Progestogens for Prevention of Preterm Birth

1
Progestogens for Prevention ofPreterm Birth

• Prepared for
• Agency for Healthcare Research and Quality (AHRQ)
  
• www.ahrq.gov

2
Outline of Material

• Introduction to preterm birth, the goals of
  preterm birth prevention, and the use of
  progestogens
• Systematic review methods
• The clinical questions addressed by the
  comparative effectiveness review
• Results of studies and evidence-based conclusions
  about effectiveness and adverse effects of
  progestogens
• Gaps in knowledge and future research needs
• What to discuss with patients and their caregivers

• Likis FE, Andrews JC, Woodworth AL, et al. AHRQ
  Comparative Effectiveness Review No. 74.
  Available at www.effectivehealthcare.ahrq.gov/pret
  ermbirth.cfm.

3
The Burden of Preterm Birth

• Preterm birth is defined as birth prior to the
  37th week of pregnancy.
• Each year in the United States, 12.5 percent of
  births (representing more than 475,000 infants)
  occur preterm.
• The risk of complications is related to how early
  the birth occurs.
• The morbidity and mortality associated with
  preterm birth represent untold distress for
  families, as well as significant costs to
  patients, health care systems, and payers.
• The estimated additional cost for neonatal care
  is 17,300 (2004 dollars) per preterm infant.

• Likis FE, Andrews JC, Woodworth AL, et al. AHRQ
  Comparative Effectiveness Review No. 74.
  Available at www.effectivehealthcare.ahrq.gov/pret
  ermbirth.cfm.

4
Risk Factors for Preterm Birth

• Women known to be at risk for preterm birth
  include those with
• Prior preterm birth
• Symptoms of preterm labor
• Multiple gestations
• Short cervix
• Other
• Abdominal surgery
• Previous or threatened spontaneous abortion
• Uterine anomalies
• Incompetent cervix

• Likis FE, Andrews JC, Woodworth AL, et al. AHRQ
  Comparative Effectiveness Review No. 74.
  Available at www.effectivehealthcare.ahrq.gov/pret
  ermbirth.cfm.

5
Approaches to Prevention of Preterm Birth

• The ultimate goals of preventing preterm birth
  are
• To eliminate the risks of neonatal death or
  complications
• To prevent long-term health consequences
• To promote normal childhood development
• To reduce maternal complications
• Interventions used once a woman has symptoms of
  preterm labor have not been reliable for
  preventing preterm birth.
• Earlier interventions based on risk rather than
  symptoms are hoped to be more effective.

• Likis FE, Andrews JC, Woodworth AL, et al. AHRQ
  Comparative Effectiveness Review No. 74.
  Available at www.effectivehealthcare.ahrq.gov/pret
  ermbirth.cfm.

6
Progestogens for Preventing Preterm Birth (1 of 2)

• Progesterone is a hormone that inhibits the
  uterus from contracting. It is involved in
  maintaining pregnancy, especially early in
  gestation.
• Progesterone has been recommended for pregnant
  women with prior preterm birth.
• This use is based on reviews of clinical research
  that indicated that progesterone can prolong
  pregnancy for women at risk of preterm birth,
  based on having a prior spontaneous preterm
  birth.
• Progestogen is an inclusive term for substances
  with biologic activity similar to the endogenous
  hormone progesterone. Progestogens include
• Natural progesterone
• Synthetic progesterone
• Synthetic progestins that are similar but not
  identical in chemical structure

• Likis FE, Andrews JC, Woodworth AL, et al. AHRQ
  Comparative Effectiveness Review No. 74.
  Available at www.effectivehealthcare.ahrq.gov/pret
  ermbirth.cfm.

7
Progestogens for Preventing Preterm Birth (2 of 2)

• Formulations of progestogens have been approved
  by the U.S. Food and Drug Administration (FDA),
  but for indications other than prevention of
  preterm birth. These forms include
• Vaginal suppositories, gels, and caps
• Oral formulations
• A commercial formulation of a progestogen for
  intramuscular injection has been approved by the
  FDA for preterm birth prevention.
• 17 alpha-hydroxyprogesterone caproate
• Formulations of progestogens may be supplied by
  compounding pharmacies.

