Research

www. AJOG.org

OBSTETRICS

Transabdominal amnioinfusion for preterm premature rupture

of membranes: a systematic review and metaanalysis
of randomized and observational studies
Shay Porat, MD; Hagai Amsalem, MD, MSc; Prakesh S. Shah, MD, MSc; Kellie E. Murphy, MD, MSc
OBJECTIVE: The purpose of this study was to review systematically the
efficacy of transabdominal amnioinfusion (TA) in early preterm premature rupture of membranes (PPROM).
STUDY DESIGN: We conducted a literature search of EMBASE,
MEDLINE, and ClinicalTrials.gov databases and identified studies in
which TA was used in cases of proven PPROM and oligohydramnios.
Risk of bias was assessed for observational studies and randomized
controlled trials. Primary outcomes were latency period and perinatal mortality rates.
RESULTS: Four observational studies (n 147) and 3 randomized

controlled trials (n 165) were eligible. Pooled latency period was 14.4

(range, 8.220.6) and 11.41 (range 3.4 to 26.2) days longer in the
TA group in the observational and the randomized controlled trials, respectively. Perinatal mortality rates were reduced among the treatment
groups in both the observational studies (odds ratio, 0.12; 95% confidence interval, 0.02 0.61) and the randomized controlled trials (odds
ratio, 0.33; 95% confidence interval, 0.10 1.12).
CONCLUSION: Serial TA for early PPROM may improve early PPROMassociated morbidity and mortality rates. Additional adequately powered randomized control trials are needed.

Key words: amnioinfusion, latency period, oligohydramnios, PPROM,

pulmonary hypoplasia

Cite this article as: Porat S, Amsalem H, Shah PS, et al. Transabdominal amnioinfusion for premature preterm rupture of membranes: a systematic review and
metaanalysis of randomized and observational studies. Am J Obstet Gynecol 2012;207:.

reterm premature rupture of membranes (PPROM) complicates approximately 3% of all pregnancies.1 It is a

major cause of neonatal death and morbidity, primarily because of preterm
birth. Lack of amniotic fluid may lead to
pulmonary hypoplasia, infection, and

From the Division of Maternal-Fetal Medicine,

Departments of Obstetrics and Gynecology
(Drs Porat and Murphy) and Pediatrics (Dr
Shah), Mt Sinai Hospital, Faculty of Medicine,
University of Toronto, Toronto, Ontario,
Canada; and the Department of Obstetrics and
Gynecology (Dr Amsalem), Hadassah Mt
Scopus, Hebrew UniversityHadassah Medical
Center, Jerusalem, Israel.
Received April 20, 2012; revised June 12,
2012; accepted Aug. 2, 2012.
The authors report no conflict of interest.
Presented as a poster at the 32nd annual
meeting of the Society for Maternal-Fetal
Medicine, Dallas, TX, Feb. 6-11, 2012.
Reprints not available from the authors.
0002-9378/free
2012 Mosby, Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ajog.2012.08.003

For Editors Commentary, see

Contents

restrictive joint deformities. Chorioamnionitis negatively affects neonatal prognosis at all gestational ages and warrants
prompt delivery. The standard management approach to mid-trimester PPROM
includes antibiotic treatment2 and corticosteroids3 to accelerate fetal lung maturity
between 24 and 32 weeks of gestation.4
Delivery is warranted if there is clinical
evidence of chorioamnionitis or fetal distress. Termination of pregnancy may be
offered for previable PPROM (22-23
weeks of gestation) because of the poor
prognosis. Despite the relatively high frequency of this condition, controversy regarding the optimal management persists.
In recent years, attempts to decrease
neonatal mortality and morbidity rates
were undertaken with different strategies
that included intracervical fibrin application,5 amniopatch,6 fetal endoscopic
tracheal occlusion,7,8 antioxidant treatment,9 gelatin sponge,10 and progesterone treatment.11 None of these strategies
have proved to be consistently effective, reproducible, or applicable for
most centers.

Amnioinfusion or instillation of physiologic solution into the amniotic cavity

was attempted initially to reduce intrapartum variable decelerations.12 Later, it
was suggested as a treatment modality to
prolong the latency period and prevent
the oligohydramnios-related sequelae in
cases of early PPROM.13,14 Both transcervical15,16 and transabdominal14 routes
have been attempted. One of the hypothetic disadvantages of the transcervical
route is the nonsterile environment
through which the infusion catheter
passes, therefore increasing the risk of the
introduction of infectious organisms from
the vaginal flora into the amniotic sac.
Transabdominal amnioinfusion (TA) theoretically surmounts this pitfall. Several articles have described serial TA as a plausible
treatment modality to prolong the latency
period between rupture of membranes
and birth.17 Recently, a Cochrane review
assessed the efficacy of TA for PPROM
with the use of data from 2 randomized
trials and concluded that the small number of subjects in those studies precluded
a definitive answer in regards to the efficacy of the intervention.18 However, additional data are available from observa-

MONTH 2012 American Journal of Obstetrics & Gynecology

1.e1

Research

Obstetrics

www.AJOG.org
outcomes of interest were pulmonary
hypoplasia, neonatal death, gestational
age at birth, birthweight, chorioamnionitis, early onset (72 hours from delivery) neonatal sepsis, bronchopulmonary
dysplasia, and cesarean delivery. Two investigators (S.P. and H.A.) independently abstracted the relevant data from
selected articles.

FIGURE 1

Study selection process

Assessment of risk of bias

Risk of bias in observational studies
was assessed with the Newcastle-Ottawa scale19 and in RCTs with the Cochrane collaborations tool.20 For observational studies, the domains of
assessment included selection, comparability, and outcome assessment biases.
For RCTs, the domains included selection, performance, detection, attrition,
reporting, and other biases. Two investigators (S.P. and H.A.) independently
assessed risk of bias; discrepancies were resolved through discussion and involvement of third author.

Porat. Transabdominal amnioinfusion for PPROM. Am J Obstet Gynecol 2012.

tional studies of TA that can shed further

light on this topic.
Our objective was to review systematically and metaanalyze studies that have
assessed efficacy and safety of TA in
women with PPROM. This systematic
review provides results of separate qualitative and quantitative analyses of randomized controlled trials (RCTs) and
observational studies.

