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
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 rela-
tionship was retained in the multivariable model; patients with pro-
longed 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

P reterm premature rupture of

membranes (PPROM) is a com-
mon cause of spontaneous preterm
birth affecting approximately 3% of
pregnancies that is associated with sig-
nicant neonatal morbidity and mor-
tality, particularly when delivery occurs
at an early gestational age.1 The man-
agement approach to PPROM for
women < 34 weeks gestation includes
the administration of antibiotics to in-
crease latency and, to reduce risk from
prematurity, expectant management
until a fetal or maternal condition arises
that warrants delivery.2 At early gesta-
tional ages, the benets of expectant
management may outweigh risks, which
include placental abruption, umbilical
cord accident, and fetal demise2; how-
ever, there is a paucity of data on the
effects of prolonged latency of PPROM.
Cite this article as: Drassinower D, Friedman AM, Obi-
can 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
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 re-
ported to occur in 15e25% of preg-
nancies 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 infec-
tion.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 sup-
ported 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 pre-
vention of cerebral palsy, conducted
through the Eunice Kennedy Shriver Na-
tional Institute of Child Health and De-
velopments 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 ce-
rebral 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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Original Research OBSTETRICS ajog.org

6 days randomized to magnesium sulfate

TABLE 1
or placebo, 86.7% of women enrolled
Patient characteristics by interval between diagnosis of PPROM and delivery
had PPROM. Women were eligible if
they were at high risk for spontaneous < 4 wks
4 wks
preterm delivery because of the rupture Characteristic (n 1390) (n 206) P value
of membranes or because of advanced Age, y, mean (SD) 26.8 (5.8) 26.0 (5.7) .07
preterm labor with dilation of 4e8 cm
Advanced maternal age, n, % 155 (11.2) 19 (9.2) .41
and intact membranes; women were
excluded if delivery was anticipated Race, n, % < .01
within 2 hours. African-American 654 (47.1) 59 (28.6)
Antibiotic administration and criteria White 492 (35.4) 109 (52.9)
for delivery were not standardized as
Hispanic 216 (15.5) 36 (17.5)
part of the parent trial; however, in
accordance with the current recom- Asian 13 (0.9) 1 (0.5)
mended guidelines, antibiotics were Native American/other 15 (1.1) 1 (0.5)
routinely administered and expectant BMI, n, % .23
management was pursued until 34 weeks
< 18.5 219 (15.8) 30 (14.6)
unless a medical indication for deliv-
ery arose. Similarly, antenatal cortico- 18.5e24.9 562 (40.4) 98 (47.6)
steroid administration for fetal lung 25e29.9 299 (21.5) 35 (17.0)
maturity occurred routinely as part of
30 310 (22.3) 43 (20.9)
the current recommended guidelines.
Nulliparous, n, % 486 (35.0) 59 (28.6) .07
Multiple courses of antenatal cortico-
steroids was dened as > 2 courses. No prenatal care, n, % 109 (7.8) 11 (9.2) .20
The current study included non- Tobacco use, n, % 416 (29.9) 51 (24.8) .13
anomalous, live singleton pregnancies Drug use, n, % 156 (11.2) 12 (5.8) .02
with PPROM. The diagnosis of PPROM
Alcohol use, n, % 140 (10.1) 19 (9.2) .70
was based on at least 2 of the following
3 criteria being met: (1) pooling of am- Magnesium treatment group, n, % 675 (48.6) 103 (50.0) .70
niotic uid in the vaginal vault, (2) a Multiple courses of steroids, n, % 38 (2.8) 18 (8.9) < .01
positive nitrazine test, and (3) the ferning Treatment with antibiotics, n, % 1290 (92.8) 190 (92.2) .77
of vaginal uid. PPROM could also be
diagnosed if there was indigo carmine Maternal education, y, mean (SD) 11.9 (2.5) 12.1 (2.4) .29
pooling in the vagina after amnioinfusion Gestational age at PPROM, wks, mean (SD) 27.8 (2.6) 29.1 (5.2) < .01
or if visible leakage of amniotic uid Drassinower et al. Prolonged PPROM and the risk of neonatal sepsis. Am J Obstet Gynecol 2016.
from the cervix was noted. Patients with
missing outcome data were excluded.
The exposure of interest was pro- during the initial hospitalization and Patient demographic variables and
longed latency, which was dened as de- was not limited to a specic period of other characteristics were compared us-
livery
4 weeks after diagnosis of time after birth. ing the c2 test for categorical variables
PPROM. For analyses, latency was cate-
gorized by number of weeks: 0 (0e6 days), TABLE 2
1 (7e13 days), 2 (14e20 days), 3 (21e27 Univariate analysis of obstetric outcomes by PPROM latency interval
days), and
4 weeks (
28 days).
The primary outcome evaluated was < 4 wks
4 wks
neonatal sepsis, dened in the parent Outcome (n 1390) (n 206) P value
trial as proven sepsis in which blood, Neonatal sepsis, n, % 239 (17.2) 14 (6.8) < .01
cerebrospinal uid, and/or urine cul- Time from PPROM to delivery, d, median (IQR) 6.2 (3.0-11.9) 43.8 (33.9-59.0) < .01
tures were positive and infection was
Gestational age at delivery, wks, mean (SD) 29.3 (2.6) 33.4 (3.4) < .01
suspected on physical examination, or,
in the absence of positive cultures, there Birthweight, g, mean (SD) 1352 (462) 2095 (723) < .01
was evidence of hemodynamic collapse Chorioamnionitis, n, % 178 (12.8) 20 (9.7) .21
and X-ray ndings supporting infection Cesarean delivery, n, % 507 (36.5) 82 (39.8) .36
in a neonate with a clinical presentation
IQR, interquartile range.
consistent with sepsis. The diagnosis of Drassinower et al. Prolonged PPROM and the risk of neonatal sepsis. Am J Obstet Gynecol 2016.
neonatal sepsis could occur at any point

