maternal preeclampsia and bone mineral density of the adult offspring

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OBSTETRICS Maternal preeclampsia and bone mineral density of the adult offspring Satu Miettola, MD; Petteri Hovi, MD, PhD; Sture Andersson, MD, PhD; Sonja Strang-Karlsson, MD, PhD; Anneli Pouta, MD, PhD; Hannele Laivuori, MD, PhD; Anna-Liisa Ja ¨rvenpa ¨a ¨, MD, PhD; Johan G. Eriksson, MD, DMSC; Outi Ma ¨kitie, MD, PhD; Eero Kajantie, MD, PhD 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 pre- eclampsia had higher lumbar spine Z score (mean 0.44, compared with 1.07 in very low birthweight unexposed adults, P ¼ .002), femoral neck Z score (0.05 vs 0.53, P ¼ .003) and whole body bone mineral density Z score (0.14 vs 0.72, P ¼ .001). Corre- sponding Z scores for those born at term were 0.02 (preeclampsia) and 0.45 (no preeclampsia) for lumbar spine (P ¼ .2), 0.78 and 0.08 for femoral neck (P ¼ .02) and 0.02 and 0.31 for whole body bone mineral density Z score (P ¼ .08). The results survived adjustment for offspring current height, body mass index, leisure time physical ac- tivity, 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. Key words: bone, hypertension, preeclampsia, premature birth, very- low-birthweight Cite this article as: Miettola S, Hovi P, Andersson S, et al. Maternal preeclampsia and bone mineral density of the adult offspring. Am J Obstet Gynecol 2013;209:x-ex-x-ex. P regnancy changes the maternal bone metabolism and mineraliza- tion 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. 1 When pregnancy ends prematurely, the offspring is at risk for insufcient bone mineralization. 2 Preeclampsia is a common reason for indicated preterm delivery. This vascular disorder of uncertain etiology compli- cates approximately 3% of pregnancies worldwide. 3 The only cure is the delivery of the placenta. In particular severe and early forms of the disease are often associated with acute maternal symp- toms 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 re- striction is present. Previous studies have shown that preeclampsia increases the offsprings risk of cardiometabolic From the National Institute for Health and Welfare and the Department of Obstetrics and Gynecology (Drs Miettola and Pouta), Oulu University Hospital, Oulu; Diabetes Prevention Unit, Department of Chronic Disease Prevention (Drs Hovi, Strang-Karlsson, Eriksson, and Kajantie), National Institute for Health and Welfare, Childrens Hospital, University of Helsinki, and Helsinki University Central Hospital (Drs Hovi, Andersson, Strang-Karlsson, Järvenpää, Mäkitie, and Kajantie); Research Programs Unit, Womens Health, and Department of Medical Genetics, Haartman Institute (Dr Laivuori); Department of General Practice and Primary Health Care, Institute of Clinical Medicine, University of Helsinki, and Unit of General Practice (Dr Eriksson), Helsinki University Central Hospital; and Folkhälsan Research Center (Drs Eriksson and Mäkitie), Helsinki, and Vasa Central Hospital (Dr Eriksson), Vasa, Finland. Received Dec. 11, 2012; revised April 2, 2013; accepted June 17, 2013. Supported by Academy of Finland, Päivikki and Sakari Sohlberg Foundation, Finnish Diabetes Research Foundation, Finnish Foundation for Cardiovascular Research, Finnish Foundation for Pediatric Research, Finnish Medical Societies (Duodecim and Finska Läkaresällskapet), Novo Nordisk Foundation, Yrjö Jahnsson Foundation, Signe and Ane Gyllenberg Foundation, Juho Vainio Foundation, and Sigrid Juselius Foundation. The authors report no conict of interest. Reprints: Eero Kajantie, MD, PhD, National Institute for Health and Welfare, Department of Chronic Disease Prevention, PL 30, 00271 Helsinki, Finland. eero.kajantie@helsinki.. 0002-9378/$36.00 ª 2013 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2013.06.028 MONTH 2013 American Journal of Obstetrics & Gynecology 1.e1 Research www. AJOG.org

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Page 1: Maternal preeclampsia and bone mineral density of the adult offspring

