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Maternal and Neonatal Outcomes of Preterm Premature Rupture of

Membranes before Viability

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DOI: 10.1055/s-0041-111174

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Maternal and Neonatal

Outcomes of Preterm
Premature Rupture of
Membranes before Viability

DOI 10.1055/s-0041-111174
Klin Padiatr 2016; 228: 69–76

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 Original Article 69

Maternal and Neonatal Outcomes of Preterm

Premature Rupture of Membranes before Viability
Maternale und neonatale Mortalität und Morbidität bei vorzeitigem
Blasensprung vor Beginn der Lebensfähigkeit des Kindes

Authors I. van der Marel1, R. de Jonge2, J. Duvekot1, I. Reiss2, I. Brussé1

1
Affiliations  Erasmus MC, Department of Obstetrics and Gynecology, Division of Obstetrics and Prenatal Medicine Rotterdam,
­Netherlands
2
 Erasmus MC, Department of Pediatrics, Division of Neonatology, Rotterdam, Netherlands

Key words Abstract Zusammenfassung

●
▶ previable PPROM
▼ ▼
●
▶ outcome
Background:  To investigate maternal and neo- Hintergrund:  Es wurden das maternale und
●
▶ morbidity
natal outcomes of previable preterm premature das neonatale Outcome bei Schwangerschaften
●
▶ mortality
rupture of membranes (PPROM) and compare mit einem vorzeitigen Blasensprung (PPROM)
outcome between previable PPROM before and untersucht und ein Vergleich zwischen PPROM
Schlüsselwörter
●
▶ Extrem vorzeitiger after 20 weeks of pregnancy, with data from one vor und nach 20 Schwangerschaftswochen mit
Blasensprung single center. Daten von einem einzigen Zentrum angestellt.
●
▶ Outcome Patients:  All women with singleton or twin Patienten:  Einlings- und Zwillingsschwanger-
●
▶ Morbidität pregnancies, from 2002 through 2011, who pre- schaften, die im Zeitraum von 2002 und 2011
●
▶ Mortalität
sented with PPROM before 24 weeks of gestation. in einem tertiären Perinatalzentrum aufgrund
Method:  A retrospective cohort study in a eines PPROM vor 24 Schwangerschaftswochen
university teaching hospital in the Netherlands. behandelt wurden.
Data were analyzed and compared between Methoden:  Retrospektive Level III Kohorten-
pregnancies with previable PPROM before and studie in den Niederlanden. Primäres Outcome
after 20 weeks of pregnancy. Main outcome waren maternale und neonatale Morbidität und
measures were maternal and neonatal morbidity Mortalität.
and mortality. Resultate:  Es wurden 160 Schwangere (164
Results:  A total of 160 women (164 fetuses) Feten) inkludiert. Neunzig Schwangere (56.2 %)
were included. 90 women (56.2 %) developed entwickelten Komplikationen. Es gab keine
complications (intra-uterine infection, retained Müttersterblichkeit. Auf der NICU wurden 68
placenta, placental abruption or sepsis). There Neonaten stationär behandelt. PPHN (64.7  %,
was no maternal mortality. 68 neonates were p = 0.001), Kontrakturen (58.8 %, p < 0.001)
admitted after birth. PPHN (64.7 %, p = 0.001) and wurden signifikant mehr diagnostiziert nach
contractures (58.8 %, p < 0.001) occurred signifi- PPROM  < 20 Wochen. Schließlich überlebten
Bibliography cantly more in neonates born after PPROM < 20 38.4 % der Neugeborenen. Neugeborene, gebor-
DOI http://dx.doi.org/ weeks of pregnancy. Eventually 38.4 % of the ne- en nach previable PPROM > 20 Wochen geboren
10.1055/s-0041-111174 onates survived. Neonates born after previable hatten eine größere Wahrscheinlichkeit bei der
Published online: PPROM > 20 weeks had a greater likelihood of be- Entlassung am Leben zu sein (22,7 vs. 46,9 %,
February 17, 2016
ing alive at discharge (22.7 vs. 46.9 %, p = 0.008). p = 0,008).
Klin Padiatr 2016; 228: 69–76
© Georg Thieme Verlag KG
Discussion:  This study of previable PPROM Diskussion:  Diese Studie zeigt, dass bei mehr
Stuttgart · New York shows that more than 50 % of the mothers devel- als 50 % der Mütter Komplikationen auftreten.
ISSN 0300-8630 op one or more complications. Neonates have a Die Neonaten haben eine hohe Mortalitätsrate,
high mortality rate, especially neonates born af- besonders die mit PPROM vor 20 Wochen. Insbe-
Correspondence ter PPROM < 20 weeks of pregnancy. In particular sondere Neugeborene, geboren nach PPROM < 20
Ingrid Brussé neonates born after PPROM < 20 weeks of preg- Wochen, sollten engmaschig auf PPHN und Kon-
Erasmus MC nancy should be watched closely for PPHN and trakturen beobachtet werden.
Obstetrics and Gynecology
contractures. Schlussfolgerung:  Diese große monozentrischen
Wytemaweg 80
3015 GJ Rotterdam
Conclusion:  This large single center study can Studie kann eine gute Grundlage für die Beratung
Netherlands provide good foundation for counseling parents von Eltern auf PPROM darstellen. Insbesondere
Tel.:  + 31/107/036 109 on previable PPROM, especially the prognosis of ist die Prognose von PPROM < 20 Wochen ein
Fax:  + 31/107/036 815 PPROM < 20 weeks of pregnancy is of additional Mehrwert.
i.brusse@erasmusmc.nl value.

