Progesterone Supplementation
and Prevention of Preterm Birth
Catherine Y Spong, MD
Chief, Pregnancy & Perinatology Branch
National Institute of Child Health & Human Development
National Institutes of Health
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
(N / 100,000 live births)
0
5
15
20
25
4,322
Preterm / LBW
3,875
Birth Defects
Maternal
complications
10
1,491
Placenta / cord
complications
998
RDS
943
Leading cause of black infant mortality
Second leading cause of all infant mortality
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
Preterm Birth: Outcome
1
out of 5 children with mental retardation
Accounts for 1 out of 3 children with vision impairment
Almost half of children with cerebral palsy
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
1.75
Birth Weight and Coronary Heart Disease
Lower BW=higher CHD risk
1.5
1.25
1

For the mother:
 Increased
risk for
subsequent preterm
delivery
0.75
0.5
0.25
0
<5.0
5.0-5.5
5.6-7.0
7.1-8.5
Birthweight (lbs)
8.6-10.0
>10.0
Rich-Edwards 1997
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 17a 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 birthweight
Odds ratio 0.46, 95% CI: 0.27-0.80
Keirse MJNC. Brit J Obstet Gynecol 1990;97:149
Progestins & Prematurity Prevention
Prior preterm birth
Multifetal gestation
Preterm
birth
Short cervix
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 wks
Da Fonseca et al
AJOG 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
Prog Placebo




Qualifying delivery (wks)
Maternal age (yrs)
Caucasian
Risk Factor



Prior PTD
Uterine malformation
Incompetent cervix
33.3
27.6
68%
33.4
26.8
71%
90%
5.6%
4.1%
97%
1.4%
1.4%
Da Fonseca et al AJOG 2003;188:419-24
Rates of Preterm Birth
35%
30%
25%
Placebo
Placebo
20%
15%
10%
Prog
Prog
Placebo
5%
Prog
0%
< 37
P<0.03
<34
P<0.002
PTL
NS
Da Fonseca et al AJOG 2003;188:419-24
Uterine contraction frequency
1 hr monitoring/wk
Placebo
Progesterone
UC/hr
P<0.004
Gestational age (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
1o outcome: delivery <37 wks
 Sample: 463 pregnant women

Meis et al, N Engl J Med 2003
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
17-P Placebo






Qualifying delivery (wks)
Maternal age (yrs)
Married
African American
Mean BMI
Smoking
30.5
26.0
51%
59%
26.9
22%
31.3
26.5
46%
58%
25.9
19%
Progesterone: Rates of Preterm Birth
70%
60%
50%
40%
30%
17P
17P
17P
20%
17P
10%
17P
0%
< 37
P<0.0001
<35
P<0.016
<32
P<0.018
African
NonAfrAfrican
Afr.
Non
American
American
American
Am
P=0.010
P=0.004
Meis
Meisetetal,
al,NNEngl
EnglJJMed
Med2003
2003
Progesterone prevents neonatal complications
16%
14%
12%
10%
8%
6%
4%
2%
0%
Placebo
17 P
Placebo
Placebo
Placebo
17 P
neonatal
death
17 P
RDS
BPD
17 P
IVH*
Placebo
NEC*
Meis
Meisetetal,
al,NNEngl
EnglJJMed
Med2003
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
Low dose ASA to prevent CVA, NNT=102
Meis
Meisetetal,
al,NNEngl
EnglJJMed
Med2003
2003
B-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
Meisetetal,
al,NNEngl
EnglJJMed
Med2003
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
Prog Placebo






Maternal age (yrs)
African American
Mean BMI
Smoking
>1 Prior PTD
CL at randomization
27.1
25%
26.6
22%
24%
3.7
27.3
28%
26.4
19%
26%
3.7
O’Brien et al, Ultrasound Obstet Gynecol 2007;30:687-96
Vaginal progesterone gel and PTD
Placebo
Progesterone
50
45
40
35
%
30
25
20
15
10
5
0
< 37w
< 35w
< 32w
O’Brien et al, Ultrasound Obstet Gynecol 2007;30:687-96
Summary: Progesterone & recurrent PTD

progesterone suppository & 17aOHPC IM:
Significant reductions in PTD
progesterone
60%
60%
50%
50%
40%
40%
PTD
30%
30%
20%
20%
10%
10%
17P
17P
0%
< 37

