Midtrimester preterm premature rupture of membranes

Author
Thomas McElrath, MD, PhD Section Editor
Charles J Lockwood, MD Deputy Editor
Vanessa A Barss, MD

Last literature review version 16.2: May 2008 | This Topic Last Updated: February 8,
2008 (More)

INTRODUCTION — Midtrimester preterm premature rupture of the fetal membranes

(PPROM) typically refers to spontaneous rupture of membranes at 16 to 26 weeks of
gestation. This is an arbitrary definition, which varies slightly among investigators.
Midtrimester PPROM complicates approximately 0.7 percent of pregnancies, and is
associated with significant fetal and neonatal morbidity/mortality [1,2] .

The etiology, diagnosis, and complications of midtrimester PPROM will be reviewed

here. The management of PPROM is discussed separately. (See "Preterm premature
rupture of membranes").

ETIOLOGY — Midtrimester PPROM may be spontaneous or iatrogenic (eg, due to

invasive procedures such as cervical surgery, amniocentesis, chorionic villus sampling).

Spontaneous — The pathogenesis of PPROM is not well understood. There are multiple
etiologies, mechanical and physiological, that probably share a final common pathway
leading to membrane rupture. (See "Fetal membranes: Anatomy and biochemistry",
section on Pathogenesis of rupture).

Risk factors for PPROM are similar to those for preterm labor (show table 1). (See
"Risk factors for preterm labor and delivery").

After invasive procedures — Genetic amniocentesis is the most common procedure

associated with midtrimester PPROM, which occurs with 1 to 2 percent of procedures.
In contrast to spontaneous PPROM, leakage of amniotic fluid shortly after genetic
amniocentesis is usually not associated with adverse outcome because the membranes
usually "reseal." Possible reasons cessation of leaking after amniocentesis is more likely
than after spontaneous rupture are that the rupture site is very small, not proximate to
the cervix, and composed of otherwise healthy membranes. (See "Resealing and
reaccumulation of fluid" below and see "Amniocentesis: Technique and complications",
section on Membrane rupture).

Other invasive midtrimester procedures, such as fetoscopy and percutaneous umbilical

blood sampling, can also cause midtrimester PPROM. The risk is highest with
fetoscopy. Clinical experience suggests that the risk is related to the number and
diameter of ports and the duration of manipulation [3] . Single port operative procedures
are associated with a 6 to 10 percent incidence; the risk is lower for diagnostic
procedures, but much higher for operative procedures using two or more ports and
involving long operating times (such as used for cord ligation).

Rupture of membranes at or after cerclage placement has a poorer outcome. (See

"Transvaginal cervical cerclage", sections on Complications and Premature rupture of
membranes).

CLINICAL MANIFESTATIONS AND DIAGNOSIS — The diagnosis of midtrimester

PPROM is based upon a characteristic history (leaking fluid from the vagina) and
physical examination (visualization of fluid flowing from the endocervical canal),
supplemented by laboratory tests in cases of diagnostic uncertainty. The clinical
manifestations and diagnosis of PROM are the same across gestation and are discussed
in detail separately. (See "Preterm premature rupture of membranes", section on Clinical
manifestations and diagnosis).

PREGNANCY COMPLICATIONS AND OUTCOME — Counseling the patient with

midtrimester PPROM is complicated by the small size and retrospective nature of the
multiple studies on this subject. The majority of these reports refer to a single
institutional experience, frequently prior to the widespread use of antepartum antibiotic
prophylaxis, antepartum glucocorticoids to accelerate fetal lung maturation, and
neonatal surfactant therapy. In addition, these studies often have differing
inclusion/exclusion and diagnostic criteria. Despite these limitations, this body of work
provides remarkably consistent conclusions and estimation of the magnitude of risk
with expectant management.

Latency — The time interval between membrane rupture and delivery is a critical factor
in determining outcome in midtrimester PPROM, given that many of these pregnancies
are previable or at the border of viability. To evaluate this relationship, we performed a
review of English language studies of outcome after midtrimester PPROM [4-17] .
Major findings from analysis of these studies were: The weighted mean gestational age
at PPROM was 23.5 weeks of gestation. The weighted mean latency from gestational
age at PPROM to delivery was 17 days. The weighted median latency was 6.8 days.

The large difference between mean and median latency is because the majority of
pregnancies complicated by midtrimester PPROM deliver soon after presentation; fewer
than 50 percent of patients remain pregnant beyond the first week after rupture. By 28
days post-rupture, 73 to 88 percent of pregnancies complicated by midtrimester
PPROM have delivered. However, for pregnancies not delivering within the first 24
hours, the mean latency is 10 to 14 days.

