16 CME REVIEW ARTICLE Volume 73, Number 6

OBSTETRICAL AND GYNECOLOGICAL SURVEY

Copyright © 2018 Wolters Kluwer Health,
Inc. All rights reserved.

CHIEF EDITOR’S NOTE: This article is part of a series of continuing education activities in this Journal through which a total of
36 AMA PRA Category 1 Credits™ can be earned in 2018. Instructions for how CME credits can be earned appear on the last page of
the Table of Contents.

Preterm Premature
Rupture of Membranes:
A Review of 3 National Guidelines
Downloaded from http://journals.lww.com/obgynsurvey by BhDMf5ePHKbH4TTImqenVLeEdd5NVDXpKbUwVoObA0E17jX21QUjMXm45uYTbz9+nqcPjDqBveI= on 07/21/2018

Ioannis Tsakiridis, MSc,* Apostolos Mamopoulos, PhD,†

Eleni-Markella Chalkia-Prapa, MD,*
Apostolos Athanasiadis, PhD,‡ and Themistoklis Dagklis, PhD§
*Resident Assistant, †Associate Professor, ‡Professor, and §Consultant in Maternal-Fetal Medicine, Third Department of
Obstetrics and Gynaecology, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece

Importance: Preterm premature rupture of membranes (PPROM) is a major cause of perinatal mortality
and morbidity.
Objective: The aim of this study was to compare recommendations from published national guidelines for
pregnancies complicated with PPROM.
Evidence Acquisition: A descriptive review of 3 national guidelines on PPROM was performed: the Royal
College of Obstetricians and Gynaecologists on “Preterm Prelabour Rupture of Membranes,” the American
College of Obstetricians and Gynecologists on “Premature Rupture of Membranes,” and the Society of Obstetri-
cians and Gynaecologists of Canada on “Antibiotic Therapy in Preterm Premature Rupture of the Membranes.”
Guidelines were compared in the diagnosis and management of PPROM. Recommendations and strength
of evidence were reviewed based on each guideline's method of reporting. The references were compared with
regard to their total number, total number of randomized controlled trials, Cochrane reviews, and systematic
reviews/meta-analyses cited.
Results: The variations stated on the guidelines reflect the heterogeneity of the literature contributing to the
guidelines and challenges of diagnosing and managing cases of PPROM.
Conclusions: An improved international guideline may improve safety and outcomes in pregnant women with
PPROM.
Target Audience: Obstetricians and gynecologists, family physicians.
Learning Objectives: After completing this activity, the learner should be better able to assess the aspects
on diagnosis of preterm premature rupture of membranes, analyze the available regimens for the manage-
ment of cases with preterm premature rupture of membranes, and identify the appropriate time of delivery
in cases of preterm premature rupture of membranes.

There is an international consensus that pregnancies
affected by preterm premature rupture of membranes
(PPROM) represent a daily challenge for the obstetrician,
All authors, faculty, and staff in a position to control the content of
this CME activity and their spouses/life partners (if any) have disclosed
that they have no financial relationships with, or financial interests in,
any commercial organizations pertaining to this educational activity.
Correspondence requests to: Ioannis Tsakiridis, MSc,
Konstantinoupoleos 49, 54642, Thessaloniki, Greece. E-mail:
igtsakir@auth.gr.
www.obgynsurvey.com | 368
and evidence-based guidelines should be available for the
best management of such pregnancies. Evidence-based
clinical practice guidelines represent a synthesis of lit-
erature and are designed to assist clinicians in making
decisions regarding clinical practice.1 Preterm premature
rupture of membranes is defined as rupture of mem-
branes occurring prior to 37 weeks of gestation.2 It com-
plicates approximately 2% of pregnancies, and 40% of
these cases result in preterm delivery, contributing signif-
icantly to increased neonatal morbidity and mortality.3–5

Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

 Preterm Premature Rupture of Membranes • CME Review Article
The etiology of PPROM is multifactorial, although
intrauterine infection is the most common risk factor,
especially at earlier gestational age.6 Moreover, women
with PPROM and preterm labor often have highly pos-
itive cultures; infection preceding PPROM is often sub-
clinical and thought to ascend from the lower genital
tract.7–9 This ascending bacterial invasion may lead
to intrauterine infection in up to 60% of cases with
PPROM.10 One of the major functions of fetal mem-
branes is to protect the fetus during its growth and de-
velopment. Moreover, they provide mechanical and
immune protection and act as a barrier for microbial
access.11,12 Compromise in the immune and mechani-
cal properties of the fetal membranes allows for micro-
bial invasion from the genital tract, activation of host
inflammatory response leading to collagenolysis-
mediated mechanical disruption, and membrane weak-
ening leading to PPROM.13,14 Abruption-associated
thrombin and matrix metalloproteinase activation and
collagenolytic processes have also been reported in
fetal membrane weakening and PPROM.15 Clearly,
PPROM is considered as a disease of the fetal mem-
branes and a separate entity from spontaneous preterm
labor without rupture of membranes. Additional risk
factors for PPROM include history of PPROM in a
previous pregnancy,16,17 short cervical length, bleeding
during pregnancy, low body mass index, low socioeco-
nomic status, smoking, and illicit-drug use.18–21
The purpose of this descriptive review is to compare
3 available national guidelines on PPROM with regard
to the diagnosis and management (including use of cor-
ticosteroids, tocolytics, antibiotics, and time of delivery).
EVIDENCE ACQUISITION
A descriptive review of 3 national guidelines on
PPROM that were published by the Royal College
of Obstetricians and Gynaecologists (October 2010)
(RCOG),22 the American College of Obstetricians and
Gynecologists (October 2016) (ACOG),23 and the So-
ciety of Obstetricians and Gynaecologists of Canada
(September 2009) (SOGC)24 was conducted. The guide-
lines were reviewed and compared in relation to diagno-
sis and management. The references were also compared
with regard to the total number of randomized con-
trolled trials, Cochrane reviews, and systematic reviews/
meta-analyses cited. Table 1 represents the summary of
recommendations of the 3 national guidelines.
DIAGNOSIS OF PPROM
Both ACOG and RCOG state that the diagnosis of
PPROM is typically confirmed by direct visualization
of the amniotic fluid passing from the cervical canal
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
369
and pooling into the vagina. Consequently, a combina-
tion of maternal history followed by a sterile speculum
examination is the key to the diagnosis. Both of these
guidelines also suggest that digital cervical examina-
tions should be avoided to decrease the risk of infection,
unless the patient is in active labor.25,26 It should be
noted that SOGC makes no mention whatsoever on
the diagnosis of PPROM.
A basic pH test of the vaginal fluid is also useful for
the diagnosis, as reported from the UK and US guide-
lines. The pH of the vaginal secretions is normally 4.5
to 6.0, whereas the amniotic fluid usually has a pH of
7.1 to 7.3. A range of tests have been used to confirm
PPROM by measuring the pH; the most widely used
is nitrazine test, which detects pH change27,28 and has
a sensitivity of 90% and specificity of 83%.29 Other
tests that have been widely used include microscopic
examination of the vaginal fluid for the characteristic
ferning of the crystalline pattern of dried amniotic fluid
owing to its sodium chloride and protein content30,31
with a reported sensitivity of 98% and specificity of
88.2%,32 examination for lanugo hair,30 and fetal epi-
thelial cells stained with Nile blue.33 However, the di-
agnosis of PPROM can be difficult when the “gush of
fluid” does not occur and there is a slow fluid leak or
in cases of active bleeding.34 In addition, a normal rel-
atively low amount of amniotic fluid early in gestation
further challenges the diagnosis of PPROM.35 Ladfors
et al36 proved that even later in pregnancy speculum
examination for the visualization of the amniotic fluid
has a 12% false-negative rate when no fluid is seen.
There are also several commercially available tests
that detect amniotic proteins, with high reported sensi-
tivity for PPROM. One such test is based on the detec-
tion of placental α-microglobulin 1, which has different
concentrations between the amniotic fluid and the
cervicovaginal secretions. Placental α-microglobulin
1 can be detected with as little as 0.25 μL of amniotic
fluid present in 1 mL of vaginal secretions.37 Further-
more, the placental α-microglobulin 1 assay appears to
be reliable over a wide range of gestational ages and
has been proven superior to conventional combined
clinical tests including visualization of fluid pooling in
the posterior fornix, arborization, and nitrazine testing.38
Both UK and US guidelines further state that an ultra-
sound examination demonstrating oligohydramnios is
also useful to confirm the diagnosis of PPROM but is
not diagnostic if used alone.39–42
MANAGEMENT OF PPROM
Both UK and US guidelines insist on the identifica-
tion of signs of clinical chorioamnionitis that constitute
 370

TABLE 1
Summary of Recommendations for PPROM
RCOG Green-Top Guideline ACOG Practice Bulletin SOGC Clinical Practice Guideline
(No. 44) (No. 172) (No. 233)
Country United Kingdom United States Canada
Issued October 2010 January 2016 September 2009
Title Preterm Prelabour Rupture Premature Rupture of Membranes Antibiotic Therapy in Preterm
of Membranes Premature Rupture of the Membranes
Pages 12 13 5
References 69 99 20
Quality evaluation and Yes, system not specified US Preventive Services Task Force Canadian Task Force on
grading of recommendation Preventive Health Care
Diagnosis (1) Visualization of the amniotic fluid (1) Visualization of the amniotic Not stated
into the vagina fluid into the vagina
(2) pH tests (2) pH tests
(3) Tests for amniotic proteins (3) Tests for amniotic proteins
(4) Ultrasound examination (4) Ultrasound examination
Management at home Insufficient data to make Not recommended Not stated
recommendations
Group B streptococcus In positive cultures In positive cultures, after fetal viability In positive cultures
prophylaxis
Corticosteroids 24+0–34+0 23+0–34+0 Recommended
Tocolytics Not recommended Not recommended Recommended
Magnesium sulfate Not stated Recommended <32 wk Not stated
Amniocentesis Not recommended Not stated Not stated
Obstetrical and Gynecological Survey

Amnioinfusion Not recommended Not stated Not stated

Fibrin glue Not recommended Not stated Not stated
Prophylactic antibiotics Erythromycin for 10 d Ampicillin IV + erythromycin IV for (1) Ampicillin 2 g IV  4 + erythromycin

Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

48 h followed by amoxicillin PO and 250 mg IV  4 for 48 h followed by
erythromycin PO for 5 d amoxicillin 250 mg PO  3 and
erythromycin 333 mg PO  3 for 5 d
(2) Erythromycin 250 mg PO  4 for 10 d
Time of delivery 34 wk (1) Consider if PPROM <24 wk 32 wk if fetal lung maturity can
(2) 34 wk be documented
 Preterm Premature Rupture of Membranes • CME Review Article
a major indication for induction of labor. Clinical
chorioamnionitis includes maternal pyrexia, tachycar-
dia, leukocytosis, uterine tenderness, offensive vaginal
discharge, and fetal tachycardia. As the sensitivity and
the false-positive rates of leukocytosis in the detection
of clinical chorioamnionitis vary widely (29%–47% and
5%–18%, respectively), RCOG and ACOG do not
recommend serial maternal full blood count.39,43 The
Royal College of Obstetricians and Gynaecologists also
states that biophysical profile and Doppler velocimetry
may also be carried out, but these tests are of limited
value in predicting fetal infection. Moreover, RCOG
and ACOG state that there are insufficient data to make
recommendations for home and outpatient monitoring
rather than continued hospital admission in women
with PPROM.
Vaginal fluid culture for group B streptococcus is
recommended by all 3 societies when expectant man-
agement is considered, and antibiotics should be given
as intrapartum prophylaxis in case of a positive result.
The Society of Obstetricians and Gynaecologists of
Canada also recommends screening for urinary tract in-
fections and sexually transmitted infections and appro-
priate treatment. In the Maternal-Fetal Medicine Units
Network Trial, women who screened positive for uri-
nary tract or sexually transmitted infections were treated
accordingly, although it is unclear whether all enrolled
patients were screened.44 The Royal College of Ob-
stetricians and Gynaecologists recommends against
weekly high vaginal swab and also does not recom-
mend amnioinfusion or fibrin glue for sealing the
chorioamniotic membranes.
All 3 guidelines mention the use of antenatal cortico-
steroids for fetal lung maturity. The Royal College of
Obstetricians and Gynaecologists suggests their use
between 24+0 and 34+0 weeks of gestation, whereas
ACOG states that they may be considered for pregnant
women as early as 23+0 gestational weeks who are at
risk of preterm delivery within 7 days.45,46 The Society
of Obstetricians and Gynaecologists of Canada recom-
mends the use of antenatal corticosteroids, but without
mentioning the appropriate gestational age.24 More-
over, when we searched the SOGC guidelines regard-
ing use of corticosteroids, we found their use is
recommended between 24+0 and 34+0 weeks of gesta-
tion.47 As a result, both RCOG and SOGC make the
same recommendation (24+0 and 34+0 weeks), whereas
ACOG states that the use of antenatal corticosteroids
could be considered from 23+0 gestational weeks. This
gestational age is regarded as periviable from ACOG,
and that is the reason for the different recommenda-
tion.45 It seems that the data are strongest for gestations
between 26+0 and 34+6 weeks. Data from pregnancies
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
371
between 24+0 and 26+0 weeks of gestation are scarce, with
only 1 trial contributing data to a Cochrane review.48 The
conclusion of this Cochrane review48 is that the reduction
in outcomes other than respiratory distress syndrome at
26+0 weeks of gestation would suggest that there is some
benefit in prophylactic corticosteroids at earlier gesta-
tions, between 24+0 and 26+0 weeks. A meta-analysis
of 15 randomized controlled trials involving more than
1400 women with PROM showed that antenatal cortico-
steroids reduce the risk of respiratory distress syndrome
(relative risk [RR], 0.56; 95% confidence interval [CI],
0.46–0.70), intraventricular hemorrhage (RR, 0.47; 95%
CI, 0.31–0.70), and necrotizing enterocolitis (RR, 0.21;
95% CI, 0.05–0.82). They may also reduce the risk of
neonatal death (RR, 0.68; 95% CI, 0.43–1.07), and they
do not appear to increase the risk of infection in either
the mother (RR, 0.86; 95% CI, 0.61–1.20) or the neo-
nate (RR, 1.05; 95% CI, 0.66–1.68).49
As for the use of tocolysis, neither RCOG nor ACOG
recommends it because it does not significantly im-
prove the perinatal outcome. The Society of Obste-
tricians and Gynaecologists of Canada, on the other
hand, considers tocolytics for the management of
PPROM. The use of tocolysis in the setting of PPROM
is controversial, and clinical practice varies.50 A meta-
analysis of 8 trials with 408 women is of limited use be-
cause women were treated with latency antibiotics and
corticosteroids in only 2 of the trials.51,52 The use of
tocolysis was associated with a longer latency period
and a lower risk of delivery within 48 hours but was
also associated with a higher risk of chorioamnionitis
in pregnancies before 34 weeks of gestation. In sum-
mary, tocolytics may be associated with a prolongation
of pregnancy but an increased risk of chorioamnionitis
without significant maternal or neonatal benefit.
The American College of Obstetricians and Gynecol-
ogists also mentions the use of magnesium sulfate for
fetal neuroprotection in PPROM before 32 weeks.
Randomized controlled trials have demonstrated that
maternal administration of magnesium sulfate when
used before 32 weeks of gestation reduces the risk of
cerebral palsy in surviving infants (RR, 0.71; 95% CI,
0.55–0.91).53
The Royal College of Obstetricians and Gynaecologists
states that there is insufficient evidence to recommend
the use of amniocentesis in the diagnosis of intrauterine
infection and also does not suggest amnioinfusion
or the use of fibrin sealants as routine treatment for
second-trimester oligohydramnios caused by PPROM.
In addition, all guidelines recommend the use of pro-
