JOURNAL OBSGryYN 7.pdf

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Pre-eclampsia is associated with, and precededby, hypertriglyceridaemia: a meta-analysisID 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 Women’s 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 [email protected]

Accepted 22 May 2013. Published Online 17 July 2013.

Background Elevated triglycerides are a feature of the metabolic

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.

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 onpregnant 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.

Data collection and analysis We collected and meta-analysed the

weighted mean differences (WMDs) of triglyceride levels from

individual studies using a random effects model.

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

case – control studies (2720 women) that pre-eclampsia is

associated with higher levels of serum triglycerides (WMD

0.78 mmol/l, 95% confidence interval 0.6 – 0.96, 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 0.13 – 0.34, P < 0.0001).

Author’s 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 womenat 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;120:1321 – 1332.

Introduction

Pre-eclampsia is a multi-organ disorder of pregnancy that

manifests after 20 weeks of gestation with new onset hyper-tension 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

foetus may suffer intrauterine growth restriction and, when

born preterm, is more likely to struggle with the conse-

quences 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 pro-

cess.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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DOI: 10.1111/1471-0528.12375

www.bjog.orgSystematic review


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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 circula-

tion.9 These factors may subsequently alter vasomotor

function,10 angiogenesis,11 endothelial permeability and

downstream activation of other cascades such as thrombo-

sis.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 sen-

sitivity may be modulated by maternal disease, including

diabetes,13 chronic hypertension,14 obesity and, impor-

tantly, 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 circulat-

ing triglycerides, fatty acid, cholesterol and phospholipids.16

As pregnancy continues, this causes hyperlipidaemia con-sisting 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 metabo-

lism 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 en-

doglin (sEng).18,19 Moreover, serum from women with

pre-eclampsia induces greater lipid accumulation in endo-

thelial 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 preg-

nant women and women were followed up until the devel-

opment of pre-eclampsia or selected on the basis of presence

of pre-eclampsia and compared with controls. The hypothe-

sis is to explore the association of hypertriglyceridaemia withpre-eclampsia. The databases searched included MEDLINE,

EMBASE, Excerpta Medica Database, ISI Web of Knowl-

edge, Cumulative Index to Nursing and Allied Health Litera-

ture (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’)

along with their associated Medical Subject and Emtree

Headings were used to search MEDLINE, EMBASE and CI-

NAHL. 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 articlesArticles were selected if they included a population of preg-

nant 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 andabstracts 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 exclu-

sion (Figure 1). We excluded 23 studies after evaluation of

the full manuscripts. The most common reason for exclu-

sion was our inability to extract raw data from the pub-

lished reports (18 studies). Finally, 29 studies were deemed

eligible for inclusion of which, 24 case – control studies21 – 44

and five comparative cohort studies.45 – 49 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 extractionData 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 fast-

ing or non-fasting status of the participants. The majority

of the papers reported triglyceride measurements in milli-

molar and for few papers that reported data in milligram

per decilitre measurements were converted to millimolar.

From eligible studies we extracted mean and standard devi-ations (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 pre-

sumed 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 Newcastle – Ottawa Quality

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Assessment Scales for observational studies. We awarded

studies a maximum of nine stars for case – control studies

and eight for cohort studies (Figure 2). Any differences

were resolved by consensus.

Data synthesisTriglyceride levels between women with pre-eclampsia com-

pared with healthy women were compared by weighed mean

differences (WMDs). The WMDs from individual studies

were meta-analysed using a random effects model. Stud-

ies 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 R EVMAN 5.0 (Cochrane

Collaboration, Oxford, UK) and STATA 9.0 (Stata Corp, Col-

lege 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 case – control studies carried out in the third trimes-

ter (Table 1). The cohort studies recruited women prospec-

tively 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 triglycer-

ide concentrations were carried out on fasting blood

samples. The definition of cases and controls was consid-

ered adequate in most case – control 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 mea-

sured 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 andpre-eclampsia

Meta-analysis of the results of the 24 case –

control studiesshows that pre-eclampsia is associated with higher levels of

serum triglycerides (WMD 0.78 mmol/l, 95% CI 0.60 – 0.96,

P < 0.00001) (Figure 3). In this meta-analysis, we encoun-

tered significant heterogeneity (I 2 = 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 analy-

sis of studies according to the gestational age and found

Figure 1. Flowchart of the study selection process.