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ajog.org OBSTETRICS Original Research

and a Student t test for continuous var-

FIGURE 1
iables. A Wilcoxon rank sum test was
Proportion of neonatal sepsis by latency period
used to compare median differences. We
then t a logistic regression model to
control for the following possible con-
founders: 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 administra-
tion 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 us-
ing 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
Prolonged PPROM latency was associated with a decreased risk of neonatal sepsis. Figure plots the 9.4 (SAS Institute, Cary, NC).
proportion of neonatal sepsis by weeks of latency among all infants that developed sepsis. Among all Our sample size was xed by the
infants that developed sepsis, 133 cases (52.6%) occurred in the shortest PPROM latency group, number of patients enrolled in the initial
66 cases (26.1%) occurred in the 1 week latency group, 25 cases (9.9%) occurred in the 2 week randomized controlled trial and by our
latency group, 15 cases (5.9%) in the 3 week latency group, 5 (2%) in the 4 week latency group, exclusions. A power analysis based on
3 (1.2%) in the 5 and 6 week latency groups, 2 cases (0.8%) in the 7 week latency group, and 1 case the xed sample size revealed a mini-
(0.4%) in the
8 week latency group. A c2 test was used to compare all groups with the shortest mum detectable effect size for PPROM
latency group (P < .01) for all comparisons. latency
4 weeks of a < 0.6 or > 1.5 risk
PPROM, preterm premature rupture of membranes.
ratio for the primary outcome based on a
Drassinower et al. Prolonged PPROM and the risk of neonatal sepsis. Am J Obstet Gynecol 2016.
power of 80% and a type I error of 5%.

FIGURE 2 Results
Rate of neonatal sepsis by latency period Of the 2444 infants included in the
parent study, 2088 had PPROM; of these,
326 were excluded for multiple gesta-
tion, 100 for missing data, 58 for major
congenital anomalies, and 8 for still-
birth, 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
The rate of neonatal sepsis was stable weeks 0e3 of PPROM latency and decreased in the latency weeks, 611 had PPROM at 24e28 weeks,

4 weeks group. This figure plots the rate of neonatal sepsis by week of latency, which was 17.5% 386 had PPROM at 28e30 weeks, and 441
(133 cases) in the shortest PPROM latency group, 18.6% (66 cases) in the 1 week latency group, women had PPROM at 31e32 weeks.
13.6% (25 cases) in the 2 week latency group, 16.7% (15 cases) in the 3 week latency group, and 6.8%
Patients in the < 4 week latency group
(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 had an earlier mean GA at rupture of
but was P < .01 when the
4 week latency group was compared with the shortest latency group. membranes than the
4 weeks latency
PPROM, preterm premature rupture of membranes. group (Table 1); additionally, these
Drassinower et al. Prolonged PPROM and the risk of neonatal sepsis. Am J Obstet Gynecol 2016. women were more likely to be white
and receive multiple courses of steroids.

