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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 prema-
ture 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 perina-
tal 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, re-
spectively. Perinatal mortality rates were reduced among the treatment
groups in both the observational studies (odds ratio, 0.12; 95% confi-
dence 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 PPROM-
associated morbidity and mortality rates. Additional adequately pow-
ered 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;207:393.e1-11.

P reterm premature rupture of mem-

branes (PPROM) complicates ap-
proximately 3% of all pregnancies.1 It is a
major cause of neonatal death and mor-
bidity, 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. Chorioam-
nionitis negatively affects neonatal prog-
nosis at all gestational ages and warrants
prompt delivery. The standard manage-
ment approach to mid-trimester PPROM
includes antibiotic treatment2 and cortico-
steroids3 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 dis-
tress. Termination of pregnancy may be
offered for previable PPROM (22-23
weeks of gestation) because of the poor
prognosis. Despite the relatively high fre-
quency of this condition, controversy re-
garding the optimal management persists.
In recent years, attempts to decrease
neonatal mortality and morbidity rates
were undertaken with different strategies
that included intracervical fibrin appli-
cation,5 amniopatch,6 fetal endoscopic
tracheal occlusion,7,8 antioxidant treat-
ment,9 gelatin sponge,10 and progester-
one treatment.11 None of these strategies
have proved to be consistently effec-
tive, reproducible, or applicable for
most centers.
Amnioinfusion or instillation of phys-
iologic solution into the amniotic cavity
was attempted initially to reduce intra-
partum 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 transcer-
vical15,16 and transabdominal14 routes
have been attempted. One of the hypo-
thetic 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) the-
oretically surmounts this pitfall. Several ar-
ticles 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 num-
ber of subjects in those studies precluded
a definitive answer in regards to the effi-
cacy of the intervention.18 However, ad-
ditional data are available from observa-

NOVEMBER 2012 American Journal of Obstetrics & Gynecology 393.e1

Research Obstetrics
FIGURE 1
Study selection process
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 systemat-
ically and metaanalyze studies that have
assessed efficacy and safety of TA in
women with PPROM. This systematic
review provides results of separate qual-
itative and quantitative analyses of ran-
domized controlled trials (RCTs) and
observational studies.
M ETHODS
Search strategy
We performed a comprehensive literature
search, assisted by an experienced librar-
ian, using the MEDLINE from 1950 to De-
cember 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 rup-
ture, rupture, membrane*, pregnancy,
amnioinfus*, premature fetus membrane
rupture, and amnioinfusion. There were
no language or geographic restrictions.
393.e2 American Journal of Obstetrics & Gynecology NOVEMBER 2012
Bibliography of identified articles was
used to screen for additional related
articles.
Study selection
We included both comparative observa-
tional and RCTs in which TA and conven-
tional treatment were compared with con-
ventional treatment alone. Case reports,
case series, and abstract publications were
excluded. Studies that included patients
with a confirmed diagnosis of PPROM-as-
sociated 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
www.AJOG.org
outcomes of interest were pulmonary
hypoplasia, neonatal death, gestational
age at birth, birthweight, chorioamnio-
nitis, early onset (72 hours from deliv-
ery) neonatal sepsis, bronchopulmonary
dysplasia, and cesarean delivery. Two in-
vestigators (S.P. and H.A.) indepen-
dently abstracted the relevant data from
selected articles.
Assessment of risk of bias
Risk of bias in observational studies
was assessed with the Newcastle-Ot-
tawa scale19 and in RCTs with the Co-
chrane collaborations tool.20 For ob-
servational studies, the domains of
assessment included selection, compara-
bility, and outcome assessment biases.
For RCTs, the domains included selec-
tion, performance, detection, attrition,
reporting, and other biases. Two investi-
gators (S.P. and H.A.) independently
assessed risk of bias; discrepancies were re-
solved through discussion and involve-
ment of third author.
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 extrac-
tors; discrepancy was resolved by con-
sensus. We did not contact authors for
missing information. For continuous
outcomes, means and standard devia-
tions were obtained from studies. When
they were not reported, they were calcu-
lated 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). Meta-
analyses were performed separately for
cohort studies and the RCTs. Where data
were sufficiently homogenous, meta-
analysis was conducted with the use of a
random effects model, with weighting of
studies according to the DerSimonian-
Laird method. Random-effect model
was used to account for between and
within study heterogeneity. Cochrans Q
www.AJOG.org Obstetrics 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 )

