European Journal of Obstetrics & Gynecology and Reproductive Biology 203 (2016) 121–126

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European Journal of Obstetrics & Gynecology and

Reproductive Biology
journal homepage: www.elsevier.com/locate/ejogrb

Outcome of pregnancies with spontaneous PPROM before

24 + 0 weeks’ gestation
Philipp Wagner a, Jiri Sonek b,c, Stefanie Mayr a, Harald Abele a, Rangmar Goelz d,
Markus Hoopmann a, Karl Oliver Kagan a,*
a
Department of Obstetrics and Gynaecology, University of Tuebingen, Germany
b
Fetal Medicine Foundation USA, Dayton, OH, USA
c
Division of Maternal Fetal Medicine, Wright State University, Dayton, OH, USA
d
Department of Neonatology, University of Tuebingen, Germany

A R T I C L E I N F O A B S T R A C T

Article history: Objective: To examine the contemporary outcome in women with rupture of membranes (PPROM)
Received 11 April 2016 before 24 + 0 weeks’ gestation.
Received in revised form 6 May 2016 Study design: Retrospective analysis of women with spontaneous PPROM before 24 + 0 weeks that were
Accepted 13 May 2016
treated at the University of Tuebingen/Germany. The search of the database included common maternal
and pregnancy characteristics as well as the neonatal outcomes.
Keywords: Results: One hundred and one pregnancies fulfilled the inclusion criteria. 32 (31.7%) women opted for
PPROM
termination of pregnancy, which were excluded from further analysis. The gestational age at PPROM in
Viability
Outcome
the 69 women with an expectant management was 21.3 (IQR 19.1–22.6) weeks. 40 (58.0%) pregnancies
Prenatal carried on beyond 24 + 0 weeks. Multiple regression analysis indicated that the time of PPROM and the
Neonatal absence of oligo-/anhydramnios were associated with a prolongation beyond 24 + 0 weeks.
In the 40 pregnancies that remained intact beyond 24 + 0 weeks’ gestation, the fetuses were born at
27.7 (IQR 25.3–30.9) weeks. Survival without major complications was observed in 22 (55.0%) fetuses.
Multiple regression analysis indicated that only the gestational age at the time of delivery was
significantly associated with such an intact survival.
Conclusion: In cases with PPROM there is a 60% chance of a prolongation beyond 24 + 0 weeks. About half
of these fetuses will be discharged alive without major complications.
ß 2016 Elsevier Ireland Ltd. All rights reserved.

Introduction Papers dealing with PPROM before 24 + 0 weeks are usually

Premature preterm rupture of membranes (PPROM) is a
relatively common pregnancy complication. It occurs in about
5–7% of pregnant women [1]. However, the incidence of PPROM
before viability (<24 + 0 weeks) is much lower. Only about 5 in
1000 women are affected by this condition [1,2]. When it does
occur, however, the clinical consequences are much worse than
with PPROM at a later gestational age. Neonatal outcome is
generally poor due to preterm delivery, due to the inflammatory
response, and due to a certain degree of pulmonary hypoplasia as a
consequence of the reduction of amniotic fluid at a very early
gestational age [3,4].
* Corresponding author at: University of Tuebingen, Calwerstrasse 7, 72076
Tuebingen, Germany. Tel.: +49 7071 29 84807.
E-mail address: KOKagan@gmx.de (K.O. Kagan).
retrospective and include a limited number of cases. In a more
recent review of Waters and Mercer, the authors combined the
results of six papers dealing with previable PPROM that were
published after 1994 [1]. It included a total of only 275 women. The
mean gestational age at the time of PPROM was about 22 weeks
with a mean latency period before delivery ranging from 6 to
39 days. The survival rates of those that delivered alive and where
neonatal care was instituted ranged between 23% and 53%
depending on the gestational age at the time of delivery [5]. Dewan
and Morris summarized outcomes of studies that were published
between 1980 and 1999. Here the survival of neonates that were
born alive was only 20% [6].
In our study, we set out to evaluate outcomes of pregnancies
with PPROM prior to 24 + 0 weeks gestation in a more recent
cohort. We used multiple regression analysis to assess the effect of
relevant covariates on prolongation of pregnancy beyond
24 + 0 weeks’ gestation and neonatal survival.

