Accepted Manuscript

17-hydroxyprogesterone caproate for preterm rupture of the membranes: a

multicenter, randomized, double-blind, placebo-controlled trial

C. Andrew Combs, MD, PhD, Thomas J. Garite, MD, Kimberly Maurel, RN, MSN,
CNS, Diana Abril, RN, MSCRM, Anita Das, PhD, William Clewell, MD, Kent
Heyborne, MD, Helen How, MD, Wilson Huang, MD, David Lewis, MD, George Lu,
MD, Hugh Miller, MD, Michael Nageotte, MD, Richard Porreco, MD, Asad Sheikh,
MD, Lan Tran, MD

PII: S0002-9378(15)00458-5
DOI: 10.1016/j.ajog.2015.05.009
Reference: YMOB 10392

To appear in: American Journal of Obstetrics and Gynecology

Received Date: 13 March 2015

Accepted Date: 5 May 2015

Please cite this article as: Combs CA, Garite TJ, Maurel K, Abril D, Das A, Clewell W, Heyborne
K, How H, Huang W, Lewis D, Lu G, Miller H, Nageotte M, Porreco R, Sheikh A, Tran L, for the
Obstetrix Collaborative Research Network, 17-hydroxyprogesterone caproate for preterm rupture of
the membranes: a multicenter, randomized, double-blind, placebo-controlled trial, American Journal of
Obstetrics and Gynecology (2015), doi: 10.1016/j.ajog.2015.05.009.

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 ACCEPTED MANUSCRIPT

17-hydroxyprogesterone caproate for preterm rupture of the membranes:

a multicenter, randomized, double-blind, placebo-controlled trial

C. Andrew Combs, MD, PhD1,2, Thomas J Garite, MD1,3, Kimberly Maurel, RN, MSN, CNS1,
Diana Abril, RN, MSCRM1, Anita Das, PhD4, William Clewell, MD5, Kent Heyborne, MD6,

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Helen How, MD7, Wilson Huang, MD8, David Lewis, MD9, George Lu, MD10,
Hugh Miller, MD11, Michael Nageotte, MD12, Richard Porreco, MD6, Asad Sheikh, MD13,

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Lan Tran, MD14, for the Obstetrix Collaborative Research Network 1

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1 The Center for Research, Education, and Quality, Obstetrix, Mednax National Medical
Group, Sunrise, FL
2 Obstetrix Medical Group, San Jose, California
3 University of California, Irvine, California
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4 Biometrics, San Francisco, CA
5 Obstetrix Medical Group, Phoenix Perinatal Associates, Phoenix, AZ
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6 Obstetrix Medical Group, Denver, CO

7 Norton Healthcare, Louisville, KY
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8 High Risk Pregnancy Center, Las Vegas, NV

9 University of South Alabama, Mobile, AL
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10 Obstetrix Medical Group, Kansas City, MO

11 Obstetrix Medical Group, Tucson, AZ
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12 Obstetrix Medical Group, Long Beach, CA

13 Spectrum Health, Grand Rapids, MI
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14 Obstetrix Medical Group, Seattle, WA

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DISCLOSURES: Financial support as noted below. The authors reported no other conflicts
of interest.

TRIAL REGISTRY: clinicaltrials.gov, NCT #01119963

https://clinicaltrials.gov/ct2/show/NCT01119963?term=progesterone+rupture&rank=2
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17-hydroxyprogesterone caproate for PROM
Combs et al.
Presented in Poster format at the 35th Annual Meeting of the Society for Maternal-Fetal
Medicine, San Diego, CA, February 2-7, 2015

FINANCIAL SUPPORT: Sponsored and funded by the Center for Research, Education, and
Quality, Mednax National Medical Group, Sunrise, FL. All of the authors are employees of

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Obstetrix Medical Group, a subsidiary of Mednax, except Drs Das, How, Huang, Lewis, and
Sheikh. KV Pharmaceutical (now Lumara Health, Chesterfield, MO) donated the Makena®

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hydroxyprogesterone caproate and placebo for this trial through an unrestricted grant and
had no involvement in the design or conduct of the trial, or in the writing or decision to

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submit the article.

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DISCLOSURES: The authors disclosed no conflicts of interest.
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REPRINTS: not available from the authors
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CORRESPONDING AUTHOR:
C. Andrew Combs MD, PhD
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Obstetrix Medical Group

900 E Hamilton Avenue #220
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Campbell, CA 95008
Tel 408.314.1792
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Fax 408.371.8111
e-mail andrewcombs@me.com
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Word Count, Abstract: 304

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Word Count, Body: 3595

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17-hydroxyprogesterone caproate for PROM
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Condensation
This placebo-controlled, randomized clinical trial found no evidence that 17-
hydroxyprogesterone caproate prolonged pregnancy or improved perinatal outcome after
preterm rupture of the membranes.

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Short Title
17-hydroxyprogesterone caproate for PROM

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Key Words

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17-hydroxyprogesterone caproate
preterm rupture of membranes
preterm birth prevention

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17-hydroxyprogesterone caproate for PROM
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Abstract
OBJECTIVE: Preterm rupture of membranes (PROM) is associated with increased risk of
preterm birth and neonatal morbidity. Prophylactic 17-hydroxyprogesterone caproate
(17OHPc) reduces the risk of preterm birth in some women at risk for preterm birth. We
sought to test whether 17OHPc would prolong pregnancy or improve perinatal outcome

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when given to mothers with preterm rupture of the membranes.

