Pregnancy Hypertension 13 (2018) 181–186

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Pregnancy Hypertension
journal homepage: www.elsevier.com/locate/preghy

Prenatal exposure to preeclampsia as an independent risk factor for long- T

term cardiovascular morbidity of the offspring☆
Kira Nahum Sacksa, Michael Frigera, Ilana Shoham-Vardia, Efrat Spiegelb, Ruslan Sergienkoa,
⁎
Daniella Landauc, Eyal Sheinerb,
a
Department of Public Health, Faculty of Health Sciences, Ben Gurion University of the Negev, Israel
b
Department of Obstetrics and Gynecology, Faculty of Health Sciences, Soroka University Medical Center, Ben-Gurion University of the Negev, Israel
c
Department of Pediatrics, Faculty of Health Sciences, Soroka University Medical Center, Ben-Gurion University of the Negev, Israel

A R T I C LE I N FO A B S T R A C T

Keywords: Introduction: Preeclampsia is a leading cause of maternal and fetal morbidity and mortality. Regarding the
Arrhythmia offspring, little is known about the long-term complications. The objective of the current study is to assess
Epidemiology whether in utero exposure to preeclampsia increases the risk of long-term cardiovascular morbidity in the off-
Heart disease spring.
Hypertension
Materials and methods: A population-based cohort study compared the incidence of cardiovascular disease be-
Pregnancy
tween singletons exposed and unexposed to preeclampsia. Deliveries occurred between 1991 and 2014 in a
regional tertiary medical center. A Cox proportional hazard model was used to control for confounders.
Results: During the study period 231,298 deliveries met the inclusion criteria; 4.1% of the births were to mothers
diagnosed with preeclampsia, of which 3.2% with mild preeclampsia (n = 7286), 0.9% with severe preeclampsia
(n = 2174) and 0.03% with eclampsia (n = 73). A significant linear association was noted between preeclampsia
(no preeclampsia, mild preeclampsia, severe preeclampsia and eclampsia) and cardiovascular disease of the
offspring (0.24%, vs. 0.33% vs. 0.51% vs. 2.73% respectively, p < 0.001 using the chi-square test for trends). In
the offspring born at term, severe preeclampsia was found to be an independent risk factor for cardiovascular
morbidity (adjusted HR = 2.32; 95% CI 1.15–4.67). In offspring born preterm, neither severe preeclampsia
(adjusted HR = 1.36; 95% CI 0.53–3.48) nor mild preeclampsia (adjusted HR = 0.37; 95% CI 0.52–2.71) were
associated with cardiovascular morbidity of the offspring.
Conclusion: Exposure to severe maternal preeclampsia is an independent risk factor for long-term cardiovascular
morbidity in the offspring born at term.

1. Introduction
Preeclampsia is a disease characterized by gestational hypertension
and proteinuria that effects 2–8% of pregnancies worldwide [1]. In
2010, the rate of preeclampsia in the Unites States was 3.8%: an in-
crease from 2.5% in 1987 [2], and in Canada the incidence of pre-
eclampsia has increased from 26.4 per 1000 deliveries in 1989, to 50.6
in 2012 [3]. This increase is disturbing since pre-eclampsia has a sub-
stantial impact on the intrauterine environment and is a leading cause
of maternal and fetal mortality and morbidity [4–6]. Regarding the
offspring, previous studies have mainly addressed the immediate ad-
verse outcomes, such as the increased the risk of fetal growth restriction
[7], perinatal death [8] and severe neonatal morbidity [9,10].
While there are studies on the long-term neurological effects of
preeclampsia on the offspring [11,12], less data exists regarding the
long-term cardiovascular effect, even though there is evidence of both
congenital cardiovascular predispositions [13–15] and a higher in-
cidence of cardiovascular risk factors amongst children prenatally ex-
posed to preeclampsia [16,17]. The congenital cardiovascular predis-
positions found in children exposed in utero to preeclampsia include
congenital heart defects [13], smaller hearts [14], increased heart rate
[14], and higher pulmonary artery pressure [15], and cardiovascular
risk factors amongst children prenatally exposed to preeclampsia in-
clude a higher blood pressure, a higher weight and a higher BMI

Abbreviations: AHA, American heart association; CVD, cardiovascular disease; GEE, generalized estimating equation; HR, hazard ratio; IUGR, intrauterine growth restriction; SUMC,
Soroka University Medical Center
☆
The study was conducted in Beer Sheva, Israel.
⁎
Corresponding author at: Department of Obstetrics and Gynecology, Soroka University Medical Center, POB 151, Beer-Sheva 84101, Israel.
E-mail address: sheiner@bgu.ac.il (E. Sheiner).

https://doi.org/10.1016/j.preghy.2018.06.013
Received 8 September 2017; Received in revised form 13 June 2018; Accepted 16 June 2018
Available online 18 June 2018
2210-7789/ © 2018 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.
K. Nahum Sacks et al. Pregnancy Hypertension 13 (2018) 181–186

