J. Perinat. Med.

2017; aop

Verena Kiver*, Vinzenz Boos, Anke Thomas, Wolfgang Henrich and Alexander Weichert

Perinatal outcomes after previable preterm

premature rupture of membranes before
24weeksof gestation
https://doi.org/10.1515/jpm-2016-0341 Keywords: Anhydramnios; hypoplasia; intraamniotic
Received October 25, 2016. Accepted July 11, 2017. infection; preterm; previable; PROM; pulmonary.
Abstract

Objective: A current descriptive assessment of perina-

tal outcomes in pregnancies complicated by previable
Introduction
preterm premature rupture of membranes (pPPROM) at
Previable preterm premature rupture of membranes
<24weeks of gestation, after expectant treatment.
(pPPROM) occurring before a gestational age (GA) of
Study design: Maternal and short-term neonatal data
24weeks (24+0) presents a medical dilemma and a psy-
were collected for patients with pPPROM.
chological burden for both patients and physicians. As
Results: Seventy-three patients with 93 fetuses were
this complication occurs in less than 1% of all pregnan-
hospitalized with pPPROM at 1524 weeks gestation.
cies [1], only limited data are available and there are no
Among these patients, 27.4% (n=20) chose pregnancy
evidence-based guidelines for pPPROM treatment.
termination, 27.4% (n=20) miscarried and 45.2% (n=33)
In the last three decades, the reported outcomes of
proceeded to live births. After a median latency period
perinatal survival after pPPROM steadily increased due to
of 38days, ranging from 1 to 126days, 24singletons and
much improved neonatal care and the increasing neona-
20 multiples were live-born, of whom 79.5% (n=35) sur-
tal survival rates at a decreasing GA at birth.
vived the perinatal period. The main neonatal sequelae
But up until now the reported overall survival
were pulmonary hypoplasia (29.5%; n=13), connatal
rates are around 50% and the neonatal survival rates
infection (56.8%; n=25), intraventricular hemorrhage
around 70%.
(25%; n=11; resulting in five neonatal deaths) and Pot-
In 1988, Beydoun and Yasin [2] reported survival
ters syndrome (15.9%; n=7). Nine newborns died, within
rates as low as 0% for infants born before 25 weeks of
an average of 2.8days (range, 110days). The overall neo-
gestation (n=22). A later report by Dowd and Permezel
natal survival rate was 51.5% including miscarriages
[3] in 1992 demonstrated survival rates of 12.5% when
but not elective terminations. The intact survival rate was
pPPROM occurred before 24 gestational weeks. In 2016,
45.5% of all live-born neonates.
Linehan et al. [4] reported a 95% perinatal mortality
Conclusions: Even with limited treatment options, overall
rate, with perinatal deaths occurring in 40 out of 42
neonatal survival is increasing. However, neonatal mortal-
pregnancies.
ity and morbidity rates remain high. The gestational age at
Other recent data illustrate a rising perinatal survival
membrane rupture does not predict neonatal outcome.
rate with expectant treatment and a prolonged latent
period. Margato etal. [5] found a 53% overall survival rate
and 72.7% neonatal survival rate among 15 patients with
pPPROM at 2024 weeks of gestation. Similarly, Everest
etal. [6] reported a 70% neonatal survival rate (n=28) in
*Corresponding author: Verena Kiver, Department of Obstetrics,
Charit Universittsmedizin Berlin, Charit Campus Mitte, 40 live-born after pPPROM before 24weeks. Newman etal.
Charitplatz 1, 10117 Berlin, Germany, Tel.: +49 (030) 450 664487, [7] reported a postpartum mortality rate of 28% (n=126)
E-mail: verena.kiver@charite.de. among newborns delivered between 24 and 27 weeks of
http://orcid.org/0000-0002-1356-9576 gestation with pPPROM.
Vinzenz Boos: Department of Neonatology, Charit
While the survival of extremely premature newborns
Universittsmedizin Berlin, Berlin, Germany
Anke Thomas, Wolfgang Henrich and Alexander Weichert: used to be highly unlikely, survival is now possible even
Department of Obstetrics, Charit Universittsmedizin Berlin, among some neonates born before 24 gestational weeks.
Berlin, Germany This is largely due to the use of peripartum antibiotic

