Objective
Preterm birth at very low birthweight (<1500 g) is associated with cardiometabolic risk factors and reduced bone mineral density in the adult offspring. Preeclampsia is a frequent cause of preterm birth and is also associated with cardiometabolic risk factors in the offspring. Whether it is associated with bone mineral density is not known.
Study Design
We evaluated skeletal health in participants of the Helsinki Study of Very Low Birthweight Adults: 144 born at very low birthweight and 139 born at term. From the very low birthweight and term offspring a respective 32 and 11 were born from pregnancy complicated by preeclampsia. We measured bone mineral density at age 18.5 to 27.1 years by dual X-ray absorptiometry.
Results
Very low birthweight adults exposed to maternal preeclampsia had higher lumbar spine Z score (mean −0.44, compared with −1.07 in very low birthweight unexposed adults, P = .002), femoral neck Z score (−0.05 vs −0.53, P = .003) and whole body bone mineral density Z score (−0.14 vs −0.72, P = .001). Corresponding Z scores for those born at term were −0.02 (preeclampsia) and −0.45 (no preeclampsia) for lumbar spine ( P = .2), 0.78 and 0.08 for femoral neck ( P = .02) and 0.02 and −0.31 for whole body bone mineral density Z score ( P = .08). The results survived adjustment for offspring current height, body mass index, leisure time physical activity, socioeconomic position, smoking, and maternal smoking during pregnancy, and maternal prepregnancy body mass index.
Conclusion
Young adults exposed to maternal preeclampsia have higher bone mineral density than those not exposed. This difference is seen among those born at very low birthweight and seems also to be present among those born at term.
Pregnancy changes the maternal bone metabolism and mineralization to meet the skeletal bone growth requirements of the fetus. These hormone-mediated adjustments begin early in pregnancy and are at a maximum during the third trimester, when the fetal demand for calcium is the greatest. When pregnancy ends prematurely, the offspring is at risk for insufficient bone mineralization.
Preeclampsia is a common reason for indicated preterm delivery. This vascular disorder of uncertain etiology complicates approximately 3% of pregnancies worldwide. The only cure is the delivery of the placenta. In particular severe and early forms of the disease are often associated with acute maternal symptoms or placental dysfunction, or both, resulting in fetal growth restriction. This frequently necessitates preterm delivery. Preeclampsia occurring at term is usually less severe and often no fetal growth restriction is present. Previous studies have shown that preeclampsia increases the offspring’s risk of cardiometabolic disease and poorer psychological functioning later in life. We are unaware of any previous studies that have investigated skeletal health of offspring born from preeclamptic pregnancies.
The survival of premature infants has improved tremendously the past decades. As a result adult health and well-being of these offspring has recently raised considerable attention. Previous studies have shown that prematurity adversely affects the skeletal mineralization and bone-mass development in children and young adults. Our aim was to assess bone mineral density and bone mineral content of offspring born from preeclamptic pregnancy. Because preeclampsia occurring earlier in pregnancy could be clinically distinct from preeclampsia at term, we performed the analyses separately among those born preterm at very low birthweight (VLBW; <1500 g) and among controls born at term.
Materials and Methods
The subjects in the study are part of the Helsinki Study of Very Low Birthweight Adults. This multidisciplinary cohort represents all subjects born preterm at very low birthweight (VLBW, <1500 g) in the province of Uusimaa, Finland, between the years 1978 and 1985 and treated in the neonatal intensive care unit of Children’s Hospital at Helsinki University Central Hospital. Of the 474 admitted to the unit 335 were discharged alive. In 2004, for each VLBW survivor a control person of same sex was selected from the records of all consecutive births. This person also had to be born at term in the same hospital as the VLBW survivor and not be small for gestational age (SGA). The recruitment of the young adults and the exclusion criteria have been described in detail.
We extracted data on hypertensive disorders during pregnancy from hospital and maternal welfare clinic records. To meet contemporary diagnostic criteria, we defined preeclampsia as blood pressure exceeding 140/90 mm Hg after midpregnancy, accompanied by proteinuria (≥0.3 g protein excretion in a 24-hour urine sample or a positive dipstick) and without history of hypertension medication before pregnancy or during the first trimester. We defined gestational hypertension according to the same blood pressure criteria but without proteinuria. Of the 144 VLBW and 139 term-born individuals participating in the clinical study 32 and 11 were born from pregnancy complicated by preeclampsia, respectively.
