Download Progesterone for the Prevention of Preterm Birth

Progesterone for the
Prevention of
Preterm Birth
Paul Meis MD
Preterm Delivery: Current Status
Overview of the problem of preterm birth
Strategies to prevent preterm delivery
Progesterone for prevention of preterm
birth
Early trials
NICHD MFMU Network trial
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Preterm Births in United States
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Preterm Births by Race
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Very Low Birthweight Births
Costs of Prematurity
 Preterm
birth is the major
determinant of infant mortality in
developed countries
 Preterm birth is a leading cause of
cerebral palsy and developmental
delay of surviving children
Costs of Prematurity
 The
Institute of Medicine estimates that
the total national cost of preterm birth to
be $26.2 billion at a minimum.
 Initial hospital care of infants born at 2527 weeks costs 28 times as much as for
those born at term
Costs of Prematurity
School Performance Age 9-11
Kirkegaard I, Pediatrics
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Kirkegaard I, Pediatrics 2006;118:1600
 “…effective
therapeutic
interventions to decrease
spontaneous preterm delivery
have not been discovered.”
R.L. Goldenberg 2002
Progesterone Treatment:
An Old Idea Revisited
 A trial
of 17 alpha Hydroxyprogesterone
Caproate (17P) conducted in the NICHD
Maternal Fetal Medicine Units Network.
 A trial of progesterone suppositories
conducted in Brazil.
Actions of Progesterone on the
Myometrium
 Decreases
conduction of contractions
 Increases threshold for stimulation
 Decreases spontaneous activity
 Decreases number of oxytocin
receptors
 Suppresses the inflammatory cascade
Actions of Progesterone on the
Myometrium
 Inhibits
T lymphocyte development
 Promotes expression of prostaglandin EP2
receptor
 Prevents formation of gap junctions
 Administration of progesterone
antagonists stimulates onset of labor in
women at term
Early Trials of Progesterone
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Patients with symptoms of preterm labor in 19561957, University of Copenhagen
Double blind study of progesterone (N = 63) vs
placebo (N = 63)
Daily dose was 200mg x3, 150mg x2, then 100mg
per day
Results showed no efficacy to prolong pregnancy
“Progesterone unable to prevent PTD once clinical
symptoms are present”
Fuchs F, AJOG 1960 79:172
Early Trials of Progesterone

Selected 99 women who were at risk for
preterm delivery using a high risk scoring
system and randomized them to treatment
with 17P or placebo
 Treated with 250 mg 17P or placebo every
three days from 28-32 weeks for a total of 8
doses
 Delivery at <37 weeks’ in 4% of the 17P
group and 18% of the placebo group
Papiernik E, 1970
Early Trials of Progesterone
 43
patients with previous recurrent
miscarriage or preterm birth
 Treated with 17P or placebo
 41% of placebo group delivered <36
weeks of pregnancy
 All of treated group delivered after 36
weeks
Johnson JWC. NEJM 1975;293:675-680
Early Trials of Progesterone
 168
pregnant women in the military
 Treated with 17P or placebo
 Low birth weight infants:
 7.5% in treated subjects
 9.0% in placebo subjects
Hauth JC. Am J Obstet Gynecol 1983;146:187
Early Trials of Progesterone

77 women with twin pregnancies, randomized
to weekly injections of 250 mg 17P or placebo
 Started after 28 weeks and continued to 37
weeks
 Delivery at <37 weeks in 31% of the 17P
group and 24% of the placebo group
 This is the only reported trial of 17P in twins
Hartikainen A. Obstet Gynecol 1980;56:692
Meta-analysis of progesterone
use in pregnancy
 15
published trials of various
progesterone compounds in women at
high risk
 Pooled analysis of the results of the
trials showed no effect on rates of:



Miscarriage
Stillbirths
Preterm births
Goldstein P. Brit J Obstet Gynecol 1989;96:265
Meta-analysis of 17P in
pregnancy
5
trials which treated high risk women
with 17P
 Pooled analysis of results showed:


