Progesterone (17P, Makena®) for Prolongation of Pregnancy in Women With Preterm Rupture of the Membranes (PROM)

Preterm rupture of the membranes (PROM) is the leading identifiable cause of prematurity and
accounts for about one-third of all preterm deliveries and 18-20% of perinatal deaths in the
USA. When PROM occurs at very early gestational ages, the clinician must make a decision
whether to attempt to prolong the pregnancy or whether to recommend prompt delivery. Both
approaches carry substantial risk. The strategy of continuing the pregnancy is commonly
called "expectant management." During expectant management, gestational age steadily
increases, and the balance naturally shifts toward favoring delivery. Once the gestational
age reaches 34 weeks, the risk of lethal or permanent sequelae of prematurity or minimal, so
most clinicians agree that delivery is warranted. Despite an attempt at expectant management,
the majority of patients with PROM will be delivered within the first week or so.
Unfortunately, no intervention other than antibiotic prophylaxis or corticosteroids have been
shown to prolong latency or reduce neonatal morbidity after PROM. Recent evidence suggests
that prophylactic administration of progesterone medications may reduce the risk of preterm
delivery in women with certain risk factors, notably those with a history of a prior preterm
delivery and those with a shortened cervix discovered by ultrasound examination. Clearly,
women with PROM are at very high risk of preterm delivery, so there is a pressing need to
study whether 17 hydroxyprogesterone caproate (17P) is effective after PROM. Progesterone
might be beneficial after PROM both because it tends to promote uterine quiescence by
suppressing the formation of myometrial gap junctions and because it has anti-inflammatory
properties, suppressing the production of inflammatory cytokines and thereby inhibiting
cervical ripening. Inflammation is a major pathway leading to preterm labor, cervical
dilation & preterm delivery. 17P would seem to be like an ideal candidate for prolongation of
pregnancy after PROM.

This is a double-blinded, placebo-controlled, multicenter, randomized clinical trial of 17P
versus placebo. The primary outcome measure will be the percentage of each group reaching
either a gestational age of 34w0d or documentation of fetal lung maturity at 32w0d to 33w6d.
Secondary outcomes will include the latency period for each group and the percentage of
newborns in each group who have major neonatal morbidity or death.

Inclusion Criteria:

1. Participant is 18 years old or older

2. Gestational Age (GA) 23w0d and 30w6d @ time of enrollment

3. Singleton pregnancy

4. PROM defined as either (a) or (b) or (c) below (a) Documentation of vaginal leakage of
indigo carmine dye instilled via amniocentesis (b) Positive Amnisure® test (c) Two or
more of (i) through (iv): i. Nitrazine test with pH of 7 or more ii. Positive fern
test iii. Gross pooling of clear fluid iv. US exam showing oligohydramnios

Exclusion Criteria:

1. Any contraindication to expectant management

2. Any fetal condition likely to cause serious neonatal morbidity independent of
gestational age

3. History of allergy to 17P

4. Any contraindications to 17P use (e.g. Thrombosis, Breast CA, abnormal vaginal
bleeding unrelated to pregnancy, jaundice, liver disease, uncontrolled HTN)

5. Any medical condition currently treated with systemic steroid medications

6. Cervical cerclage present at the time of PROM

7. Informed consent not obtained.