phylactic antibiotics in cases of PPROM. Administra-
tion of broad-spectrum antibiotics prolongs pregnancy,
reduces maternal and neonatal infections, and reduces
372 Obstetrical and Gynecological Survey
morbidity.44,54,55 The Royal College of Obstetricians and
Gynaecologists recommends erythromycin for 10 days
following the diagnosis of PPROM. The American
College of Obstetricians and Gynecologists suggests a
different approach: a 7-day course of therapy with a
combination of intravenous (IV) ampicillin and eryth-
romycin followed by oral (PO) amoxicillin and erythro-
mycin. The regimen is used in the Eunice Kennedy
Shriver National Institute of Child Health and Human
Development Maternal-Fetal Medicine Units Network
trial and includes ampicillin 2 g IV every 6 hours and
erythromycin 250 mg IV every 6 hours for 48 hours,
followed by amoxicillin 250 mg PO every 8 hours and
erythromycin base (333 mg every 8 hours) for 5 days.
The Society of Obstetricians and Gynaecologists of
Canada recommends 2 regimens similar with the previ-
ously mentioned: (1) ampicillin 2 g IV every 6 hours
and erythromycin 250 mg IV every 6 hours for 48 hours
followed by amoxicillin 250 mg PO every 8 hours and
erythromycin 333 mg PO every 8 hours for 5 days or
(2) erythromycin 250 mg PO every 6 hours for 10 days.
The Society of Obstetricians and Gynaecologists of
Canada mentions that the evidence for benefit is greater
at gestational ages earlier than 32 weeks. All guidelines
suggest that, in patients allergic to penicillin, macrolide
antibiotics (erythromycin) should be used alone. More-
over, the use of amoxicillin/clavulanic acid should not
be used because of an increased risk of necrotizing en-
terocolitis in neonates exposed to this antibiotic. It
should be noted that RCOG recommends erythromycin
based on the results of ORACLE I trial,55 whereas
ACOG states the combination of antibiotics based on
the results of another randomized clinical trial.44 The
Society of Obstetricians and Gynaecologists of Canada
adopts both the aforementioned regimens and gives the
option to the clinician to use the appropriate antibiotics
based on his/her clinical experience and opinion.
A recent (2013) Cochrane systematic review and
meta-analysis of 22 trials56 proved that the use of anti-
biotics following PROM is associated with statistically
significant reductions in chorioamnionitis (RR, 0.66;
95% CI, 0.46–0.96) and a reduction in the number
of babies born within 48 hours (RR, 0.71; 95% CI,
0.58–0.87) and 7 days of PROM (RR, 0.79; 95% CI,
0.71–0.89). In addition, the following markers of neo-
natal morbidity were reduced: neonatal infection (RR,
0.67; 95% CI, 0.52–0.85), use of surfactant (RR,
0.83; 95% CI, 0.72–0.96), oxygen therapy (RR, 0.88;
95% CI, 0.81–0.96), and abnormal cerebral ultrasound
scan prior to discharge from hospital (RR, 0.81, 95%
CI, 0.68–0.98). Kenyon et al57 published a systematic
review of 19 trials involving 6951 women, where sev-
eral different antibiotic regimens were used. Antibiotics
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
were associated with a statistically significant reduction
in the number of infants born within 48 hours (RR,
0.07; 95% CI, 0.58–0.87) and 7 days (RR, 0.80; 95%
CI, 0.71–0.90) of PPROM. In 2008, another systematic
review of 22 trials included more than 6000 women
with PPROM.58 Once again, the use of antibiotics
was associated with a prolongation of pregnancy and
a decrease in chorioamnionitis and several markers of
neonatal morbidity.58
As for the time of delivery, nonreassuring fetal status,
clinical chorioamnionitis, and placental abruption are
indications to expedite delivery. Otherwise, gestational
age is the main parameter that determines the timing
of delivery. Both RCOG and ACOG recommend that
delivery be considered at 34 weeks of gestation. If
expectant management is continued beyond this ges-
tational age, the balance between benefit and risk
should be considered and discussed with the patient.
The American College of Obstetricians and Gynecolo-
gists also states that if PPROM occurs before neonatal
viability (<24 weeks) delivery should be offered and
attempts should be made to provide parents with the
most current and accurate information.59 The Society
of Obstetricians and Gynaecologists of Canada does
not clearly state on the appropriate gestational age of
delivery in PPROM. It considers delivery at 32 gesta-
tional weeks if fetal lung maturity can be documented.
Both RCOG and ACOG agree regarding delivery at
34 weeks of gestation in cases of PPROM. It is thought
that the fetus is protected until then from intra-amniotic
infection with antibiotics, and following administration
of steroids, lung maturity is promoted, and the risk of
necrotizing enterocolitis is limited. As a result, after this
gestational age, the risk of chorioamnionitis-associated
adverse perinatal outcomes outweighs the advantages
of continuing the pregnancy. The Society of Obstetri-
cians and Gynaecologists of Canada suggests delivery
even from 32 gestational weeks if fetal lung maturity
can be documented, as conservative management has
been shown to prolong pregnancy only briefly (36 vs
14 hours, P < 0.001) and to increase the risk of
chorioamnionitis (27.7% vs 10.9%, P = 0.06).60
Morris et al61 conducted the largest randomized
controlled trial (PPROMT), where immediate delivery
was compared with expectant management in cases of
PPROM between 34 and 36+6 weeks of gestation. Ac-
cording to this study, immediate delivery increased the
risk of respiratory distress in neonates (RR, 1.6; 95%
CI, 1.1–2.3) and also time spent in the intensive care unit
(median, 4 vs 2 days; P < 0.001). On the other hand,
those assigned to the expectant management group had
higher risks of antepartum or intrapartum hemorrhage
(RR, 0.6; 95% CI, 0.4–0.9), intrapartum fever (RR, 0.4;
 Preterm Premature Rupture of Membranes • CME Review Article 373