http://dx.doi.org/10.1016/j.ejogrb.2016.05.018
0301-2115/ß 2016 Elsevier Ireland Ltd. All rights reserved.
122 P. Wagner et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 203 (2016) 121–126
Methods
A search of the database at the University of Tuebingen looking
for all women diagnosed with PPROM before 24 + 0 weeks’
gestation was performed. The study interval was 2005–2015.
Information on neonatal outcome was added to this database.
Multiple gestations, gestations complicated by a fetal anomaly,
and cases where PPROM was due to an invasive procedure were
excluded. In all pregnancies, gestational age was established or
confirmed by a first trimester crown rump length measurement
[7].
Our tertiary care center belongs to the largest ones in Germany
with about 3000 deliveries per year. The neonatal and obstetric
units are housed next to each other. We routinely treat
complications related to prematurity offering a full gamut of
therapies. The diagnosis of PPROM in our unit is generally made
using the Amni-Sure test (Germantown, USA) and is based on the
clinical observation of fluid leakage from the cervical os that turns
litmus paper blue color.
Each patient with the diagnosis of PPROM is counseled by a
maternal–fetal medicine specialist. The option of pregnancy
termination versus expectant management is offered. Unless the
patient insists on another approach, neonates whose gestational
age is below 24 + 0 weeks’ gestation receive palliative care and
those that deliver at or beyond 24 + 0 weeks or more receive
standard neonatal care. This policy was in place during the entire
period of the study and none of the patients opted for maximum
care before 24 + 0 weeks.
Women who opt for expectant management are initially
monitored in our inpatient department for about a week looking
for signs of chorioamnionitis. The treatment also involves the
prophylactic administration of antibiotics for 5–7 days. If no
infectious complications are detected, the patient is discharged to
be readmitted at 24 + 0 weeks’ gestation. At that time, steroids
(two injections of 12 mg Betamethasone 24 h apart) are adminis-
tered intramuscularly. This is repeated in 2–3 weeks if undelivered
or if the clinical status (e.g. cervical change, increasing uterine
contractions) changes.
The patient undergoes intensive antenatal monitoring through-
out her hospitalization. This includes daily fetal heart rate
monitoring, weekly ultrasound examinations, assessment of the
white blood cell count and the C-reactive protein levels as well as
vaginal cultures. The patient is delivered if chorioamnionitis,
clinically significant placental abruption, or abnormal fetal testing
are noted. Tocolysis is not used in case of labor and antibiotics
(generally cefuroxime) are administered if chorioamnionitis is
suspected [8,9]. The diagnosis of chorioamnionitis is based on
maternal fever (38 8C), fundal tenderness, fetal tachycardia,
elevated maternal white blood cell count, and C-reactive protein
levels. The decision to deliver is based on the clinical assessment by
the supervising obstetrician. The patient is routinely delivered
upon reaching 34 weeks’ gestation [10].
The following maternal characteristics were searched for and
recorded: age, gravidity and parity, and history of preterm delivery
between 14 and 34 weeks’ gestation. Maternal white blood cell
counts and C-reactive protein levels at the time of PPROM and prior
to delivery, an- or oligohydramnios before 24 + 0 weeks (defined as
single deepest pocket being continuously below 2 cm [11,12]), the
reason for delivery and the maternal outcome were also included
in our analysis. The gestational age the time of PPROM and at
delivery were recorded and latency period was calculated.
The following neonatal characteristics were searched for and
recorded: birth weight, gender, APGAR score, and pH of the
