Accuracy of body mass index in predicting

pre-eclampsia: bivariate meta-analysis

JS Cnossen,
a
MMG Leeang,
b
EEM de Haan,
a
BWJ Mol,
c
JAM van der Post,
c
KS Khan,
d
G ter Riet
e
a
Department of General Practice,
b
Department of Clinical Epidemiology and Biostatistics and
c
Department of Obstetrics and Gynaecology,
Academic Medical Center, Amsterdam, the Netherlands
d
Department of Obstetrics and Gynaecology, Birmingham Womens Hospital,
Birmingham, UK
e
Horten Center, University of Zurich, Zurich, Switzerland
Correspondence: Dr JS Cnossen, Department of General Practice, Academic Medical Center, Meibergdreef 15, 1100 DD, Amsterdam,
the Netherlands. Email j.s.cnossen@amc.uva.nl
Accepted 2 July 2007. Published OnlineEarly 28 September 2007.
Objective The objective of this study was to determine the
accuracy of body mass index (BMI) (pre-pregnancy or at booking)
in predicting pre-eclampsia and to explore its potential for clinical
application.
Design Systematic review and bivariate meta-analysis.
Setting Medline, Embase, Cochrane Library, MEDION, manual
searching of reference lists of review articles and eligible primary
articles, and contact with experts.
Population Pregnant women at any level of risk in any healthcare
setting.
Methods Reviewers independently selected studies and extracted
data on study characteristics, quality, and accuracy. No language
restrictions.
Main outcome measures Pooled sensitivities and specicities
(95% CI), a summary receiver operating characteristic curve, and
corresponding likelihood ratios (LRs). The potential value of BMI
was assessed by combining its predictive capacity for different
prevalences of pre-eclampsia and the therapeutic effectiveness
(relative risk 0.90) of aspirin.
Results A total of 36 studies, testing 1 699 073 pregnant women
(60 584 women with pre-eclampsia), met the selection criteria. The
median incidence of pre-eclampsia was 3.9% (interquartile range
1.46.8). The area under the curve was 0.64 with 93% of
heterogeneity explained by threshold differences. Pooled estimates
(95% CI) for all studies with a BMI 25 were 47% (3361) for
sensitivity and 73% (6483) for specificity; and 21% (1231) and
92% (8995) for a BMI 35. Corresponding LRs (95% CI) were
1.7 (0.311.9) for BMI 25 and 0.73 (0.222.45) for BMI < 25,
and 2.7 (1.07.3) for BMI 35 and 0.86 (0.681.07) for BMI < 35.
The number needed to treat with aspirin to prevent one case of
pre-eclampsia ranges from 714 (no testing, low-risk women) to 37
(BMI 35, high-risk women).
Conclusions BMI appears to be a fairly weak predictor for pre-
eclampsia. Although BMI is virtually free of cost, noninvasive, and
ubiquitously available, its usefulness as a stand-alone test for risk
stratication must await formal cost-utility analysis. The ndings
of this review may serve as input for such analyses.
Keywords Accuracy, body mass index, likelihood ratio, meta-
analysis, pre-eclampsia, sensitivity and specicity.
Please cite this paper as: Cnossen J, Leeang M, de Haan E, Mol B, van der Post J, Khan K, ter Riet G. Accuracy of body mass index in predicting pre-eclampsia:
bivariate meta-analysis. BJOG 2007;114:14771485.
Introduction
Pre-eclampsia is a major cause of maternal and perinatal
morbidity and mortality.
13
It has a long preclinical phase
before signs and symptoms become manifest in the second
half of pregnancy. Prediction of pre-eclampsia is important
because increased monitoring and administration of early
preventative treatment with, for example, aspirin can be more
selectively targeted at high-risk women.
4
The exact aetiology of pre-eclampsia is still unknown. Sev-
eral risk factors have been identied including obesity.
5
The
World Health Organization (WHO) estimates that currently
more than 1 billion adults are overweight, of whom at least
300 million are clinically obese.