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2Kiver etal., Perinatal outcomes after pPPROM
treatment and administration of corticosteroids to advance
lung maturity [8, 9].
When presenting this data to patients not only the
low survival chances but also the severe consequences for
the child, should it survive, must be presented. In 1993,
there was an estimated 63% chance of intact survival
after pPPROM [10]. Intact survival is usually defined as
survival without intraventricular hemorrhage (IVH) III
or IV, necrotizing enterocolitis (NEC) or retinopathy of
prematurity (ROP) requiring surgery. Although intact sur-
vival rates may be improving with increased neonatal care
standards, no current data have been reported.
According to the current data available the chances
of a child not only surviving but surviving without major
disability seem to be around 30% of all pregnancies.
Emphasis should be put on the main complications
of long-standing pPPROM: early-onset sepsis and pulmo-
nary hypoplasia (PH). This can negatively augment the
severe sequelae of prematurity, such as IVH, periventricu-
lar leukomalacia, NEC, ROP and bronchopulmonary dys-
plasia (BPD) [1113].
In clinical practice, it often seems that patients believe
the main goal of treatment is the survival of the unborn
child. Thus, it is imperative to be very clear about the
long duration of neonatal treatment and life-long conse-
quences should the pregnancy result in a surviving infant.
Up-to-date expectant management now includes pro-
phylactic treatment with antibiotics [14, 15] and in-patient
care. The rationale for antibiotic prophylaxis is that
infection appears to be both a cause and consequence of
PPROM. Infection may lead to spontaneous preterm labor
or may be the indication for medically-indicated preterm
delivery. The goal of antibiotic therapy is to reduce the fre-
quency of maternal and fetal infection and thereby delay
the onset of preterm labor (i.e. prolong latency) and the
need for preterm delivery [16].
In 2009, Waters and Mercer [17] evaluated and sum-
marized the available data and developed a management
algorithm. We applied a similar algorithm in our present
study (Figure 1).
Following the initial diagnosis, a patient must decide
whether to continue or terminate the pregnancy [18, 19].
When continuing the pregnancy, the medical challenge
is to prolong the latent period and promote the best pos-
sible neonatal outcome. Unfortunately, so far, no clinical
data has been established to reliably predict pregnancy
outcome at the time of initial diagnosis. An article recently
published by Cobo et al. [20] reported that the amount
of amniotic fluid at diagnosis, 1 week and 2 weeks after
pPPROM might be predictive of perinatal mortality, with
the largest vertical pocket being <1cm.
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With the aim of preventing intraamniotic infection
(IAI) and prolong latent period [21] the patient receives
a calculated antibiotic treatment in our department with
cefuroxime and metronidazole. Any pathogens discovered
in cervical swaps are treated according to antibiogram.
When approaching viability, i.e. 23+5weeks GA, lung
maturity is induced with corticosteroids. In selected cases
lung maturity was already induced between 22+5 and
23+4weeks of gestation. This was due to the imperative
wish of the parents after extensive counseling.
Prolonging the pregnancy up to 34 gestational weeks
reportedly improves neurological outcomes of neonates
after pPPROM [22]. However, neurological outcome is also
greatly influenced by early-onset sepsis [11, 12]. Thus, it is
desirable to prolong the pregnancy for as long as possible,
but also to deliver at the first signs of IAI.
The decision when to deliver is another major diffi-
culty for treating clinicians. The first signs of IAI can be
subtle and the laboratory markers do not always corre-
late with the clinical symptoms or the infection status of
the neonate. Some propose (repeated) amniocentesis to
exclude IAI [23], but as some IAI develops within hours,
clinical decisions in acute situations cannot be based on
amniotic fluid cultures.
The major risk factors of prolonging the latent period
for the mother can be severe endometritis and even sepsis
due to IAI, massive bleeding due to placental abruption or
uterine atony and deep vein thrombosis during modified
bed rest.
In the present study, we aimed to perform an updated
assessment of the outcomes of pregnancies with pPPROM
occurring before 24 gestational weeks and treated with the
highest level of perinatal care. We primarily analyzed data
concerning survival rate and short-term neonatal out-
comes up to first discharge. To our knowledge, this study
is among the largest analyses of the outcomes of pregnan-
cies affected by pPPROM in the last decade. Our present
findings will promote an improved understanding of sur-
vival rates, and will aid in the perinatal decision-making
process.
Materials and methods
The Charit Universittsmedizin Berlin, Campus Charit Mitte is
an university perinatal center and tertiary care referral hospital that
provides the entire spectrum of perinatal care, and performs approxi-
mately 1700 deliveries annually. For this retrospective analysis, we
reviewed the labor records from the Department of Obstetrics from
January 2010 to March 2016. We identified 73 cases of pPPROM occur-
ring before 24 weeks (24+0) GA, and these patients were included
for further analysis. Our analysis included women who opted for
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 Kiver etal., Perinatal outcomes after pPPROM3

Diagnosis confirmed by PAMP-1 test

Ultrasound for gestational age, growth and anomalies

Cervical cultures, group B streptococcus cultures

Counsel

Wait and see approach Termination of pregnancy

Broad spectrum antibiotics for latency
Modified bed rest
Monitoring for infection, labor,
abruption

Induction with oxytocin,

Amnionitis,
PEG2 or misoprostol
Fetal death
Abruption
Advanced labor

Serial ultrasound evaluation for Re-counsel

amniotic fluid (re-)accumulation and
growth of chest circumference

At limit of viability induction of lung

maturity with antenatal corticosteroids

Serial evaluation for amnionitis, labor,

abruptio, fetal well-being and growth

Deliver for amnionitis, non-reassuring

fetal testing, abruption, labor.
Deliver at 34 weeks if stable until then

Figure 1:Management algorithm for previable preterm premature rupture of membranes.