Research www.AJOG.org

OBSTETRICS

Maternal preeclampsia and bone mineral density of the adultoffspringSatu Miettola, MD; Petteri Hovi, MD, PhD; Sture Andersson, MD, PhD; Sonja Strang-Karlsson, MD, PhD;Anneli Pouta, MD, PhD; Hannele Laivuori, MD, PhD; Anna-Liisa Jarvenpaa, MD, PhD; Johan G. Eriksson, MD, DMSC;Outi Makitie, MD, PhD; Eero Kajantie, MD, PhD

OBJECTIVE: Preterm birth at very low birthweight (<1500 g) is femoral neck Z score (�0.05 vs �0.53, P ¼ .003) and whole body

associated with cardiometabolic risk factors and reduced bone mineraldensity in the adult offspring. Preeclampsia is a frequent cause ofpreterm birth and is also associated with cardiometabolic risk factorsin the offspring. Whether it is associated with bone mineral density isnot known.

STUDY DESIGN: We evaluated skeletal health in participants of theHelsinki Study of Very Low Birthweight Adults: 144 born at very lowbirthweight and 139 born at term. From the very low birthweight andterm offspring a respective 32 and 11 were born from pregnancycomplicated by preeclampsia. We measured bone mineral density atage 18.5 to 27.1 years by dual X-ray absorptiometry.

RESULTS: Very low birthweight adults exposed to maternal pre-eclampsia had higher lumbar spine Z score (mean �0.44, comparedwith �1.07 in very low birthweight unexposed adults, P ¼ .002),

From the National Institute for Health and Welfare and the Department of ObsOulu; Diabetes Prevention Unit, Department of Chronic Disease Prevention (Health andWelfare, Children’sHospital, University of Helsinki, andHelsinki UnMäkitie, and Kajantie); Research Programs Unit, Women’s Health, and DeparGeneral Practice and Primary Health Care, Institute of Clinical Medicine, UnivUniversity Central Hospital; and Folkhälsan Research Center (Drs Eriksson an

Received Dec. 11, 2012; revised April 2, 2013; accepted June 17, 2013.

Supported by Academy of Finland, Päivikki and Sakari Sohlberg FoundationCardiovascular Research, Finnish Foundation for Pediatric Research, FinnishFoundation, Yrjö Jahnsson Foundation, Signe and Ane Gyllenberg Foundatio

The authors report no conflict of interest.

Reprints: Eero Kajantie, MD, PhD, National Institute for Health and Welfare, [email protected].

0002-9378/$36.00 � ª 2013 Mosby, Inc. All rights reserved. � http://dx.doi.org/10.1

bone mineral density Z score (�0.14 vs �0.72, P ¼ .001). Corre-sponding Z scores for those born at term were �0.02 (preeclampsia)and�0.45 (no preeclampsia) for lumbar spine (P¼ .2), 0.78 and 0.08for femoral neck (P ¼ .02) and 0.02 and �0.31 for whole body bonemineral density Z score (P¼ .08). The results survived adjustment foroffspring current height, body mass index, leisure time physical ac-tivity, socioeconomic position, smoking, and maternal smoking duringpregnancy, and maternal prepregnancy body mass index.

CONCLUSION: Young adults exposed to maternal preeclampsia havehigher bone mineral density than those not exposed. This difference isseen among those born at very low birthweight and seems also to bepresent among those born at term.

Key words: bone, hypertension, preeclampsia, premature birth, very-low-birthweight

Cite this article as: Miettola S, Hovi P, Andersson S, et al. Maternal preeclampsia and bone mineral density of the adult offspring. Am J Obstet Gynecol2013;209:x-ex-x-ex.

regnancy changes the maternal

P bone metabolism and mineraliza-tion to meet the skeletal bone growthrequirements of the fetus. Thesehormone-mediated adjustments beginearly in pregnancy and are at amaximumduring the third trimester, when the fetaldemand for calcium is the greatest.1

When pregnancy ends prematurely, the

offspring is at risk for insufficient bonemineralization.2

Preeclampsia is a common reason forindicated preterm delivery. This vasculardisorder of uncertain etiology compli-cates approximately 3% of pregnanciesworldwide.3 The only cure is the deliveryof the placenta. In particular severe andearly forms of the disease are often

tetrics and Gynecology (DDrs Hovi, Strang-Karlssoniversity Central Hospital (Dtment of Medical Geneticsersity of Helsinki, and Unid Mäkitie), Helsinki, and V