Several authors have suggested there is an inverse relation between latency and
gestational age at rupture: earlier ruptures have longer latencies [5,8,10,11,14,15,18] .
However, this inverse correlation may represent the effect of 'right censoring' by
excluding patients who delivered shortly after arriving on the labor floor; these patients
are more likely to be at an advanced gestational age.

Chorioamnionitis — Chorioamnionitis complicates 8 to 77 percent of midtrimester

PPROM, with an average of 30 to 50 percent in most studies [4-16] . A portion of this
variation is due to differences in criteria used to diagnose infection and differences in
use of antibiotic prophylaxis. Chorioamnionitis is more common in pregnancies with
midtrimester PPROM than in pregnancies without PPROM delivering at a similar
gestational age [13,15,19] , or in pregnancies with PPROM occurring later in gestation
[20,21] . (See "Histopathology of placental disorders" and see "Preterm premature
rupture of membranes").

Chorioamnionitis can be a cause or a result of PPROM. It may cause PPROM because

infection of intact membranes weakens them, thereby facilitating rupture; it can be a
sequelae of PPROM because ruptured membranes are less effective as a barrier to
transcervical migration of cervicovaginal bacteria. (See "Pathogenesis of preterm birth"
and see "Fetal membranes: Anatomy and biochemistry").

Chorioamnionitis typically develops early in the latency period; more than one-half of
cases occur within the first seven days after rupture [4-6,9] . The maximum clinical
occurrence is on the second through fifth day after rupture [6,22] . After the first week
of latency, the incidence of chorioamnionitis falls dramatically [5,6,8,9,23,24] . The
higher frequency of clinical chorioamnionitis early in the latency period suggests that
subclinical infection was likely present prior to membrane rupture, and may have been
the cause.

Chorioamnionitis is associated with onset of preterm labor and delivery, thus it is the
major cause of short latency. The risk of developing chorioamnionitis after PPROM is
increased in women with very low residual amniotic fluid volumes [12] , and those who
undergo digital cervical examinations [25] . The observation that the incidence of
chorioamnionitis falls with prolonged latency implies that intrauterine infection may
actually be less associated with delivery in the longer latency cases than it is in cases
that deliver shortly after membrane rupture. This observation has been corroborated by
a report that noted that the frequency of inflammatory pathology observed on neonatal
head ultrasounds decreased in fetuses delivered after longer latency intervals compared
with those delivering after shorter latency periods [22] .

Chorioamnionitis can also lead to maternal sepsis [26] , but this is rare with appropriate
intervention (eg, antibiotic therapy and delivery).

Placental abruption — Abruptio placentae is more common in pregnancies with

midtrimester PPROM than in the general obstetric population, 2 to 44 percent and 0.4 to
1.3 percent, respectively [12] . Among PPROM pregnancies, the risk of abruption
correlates inversely with gestational age at rupture [14,27] . As an example, the
incidence of abruption is 40 to 50 percent in PPROM prior to 20 weeks [14,27] . (See
"Clinical features and diagnosis of placental abruption").

Chronic abruption is likely one cause of PPROM. There is abundant evidence that
thrombin enhances fetal membrane and/or decidual cytokine and/or protease production
and theoretically could exacerbate membrane damage [28-32] . (See "Pathogenesis of
preterm birth", section on Decidual hemorrhage).

Cord prolapse — The risk of cord prolapse during expectant management of patients
with PPROM is small, but should be considered due to the potential for an adverse
outcome. A review of nine studies including 731 patients with PPROM reported a 1.9
percent incidence of cord prolapse [1] . (See "Umbilical cord prolapse").
Fetal death — The reported incidence of fetal death after midtrimester PPROM varies
widely; we calculated a weighted average risk of 9.8 percent among 1439 pregnancies
described in 18 studies [4-8,10-16,18,23,24,33,34] . A systematic review of studies of
fetal outcome following PPROM at less than 23 weeks reported a fetal death rate of 33
percent (95% CI 27 to 40 percent) [35] . Thus, this is not a rare occurrence.

The risk of intrauterine fetal death is inversely related to gestational age at PPROM
[9,16] . This relationship was illustrated in a study of fetal death in PPROM pregnancies
[9] . The prevalence of fetal death prior to 20 weeks, prior to 24 weeks, and after 25
weeks was 33, 20, and 0 percent, respectively.