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STUDY DESIGN: This is a multicenter, double-blind, placebo-controlled, randomized
clinical trial. The study included singleton pregnancies with gestational ages between 230/7

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to 306/7 weeks at enrollment, documented PROM, and no contraindication to expectant
management. Consenting women were randomly assigned to receive weekly

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intramuscular injections of 17OHPc (250 mg) or placebo. The primary outcome was
continuation of pregnancy until a favorable gestational age, defined as either 340/7 weeks of
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gestation or documentation of fetal lung maturity at 320/7 to 336/7 weeks. The two pre-
specified secondary outcomes were interval from randomization to delivery and composite
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adverse perinatal outcome. The planned sample size was 222 total women.
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RESULTS: From October, 2011 to April, 2014, 152 women were enrolled, 74 randomly
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allocated to 17OHPc and 78 to placebo. The trial was stopped when results of a planned
interim analysis suggested that continuation was futile. The primary outcome was
achieved in 3% of the 17OHPc group and 8% of the placebo group (P=0.18). There was no
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significant between-group difference in the pre-specified secondary outcomes,

randomization-to–delivery interval (17.1 ± 16.1 versus 17.0 ± 15.8 days, respectively, P =
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0.76) or composite adverse perinatal outcome (63% versus 61%, respectively, P = 0.93).
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No significant differences were found in other outcomes, including rates of

chorioamnionitis, postpartum endometritis, cesarean delivery, individual components of
the composite outcome, or prolonged neonatal length of stay.

CONCLUSION: Compared to placebo, weekly 17OHPc did not prolong pregnancy or reduce
perinatal morbidity in patients with PROM in this trial.

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17-hydroxyprogesterone caproate for PROM
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Introduction
Preterm rupture of the fetal membranes (PROM) complicates 2%-4% of pregnancies1,2
and is responsible for about 10-30% of preterm births and perinatal deaths in the United
States1-3. When PROM occurs very early in gestation, the result is often early preterm birth

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accompanied by substantial neonatal morbidity and/or death. To minimize these risks, a
strategy of expectant management is often adopted, with a goal of prolonging the
pregnancy until a more favorable gestational age is reached1,2,4. But even with conservative

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management, 50-60% of women with PROM deliver within 1 week1, 5.

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Some adjunctive medications may improve the outcome of expectant management of
PROM according to recent metaanalyses6-8. Antenatal corticosteroids reduce the rates of
several neonatal complications, including respiratory distress syndrome, intraventricular

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hemorrhage, necrotizing enterocolitis, and death6. Antibiotics also reduce neonatal
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morbidity, in part by prolonging the latency period from PROM to delivery7. Tocolytic
agents may slightly prolong the latency period but any benefit of this may be negated by an
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increased rate of chorioamnionitis8. No other treatments have proven useful.

Progestogens have properties that might be especially beneficial in women with PROM,
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including suppression of myometrial activation, reduced expression of myometrial gap

junctions and contraction-related proteins, reduced production of inflammatory cytokines,
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inhibition of cervical ripening, and reduced cell death in the chorion and decidua9-11. In
some high risk women with intact membranes, such as those with a short cervix12 or those
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with a prior history of spontaneous preterm birth13, vaginal progesterone or 17-

hydroxyprogesterone caproate (17OHPc) appear to reduce the rate of preterm birth and
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they are recommended in these settings14. However, a previous trial found no benefit of
17OHPc for women with PROM, though the trial had limited statistical power because of
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small sample size15.

The goal of the present study was to determine whether administration of 17OHPc to
women with PROM would prolong pregnancy or reduce perinatal morbidity and mortality.
We selected intramuscular 17OHPc rather than vaginal micronized progesterone because
of the possibility that insertion of intravaginal medication might increase the risk of

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Combs et al.
chorioamnionitis or that the drug might be partly or completed washed out by amniotic
fluid leakage after PROM.

Methods
This is a multicenter, randomized, placebo-controlled, double-blind clinical trial

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performed at 14 hospitals across the United States. The study sites were acute care
hospitals with neonatal intensive care units, listed in the Acknowledgments. Before

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enrollment of any subject, the protocol was registered at clinicaltrials.gov (NCT
#01119963) and the study was approved by the Institutional Review Board of each

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hospital. No protocol amendments were made after the trial commenced. The trial is
reported according to the guidelines of the CONSORT 2010 Statement16.
A previous version of the trial under a different protocol was terminated prematurely

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because of problems with drug supply17. The present report does not include any of the
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subjects from the previous version.

Inclusion/Exclusion Criteria
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Inclusion criteria were singleton pregnancy at 230/7 to 306/7 weeks of gestation,

mother at least 18 years old, and spontaneous PROM. PROM was defined by either (a) a
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positive placental alpha-1 microglobulin test (PAMG-1, AmniSure®, QIAGEN, Germantown,

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MD) from a vaginal swab18,19, (b) vaginal leakage of indigo carmine dye instilled by
amniocentesis, or (c) 2 or more of the following: a positive nitrazine test of a vaginal swab;
ferning observed on a microscope slide of vaginal fluid; gross pooling of clear fluid in
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posterior vaginal fornix on speculum examination; and/or ultrasound exam showing

oligohydramnios.
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Exclusion criteria included any of the following: contraindications to expectant

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management (such as suspected intraamniotic infection or inflammation, active preterm

labor, nonreassuring fetal heart rate tracing, intrauterine fetal death, preeclampsia, active
uterine bleeding, documented fetal lung maturity, or other condition requiring immediate
delivery); fetal conditions likely to cause serious neonatal morbidity (such as
malformations involving vital organs or likely to require surgical repair, fetal viral
infection, hydrops); cervical cerclage present at the time of PROM; medical conditions

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Combs et al.
treated with systemic steroids; and contraindications to 17OHPc (such as allergy to drug or
vehicle, current or past thromboembolic disorder, current or past hormone-sensitive
cancer, undiagnosed vaginal bleeding, cholestatic jaundice of pregnancy or other active
liver disease, uncontrolled hypertension).