6
From 1999 to 2003, in the
total delivery population, the proportion of women who were
overweight or obese pre-pregnancy increased from 37.1 to
40.5%.
7
This worldwide increase in overweight is likely to
cause a rise in pre-eclampsia and other complications, such
as gestational diabetes.
8
The body mass index (BMI) is an
international standard for obesity measurement adjusting
bodyweight for height (weight [kg]/height squared [m
2
])
and an indicator of nutritional status.
2007 The Authors Journal compilation RCOG 2007 BJOG An International Journal of Obstetrics and Gynaecology 1477
DOI: 10.1111/j.1471-0528.2007.01483.x
www.blackwellpublishing.com/bjog
Systematic review
We conducted a systematic review to determine the accu-
racy of BMI (pre-pregnancy or at booking) to predict pre-
eclampsia and to explore its potential for clinical application.
We meta-analysed the data using a bivariate regression anal-
ysis, accounting for (negative) correlation between sensitivity
and specicity, and derived likelihood ratios (LRs) thereof.
912
Methods
Study identication and selection
We performed an electronic search targeting all procedures
used for the prediction of pre-eclampsia. We searched Med-
line, Embase, Cochrane Library, and MEDION (www.
mediondatabase.nl/) from inception to April 2006. The search
strategy
13
consisted of MeSH or keyword terms related to pre-
eclampsia combined with methodological lters for identi-
cation of studies on diagnostic tests and aetiology.
1416
We
checked reference lists of review articles and eligible primary
studies to identify cited articles not captured by electronic
searches and contacted experts. Reference Manager 10.0 data-
bases were established incorporating results of all searches.
We selected studies in a three-stage process. First, one
reviewer scrutinised titles and/or abstracts of all citations.
Second, to ensure independent duplicate selection for this
review, we performed a search based on keywords *weight*
OR body mass* OR obesity OR adipos* OR fat OR quetelet*
within the Reference Manager database for citations to be
scrutinised by a second reviewer. We obtained full manu-
scripts of all citations that were selected by at least one of
the reviewers. Final in/exclusion decisions were made after
independent and duplicate examination of the full manu-
scripts of selected citations. We included studies if they
reported numerical data allowing construction of a 2 2 table
cross-classifying BMI test results (pre-pregnancy or at
booking) and occurrence of pre-eclampsia. We included
studies examining pregnant women at any level of risk in
any healthcare setting. Language restrictions were not applied.
Any disagreements were resolved by consensus or by a third
reviewer.
For each included paper, two reviewers independently
extracted data on clinical and methodological study charac-
teristics and on test accuracy. Study characteristics consisted
of womens risk classications, characteristics of the index test
and of the reference standard, and details of the outcome,
such as onset and severity of pre-eclampsia.
Assessment of study quality
Two reviewers independently assessed all included manu-
scripts for study quality according to an adapted version of
QUADAS.
17
We considered consecutive or random entry of
pregnant women to a cohort as ensuring an appropriate spec-
trum of patients. Patient selection criteria were considered
appropriate when the study reported on parity, singleton/
multiple pregnancies, diabetes mellitus, and chronic hyper-
tension. We deemed the reference standard for pre-eclampsia
appropriate if it combined persistent systolic blood pressure
140 mmHg and/or diastolic blood pressure 90 mmHg with
proteinuria 0.3 g/24 hours or 1+ dipstick (30 mg/dl in
a single urine sample) new after 20 weeks of gestation. Sim-
ilarly, we deemed the reference standard for superimposed
pre-eclampsia appropriate when it combined the develop-
ment of proteinuria 0.3 g/24 hours or 1+ dipstick after
20 weeks of gestation in chronically hypertensive women.
18,19
A denition of pre-eclampsia according to recent (from the
year 2000 onwards) international guidelines was also consid-
ered appropriate.
1820
We also assessed if details of the index
test (kg/m
2
, pre-pregnancy or before 20 weeks) and reference
test (measurement device, position of patient, and Korotkoff
phase), and a description of reasons for withdrawals were
adequate.