NOVEMBER 2012 American Journal of Obstetrics & Gynecology 393.e3

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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 sulbactam-
ampicillin 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 150-
350 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. (continued )

393.e4 American Journal of Obstetrics & Gynecology NOVEMBER 2012

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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 be- the Observational Studies in Epidemiol- clear whether reported patients in
tween studies at the .10 level of signifi- ogy guidelines,23 respectively. these studies were included in other
cance. The I-squared statistic was used to studies,25-28 and 1 because the inter-
quantify the degree of heterogeneity. R ESULTS vention group and control group were
Our initial search yielded 141 citations. unmatched29). The remaining 7 stud-
Report After review of titles and abstracts, 126 ies met inclusion criteria and were in-
Results of the metaanalysis of RCTs and citations were excluded (Figure 1). After cluded in this review.17,30-35 Character-
the observational studies were reported full text review of the remaining 15 istics of these studies are summarized in
according to the Preferred Reporting articles, 8 articles were excluded (3 be- Table 1.
Items for Systematic Reviews and Meta- cause inclusion criteria were not ful- Of the 7 included studies, 2 studies
analyses statement22 and Metaanalysis of filled13,14,24; 4 because of it was not were RCTs (47 patients in each group);

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Research Obstetrics www.AJOG.org

TABLE 2
Quality assessment of observational cohort studies by the Newcastle-Ottawa Scale system
Selection Comparability Outcome

Demonstration Comparability of
that outcome of cohorts on the Was follow-up
Representativeness Selection of the interest was not basis of the long enough Adequacy of Total
of the exposed nonexposed Ascertainment present at start design or Assessment for outcomes follow up of stars,
Study cohort cohort of exposure of study analysis of outcome to occur? cohorts n
Ogunyemi and * * * * ** * * * 9
Thompson
(2002)32
................................................................................................................................................................................................................................................................................................................................................................................
Vergani et al * * * * * * * 7
(1997)33
................................................................................................................................................................................................................................................................................................................................................................................
Garzetti et al * * * * ** * * * 9
(1997)30
................................................................................................................................................................................................................................................................................................................................................................................
Gramellini et al * * * * * * * 7
(2003)31
................................................................................................................................................................................................................................................................................................................................................................................
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 pa- not possible. Ascertainment of rupture number of procedures per patient, suc-
tients in the control group and 37 in the of membranes was performed in all stud- cess rate, and volumes infused varied
intervention group), and 4 studies were ies by speculum examination to confirm among different studies and among dif-
observational studies (75 patients in the pooling of amniotic fluid in the posterior ferent subjects in the same study. The av-
control group and 72 in the intervention fornix. In addition, 6 studies used nitra- erage number of infusions per patient
group). In the quasirandomized study, zine, and 1 study used fetal fibronectin as ranged from 1.23 in Singla et al34 to 4.0 in
patients were admitted by chance to one a confirmatory test.35 Conventional care De Santis et al.17 Vergani et al33 reported
of 2 departments that differed in their for patients with PPROM included bed a median number of 3 infusions per pa-
management approach toward PPROM: rest in the hospital and prophylactic an- tient with a range of 19. Most of the
one department provided standard care; tibiotic therapy in all studies. Five studies studies did not report success rate;
the other department provided standard used tocolysis only when uterine con- however, Garzetti et al30 reported a
care in addition to serial amnioinfusion tractions appeared without clinical cho- success in 18 of 19 patients, and De
to consented patients. We decided to in- rioamnionitis or abruptio placenta17,31-34; Santis et al17 reported successful am-
clude the quasirandomized study with however, 2 studies used tocolysis as a pro- nioinfusion in 143 of 147 procedures.
the other 2 randomized studies because phylactic measure for all patients, regard- The infused volumes range from 140-
we believed that the risk of bias in that less of the presence of uterine contrac- 350 mL per infusion.17,30,34,35
study was not high. The gestational age at tions.30,35 Targeted antibiotic therapy De Santis et al17 reported on 5 compli-
inclusion varied from 16-33 weeks. In- based on cervical and vaginal cultures cations that occurred within 24 hours af-
formation on individual patients was was used in 3 studies.17,30,33 Corticoste- ter infusion: 2 cord prolapses (1 cephalic
provided only in 1 study32; therefore, roids for fetal lung maturation was used and 1 transverse lie); 2 abruptio placen-
subgroup analysis by gestational age was after viability in all but 1 study.30 The tae, and 1 onset of labor. Gramellini et

