catherine y spong, md chief, pregnancy & perinatology branch national institute of child health...
TRANSCRIPT
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Catherine Y Spong, MD Chief, Pregnancy & Perinatology Branch National Institute of Child Health & Human Development National Institutes of Health
Progesterone Supplementation and Prevention of Preterm Birth
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Conflict of Interest Statement
I have no conflict of interest related to the content of this presentation
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Objectives
to describe the problem of prematurity to describe the mechanism of progesterone
action to define the patient population who meets the
criteria for progesterone administration to prevent preterm birth
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Preterm Delivery: A Public Health Priority 1 in 8 infants is born preterm
542,893 preterm births each year (2006) leading cause of hospitalization among pregnant women leading cause of death among African-American infants associated with developmental disabilities
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Leading Causes of Neonatal Mortality, 2001
0 5 10 15 20 25
Preterm / LBW
Birth Defects
Maternalcomplications
Placenta / cordcomplications
RDS
(N / 100,000 live births)
4,322
3,875
1,491
998
943
http://www.cdc.gov/nchs/data/nvsr/nvsr52/nvsr52_09.pdf Table H. Deaths and percentage of total deaths for the 10 leading causes of neonatal and postneonatal deaths: United States, 2001
Leading cause of black infant mortalitySecond leading cause of all infant mortality
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Preterm Birth: Outcome
1 out of 5 children with mental retardation1 out of 3 children with vision impairmentAlmost half of children with cerebral palsy
Accounts for
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Preterm Birth: Long Term Outcome For the baby:
Increased risk for cardiovascular disease (MI, stroke, hypertension) as an adult
Increased risk for diabetes as an adult Possible increase in cancer risk
For the mother: Increased risk for
subsequent preterm delivery 0
0.25
0.5
0.75
1
1.25
1.5
1.75
<5.0 5.0-5.5 5.6-7.0 7.1-8.5 8.6-10.0 >10.0
Age
Adj
uste
d R
elat
ive
Ris
k
Birthweight (lbs) Rich-Edwards 1997
Birth Weight and Coronary Heart Disease
Lower BW=higher CHD risk
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Progestins• Steroid hormone•Exogenous or synthetic forms of progesterone• Produced by corpus luteum, adrenals, placenta
•Maintains pregnancy•Exerts biologic effects on
•Immune response•Myometrium•Chorioamniotic membranes•Cervix
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Actions
•Delays cervical collagen degradation•Myometrial:
•Decreases conduction of contractions•Increases threshold for stimulation•Decreases spontaneous activity•Decreases number of oxytocin receptors•Prevents formation of gap junctions
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Progestin formulations
17a hydroxyprogesterone caproate Esterified derivative of 17 a
hydroxyprogesterone Substantial progestational activity, long duration
of action Micronized progesterone in a gel Micronized progesterone suppositories
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Trials of Progestogens Results of several small trials in the 1960’s and
1970’s suggested progesterone therapy may be effective in preventing preterm birth
Not all trials showed positive results Meta-analyses produced conflicting results The most successful trials employed 17- a
Hydroxyprogesterone Caproate, (17P)
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Meta-analysis of 17P in pregnancy
5 trials: high risk women with 17P Pooled analysis of results showed:
Reduction in rates of preterm birth Odds ratio 0.50, 95% CI: 0.30-0.85
Reduction in rates of low birthweightOdds ratio 0.46, 95% CI: 0.27-0.80
Keirse MJNC. Brit J Obstet Gynecol 1990;97:149
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Prior preterm birth
Preterm birth
Multifetal gestation
Short cervix
Progestins & Prematurity Prevention
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Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: A randomized placebo-controlled double-blind study
University of Sao Paulo Medical School, Brazil RCT double-blind, placebo controlled 1996-2001 Rx: daily Progesterone (100 mg) vs placebo as
vaginal suppository from 24 – 34 wksDa Fonseca et alAJOG 2003;188:419-24
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Methods
157 high risk singleton pregnancies, 15(9.5%) lost to follow-up; Prior sPTD (avg 33 wks) Prophylactic cervical cerclage Uterine malformation
Analyzed remaining 142 70 placebo 72 progesterone Da Fonseca et al
AJOG 2003;188:419-24
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Characteristics
Qualifying delivery (wks) 33.3 33.4 Maternal age (yrs) 27.6 26.8 Caucasian 68% 71% Risk Factor
Prior PTD 90% 97% Uterine malformation 5.6% 1.4% Incompetent cervix 4.1% 1.4%
Prog Placebo
Da Fonseca et al AJOG 2003;188:419-24
