CLINICAL OBSTETRICS AND GYNECOLOGY
Volume 54, Number 2, 307312
Preterm PROM:
Prediction,
Prevention, Principles
THADDEUS P. WATERS, MD and BRIAN MERCER, MD
MetroHealth Medical Center, Case Western Reserve University,
Cleveland, Ohio
Abstract: Preterm premature rupture of the membranes
remains difficult to predict accurately. The majority of
those suffering preterm premature rupture of the mem-
brane lack risk factors that might lead to preventative
treatments. Its management is centered on an evaluation
of the risks and benefits of attempted pregnancy pro-
longation compared with expeditious delivery. An un-
derstanding of the gestational age specific risks for
newborn morbidity and mortality is essential to estimate
the potential benefits of conservative management.
Once the diagnosis of membrane rupture remote from
term is made, conservative management to reduce neo-
natal complications is generally attempted while main-
taining vigilance for complications such as infection,
umbilical cord compression, or abruption. Concurrent
antibiotic therapy and antenatal corticosteroid treat-
ment are typically administered to prolong pregnancy,
prevent infection, and reduce gestational age dependent
morbidities. Near and at term, particularly if fetal
pulmonary maturity has been confirmed, the patient is
generally best served by expeditious delivery.
Key words: PROM, gestational age risk, complication,
treatment
Introduction
Preterm premature rupture of the mem-
branes (preterm PROM or pPROM)
complicates approximately 3% of all
Correspondence: Thaddeus P. Waters, MD, Metro-
Health Medical Center, Case Western, Reserve
University, 2500 MetroHealth Drive, Cleveland, OH.
E-mail: twaters1@metrohealth.org
CLINICAL OBSTETRICS AND GYNECOLOGY
r 2011, Lippincott Williams & Wilkins
pregnancies in the United States. Preterm
PROM is a significant contributor to pre-
term birth and is a significant cause of
gestational age-dependent neonatal mor-
bidity and mortality. Optimally, preterm
PROM could be avoided through early
identification of those at risk followed by
effective interventions. However, as most
women who develop preterm PROM have
no identifiable risk factors, current man-
agement remains focused on interventions
to optimize outcomes once preterm PROM
is diagnosed. Management of women who
develop preterm PROM requires an accu-
rate diagnosis in addition to an individual
assessment of the benefits and risks of
continuing pregnancy versus expedited de-
livery. This evaluation requires an under-
standing of gestational age specific risks of
neonatal morbidity and mortality and the
potential benefits and risks of conservative
management.
In general, the approach to the patient
with preterm PROM remote from term
is one of continuing pregnancy to reduce
gestational age-dependent newborn compli-
cations while maintaining vigilance for po-
tential complications including intrauterine
infection, umbilical cord compression and
/ VOLUME 54 / NUMBER 2 / JUNE 2011
www.clinicalobgyn.com | 307
308 Waters and Mercer
prolapse, or placental abruption. If it is
determined that a patient might benefit from
pregnancy prolongation, current manage-
ment includes antibiotics with antenatal
corticosteroid administration. For patients
near term, and for those found to have fetal
lung maturity at 32 weeks or more, the
patient is often best served by delivery.
Prediction
As the clinical course of preterm PROM is
typically one of latency followed by deliv-
ery of a premature neonate, it would be
ideal to identify those at risk early in preg-
nancy and then offer preventative inter-
ventions. Known modifiable risks factors
include cigarette smoking,1 poor nutri-
tion, and infections (urinary tract and
sexually transmitted infections).25 Addi-
tional risks factors include a short cervical
length, maternal respiratory conditions,
polyhydramnios, and periodontal disease.6,7
However, perhaps the strongest risk factor
for preterm PROM remains a history of an
earlier preterm birth from either premature
labor or PROM. Unfortunately, despite
efforts to identify significant risks factors
for preterm PROM, the vast majority of
patients who develop this complication
have no identifiable risk factor. This under-
scores the importance of treatment of pre-
term PROM once it has occurred.