0%
<37 wks
<32
Progesterone gel: no effect on PTD
Placebo
Progesterone
50
45
40
35
30
25
20
15
10
5
0
< 37w
< 35w
< 32w
<34 wks
Progestins & Prematurity Prevention
Prior preterm birth
Multifetal gestation
Preterm
birth
Short cervix
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
Progesterone and Twins
Characteristics:
Prog




Maternal age
Caucasian
Ob history

Nulliparous

Prior PTD
BMI
(yrs)
Placebo
30
30
67%
65%
46%
6%
43%
9%
26.7
27.1
Rouse et al, NEJM 2007; 357:454-61
Twins: Delivery or Fetal Death Prior to
37, 35, 32 or 28 weeks
100%
17-OHPC
Placebo
80%
60%
Similar findings
for triplets
40%
20%
0%
<37 wks
<35 wks
<32 wks
<28 wks
Rouse et al, NEJM 2007; 357:454-61
Delivery or Fetal Death Before 35 Weeks
By Conception Method & Chorionicity
100%
17-OHPC
80%
Placebo
60%
40%
20%
0%
Spont.
Similar findings
for triplets
ART
MonoChor
DiChor
Rouse et al, NEJM 2007; 357:454-61
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
Progestins & Prematurity Prevention
Prior preterm birth
Multifetal gestation
Preterm
birth
Short cervix
Cervical length
Normal cervical length
Short cervix with funneling
Cervical length at 24 wks predicts PTB risk
Relative risk of
sPTD <35 wks
by % of cervical
length at 24 wks
Iams et al, NEJM 1996
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
Cervical length assessment
EGA at
study (wks)
Outcome
Discriminatory
point
Hibbard et al
N = 760
Taipale et al
N = 3694
16-22
< 35 weeks
30 mm (10th%)
18-22
< 37 weeks
31 mm (9th %)
Iams et al
N=2915
24
< 35 weeks
25 mm (10th %)
Fonseca
N=24,620
20-25
<37 weeks
<15mm (1.7%)
Progesterone and short cervix:
DeFranco subanalysis of O’Brien trial: progesterone gel

46 women with ≤ 28 mm cervical length


19 progesterone (4 without PTB + 15 with PTB)
27 placebo (5 without PTB + 22 with PTB)
Placebo
Progesterone
70
60
50
%
40
30
20
10
0
< 37w
< 35w
< 32w
“…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:
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
*twice the dose of the daFonseca trial AJOG 2003
Fonseca et al, NEJM 2007; 357:462-9
Progesterone and short cervix:
Fonseca trial: progesterone suppository
Prog Placebo




Maternal age
Caucasian
Ob history

Nulliparous

Prior PTD
(yrs)
Twin gestation
29
29
37%
39%
57%
12%
55%
18%
9%
10%
Fonseca et al, NEJM 2007; 357:462-9
Progesterone and short cervix:
Fonseca trial: progesterone suppository
Progesterone
n=125
PTD < 34 weeks
Composite morbidity
50%
40%
PTD<34 weeks
30%
19%
8%
Placebo
OR (95%CI)
n=125
34%
14%
0.56 (0.36 – 0.86)
0.59 (0.26 – 1.25)
• Progesterone reduced risk of
PTD in women with short cervix
• No reduction in perinatal
mortality or neonatal morbidity
20%
10%
0%
placebo
progesterone
Fonseca et al, NEJM 2007; 357:462-9
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
gestations
 Subgroup analysis of nulliparous women has
OR that crosses unity
Progesterone and short cervix:
Hassan trial: progesterone gel






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
*P < .05
PTB
%
50
45
40
35
30
25
20
15
10
5
0
Progesterone
Placebo
<33w
*
<37w
M&M
*
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:
Grobman MFMU trial: 17aOHPC




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 & 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
Progestins & Prematurity Prevention
Prior preterm birth
Multifetal gestation
Preterm
birth
Short cervix
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
• Congenital anomalies: 2% in both groups
17P
Placebo
70
60
50
40
30
17P
17P
17P
20
10
0
Height
Weight
Head Circumference
p=0.5
p=0.7
p=0.5
Northen et al, Obstet Gynecol 2007;110:865-72
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
60%
50%
40%
PTD30%
20%
17P
10%
17P
0%
< 37
<32
Future work needs to tailor the therapy to the
underlying mechanism – the heterogeneity of
preterm labor/delivery remains a limiting factor
Objectives….
Accomplished!



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
The goal: healthy children and mothers…