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Patients with PROM who were initially excluded because they were having
contractions or bleeding could become eligible later if their contractions or bleeding
subsided. We did not discriminate whether PROM had occurred before the onset of

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contractions (prelabor PROM, premature PROM) or after. This was based partly on the
belief that the distinction between spontaneous PROM after preterm labor versus prelabor

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PROM is somewhat arbitrary, as the two may merely be different manifestations of a
common “spontaneous parturition syndrome,” sharing common risk factors, antecedents,

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and covariates20-22. And it was based partly on the belief that most of the adverse
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obstetrical events that occur in a quiescent patient after PROM are directly attributable to
the consequences of PROM, such as oligohydramnios (leading to cord compression or
abruption) or loss of barrier function (leading to ascending infection or cord prolapse), or
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attributable to the underlying factors that cause PROM in the first place (such as infection
or inflammation leading to labor or chorioamnionitis, or cervical insufficiency leading to
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silent dilation and early preterm birth), regardless of whether PROM occurred before or
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after the onset of contractions. Finally, it was based partly on the observation that the
clinical management of patients with threatened preterm parturition is typically guided
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more by whether or not the membranes are intact than by which came first, contractions or
PROM.
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Patients who had been on treatment for prevention of preterm birth using 17OHPc or
vaginal progesterone at the time of PROM were not excluded. We recommended that
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vaginal progesterone be discontinued after PROM because of the risk of ascending

infection. A patient on 17OHPc treatment was eligible if she was willing to stop the
previous treatment and be randomized for the trial. If she was not willing, she was
continued on 17OHPc and not enrolled in the trial.

Procedures

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Eligible patients who gave written, informed consent were randomly allocated to
receive a weekly 1 mL intramuscular injection of either 17OHPc (Makena® 250 mg,
Lumara Health, Chesterfield, MO) or an identical-appearing placebo (castor oil vehicle).
Randomization followed a computer-generated block scheme, with 1:1 group allocation,
stratified by site and by gestational age (230/7 to 256/7, 260/7 to 286/7, or 290/7 to 306/7

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weeks). Study medications were dispensed by the hospital pharmacy in syringes that
appeared identical for 17OHPc and placebo. Subjects, research personnel, and caregivers

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had no knowledge of the group assignment, either before or after randomization. The
randomization code was not broken until the database had been finalized for analysis.

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Study medication was continued weekly until 340/7 weeks of gestation unless delivery
occurred earlier.

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Expectant management of PROM was attempted according to principles that the
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investigators agreed upon in advance. All patients were admitted to the hospital until
delivery. Prophylactic antibiotics were given. Each site had a “usual” antibiotic regimen
similar to that of Mercer et al.23, but the investigators could not agree on a single regimen
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for all sites or regimens to cover all contingencies such as allergies. A single course of
antenatal corticosteroids was given, usually betamethasone 12 mg intramuscularly, 2
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doses, 24 hours apart. A “rescue course” of corticosteroids24 was used at some sites for
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patients undelivered after 2 weeks, though the protocol discouraged this because of a lack
of data supporting efficacy of repeat steroid dosing in women with PROM and because of a
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concern that repeat dosing might increase the rate of chorioamnionitis25. A third course of
corticosteroids was not permitted. Tocolytic therapy was permitted at the caregiver’s
discretion and according to local custom during the first 48 hours after corticosteroid
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dosing but not thereafter. Magnesium sulfate for prevention of cerebral palsy, when used,
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followed each hospital’s protocol. Amniocentesis to rule-out intraamniotic infection was

encouraged. If performed prior to randomization, then randomization was postponed until
preliminary results indicated low probability of infection. Fetal heart rate monitoring was
performed at least daily. Caregivers were advised to avoid digital examination of the cervix
before the onset of labor. Amniotic fluid for fetal lung maturity testing (FLM) was collected
from vaginal secretions or via amniocentesis, if possible, at 320/7 to 336/7 weeks. The type

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of FLM test and the criteria for diagnosing maturity were based on local custom.
Peripartum and perioperative antibiotic prophylaxis were encouraged and followed local
custom. If there was no fluid leakage for >72 hours, diagnosis of membrane resealing
could be entertained after a trial of ambulation if ultrasound exam showed normal amniotic
fluid volume and at least one confirmatory test showed no evidence of amniotic fluid

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leakage (either PAMG-1, fetal fibronectin, indigo carmine leakage, or absence of pooling on
exam with negative fern and nitrazine tests). Upon diagnosis of resealing, study

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medication was discontinued and the patient was discharged from the hospital.

Data and Statistics

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Case report forms were completed based on the maternal medical record and the
neonatal record up to the first 60 days of life. Infant outcomes after the initial

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hospitalization or after 60 days of life were not captured. Data were entered into a
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centralized computer database via an online data entry system. Data entries were audited
to compare their accuracy against source documents in the medical record. Data queries
generated from the audits and from quality checks were resolved before the randomization
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code was broken.

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The primary outcome was the continuation of pregnancy either until 340/7 weeks or
until 320/7 to 336/7 weeks with documentation of fetal lung maturity, endpoints that are
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widely accepted as indications to proceed with delivery rather than continue expectant
management1,2,4. The two pre-specified secondary outcomes were: (a) the interval from
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randomization to delivery and (b) composite adverse perinatal outcome, defined as one or
more of the following: stillbirth, neonatal death, infant death, respiratory distress
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syndrome, intracranial hemorrhage (grade 3 or 4), necrotizing enterocolitis (stage 2 or 3),

culture-proven neonatal sepsis within 72 hours of birth. Each component of the composite
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was defined as per Mercer et al23. Periventricular leukomalacia was not included in the
definitions of Mercer et al23, but we included it in the composite outcome if the diagnosis
was made on ultrasound or magnetic resonance imaging within 96 hours of birth; the case
report form did not distinguish cystic versus non-cystic subtypes26.

