Cardiovascular Risk Factors in Children and Young
Adults Born to Preeclamptic Pregnancies: A Systematic
Review
abstract
BACKGROUND AND OBJECTIVE:Preeclampsia is an independent car-diovascular risk factor for the mother, and recent studies reveal that offspring of affected pregnancies also may have an increased cardio-vascular risk. Our objective was to examine evidence for increased cardiovascular risk factors in children exposed to preeclampsia in utero.
METHODS: We performed a systematic review and meta-analysis on studies reporting traditional cardiovascular risk factors in those ex-posed to preeclampsia compared to controls. Information was extracted on the classic cardiovascular risk factors, including blood pressure, lipid
profile, glucose metabolism, and BMI from articles published
be-tween 1948 and August 2011 in Medline and Embase.
RESULTS:Eighteen studies provided cumulated data on 45 249 indi-viduals. In utero exposure to preeclampsia was associated with a 2.39
mm Hg (95% confidence interval: 1.74–3.05;P,.0001) higher systolic
and a 1.35 mm Hg (95% confidence interval: 0.90–1.80; P, .00001)
higher diastolic blood pressure during childhood and young
adult-hood. BMI was increased by 0.62 kg/m2 (P, .00001). Associations
were similar in children and adolescents, for different genders, and
with variation in birth weight. There was insufficient evidence to
identify consistent variation in lipid profile or glucose metabolism.
CONCLUSIONS: Young offspring of pregnancies complicated by
pre-eclampsia already have increased blood pressure and BMI, afinding
that may need to be considered in future primary prevention strategies
for cardiovascular disease.Pediatrics2012;129:e1552–e1561
AUTHORS:Esther Frances Davis, MBBS, MBioethics,a
Merzaka Lazdam, MBChB, MRCP,aAdam James
Lewandowski, BSc (Hons),aStephanie Anne Worton,
MBChB, MRes,bBrenda Kelly, MBChB, BSc, PhD, MRCOG,b
Yvonne Kenworthy, BSc,aSatish Adwani, MBBS, MD, DM,
MRC,cAndrew R. Wilkinson, MB ChB, MA, DCH, FRCP,
FRCPCH,dKenny McCormick, MBChB, MRCP, (UK), FRCPCH,d
Ian Sargent, PhD,bChristopher Redman, MA, MB, BChir,
FRCP,band Paul Leeson, MB BChir, PhD, MRCPa
Departments ofaCardiovascular Medicine andbObstetrics and Gynaecology, University of Oxford, Oxford, United Kingdom; and Departments ofcPaediatric Cardiology anddNeonatology, John Radcliffe Hospital, Oxford, United Kingdom
KEY WORDS
preeclampsia, offspring, cardiovascular risk, systematic review
ABBREVIATION
CI—confidence interval
All authors have read and approved the submission of the article and have made substantial intellectual contribution to this work.
Accepted for publication Jan 18, 2012
www.pediatrics.org/cgi/doi/10.1542/peds.2011-3093
doi:10.1542/peds.2011-3093
Address correspondence to Paul Leeson, PhD, MRCP, Oxford Cardiovascular Clinical Research Facility, Department of Cardiovascular Medicine, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom. E-mail: paul.leeson@cardiov.ox.ac.uk
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2012 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE:The authors have indicated they have nofinancial relationships relevant to this article to disclose.
Women who develop preeclampsia have an increased risk of later
cardiovas-cular disease,1,2so guidelines propose
that a history of preeclampsia is an integral part of preventive cardiology
assessments in women.3 It has now
emerged that there also may be car-diovascular health implications for offspring of affected pregnancies. Authors of a long-term follow-up study found that these offspring had almost
double the risk of stroke in adulthood,4
and subsequent meta-analysis of early studies of blood pressure variation found they had a 2.3 mm Hg higher systolic and a 1.7 mm Hg higher diastolic
blood pressure.5Because preeclampsia
affects 2% to 5% of pregnancies,6,7
thesefindings are potentially relevant
to the cardiovascular health of.300
million people worldwide. We inves-tigated whether an increased
car-diovascular risk profile was already
evident in childhood, which may war-rant early prevention advice, and the characteristic features of this risk
profile. We performed a systematic
review of all studies that reported variation in cardiovascular risk fac-tors, including blood pressure, BMI,
lipid profile, and glucose metabolism
in children and young adults exposed to preeclampsia in utero. Furthermore, we determined whether associations vary between genders, with age, or in the presence of intrauterine growth restriction.
