Association and prediction of amniotic uid

measurements for adverse pregnancy outcome:

systematic review and meta-analysis
RK Morris,
a,b
CH Meller,
b,c
J Tamblyn,
d
GM Malin,
e
RD Riley,
f
MD Kilby,
a
SC Robson,
g
KS Khan
h
a
Birmingham Centre for Womens & Childrens Health & School of Clinical and Experimental Medicine, College of Medical and Dental Sciences,
University of Birmingham, Birmingham, UK
b
Fetal Medicine Centre, Birmingham Womens Hospital NHS Foundation Trust, Birmingham, UK
c
Obstetrics Division, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
d
University North Staffordshire NHS Trust Hospital, Stoke on
Trent, UK
e
School of Clinical Sciences, the University of Nottingham, Nottingham, UK
f
School of Health and Population Sciences, University of
Birmingham, Birmingham, UK
g
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
h
Womens Health Research
Unit, The Blizard Institute, Barts and The London School of Medicine, Queen Mary, University of London, London, UK
Correspondence: RK Morris, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham,
Birmingham B15 2TT, UK. Email r.k.morris@bham.ac.uk
Accepted 4 November 2013. Published Online 7 February 2014.
Background Measurements of amniotic uid volume are used for
pregnancy surveillance despite a lack of evidence for their
predictive ability.
Objective To evaluate the association and predictive value of
ultrasound measurements of amniotic uid volume for adverse
pregnancy outcome.
Search strategy Electronic databases (inception to October 2011),
reference lists, hand searching of journals, contact with experts.
Selection criteria Studies comparing measurements of amniotic
uid volume with adverse outcome, excluding pre-labour
ruptured membranes or congenital/structural anomalies.
Data collection Data on study characteristics, design, quality.
Random effects meta-analysis to estimate summary odds ratios
(prognostic association) and summary sensitivity, specicity and
likelihood ratios (predictive ability).
Main results Forty-three studies (244 493 fetuses) were included
demonstrating a strong association between oligohydramnios
(varying denitions) and birthweight <10th centile (summary
odds ratio [OR] 6.31, 95% condence interval [95% CI] 4.15
9.58; high-risk population [author denition] n = 6 studies,
28 510 fetuses), and mortality (neonatal death any population
summary OR 8.72, 95% CI 2.4331.26; n = 6 studies, 55 735
fetuses; and perinatal mortality high-risk population summary OR
11.54, 95% CI 4.0532.9; n = 2 studies, 27 891 fetuses). There was
a strong association between polyhydramnios (maximum pool
depth >8 cm or amniotic uid index 25 cm) and birthweight
>90th centile (OR 11.41, 95% CI 7.0918.36; n = 1 study, 3960
fetuses). Despite strong associations, predictive accuracy for
perinatal outcome was poor.
Authors conclusion Current evidence suggests that
oligohydramnios is strongly associated with being small for
gestational age and mortality, and polyhydramnios with
birthweight >90th centile. Despite strong associations with poor
outcome, they do not accurately predict outcome risk for
individuals.
Keywords Amniotic uid, oligohydramnios, predictive accuracy,
prognosis, small for gestational age.
Please cite this paper as: Morris RK, Meller CH, Tamblyn J, Malin GM, Riley RD, Kilby MD, Robson SC, Khan KS. Association and prediction of amniotic
uid measurements for adverse pregnancy outcome: systematic review and meta-analysis. BJOG 2014;121:686699.
Introduction
The amniotic uid is fundamental for proper fetal develop-
ment and growth, and amniotic uid volume measure-
ments using prenatal ultrasound have become standard in
fetal surveillance, especially in the evaluation of high-risk
pregnancies. Alterations in amniotic uid volume, espe-
cially decreased amniotic uid volume (oligohydramnios),
have classically been considered an indicator of adverse
perinatal outcome and, therefore, have led to an almost
uniform recommendation for delivery following the diag-
nosis of oligohydramnios, at least for patients at term.
1
However, the number of ultrasonographic modalities
applied to assess amniotic uid volume and the various
threshold points reect the inaccuracies inherent in each of
these modalities.
27
Moreover, the association between
686 2014 Royal College of Obstetricians and Gynaecologists
DOI: 10.1111/1471-0528.12589
www.bjog.org
Systematic review
abnormal amniotic uid volume and adverse perinatal out-
comes came from heterogeneous studies that frequently
included patients with preterm ruptured membranes or dif-
ferent underlying medical conditions, and/or fetuses with
structural anomalies, clinical situations that may affect the
amniotic uid volume.
1
A previous review of randomised controlled trials
(RCTs) has concluded that single deepest vertical pocket
measurement is the method of choice for the assessment of
amniotic uid volume
8
on the basis that neither method
was superior but that amniotic uid index (AFI) led to
more diagnoses of oligohydramnios, more inductions of
labour and more caesarean deliveries for fetal distress with-
out improving perinatal outcome.
8
The observed effect in
these RCTs is determined by both test accuracy and the
effect of the intervention
9
that follows testing; a conclusion
of this review was that a systematic review of the accuracy
of AFI versus single deepest pocket was needed.
8
Therefore we present here a systematic review and
meta-analysis of the literature to assess the prognostic asso-
ciation and predictive accuracy of measurements of amni-
otic uid for adverse pregnancy outcome and we compare
the performance of different techniques of measurement of
amniotic uid.
Methods
Sources
A systematic review was performed according to a protocol
(see Appendix S1) and in accordance with recommended
methods.
1013
Our review has been reported according to
the PRISMA guidelines.
14
The following sources were searched from inception to
October 2011: MEDLINE; EMBASE; Cumulative Index To
Nursing And Allied Health Literature (CINAHL); The
Cochrane Central Register of Systematic Reviews; The
Cochrane Central Register of Controlled Trials; DARE;
MEDION; SIGLE; Index of Scientic and Technical Pro-
ceedings, Web of Science and ClinicalTrials.gov database.
