Research

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OBSTETRICS

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% confidence 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 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% confidence
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.
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.

reeclampsia is a disease characterized by pregnancy-induced hypertension and proteinuria that affects

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

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).
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.
cw@soci.au.dk.
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

disorder associated with increased systemic vascular resistance, enhanced

platelet aggregation, activation of the coagulation system, and endothelial-cell
dysfunction.2 Preeclampsia has a substantial impact on the intrauterine environment and is a leading cause of maternal and fetal mortality and morbidity.3,4
The rate of preterm delivery is substantially increased in preeclamptic pregnancies,5 and preeclampsia is also associated
with low birthweight, especially among
preterm babies.6,7 The vast majority of
children prenatally exposed to preeclampsia survives in countries with
good antenatal health services but they
may have an increased susceptibility for
diseases later in life beyond that mediated by their preterm birth.
Previous studies have mainly addressed short-term outcomes8-11 such as
encephalopathy,12,13 febrile seizures,14
and cerebral palsy.9 Studies of longterm outcomes have reported a higher
risk of childhood hypertension,15-18 and
some19-21 but not all22,23 found that preeclampsia was associated with an increased risk of diabetes in the offspring.
In addition, a decreased risk of breast

cancer has been reported among female

offspring of preeclamptic mothers,
which may be explained by low intrauterine estrogen levels that characterize
preeclamptic pregnancies.24-30
If the observed increased risk of adverse outcomes in the offspring prenatally exposed to preeclampsia is mediated not only by preterm birth or low
birthweight, but also reflects fetal programming related to preeclampsia, we
will expect an increased risk of long-term
outcomes in children born at term who
are otherwise comparable to other children born at term. 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 offspring prenatally exposed to
preeclampsia. We expected that these
children and young adults would have
high disease susceptibility independent
of their gestational age at birth.

M ATERIALS AND M ETHODS

We identified all singletons born in Denmark between Jan. 1, 1978, and Dec. 31,
2004 (N 1,618,481) from the Danish
Civil Registration System.31 All persons

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Research

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born in Denmark are assigned a unique

personal identification number that enables accurate linkage of all individuals
in population registries and permits
long-term follow-up.31
Information on maternal preeclampsia, maternal eclampsia, and hospitalizations among the offspring was obtained
from the Danish National Hospital Register31 that holds nationwide data on all
admissions to any Danish hospital since
1977 and on all outpatient visits since
1995. The diagnostic information was
based on the Danish version of International Classification of Diseases, Eighth
Revision (ICD-8) from 1977 through
1993, and the International Classification
of 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), or
unspecified (ICD-8: 637.09; ICD-10:
O149), and eclampsia cases were also
identified (ICD-8: 637.1; ICD-10: O15).
If a mother had 1 diagnosis of preeclampsia or eclampsia, we categorized
the exposure of the child according to
this hierarchical order: eclampsia, severe
preeclampsia, mild preeclampsia, and
unspecified preeclampsia. From the register, we identified all the hospitalizations recorded for the offspring including the date of first admission to the
hospital or first contact with the outpatient clinic, which was used as the starting date of disease.
Information on gestational age, maternal age at birth, parity, and birthweight was obtained from the Danish
Medical Birth Registry,33 which includes
all births in Denmark since 1973.33 Gestational age recorded in the registry was,
in the past, mainly based on the date of
the last menstrual period, but has during
the recent years increasingly been replaced with estimates based on ultrasound measurements. Information on
maternal education and cohabitation of
parents at the time of birth from 1980
through 2003 was obtained from Statistics Denmark. We used the data from
1980 to substitute the missing values on
maternal education in 1978 and 1979
and the data from 2003 to substitute data
in 2004, which were not yet available. For
269.e2

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other missing data, we used the information from the closest year to birth if
available.
We coded children as small for gestational age (SGA) if the birthweight was in
the lowest 10th percentile of the gestational week- and sex-specific distribution of birthweight for the study period.
In the final analysis, we excluded children without any information (n 29);
adopted children (n 6895); children
with missing gestational age (n
61,291); children with a gestational age
20 weeks (n 96) or 45 weeks (n
22); children born to mothers with missing information on parity (n 258),
maternal education (n 435), or cohabitation status of parents at birth (n
3890); and children who were born on
Dec. 31, 2004 (n 122). These exclusions left 1,545,443 children in the final
study population (Figure 1).
Throughout this article, we use the
term exposed to preeclampsia to mean
a child born to a mother who was diagnosed with preeclampsia or eclampsia in
that pregnancy.