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Original Research OBSTETRICS ajog.org

Logistic regression was performed to

TABLE 3
control for possible confounders. The
Univariate analysis of demographic factors associated with neonatal sepsis
model included covariates known or
Sepsis No sepsis suspected to be associated with the pri-
Factor (n 253) (n 1343) P value mary outcome and covariates found to
Age, y, mean (SD) 27.3 (5.9) 26.4 (5.8) .04 signicantly differ in the univariate
analysis (Table 3). In the adjusted model,
Maternal age >35 y, n, % 31 (12.3) 143 (10.7) .45
PPROM
4 weeks retained signicance
Race, n, % .09 and was associated with a decreased risk
African-American 110 (43.5) 603 (44.9) of neonatal sepsis (adjusted odds ratio
White 85 (33.6) 516 (38.4) [aOR], 0.21, 95% CI, 0.10e0.41)
(Table 4). The logistic regression model
Hispanic 54 (21.3) 198 (14.7)
also demonstrated that later GA at
Asian 1 (0.4) 13 (1.0) rupture of membranes was associated
Native American/other 3 (1.2) 13 (1.0) with decreased risk neonatal sepsis,
BMI, n, % .18 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) This analysis demonstrated that pro-

30 66 (26.1) 287 (21.4) longed latency in the setting of PPROM
was associated with a decreased risk for
Nulliparous, n, % 90 (35.6) 455 (33.9) .60
neonatal sepsis and that infants that are
No prenatal care, n, % 13 (5.1) 107 (8.0) .12 delivered soon after PPROM are at
Tobacco use, n, % 61 (24.1) 406 (30.2) .05 highest risk. We hypothesize that risk
Drug use, n, % 20 (7.9) 148 (11.0) .14 associated with short latency may be due
to overt, clinical infection, resulting in a
Alcohol use, n, % 23 (9.1) 136 (10.1) .61
higher probability of both neonatal
Magnesium exposure, n, % 117 (46.3) 661 (49.2) .39 sepsis and preterm labor/short latency.
Multiple courses of steroids, n, % 5 (2.0) 51 (3.9) .14 Our ndings are consistent with those
Maternal education, y, mean (SD) 12.0 (2.7) 11.9 (2.4) .45
reported by Frenette et al10 and Melamed
a
et al,11 who found reduced prematurity-
Treatment with antibiotics, n, % 227 (89.7) 1253 (93.3) .04 related morbidity without an increase
Time from PPROM to delivery, d, median (IQD) 6.5 (3.4e12.1) 7.9 (3.4e17.2) < .01 in infectious maternal or neonatal
Gestational age at PPROM, wks, mean (SD) 25.6 (2.2) 28.4 (3.0) < .01 morbidity in patients with latency
7
days. In contrast, Gyam-Bannerman
Gestational age at delivery, wks, mean (SD) 27.2 (2.2) 30.4 (2.9) < .01
a
and Son9 found that latency
14 days
Patients received penicillin, ampicillin, or amoxicillin and a macrolide.
was associated with an increased risk
Drassinower et al. Prolonged PPROM and the risk of neonatal sepsis. Am J Obstet Gynecol 2016.
of neonatal sepsis when controlling
for gestational age at delivery.
Women in the < 4 week latency group developed sepsis and demonstrates that These differences may be explained by
were more likely to be African American neonatal sepsis is more likely to occur the different criteria utilized for pro-
and use drugs. At delivery, patients with among the women with shortest latency. longed PPROM. Additionally, neonatal
latency
4 weeks delivered at higher The median latency time in patients sepsis was reported and discussed in
mean gestational ages and higher birth- with neonatal sepsis was 6.5 days those analyses, but it was not modeled
weights, whereas the rates of cho- (interquartile range [IQR], 3.4e12.1) as the primary outcome and therefore
rioamnionitis and cesarean delivery were compared with 7.9 days (IQR, 3.4e17.2) may be less valid for addressing this
similar (Table 2). in patients without neonatal sepsis (P < specic study question.
In the unadjusted analysis for the pri- .01). Furthermore, the risk for sepsis Other studies have assessed the effects
mary outcome, patients in the PPROM
decreased with each increased week of of prolonged latency. Walker et al14
4 weeks group were signicantly less latency. found that PPROM > 28 days was
likely to develop neonatal sepsis (6.8% vs Figure 2 plots the rate of neonatal associated with increased mortality
17.2%, risk ratio, 0.40, 95% condence sepsis by week of latency and demon- and decreased likelihood of survival
interval [CI], 0.24e0.66). Figure 1 plots strates that this rate is stable in the rst without morbidity in all gestational age
the proportion of neonatal sepsis by 3 weeks and then decreases in the subgroups in a large retrospective study;
weeks of latency among all infants that PPROM
4 weeks group (P < .01). however, sepsis was not specically

