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Health of children born to mothers who had preeclampsia: a population-based cohort study

      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, 1.5–1.7), 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.

      Key words

      Preeclampsia is a disease characterized by pregnancy-induced hypertension and proteinuria that affects 2-8% of pregnancies.
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      Impact of preeclampsia and gestational hypertension on birth weight by gestational age.
      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
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      Case-control study of antenatal and intrapartum risk factors for cerebral palsy in very preterm singleton babies.
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      Delivery before 32 weeks of gestation for maternal pre-eclampsia: neonatal outcome and 2-year developmental outcome.
      such as encephalopathy,
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      febrile seizures,
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      Pre-eclampsia and febrile convulsions.
      and cerebral palsy.
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      Case-control study of antenatal and intrapartum risk factors for cerebral palsy in very preterm singleton babies.
      Studies of long-term outcomes have reported a higher risk of childhood hypertension,
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      Maternal preeclampsia predicts elevated blood pressure in 12-year-old children: evaluation by ambulatory blood pressure monitoring.
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      Blood pressure and growth at 6 years of age among offsprings of mothers with hypertension of pregnancy.
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      Blood pressure, serum lipids, fasting insulin, and adrenal hormones in 12-year-old children born with maternal preeclampsia.
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      • Danon Y.L.
      Pre-eclampsia and offspring's blood pressure, cognitive ability and physical development at 17-years-of-age.
      and some
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      Perinatal risk factors for childhood type 1 diabetes in Europe: the EURODIAB substudy 2 study group.
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      Pre-natal and early life risk factors for childhood onset diabetes mellitus: a record linkage study.
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      Perinatal and neonatal determinants of childhood type 1 diabetes: a case-control study in Yorkshire, UK.
      but not all
      • Bache I.
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      • Buschard K.
      Previous maternal abortion, longer gestation, and younger maternal age decrease the risk of type 1 diabetes among male offspring.
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      • Lie R.T.
      • 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.
      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.
      • Xue F.
      • Michels K.B.
      Intrauterine factors and risk of breast cancer: a systematic review and meta-analysis of current evidence.
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      • Lan S.J.
      Evidence of prenatal influences on breast cancer risk.
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      • Byers T.
      • Schymura M.
      Birth characteristics and subsequent risk for breast cancer in very young women.
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      • Lipworth L.
      • Adami H.Q.
      • Trichopoulos D.
      Intrauterine environment and breast cancer risk in women: a population-based study.
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      • Myers B.C.
      • Mi M.P.
      Birth characteristics of premenopausal women with breast cancer.
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      • Damber L.
      • Tavelin B.
      • Hogberg U.
      Characteristics of pregnancy and birth and malignancy in the offspring (Sweden).
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      • Williams M.A.
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      • et al.
      Maternal factors and breast cancer risk among young women.
      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.
      • Pedersen C.B.
      • Gotzsche H.
      • Moller J.O.
      • Mortensen P.B.
      The Danish Civil Registration System: a cohort of eight million persons.
      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.
      • Pedersen C.B.
      • Gotzsche H.
      • Moller J.O.
      • Mortensen P.B.
      The Danish Civil Registration System: a cohort of eight million persons.
      Information on maternal preeclampsia, maternal eclampsia, and hospitalizations among the offspring was obtained from the Danish National Hospital Register
      • Pedersen C.B.
      • Gotzsche H.
      • Moller J.O.
      • Mortensen P.B.
      The Danish Civil Registration System: a cohort of eight million persons.
      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.
      • Andersen T.F.
      • Madsen M.
      • Jorgensen J.
      • Mellemkjoer L.
      • Olsen J.H.
      The Danish National Hospital Register: a valuable source of data for modern health sciences.
      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,
      • Knudsen L.B.
      • Olsen J.
      The Danish Medical Birth Registry.
      which includes all births in Denmark since 1973.
      • Knudsen L.B.
      • Olsen J.
      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).
      Figure thumbnail gr1
      FIGURE 1Identification of study population
      Wu. Health of children born to mothers who had preeclampsia: a population-based cohort study. Am J Obstet Gynecol 2009.
      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.
