Original Research

ajog.org

OBSTETRICS

Prolonged latency of preterm premature rupture

of membranes and risk of neonatal sepsis
an, MD;
Daphnie Drassinower, MD; Alexander M. Friedman, MD; Sarah G. Obic
Heather Levin, MD; Cynthia Gyam-Bannerman, MD, MS

BACKGROUND: Preterm premature rupture of membranes (PPROM)

is associated with inflammation and infection, and it may involve the loss of
a barrier to ascending infection from the vagina, and it is possible that
prolonged PPROM could be an independent risk factor for neonatal sepsis.
OBJECTIVE: The objective of the study was to determine whether
prolonged latency after PPROM is associated with an increased risk of
neonatal sepsis.
STUDY DESIGN: This secondary analysis of the randomized controlled
trial of magnesium sulfate for the prevention of cerebral palsy evaluated
whether the time interval between diagnosis of PPROM and delivery was
associated with an increased risk of neonatal sepsis. Latency time was
categorized by weeks of latency (0 weeks to
4 weeks). The primary
outcome was confirmed neonatal sepsis. Logistic regression was used to
control for confounders.
RESULTS: A total of 1596 patients with PPROM were analyzed, of
whom 1390 had a < 4-week interval and 206 had an interval of
4

reterm premature rupture of

membranes (PPROM) is a common cause of spontaneous preterm
birth affecting approximately 3% of
pregnancies that is associated with signicant neonatal morbidity and mortality, particularly when delivery occurs
at an early gestational age.1 The management approach to PPROM for
women < 34 weeks gestation includes
the administration of antibiotics to increase latency and, to reduce risk from
prematurity, expectant management
until a fetal or maternal condition arises
that warrants delivery.2 At early gestational ages, the benets of expectant
management may outweigh risks, which
include placental abruption, umbilical
cord accident, and fetal demise2; however, there is a paucity of data on the
effects of prolonged latency of PPROM.

Cite this article as: Drassinower D, Friedman AM, Obican SG, et al. Prolonged latency of preterm premature
rupture of membranes and risk of neonatal sepsis. Am J
Obstet Gynecol 2016;214:743.e1-6.
0002-9378/$36.00
2015 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ajog.2015.12.031

weeks. Confirmed neonatal sepsis occurred in 15.5% of patients in

the cohort. In the univariate analysis, patients in the prolonged PPROM
group were less likely to have neonatal sepsis (6.8% vs 17.2%,
relative risk, 0.40 95% confidence interval, 0.24e0.66). This relationship was retained in the multivariable model; patients with prolonged PPROM
4 weeks had an adjusted odds ratio of 0.21 (95%
confidence interval, 0.10e0.41) for neonatal sepsis. Neonatal sepsis
was also significantly associated with earlier gestational age at rupture
of membranes.
CONCLUSION: Prolonged exposure to an intrauterine environment
of PPROM does not increase the risk of neonatal sepsis; prolonged
PPROM
4 weeks was associated with decreased risk of neonatal
sepsis.
Key words: neonatal sepsis, prolonged preterm premature rupture of

membranes

Although the pathophysiology of

PPROM is multifactorial, infection and
inammation are often responsible for
both the initial event of rupture of
membranes and subsequent sequalae.
Clinical chorioamnionitis has been reported to occur in 15e25% of pregnancies complicated by PPROM,3 with
subclinical infection being considerably
more common.4,5 Chorioamnionitis
may present shortly after PPROM or at a
longer interval and result in labor and
maternal symptoms suggestive of infection.6 Chorioamnionitis also poses
direct fetal risks and is associated with
increased risk for neonatal morbidity.7,8
Given that PPROM is associated with
inammation and infection and that
PPROM may involve the loss of a barrier
to ascending infection from the vagina,
it is possible that prolonged PPROM
could be an independent risk factor
for neonatal sepsis. Although some
studies have supported the relationship
between neonatal sepsis and prolonged
latency,9 other analyses have not supported this association.10-12 Given that
disentangling the relationship between
PPROM latency, gestational age, and
neonatal sepsis could provide important

prognostic information for patients and

providers, the purpose of this analysis
was to determine whether patients
with PPROM that have a prolonged
exposure to an intrauterine environment
of ruptured membranes are at increased
risk of neonatal sepsis compared with
patient with PPROM with shorter
latency.