Fetal demise in midtrimester PPROM is usually caused by abruption, cord prolapse, or

infection [9,16] . There is probably less intervention for these complications at very
early compared to later gestational ages.

Residual amniotic fluid seems to be protective against intrauterine fetal death. All
deaths in one series occurred in pregnancies in which the largest fluid pocket was <2 cm
in greatest diameter [36] .

Cesarean delivery — Fetal heart rate abnormalities necessitating cesarean delivery are
more common due to the high prevalence of oligohydramnios and chorioamnionitis.
The cesarean delivery rate is also increased because of a higher incidence of fetal
malpresentation at early gestational ages. A classical uterine incision may be required
since the lower uterine segment is often poorly developed in the second and early third
trimesters [9] .

Retained placenta — The prevalence of retained placenta (9 to 18 percent) necessitating

either uterine exploration or curettage is increased with midtrimester PPROM, and
especially if membrane rupture occurs prior to 20 weeks of gestation [5,6,9] .

Postpartum endometritis — Postpartum endometritis occurs in up to 40 percent of

women with midtrimester PPROM; we calculated a weighted cumulative average risk
of approximately 13 percent from our review of the literature. Postpartum maternal
sepsis is less common (0 to 3 percent) [4-16,24] . The risk of maternal infection is
inversely proportional to the latency period. As an example, one study reported
postpartum intrauterine infection in 67 percent of patients with latencies of 24 to 72
hours; however, this risk declined to 10 percent after the fourth day [5] . (See
"Postpartum endometritis", section on Postpartum endometritis).

NEONATAL COMPLICATIONS AND OUTCOME

Neonatal death — A systematic review of studies of fetal outcome following PPROM at

less than 23 weeks reported perinatal death (fetal and early neonatal deaths) in 80
percent [35] . The mortality rate after midtrimester PPROM is high, primarily due to the
short latency period, which results in an early gestational age at delivery (see "Latency"
above) [4-16,18,23,24,33,34,37-39] . The neonatal mortality rate in midtrimester
PPROM is similar to that for controls without PPROM matched for gestational age
(show figure 1) [15,24] .
Neonatal survival improves significantly after 24 to 25 weeks of gestation [8,10,24] .
Since mean latency in midtrimester PPROM is 17 days, PPROM occurring at 23 to 24
weeks of gestation is more likely to be associated with neonatal survival than PPROM
before 22 weeks [7,9,12,16,40,41] . This was illustrated by a study in which neonatal
survival was 84 percent for PPROM after 25 weeks of gestation versus only 50 percent
for PPROM at 19 to 22 weeks [9] . In another series, neonatal survival with membrane
rupture before and after 24 weeks of gestation was 12.5 and 65 percent, respectively
[12] .

The risk of neonatal mortality is also correlated with residual amniotic fluid volume
[12,16,34,39] . Pregnancies with a fluid pocket ≥ 2 cm have a higher neonatal survival
rate than those with a largest fluid pocket of <2 cm (98 versus 31 percent) for neonates
delivering at the same gestational age [12] .

Morbidity related to preterm birth — Short- and long-term morbidity is common and
related to gestational age at birth. The frequencies of these complications (eg,
retinopathy of prematurity, intraventricular hemorrhage, respiratory distress syndrome,
bronchopulmonary dysplasia, patent ductus arteriosus, nosocomial infection, deafness,
and necrotizing enterocolitis) by gestational age are reviewed in detail separately. (See
"Incidence and mortality of the premature infant").

Morbidity related to infection — Potential neonatal sequelae of chorioamnionitis

include neonatal pneumonia and neurodevelopmental delay. (See "Neonatal pneumonia"
and see "Intraamniotic infection", section on Fetal and neonatal complications).

Pulmonary hypoplasia — The prevalence of pulmonary hypoplasia in neonates of

pregnancies complicated by midtrimester PPROM varies widely, but averages 9 percent
[4-16,18,23,24,33,34] . The mortality rate for these neonates is 70 to 90 percent
[14,16,23,33,36] .

The gestational age at the time of membrane rupture is the critical factor in the risk of
subsequent neonatal pulmonary hypoplasia [4,16-18,23,42] . One study noted a 46
percent decrease in the odds of pulmonary hypoplasia with each additional week of
gestation after midtrimester PPROM [33] . Several series have reported a low incidence
(less than 1.4 percent) of pulmonary hypoplasia when PPROM occurred after 26 weeks
of gestation [14,17,18,23,33] . This gestational age corresponds to the end of the
canalicular stage of lung development, after which the developing acinar structure
becomes less sensitive to external perturbations (show table 2) [43] .