Table 1
Cohort characteristics by exposure to maternal preeclampsia.
Characteristics No Preeclampsia Mild Preeclampsia Severe Preeclampsia Eclampsia (n = 73) P valuea
(n = 221765) (n = 7286) (n = 2174)

Maternal Characteristics
Maternal age, y (mean ± SD) 28.22 ± 6 28.66 ± 6 29.03 ± 7 25.37 ± 8 < 0.001
Maternal obesity (%) 1.0% 1.6% 1.0% 1.4% < 0.0001
Maternal diabetes (%) 5.3% 9.4% 10.8% 4.1% < 0.0001

Pregnancy Characteristics
Birth order (%) 1 23.9% 40.0% 43.9% 60.3% < 0.001
2–4 52.2% 40.1% 31.7% 17.8%
5+ 23.8% 19.9% 24.4% 21.9%
IUGRb 1.8% 3.5% 17.0% 12.3% < 0.001
Gestational age at birth, wk (mean ± SD) 39.16 ± 2 38.68 ± 2 36.39 ± 3 37.30 ± 3 < 0.001

Offspring Characteristics
Gender of offspring (%) Male 51.2% 51.5% 50.3% 65.8% 0.06
Female 48.8% 48.5% 49.7% 34.2%
Weight at birth, grams (mean ± SD) 3222 ± 493 3140 ± 532 2498 ± 772 2701 ± 713 < 0.001
Obesity of the offspring (%) 0.2% 0.4% 0.4% 1.4% < 0.001

a
Data evaluated with Pearson test or One-way Anova accordingly.
b
Abbreviations: IUGR, Intrauterine growth restriction; SD, Standard deviation.

[16,17]. Primary and secondary diagnoses were analyzed so that cardiovas-

These predispositions may represent the first signs of a pathological
cardiovascular system, which will eventually manifest as end-point
cardiovascular morbidity. The objective of the present population-
based study is to investigate whether prenatal exposure to preeclampsia
is an independent risk factor for long-term cardiovascular morbidity in
the offspring. We also aim to investigate the association between the
severity of the preeclampsia and offspring morbidity, while addressing
term and preterm labor separately.
2. Methods
2.1. Setting
cular morbidity could be detected, even if it was not the primary cause
for hospitalization. All hospitalizations were analyzed so that multiple
diagnoses could be given to a single child. The date of the first hospi-
talization for any single cause was used to calculate time-to-event.
Data were collected from two databases that were cross-linked and
merged: the computerized perinatal database and the computerized
hospitalization database of the Soroka University Medical Center. The
perinatal database consists of information recorded directly after de-
livery by an obstetrician. Skilled medical secretaries routinely review
the information before entering it into the database. The hospitalization
database includes demographic information and ICD-9 codes for all
medical diagnoses made during hospitalization.

The study was conducted at the Soroka University Medical Center
(SUMC), a tertiary hospital that serves the entire population of southern
Israel. Thus, the study is based on a nonselective population data. The
institutional review board (in accordance with the Helsinki declaration)
approved the study (# SOR-0236-13 approved on November 2013).
2.2. Study population
The study population included all patients who delivered between
the years 1991–2014 and their offspring. Perinatal deaths, multiple
gestations, mothers with chronic hypertension or lack of prenatal care,
and children with congenital malformations were excluded from the
study.
2.4. Statistical analysis
Statistical analysis was performed with the SPSS software (version
21; SPSS Inc, Chicago, IL). Statistical significance was calculated using
Pearson x 2 test and One-way Anova accordingly. A Kaplan Meier sur-
vival curve was used to compare the cumulative incidence of pediatric
morbidity. In the multivariate analysis “Severe Preeclampsia” and
“Eclampsia” were analyzed as one group, and models were performed
on term and preterm deliveries separately. Both a cox proportional
hazard analysis, and a multivariate generalized estimating equation
(GEE) logistic regression model analysis were used to control for con-
founders and for maternal clusters. A probability value of < 0.05 was
considered statistically significant.