Data synthesis
For each study, we constructed a 2 2 table cross-classifying
BMI test results and the occurrence of pre-eclampsia. We
used receiver operating characteristic (ROC) plots to visualise
data. We used a bivariate meta-regression model to calculate
pooled estimates of sensitivity and specicity for several BMI
cutoff values and to t a summary ROC (sROC) curve. This
method has been extensively described elsewhere.
912
Briey,
rather than using a single outcome measure per study, such as
the diagnostic odds ratio, the bivariate model preserves the
two-dimensional nature of diagnostic data in a single model.
This model incorporates the correlation that may exist
between sensitivity and specicity within studies due to pos-
sible differences in threshold between studies. The bivariate
model uses a random effects approach for both sensitivity and
specicity, allowing for heterogeneity beyond chance due to
clinical or methodological differences between studies. In
addition, the model acknowledges the difference in precision
by which sensitivity and specicity have been measured in
each study. This means that studies with a larger number of
women with pre-eclampsia receive more weight in the calcu-
lation of the pooled estimate of sensitivity, while studies with
more women without pre-eclampsia are more inuential in
the pooling of specicity. We calculated a correlation coef-
cient (r) to show the strength and shape of the correlation
between sensitivity and specicity, and hence the amount of
variance that can be explained due to threshold differences
(r
2
). Despite several cutoff values for BMI, for statistical rea-
sons, each study was represented once in the sROC analysis.
This was achieved by randomly sampling one 2 2 table from
each study, ensuring that all areas of the sROC curve were
represented. For clinical usefulness, we derived LRs from the
estimated sensitivities and specicities.
We dened all subgroup analyses, except one (pre-
pregnancy or at booking), a priori requiring that at least 80%
Cnossen et al.
1478 2007 The Authors Journal compilation RCOG 2007 BJOG An International Journal of Obstetrics and Gynaecology
of studies reported clearly on a particular item and each
subgroup contained at least three studies. Data on threshold,
pre-pregnancy or booking BMI, severity and onset (before or
after 34 weeks) of pre-eclampsia, incidence (cutoff 4%), study
design, consecutive entry, prospective data collection, and
adequacy of reference standard were considered one by one
in the subgroup analyses. First, we entered the subgroup char-
acteristic as a covariate in the model. If homogeneity between
studies with and without the characteristic was rejected
(P < 0.10), the subgroup analysis was performed.
The bivariate models were tted using the Proc NLMixed
(SAS 9.1 for Windows [SAS Institute Inc, Cary, NC, USA]).
Potential for clinical application
At a (xed) relative risk (RR) reduction of aspirin of 10%
(RR = 0.90),
4
the absolute treatment effect becomes greater
as the absolute risk rises. For a woman with a risk of pre-
eclampsia of 40%, aspirin reduces it to 36%, whereas for
a woman who has a 4% risk, this is reduced to 3.6%. Testing
makes sense if treatment is conditional on obtaining a positive
test result. Therefore, the impact of risk stratication using
BMI depends on the shift that testing brings about in the pre-
test probability distribution.
21
We illustrated this impact with
an example of decision-making in clinical practice about the
use of aspirin in women at risk of pre-eclampsia, which has
been shown to be an effective preventive treatment.
4
We cal-
culated the risk, and hence the therapeutic benets associated
with BMI test results from sensitivity and specicity. The
number needed to treat (NNTreat) is the number of women
that one needs to treat (with aspirin) to prevent one case of
pre-eclampsia and is calculated by 1/(probability after testing
positive probability after treatment).
Results
Figure 1 summarises the process of literature identication
and selection. Thirty-six studies met the selection criteria.
2257
Four papers were found in reference lists, of which one was
included. The two papers from Sebire et al.
46,47
reported on
the same cohort, and therefore, we considered it as one study.
We excluded studies for a variety of reasons. The main rea-
sons for exclusion were no distinction between pre-eclampsia
and pregnancy-induced hypertension, insufcient data to
construct a 2 2 table, and reporting weight or weight gain
or a different weight-index test instead of a BMI.