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 (IRRs) of all
hospitalizations in every 1-year age band
for children prenatally exposed to preeclampsia or eclampsia compared to unexposed children.
The rates of hospitalization due to specific diseases were based on follow-up
from the day of birth until the day of first
hospitalization for that condition, death,
emigration, or Dec. 31, 2004, whichever
came first. We used Cox proportional
hazard models to estimate IRRs for disease-specific hospitalizations for children prenatally exposed to preeclampsia
or eclampsia compared to unexposed
children. In the analyses, we adjusted for
sex 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 the
time of birth (elementary, middle, and

American Journal of Obstetrics & Gynecology SEPTEMBER 2009

high school), cohabitation status of parents at birth (cohabitant, not cohabiting,

and others) and calendar year (19781981, 1982-1985, 1986-1989, 1990-1993,
1994-1997, 1998-2001, 2002-2004). Finally, we restricted the analyses to nonSGA children who were born at 37 gestational weeks.
In additional analyses, we stratified the
data according to sex (boys, girls), gestational age (37 or 37 gestational
weeks), and parity (1, 2, 3). We also
investigated IRRs of hospitalizations in
the first 5 years of life for children exposed to preeclampsia according to calendar year of birth by using Cox regression models with multiple failures. The
statistical analyses were done using software (Stata 9.2; StataCorp, College Station, TX).

R ESULTS
We followed 1,545,443 singletons for up
to 27 years, including 46,384 (3.0%) children who were prenatally exposed to
preeclampsia and 724 (0.05%) exposed
to eclampsia. Follow-up of 15 years
was available for 37.0% of the study population. Table 1 shows the characteristics
of the study population according to exposure status. As expected, women with
preeclampsia or eclampsia were more often nulliparous and younger. Children
prenatally exposed to preeclampsia were
more often born preterm and SGA than
children unexposed to preeclampsia.
The risk of being hospitalized for children born at term exposed to preeclampsia was higher than that for children unexposed. The IRRs (95% confidence
interval [CI]) for being hospitalized were
statistically significant in the first year of
life 1.51 (95% CI, 1.48 1.54) and at the age
of 1 year (IRR, 1.22; 95% CI, 1.171.28), 2
years (IRR, 1.17; 95% CI, 1.10 1.23), 3
years (IRR, 1.15; 95% CI, 1.08 1.22), 4
years (IRR, 1.25; 95% CI, 1.16 1.35), 5
years (IRR, 1.21; 95% CI, 1.121.30), 6
years (IRR, 1.18; 95% CI, 1.09 1.29), 7
years (IRR, 1.25; 95% CI, 1.14 1.36), 8
years (IRR, 1.24; 95% CI, 1.09 1.40), 9
years (IRR, 1.20; 95% CI, 1.09 1.31), 10
years (IRR, 1.26; 95% CI, 1.151.39), 11
years (IRR, 1.16; 95% CI, 1.04 1.29), 12
years (IRR, 1.14; 95% CI, 1.031.26), 13

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Research

FIGURE 1

Identification of study population

All singletons born between

Jan. 1, 1978-Dec. 31, 2004
Children excluded:
Without linking information (29)
Adopted (n = 6895)
Gestational age,
missing (n = 61,291)
<20 weeks (n = 96)
>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)
Number of singletons in the final analysis
n = 1,545,443

No
preeclampsia
n = 1,499,059

Mild
preeclampsia
n = 34,955

With
preeclampsia
n = 46,384

Severe
preeclampsia
n = 7733

Unspecified
preeclampsia
n = 2972

Eclampsia
n = 724

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

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TABLE 1

Characteristics of the study population

PE

Characteristics

No PE or eclampsia
n 1,499,059

Unspecified
n 2972

Mild
n 34,955

Severe
n 7733
%

Eclampsia
n 724
%

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

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

677,166

45.2

1900

63.9

22,245

63.6

5364

69.4

497

68.7

575,410

38.4

753

25.3

9191

26.3

1640

21.2

169

23.3

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

.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
a

SGA

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

No

1,353,111

90.5

2518

85.0

29,810

85.5

5761

74.9

553

76.8

142,075

9.5

446

15.1

5051

14.5

1929

25.1

167

23.19

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

Yes

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

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.

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

years (IRR, 1.17; 95% CI, 1.04 1.31), 16

years (IRR, 1.18; 95% CI, 1.051.31), 18
years (IRR, 1.11; 95% CI, 1.00 1.23), 19
years (IRR, 1.13; 95% CI, 1.011.26), 20
years (IRR, 1.24; 95% CI, 1.111.39), 21
years (IRR, 1.18; 95% CI, 1.051.33),
and 24 years (IRR, 1.20; 95% CI, 1.03
1.40). Figure 2 shows average number of
hospitalizations per child according to age
for children born at term exposed or unexposed to preeclampsia (0.48 for exposed
children and 0.34 for unexposed children
269.e4

in the first year of life. Children born preterm exposed to preeclampsia, however,
had a similar pattern of hospitalizations
compared to children born preterm unexposed to preeclampsia (Figure 3).
Children born preterm exposed to preeclampsia had an increased risk of being
hospitalized only in the first year of life
(IRR, 1.27; 95% CI, 1.251.30). The average number of hospitalizations in the
first year of life was 1.63 for exposed children born preterm and 1.42 for unex-

