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)

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

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

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)

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

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.

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): 10 – 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

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

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

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

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

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

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

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

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

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?