DOI: 10.1111/1471-0528.

12375

Systematic review

www.bjog.org

Pre-eclampsia is associated with, and preceded

by, hypertriglyceridaemia: a meta-analysis
ID Gallos,a K Sivakumar,b MD Kilby,c A Coomarasamy,c S Thangaratinam,d M Vatisha,b
a
Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford Radcliffe Hospitals NHS Trust, Oxford, UK b Clinical
Sciences Research Institute, Warwick Medical School, Coventry, UK c School of Clinical and Experimental Medicine (Reproduction, Genes and
Development), College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK d Womens Health Research Unit, Centre
for Primary Care and Public Health, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
Correspondence: M Vatish, Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford Radcliffe Hospitals NHS Trust,
Oxford, OX3 9DU, UK. Email manu.vatish@obs-gyn.ox.ac.uk

Accepted 22 May 2013. Published Online 17 July 2013.

Background Elevated triglycerides are a feature of the metabolic

Data collection and analysis We collected and meta-analysed the

syndrome, maternal obesity, maternal vasculitis (i.e. systemic

lupus erythematosus) and diabetes mellitus. These conditions
are all known risk factors for pre-eclampsia.
Hypertriglyceridaemia therefore may be associated with
pre-eclampsia and indeed this may precede the presence of overt
disease.

weighted mean differences (WMDs) of triglyceride levels from

individual studies using a random effects model.

Objective In this study we determine the association between

hypertriglyceridaemia and pre-eclampsia in pregnant women.

Search strategy We searched MEDLINE, EMBASE, Web

of Science, Excerpta Medica Database, ISI Web of Knowledge,

Cumulative Index to Nursing and Allied Health Literature,
Cochrane Library from inception until June 2012 and reference
lists of relevant studies.
Selection criteria Two reviewers independently selected studies on

pregnant women where triglycerides were measured 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.

Main results We found strong evidence from meta-analysis of 24

casecontrol studies (2720 women) that pre-eclampsia is
associated with higher levels of serum triglycerides (WMD
0.78 mmol/l, 95% confidence interval 0.60.96, P < 0.00001). This
finding is also confirmed in five cohort studies, that recruited
3147 women in the second trimester before the onset of
pre-eclampsia, which proves that hypertriglyceridaemia precedes
the onset of pre-eclampsia (WMD 0.24 mmol/l, 95% confidence
interval 0.130.34, P < 0.0001).
Authors conclusions Hypertriglyceridaemia is associated with and

precedes the onset of pre-eclampsia. Further research should focus

on defining the prognostic accuracy of this test to identify women
at risk and the beneficial effect of triglyceride-lowering therapies
in pregnancy.
Keywords Meta-analysis, predictive marker, pre-eclampsia,
systematic review, triglycerides.

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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foetus may suffer intrauterine growth restriction and, when

born preterm, is more likely to struggle with the consequences of premature delivery.4 Women with pre-eclampsia
are also more likely to suffer stillbirth or neonatal death.5
Of equal importance is the consistent finding that these
women have an increased lifetime risk of cardiovascular
disease compared with the rest of the population.6,7
Dyslipidaemia (especially hypertriglyceridaemia) has been
reported as being part of the pre-eclampsia disease process.8 Hypertriglyceridaemia is well documented as an
endothelial disruptor in atherosclerosis and is a potential
candidate for the endothelial dysfunction seen in this

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Gallos et al.

disease. The aim of this study was therefore to perform a

systematic review of the literature and meta-analysis to test
the hypothesis that elevated triglycerides correlate with
increased likelihood of pre-eclampsia.
One of the leading hypotheses in the aetiology of
pre-eclampsia is that circulating factors, released from the
placenta, alter endothelial function in the maternal circulation.9 These factors may subsequently alter vasomotor
function,10 angiogenesis,11 endothelial permeability and
downstream activation of other cascades such as thrombosis.12 A key variable that may be equally important in the
pathogenesis of the disease is the overall sensitivity of the
maternal endothelium to these circulating factors. This sensitivity may be modulated by maternal disease, including
diabetes,13 chronic hypertension,14 obesity and, importantly, altered lipid profile.15 In pregnancy, as a result of
both insulin resistance and increased oestrogen, metabolic
changes in both the liver and adipose tissue alter circulating triglycerides, fatty acid, cholesterol and phospholipids.16
As pregnancy continues, this causes hyperlipidaemia consisting principally of increased triglycerides. The mother
and foetus can subsequently use these, and so the increase
in triglyceride concentrations represents an accessible
energy reservoir. Several reports have suggested that women
with pre-eclampsia display further changes in lipid metabolism with increases in circulating levels of triglycerides and
non-esterified fatty acids.17 These changes have been
reported to be present at early gestation in women who
subsequently develop pre-eclampsia, with the dyslipidaemia
notably preceding clinical diagnosis far earlier than the
presence of known circulating factors associated with
pre-eclampsia such as soluble Flt-1 (sFlt-1) or soluble endoglin (sEng).18,19 Moreover, serum from women with
pre-eclampsia induces greater lipid accumulation in endothelial cells than serum from normal women.20