The National Institute of Child Health
and Human Development Maternal-Fetal
Medicine Units research network per-
formed a large prospective observational
study to identify risks factors for preterm
birth including those associated with pre-
term PROM.2,3 For women with a history
of preterm birth from PROM, 13.5% had
a subsequent preterm birth from preterm
PROM compared with 4.1% in those with-
out such a history [Relative risk (RR): 3.3;
95% confidence interval (CI), 2.1-5.2].
Other significant risk factors for preterm
birth after PROM included maternal pu-
lmonary disease (RR: 1.8; 95% CI, 1.1-3.0),
body mass index <19.8 kg/m2 (RR: 1.9
www.clinicalobgyn.com
95% CI, 1.3-2.8), cervical length <25 mm
(RR: 3.2; 95% CI, 2.2-4.7), positive fetal
fibronectin (RR: 2.5; 95% CI, 1.6-4.0), bac-
terial vaginosis (RR: 1.5; 95% CI, 1.0-2.1),
previous preterm birth from preterm labor
(RR: 1.9; 95% CI, 1.2-3.0), and symptom-
atic contractions (RR: 1.9; 95% CI, 1.3-
2.8). Race was not associated with preterm
birth due to PROM; however, other inves-
tigators have found different results.8
Getahun et al9 recently published data
confirming the association between a
history of preterm birth due to PROM
and recurrent preterm PROM. Compar-
ing women with a history of preterm
PROM in their first pregnancy with
women without such a history, odds of
preterm PROM in the second pregnancy
were significantly increased for both African
American (odds ratio = 7.2; 95% CI, 5.1-
10.1) and White women (odds ratio = 8.7;
95% CI, 6.7-11.4). In addition, short
pregnancy interval (defined as <12 mo
between delivery and conception) has also
associated with an increased risk for re-
current preterm PROM, particularly for
African Americans.
Prevention
Current interventions to prevent preterm
PROM can be broken into 3 main cate-
gories: reduction in modifiable risk fac-
tors; broad-based preventative strategies;
and treatment of nonmodifiable risk fac-
tors. Potentially, modifiable risk factors
include cigarette smoking, urogenital in-
fections, acute pulmonary diseases, and
severe polyhydramnios. Treatments for
nonmodifiable risk factors, such as a pre-
vious history of preterm birth or a short
cervix, include 17- a hydroxyprogesterone
caproate and cervical cerclage. Broad-based
preventative strategies have included
screening and treatment for bacterial va-
ginosis and antioxidant supplementation
with vitamins C and E. It is important to
note that no specific interventional trials
aimed at prevention of preterm birth have
 Preterm PROM: Prediction, Prevention, Principles
solely focused on preterm PROM as a pri-
mary outcome. Invariably, interventional
trials use a reduction in preterm birth as a
primary outcome with some investigators
reporting preterm PROM as a secondary
outcome. However, as preterm PROM is
a significant contributor to preterm birth,
therapy, which consistently shows a re-
duction in the frequency of preterm birth
should be incorporated into the preven-
tion of preterm PROM.
Although intuitively logical, attempts
to reduce preterm PROM through mod-
ification in adjustable risk factors, beyond
the treatment of urogenital infections,
have not been proven to be effective.
Women with either urinary tract or sexu-
ally transmitted infections should be trea-
ted once identified. As heavy smoking is
associated with several poor outcomes,
any reduction in tobacco use should be
encouraged with the optimal goal of ces-
sation. For women with symptomatic
polyhydramnios, interventions at redu-
cing the amniotic fluid volume, such as
amnioreduction, can be performed. How-
ever, it is unclear if this offers any real
benefit in reducing preterm PROM or
preventing preterm birth. Finally, activity
modification is often considered for
patients at risk of preterm PROM or
preterm birth, but little data supports
its routine use.10
Several trials have evaluated the bene-
fits of screening and treatment of bacterial
vaginosis in women at high risk and low
risk of preterm PROM. These trials were
recently summarized by 2 publications
by the United States Preventative Task
Force.11,12 For women at average risk of
preterm PROM (defined as representative
sample of the general population), 4 trials
found no benefit from treatment of asymp-
tomatic bacterial vaginosis in the reduction
of preterm PROM; pooled risk reduction
0.006 (95% CI, 0.030-0.018). For wo-
men defined as high risk (those with a
history of a preterm delivery), the data
were mixed with 1 study noting a decreased
309
risk of preterm PROM with treatment,13
whereas 2 others showed no benefit. No
pooled risk was calculated due to study
heterogeneity. At this time, there seems to
be no role for routine screening and treat-
ment of asymptomatic bacterial vaginosis
during pregnancy.