van der Marel I et al. Rupture of Membranes before Viability …  Klin Padiatr 2016; 228: 69–76
70 Original Article
Introduction
▼ Gestational age was determined using the ultrasound examina-
Spontaneous preterm premature rupture of membranes
(PPROM) before 24 weeks of pregnancy, also referred to as prev-
iable PPROM, occurs in less than 1 % of all pregnancies and is as-
sociated with severe complications for both mother and fetus
[5, 15, 16, 24, 25, 27, 30]. Risk factors for PPROM are urogenital
infections (mostly Group B Streptococcus (GBS)), cervical cer-
clage, history of PPROM, previous preterm delivery, smoking and
antepartum hemorrhage [2, 16, 17, 21, 27, 30]. Maternal compli-
cations are intra-uterine infection, retained placenta and pla-
cental abruption; also few cases of sepsis and maternal death
have been reported [5, 7, 21, 22, 25, 26].
Both the gestational age at previable PPROM and at birth are pre-
dictive for the neonatal outcome [7, 29]. Common neonatal com-
plications are pulmonary hypoplasia, bronchopulmonary dys-
plasia (BPD), contractures and infection [16, 21, 29]. Neonatal
survival has improved over the last decade. However, reported
neonatal mortality rates remain high after this obstetric compli-
cation and range from 34 to 82 % [2, 22, 24–26, 28, 29].
More insight into maternal, fetal and neonatal outcomes might
improve counseling of parents and treatment decision-making.
This can only be realized using studies with reasonably large
samples. Waters and Mercer showed in their review that previ-
ous studies had low sample sizes and were performed in multi-
ple centers [27]. Furthermore previous studies showed a wide
range in latency, morbidity and survival rates. These wide rang-
es can be explained by different study designs, different inclu-
sion criteria such as gestational age during PPROM or differences
in local protocol regarding treatment of this special group of
mothers and neonates. The primary objective of the study was
to investigate maternal, fetal and neonatal morbidity and mor-
tality with data obtained from a large cohort in one tertiary
perinatal center. Second, we determined whether time of occur-
rence of previable PPROM – before vs. after 20 weeks of preg-
nancy – would influence outcomes. We expected that this 20
weeks’ cut-off would be most relevant to neonatal outcome
[13, 25, 28]. With these data physicians can counsel parents ap-
propriately and together they can determine management.
Material and Methods
▼ rulent fluid from the vagina and uterine tenderness and sepsis
Study population
This retrospective cohort study included all women with single-
ton and twin pregnancies, who presented with PPROM before 24
weeks of gestation at the Department of Obstetrics of the Eras-
mus MC-Sophia Children’s Hospital, a tertiary perinatal center in
the Netherlands, between January 2002 and December 2011.
Exclusion criteria were: structural fetal abnormalities detected
by ultrasound examination or other prenatal testing methods.
The study was approved by the medical ethics committee of
­Erasmus MC, Rotterdam (MEC-2012-162).
Maternal and neonatal data were extracted from the electronic
databases of the Department of Obstetrics and the Department
of Neonatology. Neonatal data were used from birth until dis-
charge. As in the Netherlands most neonates admitted to level III
centers are transferred to level II neonatal centers before dis-
charge home, additional data were collected in the centers the
neonates were transferred to.
van der Marel I et al. Rupture of Membranes before Viability …  Klin Padiatr 2016; 228: 69–76
Measures
tion in the first trimester or menstrual history. PPROM was diag-
nosed when there was a history of fluid leakage, an observation
of pooling fluid from the cervical os by sterile speculum exami-
nation or presence of oligohydramnios or anhydramnios at ul-
trasound examination. PPROM  < 24 weeks of gestation was con-
sidered as PPROM before viability. Oligohydramnios was consid-
ered to be present when ultrasound examination did not show a
visible pocket of at least 2 cm of amniotic fluid or when the am-
niotic fluid index was less than 5 cm. Anhydramnios was defined
as a deepest pocket of less than 1 cm [14]. When previable
PPROM was diagnosed, presence of infection was assessed in
cervical or vaginal and urinary cultures.
After having been counseled by obstetricians and neonatolo-
gists, parents were invited to make an informed decision for ei-
ther active or expectant management. Active management im-
plied termination of pregnancy, which in the Netherlands is le-
gal until 24 weeks of gestation [18]. Expectant management
implied bed rest, hospital admission when the fetus reached vi-
ability and antenatal corticosteroids after 24 weeks of gestation.
Antibiotics (amoxicillin or amoxicillin/clavulanic acid) and toco-
lytic drugs (nifidipin or atosiban) were prescribed according to
the local protocol. When during expectant management signs of
intra-uterine infection or fetal distress were observed, pregnan-
cy was terminated. The latency period was defined as the period
between PPROM and delivery [5, 15, 27, 30]. Either vaginal or
­cesarean delivery was indicated in case of intra-uterine infection;
cesarean delivery in case of fetal distress. Cesarean delivery was
only performed after the fetus had reached viability.
Neonatal resuscitation was performed by a neonatologist ac-
cording to the local protocol. Preterm and term neonates were
admitted at the NICU or maternity ward.
Outcome measures
Primary outcome was neonatal mortality after previable PPROM.
Secondary outcome was morbidity of both mother and neonate
after previable PPROM. Parameters for maternal morbidity were
intra-uterine infection, sepsis, placental abruption or retained
placenta. Intra-uterine infection was defined as a maternal tem-
perature of 38 °C or higher, in combination with elevated C-reac-
tive protein and/or leukocyte count, the presence of leaking pu-
with positive blood cultures. Placental abruption was clinically
diagnosed with 2 or more of the following criteria: antepartum
hemorrhage after 20 weeks of gestational age, uterine pain or
tenderness, fetal distress or death and blood clots behind the pla-
centa [12]. The diagnosis retained placenta was made in case the
placenta was not delivered within 60 min after birth. Histological
infection was diagnosed if examination of the placenta showed
chorioamnionitis, subchorial intervillositis and/or funiculitis.
Parameters for neonatal morbidity were respiratory distress
syndrome (RDS), BPD, persistent pulmonary hypertension of the
neonate (PPHN), patent ductus arteriosus (PDA), infection, intra-
ventricular hemorrhage (IVH), contractures, retinopathy of pre-
maturity (ROP) and necrotizing enterocolitis (NEC). RDS was diag-
nosed on the basis of clinical and radiological signs consistent
with surfactant deficiency [9]. BPD was defined as need of oxy-
gen at the corrected age of 36 weeks of pregnancy [11, 19]. PPHN
was diagnosed with clinical signs of ductal right-left shunt, with
pre- and postductal differences in saturation, and confirmed by
cardiac ultrasound [8]. PDA was diagnosed with ultrasound ex-