Materials and Methods

This observational cohort secondary
analysis of the randomized controlled
trial of magnesium sulfate for the prevention of cerebral palsy, conducted
through the Eunice Kennedy Shriver National Institute of Child Health and Developments Maternal-Fetal Medicine
Units Network,13 was approved by the
Institutional Review Board at Columbia
University Medical Center (New York,
NY).
The parent trial enrolled women in
20 centers across the United States from
1997 to 2004 and sought to evaluate
whether antenatal magnesium sulfate
administration decreased the rate of cerebral palsy or death. Of a total of 2241
women at high risk for preterm delivery
between 24 weeks 0 days and 31 weeks

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OBSTETRICS

6 days randomized to magnesium sulfate

or placebo, 86.7% of women enrolled
had PPROM. Women were eligible if
they were at high risk for spontaneous
preterm delivery because of the rupture
of membranes or because of advanced
preterm labor with dilation of 4e8 cm
and intact membranes; women were
excluded if delivery was anticipated
within 2 hours.
Antibiotic administration and criteria
for delivery were not standardized as
part of the parent trial; however, in
accordance with the current recommended guidelines, antibiotics were
routinely administered and expectant
management was pursued until 34 weeks
unless a medical indication for delivery arose. Similarly, antenatal corticosteroid administration for fetal lung
maturity occurred routinely as part of
the current recommended guidelines.
Multiple courses of antenatal corticosteroids was dened as > 2 courses.
The current study included nonanomalous, live singleton pregnancies
with PPROM. The diagnosis of PPROM
was based on at least 2 of the following
3 criteria being met: (1) pooling of amniotic uid in the vaginal vault, (2) a
positive nitrazine test, and (3) the ferning
of vaginal uid. PPROM could also be
diagnosed if there was indigo carmine
pooling in the vagina after amnioinfusion
or if visible leakage of amniotic uid
from the cervix was noted. Patients with
missing outcome data were excluded.
The exposure of interest was prolonged latency, which was dened as delivery
4 weeks after diagnosis of
PPROM. For analyses, latency was categorized by number of weeks: 0 (0e6 days),
1 (7e13 days), 2 (14e20 days), 3 (21e27
days), and
4 weeks (
28 days).
The primary outcome evaluated was
neonatal sepsis, dened in the parent
trial as proven sepsis in which blood,
cerebrospinal uid, and/or urine cultures were positive and infection was
suspected on physical examination, or,
in the absence of positive cultures, there
was evidence of hemodynamic collapse
and X-ray ndings supporting infection
in a neonate with a clinical presentation
consistent with sepsis. The diagnosis of
neonatal sepsis could occur at any point

TABLE 1

Patient characteristics by interval between diagnosis of PPROM and delivery

Characteristic
Age, y, mean (SD)
Advanced maternal age, n, %

< 4 wks
(n 1390)
26.8 (5.8)
155 (11.2)

4 wks
(n 206)

P value

26.0 (5.7)

.07

19 (9.2)

.41
< .01

Race, n, %
African-American

654 (47.1)

59 (28.6)

White

492 (35.4)

109 (52.9)

Hispanic

216 (15.5)

36 (17.5)

Asian

13 (0.9)

1 (0.5)

Native American/other

15 (1.1)

1 (0.5)

BMI, n, %

.23

< 18.5

219 (15.8)

30 (14.6)

18.5e24.9

562 (40.4)

98 (47.6)

25e29.9

299 (21.5)

35 (17.0)

30

310 (22.3)

43 (20.9)

Nulliparous, n, %

486 (35.0)

59 (28.6)

.07

No prenatal care, n, %

109 (7.8)