M ETHODS
Search strategy
We performed a comprehensive literature
search, assisted by an experienced librarian, using the MEDLINE from 1950 to December 2011 and EMBASE from 1980 to
December 2011. We also searched the
ClinicalTrials.gov database for studies
that finished recruitment. We used the
terms fetal membranes, premature rupture, rupture, membrane*, pregnancy,
amnioinfus*, premature fetus membrane
rupture, and amnioinfusion. There were
no language or geographic restrictions.
1.e2

Bibliography of identified articles was

used to screen for additional related
articles.

Study selection
We included both comparative observational and RCTs in which TA and conventional treatment were compared with conventional treatment alone. Case reports,
case series, and abstract publications were
excluded. Studies that included patients
with a confirmed diagnosis of PPROM-associated oligohydramnios were included.
Studies that included oligohydramnios
from other causes (eg, intrauterine
growth restriction, renal anomalies)
were excluded. Two reviewers (S.P. and
H.A.) independently evaluated studies for
inclusion; disagreements were resolved
through consensus among the authors.
Outcome measures
The primary outcomes of interest were
latency period (interval from PPROM to
birth) and perinatal death. Secondary

American Journal of Obstetrics & Gynecology MONTH 2012

Data extraction
Data were extracted in duplicate from
published reports by 2 authors who used
a standardized data collection form. A
third reviewer was consulted in case of
disagreement between the 2 data extractors; discrepancy was resolved by consensus. We did not contact authors for
missing information. For continuous
outcomes, means and standard deviations were obtained from studies. When
they were not reported, they were calculated from range, median, and sample
size according to the method described
by Hozo et al.21 For categoric outcomes,
event rates were obtained.
Statistical analysis
Statistical analyses were performed with
the Review Manager (RevMan) software
(version 5.1.4; The Nordic Cochrane
Centre, Kbenhavn, Denmark). Metaanalyses were performed separately for
cohort studies and the RCTs. Where data
were sufficiently homogenous, metaanalysis was conducted with the use of a
random effects model, with weighting of
studies according to the DerSimonianLaird method. Random-effect model
was used to account for between and
within study heterogeneity. Cochrans Q

Obstetrics

www.AJOG.org

Research

TABLE 1

Characteristics of included studies

Study

Characteristics
17

De Santis et al, 2003

.......................................................................................................................................................................................................................................................................................................................................................................

Type of study

Quasi-randomized; patients admitted by chance to 1 of 2 divisions of the same department; both divisions
offered expectant treatment; only 1 division offered TA

.......................................................................................................................................................................................................................................................................................................................................................................

Participants

37 patients in intervention group; 34 patients in control group

..............................................................................................................................................................................................................................................................................................................................................................

Inclusion criteria

Singleton; PPROM at 26 weeks of gestation; severe and persistent oligohydramnios (AFI 30 mm, lasting 7 d)

Exclusion criteria

Clinical chorioamnionitis; active labor; autoimmune or metabolic disease; history of multiple invasive procedures;
declining treatment after informed consent; delivery in the interim 7-day waiting period from admission; transfer
from other hospitals after a period of treatment

..............................................................................................................................................................................................................................................................................................................................................................

.......................................................................................................................................................................................................................................................................................................................................................................

Diagnosis of PPROM

History; sterile speculum examination; vaginal pH 5; AFI measurement by ultrasound scanning

.......................................................................................................................................................................................................................................................................................................................................................................

Interventions

..............................................................................................................................................................................................................................................................................................................................................................

All

Hospital bed rest; antibiotic prophylaxis (mezlocillin, 2 g intravenously twice daily for at least 7 days) or targeted
treatment based on cultures; tocolytic treatment (isoxsuprine, either intravenously or orally) for contractions;
betamethasone after 25 weeks; fetal monitoring by daily heart check or cardiocotography after 26 weeks and
modified BPP every 3 days; cesarean delivery performed in the presence of chorioamnionitis, abruptio placentae,
and/or fetal distress (abnormal fetal monitoring) or at 30 weeks of gestation

..............................................................................................................................................................................................................................................................................................................................................................

Intervention

Weekly saline amnioinfusion in a sufficient amount to increase AFI to 10 cm starting 7 days at least after
PPROM; antibiotics and tocolysis on the day of amnioinfusion

.......................................................................................................................................................................................................................................................................................................................................................................

Outcomes

Latency period; gestational age at delivery; cesarean delivery; genitourinary infection, amnionitis/endometritis;
neonatal weight; orotracheal intubation; survival; deformities; pulmonary hypoplasia; bronchopulmonary
dysplasia; early-onset sepsis; early-onset pneumonitis; abnormal neurologic outcome (includes cerebral palsy,
spastic diplegia or tetraplegia, deafness, or blindness)

.......................................................................................................................................................................................................................................................................................................................................................................

Notes

Also included were women who underwent PROM after amniocentesis for prenatal diagnosis: 10 patients
(27.0%) in the amnioinfusion group and 8 patients (23.5%) in the control group

................................................................................................................................................................................................................................................................................................................................................................................
35

Tranquilli et al 2005

.......................................................................................................................................................................................................................................................................................................................................................................

Type of study

Randomized controlled trial

Participants

17 patients in each arm

.......................................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................

Inclusion criteria

Singleton pregnancy with a certain gestational age confirmed by an early second-trimester ultrasonographic
examination; gestational age 24-33 weeks; evidence of PPROM within 24 hours of admission; oligohydramnios
(amniotic fluid index, 10th percentile); absence of uterine contractions at the time of hospitalization; no
evidence of clinical chorioamnionitis at admission; no evidence of placental anomalies or major structural fetal
anomalies, and normal cardiotocography at the time of admission

.......................................................................................................................................................................................................................................................................................................................................................................

Diagnosis of PPROM

PPROM diagnosed on examination by a sterile speculum when obvious leakage of amniotic fluid from the
cervical os was confirmed by a positive fibronectin test

.......................................................................................................................................................................................................................................................................................................................................................................