American Journal of Obstetrics & Gynecology SEPTEMBER 2009

posed children born preterm (not shown

Figure 3).
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 organ; endocrine, nutritional, and metabolic diseases; diseases of the respiratory system;
and congenital malformations (Table 2).
Children prenatally exposed to severe

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C OMMENT
Overall, children born at term who were
exposed to preeclampsia were more often hospitalized throughout most of
childhood and young adult life. In contrast, children born preterm had similar
total hospitalization rates regardless of
preeclampsia exposure status. Preeclampsia was also associated with an in-

FIGURE 2

Average number of hospitalizations per child

.1
.05
.15

Average number of hospitalizations per child born at term

Preeclampsia
Nonpreeclampsia

10

15
Age (years)

20

25

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

creased risk of being hospitalized for a

number of specific diseases, especially in
children born at term.
Children prenatally exposed to preeclampsia are at a risk of being SGA,6

which itself is associated with an increased risk of several diseases in adult

life.34,35 Our findings, however, do not
suggest that the association between preeclampsia and adverse long-term out-

FIGURE 3

Average number of hospitalizations per child born preterm

Average number of hospitalizations per child
.05
.1
.15
.2
.25

preeclampsia had slightly higher IRRs

than children exposed to mild preeclampsia (Table 2). Children born at
term prenatally exposed to eclampsia
had an increased risk of cerebral palsy
(Table 2).
For children born preterm, the risks of
being hospitalized due to majority of the
specific diseases were similar among
those exposed and unexposed to preeclampsia. The hospitalization pattern
was, however, different, for certain diseases such as hemorrhagic disorders; endocrine, nutritional, and metabolic diseases; diseases of the digestive system;
diseases of the skin and subcutaneous
tissue; and congenital malformation of
the genital organs (Table 3). Notably,
children born preterm who were exposed to preeclampsia had a decreased
risk of anemia, cerebral palsy, and pneumonia (Table 3).
Male and female offspring had similar
outcomes except that boys exposed to
mild or severe preeclampsia had an increased prevalence of congenital malformations of the genital organs. Boys born
at term exposed to severe preeclampsia
had an increased risk of diseases of the
blood and blood-forming organs and
disorders of the immune system. Girls
exposed to severe preeclampsia or
eclampsia had an increased risk of cerebral palsy and of diseases of the musculoskeletal system and connective tissue
(data not shown).
The associations between preeclampsia and some outcomes in the offspring
varied only slightly with parity (1, 2, 3),
but without any consistent patterns
(data not shown). IRRs of hospitalizations in the first 5 years of life for children
exposed to preeclampsia were similar
across calendar year of birth compared
to children unexposed (data not shown).

Research

Preeclampsia
Nonpreeclampsia

10

15
Age (years)

20

25

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

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TABLE 2

Incidence rate ratios for disease-specific hospitalizations among children born at term (>37 weeks
gestation) exposed to preeclampsia or eclampsia without being born small for gestational age
Mild PE
n 34,955

Severe PE
n 7733

Eclampsia
n 724

Total
(all PE or eclampsia)

Disease-specific hospitalization

IRRa (95% CI)

IRRa (95% CI)

IRRa (95% CI)

IRRa (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)

1.1 (0.52.4)

NA

1.3 (1.01.6)

Malignant

1.2 (0.81.8)

1.0 (0.34.0)

NA

1.2 (0.91.8)

Benign

1.4 (1.01.9)

1.2 (0.53.2)

NA

1.4 (1.11.8)

1.5 (1.21.8)

2.0 (1.23.2)

1.0 (0.17.0)

1.5 (1.31.8)

................................................................................................................................................................................................................................................................................................................................................................................
b
b
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
b
b
................................................................................................................................................................................................................................................................................................................................................................................
b
b
b

Disease of blood and blood-forming organs

and disorders involving immune mechanism

.......................................................................................................................................................................................................................................................................................................................................................................
b
b

Anemias

1.3 (1.01.7)

1.8 (0.93.8)

NA

1.3 (1.01.6)

1.4 (0.92.0)

1.1 (0.34.4)

NA

1.5 (1.02.1)

1.6 (1.51.7)

1.8 (1.42.3)

1.2 (0.52.6)

1.6 (1.51.7)

.......................................................................................................................................................................................................................................................................................................................................................................
b

Purpura

................................................................................................................................................................................................................................................................................................................................................................................
b
b
b

Endocrine, nutritional, and metabolic

diseases

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

0.9 (0.81.2)

1.3 (0.72.5)

NA

1.0 (0.81.2)

Mental and behavioral disorders

Diabetes mellitus

1.1 (1.01.2)

1.2 (0.91.6)

0.2 (0.021.2)

1.1 (1.01.2)

Diseases of nervous system

1.2 (1.11.2)

1.3 (1.11.6)

1.6 (1.02.4)

1.2 (1.11.2)

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)