      TABLE 1Characteristics of the study population
      CharacteristicsNo PE or eclampsia n = 1,499,059PEEclampsia n = 724
      Unspecified n = 2972Mild n = 34,955Severe n = 7733
      n%n%n%n%n%
      Sex
       Male769,46051.3152651.418,30952.4394451.038553.2
       Female729,59948.7144648.716,64647.6378949.033946.8
      Maternal age, y
       <2040,2922.71264.212583.62813.6466.4
       20-24305,13620.474325.0880925.2176022.818425.4
       25-29581,71838.8112838.013,12937.6291637.723632.6
       30-34412,14627.567622.8792122.7184023.817924.7
       ≥35159,76710.729910.1383811.093612.17910.9
      Parity
       1677,16645.2190063.922,24563.6536469.449768.7
       2575,41038.475325.3919126.3164021.216923.3
       ≥3246,48316.431910.7351910.17299.4588.0
      Gestational age, wk
       20-2725710.2100.3310.12082.7182.5
       28-3210,0060.7592.03481.0121515.78211.3
       33-3652,3703.52337.821896.3230529.812817.7
       37-411,300,91386.8245882.729,87085.5386750.046764.5
       42-45133,1998.92127.125177.21381.8294.0
      SGA
      Children with birthweight in lowest 10th percentile of distribution of birthweight for gestational age in wk and sex.
       No1,353,11190.5251885.029,81085.5576174.955376.8
       Yes142,0759.544615.1505114.5192925.116723.19
      Maternal education
       Elementary school502,74833.5111137.413,01337.2255933.127337.7
       Middle school667,81444.6136145.815,79445.2360146.633045.6
       High school328,49721.950016.8614817.6157320.312116.7
      SGA, small for gestational age; PE, preeclampsia.
      Wu. Health of children born to mothers who had preeclampsia: a population-based cohort study. Am J Obstet Gynecol 2009.
      a Children with birthweight in lowest 10th percentile of distribution of birthweight for gestational age in wk and sex.
      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 thumbnail gr2
      FIGURE 2Average number of hospitalizations per child born at term
      Wu. Health of children born to mothers who had preeclampsia: a population-based cohort study. Am J Obstet Gynecol 2009.
      Figure thumbnail gr3
      FIGURE 3Average number of hospitalizations per child born preterm
      Wu. Health of children born to mothers who had preeclampsia: a population-based cohort study. Am J Obstet Gynecol 2009.
      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
      Disease-specific hospitalizationMild PE n = 34,955Severe PE n = 7733Eclampsia n = 724Total (all PE or eclampsia)
      IRR
      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)
      IRR
      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)
      IRR
      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)
      IRR
      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 diseases1.2 (1.2–1.3)
      The results are statistically significant (P < .05).
      1.3 (1.1–1.5)
      The results are statistically significant (P < .05).
      1.0 (0.7–1.5)1.2 (1.1–1.2)
      The results are statistically significant (P < .05).
      Neoplasms1.3 (1.0–1.6)
      The results are statistically significant (P < .05).
      1.1 (0.5–2.4)NA1.3 (1.0–1.6)
      The results are statistically significant (P < .05).
       Malignant1.2 (0.8–1.8)1.0 (0.3–4.0)NA1.2 (0.9–1.8)
       Benign1.4 (1.0–1.9)
      The results are statistically significant (P < .05).
      1.2 (0.5–3.2)NA1.4 (1.1–1.8)
      The results are statistically significant (P < .05).
      Disease of blood and blood-forming organs and disorders involving immune mechanism1.5 (1.2–1.8)
      The results are statistically significant (P < .05).
      2.0 (1.2–3.2)
      The results are statistically significant (P < .05).
      1.0 (0.1–7.0)1.5 (1.3–1.8)
      The results are statistically significant (P < .05).
       Anemias1.3 (1.0–1.7)
      The results are statistically significant (P < .05).
      1.8 (0.9–3.8)NA1.3 (1.0 –1.6)
      The results are statistically significant (P < .05).
       Purpura1.4 (0.9–2.0)1.1 (0.3–4.4)NA1.5 (1.0–2.1)
      The results are statistically significant (P < .05).