Interventions

..............................................................................................................................................................................................................................................................................................................................................................

All

Hospital bed rest; antibiotic prophylaxis (sulbactam-ampicillin 3 g, intravenously every 8 hours for 7 days);
betamethasone therapy; prophylactic tocolytic (intravenous ritodrine) in the absence of clinical signs of
chorioamnionitis or placental abruption; daily fetal heart rate monitoring

..............................................................................................................................................................................................................................................................................................................................................................

Intervention

Weekly serial amnioinfusion if the AFI fell 5th percentile and/or a median pocket of amniotic fluid was 2 cm,
with a target AFI of 10th percentile; if repeated AFI was 5, amnioinfusion repeated weekly until 27 weeks of
gestation; a nonstress test performed daily

.......................................................................................................................................................................................................................................................................................................................................................................

Outcomes

Latency period; gestational age at delivery; birthweight; admission to neonatal intensive care unit; pulmonary
hypoplasia; abnormal neurologic outcome

................................................................................................................................................................................................................................................................................................................................................................................
34

Singla et al, 2010

.......................................................................................................................................................................................................................................................................................................................................................................

Type of study

Randomized controlled trial

Participants

30 patients in each arm

.......................................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................

Inclusion criteria

Singleton pregnancy; PPROM between 26 and 33 6 week gestations; AFI 5th percentile for gestational age

Exclusion criteria

Women with evidence of clinical chorioamnionitis, placental or fetal anomalies; active labor or AFI 5th percentile

..............................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................

Porat. Transabdominal amnioinfusion for PPROM. Am J Obstet Gynecol 2012.

(continued )

MONTH 2012 American Journal of Obstetrics & Gynecology

1.e3

Research

Obstetrics

www.AJOG.org

TABLE 1

Characteristics of included studies (continued)

Study

Characteristics

Diagnosis of PPROM

Sterile speculum examination or nitrazine/litmus paper test; confirmation by ultrasound scanning

.......................................................................................................................................................................................................................................................................................................................................................................

Interventions

..............................................................................................................................................................................................................................................................................................................................................................

All

24 hours of observation after admission before randomization; hospital bed rest; antibiotic prophylaxis
(erythromycin: 250-mg tablet 4 times per day for 10 days); betamethasone prophylaxis; daily obstetric
examination; weekly BPP, complete blood cell count, and cervical/vaginal cultures

..............................................................................................................................................................................................................................................................................................................................................................

Intervention

Amnioinfusion of warmed saline solution in a sufficient amount to maintain the AFI at 5th percentile for
gestational age; weekly AFI measurement and repeated amnioinfusion if the AFI fell 5th percentile; labor
induction when there was fetal distress or chorioamnionitis

.......................................................................................................................................................................................................................................................................................................................................................................

Outcomes

Latency period; gestational age at delivery; birthweight; intrapartum fetal distress; early neonatal sepsis; rate
and causes of neonatal mortality; type and mode of delivery; postpartum sepsis

................................................................................................................................................................................................................................................................................................................................................................................
33

Vergani et al, 1997

.......................................................................................................................................................................................................................................................................................................................................................................

Type of study

Observational

Participants

18 patients in intervention group and 16 patients in historic cohort group who did not undergo the procedure

.......................................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................

Inclusion criteria

Singleton pregnancy; PPROM at 25 completed weeks of gestation; no labor; persistent oligohydramnios

(maximum pool depth 2 cm of cord-free pocket of fluid) at 4 days

..............................................................................................................................................................................................................................................................................................................................................................

Exclusion criteria

Amniotic fluid leakage after second-trimester amniocentesis; clinical chorioamnionitis; presence of uterine
contractions 4/hour; sonographic diagnosis of structural fetal abnormalities; maternal immunologic diseases;
multiple gestations

.......................................................................................................................................................................................................................................................................................................................................................................

Diagnosis of PPROM

Observation of vaginal pooling and a positive nitrazine test on sterile speculum examination

.......................................................................................................................................................................................................................................................................................................................................................................

Interventions

..............................................................................................................................................................................................................................................................................................................................................................

All

Hospital bed rest during the first week, then home bed rest until 25 weeks, after which all patients were
admitted until delivery; tocolytic treatment (intravenous ritodrine) given at 25 weeks for uterine contractions in
the absence of clinical signs of chorioamnionitis or abruption placentae; betamethasone course at least once
between 25 and 32 weeks of gestation; 1-week course of prophylactic antibiotic therapy with sulbactamampicillin 3 g intravenously every 8 hours and targeted treatment based on cervical and vaginal cultures;
sonographic determination of amniotic fluid volume twice a week for outpatients and daily for inpatients; BPP
twice a week at 25 weeks of gestation

..............................................................................................................................................................................................................................................................................................................................................................

Intervention

1-2 TA/wk to aim to restore AFI 5 cm; delivery in the presence of clinical chorioamnionitis, fetal distress,
abruption placentae, or documented fetal lung maturity on amniocentesis after 28 weeks of gestation

.......................................................................................................................................................................................................................................................................................................................................................................

Outcomes

Gestational age at delivery; latency period; survival rate; pulmonary hypoplasia; chorioamnionitis; fetal distress;
placental abruption; preterm labor; in utero death; umbilical cord prolapse

................................................................................................................................................................................................................................................................................................................................................................................
30

Garzetti et al, 1997

.......................................................................................................................................................................................................................................................................................................................................................................

Type of study

Observational

Participants

18 women in each arm; control group recruited from historic data

.......................................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................

Inclusion criteria

Singleton; PPROM between 25 and 32 weeks of gestation; oligohydramnios (AFI, 5th percentile)

Exclusion criteria

Presence of uncontrolled labor; presence of obstetric complications; maternal immunocompromise; uterine

fibroid tumors; lack of written consent

..............................................................................................................................................................................................................................................................................................................................................................

.......................................................................................................................................................................................................................................................................................................................................................................

Diagnosis of PPROM

Observation of gross vaginal pooling of amniotic fluid and a positive nitrazine test on speculum examination

.......................................................................................................................................................................................................................................................................................................................................................................