1.4 (1.11.9)

1.8 (0.93.4)

1.2 (1.11.3)

1.2 (1.01.4)

0.7 (0.31.6)

1.0 (0.16.8)

1.1 (0.91.4)

1.1 (0.81.4)

0.4 (0.11.8)

NA

1.0 (0.81.3)

1.2 (1.11.2)

1.1 (1.11.3)

1.1 (0.91.5)

1.2 (1.11.2)

Pneumonia

1.2 (1.11.3)

1.2 (0.91.5)

1.1 (0.62.0)

1.2 (1.11.3)

Asthma

1.2 (1.11.3)

1.1 (0.91.3)

1.2 (0.81.8)

1.2 (1.11.2)

Diseases of digestive system

1.2 (1.01.3)

0.9 (0.61.3)

0.6 (0.12.3)

1.1 (1.01.3)

Diseases of skin and subcutaneous tissue

1.1 (1.01.3)

1.2 (0.81.7)

1.3 (0.53.6)

1.1 (1.01.3)

Dermatitis and eczema

1.1 (1.01.3)

1.2 (0.82.0)

NA

1.1 (1.01.3)

Erythema

1.1 (0.62.2)

NA

NA

0.9 (0.51.9)

1.2 (1.01.4)

1.2 (0.72.0)

2.1 (0.76.4)

1.2 (1.01.4)

................................................................................................................................................................................................................................................................................................................................................................................
b
b
................................................................................................................................................................................................................................................................................................................................................................................
b
b
b
b
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
b
b
b
................................................................................................................................................................................................................................................................................................................................................................................
b

Diseases of circulatory system

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

Heart disease

................................................................................................................................................................................................................................................................................................................................................................................
b
b
b

Diseases of respiratory system

.......................................................................................................................................................................................................................................................................................................................................................................
b
b
.......................................................................................................................................................................................................................................................................................................................................................................
b
b

................................................................................................................................................................................................................................................................................................................................................................................
b
b
................................................................................................................................................................................................................................................................................................................................................................................
b
b
.......................................................................................................................................................................................................................................................................................................................................................................
b
b
.......................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
b
b

Diseases of musculoskeletal system and

connective tissue

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

Arthritis

1.8 (0.93.3)

2.1 (0.314.8)

NA

1.7 (0.93.0)

1.3 (1.11.5)

1.4 (0.92.1)

0.9 (0.23.6)

1.3 (1.11.4)

1.4 (0.82.2)

1.5 (0.45.9)

NA

1.5 (1.02.3)

................................................................................................................................................................................................................................................................................................................................................................................
b
b

Diseases of genitourinary system

.......................................................................................................................................................................................................................................................................................................................................................................
b

Nephritis

................................................................................................................................................................................................................................................................................................................................................................................
b
b
b

Congenital malformations

1.1 (1.11.2)

1.1 (1.01.3)

1.1 (0.81.6)

1.1 (1.11.2)

Nervous system

1.2 (1.01.6)

1.0 (0.42.2)

2.5 (0.610.0)

1.3 (1.01.5)

Circulatory system

1.3 (1.21.4)

1.6 (1.22.2)

1.3 (0.63.2)

1.3 (1.21.4)

Genital organs

1.1 (1.01.2)

1.1 (0.91.5)

0.9 (0.41.9)

1.1 (1.01.2)

.......................................................................................................................................................................................................................................................................................................................................................................
b
b
.......................................................................................................................................................................................................................................................................................................................................................................
b
b
b
.......................................................................................................................................................................................................................................................................................................................................................................
b
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 are
statistically significant (P .05).

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

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Research

TABLE 3

Incidence rate ratios for disease-specific hospitalizations among children born

preterm (<37 weeks gestation) exposed to preeclampsia or eclampsia

Disease-specific hospitalization

Mild PE
n 34,955

Severe PE
n 7733

Eclampsia
n 724

Total
(all PE or eclampsia)

IRRa (95% CI)

IRRa (95% CI)

IRRa (95% CI)

IRRa (95% CI)

Infectious and parasitic diseases

1.0 (0.91.1)

1.0 (0.91.1)

0.9 (0.71.4)

1.0 (0.91.1)

Neoplasms

0.7 (0.31.3)

1.2 (0.81.8)

0.8 (0.15.6)

1.0 (0.71.4)

Malignant

NA

1.0 (0.42.7)

NA

0.6 (0.31.6)

Benign

0.9 (0.51.8)

1.3 (0.82.1)

1.1 (0.27.6)

1.1 (0.81.7)

1.1 (0.81.5)

1.0 (0.71.3)

0.3 (0.041.8)

1.0 (0.81.2)

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

Disease of blood and bloodforming organs

and disorders involving immune mechanism

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

Anemias

1.0 (0.61.5)

0.7 (0.41.0)

0.4 (0.12.6)

0.7 (0.51.0)

1.8 (0.93.3)

1.8 (1.13.1)