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ajog.org OBSTETRICS Original Research

relatively small difference in rate of the

TABLE 4
primary outcomes. Although residual
Multivariable model for factors associated with neonatal sepsis
confounding is a possibility in any
Factor Neonatal sepsis aOR (95% CI) observational analysis, we controlled for
PPROM latency, wks many measurable factors associated with
the outcomes in the regression analysis.
0 Referent
A possible limitation in the interpre-
1 0.98 (0.67e1.44) tation of these results is that the pro-
2 0.67 (0.39e1.14) longed PPROM group had a greater
3 0.70 (0.35e1.41) gestational age at delivery compared
with the shorter latency group. We could

4 0.21 (0.10e0.41)c
not control for both gestational age at
Gestational age at rupture of membranesa 0.64 (0.60e0.69)c PPROM and gestational age at delivery
Maternal age, ya 1.01 (0.98e1.04) in the multivariable analysis because
of the high correlation between these
Nulliparous 1.04 (0.73e1.49)
2 variables.
Race The current recommended guidelines
White Referent in the treatment of PPROM includes
African American 0.98 (0.68e1.42) delivery at 34 weeks16; however, a
Cochrane metaanalysis concluded that
Hispanic 1.95 (1.16e3.28)c
there is insufcient evidence to guide
Asian 0.63 (0.07e5.46) clinical practice because all of the clinical
Native American/other 0.76 (0.15e3.98) trials to date have had methodological
Exposed to magnesium 0.90 (0.66e1.23) weaknesses or have been underpow-
2 ered.17 Given that early gestational age at
Body mass index, kg/m
delivery is associated with adverse
< 18 1.09 (0.67e1.79) neonatal outcomes and prolonged la-
18e24.9 Referent tency does not increase the risk of
25e30 1.08 (0.71e1.656) neonatal sepsis, our ndings support
expectant management for women  34
> 30 1.06 (0.70e1.60)
weeks with PPROM and prolonged
No prenatal care 1.24 (0.62e2.48) latency.
Drug use 0.91 (0.49e1.67) Our results also may be useful for
Tobacco use 0.92 (0.61e1.38) patient counseling and for future
research on the optimal timing of de-
Multiple courses of steroids 0.45 (0.16e1.27)
livery in patients with PPROM. A theo-
Treatment with antibioticsb 0.80 (0.47e1.38) retical concern with prolonging
Adjusted odds ratios (aOR) obtained using logistic regression. pregnancy past 34 weeks in patients
a
Gestational age and maternal age are continuous variables. Other conditions are listed with the risk of the condition present with PPROM is the risk for maternal
and the absence of the condition as the referent; b Patients received penicillin, ampicillin, or amoxicillin and a macrolide;
c
Statistically significant findings.
and neonatal infection. Our ndings
Drassinower et al. Prolonged PPROM and the risk of neonatal sepsis. Am J Obstet Gynecol 2016. 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
assessed. Manuck et al15 also studied the parent trial and other secondary ana- timing of delivery for this later gesta-
effect of latency on perinatal outcomes lyses, which quote a rate of neonatal tional age cohort, taking into account
and found that gestational age and sepsis of 16.2e17.2%.9,13 This is also both the immediate- and long-term
neonatal sepsis were associated with consistent with other studies with a outcomes.
perinatal morbidity; however, latency similar patient population.12 In conclusion, we found that pro-
was not. Several aspects of this analysis longed exposure to an intrauterine
There is a wide variation in the rate enhance the validity of the ndings. environment of PPROM does not inde-
of neonatal sepsis reported in the litera- Whereas the sample size was limited by pendently affect the risk of neonatal
ture, which is largely dependent on the number of patients enrolled in the sepsis. These ndings may be of impor-
the gestational age of delivery of the parent randomized controlled trial, the tance in future clinical research on
population studied. Our ndings are number of women with PPROM was PPROM and strategies regarding expec-
consistent with those reported in the large and adequately powered to nd a tant management of PPROM. n

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Original Research OBSTETRICS
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 Medi-
cine Units Network, and the study protocol
subcommittee.
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Author and article information
From the Division of Maternal-Fetal Medicine, Depart-
ment 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