11 (9.2)

.20

Tobacco use, n, %

416 (29.9)

51 (24.8)

.13

Drug use, n, %

156 (11.2)

12 (5.8)

.02

Alcohol use, n, %

140 (10.1)

19 (9.2)

.70

Magnesium treatment group, n, %

675 (48.6)

103 (50.0)

Multiple courses of steroids, n, %

38 (2.8)

18 (8.9)

Treatment with antibiotics, n, %

1290 (92.8)

190 (92.2)

.77

Maternal education, y, mean (SD)

11.9 (2.5)

12.1 (2.4)

.29

Gestational age at PPROM, wks, mean (SD)

27.8 (2.6)

29.1 (5.2)

< .01

.70
< .01

Drassinower et al. Prolonged PPROM and the risk of neonatal sepsis. Am J Obstet Gynecol 2016.

during the initial hospitalization and

was not limited to a specic period of
time after birth.

Patient demographic variables and

other characteristics were compared using the c2 test for categorical variables

TABLE 2

Univariate analysis of obstetric outcomes by PPROM latency interval

Outcome
Neonatal sepsis, n, %
Time from PPROM to delivery, d, median (IQR)
Gestational age at delivery, wks, mean (SD)

< 4 wks
(n 1390)

4 wks
(n 206)

239 (17.2)

14 (6.8)

6.2 (3.0-11.9)
29.3 (2.6)

P value
< .01

43.8 (33.9-59.0) < .01

33.4 (3.4)

< .01

1352 (462)

2095 (723)

< .01

Chorioamnionitis, n, %

178 (12.8)

20 (9.7)

.21

Cesarean delivery, n, %

507 (36.5)

82 (39.8)

.36

Birthweight, g, mean (SD)

IQR, interquartile range.

Drassinower et al. Prolonged PPROM and the risk of neonatal sepsis. Am J Obstet Gynecol 2016.

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OBSTETRICS

FIGURE 1

Proportion of neonatal sepsis by latency period

Prolonged PPROM latency was associated with a decreased risk of neonatal sepsis. Figure plots the
proportion of neonatal sepsis by weeks of latency among all infants that developed sepsis. Among all
infants that developed sepsis, 133 cases (52.6%) occurred in the shortest PPROM latency group,
66 cases (26.1%) occurred in the 1 week latency group, 25 cases (9.9%) occurred in the 2 week
latency group, 15 cases (5.9%) in the 3 week latency group, 5 (2%) in the 4 week latency group,
3 (1.2%) in the 5 and 6 week latency groups, 2 cases (0.8%) in the 7 week latency group, and 1 case
(0.4%) in the
8 week latency group. A c2 test was used to compare all groups with the shortest
latency group (P < .01) for all comparisons.
PPROM, preterm premature rupture of membranes.
Drassinower et al. Prolonged PPROM and the risk of neonatal sepsis. Am J Obstet Gynecol 2016.

Rate of neonatal sepsis by latency period

The rate of neonatal sepsis was stable weeks 0e3 of PPROM latency and decreased in the latency

4 weeks group. This figure plots the rate of neonatal sepsis by week of latency, which was 17.5%
(133 cases) in the shortest PPROM latency group, 18.6% (66 cases) in the 1 week latency group,
13.6% (25 cases) in the 2 week latency group, 16.7% (15 cases) in the 3 week latency group, and 6.8%
(14 cases) in the
4 week latency group. A c2 test was used to compare all groups with the shortest
latency group; the P value was not significant for PPROM latency for weeks 1e3 compared with 0 weeks
but was P < .01 when the
4 week latency group was compared with the shortest latency group.
Drassinower et al. Prolonged PPROM and the risk of neonatal sepsis. Am J Obstet Gynecol 2016.