For statistical analysis, comparisons between the two treatment groups on categorical
variables were made using Fisher’s exact test or Cochran-Mantel-Haenszel chi square

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stratified by gestational age at randomization. Wilcoxon rank sum test was used for
continuous variables. The randomization-to-delivery interval was tested using a Cox
regression adjusting for gestational age at randomization. Analyses were based on the
intent-to-treat principle, that is, subjects were analyzed with their allocated group
regardless of whether they withdrew or discontinued treatment, with the exception of 2

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subjects (one from each treatment group) who were lost to follow-up and had no available
maternal or neonatal outcome data. Two-sided P-values are reported, with P<0.049

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considered significant. All analyses were performed using SAS 9.2 (SAS Institute, Cary, NC).

The study sample size was planned to detect an increase in the primary outcome from

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30% in the placebo group to 50% in the 17OHPc group17. The anticipated rate in the
placebo group was based on a query of the national neonatal database of Pediatrix division

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of Mednax, Inc., our parent company. We calculated that 105 subjects per group (210 total)
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would yield 80% power to detect this difference using 2-tailed alpha at 0.049, adjusted for
1 planned interim analysis based on the O’Brien-Fleming alpha spending function. The
sample size was adjusted upward to 111 per group (222 total) to allow for up to 5% loss-
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to-follow-up. We noted a priori that this sample size would also yield 80% power to detect
a 4-day difference in randomization-to-delivery interval between the groups (assuming a
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standard deviation of 10 days) and 80% power to detect a reduction in composite adverse
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perinatal outcome from 60% in the placebo group to 40% in the 17OHPc group.

Interim Analysis
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A planned interim analysis was conducted upon completion of 50% of the case
reports17. The plan was to stop the trial if there was a significant difference between groups
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in the primary outcome (with a nominal alpha of 0.0031 based on the Lan-DeMets group
sequential method27 and O’Brien-Fleming alpha spending function), if there was a safety
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signal suggesting increased risk of adverse events in the 17OHPc group, or if analysis of the
observed trends indicated a low conditional power to show a significant difference
between groups in the primary outcome, unless mitigated by favorable trends in the two
pre-specified secondary outcomes.

The results of the analysis suggested that it was futile to continue the trial. Based on
the observed trend, the conditional power to show a between-groups difference in the

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primary outcome was <10% and no favorable trend was noted in the secondary outcomes.
With these findings, the Data Safety and Monitoring Board recommended discontinuation
of the trial. All further enrollment was stopped, but patients who were already enrolled
continued to receive weekly study medication until delivery. This report includes the
results from all the enrolled subjects.

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Results

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From October, 2011 through April, 2014, we enrolled 152 subjects, of whom 74 were
assigned to receive 17OHPc and 78 to receive placebo. Figure 1 shows the trial flow

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diagram.

Baseline characteristics were similar between the 17OHPc and placebo groups, as

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summarized in Table 1. There were no significant differences between the groups in
maternal demographics, parity, history of prior preterm birth, or gestational age at
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enrollment.

The primary outcome did not differ significantly between the groups, as shown in
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Table 2. The groups also had similar randomization-to-delivery intervals (Figure 2) and
similar mean gestational age at delivery. Although there were more women who reached
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34 weeks of gestation in the placebo group than in the 17OHPc group, this did not reach
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statistical significance.

Neonatal morbidity and mortality were similar in the two groups, as summarized in
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Table 3. There were no stillbirths in either group. There were 3 neonatal deaths in the
17OHPc group: (1) birth at 316/7 weeks, died at 1 day of age of respiratory failure
attributed to diaphragmatic hernia not detected by prenatal ultrasound; (2) birth at 284/7
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weeks, died at 10 days of age with hypotension, air leak syndrome, and probable sepsis;
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and (3) birth at 231/7 weeks, life support withdrawn at 1 day of life due to extreme
prematurity, respiratory distress, intraventricular hemorrhage. There were 2 neonatal
deaths in the placebo group: (1) birth at 313/7 weeks, died at 6 days of age from atypical
pulmonary infection, etiology undetermined; and (2) birth at 240/7 weeks, death at 4 hours
from inability to oxygenate, dilated right ventricle on echocardiogram, suspected
pulmonary hypertension.

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Other outcomes are summarized in Table 4. There were no significant between-group
differences in these outcomes. Although there was a trend toward more cesarean delivery
in the 17OHPc group, this did not reach statistical significance. Supplementary Table A
summarizes the use of several interventions that were left to the discretion of caregivers or
based on local custom, including corticosteroids, tocolysis, magnesium for

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“neuroprotection”, choice of antibiotics, and choice of FLM testing. There were no
significant between-group differences in these.

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To evaluate the efficacy of 17OHPc when used specifically for patients with prelabor
PROM (PPROM), a subgroup analysis of the primary outcome and the two secondary

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outcomes was performed after excluding the 5 subjects who had experienced preterm
labor before PROM. That analysis showed no significant difference in the 3 outcomes, as

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summarized in Supplementary Table B.
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Early withdrawal from the study occurred in 2 cases in the 17OHPc group and 3 in the
placebo group. In the 17OHPc group, the reasons for withdrawal were: (1) possible allergic
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reaction at the injection site (pain, redness, swelling itching) after the sixth injection; and
(2) the patient declined further injections after the sixth injection. In the placebo group,
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the reasons for withdrawal were: (1) patient refused further injections after the first; (2)
patient withdrew her consent without having received any study medication; and (3)
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patient left the hospital against medical advice after the second injection. Outcomes for all
these subjects were analyzed with the allocated groups, in accordance with the intent-to-
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treat principle.

Membrane resealing was documented in 3 cases in the 17OHPc group and 2 in the
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placebo group. Upon diagnosis of resealing, study medications were stopped and the
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patients discharged from the hospital. Three of them returned and delivered 10, 34, and 45
days later at gestational ages 29-32 weeks. Outcomes for these 3 were analyzed with the
originally-allocated groups, in accordance with the intent-to-treat principle. One patient
from each group delivered elsewhere, so no delivery records or neonatal records were
available. These 2 were considered lost-to-follow-up and their outcomes were not
analyzed.

