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O B S T E T R I C S

Health of children born to mothers who had preeclampsia:

a population-based cohort studyChun 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 thelong-term postnatal health of the offspring.

STUDY DESIGN: We conducted a population-based cohort study of1,618,481 singletons born in Denmark (1978-2004) with up to 27years of follow-up. We used Cox regression to estimate the associa-tions between preeclampsia and long-term health outcomes of theoffspring.

RESULTS: Children born at term exposed to preeclampsia had anincreased risk of a variety of diseases, such as endocrine, nutri-

tional, and metabolic diseases (incidence rate ratio, 1.6; 95% con-fidence interval, 1.51.7), and diseases of the blood and blood-

forming organs (incidence rate ratio, 1.5; 95% confidence interval,1.31.8). Children born preterm exposed to preeclampsia had asimilar pattern of hospitalizations compared with the children bornpreterm unexposed to preeclampsia, although they had a decreasedrisk of cerebral palsy (incidence rate ratio, 0.7; 95% confidenceinterval, 0.60.9).

CONCLUSION: Preeclampsia was associated with an increased risk ofbeing hospitalized for a number of diseases, especially in the childrenborn at term.

Key words: cohort study, eclampsia, hospitalization, preeclampsia,pregnancy

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.

Preeclampsia is a disease character-ized by pregnancy-induced hyper-tension and proteinuria that affects

2-8% of pregnancies.1 It is a multisystem

disorder associated with increased sys-

temic vascular resistance, enhanced

platelet aggregation, activation of the co-

agulation system, and endothelial-cell

dysfunction.2 Preeclampsia has a sub-stantial impact on the intrauterine envi-

ronment and is a leading cause of mater-

nal and fetal mortality and morbidity.3,4

The rate of preterm delivery is substan-

tially increasedin preeclamptic pregnan-

cies,5 and preeclampsia is also associated

with low birthweight, especially among

preterm babies.6,7 The vast majority of

children prenatally exposed to pre-

eclampsia survives in countries with

good antenatal health services but they

may have an increased susceptibility for

diseases later in life beyond that medi-

ated by their preterm birth.

Previous studies have mainly ad-

dressed short-term outcomes8-11 such as

encephalopathy,12,13 febrile seizures,14

and cerebral palsy.9 Studies of long-

term outcomes have reported a higher

risk of childhood hypertension,15-18 and

some19-21 but not all22,23 found that pre-

eclampsia was associated with an in-

creased risk of diabetes in the offspring.In addition, a decreased risk of breast

cancer has been reported among femaleoffspring of preeclamptic mothers,which may be explained by low intra-uterine estrogen levels that characterizepreeclamptic pregnancies.24-30

If the observed increased risk of ad-

verse outcomes in the offspring prena-tally exposed to preeclampsia is medi-ated not only by preterm birth or lowbirthweight, but also reflects fetal pro-gramming related to preeclampsia, wewill expect an increasedrisk of long-termoutcomes in children born at term whoare otherwise comparable to other chil-dren born at term. Preeclampsia, there-fore, provides an opportunity to studysome developmental origins of humandiseases.

We conducted a population-based co-hort study to explore long-term out-comes of offspring prenatally exposed topreeclampsia. We expected that thesechildren and young adults would havehigh disease susceptibility independentof their gestational age at birth.

MATERIALS AND METHODS

We identified all singletons born in Den-mark between Jan. 1, 1978, and Dec. 31,

2004 (N

1,618,481) from the DanishCivil Registration System.31 All persons

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

theDepartment of Epidemiology, School of

Public Health, University of California at Los

Angeles, Los Angeles, CA (Dr Olsen).

Received Nov. 9, 2008; revised April 12, 2009;

accepted June 24, 2009.

Reprints: Chun S. Wu, MD, Department of

Epidemiology, School of Public Health,

University of Aarhus, Aarhus 8000C, Denmark.

[email protected].