• Likis FE, Andrews JC, Woodworth AL, et al. AHRQ
  Comparative Effectiveness Review No. 74.
  Available at www.effectivehealthcare.ahrq.gov/pret
  ermbirth.cfm.

8
Agency for Healthcare Research and Quality (AHRQ)
Comparative Effectiveness Review (CER) Development

• Topics are nominated through a public process,
  which includes submissions from health care
  professionals, professional organizations, the
  private sector, policymakers, members of the
  public, and others.
• A systematic review of all relevant clinical
  studies is conducted by independent researchers,
  funded by AHRQ, to synthesize the evidence in a
  report summarizing what is known and not known
  about the select clinical issue. The research
  questions and the results of the report are
  subject to expert input, peer review, and public
  comment.
• The results of these reviews are summarized into
  Clinician Research Summaries and Consumer
  Research Summaries for use in decisionmaking and
  in discussions with patients. The Research
  Summaries and the full report, with References
  for included and excluded studies, are available
  at www.effectivehealthcare.ahrq.gov/pretermbirth.c
  fm.

• Likis FE, Andrews JC, Woodworth AL, et al. AHRQ
  Comparative Effectiveness Review No. 74.
  Available at www.effectivehealthcare.ahrq.gov/pret
  ermbirth.cfm.

9
Rating the Strength of Evidence From the
Comparative Effectiveness Review

• The strength of evidence was classified into four
  broad categories

High ??? High confidence that the evidence reflects the true effect. Further research is very unlikely to change our confidence in the estimate of effect.
Moderate ??? Moderate confidence that the evidence reflects the true effect. Further research may change our confidence in the estimate of effect and may change the estimate.
Low ??? Low confidence that the evidence reflects the true effect. Further research is likely to change our confidence in the estimate of effect and is likely to change the estimate.
Insufficient ??? Evidence either is unavailable or does not permit a conclusion.

• Likis FE, Andrews JC, Woodworth AL, et al. AHRQ
  Comparative Effectiveness Review No. 74.
  Available at www.effectivehealthcare.ahrq.gov/pret
  ermbirth.cfm.

10
Clinical Questions Addressed by theComparative
Effectiveness Review (1 of 2)

• Although progestogen treatment to prevent preterm
  birth has been endorsed, there are still
  unanswered questions about effectiveness and
  safety.
• Clinical questions addressed by the comparative
  effectiveness review included
• Does progestogen treatmentwhen compared with
  placebo, usual care, or other interventionsimprov
  e maternal or fetal/neonatal health outcomes?
• What are the nature and frequency of maternal and
  child adverse effects of progestogen treatment?
• How do effectiveness, adverse effects, and safety
  of progestogen treatment differ based on maternal
  risk factors for preterm birth?

• Likis FE, Andrews JC, Woodworth AL, et al. AHRQ
  Comparative Effectiveness Review No. 74.
  Available at www.effectivehealthcare.ahrq.gov/pret
  ermbirth.cfm.

11
Clinical Questions Addressed by theComparative
Effectiveness Review (2 of 2)

• How do effectiveness, adverse effects, and safety
  of progestogen treatment differ based on the
  formulation, dose, frequency of administration,
  and gestational age at initiation or
  discontinuation of progestogen therapy?
• How do effectiveness, acceptability, adherence,
  adverse effects, and safety of progestogen
  treatment differ based on the cointerventions
  used to prevent preterm birth and its
  consequences?

• Likis FE, Andrews JC, Woodworth AL, et al. AHRQ
  Comparative Effectiveness Review No. 74.
  Available at www.effectivehealthcare.ahrq.gov/pret
  ermbirth.cfm.

12
Clinically Significant Outcomes of Interest in
the Comparative Effectiveness Review (1 of 2)

• Maternal and fetal/neonatal outcomes
• Complications during pregnancy
• For example chorioamnionitis, antenatal
  hospitalizations, intrauterine growth
  restriction, preterm labor
• Mode of birth and complications
• For example cesarean birth, surgical
  complications
• Prematurity
• Gestational age at birth
• Birth weight, fetal and neonatal mortality
• Postpartum and neonatal complications
• For example maternal postpartum hemorrhage,
  intraventricular hemorrhage
• Longer term outcomes
• For example neurodevelopmental and future
  reproductive outcomes

• Likis FE, Andrews JC, Woodworth AL, et al. AHRQ
  Comparative Effectiveness Review No. 74.
  Available at www.effectivehealthcare.ahrq.gov/pret
  ermbirth.cfm.