, Finnish Diabetes ResearMedical Societies (Duoden, Juho Vainio Foundatio

epartment of Chronic Dis

016/j.ajog.2013.06.028

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associated with acute maternal symp-toms or placental dysfunction, or both,resulting in fetal growth restriction. Thisfrequently necessitates preterm delivery.Preeclampsia occurring at term is usuallyless severe and often no fetal growth re-striction is present. Previous studieshave shown that preeclampsia increasesthe offspring’s risk of cardiometabolic

rs Miettola and Pouta), Oulu University Hospital,, Eriksson, and Kajantie), National Institute forrs Hovi, Andersson, Strang-Karlsson, Järvenpää,, Haartman Institute (Dr Laivuori); Department oft of General Practice (Dr Eriksson), Helsinkiasa Central Hospital (Dr Eriksson), Vasa, Finland.

ch Foundation, Finnish Foundation forcim and Finska Läkaresällskapet), Novo Nordiskn, and Sigrid Juselius Foundation.

ease Prevention, PL 30, 00271 Helsinki, Finland.

erican Journal of Obstetrics & Gynecology 1.e1

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disease4,5 and poorer psychologicalfunctioning6-8 later in life. We are un-aware of any previous studies that haveinvestigated skeletal health of offspringborn from preeclamptic pregnancies.

The survival of premature infants hasimproved tremendously the past de-cades. As a result adult health and well-being of these offspring has recentlyraised considerable attention. Previousstudies have shown that prematurityadversely affects the skeletal mineraliza-tion and bone-mass development inchildren and young adults.2,9,10 Our aimwas to assess bone mineral density andbone mineral content of offspring bornfrom preeclamptic pregnancy. Becausepreeclampsia occurring earlier in preg-nancy could be clinically distinct frompreeclampsia at term, we performed theanalyses separately among those bornpreterm at very low birthweight (VLBW;<1500 g) and among controls born atterm.

MATERIALS AND METHODS

The subjects in the study are part of theHelsinki Study of Very Low BirthweightAdults. This multidisciplinary cohortrepresents all subjects born preterm atvery low birthweight (VLBW, <1500 g)in the province of Uusimaa, Finland,between the years 1978 and 1985 andtreated in the neonatal intensive careunit of Children’s Hospital at HelsinkiUniversity Central Hospital. Of the 474admitted to the unit 335 were dischargedalive. In 2004, for each VLBW survivor acontrol person of same sex was selectedfrom the records of all consecutivebirths. This person also had to be born atterm in the same hospital as the VLBWsurvivor and not be small for gestationalage (SGA). The recruitment of the youngadults and the exclusion criteria havebeen described in detail.9

We extracted data on hypertensive dis-orders during pregnancy from hospitaland maternal welfare clinic records. Tomeet contemporary diagnostic criteria,11

we defined preeclampsia as blood pres-sure exceeding 140/90 mm Hg after mid-pregnancy, accompanied by proteinuria(�0.3 g protein excretion in a 24-hoururine sample or a positive dipstick)and without history of hypertension

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medication before pregnancy or duringthe first trimester. We defined gestationalhypertension according to the sameblood pressure criteria but withoutproteinuria. Of the 144 VLBW and 139term-born individuals participating inthe clinical study 32 and 11 were bornfrom pregnancy complicated by pre-eclampsia, respectively.The participants were between 18.5

and 27.1 years of age. The clinical studyincluded anthropometric measurementsas well as measurements of bone mineralcontent (BMC) and bone mineral den-sity (BMD) for lumbar spine (L1-L4),femoral neck, whole body and bodycomposition by dual-energy x-ray ab-sorptiometry (DXA, Hologic DiscoveryA, software version 12.3:3; Bedford,MA). The results were transformed intoage- and sex-specific Z-scores on thebasis of an equipment-specific referencedatabase. Bone mineral apparent density(BMAD) value was calculated to mini-mize the effect of bone size on lumbarspine BMD (BMAD ¼ BMC L1-4/bonearea L1-4

1.5).We previously described themethod of the DXA bone densitometryas well as the stages of the clinical study.9

The participants filled in food diaries for2 working days and 1 day in the weekend.They were instructed and the data werereviewed by a nutritionist, and theFinnish Food Composition Databasewas used to calculate the average dailyintake of calcium, phosphate andvitamin D.12 The participants filled inquestionnaires of their current medica-tions, leisure-time physical activity,including questions on the intensity ofleisure-time conditioning physical ac-tivity,13 their frequency of alcohol con-sumption and parents’ presenteducational attainment. Maternal pre-pregnancy BMI, based on self-reportedheight and weight recorded duringearly pregnancy, was obtained from thematernal welfare clinic records.

