Progesterone for the Prevention of Preterm Birth

1
Progesterone for the Prevention of Preterm Birth

• Paul Meis MD

2
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

3

• Preterm Births in United States

4

• Preterm Births by Race

5

• Very Low Birthweight Births

6
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

7
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 25-27
  weeks costs 28 times as much as for those born at
  term

8
Costs of PrematuritySchool Performance Age 9-11

• Kirkegaard I, Pediatrics

Kirkegaard I, Pediatrics 20061181600
9

• effective therapeutic interventions to decrease
  spontaneous preterm delivery have not been
  discovered.
• R.L. Goldenberg 2002

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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.

11
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

12
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

13
Early Trials of Progesterone

• Patients with symptoms of preterm labor in
  1956-1957, 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 79172
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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 lt37 weeks in 4 of the 17P group and
  18 of the placebo group

Papiernik E, 1970
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Early Trials of Progesterone

• 43 patients with previous recurrent miscarriage
  or preterm birth
• Treated with 17P or placebo
• 41 of placebo group delivered lt36 weeks of
  pregnancy
• All of treated group delivered after 36 weeks

Johnson JWC. NEJM 1975293675-680
16
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 1983146187
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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 lt37 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 198056692
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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 198996265
19
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 199097149
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• 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 199097149
21
The existence of the NICHD supported MFMU Network
made such a large well-controlled trial possible
22
Prevention of Recurrent Preterm Delivery by 17
Alpha-Hydroxyprogesterone 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 20033482379-85.

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Participating Centers of the MFMU Network

• Wake Forest University
• University of Tennessee
• University of Alabama-Birmingham
• 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

• 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

24
Choice of Drug

• 17- ? Hydroxyprogesterone Caproate, (17P) was
  chosen because it had been used in previous
  successful trials

25
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

26
17 P and preterm birthinclusion 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

27
Exclusion Criteria

• Progesterone or heparin treatment during current
  pregnancy
• Current or planned cerclage
• Chronic hypertension
• Seizure disorder
• Delivery planned outside the Center

28
Randomization and Follow-up

• If eligible, women were invited to participate
  and consented, using a form approved by the
  Centers IRB
• Given a trial injection of the placebo inert oil,
  and asked to return in 1 week

29
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

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Power Calculations

• Primary outcome was delivery lt37 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

31
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

32
Screening and Randomization
2980 women screened
1941 ineligible
1039 eligible
463 randomized
576 refused consent or declined after trial
injection
33
Characteristics of Subjects 17P
Placebo

• Qualifying delivery 30.5 31.3 wks
• Maternal age 26.0 26.5 yrs
• Married 51 46
• African American 59 58
• Mean BMI 26.9 25.9
• Smoking 22 19
• All p gt 0.05

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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

35
Rates of Births lt 37 Weeks
54.9
36.
36
Rates of Births lt 35 Weeks
30.7
20.6
37
Rates of Births lt 32 Weeks
19.6
11.4
38
Results by Race
58.7
52.2
37.6
35.4
39
Rates of Low Birth Weight Birth
41.1
27.2
13.9
8.6
40
Effectiveness of Treatment With 17P

• 5 to 6 Women with a previous spontaneous preterm
  birth would need to be treated to prevent one
  birth lt37 weeks
• 12 Women with a previous spontaneous preterm
  birth would need to be treated to prevent one
  birth lt32 weeks

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Rates of Neonatal Death
5.9
2.6
42
Rates of Neonatal Morbidity
43
Percent preterm birth by gestational age of
previous preterm delivery
44
Percent preterm birth by number of previous
preterm deliveries
45
Prematurity prevented without evidence of
increased infection

• Chorioamnionitis 1.1 (0.4 3.1)
• Neonatal sepsis 1.1 (0.3 3.6)

46
Caveats for 17P cohort versus controls

• Fewer PTB in prior pregnancies 1.4 v 1.6, P.007
• When adjusted for variance Delivery lt37wks RR
  0.7 (0.57, 0.85)
• More stillbirths 2.0 v 1.3 PNS
• More miscarriages 1.6 v 0 PNS

47
Odds ratios for outcomes comparing previous 17P
trials with the MFMU results
Sanchez-Ramos Obstet Gynecol 2005105273
48
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

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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

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Conclusions from Trial

• Weekly injections of 17- ? Hydroxyprogesterone
  Caproate can provide significant and powerful
  protection against recurrent preterm birth and
  improve the neonatal outcome for pregnancies at
  risk

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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 lt32 weeks
• 17P treatment was also cost effective for a
  history of a prior delivery at 32-37 weeks

Odibo AO Obstet Gynecol 2006108492
52
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 2003188419-24

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Trial of progesterone suppositories

• 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 2003188419-424
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Results of Trial of Progesterone Suppositories

• Placebo Progesterone p
• lt37 wks 28.5 13.8 0.03
• lt34 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
2003188419-424
55
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

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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

57
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

58
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

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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

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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

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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

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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

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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)

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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