The search consisted of keywords and MeSH terms relating
to the tests under investigation combined with MeSH
terms of Prenatal Diagnosis, Ultrasonography, Amniotic
Fluid and Pregnancy Outcome. The full search strategy is
shown in the Appendix S2. The reference lists of all
included primary and review articles were examined to
identify cited articles not captured by electronic searches.
REFERENCE MANAGER 12.0 was used to construct a compre-
hensive database of literature. No language restrictions were
applied.
Study selection
The database was scrutinised by two reviewers (RKM,
CHM) and full articles likely to meet the selection criteria
were obtained. Translations were obtained for non-English
articles. Three reviewers made the nal inclusion/exclusion
decisions according to adherence to the following criteria.
1 Population. Pregnant women, with or without fetal
growth restriction, no evidence of premature rupture of
membranes, no evidence of congenital or structural
anomalies.
2 Index test. Any measure of amniotic uid reported by
the authors including AFI, amniotic uid volume and
maximum deepest pocket. Any threshold used to dene
low or high amniotic uid as reported by the authors of
the included studies was accepted.
3 Outcome. Any reference standard looking at compromise
of fetal or neonatal wellbeing; including: abnormal cord
pH at birth, Apgar scores, perinatal death and composite
outcomes such as adverse perinatal outcome. Any refer-
ence standard for fetal growth restriction or small for
gestational age: Birthweight <10th, <5th, <3rd centile,
absolute birthweight thresholds, ponderal index.
4 Study design. Observational studies in which the results
of the test of interest are compared with the outcome
ndings as conrmed by a reference standard, allowing
generation of a 2 9 2 table to compute indices of associ-
ation and test accuracy for each available threshold. Case
series of ten or fewer and casecontrol studies deter-
mined by outcome were excluded.
Data extraction
All articles were assessed independently by a minimum of
two reviewers (RKM, CHM, JT, GLM) and the data were
abstracted. The following were recorded; study characteris-
tics (authors, journal, year of publication, country, study
design, objectives, type of medical centre, and period or
duration of the study); characteristics of the participants
(study population, method of selection, inclusion and
exclusion criteria, whether consecutive cases, number of
participants, number of excluded participants and reasons
for exclusion, personal and medical characteristics of
enrolled women, inpatients compared with outpatients,
level of activity, gestation at time of test and at delivery as
well as test to delivery interval were recorded); information
on how the diagnostic tests were carried out and the
results; and methods for assessing the diagnostic accuracy
of the tests and the results (number of true and false posi-
tives, number of true and false negatives, sensitivity, speci-
city, positive likelihood ratio, negative likelihood ratio,
method of agreement, receiver operating characteristic
curve, area under the curve, and the threshold level(s)
used). Disagreements were resolved by consensus or
through arbitration by a third reviewer (RKM or KSK). For
multiple and/or duplicate publication of the same data set
only the most recent or most complete study was included.
All studies had to state that they excluded rupture of
687 2014 Royal College of Obstetricians and Gynaecologists
Amniotic uid measurement and adverse pregnancy outcome
membranes and congenital/structural anomalies due to the
association of renal/urinary tract anomalies and karyotypic
anomalies with abnormalities of liquor volume.
Study quality assessment
All included manuscripts were assessed by at least one
reviewer for study and reporting quality using validated
tools for test accuracy studies.
1519
Methodological quality
was dened as the condence that the study design, con-
duct and analysis have minimised biases in addressing the
research question, thereby focusing on the internal validity
(i.e. the degree to which the results of an observation are
correct for the patients being studied). Items considered
important for a good quality paper were prospective
design with consecutive/random recruitment, full verica-
tion of the test result with an outcome measure (>90%),
adequate description of the population and index test and
whether the clinicians managing the patients were blinded
to the results of the index test. Quality of the papers was
assessed by QUADAS (see Appendix S3). Quality scores
were not assigned because these have been shown to give
awed results in a diagnostic accuracy setting. Studies were
rated as high quality for subgroup analysis if they satised
at least four of the following items: adequate description
of population; adequate description of the test (measure-
ment of amniotic uid and threshold) and outcome mea-
sure; consecutive recruitment; prospective recruitment;
>90% completions of follow up; appropriate outcome
measurement; blinding of the investigators performing the
outcome measure and a statement regarding the use of
intervention between the index test and outcome. As this
review was nearing completion QUADAS 2 was published
and so all included papers were re-assessed in-line with
the recommendations from QUADAS 2.
20
Elements of
study design that were likely to have a direct relationship
to bias in a test accuracy study were assessed using the
STARD checklist.
Data synthesis for prognostic association
From the 2 9 2 tables in each study, odds ratios (OR)
were computed with their 95% condence intervals (CI)
for each measure of amniotic uid (at all reported thresh-
olds) and its outcome pair. Results were pooled using a
random effects meta-analysis model
21,22
where the deni-
tion of the measure of amniotic uid volume, the threshold
used and the outcome measure were the same. Odds ratios
were selected as the summary statistic, to assess prognostic
ability, because they represent the effect of the test on the
odds in an unbiased fashion and enable the results of case
control and cohort studies to be included.
23
They are often
used to demonstrate an epidemiological association.
23
A random effects meta-analysis model was chosen for
each test due to the expected presence of clinical and
statistical heterogeneity between studies. This approach
synthesises the log OR estimates and weights each study
by the inverse of the studys variance plus between-study
variance to produce a summary estimate of the average
prognostic effect of a test. As a tests prognostic ability
may vary from this average from setting to setting, after
each random-effects meta-analysis if I
2
> 0% we also esti-
mated a prediction interval to reveal the potential prog-
nostic effect if the test is applied in a single setting
similar to one of the studies from our analysis.