Interventions

..............................................................................................................................................................................................................................................................................................................................................................

All

Hospital bed rest until delivery with minimal activity limited to bathroom necessities; weekly complete blood cell
count and semiquantitative C-reactive protein measurement; weekly ultrasound scanning and cardiocotography;
daily nonstress test; prophylactic tocolytic treatment (intravenous ritodrine) in the absence of chorioamnionitis or
abruption placentae; prophylactic antibiotic treatment (ceftazidime 2 g/d intramuscularly) and targeted therapy
based on cultures; delivery in the presence of clinical chorioamnionitis, positive amniotic fluid culture, fetal
distress, and documented fetal lung maturity

..............................................................................................................................................................................................................................................................................................................................................................

Intervention

If AFI 10th percentile for gestational age and deepest pocket of cord-free fluid 10 mm, weekly TA of 150350 mL warmed saline solution; weekly AFI assessment before and after each procedure; biweekly fetal growth
assessment

................................................................................................................................................................................................................................................................................................................................................................................

Porat. Transabdominal amnioinfusion for PPROM. Am J Obstet Gynecol 2012.

1.e4

American Journal of Obstetrics & Gynecology MONTH 2012

(continued )

Obstetrics

www.AJOG.org

Research

TABLE 1

Characteristics of included studies (continued)

Study

Characteristics

Outcomes

Latency period duration; median amniotic fluid volume and short-term variability; relationship between amniotic
fluid volume and fetal short-term variability in the amnioinfusion group

................................................................................................................................................................................................................................................................................................................................................................................

Ogunyemi and Thompson,

200232

.......................................................................................................................................................................................................................................................................................................................................................................

Type of study

Observational

Participants

12 patients in each group

.......................................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................

Inclusion criteria

PPROM at gestational age 27 weeks; oligohydramnios with AFI 5 cm; normal fetal anatomic scan; absence
of gross infection; stable mother and fetus

..............................................................................................................................................................................................................................................................................................................................................................

Exclusion criteria

Presence of active labor; clinical chorioamnionitis

.......................................................................................................................................................................................................................................................................................................................................................................

Diagnosis of PPROM

Observation of vaginal pooling, a positive nitrazine test or ferning on speculum evaluation

.......................................................................................................................................................................................................................................................................................................................................................................

Interventions

..............................................................................................................................................................................................................................................................................................................................................................

All

Initial hospital bed rest, followed by outpatient follow-up evaluation for stable patients; corticosteroids after 24
weeks of gestation; magnesium sulfate and terbutaline were used for tocolysis as needed if preterm labor
suspected in the absence of clinical chorioamnionitis; prophylactic intravenous antibiotics

..............................................................................................................................................................................................................................................................................................................................................................

Intervention

Before the procedure, intravenous magnesium sulfate 4 g loading dose followed by 1 g/hr was initiated and
discontinued 12 hours after the procedure if preterm labor did not ensue; weekly amnioinfusion of warm 0.9%
normal saline solution with ampicillin 1 g/L until 27 weeks of gestation if AFI 5

.......................................................................................................................................................................................................................................................................................................................................................................

Outcomes

Chorioamnionitis; latency period; cesarean delivery rate; gestational age at delivery; birthweight; neonatal sepsis;
neonatal death; perinatal death; total death

................................................................................................................................................................................................................................................................................................................................................................................
31

Gramellini et al, 2003

.......................................................................................................................................................................................................................................................................................................................................................................

Type of study

Observational

Participants

24 patients in intervention group and 29 patients in historic control group

.......................................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................

Inclusion criteria

Singleton; 34 weeks gestational age; PPROM; oligohydramnios (AFI, 5 cm)

Exclusion criteria

Active labor; clinical evidence of placental abruption or chorioamnionitis

..............................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................

Diagnosis of PPROM

Observation of persistent vaginal pooling and a positive nitrazine paper test

.......................................................................................................................................................................................................................................................................................................................................................................

Interventions

..............................................................................................................................................................................................................................................................................................................................................................

All

Tocolytic treatment (ritodrine) for 4 uterine contractions/20 min; betamethasone after 24 weeks of gestation;
prophylactic antibiotic therapy (erythromycin 2 g/d) given to 90% of patients

..............................................................................................................................................................................................................................................................................................................................................................

Intervention

TA of 0.9% normal saline solution or lactated Ringers solution according to a volume criterion of 10
mL/gestational week; repeated if AFI measurement 12 hours after the procedure was 5 cm

.......................................................................................................................................................................................................................................................................................................................................................................

Outcomes

Gestational age at delivery; latency period; birthweight; rate of intrauterine death, vaginal bleeding, cesarean
delivery, and postpartum endometritis

.......................................................................................................................................................................................................................................................................................................................................................................

Notes

Refers to a group of patients in whom the oligohydramnios was not attributed to PPROM; however, all data cited
refer only to patients affected by PPROM

................................................................................................................................................................................................................................................................................................................................................................................

AFI, amniotic fluid index; BPP, biophysical profile; CBC, complete blood cell count; PPROM, preterm premature rupture of membranes; TA, transabdominal amnioinfusion.
Porat. Transabdominal amnioinfusion for PPROM. Am J Obstet Gynecol 2012.

test was used to test for heterogeneity between studies at the .10 level of significance. The I-squared statistic was used to
quantify the degree of heterogeneity.

Report
Results of the metaanalysis of RCTs and
the observational studies were reported
according to the Preferred Reporting
Items for Systematic Reviews and Metaanalyses statement22 and Metaanalysis of

the Observational Studies in Epidemiology guidelines,23 respectively.