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Adverse events are summarized in Table 5. Several newborn structural cardiac
anomalies were noted in each group, most detected by echocardiography performed to
evaluate a murmur. These were all judged by the neonatologist caregivers to be mild; none
required surgery and only 1 required medical treatment (aspirin for patent ductus
arteriosus). The Data Safety and Monitoring Board reviewed the details of each adverse

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event and concluded that all were unlikely to be related to study drug, except 1 case of
injection site irritation. The randomization code was not broken to evaluate any adverse

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event.

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Comment

Principal Findings

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The principal findings of this study were that weekly administration of 17OHPc did not
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prolong pregnancy or improve perinatal outcome in women with PROM. Our results are in
agreement with a previous, smaller, randomized trial of 17OHPc in women with PROM15.
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Strengths

Strengths of the study include the randomized, double-blind, placebo-controlled study

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design and the moderately large sample size.

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Another strength is the diversity of the patient population, which was drawn from both
private and university hospitals and included women whose educational level and
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racial/ethnic mix closely approximated that of the US population.

Another strength is that we used the formulation of 17OHPc that is approved by the US
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Food and Drug Administration, manufactured and quality-tested according to Current Good
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Manufacturing Practices. In other words, the study medication had documentation of

identity, potency, purity, sterility, and stability.

Limitations

One limitation of the study is that we studied only 1 dosage of 17OHPc (250 mg) and
only 1 frequency of administration (once per week). However, the regimen we studied was
identical to the regimen that was beneficial in a trial of women with intact membranes who

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had a prior history of spontaneous preterm birth13. It is possible that it is simply “too late”
to start 17OHPc after the membranes have ruptured. Before membrane rupture occurs,
changes to the cervix may have already taken place21 or intraamniotic inflammation may
already be present and these factors might nullify any possible benefit of the drug.

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Another limitation is that we allowed variation from site-to-site in certain details of the
protocol, such as the precise antibiotic regimen, the use of tocolytic agents, the use of
magnesium sulfate for “neuroprotection”, and the precise FLM test used at the local

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hospital. On the other hand, this lack of uniformity can also be considered a strength
because these management choices reflected the variation seen in real-world practice and

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were not artificially constrained by a rigid trial protocol. In this regard, the study is more
closely akin to a trial of “effectiveness” than a trial of “efficacy” and this may improve

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generalizability28.
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Statistical Power

The primary outcome occurred at a lower rate than expected, so the trial is
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underpowered for the primary outcome. In part, this occurred because mean gestational
age at enrollment was lower than we expected based on typical distribution of PROM
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patients; there were a disproportionately large number of patients in the 23-26 wk

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stratum (Table 1). ,From post hoc calculations, we estimate that the trial would have had a
power of 26% to achieve statistical significance given the observed between-groups
difference in the primary outcome (3% versus 8%) if the it had continued to the full
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planned enrollment of 222 subjects. However, this weak trend in the primary outcome
actually favored placebo over 17OHPc, so there appeared to be no justification to continue
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the trial.
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For the pre-specified secondary outcomes, the trial was well-powered despite the early
termination. For the interval-to-delivery outcome, post hoc calculations show that a trial of
152 subjects and a standard deviation of 16 days has 80% power to detect a 7-to-8-day
difference between the groups. For the composite adverse perinatal outcome, post hoc
calculations show that a trial of 152 subjects has 80% power to detect a difference between
groups from the observed 61% in the placebo group to 38% in the 17OHPc group, almost

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identical to the rates specified in the a priori calculations (60% and 40%, respectively).
Arguably, the composite perinatal outcome is the most clinically relevant of our pre-
specified outcomes, since the primary goal of expectant management of PROM is to reduce
perinatal morbidity, not to simply prolong pregnancy. No significant between-groups
differences were observed for either of the secondary outcomes. Indeed, there were not

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even any favorable trends.

Conclusion

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In agreement with the results of a previous study15, the present study provides no

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evidence that 17OHPc is beneficial in women with PROM. Though the trial turned out to be
underpowered for the primary outcome, it had reasonable statistical power for the
prespecified secondary outcomes, allowing us to conclude that 17OHPc does not prolong

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pregnancy or reduce perinatal morbidity after PROM. We are not aware of any other
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evidence suggesting any benefit of 17OHPc after PROM. Therefore, we conclude that
17OHPc should not be used for women with PROM outside of a controlled clinical trial.
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Acknowledgments
We thank the following members of the Obstetrix Collaborative Research Network who
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participated in this trial. Data Safety and Monitoring Board: Brian Mercer MD, Case
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Western Reserve School of Medicine, Cleveland, OH; Michael Gravett MD, University of
Washington School of Medicine, Seattle, WA; Reese Clark MD, Pediatrix Medical Group,
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Sunrise, FL; Barbara Marusiak, RN, Obstetrix Medical Group, Denver, CO. Mobile Site: David
Lewis MD, Casey Armistead BSRN, University of South Alabama, Children’s and Women’s
Hospital, Mobile, AL. Phoenix Site: William Clewell MD, Ana Braecsu RN, MSN, MPH,
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Michelle Gamez RN, BSN, Gloria Mullen RN, Obstetrix Medical Group, Phoenix Perinatal
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Associates, Banner Good Samaritan Medical Center, Phoenix, AZ and Banner Desert Medical
Center, Mesa, AZ. Denver Site: Richard Porreco MD, Kent Heyborne MD, Jeri Lech RN, Julie
Rael RN, Obstetrix Medical Group, Swedish Medical Center and Presbyterian St Luke’s
Hospital, Denver, CO. San Jose Site: C Andrew Combs MD, Kimberly Mallory RN, BSN,
Obstetrix Medical Group, Good Samaritan Hospital and O’Connor Hospital, San Jose, CA.