METHODS
Search Strategy
All studies describing the effect of preeclampsia on offspring cardiovas-cular risks in childhood and young adulthood were sought by
computer-ized Ovid search of Medline (1948–
August 2011) and Embase (1980–August
2011). The search strategy is described in Supplemental Fig 6. Review was un-dertaken with reference to the PRISMA
and the MOOSE Group guidelines8,9
(Supplemental Fig 7). Case-control stud-ies, cohort studstud-ies, and clinical trials
were included. References of identified
studies were searched, and all identified
studies were sifted by abstract for rele-vance by 2 authors (E.F.D. and M.L.). Eli-gibility was assessed without reference to results, author, or journal. Discrep-ancies were resolved by discussion. Data were extracted from eligible stud-ies by 1 author (E.F.D.) and cross-checked for accuracy by a second author (A.J.L.). When required data could not be ex-tracted, authors of the relevant studies were contacted.
Inclusion Criteria
Studies were selected if they compared cardiovascular risk factors in children exposed to preeclampsia in utero with controls. In addition to diagnosis of a risk factor, outcome measures in-cluded were blood pressure, BMI, lipid levels, insulin sensitivity, and glucose or glucose metabolism. The primary summary measure for continuous outcome variables was difference in means. Studies reporting only relative risk of an outcome such as hyperten-sion, obesity, or diabetes, rather than mean values in the study population, were excluded. Preeclampsia was
de-fined by using the current International
Society for the Study of Hypertension in
Pregnancy research definition10;
how-ever, as diagnostic criteria have varied historically, studies in which preeclamp-sia was diagnosed by de novo onset of hypertension and proteinuria also were included. When the same co-hort was reported in multiple pub-lications at similar ages, the most recent publication was included. Studies in which distinction between gesta-tional hypertension and preeclampsia was impossible and studies comparing offspring to another potential risk group were excluded. All studies were published in peer-reviewed journals, undertaken in human participants, and published in English or French.
Analysis
From each included study, definition of
preeclampsia, age of offspring at follow-up, number of cases and controls, birth weight, and the gestational age of cases and controls were collected. Outcome measures were documented and, for each, the mean and SD were recorded. Funnel plots were examined for evidence of bias (Supplemental Fig 8).
Comparative review of outcome meas-ures was undertaken, and consideration was given to whether results varied be-tween genders, with age, or in the pres-ence of intrauterine growth restriction. When informative, meta-analysis was performed by using Cochrane Collabo-rations RevMan software (Review Man-ager (RevMan) Version 5.1.1, The Nordic Cochrane Centre: The Cochrane
Col-laboration, Copenhagen)11 based on an
inverse variance method. The mean dif-ference between outcome measures and
95% confidence interval (CI) was
calcu-lated by using a fixed-effect model,
which reflects only the random error
within each study and is less affected by publication bias, which is a greater issue in observational studies compared with
randomized controlled trials.12–14 To
ensure our conclusions were not unduly
influenced by choice of model, we also
repeated the analysis with a random effects model, but no differences in
out-come were identified (data not shown).
Statistical assessment of heterogeneity
was undertaken.11
RESULTS
Study Identification
Of the 2484 articles identified by the
preeclampsia (17 studies); repeat pub-lication of data (4 studies); inability to exclude hypertension before pregnancy (12 studies); and studies reporting rel-ative risk of a diagnosis rather than mean values in the study population (2 studies).
Blood Pressure
Blood pressure data on 44 293 individ-uals, 1241 of whom were exposed to preeclampsia, was available from 10
studies (Table 1).15–24Authors of 1
ad-ditional study reported only relative risk of hypertension in adult offspring 60 to 70 years after a preeclamptic pregnancy, and the study was not
in-cluded in the analysis.4 Persons who
had been included were aged from 4 to 30 years, with all but 1 study reporting
only on those aged ,20 years. Five
studies reported increased systolic blood pressure in those exposed to
preeclampsia (range: 1.8024– 6.70
mm Hg22), and 6 studies reported
in-creased diastolic blood pressure
(range: 1.719–6.0 mm Hg22).16–20,22None
reported significant decreases.