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

For Editors Commentary,

see Table of Contents

Research www.AJOG.org

SEPTEMBER 2009 American Journal of Obstetrics &Gynecology 269.e1
mailto:[email protected]:[email protected]:[email protected]

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born in Denmark are assigned a uniquepersonal identification number that en-ables accurate linkage of all individualsin population registries and permitslong-term follow-up.31

Information on maternal preeclamp-

sia, maternal eclampsia, and hospitaliza-tions among the offspring was obtainedfrom the Danish National Hospital Reg-ister31 that holds nationwide data on alladmissions to any Danish hospital since1977 and on all outpatient visits since1995. The diagnostic information wasbased on the Danish version of Interna-tional Classification of Diseases, Eighth

Revision (ICD-8) from 1977 through1993, and the International Classificationof Diseases, 10th Revision (ICD-10) from

1994 onward.

32

Preeclampsia was categorized as mild(ICD-8: 637.03; ICD-10: O14.0), severe(ICD-8: 637.04; ICD-10: O14.1), orunspecified (ICD-8: 637.09; ICD-10:O149), and eclampsia cases were alsoidentified (ICD-8: 637.1; ICD-10: O15).If a mother had 1 diagnosis of pre-eclampsia or eclampsia, we categorizedthe exposure of the child according tothis hierarchical order: eclampsia, severepreeclampsia, mild preeclampsia, and

unspecified preeclampsia. From the reg-ister, we identified all the hospitaliza-tions recorded for the offspring includ-ing the date of first admission to thehospital or first contact with the outpa-tient clinic, which was used as the start-ing date of disease.

Information on gestational age, ma-ternal age at birth, parity, and birth-weight was obtained from the DanishMedical Birth Registry,33 which includesall births in Denmark since 1973.33 Ges-

tational age recorded in the registry was,in the past, mainly based on the date ofthe last menstrual period, but has duringthe recent years increasingly been re-placed with estimates based on ultra-sound measurements. Information onmaternal education and cohabitation ofparents at the time of birth from 1980through 2003 was obtained from Statis-tics Denmark. We used the data from1980 to substitute the missing values onmaternal education in 1978 and 1979

and the data from 2003 to substitute datain 2004, which were not yet available. For

other missing data, we used the informa-tion from the closest year to birth ifavailable.

We coded children as small for gesta-tionalage (SGA) if thebirthweightwas inthe lowest 10th percentile of the gesta-

tional week- and sex-specific distribu-tion of birthweight for the study period.In the final analysis, we excluded chil-

dren without any information (n 29);adopted children (n 6895); childrenwith missing gestational age (n

61,291); children with a gestational age20 weeks (n 96) or45 weeks (n

22); children born to mothers with miss-ing information on parity (n 258),maternal education(n 435), or cohab-itation status of parents at birth (n

3890); and children who were born onDec. 31, 2004 (n 122). These exclu-sions left 1,545,443 children in the finalstudy population (Figure 1).

Throughout this article, we use theterm exposed to preeclampsia to meana child born to a mother who was diag-nosed with preeclampsia or eclampsia inthat pregnancy.

Statistical analyses

First we divided the total number of hos-

pitalizations by the number of childreninevery1-yearagebandtodeterminetheaverage number of hospitalizations perchild. We then used Cox regressionmodels with multiple failures to estimatecrude incidence rate ratios (IRRs) of allhospitalizations in every 1-year age bandfor children prenatally exposed to pre-eclampsia or eclampsia compared to un-exposed children.

