CASAS ET AL 2012_Obesity neurodevelopment.pdf

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LIFE COURSE EPIDEMIOLOGY

Maternal pre-pregnancy overweight and

obesity, and child neuropsychologicaldevelopment: two Southern Europeanbirth cohort studiesMaribel Casas,1,2,3* Leda Chatzi,4 Anne-Elie Carsin,1,2,3 Pilar Amiano,3,5,6 Monica Guxens,1,2,3

Manolis Kogevinas,1,2,3,7 Katerina Koutra,4 Nerea Lertxundi,7,8 Mario Murcia,3,9

Marisa Rebagliato,3,9,10 Isolina Riano,11 Clara L Rodrguez-Bernal,3,9 Theano Roumeliotaki,4

Jordi Sunyer,1,2,3,12 Michelle Mendez1,2,3,13 and Martine Vrijheid1,2,3

1Centre for Research in Environmental Epidemiology (CREAL), 08003 Barcelona, Catalonia, Spain, 2IMIM (Hospital del Mar

Medical Research Institute), 08003 Barcelona, Catalonia, Spain, 3CIBER Epidemiologa y Salud Publica (CIBERESP), Instituto de

Salud Carlos III, Melchor Fernandez Almagro 3-5, 28029 Madrid, Spain, 4Department of Social Medicine, Faculty of Medicine,

University of Crete, PO Box 2208, Heraklion, 71003, Crete, Greece, 5Public Health Division of Gipuzkoa, San Sebastian, Basque

Health Department, Basque Region, Spain, 6Basque Health Research Institute (BIODONOSTIA), Po. Doctor Begiristain, s/n 20014

Donostia, Spain, 7National School of Public Health, Athens, Greece, 8University of Basque Country (UPV-EHU), Campus Gipuzkoa,

Tolosa Hiribidea, 70, 20018 San Sebastian, Spain, 9Centre of Public Health Research (CSISP), Avenida Cataluna, 21, 46020 Valencia,

Spain, 10Public Health Board, Conselleria de Sanitat, Avenida Cataluna, 21, 46020 Valencia, Spain, 11Servicio de Pediatria, Hospital

San Agustn, Camino de Heros, 6, 33401 Aviles, Asturias, Spain, 12Pompeu Fabra University, Placa de la Merce, 10-12, 08002

Barcelona, Catalonia, Spain and 13Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North

Carolina, USA

*Corresponding author. Centre for Research in Environmental Epidemiology, 08003 Barcelona, Spain. E-mail: [email protected]

Accepted 8 January 2013

Background Maternal pre-pregnancy obesity may be associated with impairedinfant neuropsychological development; however, there are fewstudies and it is unclear if reported associations are due to intra-uterine mechanisms.

Methods We assessed whether maternal pre-pregnancy overweight and obes-ity were associated with cognitive and psychomotor developmentscores (mean 100 15) of children aged 1122 months in two birthcohorts: Environment and Childhood (INMA, Spain; n 1967) andMother-Child (RHEA, Greece: n 412). Paternal body mass index(BMI) was used as a negative control exposure.

Results The percentage of overweight and obese mothers was 18% and 8%,respectively, in INMA and 20% and 11% in RHEA, respectively.

Maternal pre-pregnancy obesity was associated with reduced infantcognitive development scores in both INMA (score reduction: 2.72;95% CI: 5.35, 0.10) and RHEA (score reduction: 3.71; 95% CI:8.45, 1.02), after adjusting for socioeconomic variables and paternalBMI. There was evidence in both cohorts of a dose-response relation-ship with continuous maternal BMI. Paternal overweight/obesity wasnot associated with infant cognitive development. Associations withpsychomotor scores were not consistent between cohorts, and werestronger for paternal than maternal BMI in RHEA.

Published by Oxford University Press on behalf of the International Epidemiological Association

The Author 2013; all rights reserved.

International Journal of Epidemiology2013;42:506517

doi:10.1093/ije/dyt002

506


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Conclusions This study in two birth cohorts with moderately high obesity preva-lence suggests that maternal pre-pregnancy obesity is associatedwith reduced child cognitive development at early ages. This asso-ciation appears more likely to be due to maternal than sharedfamily and social mechanisms, but further research is needed todisentangle a direct intrauterine effect from other maternal con-

founding factors.Keywords Body weight, overweight, obesity, child development, cognition,

psychomotor performance.

