UOG Journal Club: July 2011
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Transcript of UOG Journal Club: July 2011
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?