Theratesof hospitalization due to spe-cific diseases were based on follow-up

from the day of birth until the day of firsthospitalization for that condition, death,emigration, or Dec. 31, 2004, whichevercame first. We used Cox proportionalhazard models to estimate IRRs for dis-ease-specific hospitalizations for chil-dren prenatally exposed to preeclampsiaor eclampsia compared to unexposedchildren. In the analyses, we adjusted forsex of the child, gestational age (20-27,28-32, 33-36, 37-41, 42-45 weeks), parity(1, 2,3), maternal age (20, 20, 25, 30,

35 years), maternal education at thetime of birth (elementary, middle, and

high school), cohabitation status of par-ents at birth (cohabitant, not cohabiting,and others) and calendar year (1978-1981, 1982-1985, 1986-1989, 1990-1993,1994-1997, 1998-2001, 2002-2004). Fi-nally, we restricted the analyses to non-

SGA children who were born at

37 ges-tational weeks.In additional analyses,we stratifiedthe

data according to sex (boys, girls), gesta-tional age (37 or 37 gestationalweeks), and parity (1, 2, 3). We alsoinvestigated IRRs of hospitalizations inthe first 5 years of life for children ex-posed to preeclampsia according to cal-endar year of birth by using Cox regres-sion models with multiple failures. Thestatistical analyses were done using soft-

ware (Stata 9.2; StataCorp, College Sta-tion, TX).

RESULTS

We followed 1,545,443 singletons for upto 27 years,including 46,384(3.0%) chil-dren who were prenatally exposed topreeclampsia and 724 (0.05%) exposedto eclampsia. Follow-up of15 yearswas available for 37.0% of the study pop-ulation. Table 1 shows the characteristics

of the study population according to ex-posure status. As expected, women withpreeclampsia or eclampsia were moreof-ten nulliparous and younger. Childrenprenatally exposed to preeclampsia weremore often born preterm and SGA thanchildren unexposed to preeclampsia.

The risk of being hospitalized for chil-dren born at term exposed to preeclamp-sia was higher than that for children un-exposed. The IRRs (95% confidenceinterval [CI])for beinghospitalized were

statistically significant in the first year oflife 1.51(95% CI, 1.481.54) and attheageof 1 year (IRR, 1.22; 95% CI, 1.171.28), 2years (IRR, 1.17; 95% CI, 1.10 1.23), 3years (IRR, 1.15; 95% CI, 1.08 1.22), 4years (IRR, 1.25; 95% CI, 1.16 1.35), 5years (IRR, 1.21; 95% CI, 1.121.30), 6years (IRR, 1.18; 95% CI, 1.09 1.29), 7years (IRR, 1.25; 95% CI, 1.14 1.36), 8years (IRR, 1.24; 95% CI, 1.09 1.40), 9years (IRR, 1.20; 95% CI, 1.09 1.31), 10years (IRR, 1.26; 95% CI, 1.151.39), 11

years (IRR, 1.16; 95% CI, 1.04 1.29), 12years (IRR, 1.14; 95% CI, 1.031.26), 13

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FIGURE 1

Identification of study population

Number of singletons in the final analysis

n = 1,545,443

Nopreeclampsia

n = 1,499,059

Mildpreeclampsia

n = 34,955

Severepreeclampsia

n = 7733

Unspecifiedpreeclampsia

n = 2972

Withpreeclampsia

n = 46,384

Children excluded:Without linking information (29)

Adopted (n = 6895)Gestational age,

missing (n = 61,291)

45 weeks (n = 22)Other missing information

Parity (n = 258)

Maternal education (n = 435)

Maternal marriage status (n = 3890)Children were born on Dec. 31, 2004(n = 122)

All singletons born between

Jan. 1, 1978-Dec. 31, 2004

Eclampsia

n = 724

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

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years (IRR, 1.17; 95% CI, 1.04 1.31), 16years (IRR, 1.18; 95% CI, 1.051.31), 18years (IRR, 1.11; 95% CI, 1.00 1.23), 19years (IRR, 1.13; 95% CI, 1.011.26), 20years (IRR, 1.24; 95% CI, 1.111.39), 21years (IRR, 1.18; 95% CI, 1.051.33),and 24 years (IRR, 1.20; 95% CI, 1.031.40). Figure 2 shows average number ofhospitalizations per child according to agefor children bornat term exposedor unex-

posed to preeclampsia (0.48 for exposedchildren and 0.34 for unexposed children

inthefirstyearoflife.Childrenbornpre-term exposed to preeclampsia, however,had a similar pattern of hospitalizationscompared to children born preterm un-exposed to preeclampsia (Figure 3).Children born preterm exposed to pre-eclampsia had an increased risk of beinghospitalized only in the first year of life(IRR, 1.27; 95% CI, 1.251.30). The av-erage number of hospitalizations in the

first yearof life was 1.63 for exposed chil-dren born preterm and 1.42 for unex-

posed children born preterm (not shownFigure 3).