umbilical artery. Details of neonatal care that were used in our
analysis include intubation and days of ventilation, mode of
ventilation, presence of a pneumothorax, stage 2 retinopathy,
grade 2 intracranial germinal matrix hemorrhage, periventricular
leukomalacia, bronchopulmonary dysplasia, and necrotizing en-
terocolitis with the need of surgical intervention as well as focal
intestinal perforation. Diagnosis and therapy of these conditions
are in concordance with national and international standards.
The study cohort was divided into the following categories:
those women that elected termination of pregnancy (TOP) and
those that elected for expectant management. In the TOP group,
termination was carried out due to the risk of fetal and maternal
complications. None of the women had signs of chorioamnionitis.
The expectant management group was subdivided into two
groups: late miscarriage (defined as delivery [spontaneous or
indicated] prior to 24 + 0 weeks’ gestation) and pregnancies that
survived intact to 24 + 0 weeks and beyond.
Neonates that were discharged alive without grade 2
intracranial germinal matrix hemorrhage, periventricular leuko-
malacia, stage 2 retinopathy, bronchopulmonary dysplasia, and
necrotizing enterocolitis as well as focal intestinal perforation
were classified as neonates without major complications with the
potential of long term sequelae.
The study was approved by the local ethics committee (No.
182/2016BO1).
Statistical analysis
Results are shown as median and (25th–75th interquartile
range, IQR). Differences between the expectant and the TOP group
were assessed with Student’s t-tests and Mann–Whitney-U-tests
depending on whether there was a normal distribution or not. We
used uni- and multivariate logistic regression analysis to assess
significant covariates for a prolongation of the pregnancy beyond
24 + 0 weeks and for a discharge from the neonatal unit without
major complications with the potential of long term sequelae.
Statistical significance was set at p  0.05.
Results
The search of the database identified 101 singleton pregnancies
that were treated in our hospital between 2005 and 2015. Thirty-
two (31.7%) women opted for termination of pregnancy (TOP).
These cases were excluded from the further analysis. Details about
this group are given in Table 1. In the TOP group, gestational age
was significantly lower and an/oligohydramnios were found
significantly more often than in the expectant management group
(gestational age: p < 0.001, an-/oligohydramnios: p = 0.002). In
terms of maternal age (p = 0.720), gravidity (p = 0.914), parity
(p = 0.714), history of preterm delivery (p = 0.674), white blood cell
count (p = 0.796) and CRP levels (p = 0.417), no significant
differences were found.
69 (68.3%) women elected for an expectant management. The
gestational age at PPROM in this group was 21.3 (IQR 19.1–22.6)
weeks. 40 of these pregnancies carried on beyond 24 + 0 weeks, the
remaining 29 pregnancies miscarried earlier (Fig. 1). In the group
of pregnancies that reached 24 + 0 weeks, median interval
between PPROM and delivery was 49.5 (IQR 24.3–74.5) days. In
the miscarriage group, the time interval was 4.0 (IQR 1.0–9.0) days,
respectively. At the time of PPROM, the chance for a prolongation
beyond 24 + 0 weeks was 58.0%. After seven days, 48 women were
still pregnant and the chance for a prolongation beyond 24 weeks
increased to 79.2%, respectively (Fig. 2).
In the expectant management group, uni- and multivariate
logistic regression was used to examine significant parameters
that were associated with a prolongation of pregnancy beyond
24 + 0 weeks. Multivariate regression analysis indicated that
increasing gestational age at the time PPROM and the absence
 P. Wagner et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 203 (2016) 121–126 123

