth in women with short cervix 25 50 20 40
Preterm birth < 33 weeks (%) 15
Preterm birth < 34 weeks (%) 30
45%
44% 10 20
16%
34% 5 9% 10
19%
Placebo
N=235
Progesterone
N=223
Placebo
N=125
Progesterone
N=125
N = 458
Cervix: 10 to 20 mm (median 18 mm)
GA: 20 – 23+6 weeks (median 22 weeks)
Progesterone bioadhesive gel 90 mg PV daily
Duration: 20 – 36+6 weeks
No serious adverse events
Hassan S et al., UOG 2011
N = 250
Cervix:  15 mm (median 11.5 mm)
GA: 20 – 25 weeks (median 22 weeks)
Progesterone capsule 200 mg PV daily
Duration: 20 – 34 weeks
No serious adverse events
Fonseca EB et al., NEJM 2007

12. Treatment-related adverse events
Vaginal progesterone reduces the rate of preterm birth
in women with a sonographic short cervix
Hassan et al., UOG 2011
Treatment-related adverse events
There was no difference in the incidence of treatment-related adverse events between the groups (p=0.51):
Vaginal pruritus
Vaginal discharge
Vaginal candidiasis
Nausea
No fetal or neonatal safety signal was detected for vaginal progesterone gel
One case of congenital anomaly in the progesterone group and three in the placebo group

13. Vaginal progesterone reduces the rate of preterm birth
in women with a sonographic short cervix
Hassan et al., UOG 2011
Clinical utility – Number needed to treat (NNT) to prevent adverse outcome
Progesterone for prevention of PTB < 33 weeks*
Progesterone for prevention of RDS*
MgSO4 for prevention of eclampsia†
Antenatal steroids for prevention of RDS‡ 22 14
100
NNT 13
*Hassan S et al., UOG 2011
†Altman D et al., Lancet 2002
‡Sinclair JC et al., AJOG1995

14. Strengths The first study to show improvement in neonatal morbidity
Vaginal progesterone reduces the rate of preterm birth
in women with a sonographic short cervix
Hassan et al., UOG 2011
Strengths
Multicenter
Placebo-controlled
Double-blind RCT
Rigorous standards for the allocation and concealment of treatment
Additional sensitivity analysis in the ITT analysis set to provide a “worst case” scenario
Primary results are consistent with the literature
Preterm delivery rate in the placebo arm is similar to that reported in other studies
Multi-national nature of the trial
The first study to show improvement in neonatal morbidity

15. Vaginal progesterone reduces the rate of preterm birth
in women with a sonographic short cervix
Hassan et al., UOG 2011
Limitations
The primary endpoint is a surrogate for infant outcome
Not powered to detect differences in outcome according to risk strata (presence or absence of a previous preterm birth)
In the “compliant analysis set”, there was no improvement in the neonatal morbidity apart from increased birth weight

16. Vaginal progesterone reduces the rate of preterm birth
in women with a sonographic short cervix
Hassan et al., UOG 2011
Conclusion
Vaginal progesterone reduces the rate of preterm birth before 33 weeks of gestation and improves neonatal outcomes in women with a sonographic short cervix
Discussion
Should we undertake universal mid-trimester cervical length screening?
Should vaginal progesterone gel be administered to women with a short cervix?