      Endocrine, nutritional, and metabolic diseases1.6 (1.5–1.7)
      The results are statistically significant (P < .05).
      1.8 (1.4–2.3)
      The results are statistically significant (P < .05).
      1.2 (0.5–2.6)1.6 (1.5–1.7)
      The results are statistically significant (P < .05).
       Diabetes mellitus0.9 (0.8–1.2)1.3 (0.7–2.5)NA1.0 (0.8–1.2)
      Mental and behavioral disorders1.1 (1.0–1.2)
      The results are statistically significant (P < .05).
      1.2 (0.9–1.6)0.2 (0.02–1.2)1.1 (1.0–1.2)
      The results are statistically significant (P < .05).
      Diseases of nervous system1.2 (1.1–1.2)
      The results are statistically significant (P < .05).
      1.3 (1.1–1.6)
      The results are statistically significant (P < .05).
      1.6 (1.0–2.4)
      The results are statistically significant (P < .05).
      1.2 (1.1–1.2)
      The results are statistically significant (P < .05).
       Cerebral paralysis1.1 (0.8–1.4)1.4 (0.7–2.7)3.6 (1.1–11.0)1.1 (0.9–1.4)
       Epilepsy1.2 (1.1–1.3)
      The results are statistically significant (P < .05).
      1.4 (1.1–1.9)
      The results are statistically significant (P < .05).
      1.8 (0.9–3.4)1.2 (1.1–1.3)
      The results are statistically significant (P < .05).
      Diseases of circulatory system1.2 (1.0–1.4)
      The results are statistically significant (P < .05).
      0.7 (0.3–1.6)1.0 (0.1–6.8)1.1 (0.9–1.4)
       Heart disease1.1 (0.8–1.4)0.4 (0.1–1.8)NA1.0 (0.8–1.3)
      Diseases of respiratory system1.2 (1.1–1.2)
      The results are statistically significant (P < .05).
      1.1 (1.1–1.3)
      The results are statistically significant (P < .05).
      1.1 (0.9–1.5)1.2 (1.1–1.2)
      The results are statistically significant (P < .05).
       Pneumonia1.2 (1.1–1.3)
      The results are statistically significant (P < .05).
      1.2 (0.9–1.5)1.1 (0.6–2.0)1.2 (1.1–1.3)
      The results are statistically significant (P < .05).
       Asthma1.2 (1.1–1.3)
      The results are statistically significant (P < .05).
      1.1 (0.9–1.3)1.2 (0.8–1.8)1.2 (1.1–1.2)
      The results are statistically significant (P < .05).
      Diseases of digestive system1.2 (1.0–1.3)
      The results are statistically significant (P < .05).
      0.9 (0.6–1.3)0.6 (0.1–2.3)1.1 (1.0–1.3)
      The results are statistically significant (P < .05).
      Diseases of skin and subcutaneous tissue1.1 (1.0–1.3)
      The results are statistically significant (P < .05).
      1.2 (0.8–1.7)1.3 (0.5–3.6)1.1 (1.0 –1.3)
      The results are statistically significant (P < .05).
       Dermatitis and eczema1.1 (1.0–1.3)
      The results are statistically significant (P < .05).
      1.2 (0.8–2.0)NA1.1 (1.0 –1.3)
      The results are statistically significant (P < .05).
       Erythema1.1 (0.6–2.2)NANA0.9 (0.5–1.9)
      Diseases of musculoskeletal system and connective tissue1.2 (1.0–1.4)
      The results are statistically significant (P < .05).
      1.2 (0.7–2.0)2.1 (0.7–6.4)1.2 (1.0–1.4)
      The results are statistically significant (P < .05).
       Arthritis1.8 (0.9–3.3)2.1 (0.3–14.8)NA1.7 (0.9–3.0)
      Diseases of genitourinary system1.3 (1.1–1.5)
      The results are statistically significant (P < .05).
      1.4 (0.9–2.1)0.9 (0.2–3.6)1.3 (1.1–1.4)
      The results are statistically significant (P < .05).
       Nephritis1.4 (0.8–2.2)1.5 (0.4–5.9)NA1.5 (1.0–2.3)
      The results are statistically significant (P < .05).