13
Clinically Significant Outcomes of Interest in
the Comparative Effectiveness Review (2 of 2)

• Maternal and child adverse effects
• Complications during pregnancy
• For example allergic reactions, gestational
  diabetes
• Mode of birth and complications
• For example unanticipated maternal harms
• Postpartum and neonatal complications
• For example infection and sepsis
• Longer term outcomes
• For example reproductive and neurodevelopmental
  adverse effects

• Likis FE, Andrews JC, Woodworth AL, et al. AHRQ
  Comparative Effectiveness Review No. 74.
  Available at www.effectivehealthcare.ahrq.gov/pret
  ermbirth.cfm.

14
Potential Modifiers of Progestogen Effects on
Preterm Birth Outcomes

• Modifiers are characteristics that interact with
  the treatment to change the expected outcome,
  when compared with those without the
  characteristic.
• Gestational age of prior spontaneous preterm
  birth
• Number of prior spontaneous preterm births
• Prior preterm premature rupture of membranes
• Short cervix
• Number of fetuses in multiple gestations
• Preterm labor in the current pregnancy
• Maternal age
• Body mass index
• Cerclage
• Socioeconomics
• Conception via reproductive technology

• Likis FE, Andrews JC, Woodworth AL, et al. AHRQ
  Comparative Effectiveness Review No. 74.
  Available at www.effectivehealthcare.ahrq.gov/pret
  ermbirth.cfm.

15
Summary of Study Characteristics Evaluated in the
Effectiveness Review PICOTS

• Population Adult women at risk for preterm birth
• All risk factors
• Interventions Progestogens
• All formulations, routes, and doses
• Comparators Placebo or no active intervention
• Outcomes
• Preterm birth, gestational age
• Maternal, fetal, and neonatal health outcomes
• Timing Treatment initiated at any time point
  prior to 37 weeks
• Setting Community

• Likis FE, Andrews JC, Woodworth AL, et al. AHRQ
  Comparative Effectiveness Review No. 74.
  Available at www.effectivehealthcare.ahrq.gov/pret
  ermbirth.cfm.

16
Studies Examining Progestogen Effects

• In most studies, the specific risk factors of the
  treatment and control group patients were
  identified. These risk factors include
• Prior spontaneous preterm birth
• Current multiple gestation (twins and triplets)
• Short cervix
• Threatened preterm labor
• Varied risk factors (a variety of indications
  among the patients)
• Unique indications (e.g., abdominal surgery,
  midtrimester amniocentesis, active military duty)

• Likis FE, Andrews JC, Woodworth AL, et al. AHRQ
  Comparative Effectiveness Review No. 74.
  Available at www.effectivehealthcare.ahrq.gov/pret
  ermbirth.cfm.

17
Studies and Results by Indication (1 of 3)
Outcome (n total studies n total participants) Result (95 CI)
Women with prior spontaneous preterm birth (current singleton pregnancies) Women with prior spontaneous preterm birth (current singleton pregnancies)
Prevention of birth at less than 37 weeks (4 1,318) OR 0.66 (0.53, 0.82) ARR 9.4, NNT 11 ???
Mean birth weight (3 859) No statistically significant difference Mean difference 239 g (-44.5, 523.3 g) ???
Fetal/neonatal death (3 1,318) OR 0.52 (0.25, 0.96), ARR 1.7, NNT 58 ???
Women with short cervix Women with short cervix
Prevention of birth (less than 34 weeks ) Study 1 (n 250) ARR 8.8 ???
Prevention of birth (less than 33 weeks) Study 2 (n 458) ARR 15.25 ???
These studies used vaginal formulations. 95 CI 95-percent confidence interval the range of statistically valid results ARR absolute risk reduction the difference between preterm birth rates in treatment and control groups mean difference the difference between treatment and control group means NNT number needed to treat the number of patients to be treated to observe the effect in one patient more than in the control group OR odds ratio Strength of Evidence Ratings High ???, Moderate ???, Low ??? These studies used vaginal formulations. 95 CI 95-percent confidence interval the range of statistically valid results ARR absolute risk reduction the difference between preterm birth rates in treatment and control groups mean difference the difference between treatment and control group means NNT number needed to treat the number of patients to be treated to observe the effect in one patient more than in the control group OR odds ratio Strength of Evidence Ratings High ???, Moderate ???, Low ???