Modified according to Waters and Mercer [17].

termination of pregnancy (TOP), and patients with multiple pregnan-
cies. We excluded patients presenting with pPPROM and intrauterine
fetal demise (IUFD), brisk vaginal bleeding, and/or labor uncontrol-
lable by tocolytics, as well as cases that followed iatrogenic rupture
of membranes, i.e. following amniocentesis.
This study was approved by the institutional Ethical Committee.
Data were collected from obstetric charts, ultrasonographic
records and laboratory results. We also reviewed hospital records
concerning the morbidity and mortality of live-born children. Diag-
nosis of pPPROM was based on history and was confirmed with a

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4Kiver etal., Perinatal outcomes after pPPROM
positive placental alpha microglobulin-1 (PAMG-I) protein marker test
(Amnisure; QIAGEN Sciences, AmniSure GMBH, Gieen, Germany)
and/or ultrasonographic evaluation confirming oligohydramnios or
anhydramnios. In case of a primarily negative PAMG-I test but clini-
cal and ultrasonographic signs of pPPROM, the patient was put on
bed rest and the Amnisure repeated. The patient was included in our
study if the test showed to be positive for amniotic fluid leakage. In
four cases, the time of rupture of membranes occurred at home and
the patient could not name an exact date (max. range 3days), so we
selected the latest possible date. In cases of referral from a different
hospital, our analysis included the treatment provided prior to the
patients arrival at our department and information obtained from
referral letters.
All women received extensive counseling with an interdiscipli-
nary team including obstetricians, maternal-fetal medicine (MFM)
sub-specialists, neonatologists and psychologists. The patients also
underwent laboratory testing and ultrasound examinations per-
formed by ultrasound specialists who held level II or III certifications
from the German association for medical ultrasound (DEGUM). After
the required testing, the women decided on their course of action:
to terminate or continue the pregnancy. The German criminal code
(Section 218) states that it is legal to terminate a pregnancy after
12 weeks of gestation if the mothers mental or physical health is
threatened [24]. TOP was advised later along the course of pregnancy
in cases showing signs of severe feto-maternal infection before via-
bility (which were counted as spontaneous miscarriages in our analy-
ses). Otherwise, patients were free to decide whether to continue the
pregnancy. After extensive counseling, patients who felt unable to
continue the pregnancy, could choose TOP.
Women who chose to continue their pregnancy received in-
patient care including modified bed rest, and administration of
antibiotics and tocolytics. Patients were monitored by daily measure-
ments of blood pressure and body temperature, as well as regular
(at least twice weekly) laboratory measurements of C-reactive protein
(CRP) and leukocytes. Fetal well-being was monitored by ultrasono-
graphic examinations and daily non-stress tests (NST). The women
also received regular vaginal and cervical swabs to check for signs
of cervicitis and any bacterial or fungal growth. All patients were
tested for hepatitis B, HIV, syphilis and chlamydia in accordance with
German maternity guidelines [25], as well as for cytomegalovirus.
The antibiotics regimen began with 7days of intravenous cefuro-
xime and metronidazole, which were prophylactically administered
to all patients at admission. The antibiotic regime was recently
changed to only cefuroxime, but the included cases still received
both antibiotics.
In cases of cervical infection, the causative agent was treated
according to antibiogram. Antibiotics were discontinued after deliv-
ery and patients with cesarean sections or curettage in case of incom-
plete placenta received a single shot cefuroxime i.v. during surgery.
One patient was given a second antibiotic treatment with ampicillin
and sulbactam when inflammatory markers were rising before via-
bility (22+1weeks GA) due to her explicit wish and against hospital
protocol.
All patients also received antithrombotic prophylaxis with low-
molecular-weight heparins.
In the absence of overt signs of infection, tocolytics were admin-
istered to enable the use of corticosteroids to promote lung maturity
or to reach viability for maximum 48h, and no repeated courses were
given [26]. Otherwise, tocolytics were not used to inhibit contrac-
tions, due to the risk of potentially masking the first symptoms of IAI
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[27]. For tocolysis, nifedipine was administered orally or fenoterol as
a bolus-tocolysis. In cases of multiple gestations, atosiban was used
as a bolus-tocolysis. Starting at a GA of 23+5, all patients received
intramuscular administration of 12mg betamethasone on 2 consecu-
tive days to induce lung maturity [28].
If labor could not be controlled by tocolytics before viability,
in cases showing signs of severe infection, or when IUFD occurred,
labor could progress to a spontaneous pregnancy loss or labor was
promoted using prostaglandins and/or oxytocin.
Active intervention was previously only possible after
24+0 weeks of gestation. However, since 2015, women have been
granted the possibility of active intervention after 22weeks of gesta-
tion, following extensive counseling, and due to their explicit wish,
as supported by Rysavy etal. [29].
Delivery of the child followed one of the following criteria: (1)
clinical signs of infection (e.g. maternal fever, malaise, malodor-
ous or putrid vaginal discharge, or uterine tenderness); (2) a rapid
increase in inflammatory laboratory values (CRP and leukocyte
count) not responsive to antibiotic treatment; (3) signs of fetal dis-
tress (e.g. pathological NST or abnormal fetal Doppler findings);
(4) or labor progression (only inhibited by tocolytics during induc-
tion of lung maturity without signs of infection). All newborns were
admitted to the neonatal intensive care unit. Newborns were treated
by experienced consultant neonatologists and following the latest
standard of care. Outcome measures included live birth, neonatal
morbidity, and (intact survival without IVH III or IV, NEC, ROP
requiring surgery, or hospital discharge with oxygen therapy) sur-
vival of the neonatal period.
Variables were described using means and standard deviations
for continuous variables, or frequencies and percentages for categor-
ical variables. Group comparisons were performed using the t-test,
2-test, Mann-Whitney U-test, or Fishers exact test. For correlations
Pearsonss correlation coefficients were calculated. Comparisons
were also made using analysis of variance (ANOVA) and post-hoc
analysis for estimation of P-values. P-values of less than 0.05 were
considered statistically significant. Statistical analyses were per-
formed using IBM SPSS Statistics for Windows, Version 24.0 (IBM
Corp., Armonk, NY, USA).
Results
Between January 2010 and March 2016, pPPROM
occurred before 24weeks of gestation in 73 pregnancies
with 93 fetuses. The overall median GA at pPPROM was
19+6 (range, 15+0 to 23+5). Tables 1 and 2 presents all
patient data, and Figure 2 summarizes the outcomes in
this study population. Among the 73 pregnant women,
27.4% (n=20, including three twin pregnancies) opted for
TOP, while 72.6% (n=53) elected to continue their preg-
nancy. A total of 33 patients (45.2% of all patients, 62.3%
of the patients choosing to continue their pregnancy)
proceeded to give birth to a live infant, while 20 patients
(27.4%) experienced a miscarriage (n=19) or IUFD (n=1).
The median GA at the time of the delivery was 22+4
(range, 16+2 to 34+0).
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 Kiver etal., Perinatal outcomes after pPPROM5