2.3. Study design 3. Results

We conducted a population-based cohort study. The primary ex-
posure was having been prenatally exposed to preeclampsia. Severity of
preeclampsia was diagnosed by a trained obstetrician, according to the
guidelines of the Working Group of the National High Blood Pressure
Education Program [18,19]. A retrospective follow-up of cardiovascular
morbidity of the offspring up to 18 years of age was performed.
The main outcome was defined as cardiomyopathy, hypertension,
pulmonary heart disease, arrhythmia or heart failure (Supplement
Table 1), documented during any of the offspring's hospital admissions.
These cardiovascular morbidities were chosen because they cover both
a wide range of clinical presentation and a wide range of etiologies.
Most importantly, these conditions were selected due to the associa-
tions that have already been found between cardiovascular conditions
and in utero exposure to preeclampsia [13–17].
During the study period the births of 320,875 children were docu-
mented. After excluding perinatal deaths (n = 2491), multiple gesta-
tions (n = 23,797), chronic hypertension (n = 12,203), lack of prenatal
care (n = 22,510), and congenital malformations (n = 27,501), the
remaining 231,298 deliveries were included in our analysis. Of the
231,298 deliveries, 4.1% of the births were to mothers diagnosed with
preeclampsia or eclampsia (n = 9533), in accordance with the current
literature [1–3]. Of these mothers, 3.2% were diagnosed with mild
preeclampsia (n = 7286), 0.9% with severe preeclampsia (n = 2174)
and 0.03% with eclampsia (n = 73).
Table 1 presents a comparison between the clinical characteristics of
pregnancies with varying degrees of preeclampsia. In comparison to the
no preeclampsia group, Mothers in the preeclampsia groups were sig-
nificantly more likely to be primiparous, and pregnancies in the

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K. Nahum Sacks et al.
Table 2
Incidence rates for disease specific morbidity.
Cardiovascular morbidity No Preeclampsia (n = 221765)
Cardiomyopathy (n = 38) 34 (0.02)
Hypertension (n = 153) 141 (0.06)
Pulmonary Heart Disease (n = 32) 30 (0.01)
Arrhythmias (n = 303) 285 (0.13)
Heart Failure (n = 84) 78 (0.04)
Any Cardiovascular Morbidity (n = 559) 522 (0.24)
a
Data evaluated with Pearson x 2 test.
preeclampsia groups were significantly more likely to be affected by
intra-uterine growth restriction (IUGR). Offspring in the preeclampsia
groups weighed significantly less at birth, and were significantly more
likely to be male and to suffer from obesity later on in life. Maternal
diabetes, sex of the offspring, weight and gestational week at birth,
IUGR and obesity of the offspring were all found significantly asso-
ciated with cardiovascular morbidity, in accordance with the current
literature [20–25]. These were all adjusted for in the analysis, aside
from weight which is represented by IUGR, due to a high correlation
between the two.
A significant linear association was noted between preeclampsia (no
preeclampsia, mild preeclampsia, severe preeclampsia and eclampsia)
and cardiovascular disease of the offspring (0.24%, vs. 0.33% vs. 0.51%
vs. 2.73% respectively, p < 0.001) (Table 2). During the follow-up
period, children exposed in utero to preeclampsia had significantly
higher rates of hypertension (0.06%, vs. 0.11% vs. 0.14% vs. 1.37%
respectively, p < 0.001), arrhythmias (0.13%, vs. 0.18% vs. 0.18% vs.
1.37% respectively, p = 0.016) and heart failure (0.04%, vs. 0.03% vs.
0.18% vs. 0.00% respectively, p = 0.004) (Table 2). Cardiomyopathy
(0.02%, vs. 0.04% vs. 0.05% vs. 0.00% respectively, p = 0.256) and
pulmonary heart disease (0.01%, vs. 0.01% vs. 0.05% vs. 0.00% re-
spectively, p = 0.648), were not associated with prenatal exposure to
preeclampsia.
3.1. Offspring born at term
Fig. 1 presents a Kaplan Meier curve for the cumulative incidence of
long-term cardiovascular morbidity of the offspring in each study
groups (no maternal preeclampsia, mild preeclampsia, severe pre-
eclampsia or eclampsia) for children born at term. Children born at
term to women with severe preeclampsia or eclampsia, had a sig-
nificantly higher cumulative incidence of cardiovascular morbidity and
developed their condition at a significantly younger age than their
unexposed counterparts. (χ2 = 11.354, p value = .003).
We used a Cox regression to control for sex of the offspring, IUGR,
maternal diabetes, and obesity of the offspring. In children born at