The participants were between 18.5 and 27.1 years of age. The clinical study included anthropometric measurements as well as measurements of bone mineral content (BMC) and bone mineral density (BMD) for lumbar spine (L1-L4), femoral neck, whole body and body composition by dual-energy x-ray absorptiometry (DXA, Hologic Discovery A, software version 12.3:3; Bedford, MA). The results were transformed into age- and sex-specific Z-scores on the basis of an equipment-specific reference database. Bone mineral apparent density (BMAD) value was calculated to minimize the effect of bone size on lumbar spine BMD (BMAD = BMC L1-4 /bone area L1-4 1.5 ). We previously described the method of the DXA bone densitometry as well as the stages of the clinical study. The participants filled in food diaries for 2 working days and 1 day in the weekend. They were instructed and the data were reviewed by a nutritionist, and the Finnish Food Composition Database was used to calculate the average daily intake of calcium, phosphate and vitamin D. The participants filled in questionnaires of their current medications, leisure-time physical activity, including questions on the intensity of leisure-time conditioning physical activity, their frequency of alcohol consumption and parents’ present educational attainment. Maternal prepregnancy BMI, based on self-reported height and weight recorded during early pregnancy, was obtained from the maternal welfare clinic records.
Statistical analysis
The analyses were performed using SPSS for Windows, version 18 (SPSS, Inc, Chicago, IL). Pearson’s χ 2 test was used to compare proportions and Student t test to compare means. The group mean differences were estimated with multiple linear regression. We started these analyses with a model adjusting for sex only. We then used BMI and height as covariates in the models because body size is associated with bone mass and maternal preeclampsia. As a proxy of childhood socioeconomic position, we used the educational attainment of the higher-educated parent. In the full model, we also included lifestyle factors such as smoking and maternal smoking during pregnancy, because smoking is associated with lower rates of preeclampsia and reduced BMD, and intensity of leisure time physical activity that is associated with BMD and may in part be programmed in utero. Parity was also included as covariate because of its strong association with maternal preeclampsia. Calcium, phosphate, and vitamin D intake and alcohol consumption were also considered as covariates, but were omitted from the final models because they did not change the effect of preeclampsia, and data on nutrient intake were available only for part of the subjects. To assess the effect of gestational age on the outcome, secondary analyses were performed after exclusion of SGA offspring of the VLBW group and on a subgroup including only offspring born between 28-32 weeks of gestation. For the lumbar spine and femoral neck analysis, 3 VLBW subjects were excluded because of severe spine deformity or because of foreign object that made the BMD measurement unreliable. For the whole body analysis 5 VLBW subjects were excluded because of a foreign object.
Results
Study population
The maternal and newborn characteristics of the study groups are presented in Table 1 . In the VLBW group, there was no difference in the crude birthweights between offspring born from pregnancy complicated by PE and offspring born from nonpreeclamptic pregnancy. However, the offspring in the VLBW preeclampsia group had higher gestational age by 1.8 weeks (95% confidence interval, 1.0–2.6) compared with the offspring from the VLBW nonpreeclampsia group, and accordingly their birthweight SD score was lower. Among the term born infants, differences in birthweight and gestational age between the 2 groups were not statistically significant.