The degree of oligohydramnios is an additional risk factor for pulmonary hypoplasia;

lower volumes of residual fluid confer the highest risk [16,34,36] . This was illustrated
in a study that found the incidence of pulmonary hypoplasia with severe, moderate, and
no to mild oligohydramnios was 43, 19, and 7 percent, respectively [34] .

It is less clear whether there is an association between the length of the latency period
and risk of pulmonary hypoplasia. One study found the median latency period was
longer in cases of pulmonary hypoplasia than in those without (31 and 7 days,
respectively) [15] . However, this finding may represent a relationship between earlier
gestational age at rupture and longer latency rather than an independent effect of the
latency period itself. Other authors have not confirmed this association [33,36] .
Pulmonary hypoplasia is difficult to diagnosis antepartum. A variety of sonographic
methods have been evaluated (eg, thoracic circumference, thoracic:abdominal ratio), but
no method has proven reliable enough for clinical decision-making [44] .

Musculoskeletal development — Most limb development is in the embryonic period

[45] . The appendicular skeleton is premolded in cartilage by the end of this period and
ossification centers first appear between 12 and 14 weeks postmenstrual age. The
majority of limb growth occurs in the second and third trimesters. Asymmetric
intrauterine pressure and restriction in fetal movement associated with midtrimester
PPROM can lead to deformities of variable severity in previously normally formed
extremities [46] . An increased likelihood of skeletal deformities has been observed
among infants diagnosed with pulmonary hypoplasia [18,23,33] , suggesting that the
two disorders have a common etiology. (See "Etiology of birth defects", section on
Deformations).

The frequency of skeletal deformities varies widely among studies; the mean incidence
is 7 percent [4-16,18,23,24,33,34] . In contrast to pulmonary hypoplasia, the gestational
age at PPROM is not a significant determinant of the risk of skeletal abnormalities
[18,23,33,34] . This difference is likely due to the progressive and continuous
development of the axial skeleton, which is unmarked by the phases of biochemical
maturation that are observed in the lung. Thus, a severe insult of prolonged duration,
regardless of gestational age, should be more predictive of the development of skeletal
than pulmonary abnormalities.

This hypothesis is supported by several series that observed that the duration of latency
and the severity of oligohydramnios independently increase the risk of skeletal
abnormalities and act synergistically to raise the risk beyond the effect of either variable
alone [18,23,33] . As an example, one study reported the risk of skeletal abnormality
was two-fold higher in pregnancies with midtrimester PPROM complicated by severe
oligohydramnios (defined as largest pocket less than 1 cm) than in matched pregnancies
with normal or mildly reduced fluid (26 versus 54 percent); the risk was highest after 14
days of latency [34] .

Limb deformations related to midtrimester PPROM do not generally require surgical

correction as they gradually resolve with postnatal growth and development [23] .

RESEALING AND REACCUMULATION OF FLUID — Up to 14 percent of gravidas

with spontaneous midtrimester PPROM eventually stop leaking amniotic fluid,
presumably due to "resealing" of the fetal membranes [6,13,40] . Cessation of leakage is
probably not due to actual repair and regeneration of the membranes, but rather to
changes in the decidua and myometrium that block further leakage [47] . This subgroup
of pregnancies has outcomes comparable to pregnancies uncomplicated by amniorrhexis
[6] .

A second subset of patients continue to leak fluid, but have partial reaccumulation of
amniotic fluid. Approximately 25 percent of patients with midtrimester PPROM
reaccumulate fluid on ultrasound examination with expectant management [11,12] .
Patients with iatrogenic midtrimester PPROM after amniocentesis usually "reseal"
membranes within a week and have good pregnancy outcomes. (See "Amniocentesis:
Technique and complications", section on Membrane rupture).

MANAGEMENT — Management of midtrimester PPROM is similar to that for

PPROM later in gestation, with a few differences at previable gestations. As an
example, prior to viability expectant management in the patient's home is reasonable in
stable pregnancies; antenatal glucocorticoids, tocolytics, and prophylactic antibiotics are
not usually administered; and pregnancy termination may be an option. (See "Preterm
premature rupture of membranes").

There is little evidence to support antenatal glucocorticoid use prior to 24 weeks of

gestation as there are only a few primitive alveoli at this gestational age on which
antenatal glucocorticoids may exert an effect. Glucocorticoids should be administered at
or after 24 weeks. (See "Antenatal use of glucocorticoids in women at risk for preterm
delivery").