Quanti-tative summary measures obtained by meta-analysis indicated that in childhood,
offspring of preeclamptic women have
a 2.39 mm Hg (P,.0001) greater
sys-tolic (Fig 2) and a 1.35 mm Hg (P ,
.00001) greater diastolic blood pres-sure (Fig 3).
Two studies reported increased systolic blood pressure in male individuals only16,17; for diastolic blood pressure, 2 studies reported increases in female
individuals,17,19and 1 reported
increa-ses in male individuals.16Meta-analysis
of studies in which data were reported in genders separately demonstrated
a 2.41 mm Hg (P,.0001) increase in
systolic blood pressure in those who were female, similar to the 2.48 mm Hg
(P,.0001) increase in those who were
male. For diastolic blood pressure, however, female individuals had a 1.69
mm Hg (95% CI: 0.89–2.50; P, .0001)
increase, and male individuals had
a nonsignificant 0.67 mm Hg (95% CI:2
0.312 to 1.45;P= .1) difference. We then
studied whether the blood pressure difference varied with age of follow-up.
Studies of younger children, aged,10
years at the time of follow-up, had a mean increase of 2.91 mm Hg in
sys-tolic blood pressure (95% CI: 1.55–4.27;
P,.00001), similar to the 2.24 mm Hg
increase (95% CI: 1.49–2.98;P,.00001)
in those aged$10 years. Because birth
weight25and gestational age26associate
with later blood pressure, we also
ana-lyzed 4 studies that reportedfindings in
term-born offspring and in which those born to pregnancies complicated by preeclampsia had a mean birth weight
.2.5 kg, similar to the level in controls.
In these studies, preeclampsia still was associated with a 2.26 mm Hg (95% CI:
1.35–3.16; P,.00001) higher systolic
and a 1.48 mm Hg (95% CI: 0.82–2.14;
P,.0001) higher diastolic blood
pres-sure (Fig 4).
BMI
Eight studies compared BMI with data
on 39 611 participants.15,17–21,27 In 5
studies, BMI was greater in exposed
individuals, but this finding was
sig-nificant only in 2, and then only in girls
in 1 study17and boys in the other study.27
In 1 study of adolescents living at
alti-tude, BMI was reduced significantly15;
however, meta-analysis identified a
sig-nificant increase of 0.57 (P,.00001) in
the children of preeclamptic women.
Heterogeneity was significant
(hetero-geneity:x2= 23.40, degrees of freedom =
9 [P= .005]; I2= 62%), and appeared to
be driven by the study of offspring living
at altitude.15 Because the authors of
some works have suggested that living at high altitude is associated with a lower BMI, this factor was consid-ered a plausible explanation for the
observed heterogeneity.28 When this
study was removed, an increase in BMI
without significant heterogeneity was
noted (0.62; 95% CI: 0.41–0.84;P,.0001;
Fig 5). Significant increases in BMI were
seen both when female individuals were
considered alone (0.69; 95% CI: 0.35–
1.03;P,.0001) and in studies
consid-ering male individuals alone (0.83; 95%
CI: 0.48–1.18; P , .006); however, no
difference was evident in studies that
included only children aged,10 years
(0.15; 95% CI:20.34 to 0.64;P, .55),
whereas there was a significant increase
FIGURE 1
in those$10 years (0.69; 95% CI: 0.35–
1.03; P,.0001). When studies which
reported findings in term born
off-spring and in which those born to preg-nancies complicated by preeclampsia had a mean birth weight greater than
2.5 kg were considered, a significant
increase in BMI was seen (0.67; 95% CI:
0.35–0.99;P,.0001).