      Congenital malformations1.1 (1.1–1.2)
      The results are statistically significant (P < .05).
      1.1 (1.0–1.3)
      The results are statistically significant (P < .05).
      1.1 (0.8–1.6)1.1 (1.1–1.2)
      The results are statistically significant (P < .05).
       Nervous system1.2 (1.0–1.6)
      The results are statistically significant (P < .05).
      1.0 (0.4–2.2)2.5 (0.6–10.0)1.3 (1.0–1.5)
      The results are statistically significant (P < .05).
       Circulatory system1.3 (1.2–1.4)
      The results are statistically significant (P < .05).
      1.6 (1.2–2.2)
      The results are statistically significant (P < .05).
      1.3 (0.6–3.2)1.3 (1.2–1.4)
      The results are statistically significant (P < .05).
       Genital organs1.1 (1.0–1.2)
      The results are statistically significant (P < .05).
      1.1 (0.9–1.5)0.9 (0.4–1.9)1.1 (1.0–1.2)
      The results are statistically significant (P < .05).
      CI, confidence interval; IRR, incidence rate ratio; NA, not available; PE, preeclampsia.
      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
      Disease-specific hospitalizationMild PE n = 34,955Severe PE n = 7733Eclampsia n = 724Total (all PE or eclampsia)
      IRR
      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)
      IRR
      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)
      IRR
      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)
      IRR
      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 diseases1.0 (0.9–1.1)1.0 (0.9–1.1)0.9 (0.7–1.4)1.0 (0.9–1.1)
      Neoplasms0.7 (0.3–1.3)1.2 (0.8–1.8)0.8 (0.1–5.6)1.0 (0.7–1.4)
       MalignantNA1.0 (0.4–2.7)NA0.6 (0.3–1.6)
       Benign0.9 (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 mechanism1.1 (0.8–1.5)1.0 (0.7–1.3)0.3 (0.04–1.8)1.0 (0.8–1.2)
       Anemias1.0 (0.6–1.5)0.7 (0.4–1.0)0.4 (0.1–2.6)0.7 (0.5–1.0)
       Purpura1.8 (0.9–3.3)1.8 (1.1–3.1)
      The results are statistically significant (P < .05).
      NA1.8 (1.2–2.7)
      The results are statistically significant (P < .05).
      Endocrine, nutritional, and metabolic diseases2.2 (1.9–2.5)
      The results are statistically significant (P < .05).
      1.9 (1.7–2.1)
      The results are statistically significant (P < .05).
      2.1 (1.4–3.2)
      The results are statistically significant (P < .05).
      2.0 (1.8–2.1)
      The results are statistically significant (P < .05).
       Diabetes mellitus0.9 (0.4–2.0)1.1 (0. 6–2.0)1.6 (0.2–11.5)1.0 (0.6–1.6)
      Mental and behavioral disorders1.0 (0.8–1.3)1.0 (0.8–1.3)1.1 (0.4–2.6)1.0 (0.9–1.2)
      Diseases of nervous system1.2 (1.1–1.4)
      The results are statistically significant (P < .05).
      1.0 (0.9–1.1)1.3 (0.9–2.0)1.1 (1.0–1.2)
      The results are statistically significant (P < .05).
       Cerebral paralysis0.9 (0.6–1.2)0.7 (0.5–0.9)
      The results are statistically significant (P < .05).
      0.5 (0.2–1.6)0.7 (0.6–0.9)
      The results are statistically significant (P < .05).
       Epilepsy1.2 (1.0–1.6)
      The results are statistically significant (P < .05).
      0.9 (0.7–1.1)1.3 (0.6–2.7)1.0 (0.9–1.2)
      Diseases of circulatory system1.1 (0.8–1.6)1.0 (0.7–1.3)0.3 (0.0–2.0)1.0 (0.8–1.2)
       Heart disease1.1 (0.7–1.7)0.9 (0.6–1.3)0.5 (0.1–3.4)0.9 (0.7–1.2)
      Diseases of respiratory system1.0 (0.9–1.1)1.0 (0.9–1.0)1.0 (0.9–1.0)1.0 (0.9–1.0)
       Pneumonia0.9 (0.8–1.1)0.8 (0.7–0.9)0.8 (0.7–0.9)0.8 (0.8–0.9)
       Asthma0.9 (0.8–1.1)1.0 (0.9–1.1)0.6 (0.4–1.2)0.9 (0.9–1.0)
      Diseases of digestive system1.4 (1.2–1.7)
      The results are statistically significant (P < .05).