Reduction in rates of preterm birth.
Odds ratio was 0.50, 95% CI: 0.30-0.85
Reduction in rates of low birthweight,
Odds ratio was 0.46, 95% CI: 0.27-0.80
Keirse MJNC. Brit J Obstet Gynecol 1990;97:149
 “The
present study indicates that
injections of (17P) may reduce the
occurrence of preterm birth in women
so treated.”
 “… further well-controlled research
would be necessary before it is
recommended for clinical practice.”
Keirse MJNC. Brit J Obstet Gynecol 1990;97:149
The existence of the NICHD
supported MFMU Network
made such a large wellcontrolled trial possible
Prevention of Recurrent
Preterm Delivery by 17 AlphaHydroxyprogesterone Caproate
Meis PJ, Klebanoff M, Thom E, Dombrowski M P, Sibai B, Moawad AH,
Spong CY, Hauth JC, Miodovnik M, Varner MW, Leveno KJ, Caritis SN,
Iams JD, Wapner RJ, Conway D, O'Sullivan MJ, Carpenter M, Mercer
B, Ramin SM, Thorp JM, and Peaceman AM for the NICHD MFMUN
NEJM 2003;348:2379-85.
Participating Centers of the MFMU Network
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Wake Forest University
University of Tennessee
University of AlabamaBirmingham
University of Utah
Magee-Womens Hospital
Thomas Jefferson University
University of Miami
Columbia University
University of North Carolina
Case Western Reserve
University
George Washington University
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Wayne State University
University of Chicago
University of Cincinnati
University of Texas,
Southwestern
Ohio State University
University of Texas, San Antonio
Brown University
University of Texas, Houston
Northwestern University
Choice of Drug
 Hydroxyprogesterone Caproate,
(17P) was chosen because it had been
used in previous successful trials
 17-
Choice of Subjects
 Women
who have had a previous
spontaneous preterm birth are at
especially high risk for recurrent preterm
birth
 We
chose this group of women for
eligibility to participate in this trial
17 P and preterm birth
inclusion criteria:
 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
Exclusion Criteria
 Progesterone
or heparin treatment
during current pregnancy
 Current or planned cerclage
 Chronic hypertension
 Seizure disorder
 Delivery planned outside the Center
Randomization and Follow-up
 If
eligible, women were invited to
participate and consented, using a form
approved by the Center’s IRB
 Given a trial injection of the placebo
inert oil, and asked to return in 1 week
Randomization and Follow-up

Second visit (at 160 - 206 weeks) centrally
randomized using a 2 to 1 ratio to receive
injection of 250 mg 17P or a placebo inert
oil

Then weekly injections of 17P or placebo
until delivery or 37 weeks
Power Calculations
 Primary
outcome was delivery <37 weeks’
gestation
 Estimated rate of recurrent PTB = 37%
 2 to 1 allocation of study drug to placebo
 Sample size = 500 to detect a 33%
reduction in the rate of preterm birth
Review by Data Monitoring and Safety
Committee
 A scheduled
interim analysis was
performed after 351 subjects had
delivered
 Analysis showed positive effect for the
primary outcome
 Enrollment of new subjects was halted
when 463 subjects randomized
Screening and
Randomization
2980 women screened
1941 ineligible
576 refused consent or
declined after trial injection
310 17-P
1039 eligible
463 randomized
153 placebo
Characteristics of Subjects
 Qualifying
delivery
 Maternal age
 Married
 African American
 Mean BMI
 Smoking
All p > 0.05
17P
Placebo
30.5
26.0
51%
59%
26.9
22%
31.3 wks
26.5 yrs
46%
58%
25.9
19%
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
Rates of Births < 37 Weeks
60%
54.9%
50%
36.%
40%
30%
20%
10%
0%
p = 0.0001
PLACEBO
17 P
Rates of Births < 35 Weeks
35%
30%
30.7%
25%
20.6%
20%
15%
10%
5%
0%
P = 0.0165
PLACEBO
17 P
Rates of Births < 32 Weeks
25%
20%
19.6%
15%
11.4%
10%
5%
0%
p = 0.0180
PLACEBO
17 P
Results by Race
70%
60%
50%
40%
58.7%
52.2%
37.6%
35.4%
30%
20%
10%
0%
African American p=0.0103
PLACEBO
Non African American
p=0.0044
17P
Rates of Low Birth Weight Birth
45%
40%
35%
30%
25%
20%
15%
10%
5%
0%
41.1%
27.2%
13.9%
8.6%
BIRTHS <2500 gm p=0.0029
BIRTHS <1500 gm p=0.0834
PLACEBO
17P
Effectiveness of Treatment
With 17P
5
to 6 Women with a previous
spontaneous preterm birth would need
to be treated to prevent one birth <37
weeks
 12 Women with a previous spontaneous
preterm birth would need to be treated
to prevent one birth <32 weeks
Rates of Neonatal Death
7%
6%
5.9%
5%
4%
2.6%
3%
2%
1%
0%
p = 0.0805
PLACEBO
17P
Rates of Neonatal Morbidity
16%
14%
12%
10%
PLACEBO
17P
8%
6%
4%
2%
0%
RDS
BPD
ROP
IVH*
NEC*
Percent preterm birth by
gestational age of previous preterm
delivery
70
60
50
40
Placebo
17P
30
20
10
0
20-27 weeks'
28-33 weeks'
34-37 weeks'
Percent preterm birth by number
of80 previous preterm deliveries
70
60
50
Placebo
17P
40
30
20
10
0
One
More than One
Prematurity prevented without
evidence of increased infection
Chorioamnionitis
1.1 (0.4 – 3.1)
Neonatal sepsis
1.1 (0.3 – 3.6)
Caveats for 17P cohort
versus controls:
 Fewer
PTB in prior pregnancies: 1.4 v
1.6, P=.007
 When adjusted for variance: Delivery
<37wks RR = 0.7 (0.57, 0.85)
 More stillbirths: 2.0% v 1.3% P=NS
 More miscarriages: 1.6% v 0% P=NS
Odds ratios for outcomes
comparing previous 17P trials
with
the
MFMU
results
0.8
0.7
0.6
0.5
Previous 17P Trials
MFMU Study
0.4
0.3
0.2
0.1
0
Preterm
<2500 gm
Perinatal
Death
Sanchez-Ramos Obstet Gynecol 2005;105:273
Summary of Trial