term, severe preeclampsia was found to be an independent risk factor
for long-term cardiovascular disease of the offspring (adjusted
OR = 2.32; 95% CI 1.15–4.67), and mild preeclampsia was found to be
an insignificant factor (adjusted OR = 1.30; 95% CI 0.86–1.98
(Table 3). We also used a GEE multivariable logistic regression model to
control for sex of the offspring, IUGR, maternal diabetes and obesity of
the offspring. Similarly, in children born at term, severe preeclampsia
was found to be an independent risk factor for long-term cardiovascular
disease of the offspring (adjusted OR = 2.41; 95% CI 1.16–5.01), and
mild preeclampsia was found to be an insignificant factor (adjusted
OR = 1.39; 95% CI 0.92–2.12 (Table 3)).
3.2. Offspring born preterm
Fig. 2 presents a Kaplan Meier curve for the cumulative incidence of
long-term cardiovascular morbidity off the offspring in each study
Pregnancy Hypertension 13 (2018) 181–186
Mild Preeclampsia (n = 7286) Severe Preeclampsia (n = 2174) Eclampsia (n = 73) P valuea
No. (%) of Cohort
3 (0.04) 1 (0.05) 0 (0.0) .256
8 (0.11) 3 (0.14) 1 (1.37) < .001
1 (0.01) 1 (0.05) 0 (0.0) .648
13 (0.18) 4 (0.18) 1 (1.37) .016
2 (0.03) 4 (0.18) 0 (0.0) .004
24 (0.33) 11 (0.51) 2 (2.73) < .001
groups (no maternal preeclampsia, mild preeclampsia, severe pre-
eclampsia/eclampsia) for children born preterm. There was no sig-
nificant difference in neither the cumulative incidence of cardiovas-
cular morbidity, nor the time to cardiovascular morbidity, between the
study groups. (χ2 = 1.486, p value = .476).
After controlling for sex of the offspring, IUGR, maternal diabetes,
obesity of the offspring, and time-to-event using a Cox regression, in
utero exposure to preeclampsia was found to be an insignificant factor
in the development of long-term cardiovascular disease of the offspring
(Mild preeclampsia; adjusted OR = 0.37; 95% CI 0.52–2.71, Severe
preeclampsia; adjusted OR = 1.36; 95% CI 0.53–3.48) (Table 4). Si-
milar results were found when we used a GEE multivariable logistic
regression model to control for the same confounders together with
maternal clusters (Mild preeclampsia; adjusted OR = 0.37; 95% CI
0.49–2.76, Severe preeclampsia; adjusted OR = 1.40; 95% CI
0.55–3.55) (Table 4).
4. Discussion
The major finding of the current study is that in utero exposure to
severe preeclampsia, which does not result in preterm labor, is an in-
dependent risk factor for long-term cardiovascular morbidity in the
offspring. Our results add to the data from previous studies and are
unique in that they characterize close to a quarter of a million children
with a long follow up period. The analysis which was performed se-
parately for preeclampsia resulting and not resulting in a preterm de-
livery, sheds a new light on the current understanding of the fetal
origins of disease.
The “Fetal Origins Hypothesis”, also known as “Barker’s
Hypothesis” states that fetal undernutrition in middle to late gestation,
which leads to disproportionate fetal growth, leads eventually to car-
diovascular morbidity as well [26,27]. The association between the
compromised fetal environment and long-term ailment, may be ex-
plained by a process known as “programming”, in which variations in
the supply of nutrients to the baby, permanently alters gene expression.
Therefore, when applying Barker’s Hypothesis to preeclampsia, the
compromised fetal environment is a critical factor that can substantially
affect the long-term health of the offspring.
Previous studies on preeclampsia and offspring health found a
higher incidence of morbidity primarily in the subgroup of severe early
onset preeclampsia (before 34 weeks gestation [28,29]), while our
study found a higher incidence of morbidity only in the subgroup of
severe preeclampsia which did not result in preterm labour. The sub-
group of severe preeclampsia at term consists of late onset severe pre-
eclampsia, or mild early onset preeclampsia that deteriorated to severe
preeclampsia at term, resulting in a substantially long duration of fetal
compromise.
There are two dichotomous theories regarding the potential bio-
chemical mechanisms underlying the association between preeclampsia
and long-term offspring morbidity. One theory explains that adaptive
responses to the preeclampsia intrauterine environment may result in
epigenetic changes that affect disease susceptibility later in life [30].
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K. Nahum Sacks et al. Pregnancy Hypertension 13 (2018) 181–186

