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Department of Epidemiology, School of Public Health, University of Aarhus, Aarhus, DenmarkDepartment of Epidemiology, School of Public Health, University of California at Los Angeles, Los Angeles, CA
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, 1.5–1.7), and diseases of the blood and blood-forming organs (incidence rate ratio, 1.5; 95% confidence interval, 1.3–1.8). 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.
It is a multisystem disorder associated with increased systemic vascular resistance, enhanced platelet aggregation, activation of the coagulation system, and endothelial-cell dysfunction.
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.
For Editors' Commentary, see Table of Contents
Previous studies have mainly addressed short-term outcomes
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.
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.
Materials and Methods
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.
All persons 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.
Information on maternal preeclampsia, maternal eclampsia, and hospitalizations among the offspring was obtained from the Danish National Hospital Register
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.
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,
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 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 high school), cohabitation status of parents at birth (cohabitant, not cohabiting, and others) and calendar year (1978-1981, 1982-1985, 1986-1989, 1990-1993, 1994-1997, 1998-2001, 2002-2004). Finally, we restricted the analyses to non-SGA 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).
Results
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, 1.17–1.28), 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, 1.12–1.30), 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, 1.15–1.39), 11 years (IRR, 1.16; 95% CI, 1.04–1.29), 12 years (IRR, 1.14; 95% CI, 1.03–1.26), 13 years (IRR, 1.17; 95% CI, 1.04–1.31), 16 years (IRR, 1.18; 95% CI, 1.05–1.31), 18 years (IRR, 1.11; 95% CI, 1.00–1.23), 19 years (IRR, 1.13; 95% CI, 1.01–1.26), 20 years (IRR, 1.24; 95% CI, 1.11–1.39), 21 years (IRR, 1.18; 95% CI, 1.05–1.33), 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 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, 1.25–1.30). The average number of hospitalizations in the first year of life was 1.63 for exposed children born preterm and 1.42 for unexposed children born preterm (not shown Figure 3).
FIGURE 2Average number of hospitalizations per child born at term
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 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).
TABLE 2Incidence 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
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);
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);
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);
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);
Wu. Health of children born to mothers who had preeclampsia: a population-based cohort study. Am J Obstet Gynecol 2009.
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).
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).
TABLE 3Incidence rate ratios for disease-specific hospitalizations among children born preterm (<37 weeks' gestation) exposed to preeclampsia or eclampsia
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);
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);
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);
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);
(95% CI)
Infectious and parasitic diseases
1.0 (0.9–1.1)
1.0 (0.9–1.1)
0.9 (0.7–1.4)
1.0 (0.9–1.1)
Neoplasms
0.7 (0.3–1.3)
1.2 (0.8–1.8)
0.8 (0.1–5.6)
1.0 (0.7–1.4)
Malignant
NA
1.0 (0.4–2.7)
NA
0.6 (0.3–1.6)
Benign
0.9 (0.5–1.8)
1.3 (0.8–2.1)
1.1 (0.2–7.6)
1.1 (0.8–1.7)
Disease of blood and blood–forming organs and disorders involving immune mechanism
Wu. Health of children born to mothers who had preeclampsia: a population-based cohort study. Am J Obstet Gynecol 2009.
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).
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).
Comment
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 increased 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,
Our findings, however, do not suggest that the association between preeclampsia and adverse long-term outcomes 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.
Another possibility is that heritable genetic factors that predispose to pregnancy-related disorders and disorders later in life are inherited by the offspring.
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 studies
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.
Our study did not show an increased risk of diabetes among the children prenatally exposed to preeclampsia, which is consistent with results of some studies
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 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 studies
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 Denmark
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).
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.
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.
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.
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 for children because conditions treated by psychiatrists in mental hospitals were not linked to our database.
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.
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.
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 diseases share common causes.
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.
Chun S. Wu was supported by Grants from the Danish Cancer Society (Grant number DP04127) and National Institutes of Health (Grant number 5R01AI071386-6).
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