21
This
was calculated where three or more studies were included
in the meta-analysis.
21
We plotted summary odds ratio data in forest plots and
assessed the between-study heterogeneity in prognostic
effect of each test by estimating I
2
(the amount of variabil-
ity in prognostic effects due to between-study heterogene-
ity)
24
and tau-squared.
25
Where possible we performed
meta-regression or subgroup analysis as appropriate to
examine the effect of potential confounding factors: single-
ton or multiple birth status, timing of test in relation to
delivery, gestation of pregnancy at time of testing, high-
risk or low-risk population as assessed by the study
authors, and study quality were considered to be impor-
tant factors that may inuence the strength of the associa-
tion between amniotic uid measurement and adverse
outcome.
In studies where there were cells in the 2 9 2 table with
a value of 0, 0.5 was added to all cells to allow the calcula-
tion of log odds ratios and their variances for meta-analy-
sis.
26
Meta-analyses were performed where two or more
studies reported the same index test and outcome measure.
The primary outcomes were considered to be birthweight
<10th centile and birthweight <2500 g for measurements of
small for gestational age, and perinatal mortality, abnormal
cord pH (<7.20) and adverse perinatal outcome for wellbe-
ing. A composite outcome measure (adverse perinatal out-
come) was employed by some included studies to
maximise the number of events that could be included in
the analysis and avoid the need to select a single morbid-
ity/mortality as a primary outcome measure. However, a
hazard of composite outcome measures is the assumption
that the signicance of the result applies to all compo-
nents.
27
To address this issue, we analysed the component
outcomes as subgroups when these were reported (see
Appendix S4). When the composite outcome measure was
used, care was taken to ensure that each individual was
only counted once in each analysis, particularly where stud-
ies reported multiple outcomes for a single population.
Where multiple outcomes and test thresholds were
reported, attempts were made to select the most consistent
threshold and outcome across the analysis. It should be
noted that for the outcomes of neonatal death and perina-
tal mortality, these were the outcomes as used in the
688 2014 Royal College of Obstetricians and Gynaecologists
Morris et al.
included studies and there is no overlap between the stud-
ies included in each outcome.
To explore for the presence of publication bias, the
Peters test (a weighted linear regression with ln odds ratio
as the dependent variable and the inverse of the total sam-
ple size as the independent variable) was performed
28
to
assess funnel plot asymmetry for each meta-analysis con-
taining ten or more studies, with a signicance level of
10% used.
29
Data synthesis for predictive ability
Odds ratios signicantly >1 indicate a prognostic associa-
tion between amniotic uid measurement and poor out-
come; on average in the population this measure was
associated with a worse outcome. We considered odds
ratios between 1 and 2 to be mild associations, 2 and 5 to
be moderate associations, and >5 as strong associations. In
particular, although all odds ratios >1 indicate a prognostic
association at the population level, we felt that only an
odds ratio >5 would indicate a sufcient discrepancy
between amniotic uid volumes that may have predictive
ability at the individual level. Therefore we only considered
test accuracy at the individual level (in terms of sensitivity
and specicity of a test) when its odds ratio was >5, the
95% CI did not cross 1 and there was statistical signi-
cance. We assessed the predictive ability
30
of the test by
calculating summary sensitivity, specicity and likelihood
ratios, again using data from the 2 9 2 tables and synthes-
ising using a bivariate random-effects meta-analysis
model.
31
Likelihood ratios indicate by how much a given
test result raises or lowers the odds of having the disease
and have been recommended by Evidence-based Medicine
Groups
32,33
as they show how the test result informs clini-
cal decision making.
All analyses were performed in STATA version 11.0 (Stata-
Corp, College Station, TX, USA) using the metan, metandi
and metabias commands.
3436
Summary results were dis-
played in forest plots generated using STATSDIRECT.
Results
Figure 1 summarises the process of literature identication
and selection. Of the 6259 potential citations, 43 primary
articles were included in the critical appraisal and system-
atic review. Appendix S4 details the individual study char-
acteristics of the included studies and their references.
There were 43 studies included overall, reporting on
244 493 fetuses. The commonest index tests reported were
amniotic uid index 5 cm (number of studies, n = 23)
and maximum pool depth (MPD) 2 cm (n = 6; Figure 1).
The outcome measures reported most often were birth-
weight <2500 g (n = 6), birthweight <10th centile
(n = 13), Apgar score at 1 minute <7 (n = 12), Apgar
score at 5 minute <7 (n = 17), umbilical cord pH <7.20
(n = 5), admission to neonatal intensive care unit
(n = 16), perinatal mortality (n = 9), neonatal death
(n = 5) and adverse perinatal outcome (n = 9). There were
only four papers that reported results for ponderal index
and no papers that used a measure of fetal growth restric-
tion as an outcome, e.g. fetal weight <10th centile and
abnormal Dopplers.
Figure 2 shows a summary of the quality assessment of
included studies. There was good compliance with appro-
priate population spectrum, selection criteria adequately
described and appropriate reference standard. There was
poor compliance with adequate description of index and
reference standard (Appendix S3 for adequate criteria).
Blinding of the assessors of the outcome measure to the
results of the amniotic uid measurement was also poorly
reported (6/43 studies). Only seven studies reported on
the use of any treatment in between the amniotic uid
measurement and delivery, or whether the results of the
tests were used in determining patient management.
When assessing the included papers with the QUADAS-2
recommendations the results were: patient selection, 86%
low risk of bias and 9% high concerns re applicability;
index test, 65% low risk of bias and low concerns re
applicability (mainly due to inadequate description of
index test); reference standard, only 9% had low risk of
bias (due to non-blinding and poor reporting of method
of reference standard) but applicability was high with only
3% of studies having concerns re applicability; for ow
and timing 16% of studies had low concerns regarding
possibility of bias and this was mainly due to poor
reporting of any intervention between index and reference
standard.
