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Department of Pediatrics, Kuopio University Hospital (S.T., E.R., A.M., R.V.), and Computing Center, Kuopio University (P.H.), FIN-70211 Kuopio, Finland
Address all correspondence and requests for reprints to: Dr. Raimo Voutilainen, Department of Pediatrics, Kuopio University Hospital, P.O. Box 1777, FIN-70211 Kuopio, Finland. E-mail address: raimo.voutilainen{at}uku.fi.
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Abstract |
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The PRE children had significantly higher mean systolic (116.4 vs. 113.2 mm Hg; P = 0.021) and diastolic (73.9 vs. 70.3 mm Hg; P = 0.022) BP than the non-PRE children, even when adjusted by current weight and height. At 12 yr of age, systolic BP values correlated inversely with birth weight (r = -0.459; P < 0.001) and length SD scores (r = -0.429; P = 0.001) in the PRE children. The mean concentrations of serum total, low density lipoprotein, and high density lipoprotein cholesterol; triglycerides; fasting insulin; blood glucose; serum cortisol; and dehydroepiandrosterone sulfate did not differ between the PRE and non-PRE groups. However, the mean plasma E concentration was higher in the PRE than in the non-PRE children (0.32 vs. 0.28 nmol/liter; P = 0.042), whereas the mean NE concentration did not differ between these two groups. In conclusion, 12-yr-old children born with maternal preeclampsia had elevated systolic and diastolic BPs and slightly increased E levels in the circulation. It is not known whether these changes are caused by genetic factors or by preeclampsia itself.
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Introduction |
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The aim of our study was to determine whether elevated BP and metabolic changes, such as dyslipidemia, insulin resistance, and increased adrenal hormonal activity, are found in 12-yr-old children of preeclamptic mothers (PRE). BP values, concentrations of blood glucose, serum fasting insulin, total and high density lipoprotein (HDL) cholesterol, triglycerides, cortisol, dehydroepiandrosterone sulfate (DHEAS), and plasma epinephrine (E) and norepinephrine (NE) were studied in 60 children with maternal preeclampsia and in 60 matched control subjects of normotensive mothers (non-PRE).
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Subjects and Methods |
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Preeclampsia was defined as the development of hypertension and proteinuria (>300 mg urinary protein in 24 h) after 20 wk gestation (10). Hypertension was defined as a BP greater than 140/90 mm Hg or a rise in BP of 30/15 mm Hg from the baseline level confirmed by two measurements at least 6 h apart. Full-term indicates babies born at or after wk 37 and before the 42nd wk of gestation, and preterm indicates babies born before the 37th wk of gestation (calculated from the beginning of the last menstruation). Small for gestational age (SGA) was defined as birth weight and/or length and/or ponderal index more than 2 SD scores below the respective mean for the gestational age and sex (11). The ponderal index was calculated as [weight (g)/length (cm3)] x 100. Appropriate for gestational age (AGA) was defined as birth weight, birth length, and ponderal index equal to or above -2 SD score and equal to or below +2 SD score of the respective mean for gestational age and sex (11). Parent-specific expected height (PSEH) was calculated as determined by Pere et al. (12).
Subjects
All children were born at Kuopio University Hospital during a 22-month period between 1984 and 1986. The group of children born to preeclamptic mothers consisted of every third full-term child and all preterm children, with the exception of extremely preterm children born before the 28th gestational wk. Of this group all 84 nonmalformed children with maternal preeclampsia were included in the present study as the PRE group. At 12 yr of age, 60 (71.4%) PRE children participated in this study (Fig. 1
). The PRE children (33 preterm and 27 full-term) and their 60 control subjects born to normotensive mothers were matched for sex, gestational age (±1 wk), and size at birth (SGA vs. SGA, AGA vs. AGA). Matching for size at birth did not succeed in 6 case-control pairs, because the 6 original control subjects refused to participate in the study. Consequently, 6 preterm PRE children born SGA had a control subject born AGA instead of SGA. The mean (±SD) age of the children in both study and control group was 12.3 ± 0.2 yr. None of the participating children was exposed to exogenous corticosteroids prenatally. The study protocol was approved by the research ethics committee of Kuopio University Hospital. Informed written consent was obtained from the child and the parents.