TABLE 3
Quality assessment of randomized controlled trials
Bias

Selection
Performance: blinding Detection: blinding Reporting:
Random sequence Allocation of participants of outcome Attrition: incomplete selective Other
Study generation concealment and personnel assessment outcome data reporting sources Overall
Singla et al Low risk Unclear risk Unclear Unclear Low risk Low risk Low risk Moderate risk
(2010)34
................................................................................................................................................................................................................................................................................................................................................................................
Tranquilli et al Low risk Low risk Unclear Unclear Low risk Low risk Low risk Moderate risk
(2005)35
................................................................................................................................................................................................................................................................................................................................................................................
De Santis et al High risk High risk Unclear High risk Low risk Low risk Low risk High risk
(2003)17
................................................................................................................................................................................................................................................................................................................................................................................
Porat. Transabdominal amnioinfusion for PPROM. Am J Obstet Gynecol 2012.

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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. Ogun-
yemi and Thompson32 reported on 2 neo-
natal 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 in-
cluded 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 in-
terval [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 hy-
poplasia (2 studies, 45 participants;
pooled OR, 0.17; 95% CI, 0.04 0.78;
heterogeneity: I2 0%; Figure 2) and a

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Research Obstetrics www.AJOG.org

TABLE 4
Effect of transabdominal amnioinfusion on the tested outcomes
Metaanalysis of observational studies Metaanalysis of randomized controlled trials
a
Studied outcome Studies/participants, n Effect estimate Studies/participants, n Effect estimatea
Difference in mean gestational age at preterm 4/147 12.30 (18.56 to 6.03) 3/165 1.58 (8.09 to 4.52)
premature rupture of membranes, db
................................................................................................................................................................................................................................................................................................................................................................................
Difference in mean gestational age at 3/111 4.11 (22.23 to 14.00) 3/165 3.86 (16.49 to 24.21)
delivery, db
................................................................................................................................................................................................................................................................................................................................................................................
Difference in mean latency period length, db 4/147 14.40 (8.2420.56) 3/165 11.41 (3.36 to 26.18)
................................................................................................................................................................................................................................................................................................................................................................................
Difference in mean birthweight, g b
2/77 129.52 (691.09 to 432.06) 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 N/A 1/71 1.29 (0.493.42)
................................................................................................................................................................................................................................................................................................................................................................................
Cesarean delivery 2/54 4.16 (0.9617.95) 1/71 2.35 (0.816.81)
................................................................................................................................................................................................................................................................................................................................................................................
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, Interestingly, there was a decreased rate gravity of this condition, current ob-
18 participants; OR, 0.09; 95% CI, 0.01 of infectious complications of amnionitis stetrics management has little to offer.
0.84; heterogeneity: not applicable). The or chorioamnionitis in the TA group (2 Aside from close monitoring for signs
other tested secondary outcomes did not studies, 131 participants; OR, 0.28; 95% of infection or early labor, no obstet-
reach statistical significance. CI, 0.11 0.69; heterogeneity: I2 0%). rics interventions have demonstrated
None of the other secondary outcomes the ability to reduce morbidity or mor-
Metaanalyses of RCTs reached statistical significance. tality rate that is the result of early
Primary outcomes
PPROM or specifically to address the
There was no statistically significant dif-
pathophysiologic processes that un-
ference in the latency period (3 studies, C OMMENT
derlie the cause of this condition.
165 participants; mean difference, 11.4 Mid-trimester PPROM poses a challeng-
ing clinical problem. Poor prognosis In this metaanalysis, a better short-
days increase in latency in TA group;
term prognosis in women with PPROM
however, 95% CI 3.4 to 26.2 days; het- usually results from the combination of
erogeneity: I2 89%; Figure 3) and no prematurity, pulmonary hypoplasia, and who underwent serial TA was seen in the
statistically significant difference in peri- infection. The prognosis of mid-trimes- observational studies. The intervention
natal mortality rate (2 studies, 131 par- ter PPROM at 21 weeks of gestation is group had significant latency prolonga-
ticipants; pooled OR, 0.33; 95% CI, grave because most fetuses experience tion and improved perinatal and neona-
0.10 1.12; heterogeneity: I2 45%; Fig- pulmonary hypoplasia.36 Pregnancy out- tal survival and experienced less pulmo-
ure 3). A subgroup analysis of periviable comes are correlated directly with the nary hypoplasia. These results intensify
vs potentially viable babies could not be gestational age at which the mem- in the face of significantly lower gesta-
performed because of a lack of reporting branes are ruptured and the amount tional age at rupture of membranes in
data. of residual fluid after the rupture of the intervention group, compared with
membranes. Low residual volume of the control group in the observational
Secondary outcomes amniotic fluid has been shown to be studies (12.3 days of difference; 95% CI,
Results of metaanalyses of secondary associated with a shorter latency pe- 6.0318.56). The results from the meta-
outcomes are given in Table 4. There was riod37,38 and increased risk for early analysis of RCTs demonstrated a trend
no statistically significant difference in onset neonatal sepsis and chorioam- toward benefit, but the results were not
the rate of pulmonary hypoplasia (2 nionitis.37 Lack of an effective treat- statistically significant. This is possibly
studies, 69 participants; pooled OR, 0.3; ment or intervention to prolong preg- because of the small number of partici-
95% CI, 0.051.7; heterogeneity: I2 nancy complicates this situation even pants in the studies and the lack of
52%; Figure 3). further. Despite the seriousness and power.