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Triglycerides and pre-eclampsia


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that triglycerides were significantly higher in the third tri-

mester compared with the second trimester or postpartum

(third trimester, WMD 0.86 mmol/l, 95% CI 0.64 – 1.09 ver-

sus second trimester, WMD 0.23, 95% CI 0.10 – 0.36 and

postpartum, WMD 0.41, 95% CI 0.30 – 0.53, P < 0.00001).

Meta-analysis of the five prospective cohort studies con-

firms the association of hypertriglyceridaemia, when mea-

sured in the second trimester, with pre-eclampsia (WMD0.24 mmol/l, 95% CI 0.13 – 0.34, P < 0.0001). We encoun-

tered moderate heterogeneity in this analysis (I 2 = 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.

Discussion

In this systematic review we found that hypertriglycerida-

emia 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 epidemio-logical evidence supporting that hypertriglyceridaemia may

be involved in the causal pathway of pre-eclampsia. This

inference is justified primarily by the strength of the associ-

ation found in this study for both second and third trimes-

ters. 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

Figure 2. Newcastle – Ottawa quality assessment of the studies.

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T a b l e 1 .

( C o n t i n u e d )

S t u d y , y e a r

C a s e s

C o n t r o l s

T r i g l y c e r i d e ( T G ) t e s t

H u b e l , 1 9 9 8 ( n =

4 0 )

W o m e n w i t h p r e - e c l a m p s i a ( n =

2 0 )

a t t h e t i m e o f a d m i t t a n c e

t o h o s p i t a l a t a m e d i a n

g e s t a t i o n a l a g e o f 3 4 . 5

w e e k s

E x c l u d e d : W o m e n w i t h

c i g a r e t t e o r i l l i c i t d r u g u s e ,

c h r o n i c h y p e r t e n s i o n ,

r e n a l

d i s e a s e ,

o r a p r e v i o u s

h i s t o r y o f m e t a b o l i c d i s o r d e r s

W o m e n w i t h n o r m a l p r e g n a n c i e s

m a t c h e d f o r g e s t a t i o n a l a g e ( n

=

2 0 )

B l o o d s a m p l e s w e r e o b t a i n e d

b e f o r e l a b o u r a n d

w e r e n o n - f a s t i n g .

S e r u m w a s o b t a i n e d u s i n g d r y

s t e r i l e t u b e s i n w h i c h t h e b l o o d w a s a l l o w e d t o

c o a g u l a t e f o r 6 0 m i n u t e s a t

r o o m t e m p e r a t u r e

b e f o r e c e n t r i f u g a t i o n .

S e r u m

a n d p l a s m a s a m p l e s

w e r e i m m e d i a t e l y s t o r e d a t

7 0 ° C

( w i t h o u t

t h a w i n g ) u n t i l e n z y m a t i c a n a

l y s i s o f T G

c o n c e n t r a t i o n s

K h a l i q ,

2 0 0 0 ( n =

6 0 )


4 0 )

a n d s i n g l e t o n p r e g n a n c i e s

a n d n o t o n a n y m e d i c a t i o n s

E x c l u d e d : W o m e n w i t h c a r d i a c ,

h e p a t i c , r e n a l o r m e t a b o l i c

o r h i s t o r y o f h y p e r t e n s i o n

W o m e n w i t h n o r m a l p r e g n a n c i e s

( n =

2 0 )

B l o o d s a m p l e s w e r e c o l l e c t e d

e a r l y m o r n i n g o n

e m p t y s t o m a c h .

T h e c o n c e n

t r a t i o n o f s e r u m

T G w a s m e a s u r e d b y G P O - P

A P m e t h o d

K h a r b ,

1 9 9 8 ( n =

4 5 )


2 0 )

E x c l u d e d : W o m e n w i t h d i a b e t e s ,

r e n a l d i s e a s e ,

p r i m a r y h y p e r t e n s i o n

o r o t h e r s y s t e m i c d i s e a s e

N o r m o t e n s i v e p r e g n a n t w o m e n

( n =

2 5 )

B l o o d s a m p l e s w e r e t a k e n b e f o r e a n t i -

h y p e r t e n s i v e t r e a t m e n t

L e i , 2 0 1 1 ( n =

2 3 3 )