Table 1 summarises study characteristics. We included 23
cohort studies, 11 casecontrol studies, and one randomised
trial. A total of 1 699 073 pregnant women were included, of
whom 60 584 (3.6%) developed pre-eclampsia. The median
incidence of pre-eclampsia in cohort studies was 3.9% (inter-
quartile range 1.46.8). For calculation of the median inci-
dence, we excluded casecontrol studies that did not report
the incidence in their source population. The number of
women analysed in cohort studies ranged from 281
27
to
561 770,
56
and in casecontrol studies from 54
37
to 6747.
28
Twenty-seven studies were performed in Western countries.
Eleven studies were prospectively designed. Sixteen studies
excluded all women with diabetes and/or chronic hypertension.
Primary articles retrieved for detailed evaluation
- fromelectronic searches n = 133
- from reference lists n = 4
Articles excluded n = 101
- no BMI calculated
n = 22
- insufficient data toconstruct 2 x 2 table n = 20
- no pre-pregnancy BMI versus pre-eclampsia outcome n = 13
- reviews/ letters/ comments/ editorials n = 5
- pre-eclampsia not separate outcome/
pregnancy induced hypertension only
n = 25
- matching on BMI n = 3
- gestational age unclear n = 1
- data duplication n = 7
- other n = 5
Primary articles included in meta-analysis
n = 36
Potentially relevant citations identified from electronic searches to capture primary articles
on all tests used in the prediction of pre-eclampsia n = 17847
Potentially relevant citations on BMI in the prediction of pre-eclampsia n = 1307
References excluded after screening titles and/ or abstracts n = 1170
Figure 1. Process from initial search to nal inclusion for studies on BMI in the prediction of pre-eclampsia.
Body mass index and prediction of pre-eclampsia
2007 The Authors Journal compilation RCOG 2007 BJOG An International Journal of Obstetrics and Gynaecology 1479
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(
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Cnossen et al.
1480 2007 The Authors Journal compilation RCOG 2007 BJOG An International Journal of Obstetrics and Gynaecology
Twenty-eight studies reported pre-pregnancy BMI, and seven
studies reported BMI at booking. We excluded one study for
the meta-analysis because this study excluded women with
a BMI between 27 and 34.
25
Figure 2 summarises study quality. Patient recruitment,
selection criteria, and reasons for withdrawal were poorly
reported. Eleven studies used a denition of pre-eclampsia
according to current international standards. Fifteen studies
reported a denition of pre-eclampsia according to former
guidelines. Details of how the reference test was executed were
seldom reported. Only one study reported whether women
received treatment to prevent pre-eclampsia.
48
Figure 3 shows the sROC curve for the included studies. The
area under the curve (AUC) was 0.64, which was similar to the
AUC representing all data points for all studies (AUC 0.63).
The correlation coefcient was 0.965, indicating that 93% of
heterogeneity could be explained due to differences in thresh-
old for a positive test. Subgroup analysis on pre-pregnancy
BMI versus BMI at booking yielded statistically signicant
differences (P < 0.0001), showing slightly better performance
for pre-pregnancy BMI. However, their clinical relevance seems
doubtful (sensitivity
pre-pregnancy
48.1% (47.948.2) versus
sensitivity
at booking
44.9% (44.445.5) and specificity
pre-pregnancy
61.4% (61.461.5) versus specificity
at booking
58.5% (58.558.6).
The discrepancy between statistical significance and clinical
relevance is due to some of the studies having very large sizes.
Below, we report the overall results. Incidence of pre-eclampsia,
study design, data collection, and adequacy of reference standard
did not further reduce heterogeneity. Analyses on clinical char-
acteristics and consecutive entry were hindered by a lack of
reporting. We used cutoff values that were most often used
and reported by the Institute of Medicine (IOM) and WHO
for categorisation.