Summary results for oligohydramnios and
outcome of measures of small for gestational age
Five of the 12 meta-analyses performed for oligohydram-
nios (according to threshold used and outcome denition)
provided a summary odds ratio and 95% CI that demon-
strated a signicant association between oligohydramnios
and small for gestational age as measured by birthweight
<2500 g or <10th centile (Figure 3). The summary odds
ratio estimate was generally above 2, suggesting a reason-
ably large prognostic association on average. However,
there was large heterogeneity for most meta-analyses, even
after subgrouping studies (Figure 3), with I
2
often over
70%. The heterogeneity is reected in the wide prediction
intervals, which generally include an odds ratio of 1, and
reveal that in individual settings the association might vary
considerably from the average, and may not even be
important in some situations.
For birthweight <10th centile subgroup analysis found
only a signicant effect from a high-risk population. On
689 2014 Royal College of Obstetricians and Gynaecologists
Amniotic uid measurement and adverse pregnancy outcome
average across all measures of oligohydramnios in high-risk
populations, the summary odds ratio was 6.31 (95% CI
4.159.58) and this was a rare situation where the predic-
tion interval was also entirely above 1 (2.2317.81; Fig-
ure 3). This is compared with a summary odds ratio of 2.34
(95% CI 1.763.09) and prediction interval (0.3814.43) in
a low-risk/unselected population. Given this, we also evalu-
ated the summary accuracy of oligohydramnios for correctly
predicting a birthweight <10th centile in a high-risk popula-
tion. Across all measures of oligohydramnios, the summary
sensitivity was 0.4 (0.120.76), summary specicity was 0.91
(0.660.98), summary positive likelihood ratio was 4.23
(2.387.52), and summary negative likelihood ratio was
0.66 (0.411.06).
There were insufcient papers (n = 1) for meta-analysis
of birthweight <3rd and 5th centiles as outcome measures
but individual studies showed a stronger association with
these more severe measures of SGA (Figure 3). Correspond-
ing results for predictive accuracy were for birthweight <5th
centile (MPD < 2 cm) sensitivity 0.43 (95% CI 0.180.71),
Primary articles retrieved for detailed evaluation
- From electronic searches n = 314
- From reference lists n = 9
Articles excluded n = 280
- Not prediction/not test accuracy n = 147
- Reviews/letters/comments/editorials n = 35
- Paper/translation unobtainable n = 12
- Case series<10 n = 4
- Case control studies n = 9
- Duplications n = 7
- Studies where premature rupture of membranes or congenital
anomalies could not be excluded from analysis n = 66
Primary articles included in systematic review n = 43 n = 244 493 individuals
Test No of studies No of individuals
Maximum pool depth <1 cm 5 931
Maximum pool depth <2 cm 6 2293
Maximum pool depth other thresholds 5 1374
Amniotic fluid index 5 cm 23 75 340
Amniotic fluid index 8 cm 2 27 842
Other thresholds reduced AFI 8 5332
Other measurement of reduced liquor 6 875
Measure of polyhydramnios 5 144 681
Potentially relevant citations identified from electronic searches to capture primary articles
on measurements of amniotic fluid volume to predict FGR/compromise of fetal wellbeing
n = 6259
References excluded after screening titles and/or abstracts
n = 5945
Figure 1. Process from initial search to nal inclusion for measurements of amniotic uid volume to predict small for gestational age and
compromise of fetal/neonatal wellbeing (up to October 2011). AFI, amniotic uid index.
690 2014 Royal College of Obstetricians and Gynaecologists
Morris et al.
specicity 0.92 (95% CI 0.860.96), positive likelihood ratio
5.46 (95% CI 2.3812.5) and negative likelihood ratio 0.62
(95% CI 0.390.98). For birthweight <3rd centile (AFI
5 cm), sensitivity 0.04 (95% CI 0.030.05), specicity 0.99
(95% CI 0.990.99), positive likelihood ratio 12.9 (95% CI
8.8818.7) and negative likelihood ratio 0.97 (95% CI 0.96
0.98). For birthweight <2500 g (AFI 5 cm AFI 5 cm,
n = 2 studies, 28 554 fetuses) the accuracy results were
summary sensitivity 0.09 (95% CI 0.080.11), summary
specicity 0.98 (95% CI 0.980.99), summary positive likeli-
hood ratio 5.04 (95% CI 0.6738.11) and summary negative
likelihood ratio 0.84 (95% CI 0.631.11), there was signi-
cant heterogeneity.
Summary results for outcome measures of
oligohydramnios and fetal wellbeingprimary
outcome measures
All analyses demonstrated an association between oligohy-
dramnios and neonatal death, and the majority also indi-
cated an association with perinatal mortality (Figure 4).
Heterogeneity was again large and prediction intervals were
wide. Across all measures of oligohydramnios there was a
strong association with neonatal death (summary OR 8.72,
95% CI 2.4331.26, estimated prediction interval 0.19
401.44), this was not signicantly changed when deaths
possibly due to prematurity were excluded. The summary
predictive accuracy was a sensitivity of 0.58 (0.190.89),
specicity of 0.88 (0.550.98), positive likelihood ratio of
5.00 (1.6914.76), negative likelihood ratio of 0.48 (0.20
1.14). There was no difference in any of the subgroup
analyses.
For perinatal mortality there was a strong association
when restricting to a high-risk population (summary OR
11.54, 95% CI 4.0532.90) compared with any population
(summary OR 3.44, 95% CI 0.6119.43). Predictive accu-
racy for a high-risk population was sensitivity 0.29 (0.15
0.46), specicity 0.99 (0.990.99), positive likelihood ratio
4.52 (0.9521.45), negative likelihood ratio 0.49 (0.064.06;
Figure 4).