W o m e n w i t h s i n g l e t o n p r e g n a n c i e s

a n d p r e - e c l a m p s i a ( n =

3 3 ) a t a

m e d i a n g e s t a t i o n a l a g e o f 3 6

a n d r a n g e 3 3 –

3 9 w e e k s

N o r m o t e n s i v e w o m e n a t t h e t i m

e o f

a d m i s s i o n t o h o s p i t a l ( n =

2 0 0

) a t a

m e d i a n g e s t a t i o n a l a g e o f 3 8 a n d r a n g e

3 8 –

4 0 w e e k s

B l o o d s a m p l e s w e r e c o l l e c t e d

a f t e r w o m e n h a d

f a s t e d f o r 8 –

1 0 h o u r s f o r t h

e a n a l y s i s o f T G

c o n c e n t r a t i o n s

L l u r b a ,

2 0 0 4 ( n =

8 3 )

W o m e n w i t h s i n g l e t o n p r e g n a n c i e s

a n d p r e - e c l a m p s i a ( n =

5 3 )

E x c l u d e d : W o m e n i n l a b o u r , w i t h

r u p t u r e d m e m b r a n e s , m u l t i p l e

p r e g n a n c i e s , s m o k e r s o r a n y

c o n c u r r e n t m e d i c a l c o m p l i c a t i o n s

b e f o r e o r d e v e l o p i n g d u r i n g

p r e g n a n c y ,

s u c h a s d i a b e t e s

m e l l i t u s o r i n fl a m m a t o r y d i s e a s e s

C o n s e c u t i v e w o m e n u n d e r g o i n g

r o u t i n e 3 r d

t r i m e s t e r b l o o d a n a l y s i s a n d w

i t h n o n e o f

t h e e x c l u s i o n c r i t e r i a ( n =

3 0 )

V e n o u s b l o o d s a m p l e s w e r e d

r a w n a f t e r 8 h o u r s

f a s t .

B l o o d w a s c e n t r i f u g e d

a n d p l a s m a l i p i d

p r o fi l e ( t o t a l c h o l e s t e r o l a n d

t r i g l y c e r i d e s ) a n d

u r i c a c i d w e r e m e a s u r e d b y q u a n t i t a t i v e

e n z y m a t i c a s s a y s ( S i g m a ; S t

L o u i s ,

M O ,

U S A ) )

L o r e n t z e n ,

1 9 9 5 ( n =

3 4 )

N u l l i p a r o u s w o m e n w i t h p r e - e c l a m p s i a

( n =

1 7 ) a t t e n d i n g t h e u l t r a s o u n d

s c r e e n i n g ( 1 7 –

1 9 w e e k s )

E x c l u d e d : N o n e

N o r m o t e n s i v e h e a l t h y c o n t r o l s

( n =

1 7 )

m a t c h e d f o r a g e ,

B M I , p a r i t y

a n d

g e s t a t i o n

T G s w e r e m e a s u r e d a f t e r 8 – 1

0 h o u r s f a s t

b e t w e e n 1 7 a n d 1 9 w e e k s

M a s e k i , 1 9 8 1 5 2

( n =

4 5 )


2 3 )

w i t h m e a n g e s t a t i o n a l a g e 3 6 a n d S D

2 w e e k s


W o m e n w i t h n o r m a l p r e g n a n c i e s ( n =

2 2 )

w i t h m e a n g e s t a t i o n a l a g e 3 5

a n d S D

3 w e e k s

F a s t i n g b l o o d w a s t a k e n i n t h e m o r n i n g .

S e r u m

l i p o p r o t e i n s w e r e f r a c t i o n a t e

d b y

u l t r a c e n t r i f u g a t i o n .

T G s w e r e m e a s u r e d w i t h c h

e m i c a l s o f r e a g e n t g r a d e

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T a b l e 1 .

( C o n t i n u e d )

S t u d y , y e a r

C a s e s

C o n t r o l s

T r i g l y c e r i d e ( T G ) t e s t

S p a a n ,

2 0 1 0 ( n =

5 1 )

C a u c a s i a n p r i m i p a r o u s w o m e n w i t h

p r e - e c l a m p s i a ( n =

2 2 )

E x c l u d e d : W o m e n w i t h p r e - e x i s t e n t

h y p e r t e n s i o n ,

d i a b e t e s m e l l i t u s ,

r e n a l d i s e a s e ,

c u r r e n t c a n c e r

t h e r a p y o r c h r o n i c u s e o f

c o r t i c o s t e r o i d m e d i c a t i o n

C a u c a s i a n p r i m i p a r o u s w o m e n w i t h

u n c o m p l i c a t e d p r e g n a n c i e s ( n =

2 9 )