Statistical analysisThe analyses were performed using SPSSfor Windows, version 18 (SPSS, Inc,Chicago, IL). Pearson’s c2 test was usedto compare proportions and Student ttest to compare means. The group meandifferences were estimated with multiple

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linear regression. We started these ana-lyses with a model adjusting for sex only.We then used BMI and height as cova-riates in the models because body size isassociated with bone mass and maternalpreeclampsia.14 As a proxy of childhoodsocioeconomic position, we used theeducational attainment of the higher-educated parent.9,15 In the full model,we also included lifestyle factors such assmoking and maternal smoking duringpregnancy, because smoking is associ-ated with lower rates of preeclampsia16

and reduced BMD,17 and intensity ofleisure time physical activity that isassociated with BMD and may in part beprogrammed in utero.18 Parity was alsoincluded as covariate because of itsstrong association with maternal pre-eclampsia.19 Calcium, phosphate, andvitamin D intake and alcohol con-sumption were also considered as cova-riates, but were omitted from the finalmodels because they did not change theeffect of preeclampsia, and data onnutrient intake were available only forpart of the subjects. To assess the effect ofgestational age on the outcome, sec-ondary analyses were performed afterexclusion of SGA offspring of the VLBWgroup and on a subgroup including onlyoffspring born between 28-32 weeks ofgestation. For the lumbar spine andfemoral neck analysis, 3 VLBW subjectswere excluded because of severe spinedeformity or because of foreign objectthat made the BMD measurement un-reliable. For the whole body analysis 5VLBW subjects were excluded because ofa foreign object.9

RESULTS

Study populationThe maternal and newborn characteris-tics of the study groups are presented inTable 1. In the VLBW group, there wasno difference in the crude birthweightsbetween offspring born from pregnancycomplicated by PE and offspring bornfrom nonpreeclamptic pregnancy. How-ever, the offspring in the VLBW pre-eclampsia group had higher gestationalage by 1.8 weeks (95% confidence inter-val, 1.0e2.6) comparedwith the offspringfrom the VLBW nonpreeclampsia group,and accordingly their birthweight SD

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TABLE 1Characteristics of the mothers in pregnancy and of the offspring at birth and at the time of study assessment

Characteristics

VLBW Term

Preeclampsian [ 32

Nopreeclampsian [ 112

Preeclampsian [ 11

Nopreeclampsian [ 128

Maternal prepregnancy BMI,b kg/m2 23.1 (3.4) 22.1 (3.8) 23.0 (3.1) 22.3 (3.6)

Maternal smoking in pregnancya 3 (9.4) 25 (22.3) 0 (0) 20 (15.6)

Maternal gestational hypertensiona 0 (0) 5 (4.5) 0 (0) 21 (16.4)

Primiparousa 19 (59.4) 49 (44.1) 5 (45.5) 64 (50.0)

Mena, 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/m2 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)

Smokinga 10 (31.3) 29 (26.4) 5 (45.5) 47 (36.7)

Parental educational attainmenta

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 activitya,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 usea

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)

Miettola. Preeclampsia and offspring’s bone health. Am J Obstet Gynecol 2013. (continued)

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TABLE 1Characteristics of the mothers in pregnancy and of the offspring at birth and at the time of study assessment(continued)

Characteristics

VLBW Term

Preeclampsian [ 32

Nopreeclampsian [ 112

Preeclampsian [ 11

Nopreeclampsian [ 128

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 mg/d 2.7 (2.1) 3.1 (2.0) 4.3 (1.5) 3.4 (2.0)

BMI, body mass index; PE, preeclampsia; VLBW, very low birthweight.

a Numbers represent n (%); b Numbers represent mean (SD); c Numbers represent means (geometric SDs) for the intakes of calcium, phosphate, and vitamin D, weight, height, and BMI; d Intensity ofleisure 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< .05for the difference between PE and no-PE group in VLBW offspring.

Miettola. Preeclampsia and offspring’s bone health. Am J Obstet Gynecol 2013.

Research Obstetrics www.AJOG.org

score was lower. Among the term borninfants, differences in birthweight andgestational age between the 2 groups werenot statistically significant.