Fig. 1. Kaplan Meier curve of cumulative incidence of cardiovascular hospitalizations in the term offspring exposed to varying degrees of preeclampsia.

Table 3
Multivariable analysis of cardiovascular hospitalizations in the offspring exposed in utero to preeclampsia and born at term.
Variable Model 1-Cox Regression Model 2-GEEa

HR 95% CI P value OR 95% CI P valuea

No preeclampsia ref ref

Mild preeclampsia 1.30 0.86–1.98 .217 1.39 0.92–2.12 .117
Severe preeclampsia or Eclampsia 2.32 1.15–4.67 .019 2.41 1.16–5.01 .018
Sex of the offspring 1.29 1.08–1.53 .005 1.28 1.07–1.53 .006
IUGRb 1.68 0.94–2.98 .078 1.70 0.95–3.04 .071
Maternal diabetes mellitus 1.26 0.91–1.73 .163 1.37 0.99–1.91 .057
Obesity of the offspring 29.15 21.25–39.98 < 0.001 47.92 34.26–67.04 < 0.001

a
Data evaluated by a Cox proportional hazard model and a multivariate generalized estimating equation logistic regression model analysis.
b
Abbreviations: IUGR, Intrauterine growth restriction. GEE, generalized estimating equation.

For example, the lungs and the kidney are at the lower end of the fetal
developmental hierarchy, and these do not function in utero and their
development may be “traded off” to protect higher priority systems,
leaving organs, such as the kidneys with less functional capacity
[31,32]. Another acceptable theory is that genetic and environmental
factors that predispose both the mother and the fetus to both preg-
nancy-related disorders and disorders later in life are inherited by the
offspring [10]. This theory is strengthened by the notion that the pa-
thophysiology of preeclampsia begins well before 20 weeks [33], and
recently imbalances in angiogenic biomarkers have been detected as
early as 10 weeks in women who later developed preeclampsia [34].
Today it is known that children exposed in utero to preeclampsia
have a higher risk of hypertension [16,17,29,35–37]. The most recent
of them, a prospective cohort study of 2862 pregnancies in Australia,
found that preeclampsia resulting in preterm birth was associated with
a three-fold greater risk of being hypertensive by age 20 years, with no
difference in body-mass index [37]. Our study found a similar asso-
ciation between severe preeclampsia and hypertension of the offspring,
but in contrast to the previous finding, our association was only sig-
nificant in the sub group of preeclampsia which did not result in pre-
term labour.
In our study, in utero exposure to preeclampsia was also found
significantly associated to both arrhythmia and heart failure in the
offspring. To the best of our knowledge, no previous epidemiological
study has addressed these morbidities, although animal models have
found myocardial remodeling and left ventricular hypertrophy in rats
exposed to a preeclamptic in utero environment [38–40]. Cardiomyo-
pathy and pulmonary heart disease, which were also investigated in the
current study, were not associated with prenatal exposure to pre-
eclampsia.
The strength of this study lies in the fact that our hospital is the sole
hospital of the Negev, serving the entire population of southern Israel.
The hospital provides both maternity services and pediatric services;
thus, as long as the mother and child live in this area, they would use
this hospital. Diseases diagnosed and treated in a community setting
alone without requiring hospitalization were not covered in this study,
but it is common practice that physicians add any chronic condition
that had previously been diagnosed in the community to the medical
chart. While better estimates of these morbidities could be found in
community clinics specializing in each condition, the regional hospi-
talization database is still the most appropriate database for achieving a
comprehensive follow up of a variety of conditions in a large non-se-
lective study group.
The importance of our findings is in the crucial role of hypertension

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K. Nahum Sacks et al. Pregnancy Hypertension 13 (2018) 181–186

Fig. 2. Kaplan Meier curve of cumulative incidence of cardiovascular hospitalizations in the preterm offspring exposed to varying degrees of preeclampsia.

Table 4
Multivariable analysis of cardiovascular hospitalizations in the offspring exposed in utero to preeclampsia and born preterm.
Variable Model 1-Cox Regression Model 2-GEEa,b

HR 95% CI P value OR 95% CI P valuea

No preeclampsia ref ref

Mild preeclampsia 0.37 0.05–2.71 .330 0.37 0.05–2.76 .330
Severe preeclampsia or Eclampsia 1.36 0.53–3.48 .517 1.40 0.55–3.55 .477
Sex of the offspring 1.73 0.98–3.04 .058 1.73 0.98–3.04 .058
IUGRb 1.27 0.57–3.02 .582 1.29 0.55–3.04 .552
Maternal diabetes mellitus 0.78 0.27–2.19 .626 0.78 0.29–2.06 .621
Obesity of the offspring 34.29 12.27–95.85 < 0.001 47.92 15.28–134.04 < 0.001

a
Data evaluated by a Cox proportional hazard model and a multivariate generalized estimating equation logistic regression model analysis.
b
Abbreviations: IUGR, Intrauterine growth restriction. GEE, generalized estimating equation.