Although there are many randomized trials suggesting that antibiotic prophylaxis after
membrane rupture increases latency by approximately a week, no similar trials exist
among patients with midtrimester PPROM to support either the efficacy or safety of this
therapy.

As discussed above, early gestational age at membrane rupture is associated with a

variety of adverse neonatal outcomes (infection, neurodevelopment delay); however,
gains in fetal maturity from expectant management appear to outweigh these risks at
very early gestations (show figure 1). Furthermore, prolonged latency in these patients
is not associated with an increasing frequency of abnormal neonatal cranial ultrasound
examination and there is no evidence that elective early delivery will prevent many of
these adverse sequelae [22,48] . However, evidence of clinical infection, abruptio
placenta, or fetal compromise are indications for delivery as expectant management in
these situations can increase maternal or neonatal morbidity.

Repair of leaks — A variety of tissue sealants (eg, fibrin glue, gelatin sponge,
amniopatch) have shown some success in case reports [47] . Neither the safety nor the
efficacy of these sealants has been established. Furthermore, thrombin may trigger fetal
membrane matrix and/or decidual metalloproteinase and inflammatory cytokine
production and myometrial contractions, theoretically promoting further membrane
damage and premature delivery [28,49-51] .

Intraamniotic injection of platelets and cryoprecipitate (ie, amniopatch) has also been
used to treat iatrogenic rupture [52-56] . However, the procedure was associated with
unexpected fetal death and should be considered investigational.

Coexistent cerclage — It is unclear whether the presence of foreign material in the

cervix after cerclage placement increases the risk of maternal or neonatal sepsis in the
setting of PPROM; the most appropriate management in this clinical setting remains
controversial. This topic is discussed in detail separately. (See "Transvaginal cervical
cerclage", section on Preterm premature rupture of membranes).
RECURRENCE — Women with PPROM are at high risk of recurrence in subsequent
pregnancies, if remediable factors such as invasive procedures and cigarette smoking
are not corrected. Recurrent PPROM occurs in 14 to 32 percent of patients with
PPROM and two consecutive pregnancies [57-60] . There is no clear association
between the gestational age at the time of rupture in the index pregnancy, latency
period, interval between pregnancies, and the probability of recurrent PPROM in the
next pregnancy [57] .

Patients with a history of cervical incompetence in a prior pregnancy are probably at

increased risk of midtrimester PPROM in a subsequent pregnancy, given the common
etiology of both entities. (See "Cervical insufficiency").

SUMMARY AND RECOMMENDATIONS Midtrimester preterm premature rupture of

membranes (PPROM) complicates approximately 0.7 percent of pregnancies. It is often
a complication of invasive obstetrical procedures; PPROM after amniocentesis has a
much better prognosis than spontaneous midtrimester PPROM. (See "Introduction"
above and see "Etiology" above). The time interval between membrane rupture and
delivery is a critical factor in determining outcome, given that many of these
pregnancies are previable or at the border of viability. The mean latency from
gestational age at PPROM to delivery is about 17 days and the median latency is about
one week, since the majority of pregnancies deliver soon after rupture of membranes.
(See "Latency" above). Pregnancy complications associated with midtrimester PPROM
include increased risks of infection (chorioamnionitis, endometritis), abruptio placentae,
cord prolapse, fetal death, preterm birth, and need for cesarean delivery. (See
"Pregnancy complications and outcome" above). Neonatal survival is primarily related
to gestational age at delivery, and is comparable to that in preterm deliveries matched
for gestational age without PPROM. For these very early gestations, gains in fetal
maturity with expectant management dramatically improve survival. (See "Neonatal
death" above and see "Management" above). The neonate is at risk for
morbidity/mortality related to preterm birth, infection, pulmonary hypoplasia, and
musculoskeletal deformation. (See "Neonatal complications and outcome" above).
Cessation of amniotic fluid leakage with reaccumulation of amniotic fluid confers a
prognosis comparable to that of pregnancies without PPROM. (See "Resealing and
reaccumulation of fluid" above). We recommend antenatal glucocorticoids after 24
weeks of gestation (Grade 1A). The efficacy of antenatal glucocorticoids prior to 24
weeks of gestation has not been demonstrated. The fetus has only a few primitive
alveoli this early in gestation, which may limit the effectiveness of glucocorticoid
treatment. (See "Management" above). The safety and efficacy of tissue sealants for
repair of PPROM have not been established. (See "Repair of leaks" above).

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