• Likis FE, Andrews JC, Woodworth AL, et al. AHRQ
  Comparative Effectiveness Review No. 74.
  Available at www.effectivehealthcare.ahrq.gov/pret
  ermbirth.cfm.

18
Studies and Results by Indication (2 of 3)
Outcome (n total RCTs n total participants) Result (95 CI)
Women with current multiple gestations (twins and triplets) Women with current multiple gestations (twins and triplets)
Prevention of birth at less than 35 weeks (4 900) No statistically significant difference ??? OR 1.18 (0.79, 1.39)
Mean birth weight (3 698) No statistically significant difference ??? (Treated means 1,719 554, 1,968 679, and 1,650 554 g untreated means 1,609 472, 1,934 549, and 1,754 494 g)
Fetal/neonatal death (5 2,966) No benefit ??? OR 1.75 (0.93, 2.80)
95 CI 95-percent confidence interval the range of statistically valid results OR odds ratio RCT randomized controlled trial Strength of Evidence Ratings High ???, Moderate ???, Low ??? 95 CI 95-percent confidence interval the range of statistically valid results OR odds ratio RCT randomized controlled trial Strength of Evidence Ratings High ???, Moderate ???, Low ???

• Likis FE, Andrews JC, Woodworth AL, et al. AHRQ
  Comparative Effectiveness Review No. 74.
  Available at www.effectivehealthcare.ahrq.gov/pret
  ermbirth.cfm.

19
Studies and Results by Indication (3 of 3)
Outcome (n total RCTs n total participants) Result (95 CI)
Women with threatened preterm labor Women with threatened preterm labor
Prevention of birth at less than 37 weeks (3 149) OR 0.26 (0.10, 0.49) ???
Mean birth weight (4 385) ???
Fetal/neonatal death (1 126) ???
Populations with varied risk factors Populations with varied risk factors
Prevention of birth at less than 35 weeks (4 1,194) ???
Mean birth weight (2 119) ???
Fetal/neonatal death (3 269) ???
Populations with unique indications
All outcomes single study for each indication ???
95 CI 95-percent confidence interval the range of statistically valid results OR odds ratio RCT randomized controlled trial Strength of Evidence Ratings High ???, Moderate ???, Low ??? 95 CI 95-percent confidence interval the range of statistically valid results OR odds ratio RCT randomized controlled trial Strength of Evidence Ratings High ???, Moderate ???, Low ???

• Likis FE, Andrews JC, Woodworth AL, et al. AHRQ
  Comparative Effectiveness Review
• No. 74. Available at www.effectivehealthcare.ahrq
  .gov/pretermbirth.cfm.

20
Summary of BenefitsAccording to Indication/Risk
Group (1 of 3)

• In women with current singleton pregnancies and a
  history of spontaneous preterm birth, progestogen
  treatment
• Reduces the risk of preterm birth by one-third
  (number needed to treat 11)
• Strength of Evidence Moderate
• May increase birth weight, but the summary result
  across studies is not statistically significant
• Strength of Evidence Moderate
• Reduces neonatal mortality rates, with an
  absolute risk reduction of 1.7 percent (number
  needed to treat 58)
• Strength of Evidence Low

• Likis FE, Andrews JC, Woodworth AL, et al. AHRQ
  Comparative Effectiveness Review No. 74.
  Available at www.effectivehealthcare.ahrq.gov/pret
  ermbirth.cfm.