Preeclampsia was associated with anincreased risk of hospitalization for anumber of diseases among non-SGAchildren born at term including infec-tious and parasitic diseases; diseases ofthe blood and blood-forming organ; en-docrine, nutritional, and metabolic dis-eases; diseases of the respiratory system;

and congenital malformations (Table 2).Children prenatally exposed to severe

TABLE 1

Characteristics of the study population

Characteristics

No PE or eclampsian 1,499,059

PE

Eclampsian 724

Unspecifiedn 2972

Mildn 34,955

Severen 7733

n % n % n % n % n %

Sex.......................................................................................................................................................................................................................................................................................................................................................................

Male 769,460 51.3 1526 51.4 18,309 52.4 3944 51.0 385 53.2.......................................................................................................................................................................................................................................................................................................................................................................

Female 729,599 48.7 1446 48.7 16,646 47.6 3789 49.0 339 46.8................................................................................................................................................................................................................................................................................................................................................................................

Maternal age, y.......................................................................................................................................................................................................................................................................................................................................................................

20 40,292 2.7 126 4.2 1258 3.6 281 3.6 46 6.4.......................................................................................................................................................................................................................................................................................................................................................................

20-24 305,136 20.4 743 25.0 8809 25.2 1760 22.8 184 25.4.......................................................................................................................................................................................................................................................................................................................................................................

25-29 581,718 38.8 1128 38.0 13,129 37.6 2916 37.7 236 32.6.......................................................................................................................................................................................................................................................................................................................................................................

30-34 412,146 27.5 676 22.8 7921 22.7 1840 23.8 179 24.7.......................................................................................................................................................................................................................................................................................................................................................................

35 159,767 10.7 299 10.1 3838 11.0 936 12.1 79 10.9................................................................................................................................................................................................................................................................................................................................................................................Parity

.......................................................................................................................................................................................................................................................................................................................................................................

1 677,166 45.2 1900 63.9 22,245 63.6 5364 69.4 497 68.7.......................................................................................................................................................................................................................................................................................................................................................................

2 575,410 38.4 753 25.3 9191 26.3 1640 21.2 169 23.3.......................................................................................................................................................................................................................................................................................................................................................................

3 246,483 16.4 319 10.7 3519 10.1 729 9.4 58 8.0................................................................................................................................................................................................................................................................................................................................................................................

Gestational age, wk.......................................................................................................................................................................................................................................................................................................................................................................

20-27 2571 0.2 10 0.3 31 0.1 208 2.7 18 2.5.......................................................................................................................................................................................................................................................................................................................................................................

28-32 10,006 0.7 59 2.0 348 1.0 1215 15.7 82 11.3.......................................................................................................................................................................................................................................................................................................................................................................

33-36 52,370 3.5 233 7.8 2189 6.3 2305 29.8 128 17.7.......................................................................................................................................................................................................................................................................................................................................................................

37-41 1,300,913 86.8 2458 82.7 29,870 85.5 3867 50.0 467 64.5.......................................................................................................................................................................................................................................................................................................................................................................

42-45 133,199 8.9 212 7.1 2517 7.2 138 1.8 29 4.0................................................................................................................................................................................................................................................................................................................................................................................SGAa

.......................................................................................................................................................................................................................................................................................................................................................................

No 1,353,111 90.5 2518 85.0 29,810 85.5 5761 74.9 553 76.8.......................................................................................................................................................................................................................................................................................................................................................................