and a Student t test for continuous variables. A Wilcoxon rank sum test was
used to compare median differences. We
then t a logistic regression model to
control for the following possible confounders: gestational age (GA) at rupture
of membranes, maternal age, parity,
race, exposure to magnesium sulfate,
body mass index (BMI), prenatal care,
drug use, tobacco use, and administration of multiple courses of antenatal
corticosteroids. Patients were considered
to have used recreational drugs during
the pregnancy if they tested positive on
urine toxicology studies or reported using heroin, cocaine, marijuana, or other
illicit drugs during their pregnancy.
Signicance was set at a value of P < .05.
All analyses were performed using SAS
9.4 (SAS Institute, Cary, NC).
Our sample size was xed by the
number of patients enrolled in the initial
randomized controlled trial and by our
exclusions. A power analysis based on
the xed sample size revealed a minimum detectable effect size for PPROM
latency
4 weeks of a < 0.6 or > 1.5 risk
ratio for the primary outcome based on a
power of 80% and a type I error of 5%.

Results

FIGURE 2

PPROM, preterm premature rupture of membranes.

Original Research

Of the 2444 infants included in the

parent study, 2088 had PPROM; of these,
326 were excluded for multiple gestation, 100 for missing data, 58 for major
congenital anomalies, and 8 for stillbirth, leaving 1596 patients included in
the analysis. A total of 1390 patients had
a < 4 week interval; among these, 762
patients had a latency interval of 0 weeks,
354 had PPROM for 1 week, 184 for 2
weeks, 90 for 3 weeks, and 206 patients
had an interval of
4 weeks.
All patients included in this analysis
were enrolled in the study within 48 hours
of PPROM. Of the patients included in
the analysis, 87 had PPROM at < 24
weeks, 611 had PPROM at 24e28 weeks,
386 had PPROM at 28e30 weeks, and 441
women had PPROM at 31e32 weeks.
Patients in the < 4 week latency group
had an earlier mean GA at rupture of
membranes than the
4 weeks latency
group (Table 1); additionally, these
women were more likely to be white
and receive multiple courses of steroids.

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OBSTETRICS

TABLE 3

Univariate analysis of demographic factors associated with neonatal sepsis

Sepsis
(n 253)

Factor

No sepsis
(n 1343)

P value

Age, y, mean (SD)

27.3 (5.9)

26.4 (5.8)

.04

Maternal age >35 y, n, %

31 (12.3)

143 (10.7)

.45

Race, n, %

.09

African-American

110 (43.5)

603 (44.9)

White

85 (33.6)

516 (38.4)

Hispanic

54 (21.3)

198 (14.7)

Asian

1 (0.4)

13 (1.0)

Native American/other

3 (1.2)

13 (1.0)

BMI, n, %

.18

Logistic regression was performed to

control for possible confounders. The
model included covariates known or
suspected to be associated with the primary outcome and covariates found to
signicantly differ in the univariate
analysis (Table 3). In the adjusted model,
PPROM
4 weeks retained signicance
and was associated with a decreased risk
of neonatal sepsis (adjusted odds ratio
[aOR], 0.21, 95% CI, 0.10e0.41)
(Table 4). The logistic regression model
also demonstrated that later GA at
rupture of membranes was associated
with decreased risk neonatal sepsis,
whereas Hispanic race was associated
with increased risk.

< 18.5

41 (16.2)

208 (15.5)

18.5e24.9

90 (35.6)

570 (42.4)

Comment

25e29.9

56 (22.1)

278 (20.7)

30

66 (26.1)

287 (21.4)

Nulliparous, n, %

90 (35.6)

455 (33.9)

.60

No prenatal care, n, %

13 (5.1)

107 (8.0)

.12

Tobacco use, n, %

61 (24.1)

406 (30.2)

.05

Drug use, n, %

20 (7.9)

148 (11.0)

.14

Alcohol use, n, %

23 (9.1)

136 (10.1)