      1.4 (1.2–1.6)
      The results are statistically significant (P < .05).
      1.2 (0.6–2.2)1.4 (1.2–1.6)
      The results are statistically significant (P < .05).
      Diseases of skin and subcutaneous tissue1.4 (1.0–1.8)
      The results are statistically significant (P < .05).
      1.4 (1.1–1.8)
      The results are statistically significant (P < .05).
      1.2 (0.5–3.3)
      The results are statistically significant (P < .05).
      1.4 (1.2–1.7)
      The results are statistically significant (P < .05).
       Dermatitis and eczema1.1 (0.7–1.8)0.9 (0.6–1.5)1.5 (0.4–5.9)1.1 (0.8–1.5)
       ErythemaNA2.3 (0.7–7.5)11.1 (1.5–81.8)
      The results are statistically significant (P < .05).
      1.9 (0.7–4.8)
      Diseases of musculoskeletal system and connective tissue0.8 (0.5–1.3)0.9 (0.6–1.3)NA0.8 (0.6–1.1)
       Arthritis1.1 (0.2–8.5)1.6 (0.4–6.8)NA1.3 (0.4–4.3)
      Diseases of genitourinary system1.3 (0.9–1.7)0.9 (0.7–1.2)1.4 (0.6–3.3)1.1 (0.9–1.3)
       Nephritis0.4 (0.1–2.6)1.0 (0.4–2.7)NA0.7 (0.3–1.7)
      Congenital malformations1.0 (0.9–1.1)1.0 (0.9–1.1)0.9 (0.6–1.2)1.0 (0.9–1.1)
       Nervous system1.2 (0.8–1.8)0.9 (0.6–1.3)1.6 (0.6–4.1)1.1 (0.8–1.4)
       Circulatory system1.0 (0.9–1.2)1.1 (0.9–1.2)1.2 (0.7–1.8)1.1 (1.0–1.2)
      The results are statistically significant (P < .05).
       Genital organs1.7 (1.4–2.1)
      The results are statistically significant (P < .05).
      1.5 (1.2–1.7)
      The results are statistically significant (P < .05).
      1.1 (0.5–2.3)1.5 (1.4–1.8)
      The results are statistically significant (P < .05).
      CI, confidence interval; IRR, incidence rate ratio; NA, not available; PE, preeclampsia.
      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,
      • Odegard R.A.
      • Vatten L.J.
      • Nilsen S.T.
      • Salvesen K.A.
      • Austgulen R.
      Preeclampsia and fetal growth.
      which itself is associated with an increased risk of several diseases in adult life.
      • Barker D.J.
      The origins of the developmental origins theory.
      • Barker D.J.
      • Eriksson J.G.
      • Forsen T.
      • Osmond C.
      Fetal origins of adult disease: strength of effects and biological basis.
      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.
      • Gluckman P.D.
      • Hanson M.A.
      • Cooper C.
      • Thornburg K.L.
      Effect of in utero and early-life conditions on adult health and disease.
      • Hanson M.A.
      • Gluckman P.D.
      Developmental origins of health and disease: new insights.
      Another possibility is that heritable genetic factors that predispose to pregnancy-related disorders and disorders later in life are inherited by the offspring.
      • Smith G.C.
      • Pell J.P.
      • Walsh D.
      Pregnancy complications and maternal risk of ischemic heart disease: a retrospective cohort study of 129,290 births.
      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
      • Murphy D.J.
      • Sellers S.
      • MacKenzie I.Z.
      • Yudkin P.L.
      • Johnson A.M.
      Case-control study of antenatal and intrapartum risk factors for cerebral palsy in very preterm singleton babies.
      • 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?.
      but not others.
      • Thorngren-Jerneck K.
      • Herbst A.
      Perinatal factors associated with cerebral palsy in children born in Sweden.
      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.