Yes 142,075 9.5 446 15.1 5051 14.5 1929 25.1 167 23.19................................................................................................................................................................................................................................................................................................................................................................................

Maternal education.......................................................................................................................................................................................................................................................................................................................................................................

Elementary school 502,748 33.5 1111 37.4 13,013 37.2 2559 33.1 273 37.7.......................................................................................................................................................................................................................................................................................................................................................................

Middle school 667,814 44.6 1361 45.8 15,794 45.2 3601 46.6 330 45.6.......................................................................................................................................................................................................................................................................................................................................................................

High school 328,497 21.9 500 16.8 6148 17.6 1573 20.3 121 16.7................................................................................................................................................................................................................................................................................................................................................................................

SGA, small for gestational age; PE, preeclampsia.a Children with birthweight in lowest 10th percentile of distribution of birthweight for gestational age in wk and sex.

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preeclampsia had slightly higher IRRsthan children exposed to mild pre-eclampsia (Table 2). Children born atterm prenatally exposed to eclampsiahad an increased risk of cerebral palsy(Table 2).

For children born preterm, the risks ofbeing hospitalized due to majority of thespecific diseases were similar amongthose exposed and unexposed to pre-eclampsia. The hospitalization patternwas, however, different, for certain dis-eases such as hemorrhagic disorders; en-docrine, nutritional, and metabolic dis-eases; diseases of the digestive system;diseases of the skin and subcutaneoustissue; and congenital malformation ofthe genital organs (Table 3). Notably,

children born preterm who were ex-posed to preeclampsia had a decreasedrisk of anemia, cerebral palsy, and pneu-monia (Table 3).

Male and female offspring had similaroutcomes except that boys exposed tomild or severe preeclampsia had an in-creased prevalence of congenital malfor-mations of the genital organs. Boys bornat term exposed to severe preeclampsiahad an increased risk of diseases of theblood and blood-forming organs and

disorders of the immune system. Girlsexposed to severe preeclampsia oreclampsia had an increased risk of cere-bral palsy and of diseases of the muscu-loskeletal system and connective tissue(data not shown).

The associations between preeclamp-sia and some outcomes in the offspringvaried only slightly with parity (1,2,3),but without any consistent patterns(data not shown). IRRs of hospitaliza-tionsinthefirst5yearsoflifeforchildren

exposed to preeclampsia were similaracross calendar year of birth comparedto children unexposed (data not shown).

COMMENT

Overall, children born at term who wereexposed to preeclampsia were more of-ten hospitalized throughout most ofchildhood and young adult life. In con-trast, children born preterm had similartotal hospitalization rates regardless of

preeclampsia exposure status. Pre-eclampsia was also associated with an in-

creased risk of being hospitalized for anumber of specific diseases, especially inchildren born at term.

Children prenatally exposed to pre-eclampsia are at a risk of being SGA,6

which itself is associated with an in-creased risk of several diseases in adultlife.34,35 Our findings, however, do notsuggest that the association between pre-eclampsia and adverse long-term out-

FIGURE 2

Average number of hospitalizations per child born at term

0

.05

.1

.15

A

veragenumberofhospitalizationsper

child

0 5 10 15 20 25Age (years)

Preeclampsia

Nonpreeclampsia


FIGURE 3

Average number of hospitalizations per child born preterm

.05

.1

.15

.2

.25

Averagenumberofhospitalizationsperchild

0 5 10 15 20 25Age (years)

Preeclampsia

Nonpreeclampsia




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TABLE 2

Incidence rate ratios for disease-specific hospitalizations among children born at term (>37 weeksgestation) exposed to preeclampsia or eclampsia without being born small for gestational age

Disease-specific hospitalization

Mild PEn 34,955

Severe PEn 7733

Eclampsian 724

Total(all PE or eclampsia)

IRR

a

(95% CI) IRR

a

(95% CI) IRR

a

(95% CI) IRR

a

(95% CI)Infectious and parasitic diseases 1.2 (1.21.3)b 1.3 (1.11.5)b 1.0 (0.71.5) 1.2 (1.11.2)b................................................................................................................................................................................................................................................................................................................................................................................

