UOG Journal Club: July 2011Vaginal 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)

Preterm birth

0

10

20

30

40

50

60

24 25 26 27 28 29 30 31 32 33 34

Perin

atal

mor

talit

y (%

)

Gestation (weeks)

Centre for Maternal and Child Enquiries (CMACE) Perinatal Mortality 2009:UKMathews TJ et al., Natl Vital Stat Rep 2000

Leading cause of perinatal morbidity

and mortality

Celik E et al., UOG 2008 Werner EF et al., UOG 2010

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 29

81PTB < 28 weeks 76 82

35

32

23

23

Obstetric Hx + Maternal characteristics

• For every 100,000 women screened, $12 million can be saved and 22 cases ofFor every 100,000 women screened, $12 million can be saved and 22 cases of neonatal death or long-term neurologic deficits prevented neonatal death or long-term neurologic deficits prevented

• Universal cervical length screening is cost-effectiveUniversal cervical length screening is cost-effective

Cervical length is the best predictor for preterm birthCervical length is the best predictor for preterm birth

Progesterone Cerclage Pessary

ProposedProposed strategies to reduce the risk of preterm birth

Mechanism of action of progesterone

Preterm birth prevention

• Not well understood

• Exerts biological effects on the chorioamniotic membranes and cervix (Yellon S (Yellon S et alet al., Reprod Sci 2009)., Reprod Sci 2009)

• Prevents cervical ripening (Xu H (Xu H et alet al., AJOG 2008)., AJOG 2008)

• Suppresses uterine smooth muscle activity (Grazzini E (Grazzini E et alet al., Nature 1998)., Nature 1998)

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 NS

Facchinetti 2007 0.29 0.12 – 0.69

0.15Past 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

Prenatal administration of progesterone for prevention of preterm birth Prenatal administration of progesterone for prevention of preterm birth (Cochrane Review)(Cochrane Review)

Dodd JM et al., Cochrane Review 2009

Vaginal progesterone reduces the rate of preterm birthin 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 reducingthe rate of PTB < 33 weeks in asymptomatic women with a mid-trimester sonographic short cervix.

Methodology

Inclusion criteria

1) Singleton 2) GA 19+0 – 23+6 weeks 3) Cervical length (TV US):

10 – 20 mm4) Asymptomatic (no symptoms or

signs of preterm labor)

Exclusion criteria

1) Planned cerclage2) Acute cervical dilation3) Allergy to progesterone4) Recent progestogen treatment (within

4 weeks)5) Chronic medical conditions6) Major fetal anomaly or chromosomal

abnormality7) Uterine malformations8) Vaginal bleeding9) Known/suspected chorioamnionitis

Vaginal progesterone reduces the rate of preterm birthin women with a sonographic short cervix

Hassan et al., UOG 2011

Outcomes

Primary outcome

Preterm birth <33 weeks

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

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

Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix

Hassan et al., UOG 2011

†Primary study outcome*Adjustment for study site and risk strata

Outcome

ITT analysis Treated patient Compliant analysis

Adjusted*Unadjusted Adjusted*

P value P value P value

PTB < 35 weeks

PTB < 37 weeks

PTB < 33 weeks† 0.02 0.02 0.01

0.02 0.01 0.01

NS NS NS

NSPTB < 28 weeks 0.04 0.04

NS

RDS

Any morbidity/mortality

Birth weight < 1500g 0.01 0.01 0.01

0.03 0.04 NS

0.04 NS

Neonatal morbidity

Preterm birth

Progesterone for the prevention of preterm birth in women with short cervixProgesterone for the prevention of preterm birth in women with short cervix

0

5

10

15

20

PlaceboN=235

ProgesteroneN=223

16%9%

45%45%

25

Pret

erm

birt

h

<

33 w

eeks

(%)

0

10

20

30

40

PlaceboN=125

ProgesteroneN=125

34%19%

44%44%

50

Pret

erm

birt

h

<

34 w

eeks

(%)

N = 250N = 250Cervix: Cervix: 15 mm (median 11.5 mm) 15 mm (median 11.5 mm)GA: 20 – 25 weeks (median 22 weeks)GA: 20 – 25 weeks (median 22 weeks)Progesterone capsule 200 mg PV dailyProgesterone capsule 200 mg PV dailyDuration: 20 – 34 weeksDuration: 20 – 34 weeksNo serious adverse eventsNo serious adverse events

Fonseca EB et al., NEJM 2007

N = 458N = 458Cervix: 10 to 20 mm (median 18 mm)Cervix: 10 to 20 mm (median 18 mm)GA: 20 – 23GA: 20 – 23+6+6 weeks (median 22 weeks) weeks (median 22 weeks)Progesterone bioadhesive gel 90 mg PV dailyProgesterone bioadhesive gel 90 mg PV dailyDuration: 20 – 36Duration: 20 – 36+6+6 weeks weeksNo serious adverse eventsNo serious adverse events

Hassan S et al., UOG 2011

Treatment-related adverse events

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

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

Vaginal progesterone reduces the rate of preterm birthin 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

Vaginal progesterone reduces the rate of preterm birthin women with a sonographic short cervix

Hassan et al., UOG 2011

*Hassan S et al., UOG 2011†Altman D et al., Lancet 2002‡Sinclair JC et al., AJOG1995

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 birthin women with a sonographic short cervix

Hassan et al., UOG 2011

• 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)

Limitations

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 birthin women with a sonographic short cervix

Hassan et al., UOG 2011

ConclusionVaginal progesterone reduces the rate of preterm birth before 33 weeks of gestation and improves neonatal outcomes in women with a sonographic short cervix

Vaginal progesterone reduces the rate of preterm birthin women with a sonographic short cervix

Hassan et al., UOG 2011

Discussion

• Should we undertake universal mid-trimester cervical length screening?

• Should vaginal progesterone gel be administered to women with a short cervix?