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Rates of Preterm Birth
0%
5%
10%
15%
20%
25%
30%
35%
< 37 <34 PTL
P<0.03 P<0.002 NS
Prog
Prog
Prog
Placebo
Placebo
Placebo
Da Fonseca et al AJOG 2003;188:419-24
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Gestational age (wk)
Progesterone
Placebo
P<0.004
UC/hr
Uterine contraction frequency1 hr monitoring/wk
Da Fonseca et al AJOG 2003;188:419-24
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NICHD: MFMU Progesterone Trial Aim: To establish if weekly progesterone injections in
women with prior spontaneous preterm delivery (sPTD) reduces the risk of PTD
Design: double-masked, placebo-controlled trial Eligibility criteria: singleton pregnancy 16-20 wks
with documented previous sPTD Intervention: progesterone or placebo
Meis et al, N Engl J Med 2003
1o outcome: delivery <37 wks Sample: 463 pregnant women
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19 Centers enrolled women with:
Documented history of spontaneous preterm birth at 200 to 366 weeks’ gestation in a previous pregnancy
Gestational age at entry of 15-203 weeks confirmed by ultrasound
Singleton gestation, with no major fetal anomalies
Meis et al, N Engl J Med 2003
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Characteristics
Qualifying delivery (wks) 30.5 31.3 Maternal age (yrs) 26.0 26.5 Married 51% 46% African American 59% 58% Mean BMI 26.9 25.9 Smoking 22% 19%
17-P Placebo
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Progesterone: Rates of Preterm Birth
0%
10%
20%
30%
40%
50%
60%
70%
< 37 <35 <32 Afr.Am erican
Non Afr-Am
P<0.0001 P<0.016 P<0.018
Meis et al, N Engl J Med 2003Meis et al, N Engl J Med 2003
17P
17P17P
17P
17P
P=0.010 P=0.004
AfricanAmerican
Non AfricanAmerican
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Progesterone prevents neonatal complications
0%
2%
4%
6%
8%
10%
12%
14%
16%
neonataldeath
RDS BPD IVH* NEC*
17 P
17 P17 P 17 P
Placebo
Placebo
Placebo
Placebo
Placebo
Meis et al, N Engl J Med 2003Meis et al, N Engl J Med 2003
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Compliance and Side Effects
Compliance with the weekly injections was excellent
91.5% of the women received their injections at the scheduled time
Side effects were minor and were similar in the 17P and placebo groups
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Effectiveness of Progesterone 5-6 women with a previous sPTB would need
to be treated to prevent one birth <37 wks
12 women with a previous sPTB birth would need to be treated to prevent one birth <32 wks
Meis et al, N Engl J Med 2003Meis et al, N Engl J Med 2003Low dose ASA to prevent CVA, NNT=102B-blocker use in MI patients to prevent cardiac death NNT=42
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Progesterone prevents recurrent preterm delivery
Weekly injections of progesterone prevented recurrent preterm birth and improved the neonatal outcome for pregnancies at risk
Effective in preventing very early as well as later preterm birth
Effective in both African American and Non-African American women
Meis et al, N Engl J Med 2003Meis et al, N Engl J Med 2003
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Impact of progesterone to prevent recurrent preterm birth
10,000 preterm births could have been prevented in 2002 if all eligible pregnant women at high risk for PTD received 17P
Resulting in reduction of preterm birth of ~2%
Petrini et al, Obstet Gynecol 2005; 105(2)
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Progesterone gel and PTD
659 women with prior sPTB GA 18-22.9 wks, randomized Progesterone vaginal gel or placebo
90mg natural progesterone (Replens) Primary outcome: PTB<32 wks
O’Brien et al, Ultrasound Obstet Gynecol 2007;30:687-96
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Characteristics
Maternal age (yrs) 27.1 27.3 African American 25% 28% Mean BMI 26.6 26.4 Smoking 22% 19% >1 Prior PTD 24% 26% CL at randomization 3.7 3.7
Prog Placebo
O’Brien et al, Ultrasound Obstet Gynecol 2007;30:687-96
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Vaginal progesterone gel and PTD
0
5
10
15
20
25
30
35
40
45
50
< 37w < 35w < 32w
Placebo Progesterone
%
O’Brien et al, Ultrasound Obstet Gynecol 2007;30:687-96
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Summary: Progesterone & recurrent PTD progesterone suppository & 17aOHPC IM:
Significant reductions in PTD
Progesterone gel: no effect on PTD
0
5
10
15
20
25
30
35
40
45
50
< 37w < 35w < 32w
Placebo Progesterone
0%
10%
20%
30%
40%
50%
60%
< 37 <32
17P 17P
PTD
0%
10%
20%
30%
40%
50%
60%
<37 wks <34 wks
progesterone
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Prior preterm birth
Preterm birth
Multifetal gestation
Short cervix
Progestins & Prematurity Prevention
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STTARS Seventeen alpha-hydroxyprogesterone caproate in Twins and Triplets: A Randomized Study)
Double-masked placebo-controlled trial to determine whether 17 a hydroxyprogesterone prevents preterm birth in multifetal pregnancies.