Neoplasms 1.3 (1.01.6)b 1.1 (0.52.4) NA 1.3 (1.01.6)b.......................................................................................................................................................................................................................................................................................................................................................................

Malignant 1.2 (0.81.8) 1.0 (0.34.0) NA 1.2 (0.91.8).......................................................................................................................................................................................................................................................................................................................................................................

Benign 1.4 (1.01.9)b 1.2 (0.53.2) NA 1.4 (1.11.8)b................................................................................................................................................................................................................................................................................................................................................................................

Disease of blood and blood-forming organsand disorders involving immune mechanism

1.5 (1.21.8)b 2.0 (1.23.2)b 1.0 (0.17.0) 1.5 (1.31.8)b

.......................................................................................................................................................................................................................................................................................................................................................................

Anemias 1.3 (1.01.7)b 1.8 (0.93.8) NA 1.3 (1.01.6)b.......................................................................................................................................................................................................................................................................................................................................................................

Purpura 1.4 (0.92.0) 1.1 (0.34.4) NA 1.5 (1.02.1)b................................................................................................................................................................................................................................................................................................................................................................................

Endocrine, nutritional, and metabolicdiseases

1.6 (1.51.7)b 1.8 (1.42.3)b 1.2 (0.52.6) 1.6 (1.51.7)b

.......................................................................................................................................................................................................................................................................................................................................................................Diabetes mellitus 0.9 (0.81.2) 1.3 (0.72.5) NA 1.0 (0.81.2)

................................................................................................................................................................................................................................................................................................................................................................................

Mental and behavioral disorders 1.1 (1.01.2)b 1.2 (0.91.6) 0.2 (0.021.2) 1.1 (1.01.2)b................................................................................................................................................................................................................................................................................................................................................................................

Diseases of nervous system 1.2 (1.11.2)b 1.3 (1.11.6)b 1.6 (1.02.4)b 1.2 (1.11.2)b.......................................................................................................................................................................................................................................................................................................................................................................

Cerebral paralysis 1.1 (0.81.4) 1.4 (0.72.7) 3.6 (1.111.0) 1.1 (0.91.4).......................................................................................................................................................................................................................................................................................................................................................................

Epilepsy 1.2 (1.11.3)b 1.4 (1.11.9)b 1.8 (0.93.4) 1.2 (1.11.3)b................................................................................................................................................................................................................................................................................................................................................................................

Diseases of circulatory system 1.2 (1.01.4)b 0.7 (0.31.6) 1.0 (0.16.8) 1.1 (0.91.4).......................................................................................................................................................................................................................................................................................................................................................................

Heart disease 1.1 (0.81.4) 0.4 (0.11.8) NA 1.0 (0.81.3)................................................................................................................................................................................................................................................................................................................................................................................

Diseases of respiratory system 1.2 (1.11.2)b 1.1 (1.11.3)b 1.1 (0.91.5) 1.2 (1.11.2)b.......................................................................................................................................................................................................................................................................................................................................................................

Pneumonia 1.2 (1.11.3)b 1.2 (0.91.5) 1.1 (0.62.0) 1.2 (1.11.3)b.......................................................................................................................................................................................................................................................................................................................................................................

Asthma 1.2 (1.11.3)b

1.1 (0.91.3) 1.2 (0.81.8) 1.2 (1.11.2)b

................................................................................................................................................................................................................................................................................................................................................................................

Diseases of digestive system 1.2 (1.01.3)b 0.9 (0.61.3) 0.6 (0.12.3) 1.1 (1.01.3)b................................................................................................................................................................................................................................................................................................................................................................................

Diseases of skin and subcutaneous tissue 1.1 (1.01.3)b 1.2 (0.81.7) 1.3 (0.53.6) 1.1 (1.01.3)b.......................................................................................................................................................................................................................................................................................................................................................................