For abnormal cord pH there was no strong association
with any of the measures of oligohydramnios, and sub-
group analysis showed no signicant effect in particular
0% 20% 40% 60% 80% 100%
Treatment/Intervention
Withdrawals from study
Intermediate results
Availability of clinical data
Blinding of reference standard
Blinding of index test
Adequate description of reference standard
Adequate description of index test
Independant reference standard
Number of reference standards
Verification bias
Time period between tests
Appropriate reference standard
Selection criteria
Population spectrum
7
39
39
31
6
43
4
28
43
0
40
0
41
39
43
1
2
2
11
3
0
24
15
0
0
1
0
0
0
0
35
2
2
1
34
0
15
0
0
0
2
0
2
4
0
43
43
Yes
No
Unclear
Not applicable
Q
u
a
d
a
s

i
t
e
m
Percentage compliance (numbers in bars represent absolute values)
Figure 2. Bar chart showing the methodological quality of evidence on amniotic uid measurements to predict small for gestational age/compromise
of fetal wellbeing according to quality criteria.
691 2014 Royal College of Obstetricians and Gynaecologists
Amniotic uid measurement and adverse pregnancy outcome
NOTE: Weights are from random effects analysis
I
2
84.3 0.58 EPI (0.53, 22.50) Birth weight <10
th
centile, oligohydramnios 10 35 642
3.46 (2.00, 5.98) 3.46 (2.00, 5.98)
1 0.0465 21.5
Scan within 7 days 6 4175 3.46 (2.16, 5.56) 3.46 (2.16, 5.56) I
2
65.6 0.19 EPI (0.86,13.87)
High risk population only 6 28 510
6.31 (4.15, 9.58) I
2
36.3 0.09 EPI (2.23, 17.81)
Third trimester testing only 7 5584 3.78 (2.25, 6.36) 3.78 (2.25, 6.36) I
2
71.3 0.31 EPI (0.77, 18.52)
AFI 33 387 7 5 cm 2.82 (1.43, 5.56) 2.82 (1.43, 5.56) I
2
88.4 0.67 EPI (0.29, 27.63)
AFI 5 cm , high risk 4 28 184 5.24 (2.54, 10.82) I
2
61.7 0.31 EPI (0.29, 95.55)
Birth weight <3
rd
centile, AFI 5 cm 1 27 717
13.32 (9.10, 19.50)
Ponderalindex <25
th
centile, AFI ROC 1 258
1.41 (0.72, 2.77) 1.41 (0.72, 2.77)
Birth weight <5
th
centile, MPD < 2 cm 1 154
8.80 (2.58, 29.93)
Birth weight < 2500 g 4 28 941 4.88 (1.13, 21.17) 4.88 (1.13, 21.17) I
2
95.4 1.59 EPI (0, infinity)
AFI 5 cm 2 28 554 6.42 (1.01, 40.93) 6.42 (1.01, 40.93) I
2
96.4 1.72
Odds rao (95% condence interval) Outcome measure or subgroup No of studies/fetuses
Odds ratio (95% confidence interval)
Figure 3. Forest plot of odds ratios for association of measures of oligohydramnios with birthweight outcomes. Open diamonds are sub-groups,
squares are individual studies, width of diamonds is condence intervals, width of horizontal line is estimated prediction interval (EPI). AFI, amniotic
uid index; MPD, maximum pool depth.
NOTE: Weights are from random effects analysis
1 0.00446 1 224
Neonatal death 6 55 735 8.72 (2.43, 31.26)
I
2
52.5, = 1.02, EPI (0.19, 401.44)
AFI 5 cm 2 55 223 I
2
0, = 0. 18.91 (10.82, 33.06)
Perinatal mortality 6 40 124 3.44 (0.61, 19.43) I
2
68.6 2.07 EPI (0, 4940.81) 3.44 (0.61, 19.43)
AFI 5 cm 3 8415 4.32 (0.45, 41.67) I
2
41.5, = 1.14
High risk 2 27 891 11.54 (4.05, 32.90) I
2
0, = 0
Abnormal pH 11 5422 2.52 (1.42, 4.49) I
2
56.6, = 0.43 EPI (0.5, 12.78)
AFI 5 cm 7 7570 1.77 (0.73, 4.32) 1.77 (0.73, 4.32) I
2
72.3, = 0.83 EPI (0.13, 24.25)
MPD < 2 cm 3 238 2.68 (0.77, 9.26) I
2
56, = 0.66 EPI (0, 1314451.1)
Adverse perinatal outcome 6 1123 3.47 (1.63, 7.40)
I
2
67.4, = 0.49 EPI (0.27, 44.06)
AFI 5 cm 2 528 4.57 (2.71, 7.73) 4.57 (2.71, 7.73) I
2
0, = 0
MPD < 2 cm 4 541 3.68 (1.12, 12.06) 3.68 (1.12, 12.06) I
2
76.9, = 1.12 EPI (0.02, 699.75)
Outcome measure or subgroup No of s d d O s e s u t e f / s e i d u t s rao (95% condence interval)
Odds ratio (95% confidence interval)
Figure 4. Forest plot of odds ratios for association of measures of oligohydramnios with mortality and adverse perinatal outcome. Open diamonds
are sub-groups, squares are individual studies, width of diamonds is condence intervals, width of horizontal line is estimated prediction interval (EPI).
AFI, amniotic uid index; MPD, maximum pool depth.
692 2014 Royal College of Obstetricians and Gynaecologists
Morris et al.
subgroups of interest. There was also no difference in the
association when looking at more acidotic cord pHs. In all
of these analyses for cord pH the estimated prediction
intervals crossed the line of no effect. (Figure 4).
For adverse perinatal outcome there was no strong asso-
ciation and no difference with subgroup analysis.