Table 1
Characteristics of the study population.

Maternal and pregnancy characteristics Termination (n = 32) Expectant management

Miscarriage before Prolongation beyond

24 + 0 weeks (n = 29) 24 + 0 weeks (n = 40)

Maternal age in yrs, median (IQR) 33.3 (28.8–36.0) 32.6 (27.1–35.1) 32.4 (27.5–37.8)
Gravidity in n, median (IQR) 2.0 (2.0–3.0) 2.0 (1.0–3.0) 3.0 (2.0–4.0)
Parity in n, median (IQR) 1.0 (0.0–1.0) 1.0 (0.0–1.0) 1.0 (0.0–1.5)
History of delivery between 14 and 34 wks, n (%) 2 (6.3) 1 (4.0) 5 (12.5)
Gestational age at PPROM in weeks, median (IQR) 17.7 (15.9–19.5) 20.0 (18.0–21.7) 22.3 (20.1–23.0)
Gestational age at delivery in weeks, median (IQR) 19.1 (16.1–20.3) 21.4 (19.3–22.6) 27.7 (25.3–30.9)
Time between PPROM and delivery in days, median (IQR) 5.0 (2.0–7.5) 4.0 (1.0–9.0) 49.5 (24.3–74.5)
White blood cell count at PPROM in n/ml, median (IQR) 12.830 (10.305–13.895) 13.115 (10.635–16.568) 11.245 (9.180–13.928)
C-reactive protein levels at PPROM in g/dl, median (IQR) 0.9 (0.3–1.7) 1.3 (0.8–2.8) 0.7 (0.4–1.2)
White blood cell count at delivery in n/ml, median (IQR) 12.445 (8.973–14.088) 14.050 (11.138–16.388) 11.385 (9.125–16.128)
C-reactive protein levels at delivery in g/dl, median (IQR) 0.8 (0.3–1.6) 2.6 (1.2–4.3) 1.0 (0.6–1.8)
An-/oligohydramnios before 24 wks, N (%) 32 (100) 24 (96.0) 24 (60.0)

101 cases with

spontaneous PPROM
before 24 weeks

Termination of Expectant
pregnancy mangement
n= 32 (31.7%) n=69 (68.3%)

Prolongation miscarriage
beyond 24 weeks before 24 weeks
n=40 (58.0%) n=29 (42.0%)

Livebirth
n=40 (100%)

Neonatal Intracranial Periventricular Bronchopulm.

Retinopathia NEC/FIP
death hemorrhage leucomalacia dysplasia
n=7 (17.5%) N=3 (7.5%)
n=2 (5.0%) n=5 (12.5%) n=1 (2.5%) N=13 (32.5%)

Discharged alive
without major complications
n= 22 (55.0%)

Fig. 1. Fetal and neonatal outcome of pregnancies with spontaneous pre-viable premature preterm rupture of membranes (PPROM).

of an- or oligohydramnios was associated with a prolongation of
pregnancy beyond 24 + 0 weeks (Table 2).
In the 40 pregnancies that remained intact beyond 24 + 0
weeks’ gestation, the fetuses were born at 27.7 (IQR 25.3–30.9)
weeks gestation with 1013 (IQR 721–1678 g). Delivery before
34 weeks was necessary due to signs of chorioamnionitis and
cervix effective contractions in 30 cases (75.0%) as well as due to
placental abruption in five cases (12.5%). The remainder five cases
(12.5%) reached 34 weeks and were delivered electively.
Two fetuses (5.0%) died during the neonatal care due to
pulmonary hypoplasia. Those fetuses that survived were dis-
charged after 67.5 (IQR 39.8–112.3) days. The neonatal outcome is
summarized in Table 3. Survival without major complications
with the potential of long term sequelae was observed in 22
(55.0%) fetuses (Fig. 3).
Uni- and multivariate logistic regression analysis was used to
examine significant covariates that were associated with a
discharge of a neonate from the neonatal unit that is alive without
major complications. In the multivariate analysis, only the
gestational age at the time of delivery was significantly associated
(Table 4). Among the 12 fetuses that were delivered before
26 weeks, only 1 (8.3%) were discharged without major
complications, between 26 + 0 and 29 + 6 weeks, seven (58.3%)
of the 12 were discharged without major complication and in those
16 fetuses that were delivered at 30 + 0 weeks or later, 14 (87.5%)
belonged to this group.
Three women had severe maternal complications. All of them
were in the group of patients with a prolongation beyond
24 + 0 weeks. In one case, there was placenta accreta and bleeding
due to atony after delivery. Two women suffered from peritonitis
resulting in hysterectomy.
Discussion
Main findings of this study
In this study, we have shown that in pregnancies with PPROM
before 24 + 0 weeks’ gestation, the chance of prolongation beyond
24 + 0 weeks is about 60%. This increases to about 80% if the
pregnancy survives intact for at least a week after PPROM. In a
multivariate regression analysis, predictors for a prolongation
beyond 24 + 0 weeks are gestational age and the absence of an- or
124 P. Wagner et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 203 (2016) 121–126

140.0

Time interval between PPROM and delivery (days)

130.0
120.0
110.0
100.0
90.0
80.0
70.0
60.0
50.0
40.0
30.0
Termination of pregnancy
20.0 Expectant management:
10.0 Late miscarriage
Prolongation beyond 24 wks
0

12.0 14.0 16.0 18.0 20.0 22.0 24.0

Gestational age at the time of PPROM (weeks)

Fig. 2. Gestational age distribution at PPROM and at delivery according to the pregnancy outcome.