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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along with their associated Medical Subject and Emtree

Headings were used to search MEDLINE, EMBASE and CINAHL. These two populations of keywords were combined
using the AND function of the database. The Web of
Science and The Cochrane Library were searched using the
keywords pre-eclampsia and triglycerides. There were no
limits or philtres placed on the searches, to ensure maximal
sensitivity and no language restrictions were applied. All
the reference sections of all articles were reviewed to also
identify relevant studies.

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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Triglycerides and pre-eclampsia

Figure 1. Flowchart of the study selection process.

Assessment Scales for observational studies. We awarded

studies a maximum of nine stars for casecontrol studies
and eight for cohort studies (Figure 2). Any differences
were resolved by consensus.

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.

Association between raised triglycerides and

pre-eclampsia
Meta-analysis of the results of the 24 casecontrol studies
shows that pre-eclampsia is associated with higher levels of
serum triglycerides (WMD 0.78 mmol/l, 95% CI 0.600.96,
P < 0.00001) (Figure 3). In this meta-analysis, we encountered significant heterogeneity (I2 = 94%, P < 0.00001). We
explored the possible reasons for this heterogeneity and we
identified the gestational age of triglyceride measurement as
a possible factor. We therefore undertook a subgroup analysis of studies according to the gestational age and found

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Gallos et al.

Figure 2. NewcastleOttawa quality assessment of the studies.

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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Women with pre-eclampsia (n = 51)

at a mean gestational age of 34 weeks (SD 4.8)
Excluded: Women with
significant obstetric disease or pregnancyunrelated complications

Women with pre-eclampsia (n = 50)

Excluded: Women with cardiac, renal,
hepatic dysfunction or dyslipidaemia
Women with mild (n = 23) and severe
(n = 12) pre-eclampsia at a mean
gestational of 29  3 and 30  5
weeks, respectively
Excluded: None
Women with mild (n = 20) or severe
(n = 20) pre-eclampsia and for whom
samples were available for all three trimesters
Excluded: Women with diabetes,
chronic hypertension endocrine or
metabolic disorder
Women with severe pre-eclampsia
and singleton pregnancies (n = 35)
Excluded: Women with
pre-existent hypertension, diabetes
or other chronic disease, previous
pregnancy within 6 months and
use of oral contraception
Women with pre-eclampsia and singleton
pregnancies delivered by caesarean section
(n = 40)

Belo, 2004 (n = 118)

De, 2006 (n = 100)

Francoual, 1999 (n = 50)

Harsem, 2007 (n = 81)

Gratacos, 2003 (n = 70)

Gratacos, 1996 (n = 155)

Women with pre-eclampsia (n = 62)

after 20 weeks of gestation
Excluded: None

Cases

Barden, 1999 (n = 146)

Study, year

Table 1. Characteristics of the casecontrol studies

Women with uncomplicated

pregnancies undergoing elective
caesarean section (n = 41) between
37 and 42 weeks

Women with normal pregnancies

matched for age, BMI, smoking
and parity (n = 35)

Normotensive women (n = 15) throughout

gestation without proteinuria or
hyperuricaemia with no history of chronic
hypertension, diabetes, renal or
cardiovascular disease
Normotensive healthy pregnant
women(n = 115) delivering at
term without any of the exclusion
criteria and with similar blood samples.
Matched for age and BMI

Women with normal uncomplicated

pregnancies (n = 50)

Primigravidas at different gestational ages

with samples taken at third trimester
(n = 67)

Age and gestation-matched controls (n = 84)

Controls

Blood was sampled before caesarean section from

88 of the 102 women in gel vials and left at
room temperature for 3060 minutes until
centrifugation at 2000 g for 10 minutes at
room temperature, and serum was stored at 76C
until analysis. Serum concentration of TGs was
determined by routine enzymatic methods on a
Cobas Integra instrument (Roche)

Fasting serum samples were analysed and TG

levels were measured by enzymatic methods
(Trinder, Bayer Diagnostics) adapted to a
Cobas Mira automated analyser (Hoffmann)

Blood samples were obtained after overnight fast.