| Characteristics | VLBW | Term | ||
|---|---|---|---|---|
| Preeclampsia n = 32 | No preeclampsia n = 112 | Preeclampsia n = 11 | No preeclampsia n = 128 | |
| Maternal prepregnancy BMI, b kg/m 2 | 23.1 (3.4) | 22.1 (3.8) | 23.0 (3.1) | 22.3 (3.6) |
| Maternal smoking in pregnancy a | 3 (9.4) | 25 (22.3) | 0 (0) | 20 (15.6) |
| Maternal gestational hypertension a | 0 (0) | 5 (4.5) | 0 (0) | 21 (16.4) |
| Primiparous a | 19 (59.4) | 49 (44.1) | 5 (45.5) | 64 (50.0) |
| Men a , n (%) | 13 (40.1) | 47 (42.0) | 6 (54.6) | 49 (38.3) |
| Birthweight, b g | 1128 (235) | 1127 (214) | 3502(559) | 3608(464) |
| Gestational age, b wk | 30.7 (2.1) | 28.9 (2.1) | 39.5 (0.9) | 40.2 (1.1) |
| Birthweight, b SD score | −2.5 (1.3) | −1.0 (1.4) | −0.1 (1.1) | 0.1 (1.0) |
| Placental weight, b g | 404 (221) | 445 (170) | 641 (130) | 664 (146) |
| Age at study assessment, b y | 22.5 (2.0) | 22.6 (2.2) | 21.5 (1.7) | 22.7 (2.2) |
| Height, c cm | 168.3 (10.2) | 167.6 (9.8) | 174.0 (12.9) | 172.2 (8.9) |
| Men | 176.8 (9.0) | 175.1 (6.7) | 184.1 (7.0) | 180.1 (6.1) |
| Women | 162.5 (6.1) | 162.1 (7.8) | 161.9 (4.8) | 167.3 (6.5) |
| Weight, c kg | 65.6 (16.0) | 61.8 (12.4) | 71.3 (9.7) | 68.9 (12.9) |
| Men | 76.6 (12.5) f | 66.5 (12.7) | 76.3 (9.4) | 77.1 (10.9) |
| Women | 58.1 (13.6) | 58.4 (11.0) | 65.4 (6.7) | 63.8 (11.4) |
| BMI, c kg/m 2 | 22.9 (3.7) | 22.0 (3.7) | 23.7 (3.2) | 23.2 (3.6) |
| Men | 24.4 (2.8) f | 21.7 (3.8) f | 22.5 (2.3) | 23.8 (3.1) |
| Women | 21.9 (3.9) | 22.2 (3.6) | 25.1 (3.7) | 22.8 (3.8) |
| Smoking a | 10 (31.3) | 29 (26.4) | 5 (45.5) | 47 (36.7) |
| Parental educational attainment a | ||||
| Elementary | 2 (6.5) | 13 (11.7) | 1 (9.1) | 9 (7.0) |
| Intermediate | 9 (29.0) | 22 (19.8) | 2 (18.2) | 24 (18.8) |
| University | 10 (32.3) | 47 (42.3) | 4 (36.4) | 40 (31.3) |
| Unknown | 10 (32.3) | 29 (26.1) | 4 (36.4) | 55 (43.0) |
| Physical activity a,d | ||||
| Walking | 11 (35.5) | 31 (29.0) | 1 (9.1) | 15 (11.9) |
| Walking/light running | 4 (12.9) | 35 (32.7) | 6 (54.5) | 28 (22.2) |
| Light running | 11 (35.5) | 27 (25.2) | 2 (18.2) | 38 (30.2) |
| Brisk running | 5 (16.1) | 14 (13.1) | 2 (18.2) | 45 (35.7) |
| Alcohol use a | ||||
| Daily | 0 (0) | 3 (2.7) | 0 (0) | 4 (3.1) |
| Weekly | 13 (41.9) | 48 (43.2) | 6 (54.5) | 75 (58.6) |
| Monthly | 10 (32.3) | 32 (28.8) | 3 (27.3) | 39 (30.5) |
| Few times a year | 5 (16.1) | 18 (16.2) | 1 (9.1) | 9 (7.0) |
| Not at all | 3 (9.7) | 10 (9.0) | 1 (9.1) | 1 (0.8) |
| Calcium intake, c,e mg/d | 722 (1.68) | 750 (1.83) | 1130 (1.70) | 990 (1.58) |
| Phosphate intake, c,e mg/d | 1167 (1.48) | 1196 (1.46) | 1480 (1.51) | 1422 (1.39) |
| Vitamin D intake, c,e μg/d | 2.7 (2.1) | 3.1 (2.0) | 4.3 (1.5) | 3.4 (2.0) |
c Numbers represent means (geometric SDs) for the intakes of calcium, phosphate, and vitamin D, weight, height, and BMI
d Intensity of leisure time conditioning physical activity
e Data missing for 1/12/1/31 subjects in VLBW preeclampsia/no preeclampsia and term preeclampsia/no preeclampsia groups, respectively
f P < .05 for the difference between PE and no-PE group in VLBW offspring.