At the time of the study assessmentthere was no difference in the age, height,or BMI between the preeclamptic andnonpreeclamptic groups amongVLBWoramong term offspring, although whensexes were assessed separately, VLBWmen of the preeclamptic group hadhigher BMI than nonpreeclampsiaVLBWmen (Table 2). There was no statisticallysignificant difference in parental educa-tional attainment, leisure-time physicalactivity, smoking, or calcium, phosphate,and vitamin D intake between offspringborn from preeclamptic and non-preeclamptic pregnancies among VLBWand term groups (Table 2).

Comparisons between offspring frompreeclamptic and nonpreeclampticpregnancies among those born atVLBWTable 2 and the Figure show that VLBWoffspring whose mothers had pre-eclampsia had higher BMD Z-scores oflumbar spine, femoral neck, and wholebody. Also their lumbar spine BMADand whole body BMC were higher,although the latter was not statisticallysignificant. Adjustments for currentheight, BMI, and socioeconomic posi-tion attenuated the differences; however,they still remained significant in all of theskeletal health outcome variables

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(Table 3). Further adjustment for phys-ical activity, current smoking, maternalsmoking, and parity (Table 3, model 5),and for maternal prepregnancy BMI andalcohol use (not shown), and for the 130VLBW and 107 term subjects withavailable data, also for calcium, phos-phate, and vitamin D intake (not shown)had little effect on the results. The dif-ferences we found were greater amongmen, although the interaction term sex)preeclampsia was not statistically signif-icant. VLBW men whose mothers hadpreeclampsia were heavier, had a higherBMI, and lean body mass than VLBWmen whose mothers did not have pre-eclampsia (Table 2).

Length of gestation and intrauterinegrowthTo assess whether the findings areexplained by intrauterine growth we firstran a secondary analysis excluding sub-jects born SGA from the VLBW group.The differences between the preeclampticand nonpreeclamptic groups remainedsimilar or became larger. However,these differences were attenuated whenadjusted for height and BMI (Table 4).Next, we performed the analysis in asubgroup including only VLBWoffspringborn between gestational weeks 28-32.The differences between offspringfrom preeclamptic and nonpreeclampticpregnancies remained similar, althoughno longer statistically significant infemoral neck BMD Z score and whole

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bodyBMDZ score when adjusted furtherfor height and BMI (Table 4). When theanalyses including all of the VLBWoffspring were adjusted for gestationalage or birthweight SD score, or both, ascontinuous variables, the differencesin BMD Z scores between offspringform preeclamptic and nonpreeclampticpregnancies remained statistically signif-icant (Table 4).

Comparisons between offspring frompreeclamptic and nonpreeclampticpregnancies among those born attermAmong the term born group the femoralneck and whole body BMD Z scores aswell as the whole body BMC scores werehigher among the offspring from pre-eclamptic pregnancies than those fromnonpreeclamptic pregnancies. The ad-justments did not change the results.Corresponding difference in the lumbarspine BMD Z score was statistically sig-nificant only in some of the adjustedmodels. There was also no differencebetween the 2 groups in body composi-tion (Tables 3 and 4).

Maternal gestational hypertensionThere were 5 offspring born at VLBWand21 offspring born term from pregnancycomplicated by gestational hypertension(Table 1). For the VLBW group thisnumber did not allow meaningful com-parisons; however, when these subjectswere excluded the difference in bonehealth parameters between those exposed

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TABLE 2Bone health and body composition of the young adults

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 scorea �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 BMADa 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 scorea �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 scoreb �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 BMCb, 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

Numbers represent means (and SD). P values are for the difference between PE and no PE groups within VLBW offspring and term-born offspring.

BMAD, bone mineral apparent density; BMC, bone mineral content; BMD, bone mineral density; PE, preeclampsia; VLBW, very low birthweight.

a Data missing for 3 subjects; b Data missing for 5 subjects.

Miettola. Preeclampsia and offspring’s bone health. Am J Obstet Gynecol 2013.

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FIGURELumbar spine BMD in VLBW and term offspring according to maternalpreeclampsia

Each category includes and is denoted by its highest value.

BMD, bone mineral density; VLBW, very low birthweight.

Miettola. Preeclampsia and offspring’s bone health. Am J Obstet Gynecol 2013.

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to maternal preeclampsia and those notexposed remained similar. Those 21 sub-jects who were born at term after exposedto maternal gestational hypertension hadsimilar BMD to those 107 not exposed togestational hypertension or preeclampsia.