21
Summary of BenefitsAccording to Indication/Risk
Group (2 of 3)

• Women with short cervix may benefit from
  progestogen treatment (studies used vaginal
  formulations), but the size of the effect is not
  established.
• Strength of Evidence Low
• In women with twin or triplet pregnancies there
  is no benefit of progestogen treatment.
• Birth is not delayed.
• Strength of Evidence Moderate
• Birth weights are not improved.
• Strength of Evidence Moderate
• The evidence about mortality rates is
  insufficient to permit a summary estimate of the
  effect.

• Likis FE, Andrews JC, Woodworth AL, et al. AHRQ
  Comparative Effectiveness Review No. 74.
  Available at www.effectivehealthcare.ahrq.gov/pret
  ermbirth.cfm.

22
Summary of BenefitsAccording to Indication/Risk
Group (3 of 3)

• The present review found that progestogens may
  delay preterm birth in women with preterm labor,
  but the current evidence base is imprecise and
  insufficient to permit a conclusion about the
  effect.
• The evidence is insufficient for all other
  indications.

• Likis FE, Andrews JC, Woodworth AL, et al. AHRQ
  Comparative Effectiveness Review No. 74.
  Available at www.effectivehealthcare.ahrq.gov/pret
  ermbirth.cfm.

23
Studies and Results Based on Formulation and
Route of Administration

• The authors of the comparative effectiveness
  review analyzed published study data by
  organizing it according to formulation and route
  of administration intramuscular, oral, and
  vaginal.
• The analysis did not differentiate studies
  according to indication.

Formulation/ Route of Administration (Number of studies) Risk of Preterm Birth Odds Ratio (95 CI) Risk of Fetal/Neonatal Mortality Odds Ratio (95 CI) Strength of Evidence
17OHP Intramuscular (9) OR 0.75 (0.60, 0.90) OR 1.11 (0.66, 1.73) Unrated
Oral (3) OR 0.56 (0.36, 0.79) OR 0.68 ( 0.04, 2.17) Unrated
Vaginal (4) OR 0.76 (0.57, 0.98) OR 0.77 (0.39, 1.27) Unrated
The range of weeks of gestation chosen for evaluation of preterm birth and mortality rates was from 34 to 37 weeks. 17OHP 17-hydroxyprogesterone 95 CI 95-percent confidence interval the range of statistically valid results OR odds ratio The range of weeks of gestation chosen for evaluation of preterm birth and mortality rates was from 34 to 37 weeks. 17OHP 17-hydroxyprogesterone 95 CI 95-percent confidence interval the range of statistically valid results OR odds ratio The range of weeks of gestation chosen for evaluation of preterm birth and mortality rates was from 34 to 37 weeks. 17OHP 17-hydroxyprogesterone 95 CI 95-percent confidence interval the range of statistically valid results OR odds ratio The range of weeks of gestation chosen for evaluation of preterm birth and mortality rates was from 34 to 37 weeks. 17OHP 17-hydroxyprogesterone 95 CI 95-percent confidence interval the range of statistically valid results OR odds ratio

• Likis FE, Andrews JC, Woodworth AL, et al. AHRQ
  Comparative Effectiveness Review No. 74.
  Available at www.effectivehealthcare.ahrq.gov/pret
  ermbirth.cfm.

24
Summary of Benefits Effect of Formulation and
Route of Administration

• All formulations succeeded in reducing the risk
  of spontaneous preterm birth.
• The evaluated studies were not differentiated
  according to risk factor.
• The studies evaluated spontaneous preterm birth
  at 35 to 37 weeks.
• No formulation was effective at reducing the risk
  for neonatal mortality.
• However, the evidence is insufficient to support
  conclusions about the true benefits or effect
  sizes.
• It is possible that differences associated with
  progestogen use arise solely from populations
  studied or other biases.
• Head-to-head comparisons are needed to provide
  sufficient evidence to permit conclusions about
  the comparative effectiveness of these
  formulations.

• Likis FE, Andrews JC, Woodworth AL, et al. AHRQ
  Comparative Effectiveness Review No. 74.
  Available at www.effectivehealthcare.ahrq.gov/pret
  ermbirth.cfm.