R ESULTS
Our initial search yielded 141 citations.
After review of titles and abstracts, 126
citations were excluded (Figure 1). After
full text review of the remaining 15
articles, 8 articles were excluded (3 because inclusion criteria were not fulfilled13,14,24; 4 because of it was not

clear whether reported patients in

these studies were included in other
studies,25-28 and 1 because the intervention group and control group were
unmatched29). The remaining 7 studies met inclusion criteria and were included in this review.17,30-35 Characteristics of these studies are summarized in
Table 1.
Of the 7 included studies, 2 studies
were RCTs (47 patients in each group);

MONTH 2012 American Journal of Obstetrics & Gynecology

1.e5

Research

Obstetrics

www.AJOG.org

TABLE 2

Quality assessment of observational cohort studies by the Newcastle-Ottawa Scale system

Selection

Comparability

Representativeness Selection of the

of the exposed
nonexposed
cohort
cohort

Ascertainment
of exposure

Demonstration
that outcome of
interest was not
present at start
of study

Ogunyemi and
Thompson
(2002)32

Vergani et al
(1997)33

Garzetti et al
(1997)30

Gramellini et al
(2003)31

Study

Comparability of
cohorts on the
basis of the
design or
analysis
**

Outcome

Assessment
of outcome

Was follow-up
long enough
for outcomes
to occur?

Adequacy of
follow up of
cohorts

Total
stars,
n

................................................................................................................................................................................................................................................................................................................................................................................

................................................................................................................................................................................................................................................................................................................................................................................

**

................................................................................................................................................................................................................................................................................................................................................................................

................................................................................................................................................................................................................................................................................................................................................................................

Each asterisk represents 1 star in the Newcastle-Ottawa Scale system. The maximum number of stars is 2 for comparability and 1 for each of the other categories.
Porat. Transabdominal amnioinfusion for PPROM. Am J Obstet Gynecol 2012.

1 study was quasirandomized (34 patients in the control group and 37 in the
intervention group), and 4 studies were
observational studies (75 patients in the
control group and 72 in the intervention
group). In the quasirandomized study,
patients were admitted by chance to one
of 2 departments that differed in their
management approach toward PPROM:
one department provided standard care;
the other department provided standard
care in addition to serial amnioinfusion
to consented patients. We decided to include the quasirandomized study with
the other 2 randomized studies because
we believed that the risk of bias in that
study was not high. The gestational age at
inclusion varied from 16-33 weeks. Information on individual patients was
provided only in 1 study32; therefore,
subgroup analysis by gestational age was

not possible. Ascertainment of rupture

of membranes was performed in all studies by speculum examination to confirm
pooling of amniotic fluid in the posterior
fornix. In addition, 6 studies used nitrazine, and 1 study used fetal fibronectin as
a confirmatory test.35 Conventional care
for patients with PPROM included bed
rest in the hospital and prophylactic antibiotic therapy in all studies. Five studies
used tocolysis only when uterine contractions appeared without clinical chorioamnionitis or abruptio placenta17,31-34;
however, 2 studies used tocolysis as a prophylactic measure for all patients, regardless of the presence of uterine contractions.30,35 Targeted antibiotic therapy
based on cervical and vaginal cultures
was used in 3 studies.17,30,33 Corticosteroids for fetal lung maturation was used
after viability in all but 1 study.30 The

number of procedures per patient, success rate, and volumes infused varied
among different studies and among different subjects in the same study. The average number of infusions per patient
ranged from 1.23 in Singla et al34 to 4.0 in
De Santis et al.17 Vergani et al33 reported
a median number of 3 infusions per patient with a range of 19. Most of the
studies did not report success rate;
however, Garzetti et al30 reported a
success in 18 of 19 patients, and De
Santis et al17 reported successful amnioinfusion in 143 of 147 procedures.
The infused volumes range from 140350 mL per infusion.17,30,34,35
De Santis et al17 reported on 5 complications that occurred within 24 hours after infusion: 2 cord prolapses (1 cephalic
and 1 transverse lie); 2 abruptio placentae, and 1 onset of labor. Gramellini et

TABLE 3

Quality assessment of randomized controlled trials

Bias
Selection
Random sequence
generation

Allocation
concealment

Performance: blinding
of participants
and personnel

Detection: blinding
of outcome
assessment

Attrition: incomplete
outcome data

Reporting:
selective
reporting

Other
sources

Overall

Singla et al
(2010)34

Low risk

Unclear risk

Unclear

Unclear

Low risk

Low risk

Low risk

Moderate risk

Tranquilli et al
(2005)35

Low risk

De Santis et al
(2003)17

High risk

Study

................................................................................................................................................................................................................................................................................................................................................................................

Low risk

Unclear

Unclear

Low risk

Low risk

Low risk

Moderate risk

................................................................................................................................................................................................................................................................................................................................................................................

High risk

Unclear

High risk

Low risk

Low risk

Low risk

High risk

................................................................................................................................................................................................................................................................................................................................................................................

Porat. Transabdominal amnioinfusion for PPROM. Am J Obstet Gynecol 2012.

1.e6

American Journal of Obstetrics & Gynecology MONTH 2012

Obstetrics

www.AJOG.org

Research

FIGURE 2

Effect of serial TA on neonatal outcomes

Forest plot of the results of the metaanalysis of observational studies for A, latency period length, which demonstrates the difference in latency period
lengths between the TA and control groups; B, perinatal mortality rates refer to the odds ratio; and C, pulmonary hypoplasia refers to the odds ratio.
TA, transabdominal amnioinfusion.
Porat. Transabdominal amnioinfusion for PPROM. Am J Obstet Gynecol 2012.

al31 reported on a higher rate of vaginal

bleeding in the intervention group (21%)
compared with the nonamnioinfused
group (7%), although this difference did
not reach statistical significance. Ogunyemi and Thompson32 reported on 2 neonatal complications that can be regarded as
direct injuries from the procedure: 1 baby
had a 2-cm leg laceration that was sutured,
and 1 baby had a 0.5 0.5 cm superficial
chest scar that needed no treatment.
Assessment of the risk of bias in included observational cohort studies and
RCTs are shown in Tables 2 and 3, re-

spectively. The observational studies had

minimal risk of bias, whereas 2 of 3 RCTs
had moderate risk of bias, and 1 RCT had
high risk of bias.