COMMENT

We found that young adults born pre-term at VLBW, whose mothers hadpreeclampsia, had higher lumbar spine,femoral neck, and whole body BMC Zscores than those VLBW adults whosemothers did not have preeclampsia. Thedifference was up to 0.60 units in lumbarspine and 0.41 in femoral neck. Thismeans that although VLBW adults haveon average lower BMD than their peersborn at term,9 those VLBW adults whowere exposed to preeclampsia had higherBMD Z scores, similar to those bornat term. Also among term offspringthose exposed to preeclampsia hadhigher BMC Z scores than unexposedoffspring.

Comparisons with previous studiesWe are unaware of any previous studiesassessing the effect of maternal pre-eclampsia on later life skeletal health of

1.e6 American Journal of Obstetrics & Gynecology

offspring. Skeletal health of adults bornVLBW has been previously reportedon.2,10 Some,2,10 although not all,20

findings are consistent with our reportof lower BMD in VLBW adults in thepresent study cohort,9 although in astudy of 25 VLBWand term-born adultsthe difference in BMC was considered tobe appropriate for the smaller body sizeof VLBW adults.2 In these studies thepossible reasons of prematurity such aspreeclampsia were not taken into ac-count. Our study suggests that the long-term bone health outcomes of smallpremature infants born from pregnancycomplicated by preeclampsia are sub-stantially different from the bone healthoutcomes of other preterm bornoffspring.It is of note that offspring born from

pregnancy complicated by preeclampsiahave an adverse cardiovascular riskprofile already in childhood and asyoung adults.4,5 They also have lowercognitive ability and greater cognitivedecline up to old age,6,8 higher levels ofdepressive symptoms.7 Therefore,our finding of higher BMD in youngadulthood is important also as a rarepositive association between maternal

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preeclampsia and offspring’s futurephysical health.

Possible mechanismsPregnancy is a state of high bone turn-over. Several studies have shown a greaterincrease in biochemical markers of boneturnover in pregnancies complicated bypreeclampsia as compared with normalpregnancies. 21 It is not clear what themechanism behind this increase is, orwhether it occurs in the bone-formationor bone-resorption markers, or in both.During pregnancy calcium is activelytransported through the placenta. Mostof the transfer takes place in the thirdtrimester. VLBW offspring are born inthe second trimester or early in the thirdtrimester and therefore the calciumtransfer is ended prematurely, which,according to research, results indecreased BMC in adulthood.8 However,our results suggest that in pregnancycomplicated by preeclampsia additionalmechanisms regulating bone formationmay be present. In contrast to the studiesin older children and adults discussedpreviously, previous studies in infantshave also suggested that preeclampsiamay have a neuroprotective effect onpreterm infants22,23 possibly bymaturation-promoting neuroprotectivesubstances that prevent white-matterdamage during fetal life.22 Present studyresults may suggest the existence of po-tential bone protective substances.

Women with preeclampsia haveelevated androgen levels during theirpregnancy.24 Sex hormones play animportant part in bone growth anddevelopment.25 The effect of androgenson bone growth comes apparent duringpuberty when men reach higher peakbone mass compared with women26

because of a stimulatory androgen ac-tion on periosteal bone formation,although an inhibitory estrogen-relatedaction occurs in women.27-32 Studiessuggest that excess androgens in womenare associated with higher bone mineraldensity as well as peak bonemass.33-35 Inwomen with hyperandrogenic condi-tions such as polycystic ovary syndrome,BMD has been shown to be elevated.36 Itis possible that the offspring born frompreeclamptic pregnancy have elevated

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TABLE 3Difference between offspring born from pregnancy complicated by PE vs no PE within VLBW and term group