At the time of the study assessment there was no difference in the age, height, or BMI between the preeclamptic and nonpreeclamptic groups among VLBW or among term offspring, although when sexes were assessed separately, VLBW men of the preeclamptic group had higher BMI than nonpreeclampsia VLBW men ( Table 2 ). There was no statistically significant difference in parental educational attainment, leisure-time physical activity, smoking, or calcium, phosphate, and vitamin D intake between offspring born from preeclamptic and nonpreeclamptic pregnancies among VLBW and term groups ( Table 2 ).
| Characteristics | Sex | VLBW | Term | ||||
|---|---|---|---|---|---|---|---|
| PE, n = 32 | No PE, n = 112 | P value | PE, n = 11 | No PE, n = 128 | P value | ||
| Lumbar spine BMD Z score a | −0.44 (0.91) | −1.07 (0.96) | .002 | −0.02 (1.20) | −0.45 (1.03) | .238 | |
| Male | −0.55 (0.94) | −1.37 (1.05) | .016 | −0.15 (1.55) | −0.66 (1.20) | .347 | |
| Female | −0.43 (0.91) | −0.85 (0.81) | .054 | 0.22 (0.73) | −0.32 (0.89) | .191 | |
| Lumbar spine BMAD a | 0.128 (0.011) | 0.121 (0.013) | .013 | 0.130 (0.015) | 0.127 (0.014) | .502 | |
| Male | 0.126 (0.012) | 0.116 (0.014) | .020 | 0.124 (0.017) | 0.123 (0.016) | .864 | |
| Female | 0.129 (0.011) | 0.125 (0.012) | .213 | 0.137 (0.009) | 0.130 (0.012) | .181 | |
| Femoral neck BMD Z score a | −0.05 (0.73) | −0.53 (0.86) | .003 | 0.78 (0.87) | 0.084 (0.96) | .022 | |
| Male | 0.03 (0.74) | −0.61 (0.93) | .028 | 0.73 (1.08) | 0.20 (1.12) | .271 | |
| Female | −0.13 (0.72) | −0.55 (0.84) | .044 | 0.84 (0.67) | 0.01 (0.85) | .037 | |
| Whole body BMD Z score b | −0.14 (0.70) | −0.72 (0.88) | .001 | 0.018 (1.21) | −0.31 (0.99) | .079 | |
| Male | −0.15 (0.77) | −0.94 (0.99) | .016 | 0.32 (1.67) | −0.37 (1.18) | .207 | |
| Female | −0.19 (0.71) | −0.56 (0.77) | .060 | 0.52 (0.36) | −0.28 (0.85) | .040 | |
| Whole body BMC b , g | 2259 (430) | 2105 (394) | .059 | 2618 (551) | 2318 (406) | .024 | |
| Male | 2670 (367) | 2299 (376) | .004 | 2918 (583) | 2648 (382) | .130 | |
| Female | 1992 (253) | 1926 (271) | .334 | 2258 (189) | 2113 (260) | .226 | |
| Whole body fat, % of body weight | 25.5 (7.4) | 24.5 (8.8) | .560 | 22.2 (9.2) | 25.7 (7.8) | .166 | |
| Male | 20.4 (5.3) | 17.4 (6.5) | .124 | 15.0 (3.6) | 18.7 (5.7) | .127 | |
| Female | 28.5 (7.0) | 29.8 (5.9) | .399 | 30.8 (5.1) | 30.0 (5.5) | .733 | |
| Whole body lean mass, kg | 47.4 (12.2) | 45.0 (9.4) | .325 | 54.6 (13.0) | 49.9 (11.0) | .187 | |
| Male | 59.1 (8.6) | 52.5 (7.8) | .009 | 64.1 (9.6) | 61.1 (7.6) | .391 | |
| Female | 41.0 (6.4) | 40.9 (5.7) | .954 | 45.5 (2.7) | 45.0 (5.9) | .867 | |
| Whole body lean mass adjusted for height, kg | 47.2 (1.8) | 45.1 (1.0) | .296 | 54.9 (3.4) | 49.9 (1.0) | .159 | |
| Male | 58.8 (2.3) | 52.6 (1.1) | .016 | 64.2 (3.2) | 61.1 (1.1) | .367 | |
| Female | 39.0 (1.3) | 40.0 (0.7) | .990 | 43.2 (2.4) | 43.0 (0.6) | .908 | |
Comparisons between offspring from preeclamptic and nonpreeclamptic pregnancies among those born at VLBW
Table 2 and the Figure show that VLBW offspring whose mothers had preeclampsia had higher BMD Z-scores of lumbar spine, femoral neck, and whole body. Also their lumbar spine BMAD and whole body BMC were higher, although the latter was not statistically significant. Adjustments for current height, BMI, and socioeconomic position attenuated the differences; however, they still remained significant in all of the skeletal health outcome variables ( Table 3 ). Further adjustment for physical activity, current smoking, maternal smoking, and parity ( Table 3 , model 5), and for maternal prepregnancy BMI and alcohol use (not shown), and for the 130 VLBW and 107 term subjects with available data, also for calcium, phosphate, and vitamin D intake (not shown) had little effect on the results. The differences we found were greater among men, although the interaction term sex*preeclampsia was not statistically significant. VLBW men whose mothers had preeclampsia were heavier, had a higher BMI, and lean body mass than VLBW men whose mothers did not have preeclampsia ( Table 2 ).