.61

This analysis demonstrated that prolonged latency in the setting of PPROM

was associated with a decreased risk for
neonatal sepsis and that infants that are
delivered soon after PPROM are at
highest risk. We hypothesize that risk
associated with short latency may be due
to overt, clinical infection, resulting in a
higher probability of both neonatal
sepsis and preterm labor/short latency.
Our ndings are consistent with those
reported by Frenette et al10 and Melamed
et al,11 who found reduced prematurityrelated morbidity without an increase
in infectious maternal or neonatal
morbidity in patients with latency
7
days. In contrast, Gyam-Bannerman
and Son9 found that latency
14 days
was associated with an increased risk
of neonatal sepsis when controlling
for gestational age at delivery.
These differences may be explained by
the different criteria utilized for prolonged PPROM. Additionally, neonatal
sepsis was reported and discussed in
those analyses, but it was not modeled
as the primary outcome and therefore
may be less valid for addressing this
specic study question.
Other studies have assessed the effects
of prolonged latency. Walker et al14
found that PPROM > 28 days was
associated with increased mortality
and decreased likelihood of survival
without morbidity in all gestational age
subgroups in a large retrospective study;
however, sepsis was not specically

Magnesium exposure, n, %

117 (46.3)

661 (49.2)

.39

Multiple courses of steroids, n, %

5 (2.0)

51 (3.9)

.14

Maternal education, y, mean (SD)

12.0 (2.7)

11.9 (2.4)

.45

227 (89.7)

1253 (93.3)

.04

Treatment with antibiotics, n, %

Time from PPROM to delivery, d, median (IQD)

6.5 (3.4e12.1)

7.9 (3.4e17.2) < .01

Gestational age at PPROM, wks, mean (SD)

25.6 (2.2)

28.4 (3.0)

< .01

Gestational age at delivery, wks, mean (SD)

27.2 (2.2)

30.4 (2.9)

< .01

Patients received penicillin, ampicillin, or amoxicillin and a macrolide.

Drassinower et al. Prolonged PPROM and the risk of neonatal sepsis. Am J Obstet Gynecol 2016.

Women in the < 4 week latency group

were more likely to be African American
and use drugs. At delivery, patients with
latency
4 weeks delivered at higher
mean gestational ages and higher birthweights, whereas the rates of chorioamnionitis and cesarean delivery were
similar (Table 2).
In the unadjusted analysis for the primary outcome, patients in the PPROM

4 weeks group were signicantly less
likely to develop neonatal sepsis (6.8% vs
17.2%, risk ratio, 0.40, 95% condence
interval [CI], 0.24e0.66). Figure 1 plots
the proportion of neonatal sepsis by
weeks of latency among all infants that

developed sepsis and demonstrates that

neonatal sepsis is more likely to occur
among the women with shortest latency.
The median latency time in patients
with neonatal sepsis was 6.5 days
(interquartile range [IQR], 3.4e12.1)
compared with 7.9 days (IQR, 3.4e17.2)
in patients without neonatal sepsis (P <
.01). Furthermore, the risk for sepsis
decreased with each increased week of
latency.
Figure 2 plots the rate of neonatal
sepsis by week of latency and demonstrates that this rate is stable in the rst
3 weeks and then decreases in the
PPROM
4 weeks group (P < .01).

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TABLE 4

Multivariable model for factors associated with neonatal sepsis

Factor

Neonatal sepsis aOR (95% CI)

PPROM latency, wks

0

Referent

0.98 (0.67e1.44)

0.67 (0.39e1.14)

0.70 (0.35e1.41)

4

0.21 (0.10e0.41)c

Gestational age at rupture of membranesa

0.64 (0.60e0.69)c

Maternal age, ya

1.01 (0.98e1.04)

Nulliparous

1.04 (0.73e1.49)

Race
White

Referent

African American

0.98 (0.68e1.42)

Hispanic

1.95 (1.16e3.28)c

Asian

0.63 (0.07e5.46)

Native American/other

0.76 (0.15e3.98)

Exposed to magnesium

0.90 (0.66e1.23)
2

Body mass index, kg/m

< 18

1.09 (0.67e1.79)

18e24.9

Referent

25e30

1.08 (0.71e1.656)

> 30

1.06 (0.70e1.60)