6,58
Pooled estimates (95% CI) for all studies
with a BMI 25 (18 studies) were 47% (3361) for sensitivity
and 73% (6483) for specificity. For a BMI 30 (19 studies),
these estimates were 19% (1920) and 90% (8893), and for
a BMI 35 (4 studies), the estimates were 21% (1231) and
92% (8995). Pooling data on BMI 30 required an adjusted
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0% 20% 40% 60% 80% 100%
Withdrawals explained
Adequate description reference test
Adequate description index test
Appropriate reference test
Selection criteria
Patient spectrum
Compliance with quality item
yes no unclear
Figure 2. Summary of study quality. Data are presented as 100%
stacked bars. Numbers in stacks represent numbers of studies.
Body mass index and prediction of pre-eclampsia
2007 The Authors Journal compilation RCOG 2007 BJOG An International Journal of Obstetrics and Gynaecology 1481
model of the bivariate analysis resulting in a very narrow confi-
dence interval for sensitivity. Therefore, we also calculated esti-
mates for BMI 29 (seven studies, IOM classification), which
were 22% (1232) for sensitivity and 89% (8295) for speci-
ficity. The corresponding LRs (95% CI) were 1.7 (0.311.9) for
BMI 25 and 0.73 (0.222.45) for BMI < 25, 1.9 (0.311.9) for
BMI 29 and 0.88 (0.611.29) for BMI < 29, and 2.7 (1.07.3)
for BMI 35 and 0.86 (0.681.07) for BMI < 35.
Table 2 shows that the probability of pre-eclampsia after
positive BMI testing increases strongly in moderate (say inci-
dence 7%) and high-risk (say 12%) populations to 18 and
29%, respectively, for women with a BMI 35. These latter
posttest probabilities correspond with NNTs
aspirin
of 62 and
37, respectively. BMI results < 35 lead to posttest probabilities
of 1.2, 5.9, and 10.7% in populations with a baseline risk of
1.4, 6.8, and 12.2%, respectively. These numbers, in turn,
correspond to NNTs
aspirin
of 830, 170, and 94.
Discussion and conclusion
Based on a huge body of evidence, BMI (at any cutoff), pre-
pregnancy or at booking, appears to be a fairly weak predictor
for pre-eclampsia. Although BMI is virtually free of cost, non-
invasive, and ubiquitously available, its usefulness as a stand-
alone test for risk stratication must await formal cost-utility
analysis. The ndings of this review may serve to populate
such a model.
Based on the estimates in this review, among low-risk preg-
nancies without testing, one needed to treat 714 women with
aspirin to prevent one case of pre-eclampsia. By contrast, in
high-risk women, who in addition have a BMI 35, one
needed to treat only 37 women to prevent one case. This
may seem impressive. However, it is not entirely clear how
clinicians may decide on the exact risk level a woman has
before modifying it further using BMI. Note also that a single
test with modest values of sensitivity implies that many with
a negative test result will develop pre-eclampsia and thus, in
this example, will not benet from what appears to be the
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
1-specificity
S
e
n
s
i
t
i
v
i
t
y
Figure 3. sROC curve for individual studies on the accuracy of BMI in
predicting pre-eclampsia.
Table 2. Illustration of potential impact of BMI testing at two cutoff values among pregnant women at different prevalences and numbers
of women needed to treat with aspirin to prevent one case of pre-eclampsia
Test result Prior risk
(prevalence of PET, %)*
Probability of PET after
testing positive (%)
Treatment effect
(RR)
Probability of PET
after treatment (%)
NNTreat
No test, no treatment** 1.4 1.4 1.4
6.8 6.8 6.8
12.2 12.2 12.2
No test, treat all** 1.4 0.90 714
6.8 147
12.2 82
BMI 35; sensitivity 21%; specicity 92%
Test all, treat test positives 1.4 3.6 0.90 3.2 278
6.8 16.1 14.5 62
12.2 26.7 24.0 37
BMI 25; sensitivity 47%; specicity 73%
Test all, treat test positives 1.4 2.4 0.90 2.2 417
6.8 11.3 10.2 88
12.2 19.5 17.6 51
PET, pre-eclampsia.
*Interquartile ranges of median prevalence in this review used as low and moderate prior risk. 12.2% was used as high prior risk.