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Perinatal data, e.g. birth weight, length, head circumference, and duration of gestation, had previously been obtained from hospital records. Birth weight, length, and head circumference had been measured in the delivery room immediately after birth. The birth measures were converted to SD scores by plotting them on the growth charts and adjusting the birth measures by duration of gestation and gender (11). The perinatal characteristics of the PRE and non-PRE groups are shown in Table 1. The means of birth measures and gestational age of children who had dropped out of the study were not different from those of the participating PRE children.
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At the age of 12 yr, height was measured with a calibrated Harpenden stadiometer and recorded to the nearest 0.1 cm, and weight was recorded to the nearest 0.1 kg. Height was converted to an SD score, and weight to a percentage in relation to the mean weight for height using the current Finnish reference values for height and weight for height (Pegasos V 3.9.2, Pediatric Research Foundation, Helsinki, Finland). Head circumference was measured with a metal measuring tape as the maximum circumference between the supraorbital ridge and the occiput. A complete physical examination was performed for all children by one of the authors (S.T. or E.R.). Thicknesses of the subscapular and triceps skinfolds were measured three times with a Harpenden skinfold caliper and were recorded to the nearest 0.2 mm. The mean value was used in the analysis. Pubertal stage was defined according to the Tanner scale (13, 14). For growth analysis, pubertal stages were further classified by taking account of the breast scores for girls and the genital scores for boys. Breast scores of 1–2 indicated the early stage of puberty, and scores of 3–5 indicated the late stage of puberty in girls. Knowing that the pubertal growth spurt occurs at a later stage in boys than in girls, we graded genital scores of 1–3 as the early stage of puberty and scores of 4–5 as the late stage of puberty in boys. Information on parental heights was obtained by a questionnaire, with the exception of missing data for eight fathers.
BP measurements
BP was measured with a standard sphygmomanometer during a home visit by one of the authors (S.T. or E.R.). The proper cuff was chosen according to the arm length of the subject. Korotkoff phase I was used to measure systolic BP, and Korotkoff phase V was used to measure diastolic BP. BP was measured three times in a seated position after 5 min of rest. The mean values of these three readings were used in the analysis.
We managed to measure BP in 54 PRE and 46 non-PRE mothers during our data collection. The mean (±SD) systolic BP was 139.1 ± 17.6 mm Hg, and the mean diastolic BP was 88.5 ± 11.6 mm Hg in the PRE mothers; these BP values were 132.0 ± 16.9 and 84.0 ± 10.2 mm Hg in the non-PRE mothers. The difference in systolic BPs was significant (P = 0.040), whereas the difference in diastolic BPs was not significant (P = 0.085).
Laboratory methods
Blood samples were taken in the morning, between 0900–1000 h, after an overnight fast. An iv cannula was placed in the antecubital vein for blood sampling. After the child had rested for 1 h in a recumbent position, blood samples were drawn through the cannula. For the analysis of catecholamines, the blood was collected in ice-chilled tubes and centrifuged as soon as possible at 4 C. Plasma and serum specimens were immediately frozen and stored at -70 C until analyzed. Catecholamines were analyzed by HPLC combined with electrochemical detection. The intraassay coefficients of variation (CV) were 7.8% for NE and 11.0% for E, and the interassay CV were 15.2% and 11.0%, respectively (15). Serum cortisol was analyzed by the Immulite 2000 chemiluminescent enzyme immunoassay (Diagnostic Products, Los Angeles, CA). The intraassay CV was 6.0%, and the interassay CV was 4.9% at concentrations of 90–850 nmol/liter. The cross-reactivity of cortisone was 1% in this assay. Serum DHEAS was analyzed by the Coat-A-Count DHEA-SO4 RIA (Diagnostic Products). The sensitivity of the assay was 0.03 µmol/liter, and the intraassay CV was 3.8% for low values and 5.3% for high values. The interassay CV were 6.3% and 11% for low and high values, respectively. Serum total and HDL cholesterol and triglycerides were measured enzymatically by an automatic photometric method (Roche Molecular Biochemicals, Mannheim, Germany). Low density lipoprotein (LDL) cholesterol concentrations were calculated by the Friedewald-Fredrickson formula [LDL cholesterol = total cholesterol - (HDL cholesterol + triglycerides/2.2)] (16). Serum insulin levels were determined by RIA (Phadeseph Insulin RIA, Pharmacia \|[amp ]\| Upjohn, Inc., Uppsala, Sweden), and blood glucose levels were determined by a glucose oxidase method (enzyme electrode, Nova Biomedical, Waltham, MA).