Metaanalyses of observational
studies
Primary outcomes
There was prolongation of the latency
period (4 studies, 147 participants; mean
difference, 14.4 days; 95% confidence interval [CI], 8.220.6 days; heterogeneity:
I2 17%; Figure 2) and reduction in
perinatal mortality rate (2 studies, 60

participants; pooled odds ratio [OR],

0.12; 95% CI, 0.02 0.61; heterogeneity:
I2 0%; Figure 2). A subgroup analysis
of periviable vs potentially viable babies
could not be performed because of a lack
of reporting data.
Secondary outcomes
Results of metaanalyses of secondary
outcomes are given in Table 4. There
were a decreased rate of pulmonary hypoplasia (2 studies, 45 participants;
pooled OR, 0.17; 95% CI, 0.04 0.78;
heterogeneity: I2 0%; Figure 2) and a

MONTH 2012 American Journal of Obstetrics & Gynecology

1.e7

Research

Obstetrics

www.AJOG.org

TABLE 4

Effect of transabdominal amnioinfusion on the tested outcomes

Metaanalysis of observational studies
Studied outcome

Studies/participants, n

Difference in mean gestational age at preterm

premature rupture of membranes, db

4/147

Difference in mean gestational age at

delivery, db

3/111

Difference in mean latency period length, db

4/147

Effect estimate

Metaanalysis of randomized controlled trials

a

12.30 (18.56 to 6.03)

Studies/participants, n

Effect estimatea

3/165

1.58 (8.09 to 4.52)

................................................................................................................................................................................................................................................................................................................................................................................

4.11 (22.23 to 14.00)

3/165

3.86 (16.49 to 24.21)

................................................................................................................................................................................................................................................................................................................................................................................

14.40 (8.2420.56)

3/165

11.41 (3.36 to 26.18)

................................................................................................................................................................................................................................................................................................................................................................................

Difference in mean birthweight, g

129.52 (691.09 to 432.06)

2/77

3/165

125.00 (105.68 to 355.68)

................................................................................................................................................................................................................................................................................................................................................................................

Perinatal mortality rate

2/60

0.12 (0.020.61)

2/131

0.33 (0.101.12)

Pulmonary hypoplasia

2/45

0.17 (0.040.78)

2/69

0.30 (0.051.70)

Amnionitis/endometritis

3/111

0.94 (0.332.68)

2/131

0.28 (0.110.69)

Early onset sepsis

1/18

0.10 (0.002.35)

2/83

0.38 (0.026.07)

Neonatal mortality rate

1/18

0.09 (0.010.84)

3/129

0.52 (0.073.76)

Bronchopulmonary dysplasia

1/18

2.14 (0.0860.17)

1/20

7.67 (0.32183.01)

Genitourinary infection

N/A

1/71

1.29 (0.493.42)

Cesarean delivery

2/54

1/71

2.35 (0.816.81)

................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................

N/A

................................................................................................................................................................................................................................................................................................................................................................................

4.16 (0.9617.95)

................................................................................................................................................................................................................................................................................................................................................................................

N/A, not applicable.

a

Data are given as odds ratio (95% confidence interval); b The first 4 rows of data represent mean difference with 95% confidence interval, the rest of the rows represent odds ratio with 95% confidence
interval.

Porat. Transabdominal amnioinfusion for PPROM. Am J Obstet Gynecol 2012.

reduced risk for neonatal death (1 study,

18 participants; OR, 0.09; 95% CI, 0.01
0.84; heterogeneity: not applicable). The
other tested secondary outcomes did not
reach statistical significance.

Metaanalyses of RCTs
Primary outcomes
There was no statistically significant difference in the latency period (3 studies,
165 participants; mean difference, 11.4
days increase in latency in TA group;
however, 95% CI 3.4 to 26.2 days; heterogeneity: I2 89%; Figure 3) and no
statistically significant difference in perinatal mortality rate (2 studies, 131 participants; pooled OR, 0.33; 95% CI,
0.10 1.12; heterogeneity: I2 45%; Figure 3). A subgroup analysis of periviable
vs potentially viable babies could not be
performed because of a lack of reporting
data.
Secondary outcomes
Results of metaanalyses of secondary
outcomes are given in Table 4. There was
no statistically significant difference in
the rate of pulmonary hypoplasia (2
studies, 69 participants; pooled OR, 0.3;
95% CI, 0.051.7; heterogeneity: I2
52%; Figure 3).
1.e8

Interestingly, there was a decreased rate

of infectious complications of amnionitis
or chorioamnionitis in the TA group (2
studies, 131 participants; OR, 0.28; 95%
CI, 0.11 0.69; heterogeneity: I2 0%).
None of the other secondary outcomes
reached statistical significance.

C OMMENT
Mid-trimester PPROM poses a challenging clinical problem. Poor prognosis
usually results from the combination of
prematurity, pulmonary hypoplasia, and
infection. The prognosis of mid-trimester PPROM at 21 weeks of gestation is
grave because most fetuses experience
pulmonary hypoplasia.36 Pregnancy outcomes are correlated directly with the
gestational age at which the membranes are ruptured and the amount
of residual fluid after the rupture of
membranes. Low residual volume of
amniotic fluid has been shown to be
associated with a shorter latency period37,38 and increased risk for early
onset neonatal sepsis and chorioamnionitis.37 Lack of an effective treatment or intervention to prolong pregnancy complicates this situation even
further. Despite the seriousness and

American Journal of Obstetrics & Gynecology MONTH 2012

gravity of this condition, current obstetrics management has little to offer.

Aside from close monitoring for signs
of infection or early labor, no obstetrics interventions have demonstrated
the ability to reduce morbidity or mortality rate that is the result of early
PPROM or specifically to address the
pathophysiologic processes that underlie the cause of this condition.
In this metaanalysis, a better shortterm prognosis in women with PPROM
who underwent serial TA was seen in the
observational studies. The intervention
group had significant latency prolongation and improved perinatal and neonatal survival and experienced less pulmonary hypoplasia. These results intensify
in the face of significantly lower gestational age at rupture of membranes in
the intervention group, compared with
the control group in the observational
studies (12.3 days of difference; 95% CI,
6.0318.56). The results from the metaanalysis of RCTs demonstrated a trend
toward benefit, but the results were not
statistically significant. This is possibly
because of the small number of participants in the studies and the lack of
power.