Summary results for outcome measures of
oligohydramnios and fetal wellbeingother
outcome measures
Most meta-analyses gave a summary odds ratio that sug-
gested a moderate association between oligohydramnios
and fetal/neonatal morbidity (Table 1) with the odds ratio
typically between 2 and 4. As above, heterogeneity was typ-
ically large, even when subgroup analyses were considered,
and this led to wide prediction intervals.
For assisted ventilation/intubation there was an especially
strong association but this was from a single study in a term
population (Table 1). For fetal distress the association was
generally around an odds ratio of 2 with no signicant
effects demonstrated in the subgroup analysis. When looking
at individual measures of oligohydramnios (amniotic uid
index 5 cm, or maximum pool depth <2 cm, <1 cm) only
maximum pool depth <1 cm (single study) showed a signi-
cant association (Table 1). For Apgar score at 5 minute <7
there was a signicant association when looking at tests per-
formed within 24 hour of delivery.
Summary results of predictive accuracy of
amniotic uid index versus maximum pool depth
Where a direct comparison was possible between AFI and
MPD for an individual outcome within the same study
then predictive accuracy results were calculated to directly
compare the different measures (Table 2). There was no
difference for the outcomes of Apgar scores, admission to
neonatal intensive care unit, fetal distress, neonatal death
or perinatal mortality. For adverse perinatal outcome and
birthweight <10th centile there were improved positive
Table 1. Results for other measures of adverse perinatal outcome
Outcome
measure
No. of
included
studies
No. of
fetuses
Odds ratio
(95% CI)
Tau I
2
EPI Sensitivity
(95% CI)
Specicity
(95% CI)
LR +ve
(95% CI)
LR ve
(95% CI)
Resuscitation
(AFI 5 cm,
high-risk
population)
1 565 12.02 (3.8237.89) 0.31
(0.110.59)
0.96
(0.940.98)
8.58
(3.6919.96)
0.71
(0.510.99)
Admission to
NICU
15 43 222 2.05 (1.213.45) 0.8 86.1 0.29, 14.54
AFI 5 cm 12 38 202 1.64 (0.763.53) 1.4 89.1 0.1, 26.22
Fetal distress 12 12 794 2.69 (1.275.70) 1.4 85.8 0.17, 42.3
AFI 5 cm 9 39 839 1.86 (0.953.67) 0.7 79.5 0.21, 16.69
MPD <2 cm 2 24 1.15 (0.226.12) 0.6 29.4
MPD <1 cm 1 30 7.93 (3.3518.77) 0.67
(0.470.83)
0.80
(0.720.86)
3.31
(2.195.0)
0.42
(0.250.70)
APGAR
1 minute <7
8 35 694 2.94 (1.17.91) 1.7 91.3 0.09, 93.17
AFI 5 cm 5 34 828 3.33 (0.912.27) 2 93.6 0.02, 471.07
MPD <2 cm 1 56 0.67 (0.123.65)
APGAR at
5 minute <7
19 47 431 2.61 (1.325.17) 1.2 81.7 0.22, 31.23
Test within
24 hours
2 45 090 9.77 (4.9319.37) 0.1 10.7 0.06
(0.040.08)
0.99
(0.990.99)
6
(1.4724.57)
0.95
(0.930.97)
AFI 5 cm 11 45 542 2.89 (1.127.49) 1.7 87.9 0.12, 70.5
MPD <2 cm 1 56 0.8 (0.0320.62)
Morbidity 6 11 400 1.81 (1.03.3) 0 0 0.78, 4.23
AFI 5 cm 2 6919 1.66 (0.367.68) 0 0
Preterm
delivery
<37 weeks
4 34 508 1.87 (0.3310.67) 2.9 93.4 0, 7019.56
EPI, estimated prediction interval; LR, likelihood ratio; NICU, neonatal intensive care unit.
693 2014 Royal College of Obstetricians and Gynaecologists
Amniotic uid measurement and adverse pregnancy outcome
likelihood ratios for MPD versus AFI with no signicant
change in specicity or negative likelihood ratio.
Summary results for outcome measures of
polyhydramnios and small for gestational age and
wellbeing
There were ve papers, including 144 681 fetuses, that
reported on polyhydramnios and adverse outcomes
(Table 3). Thresholds included AFI 24 cm (three papers),
AFI 25 cm (one paper) and in one paper there was no
threshold reported.
There was no evidence of an association between polyhy-
dramnios and birthweight <10th centile or <2500 g, Apgar
score at 1 minute <7, fetal distress or neonatal death. There
was a strong positive association with polyhydramnios and
birthweight >90th centile and this corresponded to low
sensitivity with high specicity. There was signicant heter-
ogeneity throughout.
Peters test was performed on all meta-analyses where
there were ten or more studies included (admission to neo-
natal intensive care unit, fetal distress, 5-minute Apgar <7,
abnormal pH and birthweight <10th centile. There was no
signicant evidence of small study effects (P values 0.21,
0.19, 0.61, 0.35, 0.62, respectively).
Discussion
This is the rst study to look at all measurements of
amniotic uid and compare their prognostic association
and, where appropriate, their ability to predict adverse
outcomes for individuals. The results demonstrate that
there is an especially strong association between oligohy-
dramnios and small for gestational age and mortality.
Polyhydramnios was associated with birthweight >90th
centile. For the measures that gave large summary odds
ratios >5, the summary positive and negative likelihood
ratios indicate that oligohydramnios and polyhydramnios
substantially change the odds of an adverse outcome.
However, the low summary sensitivity and negative likeli-
hood ratios being close to 1, reveal that a negative test
result is not good at discriminating accurately between
those who will and those who will not have the adverse
outcome. Hence, to accurately predict risk of adverse out-
come, oligohydramnios and polyhydramnios should be
Table 2. Direct comparison of amniotic uid index and maximum pool depth within individual studies
Author Index test Outcome
and test
Sensitivity 95% CI Specicity 95% CI LR+ve 95% CI LRve 95% CI
Chauhan
et al.