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www.AJOG.org Obstetrics 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/in-
flammatory processes are responsible
for the activation of the laboring pro-
cess. Thus, the theoretic benefit of am-
nioinfusion 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 in-
traamniotic fluid volume and pressure.
Theoretically, washing out or diluting
the preexisting intraamniotic bacteria
and inflammatory cells may be benefi-
cial 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 interven-
tion that include the ability to test fetal
genetics (when indicated), an im-
provement 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 sam-
ple 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, be-
cause of the small sizes of included ran-
domized studies and our inability to
conclude with confidence because of
lack of power, we suggest large ade-

NOVEMBER 2012 American Journal of Obstetrics & Gynecology 393.e9

Research Obstetrics
quately powered studies are needed for 2. Yudin MH, van Schalkwyk J, Van Eyk N, et al.
this intervention. Because of the rarity of Antibiotic therapy in preterm premature rupture
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tion of treatment for such women will Do antenatal corticosteroids help in the setting
allow adequate power and generalizabil- of preterm rupture of membranes? Am J Obstet
ity of findings. Limitations of this review Gynecol 2001;184:131-9.
4. Miracle X, Di Renzo GC, Stark A, Fanaroff A,
include the low numbers of participants Carbonell-Estrany X, Saling E. Guideline for the
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was heterogeneity in the reporting of the tracervical fibrin sealants: a potential treatment for
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erogeneity in the quality of the studies in 6. Deprest J, Emonds MP, Richter J, et al. Am-
terms of risk of bias. niopatch for iatrogenic rupture of the fetal mem-
If the superiority of serial TA over con- branes. Prenat Diagn 2011;31:661-6.
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saving effects of fetal tracheal occlusion on pul-
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C and E in the latency period in women with
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but not in RCTs; however, for both terone. Am J Obstet Gynecol 2011;204:54.e1-5.
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types of studies, the number of patients Dorchester W. Prophylactic intrapartum am-
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We thank Ms Elizabeth Uleryk, Chief Librarian at gohydramnios. Obstet Gynecol 1991;78:270-8.
the Hospital for Sick Children, Toronto, Canada, 15. Ogita S, Imanaka M, Matsumoto M, Oka T,
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