Obstetrics

www.AJOG.org

Research

FIGURE 3

Effect of serial TA on neonatal outcomes for randomized controlled trials

Forest plot of the results of the metaanalysis of randomized controlled trials for A, latency period length, which demonstrates the difference in latency period
lengths between the TA and control groups; B, perinatal mortality rates refer to the odds ratio; and C, pulmonary hypoplasia refers to odds ratio.
TA, transabdominal amnioinfusion.
Porat. Transabdominal amnioinfusion for PPROM. Am J Obstet Gynecol 2012.

The hypothesis is that infectious/inflammatory processes are responsible

for the activation of the laboring process. Thus, the theoretic benefit of amnioinfusion or the introduction of
physiologic solution into the amniotic
cavity includes (1) washout/dilution
of preexisting intraamniotic bacteria,
(2) washout/dilution of inflammatory
cells and mediators (prostaglandins,
leukotrienes, cytokines, interleukins
among others), and (3) increase in intraamniotic fluid volume and pressure.

Theoretically, washing out or diluting

the preexisting intraamniotic bacteria
and inflammatory cells may be beneficial to prolong the latent period, and
the presence of fluid may promote lung
development and prevent positional
contractures. There are also potential
secondary benefits from this intervention that include the ability to test fetal
genetics (when indicated), an improvement in ultrasound imaging of
the baby, and a decreased risk for cord
compression.

The strengths of this metaanalysis,

compared with the recently published
Cochrane review,18 include a larger sample size, the inclusion of observational
and RCT data that give the full picture of
this intervention, and the assessment of
all clinically important outcomes. The
results indicate a potentially beneficial
effect for the intervention. However, because of the small sizes of included randomized studies and our inability to
conclude with confidence because of
lack of power, we suggest large ade-

MONTH 2012 American Journal of Obstetrics & Gynecology

1.e9

Research

Obstetrics

quately powered studies are needed for

this intervention. Because of the rarity of
the condition, we suggest that a multicenter collaboration with standardization of treatment for such women will
allow adequate power and generalizability of findings. Limitations of this review
include the low numbers of participants
both in the observational studies and the
RCTs. In addition, in regards to the protocol and assessment of outcomes, there
was heterogeneity in the reporting of the
included studies. Finally, there was heterogeneity in the quality of the studies in
terms of risk of bias.
If the superiority of serial TA over conservative management is confirmed by
further studies, this directly would impact both the management and research
of early PPROM. First, this intervention
could be offered to couples who face the
grim situation in which no other interventions are available. Second, it will enable further research into the contribution of the amount and the constitution
of amniotic fluid for lung development
at different fetal developmental stages. It
will raise questions in regards to the
lower threshold of amniotic fluid volume or pressure that supports lung development, which is the role of amniotic
fluid turnover and the role of amniotic
fluid.
This metaanalysis suggests that serial TA improved pregnancy outcomes
when tested in observational studies,
but not in RCTs; however, for both
types of studies, the number of patients
that were included remains very small.
These results warrant a large, multicenter RCT to investigate the usefulness of such an intervention in a hospital-based setting.
f
ACKNOWLEDGMENT
We thank Ms Elizabeth Uleryk, Chief Librarian at
the Hospital for Sick Children, Toronto, Canada,
for her contribution in developing the search
strategies and for running the search on a periodic basis.

REFERENCES
1. Mercer BM. Preterm premature rupture of
the membranes: current approaches to evaluation and management. Obstet Gynecol Clin
North Am 2005;32:411-28.

1.e10

www.AJOG.org
2. Yudin MH, van Schalkwyk J, Van Eyk N, et al.
Antibiotic therapy in preterm premature rupture
of the membranes. J Obstet Gynaecol Can
2009;31:863-74.
3. Harding JE, Pang J, Knight DB, Liggins GC.
Do antenatal corticosteroids help in the setting
of preterm rupture of membranes? Am J Obstet
Gynecol 2001;184:131-9.
4. Miracle X, Di Renzo GC, Stark A, Fanaroff A,
Carbonell-Estrany X, Saling E. Guideline for the
use of antenatal corticosteroids for fetal maturation. J Perinat Med 2008;36:191-6.
5. Sciscione AC, Manley JS, Pollock M, et al. Intracervical fibrin sealants: a potential treatment for
early preterm premature rupture of the membranes. Am J Obstet Gynecol 2001;184:368-73.
6. Deprest J, Emonds MP, Richter J, et al. Amniopatch for iatrogenic rupture of the fetal membranes. Prenat Diagn 2011;31:661-6.
7. Kohl T, Geipel A, Tchatcheva K, et al. Lifesaving effects of fetal tracheal occlusion on pulmonary hypoplasia from preterm premature
rupture of membranes. Obstet Gynecol 2009;
113:480-3.
8. Kohl T, Muller A, Franz A, et al. Temporary
fetoscopic tracheal balloon occlusion enhanced by hyperoncotic lung distension: is
there a role in the treatment of fetal pulmonary
hypoplasia from early preterm premature rupture of membranes? Fetal Diagn Ther 2007;
22:462-5.
9. Borna S, Borna H, Daneshbodie B. Vitamins
C and E in the latency period in women with
preterm premature rupture of membranes. Int J
Gynaecol Obstet 2005;90:16-20.
10. OBrien JM, Milligan DA, Barton JR. Gelatin
sponge embolization. a method for the management of iatrogenic preterm premature rupture of the membranes. Fetal Diagn Ther
2002;17:8-10.
11. Briery CM, Veillon EW, Klauser CK, et al.
Women with preterm premature rupture of the
membranes do not benefit from weekly progesterone. Am J Obstet Gynecol 2011;204:54.e1-5.
12. Nageotte MP, Freeman RK, Garite TJ,
Dorchester W. Prophylactic intrapartum amnioinfusion in patients with preterm premature
rupture of membranes. Am J Obstet Gynecol
1985;153:557-62.
13. Szabo I, Szilagyi A, Gacs E, Szekely J. Amnioinfusion for management of preterm prelabour
rupture of membranes. Lancet 1993;341:443-4.
14. Fisk NM, Ronderos-Dumit D, Soliani A, Nicolini U, Vaughan J, Rodeck CH. Diagnostic and
therapeutic transabdominal amnioinfusion in oligohydramnios. Obstet Gynecol 1991;78:270-8.
15. Ogita S, Imanaka M, Matsumoto M, Oka T,
Sugawa T. Transcervical amnioinfusion of antibiotics: a basic study for managing premature
rupture of membranes. Am J Obstet Gynecol
1988;158:23-7.
16. Sadovsky Y, Amon E, Bade ME, Petrie RH.
Prophylactic amnioinfusion during labor complicated by meconium: a preliminary report. Am J
Obstet Gynecol 1989;161:613-7.
17. De Santis M, Scavo M, Noia G, et al. Transabdominal amnioinfusion treatment of severe