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Tucson Site: Hugh Miller MD, Diane Mercer RN, CCRC, Nadema Jones RN, Obstetrix Medical
Group, Tucson Medical Center, Tucson, AZ. Long Beach Site: Michael Nageotte MD, Deysi
Caballero LVN, Donna Guizado RN, Obstetrix Medical Group, Long Beach Memorial Medical
Center, Long Beach, CA. Grand Rapids Site: Asad Sheikh MD, Alison Dutkiewicz RN, Judy
Hancock RN, Yvonne Edgerly RN, Lori Oosterman RN, Mary Readwin RN, Spectrum Health,

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Spectrum Health Hospital, Grand Rapids, MI. Seattle Site: Lan Tran MD, Dawn Artis RN,
BSN, Tina Lopez RN, Obstetrix Medical Group, Swedish Medical Center, Seattle, WA.

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Louisville Site: Helen How MD, Christina Waldon RN, Kimberly Pruitt RN, Norton
Healthcare Korsair Children’s Hospital, Louisville, KY. Las Vegas Site: Wilson Huang MD,

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Judy Hancock MSN, High Risk Pregnancy Center, Sunrise Hospital, Las Vegas, NV. Kansas
City Site: George Lu MD, Kate Swearinen MSN, APRNc, Obstetrix Medical Group, Saint

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Luke’s Medical Center, Kansas City, MO. Biostatistics: Anita Das PhD. Administration:
Thomas J Garite MD, C. Andrew Combs MD, PhD, Kimberly Maurel RN MSN CNS, Diana Abril
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RN BSN CRM, The Center for Research, Education, & Quality, Mednax National Medical
Group, Sunrise, FL.
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1. Mercer BM. Preterm premature rupture of the membranes. Obstet Gynecol

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2003;101:178-93.

2. Caughey AB, Robinson JN, Norwitz ER. Contemporary diagnosis and management of
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4. Committee on Practice Bulletins – Obstetrics. Premature rupture of membranes.

American College of Obstetricians and Gynecologists Practice Bulletin 2013;139: 1-13.

5. Combs CA, McCune M, Clark R, Fishman A. Aggressive tocolysis does not prolong
pregnancy or reduce neonatal morbidity after preterm premature rupture of the
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6. Roberts D, Dalziel SR. Antenatal corticosteroids for accelerating fetal lung maturation for
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7. Kenyon S, Boulvain M, Neilson J. Antibiotics for preterm rupture of membranes.

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8. Mackeen AD, Seibel-Seamon J, Muhammad J, Baxter JK, Berghella V. Tocolytics for
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9. Romero R. Prevention of spontaneous preterm birth: the role of sonographic cervical

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10. Hirota Y, Cha J, Dey SK. Prematurity and the puzzle of progesterone resistance. Nature
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11. Murtha AP, Feng L, Yonish B, Leppert PC, Shomberg DW. Progesterone protects fetal
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12. Romero R, Nicolaides K, Conde-Agudelo A, et al. Vaginal progesterone in women with

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13. Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by 17
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Obstet Gynecol 2013; 208:1-2.

15. Briery CM, Veillon EW, Klauser CK, et al. Women with preterm premature rupture of
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16. Schulz KF, Altman DG, Moher D, CONSORT Group. CONSORT 2010 statement: updated
guidelines for reporting parallel group randomised trials. BMC Med 2010;8:18.

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17. Combs CA, Garite TJ, Maurel K, et al. 17-hydroxyprogesterone caproate to prolong
pregnancy after preterm rupture of the membranes: early termination of a double-
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18. Ng BK, Lim PS, Shafiee MN, et al. Comparison between Amnisure placental alpha

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microglobulin-1 rapid immunoassay and standard diagnostic methods for detection of
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19. Sosa CG, Herrera E, Restrepo JC, Strauss A, Alonso J. Comparison of placental alpha
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20. Romero R, Espinoza J, Kusanovic JP, et al. The preterm parturition syndrome. BJOG

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21. Iams JD, Cebrik D, Lynch C, Behrendt N, Das A. The rate of cervical change and the
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22. McElrath TF, Hecht JL, Dammann O, et al. Pregnancy disorders that lead to delivery
before the 28th week of gestation: an epidemiologic approach to classification. Am J
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morbidity after preterm premature rupture of the membranes: a randomized

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24. Garite TJ, Kurtzman J, Maurel K, Clark R, Obstetrix Collaborative Research Network.
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25. Crowther CA, McKinlay CJD, Middleton P, Harding JE. Repeat doses of prenatal
corticosteroids for women at risk of preterm birth for improving neonatal health
outcomes. Cochrane Database Syst Rev 2011; CD003935.

26. Deng W, Pleasure P, Pleasure D. Progress in periventricular leukomalacia. Arch Neurol

2008;65:1291-5.

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27. Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika
1983;70:659-63.

28. Bombardier C, Maetzel A. Pharmacoeconomic evaluation of new treatments: efficacy

verus effectiveness studies? Ann Rheum Dis 1999;58:(suppl I) I82-5.

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Figure Legends

Figure 1. Flow diagram for the trial. 17OHPc = 17-hydroxyprogesterone caproate

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Figure 2. Survival plots showing randomization-to-delivery interval in the two groups.
17OHPc = 17-hydroxyprogesterone caproate.