as a predictor of cardiovascular disease (CVD) in the pediatric popu-
lation [41]. CVD is the leading cause of death in the world today [42],
and it has already been found that preeclampsia is a risk factor for
future maternal CVD [43]. Now that the American Heart Association's
(AHA) guidelines recognizes preeclampsia as a risk factor for CVD in
the mother [44], our study suggests the need for further investigation of
preeclampsia as a cardiovascular risk factor in the offspring as well.
In conclusion, in this large population-based study, exposure to
severe maternal preeclampsia was found to be an independent risk
factor for long-term cardiovascular morbidity in the offspring born at
term. Surveillance strategies for offspring delivered following severe
preeclampsia should be considered, and further studies are needed in
order to determine the optimal time for delivery of mild preeclampsia.
Conflict of interest statement
The authors report no conflict of interests.
Funding/support
This study was conducted in Soroka University Medical Center and
Ben Gurion University using internal research support available to
researchers of these institutions. Kira Nahum Sacks wrote the first draft
of this manuscript, and no honorarium, grant, or other form of payment
was given to anyone to produce the manuscript.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the
online version, at https://doi.org/10.1016/j.preghy.2018.06.013.
References
[1] E.A.P. Steegers, P. von Dadelszen, J.J. Duvekot, R. Pijnenborg, Pre-eclampsia,
Lancet 376 (2010) 631–644, http://dx.doi.org/10.1016/S0140-6736(10)60279-6.
[2] C.V. Ananth, K.M. Keyes, R.J. Wapner, Pre-eclampsia rates in the United States,
1980-2010: age-period-cohort analysis, BMJ 347 (2013) f6564, http://dx.doi.org/
10.1136/bmj.f6564.
[3] N. Auger, Z.C. Luo, A.M. Nuyt, J.S. Kaufman, A.I. Naimi, R.W. Platt, W.D. Fraser,
Secular trends in preeclampsia incidence and outcomes in a large Canada database:
a longitudinal study over 24 years, Can. J. Cardiol. (2015), http://dx.doi.org/10.
1016/j.cjca.2015.12.011.
[4] B.M. Sibai, S. Caritis, J. Hauth, What we have learned about preeclampsia, Semin.
Perinatol. 27 (2003) 239–246, http://dx.doi.org/10.1016/S0146-0005(03)
00022-3.
[5] J.M. Roberts, H.S. Gammill, Preeclampsia: recent insights, Hypertension 46 (2005)
1243–1249, http://dx.doi.org/10.1161/01.HYP.0000188408.49896.c5.