Cholesterol
Ten studies considered lipid levels, representing data on 6164 individuals, of whom 423 were exposed to
pre-eclampsia18,20,23,29–35 (Table 2). Uniquely,
6 of the studies, comprising 366 par-ticipants, reported levels at birth in
cord blood.30–35 Because these studies
reflect the unique postdelivery biological
situation, we considered the studies separately. Five reported changes in
lipid profile; 4 reported an increase in
triglycerides30–32,34; 2 reported an
in-crease in total cholesterol; 2 reported an
increase in low-density lipoprotein32,33;
and 3 reported a decrease in
high-density lipoprotein.30–32In studies in
later life (considering children and
young adults aged 9–30), 1 was
per-formed on nonfasted samples.23Two
of the fasting studies found increased total cholesterol, with 1 reporting an increase in low-density lipoprotein
cho-lesterol.20,29 No other differences were
demonstrated. These studies included only 208 subjects, and in view of the small number of participants, meta-analysis was not performed.
Glucose Metabolism
Only 2 studies have considered fasting glucose, representing only 174
par-ticipants.18,20At age 12, there was no
difference in serum insulin, glucose, or
glucose-to-insulin ratio.18In young
adult-hood, preterm offspring of preeclamptic mothers had increased fasting glucose
(5.04 vs 4.57 mmol/L;P= .0001).20In view
of the limited number of studies, no meta-analysis was performed.
DISCUSSION
This study generates thefirst
compre-hensive analysis of the cardiovascular phenotype of children and young adults whose mothers had preeclampsia. The results are based on published data, on
FIGURE 2
Mean difference in systolic blood pressure in mm Hg between those who were exposed to preeclampsia in utero and controls. IV, inverse variance.
FIGURE 3
multiple outcomes, on ∼45 000 indi-viduals. In childhood and early adult life, these offspring have higher blood pressure and a small increase in BMI. Differences are evident in both male individuals and female individuals and in those with normal birth weight. Based on current reports, there are
insufficient studies to allow an
appre-ciation of the long-term effects, if any, of preeclampsia on the glucose me-tabolism or lipid levels of offspring, except for probable acute changes in
perinatal lipid profiles.
If the 2.4 mm Hg difference in systolic blood pressure tracks into
adult-hood,36this difference would be
asso-ciated with an∼8% increased risk of
mortality from ischemic heart disease
and a 12% increased risk from
stroke.37The only long-term mortality
follow-up study reported so far showed a 1.9-fold increased risk of stroke mor-tality in the offspring of preeclamptic
pregnancies.4Together, these data
sug-gest that this population of children may be one in which intensive monitoring and early primary prevention advice may be warranted. Current data are limited almost exclusively to young cohorts, and it is possible the blood pressure difference increases with age to explain the greater observed stroke risk. We found no evidence that the observed increase in blood pressure varies between childhood and young
adulthood, however, and it is possible that preeclampsia exposure is asso-ciated with other biological variations that alter risk. Some studies found
gender-specific variation in associations
between preeclampsia and offspring
blood pressure38; however, our
com-bined analysis indicates gender is
un-likely to be a further significant factor,
certainly for systolic blood pressure, al-though there was some evidence for differences in diastolic pressure that may warrant investigation.
Preeclampsia is a recognized cause of
fetal growth restriction,39 which is
itself associated with increased blood pressure in adult life. We therefore performed an analysis restricted to
FIGURE 4
A, Mean difference in systolic blood pressure in term-born infants of normal birth weight. B, Mean difference in diastolic blood pressure in term-born infants of normal birth weight.
FIGURE 5
studies of individuals who were born at term, and in which the mean birth
weight of the cases was.2.5 kg. These
offspring still had a 2.26 mm Hg higher systolic and a 1.48 mm Hg higher di-astolic blood pressure and a 0.67 in-crease in BMI. Currently available data do not allow for more detailed analysis of the effects of various degrees of growth restriction. Interestingly, some evidence suggests that very low birth weight in-dividuals born preterm have higher blood pressure regardless of whether
the mother had preeclampsia17,37,38;
however, the underlying mechanistic link with later blood pressure may vary, de-pending on the blood pressure of the
mother.17More focused studies will
pro-vide interesting insight into the potential highly complex interaction of growth re-striction and exposure to preeclampsia in modulating offspring cardiovascular phenotype.