Intervention: 17-OHPC (250mg IM) or placebo weekly beginning at 16-20 weeks
Primary outcome: Preterm delivery < 35 wks 661 women randomized
Rouse et al, NEJM 2007; 357:454-61
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Characteristics:
Maternal age (yrs) 30 30 Caucasian 67% 65% Ob history
Nulliparous 46% 43% Prior PTD 6% 9%
BMI 26.7 27.1
Prog Placebo
Rouse et al, NEJM 2007; 357:454-61
Progesterone and Twins
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0%
20%
40%
60%
80%
100%
<37 wks <35 wks <32 wks <28 wks
Twins: Delivery or Fetal Death Prior to 37, 35, 32 or 28 weeks
Rouse et al, NEJM 2007; 357:454-61
17-OHPC
Placebo
Similar findings for triplets
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Delivery or Fetal Death Before 35 WeeksBy Conception Method & Chorionicity
0%
20%
40%
60%
80%
100%
Spont. ART MonoChor DiChor
17-OHPC Placebo
Rouse et al, NEJM 2007; 357:454-61Similar findings
for triplets
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STTARS Seventeen alpha-hydroxyprogesterone caproate in Twins and Triplets: A Randomized Study) 17P did not reduce the rate of PTB in women with twins This lack of benefit applied:
- whether conception was spontaneous or after ART or - whether there was a di- or monochorionic placentation - regardless of gestational age cutoff
17-OHPC was well tolerated with side effects limited to the injection site
The rate of PTB in the placebo group was similar to national norms (34.9 vs 35.2 weeks)
Rouse et al, NEJM 2007; 357:454-61
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Prior preterm birth
Preterm birth
Multifetal gestation
Short cervix
Progestins & Prematurity Prevention
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Cervical length
Normal cervical length Short cervix with funneling
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Relative risk ofsPTD <35 wks by % of cervical length at 24 wks
Iams et al, NEJM 1996
Cervical length at 24 wks predicts PTB risk
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Considerations Study population heterogeneity
Other risk factors for PTB multiple gestation prior preterm birth
Gestational age assessment of cervical length Cervical length varies across gestational age Cut-off selected depends on time of screening
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EGA at study (wks)
Outcome Discriminatory point
Hibbard et al N = 760
16-22 < 35 weeks 30 mm (10th%)
Taipale et alN = 3694
18-22 < 37 weeks 31 mm (9th %)
Iams et al N=2915
24 < 35 weeks 25 mm (10th %)
Fonseca 20-25 <37 weeks <15mm (1.7%) N=24,620
Cervical length assessment
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46 women with ≤ 28 mm cervical length 19 progesterone (4 without PTB + 15 with PTB) 27 placebo (5 without PTB + 22 with PTB)
0
10
20
30
40
50
60
70
< 37w < 35w < 32w
Placebo Progesterone
%
“…these conclusions must be considered tentative...(and) hypothesis generating…(and)… further investigation is necessary. Specifically randomized clinical trials designed to test the effect of progesterone in women with a short cervix…”
DeFranco et al, Ultrasound Obstet Gynecol 2007;30:697-705
Progesterone and short cervix: DeFranco subanalysis of O’Brien trial: progesterone gel
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Progesterone and short cervix: Fonseca trial: progesterone suppository
Cervical length 20-25 wks (24,620 women) 413 CL <15mm (1.7%)
RCT: 250 women with cervical length ≤ 15mm Progesterone 200 mg* PV daily vs. placebo
Micronized progesterone (Utrogestan, Besins International Belgium)
Initiation of treatment at 24 weeks
Fonseca et al, NEJM 2007; 357:462-9
*twice the dose of the daFonseca trial AJOG 2003
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Maternal age (yrs) 29 29 Caucasian 37% 39% Ob history
Nulliparous 57% 55% Prior PTD 12% 18%
Twin gestation 9% 10%
Prog Placebo
Fonseca et al, NEJM 2007; 357:462-9
Progesterone and short cervix: Fonseca trial: progesterone suppository
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Progesterone Placebo OR (95%CI)
PTD < 34 weeks 19% 34% 0.56 (0.36 – 0.86)
Composite morbidity 8% 14% 0.59 (0.26 – 1.25)
Fonseca et al, NEJM 2007; 357:462-9
n=125 n=125
• Progesterone reduced risk of PTD in women with short cervix
• No reduction in perinatal mortality or neonatal morbidity
0%
10%
20%
30%
40%
50%
placebo progesterone
PTD<34 weeks
Progesterone and short cervix: Fonseca trial: progesterone suppository
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Progesterone and short cervix: Fonseca trial: progesterone suppository
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Very heterogeneous study group Includes women with prior PTD, multiple