46
AFI 5 cm Birthweight
<10th centile
0.14 0.040.33 0.97 0.920.99 4.2 1.2014.68 0.89 0.761.04
MPD 2 cm 0.04 0.000.18 1 0.981.0 15.31 0.64366.61 0.95 0.871.04
Youssef
et al.
47
AFI 5 cm 0.79 0.620.91 0.69 0.610.77 2.59 1.913.50 0.3 0.150.58
MPD 1 cm 0.56 0.380.73 0.79 0.710.85 2.61 1.694.03 0.56 0.380.83
Desari
et al.
48
AFI 5 cm Admission
to NICU
0.22 0.030.60 0.65 0.540.75 0.63 0.182.21 1.2 0.821.76
MPD 3 cm 0.44 0.140.79 0.4 0.300.50 0.74 0.351.56 1.4 0.742.66
Morris
et al.
49
AFI 5 cm 0.12 0.050.21 0.92 0.910.94 1.5 0.792.84 0.96 0.881.04
MPD 2 cm 0.01 00.07 0.99 0.980.99 0.92 0.136.75 1 0.981.03
Myles
et al.
50
AFI 5 cm 0 00.6 0.87 0.820.91 0.74 0.0510.46 1.04 0.771.40
MPD 2.5 cm 0 00.6 0.86 0.810.90 0.68 0.059.63 1.05 0.781.42
Morris
et al.
49
AFI 5 cm Fetal distress 0.29 0.040.71 0.92 0.910.94 3.66 1.1211.96 0.78 0.491.24
MPD 2 cm 0 00.41 0.99 0.980.99 4.38 0.2966.21 0.95 0.801.14
Myles
et al.
50
AFI 5 cm 0.2 0.100.32 0.89 0.840.93 1.72 0.903.29 0.91 0.791.04
MPD 2.5 cm 0.18 0.090.30 0.87 0.810.91 1.34 0.692.59 0.95 0.831.08
Youssef
et al.
47
AFI 5 cm 0.87 0.690.96 0.69 0.610.77 2.84 2.143.78 0.19 0.080.48
MPD 1 cm 0.67 0.470.83 0.8 0.720.86 3.31 2.195.00 0.42 0.250.70
Youssef
et al.
47
AFI 5 cm Apgar at
5 minutes <7
0.89 0.650.99 0.65 0.570.73 2.57 1.963.37 0.17 0.050.63
MPD 1 cm 0.72 0.470.90 0.77 0.700.83 3.13 2.094.69 0.36 0.170.76
Fischer
et al.
51
AFI 5 cm Adverse
perinatal
outcome
0.29 0.130.51 0.89 0.840.93 2.67 1.265.69 0.8 0.611.03
MPD 2 cm 0.25 0.100.47 0.96 0.920.98 6.21 2.2816.95 0.78 0.620.99
MPD 1 cm 0.13 0.030.32 1 0.981.00 49 2.61920.79 0.86 0.741.01
Desari
et al.
48
AFI 5 cm Neonatal
death
0.33 0.010.91 0.66 0.560.75 0.98 0.194.97 1.01 0.452.28
MPD 3 cm 0.33 0.010.91 0.4 0.300.51 0.56 0.112.79 1.67 0.723.83
Youssef
et al.
47
AFI 5 cm Perinatal
mortality
0.88 0.470.99 0.62 0.540.70 2.31 1.663.20 0.2 0.031.27
MPD 1 cm 0.75 0.350.97 0.74 0.670.81 2.9 1.804.66 0.34 0.101.12
LR, likelihood ratio; NICU, neonatal intensive care unit.
694 2014 Royal College of Obstetricians and Gynaecologists
Morris et al.
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695 2014 Royal College of Obstetricians and Gynaecologists
Amniotic uid measurement and adverse pregnancy outcome
used in conjunction with other prognostic factors as part
of a prognostic model.
37
The inferences for clinical practice that can be made
from the results of this study are limited by the biases
introduced from the designs of the included studies and in
particular the treatment/intervention paradox, this is dis-
cussed further below.
Strengths and limitations of the review
This review provides the most up-to-date summary and
meta-analysis of the association and predictive ability of
abnormal liquor volume with small for gestational age and
adverse fetal and neonatal wellbeing. The strengths of our
review are in the methodology used complying with exist-
ing guidelines for systematic reviews of diagnostic studies
and contemporary methods for meta-analysis.
1013,31
Our
search was extensive across many databases with no lan-
guage restrictions. We have rigorously assessed study qual-
ity and reporting quality looking at risk of bias and
applicability and assessed for publication bias. Heterogene-
ity has been explored using meta-regression and subgroup
analysis. A further strength to our review is the exclusion
of patients with ruptured membranes and structural or
chromosomal anomalies.
The limitations to our review lie in the limitations from
the quality of the primary research. Our quality assessment
revealed concerns regarding possibility of bias through
patient selection, performance of the index test and refer-
ence standard. We were unable to perform subgroup analy-
sis for preterm versus term pregnancies and some studies
reported insufcient data to determine whether thresholds
for amniotic uid measurement were adjusted for gesta-
tion. Where possible we used the results obtained closest to
delivery and have performed subgroup analysis for those
where the test was performed within 7 days of delivery. In
particular, there was very poor reporting regarding the
exact methods of the reference standards and whether there
was any treatment used between the performance of the
index and reference standard. A major concern therefore is
in how many pregnancies was induction of labour per-
formed due to the nding of oligohydramnios, which inu-
ences the results for pregnancy outcome, i.e. intervention
bias. This bias can only truly be removed by performing an
RCT, this would be impossible to perform as measure-
ments of amniotic uid volume have become the standard
in fetal surveillance and management of high-risk pregnan-
cies and so recruitment to such a trial would be very dif-
cult. Finally, the outcome measures used in this review
were those that were reported by the authors of the
included studies, it is recognised that many of the outcome
measures are subjective (e.g. admission to neonatal inten-
sive care unit, need for resuscitation). The only real objec-
tive measure of poor fetal outcome is paired samples of
cord pH and longer-term outcomes such as cerebral palsy,
which were not reported.