Rapid postnatal growth also may
im-pact blood pressure,25and offspring of
mothers with affected pregnancies ap-pear to have a consistently higher BMI
of∼0.6. It remains unlikely that this
in-crease alone accounts for the variation in blood pressure, because based on previous reports, at least a 1 to 2 dif-ference in BMI would be needed to
ex-plain the .2 mm Hg difference.40–42
Although some studies have shown an attenuation of the difference in blood pressure when offspring BMI was
ad-justed for,27 more recent data in
chil-dren exposed to preeclampsia in utero suggest that the increase in blood pressure remains after adjustment for
BMI43and childhood growth trajectory.44
Furthermore, the increase in BMI was most evident in early adulthood, whereas the blood pressure difference was al-ready established in childhood. Nev-ertheless, it remains possible that raised BMI contributes in part to increased blood pressure in later life or that the impact of preeclampsia exposure on body fat distribution, and thereby blood pressure, in childhood has so far been underestimated. BMI may not be the best predictor of adiposity in
chil-dren, particularly in thin individuals.45
Alternatively, because raised maternal BMI is a risk for both preeclampsia and
offspring obesity,46,47shared
environ-mental influences may be important
in this association.
The data available on lipid, glucose, and insulin levels were more limited, so the
available publications are insufficient
to allow definitive conclusions on the
ef-fect, if any, of preeclampsia on offspring glucose metabolism or lipids. There did
appear to be changes in lipid profile in
cord blood. These samples likely reflect
acute conditions at delivery in a mother with increased circulating oxidative and
inflammatory stimuli. Samples from
later in life suggest that, if preeclampsia exposure has a longer-term impact on childhood cholesterol levels, it is likely to account for up to 1 mmol/L variation in total cholesterol. Further data will be
useful to refine this estimate.
There are several potential limitations to our analysis. Our study cannot pro-vide insight into mechanisms underlying this phenotype. It seems probable that there are links with the etiology and
TABLE 2 Lipid Studies in Offspring of Preeclamptic Pregnancies
Total Cholesterol HDL LDL Triglyceride
Studies on cord blood Akcakus et al,
201030, mg/dL
No difference: 73.3 vs 80.5;P= .72
Decreased: 17.3 vs 27.6;P= .002
No difference: 48.2 vs 49.9;P= .82
Increased: 39.2 vs 14.9;
P= .039 Catarino et al,
200831, mg/dL
No difference: 73 vs 86;P= .09
Decreased: 32 vs 53;P,.001
No difference: 34 vs 32;P= .68
Increased: 49 vs 39;
P= .049 Howlander et al,
200932, mg/dL
Increased: 70.9 vs 48.2;P,.001
Decreased: 10.3 vs 13.3;P,.001
Increased: 65.6 vs 28.0;P,.001
Increased: 52.4 vs 31.6;
P,.01 Ophir et al, 200633,
mg/dL
No difference: 70.6 vs 82.0;P= NS
Not reported:— Increased: 42 vs 36.8;
P,.01
No difference: 46.5 vs 45.0;
P= NS Rodie et al, 200434,
log mmol/L
Increased: 0.36 vs 0.11;P= .003
No differencea Not reported:— Increased:20.21 vs20.49; P= .02
Yavuz et al, 200635, mg/dL
No difference: 65 vs 56;P= NS
No difference: 28.3 vs 25.2;P= NS
No difference: 30.4 vs 25.5;P= NS
No difference: 30.6 vs 32.6;
P= NS Studies in children and
young adults
Kvehaugen et al, 201129, mmol/L
Increased: 5.01 vs 4.43;P= .04
No difference: 1.60 vs 1.41;P= .1
No difference: 1.81 vs 1.53;P= .3
No difference: 0.60 vs 0.58;
P= .9 Lazdam et al, 201020,
mmol/L
Increased: 4.7 vs 3.87;P= .001
No difference: 1.6 vs 1.46;P= .42
Increased: 2.65 vs 2.00;P= .0001
No difference: 0.99 vs 0.89;
P= .44 Lawlor et al, 201123,
mmol/L
Not reported No difference: 1.37 vs 1.40;P= .21
No difference: 2.87 vs 2.87;P= .76
No difference: 0.99 vs 1.03;
P= .78 Tenhola et al, 200318,
mmol/L
No difference: 4.54 vs 4.50;P= .618
No difference: 1.31 vs 1.36;P= .468
No difference: 2.82 vs 2.75;P= .342
No difference: 0.90 vs 0.86;
P= .617
HDL, high-density lipoprotein; LDL, low-density lipoprotein; NS, not significant.