Deliveries Previable PPROM
during study period deliveries
n = 20 003 n = 160 (0.8 %)
Fetal and
neonatal deaths
n = 116 (70.7 %)
Total fetuses
n = 164
Neonates alive
at discharge
n = 48 (29.3 %)
amination in the presence of clinical signs [23]. Infection was
suspected with clinical signs of infection, elevated C-reactive
protein or leukocyte count. Sepsis was confirmed when blood
cultures were positive. IVH (grade 3 or higher) was diagnosed by
cranial ultrasound [20]. Neonates were monitored for signs of
contractures, ROP and NEC (Bell stage 2 or higher) [1, 3, 4].
In addition, differences were studied between previable PPROM
before and after 20 weeks of pregnancy. As mentioned earlier,
we expected that this cut-off was most influential with neonatal
outcome (in particular neonatal survival and pulmonary hypo-
plasia) [13, 25, 28].
Data analysis
Univariable comparison of patient characteristics and clinical
data was performed with an independent sample students t-test
for continuous and a χ2-test for nominal data. If data did not
meet the criteria for a valid χ2-test, a Fisher’s exact test was used.
Multivariable logistic regression served to adjust for possible
confounding factors. In this analysis missing values were imput-
ed once with single imputation [6, 10]. To analyze the associa-
tion between the central determinant ‘‘PPROM < 20 weeks of
pregnancy’’ and outcome (defined as “mortality”, “contrac-
tures”, “PPHN” and “BPD”) multiple logistic regression analysis
was performed. 2 association models were produced, one crude
model unadjusted for confounding and a model adjusted for con-
founders. Adjusted estimates for PPROM < 20 weeks as a risk fac-
tor for the outcome measures were obtained by entering poten-
tial confounders in the model one by one. Potential confounders
were twin pregnancies, gestational age at PPROM, risk factors of
PPROM, oligo- or anhydramnios, tocolytic drugs, antenatal ster-
oids, latency period, mode of delivery, gestational age at deliv-
ery, histologic evidence of infection, birthweight, gender, sur-
van der Marel I et al. Rupture of Membranes before Viability …  Klin Padiatr 2016; 228: 69–76
Original Article 71
Fig. 1  Study popula-
tion/Abbreviations:
Stillborn PPROM, preterm
n = 74 (63.8 %)
premature rupture of
membranes; n, num-
ber; h, hours; d, days.
Death < 24 h
n = 31 (26.7 %)
Death > 24 h < 7 d
n = 5 (4.3 %)
Death > 7 d
n = 6 (5.2 %)
Previable
PPROM < 20 weeks
n = 10 (20.8 %)
Previable
PPROM > 20 weeks
n = 38 (79.2 %)
factant, dexamethasone, nitric oxide, RDS, BPD, PPHN, contrac-
tures, neonatal infection, PDA, NEC, ROP and IVH. The presence
of confounding, defined as a change in the regression coefficient
of the central determinant of 10 %, was investigated for all poten-
tial confounders in the model in a predefined order. A sensitivity
analysis was performed among twin pregnancies to investigate
correlations between variables that could influence the results.
Statistical significance was considered with 2-tailed p-values
of < 0.050. Data were analyzed with SPSS Statistics 20.0 (IBM
Corporation, Somers, NY).
Results
▼
From January 2002 until December 2011 a total of 20 003 babies
were delivered in our perinatal center. A total of 160 pregnancies
met the selection criteria of this study, including 25 twin pregnan-
cies. Solely data of the fetus whose membrane was ruptured was
used. In 4 twin pregnancies both fetuses had previable PPROM;
where appropriate only the data of the first of these twins with
PPROM was used for analysis. Consequently, 164 fetuses with
previable PPROM were included. No fetuses were excluded. In 74
pregnancies previable PPROM occurred before 20 weeks; in 86 af-
ter 20 weeks. ● ▶  Fig. 1 presents a flow chart of the study population.
Patient characteristics
Characteristics of the 160 pregnancies are listed in ●  ▶  Table 1. Of
the initially selected 164 fetuses, 125 fetuses were treated by ex-
pectant management, since 121 parents (75.6 %) opted for ex-
pectant management. The median latency after expectant man-
agement was 17.5 days. The median gestational age at delivery
after expectant management was 25.1 weeks. The median gesta-
72 Original Article

Table 1  Characteristics of pregnancies (n = 160).