Dermatitis and eczema 1.1 (1.01.3)b 1.2 (0.82.0) NA 1.1 (1.01.3)b.......................................................................................................................................................................................................................................................................................................................................................................

Erythema 1.1 (0.62.2) NA NA 0.9 (0.51.9)................................................................................................................................................................................................................................................................................................................................................................................

Diseases of musculoskeletal system andconnective tissue

1.2 (1.01.4)b 1.2 (0.72.0) 2.1 (0.76.4) 1.2 (1.01.4)b

.......................................................................................................................................................................................................................................................................................................................................................................

Arthritis 1.8 (0.93.3) 2.1 (0.314.8) NA 1.7 (0.93.0)................................................................................................................................................................................................................................................................................................................................................................................

Diseases of genitourinary system 1.3 (1.11.5)b 1.4 (0.92.1) 0.9 (0.23.6) 1.3 (1.11.4)b.......................................................................................................................................................................................................................................................................................................................................................................

Nephritis 1.4 (0.82.2) 1.5 (0.45.9) NA 1.5 (1.02.3)b................................................................................................................................................................................................................................................................................................................................................................................

Congenital malformations 1.1 (1.11.2)b

1.1 (1.01.3)b

1.1 (0.81.6) 1.1 (1.11.2)b

.......................................................................................................................................................................................................................................................................................................................................................................

Nervous system 1.2 (1.01.6)b 1.0 (0.42.2) 2.5 (0.610.0) 1.3 (1.01.5)b.......................................................................................................................................................................................................................................................................................................................................................................

Circulatory system 1.3 (1.21.4)b 1.6 (1.22.2)b 1.3 (0.63.2) 1.3 (1.21.4)b.......................................................................................................................................................................................................................................................................................................................................................................

Genital organs 1.1 (1.01.2)b 1.1 (0.91.5) 0.9 (0.41.9) 1.1 (1.01.2)b................................................................................................................................................................................................................................................................................................................................................................................

CI, confidence interval; IRR, incidence rate ratio; NA, not available; PE, preeclampsia.a Adjusted for sex of child, gestational age (20-27, 28-32, 33-36, 37-41, 42-45 wk), parity (1, 2, 3), maternal age (20, 20-24, 25-29, 30-34, 35 y), maternal education (high, middle, low),

marriage status at birth of child (cohabitant, not cohabiting, others), and calendar year (1978-1981, 1982-1985, 1986-1989, 1990-1993, 1994-1997, 1998-2001, 2002-2004); b The results arestatistically significant (P .05).

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TABLE 3

Incidence rate ratios for disease-specific hospitalizations among children bornpreterm (

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comes in the offspring is mediated by

SGA. Potential biological mechanisms

underlying the association between pre-

eclampsia and long-term postnatal off-

spring health remain unknown, but

adaptive responses to the preeclamptic

intrauterine environment may result inepigenetic changes that affect disease

susceptibility later in life.36,37 Another

possibility is that heritable genetic fac-

tors that predispose to pregnancy-re-

lated disorders and disorders later in life

are inherited by the offspring.38

Preterm birthis a well known risk factor

for a variety of adverse offspring health

outcomes, but the associations that we de-

tected did not appear to be mediated by

preterm birth. For children born preterm,

we found rather similar patterns of hospi-talizations regardless of preeclampsia ex-

posure status. These findings may indicate

that other causes of preterm birth may

have similar or even worse adverse effects

on the fetus than preeclampsia. Alterna-

tively, the intrauterine environment re-

lated to preeclampsiamayneedlongerges-

tational exposure time to have an adverse

effect. If this is the case it offers an argu-

ment for early delivery of preeclamptic

pregnancies.