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Table 1. Baseline Characteristics

17-
Hydroxyprogesterone Placebo Group P-value
Caproate Group (N=78)
(N=74)
Maternal age (years) 29.3 ± 5.8 29.5 ± 5.7 0.84 *

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Maternal weight (pounds) 164 ± 50 162 ± 45 0.98 *
Nulliparous 29 (39) 27 (35) 0.62 †

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Prior preterm birth 13 (18) 18 (23) 0.43 †
Using progestogen at time of PROM 3 (4) 5 (6) 0.72 †

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Onset of labor before PROM †† 1 (1) 4 (5) 0.37 †
Race/Ethnicity 0.36 †
America Indian/Alaska native 3 (4) 4 (5)

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Asian 4 (5) 1 (1)
Black 8 (11) 14 (18)
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Hispanic/Latino 21 (28) 16 (21)
Pacific Islander/Hawaiian native 1 (1) 0
White 37 (50) 42 (54)
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Other 0 1 (1)
Marital Status 0.19 †
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Married/Living with Partner 44 (59) 46 (59)

Single/Widowed 27 (36) 30 (38)
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Divorced Separated 3 (4) 0

Other 0 2 (3)
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Education 0.39 †
<High School Graduate 6 (8) 10 (13)
High School Graduate or Equivalent 11 (15) 18 (23)
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Some College 22 (30) 15 (19)

College Graduate 17 (23) 15 (19)
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Not reported 18 (24) 20 (26)

Tobacco use 4 (5) 5 (6) 0.87 †
Illicit drug use 7 (10) 14 (18) 0.09 †
Gestational age at membrane rupture 25.9 ± 3.0 26.6 ±2.9 0.16 *
(wks)‡
Gestational Age at Randomization (wks) 26.7 ± 2.5 27.1 ± 2.4 0.34 *
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17-
Hydroxyprogesterone Placebo Group P-value
Caproate Group (N=78)
(N=74)
Gestational Age Stratum at Randomization
230/7 – 256/7 weeks 31 (42) 28 (36) 0.75 †

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260/7 – 286/7 weeks 24 (32) 27 (35)
290/7 – 306/7 weeks 19 (26) 23 (29)
Diagnosis of Ruptured Membranes **

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Fluid pooling on exam 45 (61) 53 (68)
Oligohydramnios on ultrasound 33 (45) 41 (53)
Positive nitrazine test 32 (43) 27 (35)

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Positive fern test 31 (42) 39 (50)
Positive Amnisure® test 27 (36) 27 (35)
Indigo carmine leakage 4 (5) 3 (4)
Data are Mean ± SD or N (%).
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*Wilcoxon rank sum test for continuous variables
†Fisher’s exact test for categorical variables
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‡Date of membrane rupture unknown for 2 patients in 17OHPc group, 5 in Placebo group
** Sum is >100% because of multiple positive results per patient
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†† Contractions with cervical dilation ≥ 2 cm

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Table 2. Maternal Efficacy Outcomes

17- Placebo Group

Hydroxyprogesterone (N=77) P-value
Caproate Group
(N=73)

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Primary outcome 2 (3) 6 (8) 0.18*

Components of the primary outcome

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Delivery at ≥34 weeks 1 (1) 5 (6) 0.12**

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Delivery at 320/7 to 336/7 weeks 0.95**

FLM mature 1 (1) 1 (1)

FLM not tested

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FLM immature 2 (3) 1 (1)

Randomization-to-delivery interval (days) 17.1 ± 16.1 17.0 ± 15.8 0.76†

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Gestational age at delivery (weeks) 29.2 ± 2.7 29.5 ± 2.7 0.57‡

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Data are N(%) or mean ± SD.

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Primary outcome is continuation of pregnancy until 340/7 weeks or a mature result on fetal
lung maturity (FLM) test at 320/7 to 336/7 weeks.
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*Cochran-Mantel-Haenszel chi-square stratified by gestational age at randomization.

** Fisher’s exact test, unadjusted because of the small number of events.

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†Cox regression model adjusted for gestational age at randomization.

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‡ Wilcoxon Rank Sum test.

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Table 3. Secondary Perinatal Efficacy Outcomes

17- Placebo Group

Hydroxyprogesterone (N=77) P-value
Caproate Group
(N=73)

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Composite adverse perinatal outcome 46 (63) 49 (64) 0.64*

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Components of the composite

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Stillbirth 0 0 NA

Neonatal death 3 (4) 2 (3) 0.67†

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Infant death before hospital discharge 0 0 NA

Respiratory distress syndrome 44 (60) 46 (60) 0.72*

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Intraventricular hemorrhage, grade 3 or 4 1 (1) 1 (1) 1.00†

Necrotizing enterocolitis, stage 2 or 3 3 (4) 2 (3) 0.67†

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Sepsis within 72 hours of birth 3 (4) 1 (1) 0.36†

Periventricular leukomalacia 1 (1) 2 (3) 1.00†

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All data are N (%).

Neonatal death = death at ≤ 28 days of life
Infant death = death at 29-60 days of life
*Cochran-Mantel-Haenszel chi-square stratified by gestational age at randomization.
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†Fisher’s exact test, unadjusted because of the small number of events.

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Table 4. Selected Other Outcomes

17- Placebo Group

Hydroxyprogesterone (N=77) P-value
Caproate Group
(N=73)

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Route of Delivery
Vaginal 29 (40) 43 (56) 0.06*

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Cesarean (primary indication below) 44 (60) 34 (44)
Malpresentation 17 18

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Abnormal fetal heart rate monitoring 10 6
Repeat cesarean 9 3
Cord prolapse 3 2
Abruption
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Other Indication 3 2
Clinical chorioamnionitis 12 (16) 17 (22) 0.36*
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Postpartum endometritis 4 (5) 3 (4) 0.67*

Birth weight, grams 1352 ± 501 1405 ± 470 0.46†
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Apgar score <7 at 1 minute 40 (55) 38 (49) 0.65*

Apgar score <7 at 5 minutes 14 (19) 15 (19) 0.79*
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Neonatal length of stay ≥8 weeks 35 (48) 32 (42) 0.87*

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Data are N(%) or mean ± SD.