Characteristic n a,b Total n a,c n a, c, d Neonatal survivors n a, c, d Fetal and neonatal P-value e
non-survivors
Age (y) f 160 32 (18.3–50.2) 164 48 30.5 (21.7–40.5) 116 32.3 (18.3–50.2) 0.078
Twin pregnancy g 160 25 (15.6 %) 164 48 3 (6.3 %) 116 26 (22.4 %) 0.014
Gravidity f 160 2 (1–16) 164 48 2 (1–10) 116 2 (1–16) 0.791
Parity f 160 1 (0–15) 164 48 1 (0–5) 116 1 (0–15) 0.826
Gestational age at PPROM (w) f 159 20.3 (12.4–23.9) 163 47 22 (12.4–23.9) 116 19 (14.0–23.7)  < 0.001
   < 20 weeks g 160 74 (46.3 %) 164 48 10 (20.8 %) 116 66 (56.9 %)  < 0.001
Risk factors PPROM present g 160 122 (76.3 %) 164 48 36 (75.0 %) 116 90 (77.6 %) 0.721
 Infection 158 64 (40.5 %) 162 48 17 (35.4 %) 114 48 (42.1 %) 0.428
  GBS 157 32 (20.4 %) 161 48 9 (18.8 %) 113 23 (20.4 %) 0.816
  History of PPROM 154 16 (10.4 %) 158 47 2 (4.3 %) 111 14 (12.6 %) 0.152
  Antepartum hemorrhage 149 57 (38.3 %) 153 47 21 (44.7 %) 106 38 (38.0 %) 0.300
  Cervical cerclage 159 19 (11.9 %) 163 48 3 (6.3 %) 115 16 (13.9 %) 0.165
Oligo- or anhydramnios g 135 110 (81.5 %) 138 46 33 (71.7 %) 92 80 (87.0 %) 0.029
Tocolytic drugs g 151 48 (31.8 %) 155 42 29 (69.0 %) 113 21 (18.6 %)  < 0.001
Steroids g 150 73 (48.7 %) 153 45 45 (100 %) 108 29 (26.9 %)  < 0.001
Latency period (d) f 153 10 (0–136) 159 44 53 (5–136) 115 5 (0–85)  < 0.001
Gestational age at delivery (w) f 160 23.8 (15.1–36.7) 164 48 29.3 (23.9–36.7) 116 21.7 (15.1–31.3)  < 0.001
Mode of delivery: vaginal g 160 134 (83.7 %) 164 48 27 (56.3 %) 116 110 (94.9 %)  < 0.001
Histological evidence infection g 141 108 (76.6 %) 145 41 24 (58.5 %) 104 17 (83.7 %) 0.001
a
 Number of patients the variable was obtained from; b Total number of pregnancies (n = 160); c Total number of fetuses (n = 164); d Survivors (n =  48) and non-survivors (n = 116)
were obtained from number of fetuses; e P-value is obtained from survivors vs. non-survivors; f Median (range); g Number of patients (%)
n, number; y, years; PPROM, preterm premature rupture of membranes; w, weeks; GBS, Group B Streptococcus; d, days

Table 2  Characteristics of admitted neonates (n = 68).

Characteristics n a Total n a,b Neonatal survivors n a,b Fetal and neonatal P-value c
non-survivors
Gestational age at PPROM (w) d 67 21.6 (12.4–23.9) 47 22.0 (12.4–23.9) 20 20.6 (16.4–23.7) 0.419
  < 20 weeks e 67 17.0 (25.4 %) 47 9.0 (19.1 %) 20 8.0 (40.0 %) 0.073
Oligo- or Anhydramnios e 63 49.0 (77.8 %) 46 33.0 (71.1 %) 17 16.0 (94.1 %) 0.088
Latency period (d) d 62 51.5 (4–136) 44 53.0 (5–136) 18 46.0 (4–85) 0.046
Gestational age at delivery (w) d 68 28.1 (23.9–36.7) 48 29.3 (23.9–36.7) 20 26.0 (24.0–31.3)  < 0.001
Gender e 0.092
 Male 68 20.0 (29.4 %) 48 31.0 (64.6 %) 20 17.0 (85.0 %)
 Female 68 48.0 (70.6 %) 48 17.0 (35.4 %) 20 3 (15.0 %)
Birthweight (g) d 68 1097.5 (460–2900) 48 1195.0 (600–2900) 20 775 (460–1485) 0.001
Head circumference (cm) d 50 25.0 (20.5–33.0) 39 26.0 (21.0–33.0) 11 23.0 (20.5–29.5) 0.008
Apgar score d
  1 min 67 5 (0–9) 48 6 (0–9) 19 1 (1–7) 0.001
  5 min 68 7 (2–10) 48 7.5 (2–10) 20 2 (2–9) 0.002
  10 min 59 8 (1–10) 41 8 (4–10) 18 1 (1–9) 0.003
Resuscitation at birth e 67 32.0 (47.8 %) 48 21.0 (43.8 %) 19 11.0 (57.9 %) 0.296
a
 Number of patients the variable was obtained from; b Survivors (n = 48) and non-survivors (n = 20) were obtained from number of neonates admitted at NICU (n = 67) or mater-
nity ward (n = 1); c P-value is obtained from survivors vs. non-survivors; d Median (range); e Number of patients (%); f Mean ± SD
NICU, neonatal intensive care unit; n, number; w, weeks; d, days; g, grams; cm, centimeters