Characteristics Model

VLBW Term

Mean difference (95% CI) P value Mean difference (95% CI) P value

Lumbar spine BMD Z score 1 0.60 (0.24e0.98) .002 0.52 (�0.12 to 1.17) .112

2 0.58 (0.18e0.90) .002 0.53 (�0.11 to 1.17) .101

3 0.47 (0.13e0.81) .008 0.48 (�0.11 to 1.05) .108

4 0.41 (0.06e0.75) .021 0.64 (0.05e1.24) .035

5 0.42 (0.08e0.76) .016 0.70 (0.13e1.27) .017

Lumbar spine BMADa 1 6.39 (1.42e11.37) .012 4.17 (�4.52 to 12.85) .345

2 6.74 (1.82e11.66) .008 4.04(�4.60 to 12.68) .357

3 5.78 (1.28e10.28) .012 3.48 (�4.46 to 11.41) .388

4 5.35 (0.77e9.94) .022 3.24 (-4.58 to 11.05) .414

5 4.72 (0.10e9.34) .046 6.20 (�1.48 to 13.88) .113

Femoral neck BMD Z score 1 0.41 (0.11e0.70) .007 0.63 (0.11e1.15) .019

2 0.45 (0.12e0.78) .008 0.67 (0.08e1.27) .028

3 0.38 (0.08e0.68) .013 0.63 (0.11e1.15) .019

4 0.37 (0.07e0.68) .016 0.62 (0.10e1.14) .020

5 0.37 (0.06e0.68) .020 0.70 (0.17e1.23) .010

Whole body BMD Z score 1 0.56 (0.23e0.90) .001 0.74 (0.11e1.37) .022

2 0.53 (0.20e0.86) .002 0.75 (0.12e1.37) .019

3 0.49 (0.17e0.80) .003 0.72 (0.12e1.32) .019

4 0.45 (0.13e0.77) .006 0.70 (0.11e1.29) .020

5 0.46 (0.15e0.76) .003 0.87 (0.28e1.46) .004

Whole body BMC, g 1 187 (59e314) .004 211 (10e412) .040

2 153 (57e250) .002 221 (43e399) .015

3 136 (49e223) .002 208 (50e366) .010

4 124 (36e213) .011 204 (47e360) .011

5 127 (41e214) .004 248 (92e404) .002

Model 1. Adjusted for sex. Model 2. Model 1þ current height. Model 3. Model 2þ current BMI. Model 4. Model 3þ parental education (Data missing for 2 cases in VLBW group). Model 5. Model4 þ physical activity, smoking, maternal smoking during pregnancy (data missing for 2 cases in VLBW PE group, 8 cases in VLBW no PE group, and 2 cases in term no PE group).

BMAD, bone mineral apparent density; BMC, bone mineral content; BMD, bone mineral density; BMI, body mass index; CI, confidence interval; PE, preeclampsia; VLBW, very low birthweight.

a The numbers are multiplied by thousand for readability.

Miettola. Preeclampsia and offspring’s bone health. Am J Obstet Gynecol 2013.

www.AJOG.org Obstetrics Research

levels of androgens that then havestrengthening effect on the bone.

Body weight is directly associated withBMD so that higher BMI increasesBMD.37 Preeclampsia is associated withhigher BMI both in the mother andoffspring.38,39 In our study especially themale offspring exposed to preeclampsiawere heavier and had a higher BMIcompared with unexposed. However,this did not explain our findings.Maternal prepregnancy BMI did not

differ between the study groups, nor didthis influence our main results in theadjusted analysis.Calcium substitution is one of the

most efficient interventions to preventpreeclampsia at least among womenwith low calcium intake.40,41 In addition,maternal vitamin D deficiency is an in-dependent risk factor for preeclamp-sia,42 and has also been shown toadversely affect the bone mineral statusof the newborn.43 In our study we had

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no data on the maternal calcium orvitamin D levels or consumption. Ac-cording to the dietary survey performedin 1982 the average daily calcium intakeof Finnish womenwas 1200 mg,44 whichexceeds the recommended intake of 900mg/d for pregnant women.45 There is noinformation available for the dailyvitamin D intake in 1982; however, in1992 the average daily intake of vitaminD was 3.7 mg,44 which is below the rec-ommended 10 mg for pregnant women.

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TABLE 4Difference between VLBW offspring born form pregnancy complicated by PE vs no PE, accounting for length ofgestation and intrauterine growth

Characteristic

Outcome

Lumbar spine BMD Z score Femoral neck BMD Z score Whole body BMD Z scorea

Mean difference(95% CI)

Pvalue

Mean difference(95% CI)

Pvalue

Mean difference(95% CI)

Pvalue

Offspring born VLBW AGA, n ¼ 11/90

Adjusted for sex 0.88 (0.28e1.48) .004 0.67 (0.10e1.23) .021 0.61 (0.03e1.18) .039

Adjusted for sex, current height and BMI 0.58 (0.04e1.12) .035 0.33 (�0.14 to 0.82) .166 0.36 (�0.16 to 0.89) .173