NA

1.8 (1.22.7)

2.2 (1.92.5)

1.9 (1.72.1)

2.1 (1.43.2)

2.0 (1.82.1)

.......................................................................................................................................................................................................................................................................................................................................................................
b
b

Purpura

................................................................................................................................................................................................................................................................................................................................................................................
b
b
b
b

Endocrine, nutritional, and metabolic

diseases

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

0.9 (0.42.0)

1.1 (0. 62.0)

1.6 (0.211.5)

1.0 (0.61.6)

Mental and behavioral disorders

Diabetes mellitus

1.0 (0.81.3)

1.0 (0.81.3)

1.1 (0.42.6)

1.0 (0.91.2)

Diseases of nervous system

1.2 (1.11.4)

1.0 (0.91.1)

1.3 (0.92.0)

1.1 (1.01.2)

0.9 (0.61.2)

0.7 (0.50.9)

0.5 (0.21.6)

0.7 (0.60.9)

................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
b
b
.......................................................................................................................................................................................................................................................................................................................................................................
b
b

Cerebral paralysis

.......................................................................................................................................................................................................................................................................................................................................................................
b

Epilepsy

1.2 (1.01.6)

0.9 (0.71.1)

1.3 (0.62.7)

1.0 (0.91.2)

1.1 (0.81.6)

1.0 (0.71.3)

0.3 (0.02.0)

1.0 (0.81.2)

1.1 (0.71.7)

0.9 (0.61.3)

0.5 (0.13.4)

0.9 (0.71.2)

1.0 (0.91.1)

1.0 (0.91.0)

1.0 (0.91.0)

1.0 (0.91.0)

Pneumonia

0.9 (0.81.1)

0.8 (0.70.9)

0.8 (0.70.9)

0.8 (0.80.9)

Asthma

0.9 (0.81.1)

1.0 (0.91.1)

0.6 (0.41.2)

0.9 (0.91.0)

Diseases of digestive system

1.4 (1.21.7)

1.4 (1.21.6)

1.2 (0.62.2)

1.4 (1.21.6)

Diseases of skin and subcutaneous tissue

1.4 (1.01.8)

1.4 (1.11.8)

1.2 (0.53.3)

1.4 (1.21.7)

Dermatitis and eczema

1.1 (0.71.8)

0.9 (0.61.5)

1.5 (0.45.9)

1.1 (0.81.5)

Erythema

NA

2.3 (0.77.5)

11.1 (1.581.8)

1.9 (0.74.8)

0.8 (0.51.3)

0.9 (0.61.3)

NA

0.8 (0.61.1)

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

Diseases of circulatory system

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

Heart disease

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

Diseases of respiratory system

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

................................................................................................................................................................................................................................................................................................................................................................................
b
b
b
................................................................................................................................................................................................................................................................................................................................................................................
b
b
b
b
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
b
................................................................................................................................................................................................................................................................................................................................................................................

Diseases of musculoskeletal system and

connective tissue

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

Arthritis

1.1 (0.28.5)

1.6 (0.46.8)

NA

1.3 (0.44.3)

1.3 (0.91.7)

0.9 (0.71.2)

1.4 (0.63.3)

1.1 (0.91.3)

0.4 (0.12.6)

1.0 (0.42.7)

NA

0.7 (0.31.7)

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

Diseases of genitourinary system

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

Nephritis

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

Congenital malformations

1.0 (0.91.1)

1.0 (0.91.1)

0.9 (0.61.2)

1.0 (0.91.1)

Nervous system

1.2 (0.81.8)

0.9 (0.61.3)

1.6 (0.64.1)

1.1 (0.81.4)

Circulatory system

1.0 (0.91.2)

1.1 (0.91.2)

1.2 (0.71.8)

1.1 (1.01.2)

Genital organs

1.7 (1.42.1)

1.5 (1.21.7)

1.1 (0.52.3)

1.5 (1.41.8)

.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
b
.......................................................................................................................................................................................................................................................................................................................................................................
b
b
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 are
statistically significant (P .05).

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comes in the offspring is mediated by