tional age at delivery for pregnancies complicated by oligo- or
anhydramnios was 24.9 weeks (p = 0.048). Complications were
documented for 90 women (56.2 %); 44/160 women had an in-
fection (27.5 %), 47/160 women had a retained placenta (29.4 %),
9/160 women had a placental abruption (5.6 %)
2 women developed sepsis and underwent a hysterectomy
(1.3 %); one of them even developed multiple organ failure
(0.6 %). Both women chose active management and already had
signs of intra-uterine infection when they presented at the hos-
 ▶  Table 2. The overall median gestational age at de-
­presented in ●
livery was in this group 28.1 weeks. In neonates born after a
pregnancy complicated by oligo- or anhydramnios median
­gestational age at delivery was lower at 27.7 weeks (p < 0.030).
Previable PPROM < 20 weeks vs. > 20 weeks of
pregnancy
Fetal and neonatal mortality is compared between previable
PPROM before and after 20 weeks of pregnancy ( ● ▶  Table 3). Of

pital. There were no maternal deaths. The incidence of maternal the 116 fetal and neonatal deaths, 77 cases (66.4 %) were origi-
complications did not differ between active and expectant man- nally expectant management cases. 28 neonates (22.4 %) died
agement (p = 0.693). within 24 h postpartum. After these first 24 h, mortality de-
A total of 68 neonates were admitted at the NICU (n = 67) or creases substantially (8.8 %). 48 neonates (38.4 %) born after ex-
maternity ward (n = 1). Characteristics of these neonates are
­ pectant management survived until discharge (22.7 vs. 46.9 %;

van der Marel I et al. Rupture of Membranes before Viability …  Klin Padiatr 2016; 228: 69–76
 Original Article 73

Table 3  Fetal and neonatal mortality (n = 164).

na Total na Previable na Previable P-value b

PPROM < 20 weeks PPROM > 20 weeks
Total deaths 164 116 (70.7 %) 76 66 (86.8 %) 88 50 (56.8 %)  < 0.001
Fetal and neonatal mortality after EM
c,d
 Stillborn  125 38 (30.4 %) 44 20 (45.5 %) 81 18 (22.2 %) 0.007
  Death at < 24 h c 125 28 (22.4 %) 44 11 (25.0 %) 81 17 (21.0 %) 0.607
  Death at  > 24 h < 7 d c 125 5 (4.0 %) 44 1 (2.3 %) 81 4 (4.9 %) 0.656
  Death at > 7 d c 125 6 (4.8 %) 44 2 (4.5 %) 81 4 (4.9 %) 1.000
  Total deaths 125 77 (61.6 %) 44 34 (77.3 %) 81 43 (53.1 %) 0.008
a
 Number of patients the variable was obtained from; b P-value is obtained from previable PPROM < 20 weeks vs. > 20 weeks of pregnancy; c Number of patients (%); d Stillborn is
defined as death due to TOP, death before or during labor
n, number; h, hours; d, days; EM, expectant management; TOP, termination of pregnancy

Characteristic n b Previable PPROM  < 20 n b Previable PPROM > 20 P-value c Table 4  Pregnancies characteris-
tics compared between previable
weeks weeks
PPROM before and after 20 weeks
Twin pregnancy d 76 19 (25.0 %) 88 10 (11.4 %) 0.022 of pregnancy a.
Gravidity e 76 2.5 (1–10) 88 2 (1–16) 0.894
Parity e 76 1 (0–4) 88 1 (0–15) 0.714
Gestational age at PPROM (w) e 75 17.7 (12.4–19.9) 88 22.5 (20.0–23.9)  < 0.001
Risk factors PPROM d
  Risk factors present 76 59 (77.6 %) 88 67 (76.1 %) 0.821
 Infection 74 31 (41.9 %) 88 34 (38.6 %) 0.674
  GBS 73 17 (23.3 %) 88 15 (17.0 %) 0.214
  History of PPROM 72 9 (11.8 %) 86 7 (8.1 %) 0.366
  Antepartum hemorrhage 73 30 (41.1 %) 80 29 (36.3 %) 0.538
  Cervical cerclage 76 3 (3.9 %) 87 16 (36.3 %) 0.004
Oligo- or Anhydramnios d 60 53 (88.3 %) 78 60 (76.9 %) 0.084
Management d
 Active 76 32 (42.1 %) 88 7 (8.0 %)  < 0.001
 Expectant 76 44 (57.9 %) 88 81 (92.0 %)  < 0.001
Tocolytic drugs d 74 9 (12.2 %) 81 41 (50.6 %)  < 0.001
Steroids d 72 17 (23.6 %) 81 57 (70.4 %)  < 0.001
Latency period (d) e,f 43 35 (0–136) 75 12 (0–103) 0.177
Gestational age at delivery (w) e,f 44 23.1 (15.3–36.7) 81 25.3 (21.0–35.9) 0.010
Mode of delivery: vaginal d 76 65 (85.5 %) 88 72 (81.8 %) 0.523
Histological evidence infection d 69 51 (73.9 %) 76 60 (78.9 %) 0.475
a
 Number of previable PPROM < 20 weeks (n = 76) and previable PPROM > 20 weeks of pregnancy (n = 88) were obtained from number
of fetuses (n = 164); b Number of patients the variable was obtained from; c P-value is obtained from previable PPROM < 20 weeks vs.
previable PPROM > 20 weeks of pregnancy; d Number of patients (%); e Median (range); f With expectant management data. Expectant
management (n = 125) was obtained from number of fetuses (n = 164)
n, number; PPROM, preterm premature rupture of membranes; w, weeks; d, days