*Cochran-Mantel-Haenszel chi-square stratified by gestational age at randomization

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†Wilcoxon Rank Sum test

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17OHPc = 17-hydroxyprogesterone caproate

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Table 5. Adverse Events

GA at GA at GA at
Group Type Event PROM Entry Birth Doses

17OHPc SAE Neonatal death, respiratory failure, air leak, sepsis 265/7 276/7 284/7 1
17OHPc SAE Neonatal death, congenital diaphragmatic hernia 294/7 295/7 316/7 1

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17OHPc SAE Neonatal death, respiratory distress 225/7 230/7 231/7 1
17OHPc SAE Newborn: VSD, pulmonic stenosis, mild 304/7 306/7 312/7 1
17OHPc SAE Newborn: VSD, PFO, mild 252/7 285/7 301/7 2

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17OHPc SAE Newborn: Pelvic mass, regressed spontaneously 226/7 233/7 326/7 10
17OHPc SAE Newborn: Osteomyelitis, extremity contractures 194/7 240/7 242/7 1
17OHPc SAE Newborn: Epispadias diagnosed 292/7 300/7 313/7 2

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17OHPc AE Mother: Ruptured appendix discovered at cesarean 272/7 273/7 276/7 1
17OHPc SAE Mother: Uterine dehiscence discovered at repeat unk 243/7 283/7 5
C/S, pulmonary embolism on postoperative day 1
17OHPc AE Mother: Uterine dehiscence discovered at repeat 263/7 265/7 280/7 2

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17OHPc SAE Mother: Wound infection after cesarean delivery 215/7 244/7 275/7 4
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17OHPc SAE Mother: Wound infection after cesarean delivery 243/7 244/7 255/7 1
17OHPc SAE Mother: Wound infection after cesarean delivery 286/7 292/7 314/7 3
17OHPc AE Mother: Redness, itching, swelling, at injection site 244/7 251/7 312/7 6
Placebo SAE Neonatal death, atypical pulmonary infection 301/7 301/7 313/7 1
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Placebo SAE Neonatal death, suspected pulmonary hypertension 234/7 236/7 240/7 1
Placebo SAE Newborn: Peripheral pulmonary stenosis, ASD, mild unk 253/7 326/7 8
Placebo SAE Newborn: ASD, PDA 285/7 286/7 300/7 2
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Placebo SAE Newborn: VSD, ASD, PDA 185/7 242/7 270/7 3

Placebo SAE Newborn: VSD, ASD 246/7 250/7 300/7 6
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Placebo SAE Newborn: ASD versus PFO 263/7 265/7 283/7 2

Placebo AE Newborn: Inguinal hernia at 8 days of age 261/7 261/7 285/7 3
Placebo AE Newborn: Leakage from umbilicus, cauterized with 296/7 294/7 300/7 1
silver nitrate
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17OHPc = 17-hydroxyprogesterone caproate

GA = gestational age, weeks
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Doses = number of doses of 17OHPc or placebo given before adverse event observed
SAE = serious adverse event
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AE = adverse event
VSD = ventriculoseptal defect
PFO = patent foramen ovale
ASD = atrial septal defect
PDA = patent ductus arteriosus
C/S = cesarean delivery
Unk = unknown
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Supplemental Table A. Management at Discretion of Caregivers or Based on Local Custom

17-Hydroxyprogesterone
Caproate Group Placebo Group P-value *
(N=74) (N=78)
Antenatal Corticosteroids 0.55

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Complete course 57 (77) 63 (81)
Complete course + “rescue” course 17 (23) 14 (18)
Incomplete course 0 1 (1)

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None 0 0
Tocolysis in first 48 hours after Antenatal 0.87

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Corticosteroids
Magnesium sulfate alone 28 (38) 32 (41)
Magnesium sulfate plus another agent 4 (5) 6 (8)

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Terbutaline 1 (1) 0
Nifedipine 1 (1) 1 (1)
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Indomethacin 0 1 (1)
None 40 (54) 38 (49)
Magnesium sulfate within 12 hours of delivery
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(“neuroprotection”)
Those delivered < 28 wks 8/23 (35) 7/21 (33) 1.00
Those delivered 280/7 to 316/7 wks 14/41 (34) 15/43 (35) 1.00
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Those delivered ≥320/7 wks 2/9 (22) 2/13 (15) 1.00

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Antibiotic Regimen 0.61

Ampicillin + Macrolide 50 (68) 56 (72)
Cephalosporin + Macrolide 5 (7) 3 (4)
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Ampicillin only 4 (5) 1 (1)

Other 14 (19) 17 (22)
None 1 (1) 1 (1)
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Fetal lung maturity testing 2 (3) 3 (4) 1.00

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Lamellar bodies via amniocentesis 1 (1) 1 (1)

Lamellar bodies via vaginal collection 1 (1) 1 (1)
L/S and PG via vaginal collection 0 1 (1)
Data are N (%).
*Fisher’s exact test
L/S = lecithin/sphingomyelin ratio, PG=phosphatidyl glycerol.
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Supplemental Table B. Efficacy outcomes in women with preterm prelabor rupture of membranes (PPROM)

17-Hydroxyprogesterone

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Caproate Group Placebo Group P-value
(N=72) (N=73)
Primary Outcome: Reached 34 weeks of gestation or 2 (3%) 6 (8%) 0.16*

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reached 32 weeks of gestation with fetal lung maturity
Secondary Outcome: Interval to delivery (days) 17.3 ± 16.1 17.4 ± 16.1 0.62†

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Secondary Outcome: Composite adverse perinatal 45 (63%) 47 (64%) 0.60*
outcome

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Data are N (%) or Mean ± SD.

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*Cochran-Mantel-Haenszel chi-square stratified by gestational age at randomization.
†Cox regression model adjusted for gestational age at randomization.

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