Table 1:Overall patient data.

All patients Proceeding to live birth Spontaneous miscarriage Termination of pregnancy

Patients (n) 73 33 20 20
Singleton gestations (n) 55 24 14 17
Multiple gestations, n gestation/n 17/38 (23.3%) 9/20 (27.3%) 6/12 (30%) 3/6 (15%)
fetuses (percentage pregnancies)
Maternal age in years, mean (range) 31.6 (2145) 31 (2145) 32.5 (2342) 31.5 (2141)
Median gravidity, n (range) 2 (19) 2 (15) 2 (19) 2 (16)
Median parity, n (range) 1 (05) 1 (05) 0 (03) 1 (02)
Prior miscarriage, n (percentage) 11 (15.11%) 4 (12.1%) 3 (15%) 5 (25%)

Table 2:Comparison of gestational weeks at pPPROM and birth.

Proceeding to live birth Spontaneous miscarriage

Weeks GA at pPPROM, median (range) 21+4 (15+0 to 23+5) 18+2 (16+0 to 22+4)
Singleton gestations, median (range) 21+4 (15+0 to 23+5) 18+2 (16+0 to 22+4)
Multiple gestations, median (range) 22+2 (16+0 to 23+3) 19+5 (15+6 to 21+6)
Weeks GA at end of pregnancy/delivery, median (range) 25+3 (22+0 to 34+0) 20+5 (16+1 to 24+2)
Singleton gestations, median (range) 26+0 (22+6 to 32+6) 20+5 (17+1 to 24+2)
Multiple gestations, median (range) 27+5 (22+4 to 34+0) 20+6 (17+1 to 22+2)
Latency period, median (range) 38 (1126) 2.5 (040)
Singleton gestations, median (range) 37 (1114) 7 (040)
Multiple gestations, median (range) 38 (2126) 1.5 (031)

GA=Gestational age, pPPROM=previable preterm premature rupture of membranes.

Termination of
pregnancy (n = 20)
27.4%
Patients with
pPPROM Spontaneous miscarriage
(n = 73) (n = 20) 27.4%

Expectant
management Surviving infant
(n = 53) 72.6% (n = 35) 79.5%
Delivery of a life infant
(npregnancy = 33) 45.2%
(ninfant = 44)

Neonatal demise
(n = 9) 20.5%

Figure 2:Overview of patient outcome.

The choice of TOP was made a median of 4 days
(5.8 days) after pPPROM. Post-hoc analysis (Sidak)
revealed that the GA at which pPPROM occurred in women
who opted for TOP significantly differed from that among
patients who gave birth to a live infant (P=0.006), but
not from the GA at pPPROM among patients who suffered
from a spontaneous miscarriage (P=0.733). A previous
miscarriage in the second trimester or at least two mis-
carriages in the first trimester was noted in the medical
history of 12.1% (n=4) of patients who proceeded to live-
birth, 15% (n=3) of patients who suffered a miscarriage
in this pregnancy, and 25% (n=5) of patients who chose
pregnancy termination.
A total of 20 patients (14 singleton and six twin
pregnancies) miscarried after a median of 2.5 days after
pPPROM (11.5days; range, 040days). One of the mis-
carriage was a IUFD in 24+2 weeks GA after a rapidly
ascending infection and consecutive partial placental
abruption. The median GA at pPPROM in this group was
18+2 (range, 16+0 to 22+4), which did not significantly
differ from the GA at pPPROM among patients who pro-
ceeded to a live birth (P=0.092; post-hoc analysis, Sidak).