SGA. Potential biological 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.36,37 Another
possibility is that heritable genetic factors that predispose to pregnancy-related disorders and disorders later in life
are inherited by the offspring.38
Preterm birth is a well known risk factor
for a variety of adverse offspring health
outcomes, but the associations that we detected did not appear to be mediated by
preterm birth. For children born preterm,
we found rather similar patterns of hospitalizations regardless of preeclampsia exposure status. These findings may indicate
that other causes of preterm birth may
have similar or even worse adverse effects
on the fetus than preeclampsia. Alternatively, the intrauterine environment related to preeclampsia may need longer gestational exposure time to have an adverse
effect. If this is the case it offers an argument for early delivery of preeclamptic
pregnancies.
Our results even suggested that children
born preterm who were exposed to preeclampsia had a decreased risk of cerebral
palsy compared to other children born
preterm, which is in line with some studies9,39 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 risk of 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 prenatally exposed to preeclampsia, which is
consistent with results of some studies22,23 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 exposed to preeclampsia, which may be a
marker of susceptibility to inflammatory
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disorders, cardiovascular diseases, or diabetes in adult life.
Preeclampsia in our data was associated with an increased prevalence of congenital malformations of genital organs,
especially among boys. This finding is in
accordance with several studies42-45 but
not all.46 We doubt that preeclampsia is
causally associated with congenital malformations because preeclampsia is
usually not manifest at the time of organogenesis, but it is possible that preeclampsia and some congenital malformations may share common genetic or
environmental factors.
The criteria for the diagnosis of mild
preeclampsia in Denmark47,48 were similar
to that used by the American College of
Obstetricians and Gynecologists (ACOG)
(diastolic blood pressure 90 mm Hg or
systolic blood pressure 140 mm Hg and
proteinuria with total loss of protein in a
24-hour urine specimen 0.3 g).49 The diagnostic guideline for severe preeclampsia,
however, was 180 mm Hg, which is different than 160 mm Hg as used in the ACOG;
and 3-g loss of protein in a 24-hour urine
specimen was used rather than 5 g as in the
ACOG. In practice, however, the criteria of
ACOG are also used in Denmark to diagnose severe preeclampsia.50 Information
on preeclampsia and eclampsia was obtained from the Danish National Hospital
Register. In a recent study, the positive predictive value of a preeclampsia diagnosis in
the register has been estimated to be 74%,
and almost 100% predictive for severe preeclampsia.51 The sensitivity of the preeclampsia diagnosis in the register was
about 69%.51 Use of 1 set of criteria for
diagnosing preeclampsia will probably
generate some misclassification between
mild and severe types of the disorder, but
because the registration of preeclampsia
took place before the outcomes under
study, any misclassification of preeclampsia is expected to be nondifferential. And
nondifferential misclassification will often
attenuate relative effect estimates.52
Regrettably, we were not able to differentiate between early and late onset of
preeclampsia. We also lacked data on
health outcomes that do not lead to hospitalization, such as hypertension or
childhood obesity. We also had limited
data on mental and behavior disorders

American Journal of Obstetrics & Gynecology SEPTEMBER 2009

for children because conditions treated

by psychiatrists in mental hospitals were
not linked to our database.53
We used a large population-based cohort including all children born in Denmark with up to 27 years of follow-up. We
expect the number of children with severe
diseases treated entirely outside hospitals
to be small, because all health services, including 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 associated with a decreased risk of preeclampsia.54-56 And analyses without adjusting for
maternal smoking may therefore underestimate associations if smoking is a risk factor for the outcomes. Preexisting maternal
obesity and being overweight is associated
an increased risk of preeclampsia.57 Analyses without adjusting for maternal body
mass index may therefore overestimate associations if obesity is a risk factor for the
outcomes.
In conclusion, preeclampsia was associated with an increased risk among offspring of being hospitalized for a number 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 disf
eases share common causes.
REFERENCES
1. Duley L, Meher S, Abalos E. Management of
pre-eclampsia. BMJ 2006;332:463-8.
2. Report of the national high blood pressure
education program working group on high
blood pressure in pregnancy. Am J Obstet Gynecol 2000;183:S1-22.
3. Sibai B, Dekker G, Kupferminc M. Preeclampsia. Lancet 2005;365:785-99.
4. Ilekis JV, Reddy UM, Roberts JM. Preeclampsiaa pressing problem: an executive
summary of a National Institute of Child Health
and Human Development workshop. Reprod
Sci 2007;14:508-23.
5. Basso O, Rasmussen S, Weinberg CR, Wilcox AJ, Irgens LM, Skjaerven R. Trends in fetal