Table 2 oligohydramnios. Mean gestational age at the time of delivery in

Univariate and multivariate regression analysis to assess the significant covariates this group was about 29 weeks. 95% of these neonates were
that are associated with prolongation beyond 24 weeks.
discharged alive and more than half without major neonatal
Covariates Univariate regression Multivariate regression complications that place them at a high risk for long term sequelae.
analysis, OR (95% CI) analysis, OR (95% CI) The best predictor of survival without major complications is
p p
gestational age at delivery.
Maternal age 1.028 (0.941–1.123)
0.537 Comparison with previous studies
Gravidity 1.451 (1.007–2.090) 1.351 (0.889–2.052)
0.046 0.159
Parity 1.341 (0.801–2.244) In the past few years, there are only few studies that report on
0.264 the outcome of women with pre-viable PPROM who were treated
Gestational age at 1.351 (1.090–1.676) 1.334 (1.038–1.715) since 2000. These studies include a total of 769 patients [13–
PPROM 0.006 0.024
20]. Mean gestational age at the time of PPROM in these studies
White blood cell count 1.000 (1.000–1.000)
at PPROM 0.116 was between 18 and 24 weeks and the gestational age at the time
C-reactive protein 0.809 (0.624–1.040) of delivery was between 21 and 30 weeks, respectively. There were
levels at PPROM 0.108 417 (54.2%) neonates that were born alive of whom 175 (42.0%)
An-/oligohydramnios 0.054 (0.007–0.434) 0.063 (0.007–0.586) died postnatally. Our data compares favorably with these studies.
before 24 wks 0.006 0.015
(0 = no, 1 = yes)
Although the gestational age at delivery was similar, of those that

40.0
38.0
Gestational age at the time of delivery (weeks)

36.0
34.0
32.0
30.0
28.0
26.0
24.0
22.0
20.0
18.0
Neonatal death or survival with long term complications
16.0 Discharged alive without major complications
14.0
12.0
10.0

10.0 12.0 14.0 16.0 18.0 20.0 22.0 24.0 26.0

Gestational age at the time of PPROM (weeks)

Fig. 3. Gestational age distribution at PPROM and at delivery in pregnancies with live born fetuses.
 P. Wagner et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 203 (2016) 121–126 125