F a s t i n g s a m p l e s w e r e a n a l y s e d

b y s t a n d a r d a u t o m a t e d

l a b o r a t o r y t e c h n i q u e s ( B e c k m

a n C o u l t e r L X 2 0 P R O ,

F u l l e r t o n ,

C A ,

U S A ) 2 3 y e a r s

a f t e r p r e g n a n c y

V a n d e r j a g t , 2 0 0 4 ( n =

1 7 3 )


4 3 )

a t a m e a n g e s t a t i o n a l a g e o f 3 5 . 7

a n d a s t a n d a r d e r r o r o f 4 w e e k s


P r e g n a n t w o m e n w i t h n o o b v i o

u s m e d i c a l

p r o b l e m s ( n =

1 4 3 ) a t a m e a n

g e s t a t i o n a l a g e o f 3 1 . 6

a n d a

s t a n d a r d

e r r o r o f 7 w e e k s

T G c o n c e n t r a t i o n w a s d e t e r m i n e d b y t h e m e t h o d o f

S p a y d a n d c o - w o r k e r s

5 1

w i t h

a V i t r o s a n a l y z e r c l i n i c a l

c h e m i s t r y s l i d e a n d a V i t r o s 9 5 0 a n a l y z e r ( O r t h o

D i a g n o s t i c s , R o c h e s t e r , N Y , U S A )

W a r e - J a u r e g u i , 1 9 9 9 ( n =

3 0 4 )


1 2 5 )

E x c l u d e d : W o m e n w i t h c h r o n i c

h y p e r t e n s i o n a n d p o s t p a r t u m

W o m e n w i t h u n c o m p l i c a t e d p r e g n a n c i e s

m a t c h e d f o r g e s t a t i o n a l a n d m

a t e r n a l

a g e ( n =

1 7 9 )

T G c o n c e n t r a t i o n s w e r e m o s t l y f a s t i n g ( 9 4 % ) a n d

m e a s u r e d e n z y m a t i c a l l y e m p

l o y i n g a s s a y s

s t a n d a r d i s e d b y t h e L i p i d S t a

n d a r d i z a t i o n P r o g r a m m e

o f t h e C e n t r e s f o r D i s e a s e C o n t r o l a n d P r e v e n t i o n ,

A t l a n t a ,

G A ,

U S A

W i l l i a m s , 2 0 0 3 ( n =

3 5 9 )

W o m e n i n t h e i r p o s t p a r t u m

w i t h p r e - e c l a m p s i a ( n =

1 7 3 )

E x c l u d e d : W o m e n w i t h c h r o n i c

h y p e r t e n s i o n

W o m e n w i t h u n c o m p l i c a t e d p r e g n a n c i e s

d e l i v e r e d w i t h i n 2 h o u r s o f t h e

c a s e s ( n =

1 8 6 )

T G c o n c e n t r a t i o n s w e r e m e a s u r e d 1 2 –

7 2 h o u r s

p o s t p a r t u m e n z y m a t i c a l l y u s i n g a s s a y s s t a n d a r d i s e d

b y t h e L i p i d S t a n d a r d i z a t i o n

P r o g r a m m e o f t h e

C e n t r e s f o r D i s e a s e C o n t r o l a n d P r e v e n t i o n ,

A t l a n t a ,

G A ,

U S A

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changes may happen that lead to pre-eclampsia, and hyper-

triglyceridaemia 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. Beforesuch an intervention it would be important to define the

normal triglyceride levels in pregnancy and correctly iden-

tify 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 case – control studies, but this was also

proven in five prospective cohort studies when analysed

separately. The case – control studies were significantly

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 case – control studies because the cases

were not always representative of women with pre-eclamp-sia. 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 compa-

rability 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 hypertri-

glyceridaemia may be associated with nutrition, and indeed,

it was our aim also to adjust our estimates for BMI, which

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.

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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 sec-

ond trimester preceded the onset of pre-eclampsia, which

was often diagnosed in the third trimester. This is clini-

cally attractive because measurement of triglycerides is wellestablished 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 interestsNone to be declared.

Contribution to authorshipIDG 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 approvalNot required.

Funding No funding was sought for this study.

AcknowledgementsNone.&

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