Data analysis
Data were analyzed using the SPSS for Windows statistical package (version 10.0, SPSS, Inc., Chicago, IL). All continuous variables were examined for normality with the Kolmogorov-Smirnov test. Because the data were based on matched pairs, and some variables were distributed nonnormally, the Wilcoxon matched pairs, signed rank test was used to compare the means. The paired sample t test was used for comparing E and NE concentrations after logarithmic transformation. The McNemar test was used to compare the dichotomous variables. Confidence intervals were calculated using a critical value from the t distribution because of nonnormal distributions. BP variables were distributed normally and were analyzed by paired samples t test and repeated measures ANOVA adjusted by current weight and height. BP values of the mothers were analyzed by Mann-Whitney test. Either Pearson or Spearman correlation coefficients were computed. Correlations between BP and birth measures were adjusted by weight and height at 12 yr of age. P < 0.05 was accepted as significant for all analyses.
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Results |
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The mean height, expressed as an SD score, was significantly lower in PRE than in non-PRE children. No difference was found in mean height between PRE and non-PRE mothers (164.7 vs. 164.5 cm; P = 0.631). Surprisingly, fathers of PRE children were significantly shorter than those of non-PRE children (175.3 vs. 178.9 cm; P = 0.001). The mean PSEH did not differ between the two groups, but adjustment for PSEH eliminated the difference in the current height between PRE and non-PRE groups (Table 2). The means of weight, weight for height, head circumference, body mass index, and skinfold thicknesses did not differ between PRE and non-PRE groups. Furthermore, the progress of puberty was very similar in these two groups (Table 2).
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The mean concentrations of serum total, LDL, and HDL cholesterol and triglycerides did not differ between PRE and non-PRE children. The same was true for serum fasting insulin, blood glucose, and the insulin/glucose ratio. Moreover, no differences were found in the means of serum cortisol and DHEAS. The mean plasma E concentration was slightly higher in PRE than in non-PRE children, whereas NE concentrations did not differ between these groups (Table 3). When the PRE and non-PRE groups were subdivided into SGA and AGA subjects, the SGA PRE children (n = 16) had the highest mean cortisol concentration (369.7 nmol/liter). These children had also the highest levels of total cholesterol (mean, 4.78 mmol/liter), LDL cholesterol (3.01 mmol/liter), triglycerides (0.99 mmol/liter), insulin (10.9 mU/liter), and plasma E (0.35 nmol/liter) compared with AGA PRE children or non-PRE children. However, these differences were not significant.
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PRE children had significantly higher systolic and diastolic BP values than non-PRE children. After adjusting the BP values by current weight and height, the differences between the groups were still significant (Table 3
). The SGA PRE children had the highest mean systolic (120.0 mm Hg) and diastolic (76.3 mm Hg) BP values. Systolic BP correlated inversely with birth weight (r = -0.459; P < 0.001) and length SD scores (r = -0.429; P = 0.001) in PRE children, but not in non-PRE children. Significant positive correlations were found between systolic BP and weight and body mass index at 12 yr in both PRE and non-PRE groups. The BP values correlated with neither serum lipids nor catecholamines in PRE children; however, systolic BP correlated positively with serum cortisol (r = 0.307; P = 0.018). Furthermore, systolic BP had a positive correlation to serum insulin in PRE children (r = 0.331; P = 0.010). In non-PRE children diastolic BP correlated positively with total (r = 0.310; P = 0.017) and LDL cholesterol (r = 0.307; P = 0.018).
Correlations between serum insulin and anthropometric measures, serum lipids, and adrenal hormones
Serum insulin had a positive correlation with current weight in PRE (r = 0.361; P = 0.005) and non-PRE (r = 0.640; P < 0.001) groups. No correlations were found between insulin levels and serum lipid concentrations in PRE children, whereas in non-PRE children insulin correlated positively with triglycerides (r = 0.412; P = 0.001). Serum insulin did not correlate with adrenal hormones in the PRE or non-PRE group. Serum cortisol and plasma E correlated positively in both the PRE and non-PRE groups (r = 0.381; P = 0.003 and r = 0.361; P = 0.005, respectively). In PRE children serum cortisol correlated inversely with birth weight (r = -0.326; P = 0.011) and length (r = -0.332; P = 0.010) SD scores.