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6Kiver etal., Perinatal outcomes after pPPROM
Table 3:Outcome compared by gestational age at pPPROM.
TpPPROM <18weeks GA
Continued pregnancies (% of all patients)
Proceeding to live birth (% of all continued pregnancies)
Surviving infants
Non-surviving infants
TpPPROM=Time of membrane rupture, GA=gestational age.
The GA at pPPROM was categorized into three
groups: Group 1, pPPROM before 18+0; Group 2, pPPROM
between 18+0 and 21+6; and Group 3, pPPROM between
22+0 and 23+4 (Table 3). Group 1 included 21 patients, of
whom 13 chose to continue the pregnancy. Seven of these
pregnancies proceeded to a live birth (53.8%), includ-
ing two twin pregnancies. Of the nine infants born to
this group, eight survived (88.9%). Group 2 included 31
patients, of whom 20 chose to continue the pregnancy.
Nine (45%) of them proceeded to a live birth, including
one twin pregnancy. Of the 10 infants born to this group,
nine survived (90%). Group 3 included 21 patients, 20 of
whom chose to continue the pregnancy. Seventeen (85%)
of these pregnancies proceeded to a live birth, including
two triplet pregnancies and four twin pregnancies. Of the
25 infants born to this group, 18survived (72%). The rates
of women suffering a miscarriage significantly differed
between groups 2 and 3 (P=0.019, Fishers exact test), but
not between groups 1 and 2 (P=0.728) or between groups
1 and 3 (P=0.107).
Comparing the inflammatory markers at admission
and at time of miscarriage or delivery did not yield rep-
resentable results due to the substantially different latent
periods. There was a statistically significant difference
between the CRP (P=0.028) but not between the leukocyte
counts (P=0.1).
A CRP>5mg/L or leukocyte count above 10,000/L at
the time of delivery did not correlate with connatal infec-
tion of the newborn (P=0.150 and P=0.156), respectively.
Among the 33 patients who gave birth to a live infant,
only seven (21.2%) delivered vaginally. The remaining
infants were delivered by cesarean section. The most
common indications for delivery were IAI indicated by
rising inflammatory markers, labor progression, or a path-
ological NST. In most cases, these factors occurred simul-
taneously. In two cases an emergency cesarean section
was performed due to the urgent suspicion of placental
abruption.
In the gray area at the limits of viability between 22+0
and 23+6weeks of gestation the patients were counseled
comprehensively by neonatologists. In accordance with
explicit parental wishes and due to signs of life at birth,
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TpPPROM <22weeks GA TpPPROM <24weeks GA
12 (57.1%) 18 (58.1%) 19 (90.4%)
7 (53.8%) 9 (45%) 17 (85%)
8 (88.9%) 9 (90.0%) 18 (72.0%)
1 1 7
extensive neonatal care was administered in seven cases
with nine neonates.
One birth occurred at 22+0 weeks GA, the neonate
was resuscitated and released into ambulatory care after
7 months in the neonatal intensive care unit with home
oxygen therapy, after suffering a bilateral IVH I, NEC
requiring surgery and bilateral ROP IV requiring surgery.
Five singletons were born between 22+6 and 23+6weeks
GA after receiving induction of lung maturity. Three of
them were released as intact survivals, one with a ROP
IV requiring surgery and one being released with home
oxygen treatment and ROP IV.
Triplets born at 22+4 weeks of gestation deceased
after 1, 3 and 10days, respectively.
Among patients who proceeded to a live delivery, the
median GA at pPPROM was 22+1 (19.2days; range, 15+0
to 23+5), the median GA at delivery was 25+3 (20.7days;
range, 22+0 to 34+0), and the median latency period
was 38 days (31.5 days; range, 1126 days). The GA at
pPPROM, GA at birth, and latency period did not signifi-
cantly differ for singletons vs. twins vs. triplets (ANOVA).
We conducted a one-sided t-test for time of birth, with
H0 being that the survival rates would be higher among
infants born at a higher GA compared to infants born at
an earlier GA. The results showed a significant difference
between surviving and non-surviving infants (P=0.0495).
Excluding patients who opted for TOP, and includ-
ing pregnancies that ended in miscarriage, the overall
fetus survival rate was 51.5%. Among the live-born infants
(n=44), the survival rate was 79.5% (n=35).
Maternal sequelae like deep vein thrombosis or sepsis
did not occur in our population. In 11 cases the patients
showed signs of intrauterine infection and had fever. They
were given antibiotics for 37days i.v. or orally to prevent
postpartum endometritis or sepsis. In one case antibiot-
ics were given as a preemptive measurement in an emer-
gency cesarean section, where sterile conditions could
not be guaranteed. One patient had a wound infection
of the cesarean section and was treated with i.v. antibi-
otics 3days postpartum. An increased blood loss of over
1000mL occurred in two patients during and after cesar-
ean section of twins and in one case after spontaneous
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 Kiver etal., Perinatal outcomes after pPPROM7

Table 4:Neonatal morbidity and mortality.