No prenatal care

1.24 (0.62e2.48)

Drug use

0.91 (0.49e1.67)

Tobacco use

0.92 (0.61e1.38)

Multiple courses of steroids

0.45 (0.16e1.27)

Treatment with antibioticsb

0.80 (0.47e1.38)

Adjusted odds ratios (aOR) obtained using logistic regression.

a

Gestational age and maternal age are continuous variables. Other conditions are listed with the risk of the condition present
and the absence of the condition as the referent; b Patients received penicillin, ampicillin, or amoxicillin and a macrolide;
c
Statistically significant findings.
Drassinower et al. Prolonged PPROM and the risk of neonatal sepsis. Am J Obstet Gynecol 2016.

assessed. Manuck et al15 also studied the

effect of latency on perinatal outcomes
and found that gestational age and
neonatal sepsis were associated with
perinatal morbidity; however, latency
was not.
There is a wide variation in the rate
of neonatal sepsis reported in the literature, which is largely dependent on
the gestational age of delivery of the
population studied. Our ndings are
consistent with those reported in the

parent trial and other secondary analyses, which quote a rate of neonatal
sepsis of 16.2e17.2%.9,13 This is also
consistent with other studies with a
similar patient population.12
Several aspects of this analysis
enhance the validity of the ndings.
Whereas the sample size was limited by
the number of patients enrolled in the
parent randomized controlled trial, the
number of women with PPROM was
large and adequately powered to nd a

Original Research

relatively small difference in rate of the

primary outcomes. Although residual
confounding is a possibility in any
observational analysis, we controlled for
many measurable factors associated with
the outcomes in the regression analysis.
A possible limitation in the interpretation of these results is that the prolonged PPROM group had a greater
gestational age at delivery compared
with the shorter latency group. We could
not control for both gestational age at
PPROM and gestational age at delivery
in the multivariable analysis because
of the high correlation between these
2 variables.
The current recommended guidelines
in the treatment of PPROM includes
delivery at 34 weeks16; however, a
Cochrane metaanalysis concluded that
there is insufcient evidence to guide
clinical practice because all of the clinical
trials to date have had methodological
weaknesses or have been underpowered.17 Given that early gestational age at
delivery is associated with adverse
neonatal outcomes and prolonged latency does not increase the risk of
neonatal sepsis, our ndings support
expectant management for women  34
weeks with PPROM and prolonged
latency.
Our results also may be useful for
patient counseling and for future
research on the optimal timing of delivery in patients with PPROM. A theoretical concern with prolonging
pregnancy past 34 weeks in patients
with PPROM is the risk for maternal
and neonatal infection. Our ndings
suggest that in patients with PPROM,
time of latency does not increase the
risk of neonatal sepsis. Further research
is needed to establish the optimal
timing of delivery for this later gestational age cohort, taking into account
both the immediate- and long-term
outcomes.
In conclusion, we found that prolonged exposure to an intrauterine
environment of PPROM does not independently affect the risk of neonatal
sepsis. These ndings may be of importance in future clinical research on
PPROM and strategies regarding expectant management of PPROM.
n

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Acknowledgment
This work could not have been completed
without the assistance of the Eunice Kennedy
Shriver National Institute of Child Health and
Human Development, the Maternal-Fetal Medicine Units Network, and the study protocol
subcommittee.

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Author and article information

From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Columbia University
Medical Center, New York, NY.
Received Aug. 7, 2015; revised Nov. 14, 2015;
accepted Dec. 17, 2015.
The contents of this report represent the views of the
authors and do not represent the views of the Eunice
Kennedy Shriver National Institute of Child Health and
Human Development, Maternal-Fetal Medicine Units
Network, or the National Institutes of Health.
The authors report no conflict of interest.
The abstract was presented at the 35th annual
meeting of the Society for Maternal-Fetal Medicine, San
Diego, CA, Feb. 2e7, 2015.
Corresponding author: Daphnie Drassinower, MD.
daphniedrassinower@yahoo.com