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Discussion |
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Previous reports indicate that maternal preeclampsia may be associated with elevated BP in offspring (8, 9). According to Palti and Rothschild (8), 6-yr-old children born to preeclamptic mothers had higher diastolic BPs than control subjects born to normotensive mothers. Seidman et al. (9) reported that girls with maternal preeclampsia had higher BPs than their control subjects at 17 yr of age. On the other hand, Ounsted and co-workers (17) found no BP differences in 7-yr-old children born with maternal preeclampsia compared with children born after hypertensive pregnancy. In our study both systolic and diastolic BPs were higher in PRE children than in non-PRE children, and the differences were significant after adjusting the BPs by current weight and height. In particular, the SGA PRE children had the highest systolic and diastolic BPs. The relationship between low birth weight and elevated BP in children and adults has been shown in many studies (18). Accordingly, being born SGA could be an additional risk factor for elevated BP in children born after preeclamptic pregnancy.
We are not aware of previously published data concerning serum lipid concentrations in offspring of preeclamptic mothers. We found no significant differences in lipid concentrations between the PRE and non-PRE groups. However, the SGA PRE children had the highest concentrations of serum total and LDL cholesterol; the concentrations were higher than those in AGA PRE children or in SGA or AGA non-PRE children even though the differences were not significant. In a recent study, full-term SGA 12-yr-old children more commonly had high concentrations of total cholesterol than their AGA control subjects (19).
Preeclampsia leads to fetal growth retardation in about 30% of cases (20). Previous growth studies have indicated that children born SGA have many times greater risk of being short adults (less than -2 SD score) than those born AGA (21, 22, 23). Presumably, some children born after preeclamptic pregnancy may become short adults. In the study by Palti and Rothschild (8), low birth weight was seen in 12.7% of the preeclamptic children. At 6 yr of age, height and weight did not differ between the children born after preeclamptic or normotensive pregnancy in that study (8). In our study, PRE children were shorter than their non-PRE control subjects at 12 yr of age, also after excluding SGA subjects from the analysis. However, after adjusting the current height by PSEH, the difference disappeared; the shortness of the fathers in the PRE group explained the difference.
We found that birth weight and length correlated inversely with serum cortisol in PRE children, but not in control subjects. Phillips and co-workers (24, 25) showed that in adults low birth weight predicted elevated plasma cortisol concentrations, which were further associated with insulin resistance, increased concentrations of triglycerides, and elevated BP. It has been suggested that dysfunction of 11ß-hydroxysteroid dehydrogenase type 2 (11ßHSD2), which converts cortisol to inactive cortisone, could be involved in fetal growth retardation (26, 27). A recent study revealed that placental expression of the 11ßHSD2 gene was reduced in preeclampsia (28). Furthermore, McCalla et al. (29) reported that in preeclampsia elevated umbilical cord cortisol levels resulting from reduced 11ßHSD2 activity may contribute to impaired fetal growth.
The role of the sympathetic system in the pathogenesis of preeclampsia is obscure. In previous studies, plasma catecholamine concentrations have been found to be increased in preeclamptic pregnant women (2, 30, 31), and increased catecholamine secretion was supposed to be of placental origin (31). In our study, PRE children had slightly higher circulating E levels than non-PRE children. This finding needs to be confirmed in independent studies; the methodology for plasma catecholamine measurements is demanding, as shown by the relatively high CV in our study. The highest concentrations of plasma E were found in the SGA PRE and non-PRE children (0.35 and 0.37 nmol/liter, respectively). This finding is in accordance with our recent study, in which 12-yr-old children born SGA at term had higher plasma E levels than their control subjects born AGA (32).
In summary, systolic and diastolic BP values as well as circulating E levels were elevated in our PRE children. We speculate that endocrine programming might provide an explanation for the relationship between maternal preeclampsia and elevated BP in offspring. However, the consequences of maternal preeclampsia to offspring are probably caused by many factors, including genetic ones and influences of retarded intrauterine growth.
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Footnotes |
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Abbreviations: AGA, Appropriate for gestational age; BP, blood pressure; CV, coefficient(s) of variation; DHEAS, dehydroepiandrosterone sulfate; E, epinephrine; HDL, high density lipoprotein; 11ßHSD2, 11ß-hydroxysteroid dehydrogenase type 2; LDL, low density lipoprotein; NE, norepinephrine; non-PRE, normotensive pregnancy; PRE, preeclamptic pregnancy; PSEH, parent-specific expected height; SGA, small for gestational age.
Received June 10, 2002.
Accepted December 2, 2002.
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