Serum TG were measured by enzymatic methods
(Trinder, Bayer Diagnostics, Tarrytown, NY, USA)
adapted to a Cobas Mira automated analyser
(Hoffmann Larroche, Basel, Switzerland)

TGs were determined antenatally without fasting.

Determined enzymatically using Abbott reagents
on a COVASMIRA analyser (Roche Diagnostics,
Basel, Switzerland)
Non-fasted serum samples were obtained at the
third trimester of gestation. Serum lipid analysis
was performed in an auto-analyser (Cobas
Mira S, Roche; Basel, Switzerland) using
commercially available kits. TG concentrations
were determined by enzymatic colorimetric tests
(GPOPAP methods, Roche)
Blood samples were drawn from all the women
following a fast of 12 hours and analysed for
TG by enzymatic methods with the help of Glaxo
kits on ERBA Chem-5 semi auto analyser
Blood samples were obtained after 12 hours of
fasting. Serum total TG were analysed on a
Hitachi 717 analyser (Boehringer Mannheim,
Mannheim, Germany)

Triglyceride (TG) test

Triglycerides and pre-eclampsia

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Maseki, 198152 (n = 45)

Lorentzen, 1995 (n = 34)

Llurba, 2004 (n = 83)

Lei, 2011 (n = 233)

Kharb, 1998 (n = 45)

Khaliq, 2000 (n = 60)

Hubel, 1998 (n = 40)

Study, year

Table 1. (Continued)

Women with pre-eclampsia (n = 20)

at the time of admittance
to hospital at a median
gestational age of 34.5 weeks
Excluded: Women with
cigarette or illicit drug use,
chronic hypertension, renal
disease, or a previous
history of metabolic disorders
Women with pre-eclampsia (n = 40)
and singleton pregnancies
and not on any medications
Excluded: Women with cardiac,
hepatic, renal or metabolic
or history of hypertension
Women with pre-eclampsia (n = 20)
Excluded: Women with diabetes,
renal disease, primary hypertension
or other systemic disease
Women with singleton pregnancies
and pre-eclampsia (n = 33) at a
median gestational age of 36
and range 3339 weeks
Women with singleton pregnancies
and pre-eclampsia (n = 53)
Excluded: Women in labour, with
ruptured membranes, multiple
pregnancies, smokers or any
concurrent medical complications
before or developing during
pregnancy, such as diabetes
mellitus or inflammatory diseases
Nulliparous women with pre-eclampsia
(n = 17) attending the ultrasound
screening (1719 weeks)
Excluded: None
Women with pre-eclampsia (n = 23)
with mean gestational age 36 and SD
2 weeks
Excluded: None

Cases

Normotensive healthy controls (n = 17)

matched for age, BMI, parity and
gestation
Women with normal pregnancies (n = 22)
with mean gestational age 35 and SD
3 weeks

Normotensive women at the time of

admission to hospital (n = 200) at a
median gestational age of 38 and range
3840 weeks
Consecutive women undergoing routine 3rd
trimester blood analysis and with none of
the exclusion criteria (n = 30)

Normotensive pregnant women (n = 25)

Women with normal pregnancies

(n = 20)

Women with normal pregnancies

matched for gestational age (n = 20)

Controls

Fasting blood was taken in the morning. Serum

lipoproteins were fractionated by
ultracentrifugation.
TGs were measured with chemicals of reagent grade

TGs were measured after 810 hours fast

between 17 and 19 weeks

Venous blood samples were drawn after 8 hours

fast. Blood was centrifuged and plasma lipid
profile (total cholesterol and triglycerides) and
uric acid were measured by quantitative
enzymatic assays (Sigma; St Louis, MO, USA))

Blood samples were collected after women had

fasted for 810 hours for the analysis of TG
concentrations

Blood samples were taken before antihypertensive treatment

Blood samples were collected early morning on

empty stomach. The concentration of serum
TG was measured by GPO-PAP method

Blood samples were obtained before labour and

were non-fasting. Serum was obtained using dry
sterile tubes in which the blood was allowed to
coagulate for 60 minutes at room temperature
before centrifugation. Serum and plasma samples
were immediately stored at 70C (without
thawing) until enzymatic analysis of TG
concentrations

Triglyceride (TG) test

Gallos et al.