pathogenesis of maternal preeclampsia. Disturbed placentation is thought to be
a key factor in preeclampsia,6with
rela-tive placental ischemia and decreased
uterine and placental flow.48 There is
extensive literature on developmental programming of offspring in response
to placental insufficiency and in utero
insults49–51; however, most of these
stud-ies considered the effects of intrauterine growth restriction, and it remains un-clear as to whether this model accurately represents the situation of preeclamp-sia. More relevant may be studies that have investigated programming of vas-cular function, which appear to show
effects independent of birth weight.52
Alternatively, blood pressure program-ming may occur in response to unique biological features of preeclampsia or
reflect shared genetic factors relevant to
both preeclampsia and blood pressure
control.53 We have considered only the
effect of preeclampsia on traditional cardiovascular risk factors. Recent studies have linked preeclamptic preg-nancy to alterations in other recognized cardiovascular risk factors, such as
de-pression in the offspring.54 Other novel
cardiovascular risk factors will warrant further consideration in future studies. Furthermore, the data available in the current literature do not allow for full exploration of potential confounding
factors. It is possible that ourfindings
may, in part, reflect such factors. For
example, raised maternal BMI is a risk for both preeclampsia and offspring
obesity,46,47 and raised maternal
preg-nancy BMI is associated with higher off-spring blood pressure, although this
relationship attenuates when childhood
BMI is considered.44Conversely, some
potential confounding factors may lead to underestimation of the true effect size of in utero exposure to preeclampsia. For example, maternal smoking reduces the
risk of preeclampsia by up to 50%,55but
it increases offspring blood pressure in
adult life.56
Interpretation of our findings also
needs to take into account the fact that observational studies are more prone to publication bias than randomized
clinical trials12; however, funnel plots
for considered outcome measures were grossly symmetrical. Meta-analysis of continuous outcome variables also can
be affected significantly by heterogeneity,
and without source data, it can be diffi
-cult to explore subgroup variation. Nev-ertheless, our review did not highlight heterogeneity. It did highlight a striking paucity of end-point data in this research area. In this situation, meta-analysis of continuous variables previously has been used effectively to provide clinically
in-terpretable assessment of effects.57The
studies also had been published during
a period when preeclampsia definitions
varied, and we cannot exclude the
pos-sibility that studies misidentified cases
or included individuals who would not meet current diagnostic criteria. We did not include studies examining gesta-tional hypertension, because it may have
a different pathophysiology.58
Never-theless, offspring of hypertensive preg-nancies have been noted to have an
increased blood pressure,59–61 and this
literature warrants review. We also
identified increasing reports of variation
in other biological measures in offspring
of preeclamptic pregnancies,32,62–65 but
these reports were excluded because they did not report established prog-nostic markers of cardiovascular dis-ease. Finally, nearly all studies were of infants born close to term, presumably to mothers with less severe preeclamp-sia. The one study that considered the risk of hypertension found this risk to be greater in those born to mothers with
more severe preeclampsia,4 and there
was some evidence that the blood pres-sure differences may be greater in those
born preterm.20The impact on the
off-spring of maternal disease severity needs further exploration.
CONCLUSIONS
Children and young adults born to pregnancies complicated by preeclamp-sia have adverse changes in cardio-vascular risk factors present from early life. The predominant phenotype that is now evident in multiple studies is of changes in blood pressure and BMI. Greater mechanistic understanding of these differences in blood pressure may provide useful insights into why some people are predisposed to hyper-tension and preeclampsia. From a public health perspective, children born to a pregnancy complicated by pre-eclampsia appear to have a unique,
life-time cardiovascular risk profile that is
present from early life, and so may constitute a population that may
ben-efit from risk profile monitoring and
early implementation of primary pre-vention strategies.
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DOI: 10.1542/peds.2011-3093 originally published online May 21, 2012;
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