The women in this trial encountered very high
rates of preterm delivery
 The previous preterm delivery was very early,
mean = 30-31 weeks’
 One third of the women had had more than
one previous preterm delivery
 This rate of preterm birth was similar to other
observational studies of high risk women in
the MFMU Network
Summary of Trial

17P treatment was effective in both African
American and Non-African American
women
 17P treatment was effective in preventing
very early as well as later preterm births
 17P Treatment of the women resulted in
significant reductions in the rates of IVH
and NEC for their infants
Conclusions from Trial
injections of 17- 
Hydroxyprogesterone Caproate can
provide significant and powerful
protection against recurrent preterm
birth and improve the neonatal outcome
for pregnancies at risk
 Weekly
Decision Analysis
 Model
estimated costs of 17P treatment
and the costs of preterm birth
 17P treatment was cost effective for
women with a prior delivery <32 weeks
 17P treatment was also cost effective for
a history of a prior delivery at 32-37 weeks
Odibo AO Obstet Gynecol 2006;108:492
Prophylactic administration of progesterone
by vaginal suppository to reduce the
incidence of spontaneous preterm birth in
women at increased risk: a randomized
placebo-controlled trial
Da Fonseca EB, Bittar RE, Carvalho MHB, Zugaib M
Am J Obstet Gynecol 2003;188:419-24
Trial of progesterone suppositories
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Tertiary medical center in Brazil
144 women, 70% white
Singleton pregnancies with no symptoms of
preterm labor
Main risk factor was history of a previous preterm
delivery (33 weeks both arms)
Randomized to daily progesterone (100mg) or
placebo suppositories
Treated from 24 to 34 weeks’ gestation
da Fonseca EB Am J Obstet Gynecol
2003;188:419-424
Results of Trial of Progesterone
Suppositories
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Placebo
<37 wks
28.5%
Progesterone
13.8%

p
0.03
<34 wks
18.6%
2.8%
0.002
 No information was given about neonatal
outcomes
 Results were not analyzed by intent to treat
da Fonseca EB Am J Obstet
Gynecol 2003;188:419-424
Conclusions from Progesterone
Suppository Trial
 The
results of this trial show positive
results in a population at lower risk for
preterm birth than the MFMU Network
progesterone study
 Suggest a possible alternative method
of progesterone treatment
Progesterone as a Tocolytic
6
trials have been reported
 Various progesterone compounds used
 Design of studies varied
 None of the trials found a significant
prolongation of pregnancy with the use of
the progesterone treatment
 Progesterone treatment of women with
active uterine contractions should be
discouraged outside of research protocols
Progesterone Treatment for
Prevention of Preterm Birth

The results of these trials do not represent
the solution to the over-all problem of preterm
birth
 They apply only to women with a previous
spontaneous preterm delivery
Progesterone Treatment for
Prevention of Preterm Birth

These results represent a hopeful beginning: the
first effective treatments to reduce the risk of
preterm delivery in women at risk
 A major health insurance provider in the U.S.
has developed a program of treatment with 17P
at a cost of $120 per pregnancy
 This treatment is cost effective in the prevention
of preterm delivery
Current Problems with 17P
Treatment
 The
drug is currently available in the U.S.
only from compounding pharmacies
 Some insurance plans, including Medicaid
do not currently pay for this treatment
Gestiva
 Adeza
Biomedical has applied to the FDA
to produce 17P for the indication of
prevention of preterm delivery
 FDA approval should improve
reimbursement by insurance providers
including Medicaid
 Cost of drug will be higher
Further Research Questions

Mechanism of action of progesterone treatment
 Comparative efficacy of different progesterone
compounds
 Effectiveness of progesterone treatment for
women in other risk categories
 Multiple gestation
 Shortened cervix
Continuing Prematurity Prevention
Trials in the MFMU Network
 Trial
of 17P vs. placebo in women with
multiple gestation
 Trial of 17P with Omega-3 fatty acid
supplement vs. 17P and placebo to
prevent recurrent preterm delivery
 Trial of 17P vs. placebo in primigravid
women with a short cervix
Some Other Current Trials
 17P
vs. placebo in twins and triplets
(Obstetrix group)
 Progesterone suppositories vs. placebo
suppositories in women with a previous
preterm delivery (Columbia Lab sponsored)
Reducing Rates of Prematurity
 Future
progress in prevention of preterm
delivery is likely to come from primary or
secondary prevention strategies
 Once the parturition process has begun,
attempts to prevent preterm birth are not
effective