n GA at pPPROM GA at birth Lateny Perinatal IVH Pulmonary BPD

(weeks) (weeks) period (days) infection hypoplasia

Life born infants 44 22+1 26+1 38 25 (57%) 10 (23%) 13 (30%) 21 (48%)

Multiples 20 (47.6%) 22+2 27+5 38 13 (65%) 4 (20%) 6 (30%) 6 (30%)
Surviving 35 (79.5%) 22+0 26+3 39 19 (54%) 7 (20%) 7 (20%) 21 (60)
Non-surviving 9 (21.4%) 22+9 26+1 38 5 (55%) 4 (44%) 6 (66%)

GA=Gestational age, IVH=intraventricular hemorrhage, BPD=bronchopulmonary dysplasia.

miscarriage and placental retention in a patient with a
medical history of curettage and placenta accreta. Neither
patient required a blood transfusion.
Table 4 presents the overall neonatal data. Among the
44 live-born infants (24 singletons, 14 twins, and six tri-
plets), nine died within the perinatal period (two singletons,
three triplets, and four twins). Time of pPPROM (P=0.471),
time of birth (P=0.099), and latency period (P=0.138) did
not significantly differ for surviving infants vs. cases of
fetal demise (ANOVA). Moreover, Fishers exact test did not
reveal any significant difference in survival rates among the
three groups of GA at pPPROM. Survival rates did not signif-
icantly differ between female and male neonates. Sixteen
(36.4%) of the live-born infants were female, of whom six
were from multiple gestations and three died.
Multiple gestations accounted for 27.3% (n=9) in the
group giving live birth and 30% (n=6) among patients
having a miscarriage.
There was no statistical difference for multiple gesta-
tions proceeding to a live birth or a miscarriage (OR, 1.143;
P=0.416, 2-test). The nine multiple gestations included
two triplet pregnancies, both of which proceeded to live
births. One triplet set was born at a GA of 22+4, and the
neonates died during the neonatal period. The other
triplet set was born at a GA of 26+4, and the neonates sur-
vived. Our analysis included seven twin pregnancies. One
pair was born at a GA of 27+5, 38days after pPPROM, and
both neonates died. Another set of twins had rupture of
membranes confirmed by ultrasound at different GAs. For
twin B, pPPROM occurred at a GA of 16+4, while for twin
A pPPROM occurred at a GA of 22+3. The twins were born
in 28+0 weeks GA. Twin A died of infection on the first
day of life while twin B survived.
The survival rate of singletons was 91.6% compared
to a survival rate of 65% for infants from multiple gesta-
tions. There was a statistical difference between the sur-
vival rates for singletons and multiples (P=0.035; Fishers
exact test) with an odds ratio of 5.923.
Our sample size was too small to evaluate the survival
rate of the neonate with pPPROM vs. the survival rate of
the neonate without pPPROM in multiple gestations.
Time of pPPROM (P=0.787), time of birth (P=0.136)
and latency period (P=0.426) did not differ between mul-
tiples and singletons (ANOVA).
The main neonatal sequelae were respiratory distress
syndrome (RDS; 100%), pulmonary hypoplasia (29.5%;
n=13), and connatal infection (56.8%; n=25). Eleven
patients developed IVH, of whom five died within several
days. Among the 35 surviving infants, one developed
NEC, and two developed ROP that required surgery. BPD
occurred in 65.7% of the survivors, and five infants were
discharged with oxygen therapy.
The rate of intact survivals vs. the rate of survivals
with severe sequelae did not show significantly whether a
connatal infection was present or not (P=0.647, 2-test) as
well as the all-over survival rate with or without connatal
infection (P=0.681, Fishers exact test).
Neonatal demise occurred in nine cases. Five deaths
occurred within a few hours to 2 days after birth due to
severe pulmonary hypoplasia. Two deaths occurred due
to sepsis after 5 and 10days, respectively. One infant died
due to hemorrhagic shock during severe intraventricular
hemorrhage, and another infant died after 10days due to
multiple organ failure.
Potters syndrome with pulmonary hypoplasia and
contractures was diagnosed in eight cases (18.2%). Most
infants had only mild contractures that were treated with
physical therapy.
The intact survival rate here defined as survival
without IVH III or IV, NEC, ROP requiring surgery, or
hospital discharge with oxygen therapy was 45.5%
(20/44).
Discussion
Only limited data are available regarding pPPROM out-
comes in recent years. Our present results showed that the
median GA at the time of pPPROM did not significantly
differ between patients who gave birth to a live infant and
those who suffered a miscarriage. The miscarriage rates