Table 3 incidence of bronchopulmonary dysplasia was comparable in

Neonatal outcome characteristics of fetuses with PPROM before 24 weeks.
the two groups as well. However, fetuses with PPROM were
n = 40 dependent on a respiratory support system longer, had a longer
Birth weight in g, median (IQR) 1013 (721–1678) hospital stay, and had a higher readmission rate than fetuses in the
Gender (male), N (%) 22 (55.0%) control group. In addition to the complications of an affected
Arterial pH, median (IQR) 7.34 (7.29–7.39) pregnancy, patients with PPROM in the previous pregnancy should
Time interval between birth/PPROM and 67.5 (39.8–112.3) and be informed that there is a 10% risk of recurrence of PPROM in the
discharge from the neonatal unit in days, 118.5 (102.3–142.3)
subsequent pregnancy [22].
median (IQR)
Intubation and days of ventilation, 32 (80.0) and 5.0 (3.0–9.0) We have shown that the absence of oligohydramnios is
N (%) and median (IQR) associated with a significant prolongation of pregnancy beyond
High frequency ventilation, N (%) 22 (55.0) 24 + 0 weeks. This is consistent with the findings in some
NO inhalation, N (%) 14 (35.0)
previously published studies [23–26]. As a consequence, some
CPAP ventilation and days of ventilation, 37 (92.5) and 32.0 (4.3–55.8)
N (%) and median (IQR)
authors have recommended the use of amnioinfusion. However,
Pneumothorax, N (%) 5 (12.5) the results of this intervention are inconclusive [27]: Miyazaki
Retinopathia  grade 28, N (%) 7 (17.5) et al. reported on 45 pregnancies that were treated with
intracranial germinal, matrix 5 (12.5) amnioinfusion of 500 to 1500 ml per day. 85% of the fetuses were
hemorrhage  grade 2, N (%)
born alive but only 40% survived without serious sequelae [28].
Periventricular leucomalacia, N (%) 1 (2.5)
Necrotizing enterocolitis and focal 3 (7.5) Vergani et al. treated 18 women with PPROM before 25 weeks with
intestinal perforation, N (%) serial amnioinfusion and compared the results with 16 untreated
Bronchopulmonary dysplasia, N (%) 13 (32.5) patients [29]. The proportion of neonates with pulmonary
Neonatal death 2 (5.0)
hypoplasia was significantly lower in the treatment group.
No major complicationsa, N (%) 22 (55.0)
However, the rate of pulmonary hypoplasia in the control group
a
Neonates that were discharged alive without intracranial germinal matrix was 86%, which is much higher than the rates reported in other
hemorrhage  grade 2, periventricular leucomalacia, retinopathia  grade 2, NEC/
studies where expectant management was employed. In a
FIP and bronchopulmonary dysplasia.
randomized controlled study, 34 patients with PPROM between
24 and 32 weeks were either treated with weekly amnioinfusion or
Table 4 expectantly. The risk of a delivery within 7 days and risk of
Univariate and multivariate regression analysis to the assess the significant
pulmonary hypoplasia was significantly reduced in the therapy
covariates that are associated with discharge from the neonatal unit without long
term complications. group [30]. In contrast, Roberts et al. treated 58 women with
PPROM before 24 weeks either with amnioinfusion or expectantly
Covariates Univariate regression Multivariate regression
and did not find any difference in the short and long term outcome
analysis, OR (95% CI) analysis, OR (95% CI)
p p
[31,32].

Maternal age 1.011 (0.921–1.110)

Limitations of this study
0.817
Gravity 1.002 (0.720–1.394)
0.992 The main limitation of our study is its retrospective nature.
Parity 1.247 (0.755–2.059) Additionally, about a third of our study population opted for
0.389
termination of pregnancy after PPROM. Even though review of the
Gestational age at 1.003 (0.753–1.335)
PPROM 0.985 medical records failed to reveal any signs of chorioamnionitis in
Gestational age at 2.077 (1.463–2.949) 2.090 (1.203–3.633) these patients, it is possible that their decision was influenced by
delivery <0.001 0.009 some unfavorable factors such as early gestational age and an-/
Time between PPROM 1.081 (1.044–1.119) 0.999 (0.943–1.059) oligohydramnios. If this were the case, our data would be skewed
and delivery <0.001 0.976
toward improved survival. However, Azria et al. showed that a high
White blood cell count 1.000 (1.000–1.000)
at PPROM 0.381 rate of TOP is not associated with a better perinatal outcome [17].
C-reactive protein 0.938 (0.730–1.204)
levels at PPROM 0.613 Conclusion
White blood cell count 1.000 (1.000–1.000)
at delivery 0.183
C-reactive protein 0.806 (0.607–1.069)
Our study has shown that in cases with very early PPROM there
levels at delivery 0.134 is a 60% chance of pregnancy prolongation beyond 24 + 0 weeks.
An-/oligohydramnios 0.579 (0.186–1.806) Approximately 95% of the neonates will be discharged from the
before 24 wks 0.346 neonatal unit alive and more than half of those will not have
experienced any neonatal complications that have a high
association with long term sequelae. The best predictor for the
were born alive in our study, more than half did not have these latter is gestational age.
types of complications. This is most probably due to the fact that
neonatal care has improved over last 15 years and underscores the
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