185
K. Nahum Sacks et al.
[6] J.A. Hutcheon, S. Lisonkova, K.S. Joseph, Epidemiology of pre-eclampsia and the
other hypertensive disorders of pregnancy, Best Pract. Res. Clin. Obstet. Gynaecol.
25 (2011) 391–403, http://dx.doi.org/10.1016/j.bpobgyn.2011.01.006.
[7] R.A. Ødegård, L.J. Vatten, S.T. Nilsen, K.Å. Salvesen, R. Austgulen, Preeclampsia
and fetal growth, Obstet. Gynecol. 96 (2000) 950–955, http://dx.doi.org/10.1016/
S0029-7844(00)01040-1.
[8] Q.E. Harmon, L. Huang, D.M. Umbach, K. Klungsøyr, S.M. Engel, P. Magnus,
R. Skjærven, J. Zhang, A.J. Wilcox, Risk of fetal death with preeclampsia, Obstet.
Gynecol. 125 (2015) 628–635, http://dx.doi.org/10.1097/AOG.
0000000000000696.
[9] S. Lisonkova, K.S. Joseph, Incidence of preeclampsia: risk factors and outcomes
associated with early-versus late-onset disease, Am. J. Obstet. Gynecol. 209 (2013),
http://dx.doi.org/10.1016/j.ajog.2013.08.019.
[10] C.S. Wu, E.A. Nohr, B.H. Bech, M. Vestergaard, J.M. Catov, J. Olsen, Health of
children born to mothers who had preeclampsia: a population-based cohort study,
Am. J. Obstet. Gynecol. 201 (2009) 269–270, http://dx.doi.org/10.1016/j.ajog.
2009.06.060.
[11] S. Johnson, T.A. Evans, E.S. Draper, D.J. Field, B.N. Manktelow, N. Marlow,
R. Matthews, S. Petrou, S.E. Seaton, L.K. Smith, E.M. Boyle, Neurodevelopmental
outcomes following late and moderate prematurity: a population-based cohort
study, Arch. Dis. Child. Fetal Neonatal Ed. 100 (2015) F301–F308, http://dx.doi.
org/10.1136/archdischild-2014-307684.
[12] C. Sen Wu, Y. Sun, M. Vestergaard, J. Christensen, R.B. Ness, C.L. Haggerty,
J. Olsen, Preeclampsia and risk for epilepsy in offspring, Pediatrics 122 (2008)
1072–1078, http://dx.doi.org/10.1542/peds.2007-3666.
[13] N. Auger, W.D. Fraser, J. Healy-Profitós, L. Arbour, Association between pre-
eclampsia and congenital heart defects, Jama 314 (2015) 1588, http://dx.doi.org/
10.1001/jama.2015.12505.
[14] D. Fugelseth, H.B. Ramstad, A.S. Kvehaugen, E. Nestaas, A. Støylen, A.C. Staff,
Myocardial function in offspring 5–8years after pregnancy complicated by pre-
eclampsia, Early Hum. Dev. 87 (2011) 531–535, http://dx.doi.org/10.1016/j.
earlhumdev.2011.04.006.
[15] P.Y. Jayet, S.F. Rimoldi, T. Stuber, C. Salinas Salmòn, D. Hutter, E. Rexhaj,
S. Thalmann, M. Schwab, P. Turini, C. Sartori-Cucchia, P. Nicod, M. Villena,
Y. Allemann, U. Scherrer, C. Sartori, Pulmonary and systemic vascular dysfunction
in young offspring of mothers with preeclampsia, Circulation 122 (2010) 488–494,
http://dx.doi.org/10.1161/CIRCULATIONAHA.110.941203.
[16] E.F. Davis, M. Lazdam, A.J. Lewandowski, S.A. Worton, B. Kelly, Y. Kenworthy,
S. Adwani, A.R. Wilkinson, K. McCormick, I. Sargent, C. Redman, P. Leeson,
Cardiovascular risk factors in children and young adults born to preeclamptic
pregnancies: a systematic review, Pediatrics 129 (2012) e1552–e1561, http://dx.
doi.org/10.1542/peds.2011-3093.
[17] L.J. Vatten, P.R. Romundstad, T.L. Holmen, C.C. Hsieh, D. Trichopoulos,
S.O. Stuver, Intrauterine exposure to preeclampsia and adolescent blood pressure,
body size, and age at menarche in female offspring, Obstet. Gynecol. 101 (2003)
529–533, http://dx.doi.org/10.1016/S0029-7844(02)02718-7.
[18] W.G.O.A.B.P. Monitoring, National High Blood Pressure Education Program
Working Group report on ambulatory blood pressure monitoring., Arch. Intern.
Med. 150 (1990) 2270–2280.
[19] N. Heart, Report of the national high blood pressure education program working
group on high blood pressure in pregnancy, Am. J. Obstet. Gynecol. 183 (2000)
S1–S22, http://dx.doi.org/10.1067/mob.2000.107928.
[20] U. Simeoni, D.J. Barker, Offspring of diabetic pregnancy: long-term outcomes,
Semin. Fetal Neonatal Med. 14 (2009) 119–124, http://dx.doi.org/10.1016/j.siny.
2009.01.002.
[21] E. Sheiner, T. Wainstock, D. Landau, A. Walfisch, The association between sex and
long-term pediatric cardiovascular morbidity, J. Pediatr. (2016) 1–7, http://dx.doi.
org/10.1016/j.jpeds.2016.09.014.
[22] J.S. Forsyth, J. Reilly, C.G. Fraser, A.D. Struthers, Angiotensin converting enzyme
activity in infancy is related to birth weight, Arch. Dis. Child Fetal Neonatal Ed. 89
(2004) F442–F444 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=
Retrieve&db=PubMed&dopt=Citation&list_uids=15321967.
[23] A.J. Lewandowski, W.M. Bradlow, D. Augustine, E.F. Davis, J. Francis, A. Singhal,
A. Lucas, S. Neubauer, K. McCormick, P. Leeson, Right ventricular systolic dys-
function in young adults born preterm, Circulation 128 (2013) 713–720, http://dx.
doi.org/10.1161/CIRCULATIONAHA.113.002583.
[24] C.F. Rueda-Clausen, J.S. Morton, G.D. Lopaschuk, S.T. Davidge, Long-term effects of
intrauterine growth restriction on cardiac metabolism and susceptibility to
ischaemia/reperfusion, Cardiovasc. Res. 90 (2011) 285–294, http://dx.doi.org/10.
1093/cvr/cvq363.
186
Pregnancy Hypertension 13 (2018) 181–186