Obstetrics

www.AJOG.org
and infant survival following preeclampsia.
JAMA 2006;296:1357-62.
6. Odegard RA, Vatten LJ, Nilsen ST, Salvesen
KA, Austgulen R. Preeclampsia and fetal
growth. Obstet Gynecol 2000;96:950-5.
7. Xiong X, Demianczuk NN, Saunders LD, Wang
FL, Fraser WD. Impact of preeclampsia and gestational hypertension on birth weight by gestational age. Am J Epidemiol 2002;155:
203-9.
8. Baud O, Zupan V, Lacaze-Masmonteil T, et
al. The relationships between antenatal management, the cause of delivery and neonatal
outcome in a large cohort of very preterm singleton infants. BJOG 2000;107:877-84.
9. Murphy DJ, Sellers S, MacKenzie IZ, Yudkin
PL, Johnson AM. Case-control study of antenatal and intrapartum risk factors for cerebral
palsy in very preterm singleton babies. Lancet
1995;346:1449-54.
10. Szymonowicz W, Yu VY. Severe preeclampsia and infants of very low birth weight.
Arch Dis Child 1987;62:712-6.
11. Cheng SW, Chou HC, Tsou KI, Fang LJ,
Tsao PN. Delivery before 32 weeks of gestation
for maternal pre-eclampsia: neonatal outcome
and 2-year developmental outcome. Early Hum
Dev 2004;76:39-46.
12. Badawi N, Kurinczuk JJ, Keogh JM, et al.
Antepartum risk factors for newborn encephalopathy: the Western Australian case-control
study. BMJ 1998;317:1549-53.
13. Impey L, Greenwood C, Sheil O, MacQuillan K, Reynolds M, Redman C. The relation between pre-eclampsia at term and neonatal encephalopathy. Arch Dis Child Fetal Neonatal Ed
2001;85:F170-2.
14. Vestergaard M, Basso O, Henriksen TB,
Ostergaard J, Secher NJ, Olsen J. Pre-eclampsia and febrile convulsions. Arch Dis Child
2003;88:726-7.
15. Tenhola S, Rahiala E, Halonen P, Vanninen
E, Voutilainen R. Maternal preeclampsia predicts elevated blood pressure in 12-year-old
children: evaluation by ambulatory blood pressure monitoring. Pediatr Res 2006;59:320-4.
16. Palti H, Rothschild E. Blood pressure and
growth at 6 years of age among offsprings of
mothers with hypertension of pregnancy. Early
Hum Dev 1989;19:263-9.
17. Tenhola S, Rahiala E, Martikainen A,
Halonen P, Voutilainen R. Blood pressure, serum lipids, fasting insulin, and adrenal hormones in 12-year-old children born with maternal preeclampsia. J Clin Endocrinol Metab
2003;88:1217-22.
18. Seidman DS, Laor A, Gale R, Stevenson
DK, Mashiach S, Danon YL. Pre-eclampsia and
offsprings blood pressure, cognitive ability and
physical development at 17-years-of-age. Br J
Obstet Gynaecol 1991;98:1009-14.
19. Dahlquist GG, Patterson C, Soltesz G. Perinatal risk factors for childhood type 1 diabetes
in Europe: the EURODIAB substudy 2 study
group. Diabetes Care 1999;22:1698-702.

20. Jones ME, Swerdlow AJ, Gill LE, Goldacre

MJ. Pre-natal and early life risk factors for childhood onset diabetes mellitus: a record linkage
study. Int J Epidemiol 1998;27:444-9.
21. McKinney PA, Parslow R, Gurney KA, Law
GR, Bodansky HJ, Williams R. Perinatal and
neonatal determinants of childhood type 1 diabetes: a case-control study in Yorkshire, UK.
Diabetes Care 1999;22:928-32.
22. Bache I, Bock T, Volund A, Buschard K.
Previous maternal abortion, longer gestation,
and younger maternal age decrease the risk of
type 1 diabetes among male offspring. Diabetes
Care 1999;22:1063-5.
23. Stene LC, Magnus P, Lie RT, Sovik O, Joner
G. No association between preeclampsia or cesarean section and incidence of type 1 diabetes
among children: a large, population-based cohort study. Pediatr Res 2003;54:487-90.
24. Xue F, Michels KB. Intrauterine factors and
risk of breast cancer: a systematic review and
meta-analysis of current evidence. Lancet Oncol 2007;8:1088-100.
25. Ekbom A, Trichopoulos D, Adami HO,
Hsieh CC, Lan SJ. Evidence of prenatal influences on breast cancer risk. Lancet 1992;
340:1015-8.
26. Innes K, Byers T, Schymura M. Birth characteristics and subsequent risk for breast cancer in very young women. Am J Epidemiol
2000;152:1121-8.
27. Ekbom A, Hsieh CC, Lipworth L, Adami
HQ, Trichopoulos D. Intrauterine environment
and breast cancer risk in women: a population-based study. J Natl Cancer Inst 1997;
89:71-6.
28. Le ML, Kolonel LN, Myers BC, Mi MP. Birth
characteristics of premenopausal women with
breast cancer. Br J Cancer 1988;57:437-9.
29. Mogren I, Damber L, Tavelin B, Hogberg U.
Characteristics of pregnancy and birth and malignancy in the offspring (Sweden). Cancer
Causes Control 1999;10:85-94.
30. Sanderson M, Williams MA, Daling JR, et al.
Maternal factors and breast cancer risk among
young women. Paediatr Perinat Epidemiol
1998;12:397-407.
31. Pedersen CB, Gotzsche H, Moller JO,
Mortensen PB. The Danish Civil Registration
System: a cohort of eight million persons. Dan
Med Bull 2006;53:441-9.
32. Andersen TF, Madsen M, Jorgensen J, Mellemkjoer L, Olsen JH. The Danish National Hospital Register: a valuable source of data for
modern health sciences. Dan Med Bull
1999;46:263-8.
33. Knudsen LB, Olsen J. The Danish Medical
Birth Registry. Dan Med Bull 1998;45:320-3.
34. Barker DJ. The origins of the developmental
origins theory. J Intern Med 2007;261:412-7.
35. Barker DJ, Eriksson JG, Forsen T, Osmond
C. Fetal origins of adult disease: strength of effects and biological basis. Int J Epidemiol
2002;31:1235-9.