TABLE 2
Main Differences of Recommendations for PPROM
RCOG Green-Top ACOG Practice SOGC Clinical Practice
Guideline (No. 44) Bulletin (No. 172) Guideline (No. 233)
Corticosteroids 24+0–34+0 23+0–34+0 24+0–34+0
Tocolytics No No Yes
Magnesium sulfate Not stated <32 wk Not stated
Prophylactic antibiotics Erythromycin Ampicillin, erythromycin, Ampicillin, erythromycin,
amoxicillin amoxicillin
Time of delivery 34 wk (1) <24 wk 32 wk
(2) 34 wk

95% CI, 0.2–0.9), and longer maternal hospital stay for gestations of less than 34 weeks, but the manage-
(P < 0.0001) but lower risk of caesarean delivery ment of pregnancies complicated with PPROM be-
(RR, 1.4; 95% CI, 1.2–1.7). A recent Cochrane review tween 34 and 37 weeks continues to be a contentious
and meta-analysis (2017) of 12 trials, where PPROMT issue.64 Table 2 summarizes the main differences of
was included, compared planned early birth versus ex- the 3 guidelines in management options.
pectant management for women with PPROM before
37 gestational weeks.62 For the subgroup analysis for REFERENCES
PPROM between 34 and 37 weeks, no significant dif- The number of references for each guideline ranged
ferences were identified between the 2 groups for endo- from 20 (SOGC) to 99 (ACOG) with publications be-
metritis, neonatal infection, and neonatal infection tween 1938 and 2016. Table 3 summarizes the number
confirmed with a positive culture. On the other hand, of randomized controlled trials, Cochrane reviews, and
early birth could lead to increased risk of respiratory systematic reviews referenced in the guidelines. All the
distress syndrome (RR, 1.45; 95% CI, 1.10–1.90) and guidelines state that the specific recommendations were
cesarean delivery (RR, 1.22; 95% CI, 1.05–1.42) but developed after an extensive search of electronic da-
minimized the risk of chorioamnionitis (RR, 0.26; tabases. Furthermore, they reviewed the evidence
95% CI, 0.12–0.57). The main limitations of this study according to a rating scheme (SOGC guidelines used
are as follows: first, it is dominated by the results of the the ranking of the Canadian Task Force on Preven-
PPROMT trial,61 which has the largest sample size; tive Health Care; ACOG guidelines used the ranking
second, included trials were conducted over a 10-year system of the US Preventive Services Task Force,
period in which significant changes occurred in obstet- and RCOG used the GRADE [Grading of Recom-
ric and neonatal management; and third, the studies en- mendations, Assessment, Development and Evaluation]
rolled different patient populations in different settings. system). Expert consensus as a method of recommen-
A meta-analysis of 7 trials including 690 women con- dation was performed, and all rated the strength of their
cluded that there was insufficient evidence to guide recommendations. Only RCOG suggested audit topics,
clinical practice regarding the risks and benefits of and they are represented in Table 4.
expectant management versus delivery in the setting
of PPROM.63 At gestational ages greater than 34 weeks,
CONCLUSIONS
conservative management is associated with an in-
creased risk of amnionitis (16% vs 2%, P = 0.001), pro- Preterm premature rupture of membranes is a major
longed maternal hospitalization (5.2 vs 2.6 days, cause of preterm delivery, which contributes to adverse
P = 0.006), and a lower mean umbilical cord pH at de-
livery (7.25 vs 7.35, P = 0.009) without the benefit of TABLE 3
any reduction in perinatal complications.64 A retrospec- References Used From 3 National Guidelines
tive series examining neonatal outcome following cases Variable RCOG ACOG SOGC
with PPROM that happened between 32 and 36 weeks
Total references, n 69 99 20
of gestation showed that 34 weeks appeared to be the
Range of the years of the 1938–2010 1982–2016 1993–2008
turning point for reduced morbidity65 as the incidence publications cited
of respiratory distress syndrome and the length of Randomized trials cited, n 19 22 7
hospital stay were reduced in infants delivered after Cochrane reviews cited, n 3 8 1
that gestational age.65 In addition, many studies have Systematic reviews or 1 8 1
meta-analyses cited, n
demonstrated benefits of conservative management

Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

374 Obstetrical and Gynecological Survey
TABLE 4
Suggested Audit Topics From 3 National Guidelines
Topic RCOG ACOG SOGC
Proportion of women with PPROM X
receiving erythromycin for 10 d
Proportion of women with PPROM X 8. Romero R, Espinoza J, Chaiworapongsa T, et al. Infection and
receiving a complete course of
antenatal corticosteroids
Proportion of women with PPROM X 9. Gonçalves LF, Chaiworapongsa T, Romero R. Intrauterine in-
being delivered at 34 wk
of gestation
Proportion of women with PPROM X 10. Mercer BM. Preterm premature rupture of the membranes.
delivered after 34 wk of gestation
with documented advice of
increased risk of chorioamnionitis
and decreased risk of neonatal
respiratory problems
Not provided X X
perinatal outcomes. The strengths of our analysis include
the synthesis of the major guidelines in the recommenda-
tions for PPROM including diagnosis and management.
This analysis has several limitations. First, the review is
limited to 3 English-language national guidelines, but it
was the aim of this study in order to compare guidelines
from similarly resourced settings. Second, SOGC
states only in the antibiotic therapy of PPROM, and
no comments are made regarding diagnosis or other
methods of management (there is no published guide-
line of SOGC stated on diagnosis and management
of PPROM).
To summarize, in cases of PPROM, expectant man-
agement seems to be the appropriate approach. Group
B streptococcus prophylaxis if indicated and a course
of corticosteroids and antibiotics are recommended to
prolong latency if there are no contraindications.
Magnesium sulfate should be considered in cases of
PPROM before 32 weeks for fetal neurodevelopment.
As for the appropriate timing of delivery, RCOG and
ACOG recommend 34 weeks, whereas 32 weeks should
be considered if fetal lung maturity is documented ac-
cording to SOGC. Finally, a synthesis of an international
guideline would promote the safety and outcomes of
women with PPROM.
REFERENCES
1. Al-Niaimi A, Chauhan SP, Gupta LM, et al. Factors influencing the
evolving practice of obstetricians in Eastern Wisconsin: a survey.
Am J Perinatol. 2008;25:321–324.
2. Waters TP, Mercer B. Preterm PROM: prediction, prevention,
principles. Clin Obstet Gynecol. 2011;54:307–312.
3. Maxwell GL. Preterm premature rupture of membranes. Obstet
Gynecol Surv. 1993;48:576–583.
4. Merenstein GB, Weisman LE. Premature rupture of the mem-
branes: neonatal consequences. Semin Perinatol. 1996;20:
375–380.
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
5. Douvas SG, Brewer MJ, McKay ML, et al. Treatment of premature
rupture of the membranes. J Reprod Med. 1984;29:741–744.
6. Garite TJ, Freeman RK. Chorioamnionitis in the preterm gesta-
tion. Obstet Gynecol. 1982;59:539–545.
7. Klein LL, Gibbs RS. Use of microbial cultures and antibiotics in
the prevention of infection-associated preterm birth. Am J Obstet
Gynecol. 2004;190:1493–1502.
prematurity and the role of preventive strategies. Semin Neonatol.
2002;7:259–274.
fection and prematurity. Ment Retard Dev Disabil Res Rev.
2002;8:3–13.
Obstet Gynecol. 2003;101:178–193.
11. Moore RM, Mansour JM, Redline RW, et al. The physiology of fe-
tal membrane rupture: insight gained from the determination of
physical properties. Placenta. 2006;27:1037–1051.
12. Moço NP, Martin LF, Pereira AC, et al. Gene expression and protein
localization of TLR-1, -2, -4 and -6 in amniochorion membranes of
pregnancies complicated by histologic chorioamnionitis. Eur J
Obstet Gynecol Reprod Biol. 2013;171:12–17.
13. DiGiulio DB, Romero R, Kusanovic JP, et al. Prevalence and di-
versity of microbes in the amniotic fluid, the fetal inflammatory
response, and pregnancy outcome in women with preterm pre-
labor rupture of membranes. Am J Reprod Immunol. 2010;64:
38–57.
14. Vadillo-Ortega F, Estrada-Gutiérrez G. Role of matrix metallopro-
teinases in preterm labour. BJOG. 2005;112(suppl 1):19–22.
15. Puthiyachirakkal M, Lemerand K, Kumar D, et al. Thrombin
weakens the amnion extracellular matrix (ECM) directly rather
than through protease activated receptors. Placenta. 2013;34:
924–931.
16. Mercer BM, Goldenberg RL, Moawad AH, et al. The preterm pre-
diction study: effect of gestational age and cause of preterm birth
on subsequent obstetric outcome. National Institute of Child
Health and Human Development Maternal-Fetal Medicine Units