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Primigravida women with pre-eclampsia (n = 30)

attending the hospital in their third trimester
Excluded: Women with diabetes mellitus with
or without treatment, obesity, severe anaemia,
eclampsia or women suffering from any other
systemic or endocrine disorder
Women with pre-eclampsia (n = 200) with
a mean gestational age of 35.6 weeks
and range from 27 to 40 weeks
Excluded: Women with essential hypertension,
diabetes, nephrotic syndrome or thyrotoxicosis

Sahu, 2009 (n = 60)

Schjetlein, 1999 (n = 297)

Women with pre-eclampsia (n = 40)

with a median gestational age of 30
weeks and range from 24 to 36 weeks

Raijmakers, 2004 (n = 64)

Powers, 1998 (n = 54)

Ozan, 1997 (n = 59)

Women with pre-eclampsia (n = 39)

Excluded: Women with a history of
antihypertensive medication, cardiac
disorder, diabetes mellitus, hyperlipidaemia,
hepatic or renal disorder, the smokers
and the drinkers
Women with pre-eclampsia (n = 21)
Excluded: None

Pregnant women with pre-eclampsia

(n = 29) and singleton pregnancies
from 28 to 42 weeks
Excluded: Women with ruptured
membranes, in labour or with medical complications
Women with singleton pregnancies and
pre-eclampsia (n = 31)
Excluded: None

Mikhail, 1995

Murai, 1997 (n = 62)

Cases

Study, year

Table 1. (Continued)

Women with uncomplicated

pregnancies (n = 97) with
a mean gestational age
of 36.3 weeks and range
from 24 to 42 weeks

Women with uncomplicated pregnancies

matched for gestational age (n = 24)
with a median gestational age of 31
weeks and range from 30 to 32 weeks
Primigravida women matched for
age in their third trimester (n = 30)

Women with uncomplicated pregnancy

with no medical problems (n = 21)

Women with uncomplicated pregnancies

(n = 20)

Women with normal pregnancies

matched for nulliparity, race, maternal
age at delivery (within 3 years), and
duration of pregnancy (within
2 weeks) (n = 31)

Controls were recruited from

the antenatal clinics (n = 46)

Controls

Fasting samples were analysed for TG levels with

conventional routine methods

Fasting samples were analysed by enzymatic

colorimetric methods in the autoanalyser (Dimension
AR, Dade Behring Limited, Milton Keynes, UK)

Plasma samples were obtained 6 hours after each

womans most recent meal and all measurements
were performed with appropriate diagnostic
kits supplied by Sigma Chemical Co
Fasting status is unreported or technique of
measurement

Non-fasting serum samples were collected during

the late third trimester of pregnancy before labour
or administration of antihypertensive agents or
intravenous fluids. Blood samples were drawn
at 3638 weeks of gestation from asymptomatic
women. Plasma TGs were quantified in matched
women using a microtitre-plate modification of the
Sigma triglycerides diagnostic kit
Fasting serum TG level measurements were obtained
at admission to hospital. Serum triglyceride levels
were determined by enzymatic-spectrophotometric
methods (BioSystems, American Biosystems, Inc.,
Roanoke, VA, USA)

Fasting blood samples were obtained and TG

measurements were made using standardised
techniques

Triglyceride (TG) test

Triglycerides and pre-eclampsia

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Williams, 2003 (n = 359)

Ware-Jauregui, 1999 (n = 304)

Vanderjagt, 2004 (n = 173)

Spaan, 2010 (n = 51)

Study, year

Table 1. (Continued)

Women in their postpartum

with pre-eclampsia (n = 173)
Excluded: Women with chronic
hypertension

Caucasian primiparous women with

pre-eclampsia (n = 22)
Excluded: Women with pre-existent
hypertension, diabetes mellitus,
renal disease, current cancer
therapy or chronic use of
corticosteroid medication
Women with pre-eclampsia (n = 43)
at a mean gestational age of 35.7
and a standard error of 4 weeks
Excluded: None
Women with pre-eclampsia (n = 125)
Excluded: Women with chronic
hypertension and postpartum

Cases

Women with uncomplicated pregnancies

delivered within 2 hours of the
cases (n = 186)

Pregnant women with no obvious medical

problems (n = 143) at a mean
gestational age of 31.6 and a standard
error of 7 weeks
Women with uncomplicated pregnancies
matched for gestational and maternal
age (n = 179)

Caucasian primiparous women with

uncomplicated pregnancies (n = 29)

Controls

TG concentration was determined by the method of

Spayd and co-workers51 with a Vitros analyzer clinical
chemistry slide and a Vitros 950 analyzer (Ortho
Diagnostics, Rochester, NY, USA)
TG concentrations were mostly fasting (94%) and
measured enzymatically employing assays
standardised by the Lipid Standardization Programme
of the Centres for Disease Control and Prevention,
Atlanta, GA, USA
TG concentrations were measured 1272 hours
postpartum enzymatically using assays standardised
by the Lipid Standardization Programme of the
Centres for Disease Control and Prevention, Atlanta,
GA, USA

Fasting samples were analysed by standard automated

laboratory techniques (Beckman Coulter LX20 PRO,
Fullerton, CA, USA) 23 years after pregnancy

Triglyceride (TG) test

Gallos et al.