| Characteristics | Model | VLBW | Term | ||
|---|---|---|---|---|---|
| Mean difference (95% CI) | P value | Mean difference (95% CI) | P value | ||
| Lumbar spine BMD Z score | 1 | 0.60 (0.24–0.98) | .002 | 0.52 (−0.12 to 1.17) | .112 |
| 2 | 0.58 (0.18–0.90) | .002 | 0.53 (−0.11 to 1.17) | .101 | |
| 3 | 0.47 (0.13–0.81) | .008 | 0.48 (−0.11 to 1.05) | .108 | |
| 4 | 0.41 (0.06–0.75) | .021 | 0.64 (0.05–1.24) | .035 | |
| 5 | 0.42 (0.08–0.76) | .016 | 0.70 (0.13–1.27) | .017 | |
| Lumbar spine BMAD a | 1 | 6.39 (1.42–11.37) | .012 | 4.17 (−4.52 to 12.85) | .345 |
| 2 | 6.74 (1.82–11.66) | .008 | 4.04 (−4.60 to 12.68) | .357 | |
| 3 | 5.78 (1.28–10.28) | .012 | 3.48 (−4.46 to 11.41) | .388 | |
| 4 | 5.35 (0.77–9.94) | .022 | 3.24 (−4.58 to 11.05) | .414 | |
| 5 | 4.72 (0.10–9.34) | .046 | 6.20 (−1.48 to 13.88) | .113 | |
| Femoral neck BMD Z score | 1 | 0.41 (0.11–0.70) | .007 | 0.63 (0.11–1.15) | .019 |
| 2 | 0.45 (0.12–0.78) | .008 | 0.67 (0.08–1.27) | .028 | |
| 3 | 0.38 (0.08–0.68) | .013 | 0.63 (0.11–1.15) | .019 | |
| 4 | 0.37 (0.07–0.68) | .016 | 0.62 (0.10–1.14) | .020 | |
| 5 | 0.37 (0.06–0.68) | .020 | 0.70 (0.17–1.23) | .010 | |
| Whole body BMD Z score | 1 | 0.56 (0.23–0.90) | .001 | 0.74 (0.11–1.37) | .022 |
| 2 | 0.53 (0.20–0.86) | .002 | 0.75 (0.12–1.37) | .019 | |
| 3 | 0.49 (0.17–0.80) | .003 | 0.72 (0.12–1.32) | .019 | |
| 4 | 0.45 (0.13–0.77) | .006 | 0.70 (0.11–1.29) | .020 | |
| 5 | 0.46 (0.15–0.76) | .003 | 0.87 (0.28–1.46) | .004 | |
| Whole body BMC, g | 1 | 187 (59–314) | .004 | 211 (10–412) | .040 |
| 2 | 153 (57–250) | .002 | 221 (43–399) | .015 | |
| 3 | 136 (49–223) | .002 | 208 (50–366) | .010 | |
| 4 | 124 (36–213) | .011 | 204 (47–360) | .011 | |
| 5 | 127 (41–214) | .004 | 248 (92–404) | .002 | |
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