      Report of the national high blood pressure education program working group on high blood pressure in pregnancy.
      • Shankaran S.
      Prevention, diagnosis, and treatment of cerebral palsy in near-term and term infants.
      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
      • 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.
      • Stene L.C.
      • Magnus P.
      • Lie R.T.
      • 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.
      but not all.
      • Dahlquist G.G.
      • Patterson C.
      • Soltesz G.
      Perinatal risk factors for childhood type 1 diabetes in Europe: the EURODIAB substudy 2 study group.
      • Jones M.E.
      • Swerdlow A.J.
      • Gill L.E.
      • Goldacre M.J.
      Pre-natal and early life risk factors for childhood onset diabetes mellitus: a record linkage study.
      • McKinney P.A.
      • Parslow R.
      • Gurney K.A.
      • Law G.R.
      • Bodansky H.J.
      • Williams R.
      Perinatal and neonatal determinants of childhood type 1 diabetes: a case-control study in Yorkshire, UK.
      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
      • Aschim E.L.
      • Haugen T.B.
      • Tretli S.
      • Daltveit A.K.
      • Grotmol T.
      Risk factors for hypospadias in Norwegian boy–association with testicular dysgenesis syndrome?.
      • Akre O.
      • Lipworth L.
      • Cnattingius S.
      • Sparen P.
      • Ekbom A.
      Risk factor patterns for cryptorchidism and hypospadias.
      • Chong J.H.
      • Wee C.K.
      • Ho S.K.
      • Chan D.K.
      Factors associated with hypospadias in Asian newborn babies.
      • Sorensen H.T.
      • Pedersen L.
      • Norgaard M.
      • Wogelius P.
      • Rothman K.J.
      Maternal asthma, preeclampsia and risk of hypospadias.
      but not all.
      • Hussain N.
      • Chaghtai A.
      • Herndon C.D.
      • Herson V.C.
      • Rosenkrantz T.S.
      • McKenna P.H.
      Hypospadias and early gestation growth restriction in infants.
      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
      • Lange A.P.
      Obstetric guidelines in coding and definitions.
      • Johansen M.
      • Kjaergaard N.
      • Legarth J.
      • Salvig J.D.
      • Skajaa K.
      • Wilken-Jensen C.
      Hypertension in pregnancy Sandbjerg guidelines.
      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).
      American College of Obstetricians and Gynecologists
      National high blood pressure education program working group on high blood pressure in pregnancy.
      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.
      • Klemmensen A.K.
      • Olsen S.F.
      • Wengel C.M.
      • Tabor A.
      Diagnostic criteria and reporting procedures for pre-eclampsia: a national survey among obstetrical departments in Denmark.
      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.
      • Klemmensen A.K.
      • Olsen S.F.
      • Osterdal M.L.
      • Tabor A.
      Validity of preeclampsia-related diagnoses recorded in a national hospital registry and in a postpartum interview of the women.
      The sensitivity of the preeclampsia diagnosis in the register was about 69%.
      • Klemmensen A.K.
      • Olsen S.F.
      • Osterdal M.L.
      • Tabor A.
      Validity of preeclampsia-related diagnoses recorded in a national hospital registry and in a postpartum interview of the women.
      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.
      • Rothman K.J.
      • Greenland S.
      Modern epidemiology.
      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.
      • Munk-Jorgensen P.
      • Mortensen P.B.
      The Danish Psychiatric Central Register.
      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.
      • Conde-Agudelo A.
      • Althabe F.
      • Belizan J.M.
      • Kafury-Goeta A.C.
      Cigarette smoking during pregnancy and risk of preeclampsia: a systematic review.
      • England L.J.
      • Kendrick J.S.
      • Gargiullo P.M.
      • Zahniser S.C.
      • Hannon W.H.
      Measures of maternal tobacco exposure and infant birth weight at term.
      • Newman M.G.
      • Lindsay M.K.
      • Graves W.
      Cigarette smoking and pre-eclampsia: their association and effects on clinical outcomes.
      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.
      • Catov J.M.
      • Ness R.B.
      • Kip K.E.
      • Olsen J.
      Risk of early or severe pre-eclampsia related to pre-existing conditions.
      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.

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