Network. Am J Obstet Gynecol. 1999;181(5 pt 1):1216–1221.
17. Asrat T, Lewis DF, Garite TJ, et al. Rate of recurrence of preterm
premature rupture of membranes in consecutive pregnancies.
Am J Obstet Gynecol. 1991;165(4 pt 1):1111–1115.
18. Mercer BM, Goldenberg RL, Meis PJ, et al. The Preterm Prediction
Study: prediction of preterm premature rupture of mem-
branes through clinical findings and ancillary testing. The Na-
tional Institute of Child Health and Human Development
Maternal-Fetal Medicine Units Network. Am J Obstet Gynecol.
2000;183:738–745.
19. Harger JH, Hsing AW, Tuomala RE, et al. Risk factors for preterm
premature rupture of fetal membranes: a multicenter case-control
study. Am J Obstet Gynecol. 1990;163(1 pt 1):130–137.
20. Berkowitz GS, Blackmore-Prince C, Lapinski RH, et al. Risk fac-
tors for preterm birth subtypes. Epidemiology. 1998;9:279–285.
21. Treadwell MC, Bronsteen RA, Bottoms SF. Prognostic factors
and complication rates for cervical cerclage: a review of 482
cases. Am J Obstet Gynecol. 1991;165:555–558.
22. Royal College of Obstetricians & Gynaecologists. Preterm Prelabour
Rupture of Membranes Green–Top Guideline No. 44 November
2006 I Minor Amendment October 2010.
23. The American College of Obstetricians and Gynecologists.
Premature Rupture of Membranes. Practice Bulletin No. 172,
October 2016.
24. Yudin MH, van Schalkwyk J, Eyk NV, et al. Antibiotic therapy in
preterm premature rupture of the membranes. J Obstet Gynaecol
Can. 2009;31:863–867.
25. Alexander JM, Mercer BM, Miodovnik M, et al. The impact of
digital cervical examination on expectantly managed preterm
rupture of membranes. Am J Obstet Gynecol. 2000;183:
1003–1007.
26. Munson LA, Graham A, Koos BJ, et al. Is there a need for digital
examination in patients with spontaneous rupture of the mem-
branes? Am J Obstet Gynecol. 1985;153:562–563.
 Preterm Premature Rupture of Membranes • CME Review Article
27. Baptisti A. Chemical test for the determination of ruptured mem-
branes. Am J Obstet Gynecol. 1938;35:688–690.
28. Abe T. The detection of rupture of the fetal membranes with the
nitrazine indicator. Am J Obstet Gynecol. 1940;39:400–404.
29. Friedman ML, McElin TW. Diagnosis of ruptured fetal mem-
branes. Clinical study and review of the literature. Am J Obstet
Gynecol. 1969;104:544–550.
30. Paavola A. Methods based on the study of crystais and fat stain-
ing; use in diagnosing rupture of the membranes. Ann Chir
Gynaecol Fenn. 1958;47:22–28.
31. Volet B, Morier-Genoud J. The crystallization test in amniotic
fluid. Gynaecologia. 1960;149:151–161.
32. de Haan HH, Offermans PM, Smits F, et al. Value of the fern test
to confirm or reject the diagnosis of ruptured membranes is
modest in nonlaboring women presenting with nonspecific
vaginal fluid loss. Am J Perinatol. 1994;11:46–50.
33. Brosens I, Gordon H. The cytological diagnosis of ruptured using
Nile blue sulphate staining. J Obstet Gynaecol Br Commonw.
1965;72:342–346.
34. Bornstein J, Geva A, Solt I, et al. Nonintrusive diagnosis of pre-
mature ruptured amniotic membranes using a novel polymer.
Am J Perinatol. 2006;23:351–354.
35. Brace RA. Physiology of amniotic fluid volume regulation. Clin
Obstet Gynecol. 1997;40:280–289.
36. Ladfors L, Mattsson LA, Eriksson M, et al. Is a speculum exami-
nation sufficient for excluding the diagnosis of ruptured fetal
membranes? Acta Obstet Gynecol Scand. 1997;76:739–742.
37. Cousins LM, Smok DP, Lovett SM, et al. AmniSure placental
alpha microglobulin-1 rapid immunoassay versus standard di-
agnostic methods for detection of rupture of membranes. Am
J Perinatol. 2005;22:317–320.
38. Lee SE, Park JS, Norwitz ER, et al. Measurement of placental
alpha-microglobulin-1 in cervicovaginal discharge to diagnose
rupture of membranes. Obstet Gynecol. 2007;109:634–640.
39. Ismail MA, Zinaman MJ, Lowensohn RI, et al. The significance of
C-reactive protein levels in women with premature rupture of
membranes. Am J Obstet Gynecol. 1985;151:541–544.
40. Carlan SJ, O'Brien WF, Parsons MT, et al. Preterm premature
rupture of membranes: a randomized study of home versus hos-
pital management. Obstet Gynecol. 1993;81:61–64.
41. Carroll SG, Papaioannou S, Nicolaides KH. Assessment of fetal
activity and amniotic fluid volume in the prediction of intrauterine
infection in preterm prelabor amniorrhexis. Am J Obstet Gynecol.
1995;172:1427–1435.
42. Combs CA, McCune M, Clark R, et al. Aggressive tocolysis does
not prolong pregnancy or reduce neonatal morbidity after pre-