Interpretation
Comparison with other studies
This study looks at the strength of association of measures
of amniotic uid with adverse outcomes and where appro-
priate, their predictive accuracy, and to our knowledge this
is the rst systematic review and meta-analysis to do this.
However, for a test to be recommended in clinical practice
it must be reliable, accurately reect the condition it is
diagnosing and usefully predict adverse outcome such that
when used to determine management it ultimately
improves pregnancy outcome. The reliability of measures
of amniotic uid has been assessed in previous studies.
These have concluded that reproducibility can be affected
by fetal position, transducer pressure, maternal hydration
and use of colour Doppler due to the observer variation or
variations in the uid volume.
3841
To determine which
measure (AFI versus MPD) more accurately reects true
oligohydramnios requires comparison with dye dilution
techniques or comparison with volumes assessed at caesar-
ean section. This has been performed by Magann et al. in
2000 and the authors concluded that both techniques were
unreliable in determining true amniotic volume.
42
Two
previous systematic reviews and meta-analyses have looked
at the effect of measurements of amniotic uid on preg-
nancy outcome, the rst by Magann et al.
43
included
non-randomised and randomised controlled trials, the sec-
ond by Nabhan et al.
8
included only RCTs. Both of these
studies concluded that there was no evidence that either
method (AFI or MPD) was superior to the other in pre-
venting adverse pregnancy outcome and noted that AFI
characterised more women as having oligohydramnios
leading to an increase in obstetric interventions without
any improvement in pregnancy outcome.
8,43
Conclusion
Oligohydramnios is associated with small for gestational
age and mortality. Polyhydramnios is associated with birth-
weight >90th centile. The strong associations mean oligohy-
dramnios and polyhydramnios modify the odds of an
adverse outcome if test positive. However, to improve the
accuracy of predicting future outcome risk for individuals,
oligohydramnios and polyhydramnios need to be combined
with other prognostic factors within a prognostic model.
Implications for clinical practice
Despite some strong associations demonstrated with oligo-
hydramnios and birthweight <10th centile and mortality, the
predictive ability for individuals was poor with generally
good specicity and positive likelihood ratios but low sensi-
696 2014 Royal College of Obstetricians and Gynaecologists
Morris et al.
tivity (<0.5) and negative likelihood ratios near 1. This can
be interpreted as an increased risk (odds) of adverse out-
come for those that test positive (compared with pretest risk)
but for those that test negative there is minimal change in
the risk of an adverse outcome. There was no signicant dif-
ference in association or predictive accuracy comparing AFI
to MPD apart from improved positive likelihood ratios (not
signicantly) for maximum pool depth for adverse perinatal
outcome and birthweight <10th centile.
Although not accurate for individual prediction, the evi-
dence indicates that oligohydramnios is a prognostic factor
for birthweight <10th centile and mortality. As such, it has
many potential uses.
44
For example, informing randomisa-
tion strategies in clinical trials; as a confounder to adjust
for in observational studies and unbalanced trials; and
combined with other prognostic factors to allow more
accurate predictions for individuals. However, due to the
limitations discussed it would seem prudent to limit its use
to high-risk pregnancies in whom intervention (such as
early delivery) would be considered.
Implications for future research
Future research needs to investigate further the test accu-
racy of measures of amniotic uid volume using appropri-
ately designed test accuracy studies, with suitable sample
size calculations but also considering the value of the test
within the diagnostic and management pathway and what
can be done to improve the tests diagnostic and therapeu-
tic yield.
45
For example, the use of amniotic uid measures
within the biophysical prole assessment and in combina-
tion with umbilical artery Doppler needs to be assessed in
the same rigorous manner. It is important that any future
research addresses the issue of the different types of mea-
surements, the varying thresholds used and the unexplained
heterogeneity identied within this review. The present evi-
dence demonstrates that there is no signicant improve-
ment with accuracy for MPD versus AFI and effectiveness
evidence has also supported the use of MDP. As this is a
much easier technique to perform, this should become rec-
ommended practice until more robust evidence becomes
available.
Disclosure of interests
We declare no conicts of interest.
Contribution to authorship
All authors were responsible for the design of the study.
RKM, CHM, JT and GLM were responsible for the data
extraction and RKM, GLM, RR, CHM, JT, MDK, SCR and
KSK for the analysis. All authors checked the analysis and
were involved in the drafting and critical revision of the
manuscript and accept responsibility for the manuscript as
published.
Details of ethics approval
As this was a systematic review of published data, ethical
approval was not required.
Funding
Dr R K Morris is funded by an NIHR Clinical Lectureship.
Dr Richard Riley is supported by funding from the MRC
Midlands Hub for Trials Methodology Research, at the
University of Birmingham (Medical Research Council
Grant ID G0800808).
Acknowledgements
Dr Pradeep Jayaram who helped with some of the data
extraction.
Supporting Information
Additional Supporting Information may be found in the
online version of this article:
Appendix S1. Protocol for systematic review of accuracy
of amniotic uid measurements to predict small for gesta-
tional age and compromise of fetal and neonatal wellbeing.
Appendix S2. Search strategy for systematic review of
amniotic uid measurements to predict small for gesta-
tional age and compromise of fetal wellbeing.
Appendix S3. Guide to QUADAS for amniotic uid
measurements to predict small for gestational age/compro-
mise of fetal wellbeing.
Appendix S4. Characteristics of included studies in
systematic review of amniotic uid measurements to pre-
dict small for gestational age and compromise of fetal well-
being.
&
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