respectively previable PPROM before and after 20 weeks). Neo-
nates born after previable PPROM > 20 weeks of pregnancy had a
greater probability of being alive at discharge (p = 0.008).
Differences in pregnancy characteristics between previable
PPROM < 20 weeks vs. > 20 weeks are showed in ●  ▶  Table 4. More
parents opted for expectant management with previable PPROM
> 20 weeks (p < 0.001). ●  ▶  Table 5 demonstrates neonatal morbid-
ity and mortality and the comparison between previable PPROM
before and after 20 weeks of pregnancy. Both PPHN and contrac-
tures are significantly more frequent with PPROM < 20 weeks
(64.7 %; p = 0.001 and 58.8 %; p < 0.001 respectively).
Factors associated with gestational age during PPROM were ex-
amined in a multivariable analysis to control for potential con-
founders ( ●▶  Table 6). Because all selected participants received
antenatal steroids, this characteristic was not used in the analy-
sis. Oligo- and anhydramnios were not confounding factors of
neonatal mortality and were therefore not used in the analysis.
Previable PPROM < 20 weeks of pregnancy is found to be an inde-
pendent predictor, corrected for confounders, of the outcome
measures neonatal mortality after expectant management. Con-
tractures and PPHN continued to be related to PPROM < 20 weeks
of pregnancy.
Discussion
▼
This study of previable PPROM, with a relatively large study pop-
ulation of 164 fetuses from one tertiary perinatal center, shows
that more than 50 % of the mothers develop one or more compli-
cations (intra-uterine infection, retained placenta, placental
abruption or sepsis). Neonates have a high mortality rate, espe-
cially neonates born after PPROM < 20 weeks of pregnancy. The
overall neonatal survival rate after expectant management was
38.4 %. In particular neonates born after PPROM < 20 weeks of
pregnancy should be watched closely for PPHN and contractures.
Previous studies showed that the mother has a relatively high
incidence of intra-uterine infections (range 24.7–46.4 %), retained
placenta (> 10 %) and placental abruption (> 5 %) [5, 15, 26, 27, 29].

van der Marel I et al. Rupture of Membranes before Viability …  Klin Padiatr 2016; 228: 69–76
74 Original Article

In the present study, 27.5 % of women showed clinical signs of As above mentioned, the amount of remaining amniotic fluid is
intra-uterine infection, 29.4 % of retained placenta and 5.6 % of an important predictive factor for neonatal outcome [14, 28]. In

Table 5  Morbidity and mortality of admitted neonates (n = 68)a.

Characteristics n b Total n b Previable PPROM < 20 n b Previable PPROM > 20 P-value c
weeks weeks
Oligo- or anhydramnios d 63 49 (77.8 %) 15 14 (93.3 %) 48 35 (72.9 %) 0.156
Latency period (d) e 62 51.5 (4–136) 17 85 (51–136) 45 41 (4–103)  < 0.001
Gestational age at delivery (w) e 68 28.1 (23.9–36.7) 18 29.2 (25.1–36.7) 50 27.7 (23.9–35.9) 0.101
Gender d 0.670
 Male 68 20 (29.4 %) 18 12 (66.7 %) 50 36 (72.0 %)
 Female 68 48 (70.6 %) 18 6 (33.3 %) 50 14 (28.0 %)
Birthweight (g) e 68 1 097.5 (460–2900) 18 1 174.5 (690–2575) 50 1 090 (460–2900) 0.483
Head circumference (cm) e 50 25 (20.5–33.0) 10 24.8 (22.7–30.2) 40 25.3 (20.5–33.0) 0.875
Resuscitation at birth d 67 32 (47.8 %) 18 7 (38.9 %) 49 25 (51.0 %) 0.378
Duration invasive ventilation (d) e 68 2.0 (0–35) 18 3 (0–13) 50 2 (0–35) 0.556
Surfactant d 65 41 (63.1 %) 17 14 (82.4 %) 48 27 (56.3 %) 0.084
Dexamethasone d 65 10 (15.4 %) 16 2 (12.5 %) 49 8 (16.3 %) 1.000
NO d 66 15 (22.7 %) 17 7 (41.2 %) 49 8 (16.3 %) 0.048
Complications d
 RDS 66 39 (59.1 %) 18 12 (66.7 %) 48 27 (56.3 %) 0.443
 BPD
   Need of oxygen 28 days pp 65 33 (50.8 %) 18 8 (44.4 %) 47 25 (53.2 %) 0.528
   Need of oxygen 36 weeks g 60 25 (41.7 %) 18 7 (38.9 %) 42 18 (42.9 %) 0.775
 PPHN 66 21 (31.8 %) 17 11 (64.7 %) 49 10 (20.4 %) 0.001
 Contractures 66 14 (21.2 %) 17 10 (58.8 %) 49 4 (8.2 %)  < 0.001
  Early infection (< 7 days pp) 67 12 (17.9 %) 17 2 (11.8 %) 50 10 (20.0 %) 0.716
  Late infection (> 7 days pp) 66 28 (42.4 %) 16 4 (25.0 %) 50 24 (48.0 %) 0.105
 PDA 61 15 (24.6 %) 15 2 (13.3 %) 46 13 (28.3 %) 0.317
 NEC 67 4 (6.0 %) 17 0 (0.0 %) 50 4 (8.0 %) 0.565
 ROP 43 7 (16.3 %) 9 0 (0.0 %) 34 7 (20.6 %) 0.314
 IVH 68 5 (7.3 %) 18 0 (0.0 %) 50 5 (10.0 %) 0.315
Alive at discharge d 68 48 (70.6 %) 18 10 (55.6 %) 50 38 (76.0 %) 0.103
Duration NICU stay (d) e 68 10.5 (0–145) 18 7.5 (1–145) 50 18 (0–119) 0.130
Duration of hospitalization (d) e 63 46 (1–188) 17 30 (1–145) 46 56 (1–188) 0.135
a
 Number of previable PPROM < 20 weeks (n = 18) and previable PPROM > 20 weeks (n = 50) were obtained from neonates admitted at NICU (n = 67) or maternity ward (n = 1);
b
 Number of patients the variable was obtained from; c P-value is obtained from previable PPROM < 20 weeks vs. previable PPROM > 20 weeks of pregnancy; d Number of patients
(%); e Median (range); f Mean ± SD; g Need of oxygen at the corrected age of 36 weeks amenorrhea
n, number; d, days; w, weeks; g, grams; cm, centimeters; NO, nitric oxide; RDS, respiratory distress syndrome; BPD, bronchopulmonary dysplasia; pp, post-partum; PPHN,
persistent pulmonary hypertension of the neonate; PDA, patent ductus arteriosus; NEC, necrotizing enterocolitis; ROP, retinopathy of prematurity; IVH, intraventricular hemor-
rhage; NICU, neonatal intensive care unit