[25] N.M.A. van Emmerik, C.M. Renders, M. van de Veer, S. van Buuren, O.H. van der
Baan-Slootweg, J.E. Kist-van Holthe, R.A. Hirasing, High cardiovascular risk in
severely obese young children and adolescents, Arch. Dis. Child. 97 (2012)
818–821, http://dx.doi.org/10.1136/archdischild-2012-301877.
[26] D. Barker, The fetal and infant origins of adult disease, BMJ Br. Med. J. 301 (1990)
1111, http://dx.doi.org/10.1136/bmj.301.6761.1111.
[27] D.J. Barker, Fetal origins of coronary heart disease, Bmj 311 (1995) 171–174,
http://dx.doi.org/10.1136/bmj.311.6998.171.
[28] D. Raymond, E. Peterson, A critical review of early-onset and late-onset pre-
eclampsia, Obstet. Gynecol. Surv. 66 (2011) 497–506, http://dx.doi.org/10.1097/
OGX.0b013e3182331028.
[29] M. Lazdam, A. De La Horra, J. Diesch, Y. Kenworthy, E. Davis, A.J. Lewandowski,
C. Szmigielski, A. Shore, L. MacKillop, R. Kharbanda, N. Alp, C. Redman, B. Kelly,
P. Leeson, Unique blood pressure characteristics in mother and offspring after early
onset preeclampsia, Hypertension 60 (2012) 1338–1345, http://dx.doi.org/10.
1161/HYPERTENSIONAHA.112.198366.
[30] P.D. Gluckman, M.A. Hanson, C. Cooper, K.L. Thornburg, Effect of in utero and
early-life conditions on adult health and disease, N. Engl. J. Med. 359 (2014) 61–73,
http://dx.doi.org/10.1056/NEJMra0708473.Effect.
[31] D.J.P. Barker, K.L. Thornburg, The obstetric origins of health for a lifetime, Clin.
Obstet. Gynecol. 56 (2013) 511–519, http://dx.doi.org/10.1097/GRF.
0b013e31829cb9ca.
[32] B.M. Brenner, G.M. Chertow, Congenital oligonephropathy and the etiology of adult
hypertension and progressive renal injury, Am. J. Kidney Dis. 23 (1994) 171–175,
http://dx.doi.org/10.1016/S0272-6386(12)80967-X.
[33] J.M. Roberts, M.J. Bell, If we know so much about preeclampsia, why haven’t we
cured the disease? J. Reprod. Immunol. 99 (2013) 1–9, http://dx.doi.org/10.1016/
j.jri.2013.05.003.
[34] M. Noori, A.E. Donald, A. Angelakopoulou, A.D. Hingorani, D.J. Williams,
Prospective study of placental angiogenic factors and maternal vascular function
before and after preeclampsia and gestational hypertension, Circulation 122 (2010)
478–487, http://dx.doi.org/10.1161/CIRCULATIONAHA.109.895458.
[35] H. Palti, E. Rothschild, Blood pressure and growth at 6 years of age among off-
springs of mothers with hypertension of pregnancy, Early Hum. Dev. 19 (1989)
263–269 http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=med3
&NEWS=N&AN=2806155.
[36] S. Tenhola, E. Rahiala, Blood pressure, serum lipids, fasting insulin, and adrenal
hormones in 12-year-old children born with maternal preeclampsia, J. .... 88 (2003)
1217–1222. doi: 10.1210/jc.2002-020903.
[37] E.F. Davis, A.J. Lewandowski, C. Aye, W. Williamson, H. Boardman, R.-C. Huang,
T.A. Mori, J. Newnham, L.J. Beilin, P. Leeson, Clinical cardiovascular risk during
young adulthood in offspring of hypertensive pregnancies: insights from a 20-year
prospective follow-up birth cohort, BMJ Open 5 (2015) e008136–e008136. doi:
10.1136/bmjopen-2015-008136.
[38] Y. Wei, W. Du, X. Xiong, X. He, P. Yi, Y. Deng, D. Chen, Prenatal exposure to li-
popolysaccharide results in myocardial remodelling in adult murine offspring, J.
Inflamm. 10 (35) (2013) 1–10, http://dx.doi.org/10.1186/1476-9255-10-35.
[39] X. Chen, Y. Tang, M. Gao, S. Qin, J. Zhou, X. Li, Prenatal exposure to lipopoly-
saccharide results in myocardial fibrosis in rat offspring, Int. J. Mol. Sci. 16 (2015)
10986–10996, http://dx.doi.org/10.3390/ijms160510986.
[40] Z. Jin, W. Zhang, H. Yang, X. Wang, Y. Zheng, Q. Zhang, J. Zhi, Maternal treatment
with agonistic autoantibodies against type-1 angiotensin II receptor in late preg-
nancy increases apoptosis of myocardial cells and myocardial susceptibility to
ischemia-reperfusion injury in offspring rats, PLoS One 8 (2013) 1–8, http://dx.doi.
org/10.1371/journal.pone.0080709.
[41] R. Weiss, A.A. Bremer, R.H. Lustig, What is metabolic syndrome, and why are
children getting it? Ann. N. Y. Acad. Sci. 1281 (2013) 123–140, http://dx.doi.org/
10.1111/nyas.12030.
[42] WHO, The top 10 causes of death, World Heal. Organ. (2017) http://www.who.int/
mediacentre/factsheets/fs310/en. doi:/entity/mediacentre/factsheets/fs310/en/
index.html.
[43] R. Kessous, I. Shoham-Vardi, G. Pariente, R. Sergienko, E. Sheiner, Long-term ma-
ternal atherosclerotic morbidity in women with pre-eclampsia, Heart 101 (2015)
442–446, http://dx.doi.org/10.1136/heartjnl-2014-306571.
[44] C. Bushnell, L.D. McCullough, I.A. Awad, M.V. Chireau, W.N. Fedder, K.L. Furie,
V.J. Howard, J.H. Lichtman, L.D. Lisabeth, I.L. Piña, M.J. Reeves, K.M. Rexrode,
G. Saposnik, V. Singh, A. Towfighi, V. Vaccarino, M.R. Walters, Guidelines for the
prevention of stroke in women: a statement for healthcare professionals from the
American heart association/American stroke association, Stroke 45 (2014)
1545–1588, http://dx.doi.org/10.1161/01.str.0000442009.06663.48.