American Journal of Obstetrics & Gynecology MONTH 2012

oligohydramnios in preterm premature rupture

of membranes at less than 26 gestational
weeks. Fetal Diagn Ther 2003;18:412-7.
18. Hofmeyr GJ, Essilfie-Appiah G, Lawrie TA.
Amnioinfusion for preterm premature rupture of
membranes. Cochrane Database Syst Rev
2011;12:CD000942.
19. Wells GA, Shea B, OConnell D, Peterson J,
Welch V, Losos M, Tugwell P. The NewcastleOttawa Scale (NOS) for assessing the quality
of nonrandomised studies in meta-analyses.
Available at: http://www.ohri.ca/programs/
clinical_epidemiology/oxford.htm. Accessed
Sept. 13, 2012.
20. Higgins JPT, Green S, eds. Cochrane
Handbook for Systematic Reviews of Interventions, version 5.1.0 [updated March 2011]. The
Cochrane Collaboration 2011. Available at:
www.cochrane-handbook.org. Accessed Sept.
13, 2012.
21. Hozo SP, Djulbegovic B, Hozo I. Estimating
the mean and variance from the median, range,
and the size of a sample. BMC Med Res Methodol 2005;5:13.
22. Moher D, Liberati A, Tetzlaff J, Altman DG.
Preferred reporting items for systematic reviews
and meta-analyses: the PRISMA statement.
PLoS Med 2009;6:e1000097.
23. Stroup DF, Berlin JA, Morton SC, et al.
Meta-analysis of observational studies in epidemiology: a proposal for reporting: Meta-analysis of
Observational Studies in Epidemiology (MOOSE)
group. JAMA 2000;283:2008-12.
24. Chhabra S, Dargan R, Nasare M. Antepartum
transabdominal amnioinfusion. Int J Gynaecol
Obstet 2007;97:95-9.
25. Locatelli A, Ghidini A, Verderio M, et al. Predictors of perinatal survival in a cohort of pregnancies with severe oligohydramnios due to premature rupture of membranes at 26 weeks
managed with serial amnioinfusions. Eur J Obstet
Gynecol Reprod Biol 2006;128:97-102.
26. Locatelli A, Vergani P, Di Pirro G, Doria V,
Biffi A, Ghidini A. Role of amnioinfusion in the
management of premature rupture of the membranes at 26 weeks gestation. Am J Obstet
Gynecol 2000;183:878-82.
27. Vergani P, Locatelli A, Verderio M, Assi F.
Premature rupture of the membranes at 26
weeks gestation: role of amnioinfusion in the
management of oligohydramnios. Acta Biomed
2004;75(suppl):62-6.
28. De Carolis MP, Romagnoli C, De Santis M,
Piersigilli F, Vento G, Caruso A. Is there significant improvement in neonatal outcome after
treating pPROM mothers with amnio-infusion?
Biol Neonate 2004;86:222-9.
29. Turhan NO, Atacan N. Antepartum prophylactic transabdominal amnioinfusion in preterm
pregnancies complicated by oligohydramnios.
Int J Gynaecol Obstet 2002;76:15-21.
30. Garzetti GG, Ciavattini A, De Cristofaro F,
La Marca N, Arduini D. Prophylactic transabdominal amnioinfusion in oligohydramnios for
preterm premature rupture of membranes: increase of amniotic fluid index during latency period. Gynecol Obstet Invest 1997;44:249-54.

Obstetrics

www.AJOG.org
31. Gramellini D, Fieni S, Kaihura C, Faiola S,
Vadora E. Transabdominal antepartum amnioinfusion. Int J Gynaecol Obstet 2003;
83:171-8.
32. Ogunyemi D, Thompson W. A case controlled study of serial transabdominal amnioinfusions in the management of second trimester
oligohydramnios due to premature rupture of
membranes. Eur J Obstet Gynecol Reprod Biol
2002;102:167-72.
33. Vergani P, Locatelli A, Strobelt N, et al.
Amnioinfusion for prevention of pulmonary
hypoplasia in second-trimester rupture of

membranes. Am J Perinatol 1997;14:

325-9.
34. Singla A, Yadav P, Vaid NB, Suneja A, Faridi
MM. Transabdominal amnioinfusion in preterm
premature rupture of membranes. Int J Gynaecol Obstet 2010;108:199-202.
35. Tranquilli AL, Giannubilo SR, Bezzeccheri V, Scagnoli C. Transabdominal amnioinfusion in preterm
premature rupture of membranes: a randomised
controlled trial. BJOG 2005;112:759-63.
36. Deutsch A, Deutsch E, Totten C, Downes
K, Haubner L, Belogolovkin V. Maternal and
neonatal outcomes based on the gestational

Research

age of midtrimester preterm premature rupture

of membranes. J Matern Fetal Neonatal Med
2010;23:1429-34.
37. Vermillion ST, Kooba AM, Soper DE. Amniotic fluid index values after preterm premature
rupture of the membranes and subsequent
perinatal infection. Am J Obstet Gynecol
2000;183:271-6.
38. Coolen J, Kabayashi K, Wong K, Mayes
DC, Bott N, Demianczuk N. Influence of oligohydramnios on preterm premature rupture of
the membranes at 30 to 36 weeks gestation. J
Obstet Gynaecol Can 2010;32:1030-4.

MONTH 2012 American Journal of Obstetrics & Gynecology

1.e11