placental abruption. The higher percentage of retained placentas
can be explained by the fact that previous studies described
higher gestational ages during PPROM and neonates where
therefore more likely to be delivered at higher gestational ages,
which decreases the chance of a retained placenta.
The median latency period, after expectant management, with
previable PPROM < 20 weeks was significantly longer than with
previable PPROM > 20 weeks of pregnancy (35 vs. 12 days). Pre-
vious studies show latency ranges from 62 h until 63 days
[5, 7, 13, 22, 25–27, 29]. A longer latency period is proven to be a
predictor for pulmonary hypoplasia, which is associated with
high morbidity (PPHN, chronic pulmonary hypertension, BPD)
and mortality rates [28]. Nevertheless, neonatal survival is high-
er when delivery is at a higher gestational age. Oligohydramnios
due to PPROM is partly responsible for poorer fetal lung develop-
ment. During midtrimester, fetal lung development coincides
with the critical canalicular stage. Therefore, pulmonary hypo-
plasia is associated with gestational age at PPROM [24, 28]. The
prevalence of BPD was 41.7 vs. 13–60 % in previous studies
[7, 15, 24, 25, 28, 29]. Because this study only involved previable
PPROM, we had expected this high prevalence of BPD.
the present study oligohydramnios was mostly seen with
PPROM < 20 weeks of pregnancy and in neonatal non-survivors.
Gestational age at delivery was lower in the presence of oligohy-
dramnios after expectant management and with admitted neo-
nates. However, in the latter group, the presence of oligohy-
dramnios did not exert an influence on survival.
The overall neonatal mortality rate was 70.7 vs. 34 %–82 % in pre-
vious studies [15,  24, 26, 
27, 
29]. Most were stillborn and
deaths < 24 h postpartum. These are often related with pulmo-
nary hypoplasia or neonatal sepsis. These deaths were particu-
larly seen with PPROM < 20 weeks of pregnancy. The chance of
survival was 91.2 % after the first 24 h postpartum, and was
­irrespective of time of occurrence of PPROM.
The neonatal survival rate with expectant management was
38.4 vs. 17–80 % in previous studies [5, 7, 13, 15, 22, 24, 26–28]. It
was highest for neonates born after previable PPROM > 20 weeks,
despite the fact that neonates born after PPROM < 20 weeks of
pregnancy were born at a higher gestational age. These neo-
nates’ higher risk to develop pulmonary morbidity might con-
tribute to the higher mortality rate. After adjustment for possi-
ble confounders, PPROM < 20 weeks appeared to be indepen-
dently associated with neonatal mortality.

van der Marel I et al. Rupture of Membranes before Viability …  Klin Padiatr 2016; 228: 69–76

