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Obstetrics

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Health of children born to mothers who had preeclampsia: a population-based cohort study
Chun S. Wu, MD; Ellen A. Nohr, PhD; Bodil H. Bech, PhD; Mogens Vestergaard, PhD; Janet M. Catov, PhD; Jrn Olsen, PhD
OBJECTIVE: We assessed whether preeclampsia correlates with the

long-term postnatal health of the offspring. STUDY DESIGN: We conducted a population-based cohort study of 1,618,481 singletons born in Denmark (1978-2004) with up to 27 years of follow-up. We used Cox regression to estimate the associations between preeclampsia and long-term health outcomes of the offspring. RESULTS: Children born at term exposed to preeclampsia had an increased risk of a variety of diseases, such as endocrine, nutritional, and metabolic diseases (incidence rate ratio, 1.6; 95% condence in-

terval, 1.51.7), and diseases of the blood and blood-forming organs (incidence rate ratio, 1.5; 95% condence interval, 1.31.8). Children born preterm exposed to preeclampsia had a similar pattern of hospitalizations compared with the children born preterm unexposed to preeclampsia, although they had a decreased risk of cerebral palsy (incidence rate ratio, 0.7; 95% condence interval, 0.6 0.9). CONCLUSION: Preeclampsia was associated with an increased risk of being hospitalized for a number of diseases, especially in the children born at term.

Cite this article as: Wu CS, Nohr EA, Bech BH, et al. Health of children born to mothers who had preeclampsia: a population-based cohort study. Am J Obstet Gynecol 2009;201:269.e1-10.

B ACKGROUND AND O BJECTIVE

Preeclampsia is a disease characterized by pregnancy-induced hypertension and proteinuria that affects 2-8% of pregnancies. The vast majority of children prenatally exposed to preeclampsia survives in countries with good antenatal health services but may have increased susceptibility for diseases later in life beyond that mediated by their preterm birth. Preeclampsia therefore provides an opportunity to study some developmental origins of human diseases. We conducted a population-based cohort study to explore long-term outcomes of the offspring prenatally exposed to preeclampsia.

M ATERIALS AND M ETHODS

We identied all singletons born in Denmark from Jan. 1, 1978, through Dec. 31, 2004 (N 1,618,481), from the Danish Civil Registration System. Information on maternal preeclampsia and eclampsia and on hospitalizations among the offspring was obtained from the Danish National Hospital Register. Information on gestational age, maternal age at birth, parity, and birthweight was obtained from the Danish Medical Birth Registry. We coded children as small for gestational age (SGA) if the birthweight was in the lowest 10th percentile of the gestational week- and sex-specic distribution of birthweight for the study period. After exclusions, 1,545,443 children were in the nal study population.

From the Departments of Epidemiology (Drs Wu, Nohr, Bech, and Olsen) and General Practice (Dr Vestergaard), School of Public Health, University of Aarhus, Aarhus, Denmark; the Department of Obstetrics, Gynecology, and Reproductive Sciences, School of Medicine, University of Pittsburgh, Pittsburgh, PA (Dr Catov); and the Department of Epidemiology, School of Public Health, University of California at Los Angeles, Los Angeles, CA (Dr Olsen).
Chun S. Wu was supported by Grants from the Danish Cancer Society (Grant number DP04127) and National Institutes of Health (Grant number 5R01AI071386-6). 0002-9378/free 2009 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2009.06.060

talizations in every 1-year age band for children prenatally exposed to preeclampsia or eclampsia compared to unexposed children. The rates of hospitalization due to specic diseases were based on follow-up from the day of birth until the day of rst hospitalization for that condition, death, emigration, or Dec. 31, 2004, whichever came rst. We used Cox proportional hazard models to estimate incidence rate ratios for disease-specic hospitalizations for children prenatally exposed to preeclampsia or eclampsia compared to unexposed children. Finally, we restricted the analyses to non-SGA children who were born at 37 gestational weeks.