gestationsSubgroup analysis of nulliparous women has
OR that crosses unity
Progesterone and short cervix: Fonseca trial: progesterone suppository
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19 to 23 6/67 weeks Singleton Cervix 10-20 mm Nullips and multips (with prior term and
preterm birth) Outcome: PTB < 33 weeks N = 465
Hassan et al, 2011 Ultrasound Obstet Gynecol
Progesterone and short cervix: Hassan trial: progesterone gel
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05
101520253035404550
<33w <37w M&M
Progesterone
Placebo
* *
*P < .05
PTB
%
Hassan et al, 2011 Ultrasound Obstet Gynecol
Progesterone and short cervix: Hassan trial: progesterone gel
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Primary outcome PTB<33wks
RR 0.55 (95% CI 0.33-0.92) Number needed to treat = 14 60 women enrolled in violation of protocol
55 were with respect to EGA at enrollment Significantly more women who were enrolled early
randomized to placebo Significantly more women who were enrolled late
randomized to progesterone
Progesterone and short cervix: Hassan trial: progesterone gel
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Progesterone and short cervix: Hassan trial: progesterone gel
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Double-masked placebo-controlled trial to determine whether 17a hydroxyprogesterone prevents preterm birth in nulliparous women with short cervix (< 30mm) assessed between 16 and 22 3/7 wks.
Intervention: 17-OHP (1 ml IM with 250mg) or placebo weekly
Primary outcome: PTD < 37 wks Status: ongoing
Progesterone and short cervix: Grobman MFMU trial: 17aOHPC
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Progesterone & short cervix None of the trials were “screening” trials
All screened and treated if positive Control group is not the same in treatment vs
screening trial Applies to small % of the population
1.7% <15 mm 2.3% 10-20 mm
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Prior preterm birth
Preterm birth
Multifetal gestation
Short cervix
Progestins & Prematurity Prevention
Safety
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Progestins: Safety Commonly used in first trimester
“progesterone deficiency” ART – REI colleagues
Follow-up studies Schardein Teratology 22, 251-70 (1980) Raman-Wilms et al Obstet Gynecol 85;141-9(1995) Northen et al Obstet Gynecol 110;865-72(2007)
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Progesterone Follow-up study
Aim: To determine whether there is a difference in achievement of developmental milestones and physical health between children exposed to progesterone and those exposed to placebo
Northen et al, Obstet Gynecol 2007;110:865-72
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• No difference in physical exam
0
10
20
30
40
50
60
70
Height Weight Head Circumference
17P Placebo
p=0.5 p=0.7 p=0.5
17P 17P 17P
Northen et al, Obstet Gynecol 2007;110:865-72
• Congenital anomalies: 2% in both groups
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Conclusions
No difference in children exposed to 17P and placebo: achievement of developmental milestones or
gender roles physical health congenital anomalies
Northen et al, Obstet Gynecol 2007;110:865-72
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What are we left with?
Progesterone reduces recurrent PTB Progesterone for this indication will make
little dent in the burden of preterm birth Not beneficial for multiple gestations Two studies show benefit for short cervix
Anyone with cervix < 15 mm (1.7%) Singletons with cervix 10-20 mm (2.3%)
Routine screening to identify 1-2% of population would be a large undertaking with minimal effect on PTB rate
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Recommends the use of progesterone to prevent PTD for women with prior sPTD
May be considered for use in asymptomatic women with a very short cervix
Obstet Gynecol 2008;112:963-5
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End notes Progesterone supplementation to high risk
women is one opportunity for prevention It is not THE answer to PTD
Future work needs to tailor the therapy to the underlying mechanism – the heterogeneity of preterm labor/delivery remains a limiting factor
0%
10%
20%
30%
40%
50%
60%
< 37 <32
17P
17P
PTD
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to describe the problem of prematurity to describe the mechanism of progesterone
action to define the patient population who meets the
criteria for progesterone administration to prevent preterm birth
Objectives….Accomplished!
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The goal: healthy children and mothers…