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8Kiver etal., Perinatal outcomes after pPPROM
differed between the group that experienced pPPROM
between 1822 weeks and the group that experienced
pPPROM between 2224 gestational weeks. However, sur-
vival rates did not significantly differ between patients
who experienced very early pPPROM (<18 weeks) and
those who experienced pPPROM close to viability (22
24weeks). Moreover, the survival rates of live-born infants
did not significantly differ between patient groups with
pPPROM occurrence at different GAs. We assume the dif-
ference in miscarriage rate between 1822 and 2224 ges-
tational weeks can be explained by the chances of signs
of life after birth. If an infant was born alive but died after
a few hours of life, the pregnancy was counted as a life
birth.
GA at the time of pPPROM was significantly lower
in the group that opted to terminate their pregnancies
compared to in the groups that chose to continue their
pregnancies. This trend is also reflected in the marked
difference in the rate of termination between the first two
groups and the third group. However, in our opinion, this
difference might be a result of counseling, following the
opinion that earlier pPPROM is associated with lower
chances that the child will survive [30]. Our present find-
ings as well as other previously reported outcomes [20]
showed no significant difference in neonatal survival
rates depending on the time of rupture of membranes.
Within our cohort, women with pPPROM at as early
as 15weeks gestation gave birth to a live infant who sur-
vived the neonatal period, and could be released into
ambulatory care.
Based on our data, it is not possible to predict preg-
nancy outcome at the time of pPPROM. Prediction of
pregnancy outcomes based on inflammatory markers
at admission did not yield solid results or cut-off values
that could be included in the decision-making process.
Especially these findings make patient counseling after
pPPROM very challenging.
Neonatal outcome is greatly influenced by individual
factors, such as the amount of amniotic fluid lost and
replaced, the severity of oligohydramnios, and espe-
cially the occurrence of Potters syndrome. Lung maturity
largely depends on the amount of amniotic fluid avail-
able to the fetus. Thus, patient counseling should include
assessment of the ultrasonographic findings and evalua-
tion of the amount of amniotic fluid, and patients should
not be given a prognosis based solely on GA at the time of
pPPROM or the estimated latency period.
Unfortunately, the presently analyzed data included
only inconsistent serial documentation of amniotic fluid.
Therefore, although there is (in our clinical opinion) a
clear trend of amniotic fluid amount correlating with
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latency period and neonatal lung maturity, the data is
insufficient for statistical analysis. Notably, the repro-
ducibility of amniotic fluid index (AFI) is limited and is
especially low among patients with oligohydramnios, as
reported by several groups, including Chang et al. [31].
Moreover, interobserver reproducibility is even lower than
intraobserver reproducibility. In a larger hospital, it is not
possible for a patient to be examined only by a single phy-
sician; therefore, our present assessment of amniotic fluid
amount did not yield statistically useful data. This was a
major limitation of our study regarding this issue.
In contrast to previous studies, we did not perform
amniocentesis to determine sub-clinical IAI or amnioinfu-
sion to promote fetal lung development. We also refrained
from techniques such as gelatin-sponge cervical plugging
[32]. These methods are still under evaluation [33], and
we believe that the possible benefits of these measures
are outweighed by the risk of inducing a fulminant IAI or
enclosing an already ascended infection inside the uterine
cavity, given that the continuous vaginal discharge of
amniotic fluid can be viewed as a cleansing mechanism.
Further studies to evaluate the benefit of cervical plugging
and amnioinfusion are needed. Additionally, aside from
vaginal and cervical swabs, vaginal manipulation was
minimized to prevent the introduction of infection. Sus-
pected IAI was the main cause for delivery in our study
and connatal infection was a prominent sequel, thus war-
ranting further research into IAI prevention. Our study did
not provide evidence that increased levels of CRP and leu-
kocyte counts at the time of delivery predict the presence
of connatal infection of the newborn. The indication for
delivery due to suspected IAI remains therefore a clinical
decision and is not a predictable or quantifiable by labora-
tory values.
We could not show a statistically significant differ-
ence in short-term neonatal outcome, depending on the
presence of connatal infection. Our sample size was too
small to draw a statistically tangible conclusion if conna-
tal infection influences neonatal outcome. A recent study
by Rodrguez-Trujillo etal. [34] showed that IAI and micro-
bial invasion of the amniotic cavity have less influence
on the short-term neonatal outcome than GA at delivery.
This concurs partially with our data. Nevertheless, con-
natal infection and early-onset neonatal sepsis are major
determining factors of neonatal outcome, as supported by
previous studies, i.e. by Klinger etal. [12] and Stoll etal.
[11]. A limitation as well as challenge in clinical practice is
that there is no clear definition or cut-off value for IAI as
an indication for delivery. The decision to deliver a child
is often based on clinical presentation, and laboratory
values do not always correlate with symptoms. Possible
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interactions between placental histology and maternal
blood values as well as neonatal infections were not part
of this study. However, since IAI strongly influences the
duration of expectant management and the risk of neo-
natal sepsis, this subject must also be evaluated in future
studies.
Although the available data in our study showed that
the survival rate was influenced by GA at delivery, we rou-
tinely delivered at emerging clinical signs of infection.
Our monitoring protocol placed emphasis on regular cer-
vical swabs for signs of pathogenic growth, i.e. bacterial
vaginosis, Escherichia coli or Group B streptococcus, and
included treatment according to antibiogram. Moreover,
we communicated all swab results to the neonatologists