Table 6  Multivariable analysis: neonatal mortality, contractures, PPHN and
BPD with PPROM < 20 weeks of pregnancy.
Outcome measure Crude OR (95 % CI) Adjusted OR (95 % CI)
Neonatal mortality with 3.01 (1.31–6.89) 9.78 (1.85–51.66)
fetal data a, b
Neonatal mortality 2.53 (0.82–7.87) 2.11 (0.23–19.16)
with fetal- and neonatal
data c, d
Contractures d, e 14.38 (3.61–57.22) 17.78 (2.41–131.20)
PPHN d, f 7.09 (2.16–23.23) 8.69 (1.88–40.09)
BPD d, g, h 0.88 (0.29–2.64) 0.97 (0.22–4.25)
a
 Adjusted for histological infection, latency period, cervical cerclage, tocolytic drugs,
antenatal steroids, mode of delivery, twin pregnancies; b Only data of patients with
expectant management was used (n = 125); c Adjusted for gender, birthweight,
steroids, nitric oxide, RDS, contractures, NEC, early infection, PDA, IVH; d Only data
of neonates who were admitted at NICU or maternity ward were used (n = 68); e Ad-
justed for oligo- or anhydramnios, latency period, gestational age at delivery, twin
pregnancies; f Adjusted for oligo- or anhydramnios, latency period, gestational age
at delivery, RDS; g Adjusted for oligo- or anhydramnios, latency period, gestational
age at delivery, mode of delivery, steroids, surfactant, neonatal infection; h Need of
oxygen at the corrected age of 36 weeks amenorrhea
PPROM, preterm premature rupture of membranes; PPHN, persistent pulmonary
hypertension of the neonate; BPD, bronchopulmonary dysplasia; OR, odds ratio; CI,
confidence interval; RDS, respiratory distress syndrome; NEC, necrotizing enterocol-
itis; PDA, patent ductus arteriosus; IVH, intraventricular hemorrhage
All admitted neonates were born preterm with a median gesta-
tional age of 28.1 weeks. Neonates born after previable PPROM
appear to be a special group of neonates, faced with both com-
plications due to previable PPROM and due to prematurity. The
most frequent complications were respiratory failure and late
infection. PPHN and contractures were most frequent in neo-
nates born after PPROM < 20 weeks and continued to be inde-
pendently related to PPROM < 20 weeks of pregnancy after mul-
tivariable analysis. These serious complications may affect
short- and long term outcome. PPHN carries high mortality and
morbidity risks (BPD, chronic pulmonary hypertension and neu-
rological complications). Due to the high prevalence of PPHN
after PPROM < 20 weeks, physicians should manage these preg-
nancies in tertiary centers where appropriate treatment is avail-
able for these neonates. Contractures carry a risk of movement
restriction, but can be reversed. However, proper guidance is
necessary [3, 4, 8].
Strengths and limitations
To appreciate the results of this study some strengths and limi-
tations must be addressed.
Previable PPROM is rare and therefore it is not easy to create a
large sample of patients. Still, the sample collected over 10 years
is one of the largest so far [5, 13, 27, 29]. Furthermore, this study
was a single-center study in the biggest tertiary university cent-
er in the Netherlands with a large referral area, which is a
strength compared to other previous multicenter studies. More-
over, this study investigated both maternal and neonatal data.
This allowed us to perform multivariable analyses on both ma-
ternal and neonatal variables that could have influenced the out-
come. Neonatal data were collected from birth until discharge
from the hospital, consequently all neonatal short term morbid-
ity during the entire admission period could be considered. We
chose to include twin pregnancies which allowed us to have a
complete representation of our patient population, if necessary
we adjusted for twin pregnancies in the multivariable analysis.
Furthermore, we performed a sensitivity analysis of twin preg-
van der Marel I et al. Rupture of Membranes before Viability …  Klin Padiatr 2016; 228: 69–76
Original Article 75
nancies for maternal morbidity, neonatal morbidity, neonatal
survival and also the multivariable analysis, which did not alter
any results.
A major limitation was the retrospective design. This precluded
analyzing fetal growth restriction, which was not properly regis-
tered in the medical files. Nevertheless, few other data were
missing. Furthermore, patients were not managed identical due
to changes in the medical protocol during the study period. Ad-
ditionally, neonatal care has also improved over time, guidelines
for resuscitation of the neonate and the policy for providing care
at the threshold of viability also changed during our study peri-
od; until 2009 most neonates born< 25weeks of gestational age
were expectantly managed, after 2009 neonates born > 24weeks
of gestational age received all necessary care. All above mentioned
changes could have affected the results. Counseling parents be-
tween active or expectant management was dependent on the
then available medical knowledge on this particular subject. Due
to its retrospective nature a preadmission bias may exist and out-
come measures, except mortality, were not standardized.
Finally, we did not include a control group with matched pre-
term delivered neonates without previable PPROM. This would
have strengthened the study design, but was not the primary
objective of this retrospective cohort study. The primary objec-
tive was to investigate incidence of maternal, fetal and neonatal
outcome with a large study population using data from one ter-
tiary perinatal center.
Conclusion
▼
Outcomes after previable PPROM can be severe for both mother
and neonate, especially for neonates born after previable
PPROM < 20 weeks of pregnancy. The results of this study will
help parents and the perinatal team further with optimal coun-
seling and tailored decision-making. A sequel prospective study
of previable PPROM needs to include a control group so as to
obtain better evidence on important determinants. Further-
more, a clinical prediction model of previable PPROM should be
developed for better risk assessment of morbidity and mortality.
Neonates born after previable PPROM are at high risk for long
term morbidity, but the actual consequences remain unclear
[15, 16, 25, 27, 30]. We suggest long term follow up studies on the
complications and sequelae of previable PPROM.
Funding Statement
▼
No funding was needed for this study.
Contributor’s Statement
▼
a. Study coordination and design, data collection, data analysis,
writing of manuscript, approval of final version b. I van der Marel,
R de Jonge and I Brussé. a. Critical review of the manuscript,
­approval of final version b. J Duvekot, I Reiss.
Acknowledgements
▼
This paper benefited from the input of colleague J. Hagoort who
provided valuable comments on readability.
76 Original Article
Conflict of interest: The authors declare no conflict of interest.
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