In 2001, Woods et al14 proposed reac-
tive oxygen species to be a potential con-
tributor to preterm PROM. The authors
suggested that the process might be rever-
sible through antioxidant (Vitamins C
and E) supplementation. Although an
initial investigation15 evaluating Vitamin
C supplementation alone showed promise
for preventing preterm PROM (7.6% vs.
24.5%, P = 0.02), subsequent investiga-
tions including a recent publication by
Spinnato et al16 have suggested an in-
creased risk of preterm PROM with anti-
oxidant supplementation. This hypothesis
was further rebuked by the finding of
increased serum lutin concentrations (a
potent antioxidant) among women with
preterm PROM.17 At this time, routine
supplementation with antioxidants to
prevent preterm PROM is not recom-
mended.
In 2003, Meis et al18 published the
findings of a randomized trial which iden-
tified a significant reduction in recurrent
spontaneous preterm birth for patients
treated with weekly intramuscular 17 a-
hydroxyprogesterone caproate. An addi-
tional investigation of vaginal progesterone
supplementation found a similar benefit for
the prevention of preterm birth in high risk
patients.19 Although neither investigation
reported outcomes specific to preterm
PROM, both included patients with an
earlier preterm birth due to PROM. Re-
cently, studies of omega 3 supplementa-
tion and cervical cerclage for the pre-
vention of preterm birth have had mixed
results.20,21 On the basis of the available
data, weekly intramuscular progesterone
should be used for patients with a history
of preterm PROM to reduce the risk of a
recurrent preterm birth.
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310 Waters and Mercer
Recently, investigators have focused
on the possible contribution of infectious
or inflammatory processes at sites distant
from the female genital tract to preterm
birth and preterm PROM. Of particular
interest is maternal periodontal disease,
which if untreated and severe, can lead to
increased levels of circulating proinflam-
matory cytokines and chemokines, and
potentially preterm birth. Although severe
untreated periodontal disease has been
associated with preterm birth,6,7 no clear
relationship with this condition and pre-
term PROM has been elucidated. In addi-
tion, investigations aimed at treatment
have been inconclusive.22
General Management
Considerations
At term, approximately 8% of patients
will experience rupture of the membranes
before the onset of labor. For these pa-
tients, 95% will deliver within 28 hours of
PROM.23 The clinical course of preterm
PROM is also characterized by a brief
period of latency from membrane rupture
to delivery, with the duration of latency
increasing with decreasing gestational
age. For example, when PROM occurs
before 34 weeks gestational age, 93% of
patients will deliver within 7 days com-
pared with only 60% of those who present
with PROM near the threshold of viabili-
ty. As neonatal morbidities are closely
correlated with gestational age at deliv-
ery, the optimal goal in the management
of preterm PROM is to extend latency for
those pregnancies that may benefit from
a delay in delivery. To achieve this goal,
preterm PROM requires accurate diagno-
sis in addition to an understanding of the
gestational age specific risks for neonatal
morbidity and mortality. After the exclu-
sion of significant maternal complications
including infection, abruption, or cord pro-
lapse, the management of preterm PROM
is heavily determined on the estimation of
www.clinicalobgyn.com
risks for fetal and neonatal complications
with immediate delivery compared with
the risks and benefits of conservative
management.