so the neonate could receive immediate appropriate anti-
biotic treatment. Additionally, all neonates received a
nasal and ear swab directly after birth.
Kilpatrick et al. [35] found that smoking and gesta-
tion history are the main risk factors for the development
of pPPROM and/or cervical shortening. However, in our
present study, smoking was recorded for very few patients
and was probably underreported; thus, we could not
confirm those results. Additionally, among the patients
in our study whose medical history included one or more
miscarriages, similar percentages miscarried (15%) or pro-
ceeded to a live birth (12.1%).
Two-thirds of our patients with pPPROM chose
to continue their pregnancies, at minimal risk to the
mother. Multiple gestations, cesarean section and pla-
cental retention are known risk factors for postpartum
hemorrhage [36]. The risks [37] for postpartum infec-
tion, placental abruption and increased blood loss are
also presented to the patient during the initial discus-
sions. Signs of maternal infection or placental abrup-
tion prompted an immediate discontinuation of the
pregnancy, also before fetal viability was reached. In our
study population there was no case of postpartum sepsis
or postpartum hemorrhage. As such we did not see the
maternal risks to be a contraindication to prolonging the
latency period.
Among these continued pregnancies, two-thirds
were successfully prolonged, proceeding to a live birth
in an average of 38 days latency. Our 51.5% overall sur-
vival rate (35 take-home babies) is comparable to the 47%
rate reported by Dinsmoor etal. [38]. Farooqui etal. [39]
described a 40% survival rate when pPPROM occurred
before a GA of 20 weeks, and a 92% survival rate when
pPPROM occurred before a GA of 25weeks. Notably, our
survival rate was substantially higher than the 5% survival
rate recently reported by Linehan etal. [4] in their study of
patients suffering pPPROM before 24weeks of gestation.
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Kiver etal., Perinatal outcomes after pPPROM9
We found no statistical difference between singleton
and multiple pregnancies with regards to the GA at the
time of pPPROM, the latency period, or the ratio between
live births and miscarriages. However, we found a statisti-
cal difference in neonatal survival rates between single-
tons and multiples, with an odds ratio of 5.923. This is in in
line with other studies. For example, Petit etal. [40] per-
formed a case-controlled study showing odds ratios of 1.71
and 2.09 for the first-born and second-born twin, respec-
tively, compared to singletons born at a GA of less than
28 weeks without the added factor of pPPROM. So even
though the pregnancy outcome at the time of pPPROM
cannot be predicted for multiple gestations, the parents
should be informed about the significantly lower survival
rates of live born multiples.
A take-home baby outcome was achieved in 79.5% of
the cases (35/44), which is comparable to the 90% survival
rate of neonates after pPPROM reported by Brumbaugh
et al. [41]. However, the rate of intact survival (without
IVH III or IV, NEC, ROP requiring surgery, or hospital
discharge with oxygen therapy) is also highly important
when counseling parents. In our present study, the intact
survival rate was 45.5% (20/44). Severe neonatal sequelae
are an important factor in the decision-making process,
and the parents should be extensively counseled with
regards to all of the possible consequences of a prema-
ture birth [42]. Counseling should also be influenced by
the fact that many of these pregnancies can be prolonged,
thus substantially reducing the perinatal risks. In our
department, the mother received counseling at the time of
admission, at 22weeks of gestation to discuss the timing
of induction of lung maturity (which is now also offered
before a GA of 23+5), and again at 27weeks as the chances
of a favorable neonatal outcome of an intact survival are
higher with progressing GA.
Strengths of our study are that we analyzed a relatively
large sample size, and that twin and triplet pregnancies
were included. The main limitations were that many clini-
cal observations (e.g. signs of IAI and amount of amniotic
fluid) are not statistically comparable. This prevented us
from providing specific cut-off values or clear guidelines
to help with the patients decision-making process or the
perinatal management.
Comments
It appears that the advisable course of action in any case
of pPPROM is to take an individualized approach and to
prolong the latency period for as long as possible. The GA
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10Kiver etal., Perinatal outcomes after pPPROM
at pPPROM as well as the inflammatory markers at admis-
sion do not predict pregnancy outcome. In our clinical
experience, important determining factors include the GA
at birth and the amount of amniotic fluid, as well as con-
stant monitoring of the mother and a prompt reaction to
signs of infection (i.e. delivery).
Moreover, frequent cervical swab testing can assist
in guiding possible antibiotic treatment. Performing
timely delivery to prevent severe early-onset neonatal
sepsis seems to be a determining factor of neonatal sur-
vival and especially intact survival. Notably, prematu-
rity combined with inferior lung function can lead to
severe limitations in the childs development. When
counseling patients with pPPROM, it is of tantamount
importance to mention both, the neonatal survival rate
and the possibility of severe consequences for the sur-
viving child.
Authors statement
Conflict of interest: Authors state no conflict of interest.
Material and methods: Informed consent: Informed
consent has been obtained from all individuals included
in this study.
Ethical approval: The research related to human subject
use has complied with all the relevant national regula-
tions, and institutional policies, and is in accordance
with the tenets of the Helsinki Declaration, and has been
approved by the authors institutional review board or
equivalent committee.
Disclosure statement: The authors report no conflict of
interest. We have not disclosed any information that could
reveal the identity of our patients. The authors affirm
that this research was conducted in accordance with the
ethical standards of all applicable national and institu-
tional committees and of the World Medical Associations
Helsinki Declaration.
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