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12375
Systematic review
www.bjog.org
Please cite this paper as: Gallos I, Sivakumar K, Kilby M, Coomarasamy A, Thangaratinam S, Vatish M. Pre-eclampsia is associated with, and preceded by,
hypertriglyceridaemia: a meta-analysis. BJOG 2013;120:13211332.
Introduction
Pre-eclampsia is a multi-organ disorder of pregnancy that
manifests after 20 weeks of gestation with new onset hypertension and proteinuria. Pre-eclampsia is defined as blood
pressure 140 mmHg systolic and 90 mmHg diastolic
diagnosed for the first time after 20 weeks of gestation
together with >300 mg proteinuria/24 hours as defined in
the proceedings of the 16th Scientific Study Group of the
Royal College of Obstetricians and Gynaecologists.1 This
disease can progress to cause maternal liver dysfunction,1
renal impairment2 and ultimately seizures and death.3 The
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Methods
Data sources and search strategy
We conducted a thorough search to identify eligible studies
that measured and reported the triglyceride levels in pregnant women and women were followed up until the development of pre-eclampsia or selected on the basis of presence
of pre-eclampsia and compared with controls. The hypothesis is to explore the association of hypertriglyceridaemia with
pre-eclampsia. The databases searched included MEDLINE,
EMBASE, Excerpta Medica Database, ISI Web of Knowledge, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and The Cochrane Library from inception
until June 2012. A combination of keywords for pre-eclampsia
(Pre-eclampsia,
pregnancy-induced
hypertension,
eclampsia, pregnancy and hypertension), for triglycerides
(triglycerides, lipids, hyperlipid*, dyslipidemia, cholesterol)
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Selection of articles
Articles were selected if they included a population of pregnant women, tested for triglyceride levels and followed up
until the diagnosis of pre-eclampsia. These studies were
expected to be of cohort design. We also selected studies
that they measured the triglyceride levels on women with
known pre-eclampsia and compared those with controls.
Of the 1017 identified articles, 965 did not match our
selection criteria based on review of their titles and
abstracts conducted by two authors (MV and IDG). These
two authors then independently reviewed the full text of
the remaining 52 articles to determine inclusion or exclusion (Figure 1). We excluded 23 studies after evaluation of
the full manuscripts. The most common reason for exclusion was our inability to extract raw data from the published reports (18 studies). Finally, 29 studies were deemed
eligible for inclusion of which, 24 casecontrol studies2144
and five comparative cohort studies.4549 When duplicate
data were published, only the most up-to-date, larger series
was included. Any disagreements about study eligibility
were resolved by consensus, with arbitration by a third
reviewer (AC) if necessary.
Data extraction
Data were extracted from the eligible studies by two
authors (MV and IDG) using a piloted data extraction
form. We collected information on definition and diagnosis
of pre-eclampsia, gestational age at testing and diagnosis,
timing and method of triglyceride measurements and fasting or non-fasting status of the participants. The majority
of the papers reported triglyceride measurements in millimolar and for few papers that reported data in milligram
per decilitre measurements were converted to millimolar.
From eligible studies we extracted mean and standard deviations (SDs) of triglyceride measurements from women
with pre-eclampsia compared with controls. When medians
and 95% confidence intervals (95% CI) were reported
instead we assessed the skewness and if acceptable we presumed a normal distribution of the triglyceride levels across
women included in the study and we computed the means
and SDs. Two reviewers (MV and IDG) completed the
quality assessment using the NewcastleOttawa Quality
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Data synthesis
Triglyceride levels between women with pre-eclampsia compared with healthy women were compared by weighed mean
differences (WMDs). The WMDs from individual studies
were meta-analysed using a random effects model. Studies were weighted by the inverse of the variance and
random effects models were used as standard, as they give
conservative estimates of effect.50 We planned a priori
subgroup analyses for important confounders that include
gestational age, fasting status and body mass index (BMI), at
the time of triglyceride measurement, and study design for
potential clinical heterogeneity across the studies. Statistical
analyses were performed using REVMAN 5.0 (Cochrane
Collaboration, Oxford, UK) and STATA 9.0 (Stata Corp, College Station, TX, USA).
Results
The studies involved 5857 participants: 1467 women with
pre-eclampsia and 4400 healthy women. The main study
characteristics of the studies included in this review are
summarised in Tables 1 and 2. The included studies were
mainly casecontrol studies carried out in the third trimes-
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ter (Table 1). The cohort studies recruited women prospectively in the second trimester and followed up women
during their pregnancy until the diagnosis of pre-eclampsia
(Table 2). In 17 studies the measurements of the triglyceride concentrations were carried out on fasting blood
samples. The definition of cases and controls was considered adequate in most casecontrol studies (2/24 and 23/
24, respectively). Often the recruitment of the cases and
controls was poorly defined and it was not representative
of the population (15/29 for both quality criteria). Controls
were commonly matched for gestational and/or maternal
age (6/24) and the triglyceride concentrations were measured in similar manner with a similar non-response rate.