Research

36. Gluckman PD, Hanson MA, Cooper C,

Thornburg KL. Effect of in utero and early-life
conditions on adult health and disease. N Engl
J Med 2008;359:61-73.
37. Hanson MA, Gluckman PD. Developmental
origins of health and disease: new insights. Basic Clin Pharmacol Toxicol 2008;102:90-3.
38. Smith GC, Pell JP, Walsh D. Pregnancy
complications and maternal risk of ischemic
heart disease: a retrospective cohort study of
129,290 births. Lancet 2001;357:2002-6.
39. Greenwood C, Yudkin P, Sellers S, Impey L,
Doyle P. Why is there a modifying effect of gestational age on risk factors for cerebral palsy?
Arch Dis Child Fetal Neonatal Ed 2005;
90:F141-6.
40. Thorngren-Jerneck K, Herbst A. Perinatal
factors associated with cerebral palsy in children born in Sweden. Obstet Gynecol 2006;
108:1499-505.
41. Shankaran S. Prevention, diagnosis, and
treatment of cerebral palsy in near-term and term
infants. Clin Obstet Gynecol 2008;51:829-39.
42. Aschim EL, Haugen TB, Tretli S, Daltveit AK,
Grotmol T. Risk factors for hypospadias in Norwegian boyassociation with testicular dysgenesis syndrome? Int J Androl 2004;27:213-21.
43. Akre O, Lipworth L, Cnattingius S, Sparen
P, Ekbom A. Risk factor patterns for cryptorchidism and hypospadias. Epidemiology
1999;10:364-9.
44. Chong JH, Wee CK, Ho SK, Chan DK.
Factors associated with hypospadias in Asian
newborn babies. J Perinat Med 2006;34:
497-500.
45. Sorensen HT, Pedersen L, Norgaard M,
Wogelius P, Rothman KJ. Maternal asthma,
preeclampsia and risk of hypospadias. Epidemiology 2005;16:806-7.
46. Hussain N, Chaghtai A, Herndon CD, Herson VC, Rosenkrantz TS, McKenna PH. Hypospadias and early gestation growth restriction in
infants. Pediatrics 2002;109:473-8.
47. Lange AP. Obstetric guidelines in coding and
definitions. 1st ed. Copenhagen: DSOG; 1996.
48. Johansen M, Kjaergaard N, Legarth J, Salvig
JD, Skajaa K, Wilken-Jensen C. Hypertension in
pregnancy. Sandbjerg guidelines. 2001. Available
at: www.dsog.dk/files/Praeeklampsi%202001.
htm. Accessed Nov. 9, 2008.
49. American College of Obstetricians and Gynecologists. National high blood pressure education program working group on high blood
pressure in pregnancy. Am J Obstet Gynecol
1990;163:1691-712.
50. Klemmensen AK, Olsen SF, Wengel CM, Tabor A. Diagnostic criteria and reporting procedures for pre-eclampsia: a national survey among
obstetrical departments in Denmark. Eur J Obstet
Gynecol Reprod Biol 2005;123:41-5.
51. Klemmensen AK, Olsen SF, Osterdal ML,
Tabor A. Validity of preeclampsia-related diagnoses recorded in a national hospital registry
and in a postpartum interview of the women.
Am J Epidemiol 2007;166:117-24.

SEPTEMBER 2009 American Journal of Obstetrics & Gynecology

269.e9

Research

Obstetrics

52. Rothman KJ, Greenland S. Modern epidemiology. 2nd ed. Philadelphia: LippincottRaven Publisher; 1998.
53. Munk-Jorgensen P, Mortensen PB. The
Danish Psychiatric Central Register. Dan Med
Bull 1997;44:82-4.
54. Conde-Agudelo A, Althabe F, Belizan JM,
Kafury-Goeta AC. Cigarette smoking during

269.e10

www.AJOG.org
pregnancy and risk of preeclampsia: a
systematic review. Am J Obstet Gynecol 1999;
181:1026-35.
55. England LJ, Kendrick JS, Gargiullo PM,
Zahniser SC, Hannon WH. Measures of maternal tobacco exposure and infant birth
weight at term. Am J Epidemiol 2001;153:
954-60.

American Journal of Obstetrics & Gynecology SEPTEMBER 2009

56. Newman MG, Lindsay MK, Graves W. Cigarette smoking and pre-eclampsia: their association and effects on clinical outcomes. J Matern Fetal Med 2001;10:166-70.
57. Catov JM, Ness RB, Kip KE, Olsen J. Risk of
early or severe pre-eclampsia related to preexisting conditions. Int J Epidemiol 2007;36:
412-9.