For the patient with possible preterm
PROM, the initial steps include confirma-
tion of membrane rupture in addition to
assessments of estimated gestational age,
duration of membrane rupture, exclusion
of maternal infection or abruption, and
assessment of fetal well being. Cervico-
vaginal cultures should be obtained for
Chlamydia trachomatis, Neisseria gonor-
rhea, and anovaginal group B strepto-
coccus cultures should be obtained. If
the patient is determined to have chor-
ioamnionitis or abruption, conservative
management is not advised. Fetal well
being should also be assessed by methods
appropriate for gestational age. If a preg-
nancy is beyond the threshold of viability,
conservative management is not advised
in the setting of nonreassuring fetal testing.
At any gestational age, the management
of PROM is guided by the gestational age
at the time of membrane rupture. For the
patient at term, there is no substantial
benefit of pregnancy prolongation in the
setting of PROM due to the relatively
infrequent occurrence of significant neo-
natal complications at this gestational age.
Therefore, delivery should be undertaken
in this situation. This is contrasted by the
patient with preterm PROM between 23
to 31 weeks where there are significant
risks of neonatal morbidities, long-term
complications, and perinatal death from
premature delivery.24 In the absence of
significant contraindications to conserva-
tive management, including infection,
abruption, advanced labor, or nonreas-
suring fetal testing, these patients are best
served with conservative management to
prolong pregnancy.
The management of patients with
preterm PROM between 32 weeks and
36 weeks 6 days is not as clear-cut as those
patients on the extremes of the gestational
age continuum. In a randomized trial of
 Preterm PROM: Prediction, Prevention, Principles
conservative management of preterm
PROM at 32 to 36 weeks, Mercer et al25
reported a modest prolongation of preg-
nancy (36 h vs. 14 h, P<0.001) with conser-
vative management. However, this benefit
was potentially offset by an increased
frequency of chorioamnionitis and need
for neonatal septic evaluation with anti-
biotic treatments. For patients with pre-
term PROM between 34 to 36 weeks,
conservative management has also been
associated with increased risks of chor-
ioamnionitis and lower cord pH at delivery
with no demonstrable neonatal bene-
fit.26,27 Confounding the estimation of
risks versus benefits of pregnancy prolon-
gation is the limited potential for successful
latency beyond 34 weeks. Most patients
with PROM between 34 to 36 weeks will
progress to labor within 24 hours after
presentation and the benefits of attempt-
ed conservative management with antena-
tal steroid administration are difficult
to determine, as many patients may not
achieve adequate treatment before delivery.
For the patient PROM between 32
weeks and 33 weeks and 6 days gestational
age, neonatal morbidities, particularly re-
spiratory morbidities, can be significant.
However, unlike patient with preterm
PROM before 32 weeks, the likelihood
of survival is high and other complica-
tions of prematurity are rare. Therefore, a
reasonable approach to patients with pre-
term PROM at this gestational age should
include an assessment of fetal pulmonary
maturity. The optimal approach after ste-
roid benefit achieved is unclear. However,
as conservative management at this gesta-
tional age with mature pulmonary testing
is associated with increased risk, a reason-
able approach would be to initiate expe-
ditious delivery after corticosteroid benefit,
particularly if delivery would have been
planned within 7 days otherwise. This
would pertain to the patient with PROM
at 33 weeks who would be delivered at
34 weeks. For the patient with preterm
PROM at 32 weeks, attempting to prolong
311
latency with delivery at 34 weeks is a
reasonable approach.
Before 32 weeks gestation, conserva-
tive management should generally be pur-
sued unless immediate delivery is indicated.
During conservative management, anti-
biotics are administered to prolong la-
tency and reduce gestational age specific
morbidities. Antenatal corticosteroids are
administered to reduce pulmonary com-
plications and intraventricular hemor-
rhage. The patient is evaluated regularly
for signs or symptoms of labor, infection,
or abruption with delivery undertaken if
any of these develop. Fetal well being is
evaluated at least daily as umbilical cord
compression is a common complication
(32% to 76%). For the rare patient who ex-
periences prolonged latency, delivery is
typically pursued once the patient achieves
34 weeks gestation.
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