The five cohort studies were considered of high quality
except for three studies that did not adequately describe
the selection of the cases and the controls.
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that triglycerides were significantly higher in the third trimester compared with the second trimester or postpartum
(third trimester, WMD 0.86 mmol/l, 95% CI 0.641.09 versus second trimester, WMD 0.23, 95% CI 0.100.36 and
postpartum, WMD 0.41, 95% CI 0.300.53, P < 0.00001).
Meta-analysis of the five prospective cohort studies confirms the association of hypertriglyceridaemia, when measured in the second trimester, with pre-eclampsia (WMD
0.24 mmol/l, 95% CI 0.130.34, P < 0.0001). We encountered moderate heterogeneity in this analysis (I2 = 62%,
P = 0.03). The triglyceride levels were significantly different
across studies according to the fasting status of the women
when the blood samples were taken (v2 = 15.73,
P < 0.00001). Our planned adjustment of our inferences for
BMI was not performed, as the primary studies did not
stratify the results according to BMI.
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Discussion
In this systematic review we found that hypertriglyceridaemia is associated with and precedes the onset of
pre-eclampsia. We found this association mostly in case
control studies performed in the third trimester, but also
in cohort studies that included women from the second
trimester of pregnancy. From this study, we add epidemiological evidence supporting that hypertriglyceridaemia may
be involved in the causal pathway of pre-eclampsia. This
inference is justified primarily by the strength of the association found in this study for both second and third trimesters. All the included studies were consistent in suggesting
this association and in only three studies (3/29) the 95%
confidence intervals marginally crossed the line of the null
hypothesis being true. Even so, a constellation of metabolic
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Cases
Study, year
Controls
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Study, year
Table 1. (Continued)
Cases
Controls
Gallos et al.
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Mikhail, 1995
Cases
Study, year
Table 1. (Continued)
Controls
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Study, year
Table 1. (Continued)
Cases
Controls
Gallos et al.
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colname="col2">Pregnant women
referred to antenatal care before
the week 16
Excluded: Women with diabetes,
chronic hypertension, previous
obstetric complications or other
systemic disease
Pregnant over 35 years of age
women with ongoing gestations
(>13 weeks) of single foetuses
Excluded: Women with a history
of cardiovascular or kidney disease,
and/or diabetes mellitus
Women in their first pregnancy
between 28 and 32 weeks
(n = 470) Exclusion: Women
with diabetes mellitus or any
other endocrine or metabolic
disorder, any history of
cardiovascular disease and
hypertension, smoking, and
nonsingleton pregnancy
Clausen, 2001
(n = 2157)
Enquobahrie,
2004 (n = 567)
Setareh, 2009
(n = 343)
Ziaei, 2006
(n = 470)
Takahashi, 2008
(n = 48)
Population
Study, year
Outcome
Study Design/Follow up
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Figure 3. Forest plot showing the results of meta-analysis of studies along with calculated exact binomial confidence intervals that examine the
difference in triglyceride concentrations in women with pre-eclampsia compared with normal controls. Results subgrouped according to the study design.
changes may happen that lead to pre-eclampsia, and hypertriglyceridaemia may only explain a part of this pathway.
This prevents us from drawing strong conclusions about
causality from this study. The temporality, though, where
hypertriglyceridaemia clearly precedes the onset of
pre-eclampsia, leads us to generate the hypothesis that we
may be able to change the natural history of the disease if
we intervene early by lowering the triglyceride levels. Before
such an intervention it would be important to define the
normal triglyceride levels in pregnancy and correctly identify women that could benefit most from this therapy.
A weakness, which is difficult to account for, is that the
observed association may be overestimated because of the
study design in casecontrol studies, but this was also
proven in five prospective cohort studies when analysed
separately. The casecontrol studies were significantly
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Conclusion
The association between hypertriglyceridaemia and
pre-eclampsia were significant in both analyses of case
control and cohort studies. The cohort design of five
included studies also highlights the temporality of this
association where hypertriglyceridaemia present in the second trimester preceded the onset of pre-eclampsia, which
was often diagnosed in the third trimester. This is clinically attractive because measurement of triglycerides is well
established in all clinical laboratories and may represent a
cost-effective way of identifying at-risk pregnancies. The
role of hypertriglyceridaemia in the pathogenesis of the
disease and particularly potential mechanisms by which it
might be modulated are potential avenues for further
research.
Disclosure of interests
None to be declared.
Contribution to authorship
IDG and MV conceptualised this study. IDG, KS and MV
performed the search, selected abstracts, obtained the full
manuscripts and extracted the data. IDG performed the
meta-analysis and wrote all versions of the manuscript.
MK, AC, ST and MV critically revised the manuscript and
all authors approved the final version.
Funding
No funding was sought for this study.
Acknowledgements
None. &
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