Our results even suggested that childrenborn preterm who were exposed to pre-

eclampsia had a decreased risk of cerebral

palsy compared to other children born

preterm, which is in line with some stud-

ies9,39 but not others.40 It should also be

kept in mind that we found that children

born at term exposed to eclampsia had an

increased riskof cerebral palsy, which may

be due to a hypoxic-ischemic brain injury

related to eclampsia.2,41

Our study did not show an increased

risk of diabetes among the children pre-

natally exposed to preeclampsia,which is

consistent with results of some stud-

ies22,23 but not all.19-21 Neither did we

find an increased risk of cardiovascular

diseases, which could be due to too short

a follow-up time and the low prevalence

of cardiovascular diseases in young

adults. We did find an increased risk of

purpura and endocrine and metabolic

diseases among children prenatally ex-

posed to preeclampsia, which may be amarker of susceptibility to inflammatory

disorders, cardiovascular diseases, or di-abetes in adult life.

Preeclampsia in our data was associ-ated with an increasedprevalence of con-genital malformations of genital organs,especially among boys. This finding is in

accordance with several studies

42-45

butnot all.46 We doubt that preeclampsia iscausally associated with congenital mal-formations because preeclampsia isusually not manifest at the time of orga-nogenesis, but it is possible that pre-eclampsia and some congenital malfor-mations may share common genetic orenvironmental factors.

The criteria for the diagnosis of mildpreeclampsiain Denmark47,48weresimilarto that used by the American College of

Obstetricians and Gynecologists (ACOG)(diastolic blood pressure90 mm Hg orsystolic blood pressure140 mm Hg andproteinuria with total loss of protein in a24-hour urinespecimen0.3g).49The di-agnostic guideline for severe preeclampsia,however, was 180 mm Hg, which is differ-entthan160mmHgasusedintheACOG;and 3-g loss of protein in a 24-hour urinespecimen was usedrather than5 g asin theACOG.In practice, however, thecriteriaofACOG are also used in Denmark to diag-

nose severe preeclampsia.

50

Informationon preeclampsia and eclampsia was ob-tained from the Danish National HospitalRegister. In a recentstudy, thepositive pre-dictivevalue of a preeclampsia diagnosis inthe register has been estimated to be 74%,andalmost 100%predictiveforsevere pre-eclampsia.51 The sensitivity of the pre-eclampsia diagnosis in the register wasabout 69%.51 Use of1 set of criteria fordiagnosing preeclampsia will probablygenerate some misclassification between

mild and severe types of the disorder, butbecause the registration of preeclampsiatook place before the outcomes understudy, any misclassification of preeclamp-sia is expected to be nondifferential. Andnondifferential misclassification will oftenattenuate relative effect estimates.52

Regrettably, we were not able to differ-entiate between early and late onset ofpreeclampsia. We also lacked data onhealth outcomes that do not lead to hos-pitalization, such as hypertension or

childhood obesity. We also had limiteddata on mental and behavior disorders

for children because conditions treated

by psychiatrists in mental hospitals were

not linked to our database.53

We used a large population-based co-

hort including all children born in Den-

mark with up to 27 years of follow-up. We

expect the number of children with severediseases treated entirely outside hospitals

to be small, because all health services, in-

cluding hospitalizations, are free of charge

in Denmark. We were able to adjust for

some potential confounders including

maternal age, parity, education, marriage

status, and calendar year but we have no

data on other factors, such as maternal

smoking status and prepregnancy body

mass index. And the observed associations

may therefore be subject to uncontrolled

confounding. Maternal smoking is associ-ated with a decreased risk of preeclamp-

sia.54-56Andanalyses without adjusting for

maternal smokingmay therefore underes-

timate associations if smoking is a risk fac-

tor for the outcomes. Preexisting maternal

obesity and being overweight is associated

an increased risk of preeclampsia.57 Anal-

yses without adjusting for maternal body

mass index maytherefore overestimateas-

sociations if obesity is a risk factor for the

outcomes.In conclusion, preeclampsia was asso-

ciated with an increased risk among off-

spring of being hospitalized for a num-

ber of diseases, 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 dis-

eases share common causes. f

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