term premature rupture of the membranes. Am J Obstet Gynecol.
2004;190:1723–1728; discussion 8–31.
43. Romem Y, Artal R. C-reactive protein as a predictor for
chorioamnionitis in cases of premature rupture of the mem-
branes. Am J Obstet Gynecol. 1984;150(5 pt 1):546–550.
44. Mercer BM, Miodovnik M, Thurnau GR, et al. Antibiotic therapy
for reduction of infant morbidity after preterm premature rupture
of the membranes. A randomized controlled trial. National Institute
of Child Health and Human Development Maternal-Fetal Medicine
Units Network. JAMA. 1997;278:989–995.
45. American College of Obstetricians and Gynecologists; Society
for Maternal-Fetal Medicine. ACOG obstetric care consensus
no. 3: periviable birth. Obstet Gynecol. 2015;126:e82–e94.
46. Antenatal corticosteroids revisited: repeat courses. NIH Consens
Statement. 2000;17:1–18.
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
375
47. Crane J, Armson A, Brunner M, et al. Antenatal corticosteroid
therapy for fetal maturation. J Obstet Gynaecol Can. 2003;25:
45–52.
48. Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fe-
tal lung maturation for women at risk of preterm birth. Cochrane
Database Syst Rev. 2006:CD004454.
49. Harding JE, Pang J, Knight DB, et al. Do antenatal corticosteroids
help in the setting of preterm rupture of membranes? Am J Obstet
Gynecol. 2001;184:131–139.
50. Fox NS, Gelber SE, Kalish RB, et al. Contemporary practice pat-
terns and beliefs regarding tocolysis among U.S. maternal-fetal
medicine specialists. Obstet Gynecol. 2008;112:42–47.
51. Dunlop P, Crowley P, Lamont R, et al. Preterm ruptured mem-
branes, no contractions. J Obstet Gynaecol. 1986;7:92–96.
52. Ehsanipoor RM, Shrivastava VK, Lee RM, et al. A randomized,
double-masked trial of prophylactic indomethacin tocolysis ver-
sus placebo in women with premature rupture of membranes.
Am J Perinatol. 2011;28:473–478.
53. Doyle LW, Crowther CA, Middleton P, et al. Magnesium sulphate
for women at risk of preterm birth for neuroprotection of the fetus.
Cochrane Database Syst Rev. 2009:CD004661.
54. Kenyon S, Boulvain M, Neilson JP. Antibiotics for preterm rupture
of membranes. Cochrane Database Syst Rev. 2010:CD001058.
55. Kenyon SL, Taylor DJ, Tarnow-Mordi W, et al. Broad-spectrum
antibiotics for preterm, prelabour rupture of fetal membranes:
the ORACLE I randomised trial. ORACLE Collaborative Group.
Lancet. 2001;357:979–988.
56. Kenyon S, Boulvain M, Neilson JP. Antibiotics for preterm rupture
of membranes. Cochrane Database Syst Rev. 2013:CD001058.
57. Kenyon S, Boulvain M, Neilson J. Antibiotics for preterm rupture
of the membranes: a systematic review. Obstet Gynecol.
2004;104(5 pt 1):1051–1057.
58. Kenyon S, Boulvain M, Neilson J. Antibiotics for preterm rupture
of membranes. Cochrane Database Syst Rev. 2003:CD001058.
59. American College of Obstetricians and Gynecologists. ACOG
Practice Bulletin: Clinical Management Guidelines for Obstetri-
cian-Gynecologists: number 38, September 2002. Perinatal care
at the threshold of viability. Obstet Gynecol. 2002;100:617–624.
60. Mercer BM, Crocker LG, Boe NM, et al. Induction versus expec-
tant management in premature rupture of the membranes with
mature amniotic fluid at 32 to 36 weeks: a randomized trial. Am
J Obstet Gynecol. 1993;169:775–782.
61. Morris JM, Roberts CL, Bowen JR, et al. Immediate delivery com-
pared with expectant management after preterm pre-labour
rupture of the membranes close to term (PPROMT trial): a
randomised controlled trial. Lancet. 2016;387:444–452.
62. Bond DM, Middleton P, Levett KM, et al. Planned early birth versus
expectant management for women with preterm prelabour rupture
of membranes prior to 37 weeks' gestation for improving preg-
nancy outcome. Cochrane Database Syst Rev. 2017;3:CD004735.
63. Buchanan SL, Crowther CA, Levett KM, et al. Planned early birth
versus expectant management for women with preterm
prelabour rupture of membranes prior to 37 weeks' gestation
for improving pregnancy outcome. Cochrane Database Syst
Rev. 2010:CD004735.
64. Naef RW 3rd, Allbert JR, Ross EL, et al. Premature rupture of mem-
branes at 34 to 37 weeks' gestation: aggressive versus conservative
management. Am J Obstet Gynecol. 1998;178(1 pt 1):126–130.
65. Neerhof MG, Cravello C, Haney EI, et al. Timing of labor induction
after premature rupture of membranes between 32 and 36 weeks'
gestation. Am J Obstet Gynecol. 1999;180(2 pt 1):349–352.