Offspring born between 28 and 32 weeks ofgestation, n ¼ 25/77

Adjusted for sex 0.67 (0.30e1.05) .001 0.52 (0.13e0.91) .010 0.50 (0.12e0.87) .010

Adjusted for sex, current height and BMI 0.52 (0.15e0.90) .007 0.30 (�0.07 to 0.66) .109 0.31 (�0.05 to 0.67) .094

All VLBW offspring , n ¼ 31/110

Adjusted for sex and birthweight SD score 0.64 (0.23e1.04) .002 0.47 (0.10e0.84) .012 0.54 (0.17e0.91) .004

Adjusted for sex and gestational age 0.52 (0.12e0.91) .011 0.36 (0.003e0.71) .048 0.48 (0.12e0.84) .009

Adjusted for sex and birthweight SD score þgestational age

0.59 (0.19e1.0) .004 0.43 (0.07e0.79) .020 0.51 (0.14e0.88) .007

AGA, appropriate for gestational age; BMD, bone mineral density; BMI, body mass index; CI, confidence interval; PE, preeclampsia; VLBW, very low birthweight.

a Data missing for 2 cases.

Miettola. Preeclampsia and offspring’s bone health. Am J Obstet Gynecol 2013.

Research Obstetrics www.AJOG.org

Offspring in both VLBW and termgroups reported low vitamin D intake inadulthood that might explain why themean BMD Z scores were below 0.0 SDin the reference population. Calciumand vitamin D metabolism are crucialfor bone development and in these termsour findings of higher BMD in offspringexposed to maternal preeclampsia mightsound paradoxical.

Alternative explanationsA number of alternative explanationsshould be considered when interpretingthe findings. Preeclampsia is frequentlyaccompanied by intrauterine growthrestriction (IUGR). However, based onfindings in people born at term, IUGRwould rather be expected to predictlower BMD in the adult offspring.46

Moreover, we found that the associa-tion with preeclampsia was present evenwhen VLBW adults born SGA (a proxyof IUGR) were excluded from analysis.When the inclusion criteria are based onbirthweight, VLBW subjects born at thelater gestational age are included onlyif sufficiently growth retarded, which

1.e8 American Journal of Obstetrics & Gynecology

could lead to a distorted sample. How-ever, this explanation is unlikely, as ourfindings were present even when onlysubjects born between 28 and 32 weeksof gestation were included in the VLBWgroup, and the results were little changedwhen the comparisons were adjusted forbirth weight SD score and gestationalage. Misinterpretation caused by con-founding is unlikely as we adjustedfor the most important potential con-founders such as differences in body size,family socio-economic position, leisuretime physical activity, maternal andsubject’s own smoking and intake ofcalcium, phosphate, and vitamin D. Wecannot exclude selection bias, whichwould, however, be expected to affectthe results only if the reasons fornonparticipation were different betweenthe offspring exposed to maternal pre-eclampsia and unexposed offspring andbetween offspring with different BMDstatus. That the finding would be duepurely to chance seems very unlikelyeven when the number of comparisonswe have previously reported on in thisstudy9 is taken into account as the

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finding was consistent among both theVLBWand term groups and among bothmen and women. We therefore believethat our findings represent biologic ef-fects of maternal preeclampsia on off-spring’s skeletal health.

Study limitationsThe main limitation of our study wasthat the cohort was originally designed tostudy the long-term offspring effects ofVLBW birth rather than maternal pre-eclampsia. Hence, the power of com-parisons within the term-born group islimited. Despite this the differences be-tween exposed and unexposed groupsare remarkably consistent within theVLBW and term groups. The originalcohort comprised all infants dischargedalive from the neonatal intensive careunit in Helsinki area but because ofnonparticipation our study populationmay not be representative of the originalcohort. However, the study populationwas the same size or larger than in otherstudies assessing the bone health of pre-term born offspring in adulthood.47,48

Nutrient-intake was estimated by 3-day

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food diary that is not ideal in particularin estimating vitamin D intake. We hadno data on maternity lifestyle that is alsoassociated with neonatal bone mass.49

CONCLUSIONS

We found that young adult offspringexposed to maternal preeclampsia hadhigher BMD than those not exposed.This difference was seen among thoseborn at preterm VLBWand seemed alsoto be present among those born at term.These preliminary results suggest thatpreeclampsia may have a protective ef-fect on long-term bone health of theoffspring. -

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