**Numbers are equal for all tests regardless of threshold and sensitivity and specicity.
Cnossen et al.
1482 2007 The Authors Journal compilation RCOG 2007 BJOG An International Journal of Obstetrics and Gynaecology
cheap and safe treatment of aspirin. The moderate positive
and negative LRs of a BMI > 35 underscore these conclusions.
In 2003, OBrien et al.
59
reviewed 13 studies and also reported
on the predictive power of BMI for pre-eclampsia. However,
they pooled predictive values, an accuracy parameter that is
generally considered too sensitive to variations in preva-
lence.
60
Duckitt and Harrington,
61
in their review, covering
different tests at booking, included ten studies on BMI and
reported different summary estimates, without explaining
why they selected a RR of pre-eclampsia of 2.47 in their
abstract. In addition, their methodology is awed by the
adoption of a cause-effect framework discarding studies with
baseline incomparability, although this is unimportant in
(noncausal) studies on prediction.
62
Finally, a pooled RR
(of 2.47) does not allow clinicians to update their pre-test
pre-eclampsia probabilities for women below the cutoff value,
since such women remain on their prior probability. In con-
trast, we pooled sensitivities and specicities, which are less
susceptible to variations in prevalence
60
and are more useful
in determining whether the posttest probability increases or
decreases for the various BMI categories.
The mechanism by which obesity causes pre-eclampsia is
not completely understood, although establishing a causal
link is not particularly relevant for purposes of developing
a predictive test. Obesity has a strong link with insulin resis-
tance and predisposes for type II diabetes and gestational
diabetes. Both obesity and diabetes are associated with
a higher risk of cardiovascular diseases, and hence pre-
eclampsia.
5,63,64
Hyperinsulinaemia may directly predispose
to hypertension by increased renal sodium reabsorption and
stimulation of the sympathetic nervous system. Another
possible explanation is that insulin resistance and/or associ-
ated hyperglycaemia impair endothelial function.
5,64
Studies
that include a high proportion of women with diabetes
or chronic hypertensive may thus nd higher estimates for
test accuracy of BMI. In contrast, smoking reduces the risk
of pre-eclampsia and has no effect on the risk of gestational
diabetes.
65,66
Smokers usually have a lower BMI than non-
smokers, however, this effect is reduced when they quit
smoking.
67
Our estimates of predictive accuracy may be
biased due to the inability to adjust for these factors. How-
ever, this drawback holds for all meta-analyses focusing on
evaluation of a single test, whereas in clinical practice more
information is available.
Identication of primary studies on pre-eclampsia and
BMI in database searches is difcult. In primary studies,
BMI is often reported as a secondary exposure in a table
showing some general population characteristics. Electronic
retrieval is possible only when BMI is mentioned in the title,
abstract, or as a keyword. Factors that may inuence the pre-
dictive accuracy of BMI are poor reporting of selection crite-
ria, preventive treatment, and self-reported weight and
height. Self-reported weight in particular may be underesti-
mated in women
68
and may result in a lower BMI (more test
negatives), thus lowering sensitivity and raising specicity.
However, a subgroup analysis on pre-pregnancy BMI versus
BMI at booking did not indicate this to be a strong phenom-
enon, although statistically signicant. Due to lack of report-
ing on early and late onset, and on severity of pre-eclampsia,
we were unable to estimate the predictive accuracy of BMI for
severe early onset pre-eclampsia, which has considerable
maternal and perinatal morbidity and mortality.
2,3
Future research should focus on undertaking high-quality
primary studies of test accuracy including all risk indicators
that clinicians normally use. This will enable future reviewers
to focus on meta-analysis of adjusted accuracy parameters or,
even better, on meta-analysis using individual patient data.
69
The proper role of BMI among other tests in rational risk
stratication strategies for pre-eclampsia must await the
results from such analyses ideally incorporating the costs
and benets of preventive treatment.
Funding
This study is supported by the UK NHS Health Technology
Assessment Programme, project code 01/64/04. j
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