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Pregnant women at their ultrasound

scan (1719 weeks)
Excluded: Women with twin
pregnancies

Pregnant women attending prenatal

care clinic before 16 weeks of
gestation
Excluded: Women with chronic
hypertension, diabetes mellitus and
spontaneous or induced abortions

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

Table 2. Characteristics of the cohort studies

Triglycerides were measured

at 2832 weeks of pregnancy

In the first trimester (until the 13th week)

and second trimester TGs were measured.
The measurement of serum TG was done
using the enzymatic colorimetric method
on an Advia 1650 (Bayer) device

Triglycerides were measured at

the time of recruitment in a non-fasting
state (1719 weeks) and allowed to
coagulate before centrifugation
at 400 g for 10 minutes. The serum
samples were transferred on ice to
a 708C freezer within 140 minutes
after venepuncture
Maternal nonfasting samples, collected
at an average of 13 weeks gestation.
Maternal plasma TG concentrations were
measured enzymatically using assays
standardised by the Lipid Standardization
Programme of the Centres for Disease
Control and Prevention (Atlanta, GA, USA)
Fasting blood samples were taken on week
16 for TG measurement. Enzymatic
colorimetric test was used to define TG

Triglyceride (TG) test

Women were observed once every

other week until 36 weeks of
gestational age. Afterward,
they were checked once a
week until 40 weeks of gestational age.
For each woman who experienced
pre-eclampsia, a non-hypertensive
healthy pregnant participant
delivering at term was matched
for age, body mass index,
educational level, family
income, and occupation.
Triglyceride levels from
women with pre-eclampsia
were compared with the
matched women with
normal pregnancies

In follow up, blood pressure

of both severe pre-eclampsia
and control group were recorded
again in week 38 of pregnancy
and pre delivery. Only severe
pre-eclampsia is compared
with control
Women were observed and groups
were separated into those who
developed pre-eclampsia and
those who did not

Women were observed

routinely for pre-eclampsia,
pregnancy-induced
hypertension according to
early or late onset
(before or after 37 weeks)

Women were observed

routinely for pre-eclampsia,
pregnancy-induced
hypertension according
to early or late onset
(before or after 37 weeks)

Outcome

Prospective cohort study

Follow up: No losses

Prospective cohort study

Follow up: No losses

Prospective cohort study

Follow up: None reported

Prospective cohort study

Follow up: n = 45 of
women delivered elsewhere,
moved or their medical
records were missing

Prospective cohort study

Follow up: 6.7% of
women delivered elsewhere

Study Design/Follow up

Triglycerides and pre-eclampsia

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Gallos et al.

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

1330

different between themselves, which is reflected in the high

heterogeneity we encountered in this meta-analysis. This
was partially explained from the different gestational age
and fasting status of the targeted populations across the
studies. The selection of controls varied across the studies,
which introduced further heterogeneity. Potential bias is
also possible in the casecontrol studies because the cases
were not always representative of women with pre-eclampsia. The selection of controls did not include community
controls and convenient hospital controls were often used.
This introduces bias and in most of the studies the comparability of cases and controls was found to be poor. The
cohort studies were of higher quality and their results are
likely to be more reliable. Of note, is the fact that hypertriglyceridaemia may be associated with nutrition, and indeed,
it was our aim also to adjust our estimates for BMI, which

2013 RCOG

Triglycerides and pre-eclampsia

is a potential confounder, but the primary studies did not

stratify their results according to BMI. However, BMI in
women with pre-eclampsia compared with healthy women
was reported and statistically tested in 12 studies. In the
majority of the studies there was only weak evidence that
groups were different for BMI with P-values >0.05 in 11
studies. However, the direction of the association was not
different for any of the included studies and only the
strength of the association differed.

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.

Details of ethics approval

Not required.

Funding
No funding was sought for this study.

Acknowledgements
None. &

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