R ESULTS
We followed 1,545,443 singletons for up to 27 years, including 45,660 (3.0%) children who were prenatally exposed to preeclampsia and 724 (0.05%) exposed to eclampsia. The risk of being hospitalized for children born at term exposed to preeclampsia was higher than that for unexposed children. The Figure shows the average number of hospitalizations per child according to age for children born at term exposed or unexposed to preeclampsia. The pattern of hospitalizations in those born preterm exposed to preeclampsia was, however, similar to 269

For Editors Commentary, see Table of Contents

Statistical analyses First we divided the total number of hospitalizations by the number of children in every 1-year age band to determine the average number of hospitalizations per child. We then used Cox regression models with multiple failures to estimate crude incidence rate ratios of all hospi-

SEPTEMBER 2009 American Journal of Obstetrics & Gynecology

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other possibility is that heritable genetic factors that predispose to pregnancy-related disorders and disorders later in life are inherited by the offspring. For children born preterm, we found rather similar patterns of hospitalizations regardless of preeclampsia exposure status. These ndings may indicate that other causes of preterm birth may have adverse effects on the fetus that are similar to or worse than those of preeclampsia. Alternatively, the intrauterine environment related to preeclampsia may need longer gestational exposure time to have an adverse effect. If so, it offers an argument for early delivery of preeclamptic pregnancies. Preeclampsia in our data was associated with an increased prevalence of congenital malformations of genital organs, especially among boys. This nding is in accordance with several studies, but not all. We doubt that preeclampsia is causally associated with congenital malformations because preeclampsia is usually not manifested at the time of organogenesis, although it is possible that preeclampsia and some congenital malformations share genetic or environmental factors. In conclusion, preeclampsia was associated with an increased risk of being hospitalized for a number of diseases among offspring, especially in children born at term. The excess disease risks were not mediated by growth restriction or preterm birth and may suggest a fetal programming effect or that these diseases share common causes.

Average number of hospitalizations per child born at term

Average number of hospitalizations per child .1 .05 .15 Preeclampsia Nonpreeclampsia

0 0

10

15 Age (years)

20

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Wu. Health of children born to mothers who had preeclampsia: a population-based cohort study. Am J Obstet Gynecol 2009.

that for children born preterm and unexposed to preeclampsia. Preeclampsia was associated with an increased risk of hospitalization for a number of diseases among non-SGA children born at term, including infectious and parasitic diseases; diseases of the blood and blood-forming organs; endocrine, nutritional, and metabolic diseases; diseases of the respiratory system; and congenital malformations. Risk for cerebral palsy was increased in children born at term prenatally exposed to eclampsia. For children born preterm, the risks of being hospitalized for a majority of the diseases examined were similar among those exposed and unexposed to preeclampsia. Notably, risk for anemia, cerebral palsy, and pneumonia was decreased in children born preterm who were exposed to preeclampsia.

C OMMENT
Overall, children born at term who were exposed to preeclampsia were more of-

ten hospitalized throughout most of their childhood and young adulthood. In contrast, children born preterm had similar total hospitalization rates regardless of their preeclampsia exposure status. Preeclampsia was also associated with an increased risk of being hospitalized for a number of specic diseases, especially in children born at term. Children prenatally exposed to preeclampsia are at risk for being SGA, which itself is associated with an increased risk of contracting several diseases in adult life. Our ndings, however, do not suggest that the association between preeclampsia and adverse longterm outcomes in the offspring is mediated by SGA. Potential biologic mechanisms underlying the association between preeclampsia and long-term postnatal offspring health remain unknown, but adaptive responses to the preeclamptic intrauterine environment may result in epigenetic changes that affect disease susceptibility later in life. An-

CLINICAL IMPLICATIONS

Children born at term exposed to preeclampsia had an increased risk of being hospitalized. Children born preterm exposed to preeclampsia had a similar risk of being hospitalized later in life compared with unexposed children born preterm. f

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