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

Conflict of Interest Statement

I have no conflict of interest related to the content of this presentation

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

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

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

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

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

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

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

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

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)

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

Prior preterm birth

Preterm birth

Multifetal gestation

Short cervix

Progestins & Prematurity Prevention

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

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

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

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

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

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

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

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

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

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

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

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

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

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)

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

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

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

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

Prior preterm birth

Preterm birth

Multifetal gestation

Short cervix

Progestins & Prematurity Prevention

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

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

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

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

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

Prior preterm birth

Preterm birth

Multifetal gestation

Short cervix

Progestins & Prematurity Prevention

Cervical length

Normal cervical length Short cervix with funneling

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

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

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

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

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

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

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

Progesterone and short cervix: Fonseca trial: progesterone suppository

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

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

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

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

Progesterone and short cervix: Hassan trial: progesterone gel

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

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

Prior preterm birth

Preterm birth

Multifetal gestation

Short cervix

Progestins & Prematurity Prevention

Safety

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)

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

• 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

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

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

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

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

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!

The goal: healthy children and mothers…