25
Evidence About the Adverse Effectsof
Progestogens

• Study withdrawals were similar for treated and
  control groups.
• The most common adverse effects were related to
  route of administration.
• Injection site discomfort
• Vaginal irritation
• The evidence is insufficient to understand the
  short- and long-term maternal and fetal adverse
  effects.
• Potential adverse events were not uniformly
  assessed in the clinical literature.
• There are no registries to accumulate data on
  rare or long-term adverse effects for either
  mothers or children.

• Likis FE, Andrews JC, Woodworth AL, et al. AHRQ
  Comparative Effectiveness Review No. 74.
  Available at www.effectivehealthcare.ahrq.gov/pret
  ermbirth.cfm.

26
Effects of Modifiers of Outcomes and Safety

• None of the studies of maternal characteristics
  had sufficient statistical precision and power to
  determine the effects of modifiers on benefits
  and adverse effects of progestogens.
• No data inform whether effectiveness of
  progestogen treatment varies among women with
  prior preterm premature rupture of membranes,
  cerclage, uterine malformation, or conceptions
  via assisted reproduction technology when
  compared with other women.
• No dose-finding studies focused on efficacy or
  effectiveness were identified in this review.
• No literature addresses whether adherence or
  acceptability to patients varies by formulation,
  dose, or route.
• For all the modifiers evaluated, the evidence is
  insufficient to guide care.

• Likis FE, Andrews JC, Woodworth AL, et al. AHRQ
  Comparative Effectiveness Review No. 74.
  Available at www.effectivehealthcare.ahrq.gov/pret
  ermbirth.cfm.

27
Conclusions About Benefits and Adverse Effects

• For women with prior spontaneous preterm birth
  and current singleton pregnancies, progestogens
  reduce the risk of preterm birth.
• Women with a short cervix may benefit, but the
  research is too limited to estimate the
  likelihood.
• There is no benefit for women with multiple
  gestations.
• For all other indications, the evidence is
  insufficient to guide care.
• The incidence of rare adverse events is not
  known.
• The effects of modifiers are unknown.
• The evidence is insufficient to know whether
  progestogen use prevents morbidity or promotes
  normal childhood development.

• Likis FE, Andrews JC, Woodworth AL, et al. AHRQ
  Comparative Effectiveness Review No. 74.
  Available at www.effectivehealthcare.ahrq.gov/pret
  ermbirth.cfm.

28
Gaps in Knowledge

• The effectiveness review revealed areas where the
  evidence is inadequate to support decisionmaking
  that balances the benefits and adverse effects of
  progestogens used to prevent spontaneous preterm
  birth.
• The thresholds where improved gestational age and
  birth weight translate into improved neonatal and
  childhood outcomes are not known.
• The differences in effectiveness between
  different formulations and dosages, timing of
  initiation, and duration of treatment have not
  been studied in head-to-head comparisons.
• The influence of potential modifiers (e.g., body
  mass index, short cervix) has not been
  determined.
• The effects on maternal outcomes (e.g., prenatal
  hospitalization, tocolysis, gestational diabetes,
  hypertension) are not known.
• Patient adherence to treatment and reasons for
  discontinuation are rarely reported or
  investigated.
• Long-term risks are not known, and no
  surveillance database is available for reporting
  adverse events.

• Likis FE, Andrews JC, Woodworth AL, et al. AHRQ
  Comparative Effectiveness Review No. 74.
  Available at www.effectivehealthcare.ahrq.gov/pret
  ermbirth.cfm.

29
What To Discuss With Your Patientsand Their
Caregivers

• Progestogens reduce the risk of preterm birth for
  women who previously had a spontaneous preterm
  birth and who currently have a singleton
  pregnancy. They may also benefit women with a
  short cervix. They do not prevent preterm birth
  for multiple gestations.
• There is little evidence about using progestogens
  for women with preterm labor or other risk
  factors for preterm birth.
• The evidence about differences between the oral,
  injection, and vaginal methods for treatment is
  limited.
• It is not known if progestogens will provide
  short- or long-term health benefits to the infant
  or mother, other than delaying birth, and there
  is little evidence about short- and long-term
  adverse effects.

• Likis FE, Andrews JC, Woodworth AL, et al. AHRQ
  Comparative Effectiveness Review No. 74.
  Available at www.effectivehealthcare.ahrq.gov/pret
  ermbirth.cfm.