IntroductionObesity is increasing worldwide and its prevalence isparticularly high in Central, Eastern and SouthernEurope;1 in Southern Europe prevalence can reach30%.1 Obesity is well characterized as a systemic in-flammatory condition.2 There is evidence that suchinflammation during pregnancy may be transferredto the offspring brain, decrease neurogenesis and in-crease oxidative stress, changes that can result in cog-nitive disruption.3,4 Few epidemiological studies5-12

have examined evidence of neuropsychological effectsin children associated with maternal obesity and ofthese, only six evaluated cognitive function5,8-12 andtwo evaluated psychomotor development.5,10 Fourstudies reported maternal pre-pregnancy obesity[body mass index (BMI) 530 kg/m2] t o b e relatedto an increased risk of lower cognitive function5,10,11

and an increased risk of intellectual disability.9 Thesestudies did not find any associations with maternaloverweight5,10,11 or motor ability.5,10 One study

showed a decrease in cognitive performance withincreasing continuous BMI.12 An analysis of twoEuropean cohorts observed no consistent associationbetween maternal pre-pregnancy overweight/obesitycombined and child behavioural problems and meas-ures of cognitive abilities.8 Challenges for future stu-dies include having adequate sample sizes toseparately assess maternal overweight and obesityand disentangling the role of intrauterine mechan-isms from those of confounding variables linked tomaternal weight status.

The mechanisms underlying the potential effects ofmaternal pre-pregnancy overweight and obesity onchild neurodevelopment are still unknown. Besides

the potential effects on brain development fromanti-inflammatory processes, high levels of leptin, ahormone synthesized by adipose tissue and associated

with obesity,13 have been associated with gestationaldiabetes. Gestational diabetes can delay brain maturityand induce neurobehavioural abnormalities in off-spring.14 Thyroid dysfunction, as well as nutrient defi-ciencies such as folic acid or vitamin D, all morecommon in obese women,15,16 have also been impli-cated as potential mechanisms linking maternal over-

weight/obesity and child neurodevelopment.17,18

Further, some environmental neurotoxicants, such aspolychlorinated biphenyls (PCBs) and mercury (Hg),can bio accumulate in adipose tissue. Rodriguez et al.7

proposed that adipose tissue of overweight and obesewomen may contain higher levels of neurotoxins thatwill negatively affect foetal brain development.

This study aimed to assess whether maternal

pre-pregnancy overweight and obesity were associatedwith neuropsychological development of children be-tween 1122 months in two countries with moderatelyhigh obesity prevalence (Spain and Greece). We usedindividual neuropsychological tests, assessed theimpact of possible intermediate factors and assessedthe association between paternal overweight and obes-ity with childrens neuropsychological development, asa negative control exposure.19,20 We hypothesized that adirect maternal intrauterine mechanism would producestronger associations than an indirect paternal effect.This approach has previously been used to disentangleintrauterine influences from social and other confound-ing variables forprenatal smoking19 and maternal over-

weight/obesity.8

MethodsStudy participants

The population-based birth cohort study INMA(INfancia y Medio AmbienteEnvironment andChildhood) recruited pregnant women during the firsttrimester of pregnancy from four Spanish regions(Asturias, Gipuzkoa, Sabadell and Valencia) between2004 and 2008, following a common protocol.21

Inclusion criteria were: age 516 years, singleton preg-nancy, no assisted conception, intention to deliver

at the reference hospital and no communication prob-lems.21 A total of 2644 mothers were recruited and2226 children undertook the neuropsychological testat around 14 months of age. After the exclusion of pre-term births, neuropsychological tests of uncertain val-idity due to less than optimal cooperation of the child,basic pathologies (i.e. epilepsy, plagiocephaly) and ageat examination 523 months, 1967 mother-child pairs

were included in the analyses (Table 1).The RHEA (Mother-Child) Study in Crete (Greece)22

enrolled pregnant women during 20072009 at the

MATERNAL OBESITY AND CHILD NEUROPSYCHOLOGICAL DEVELOPMENT 507


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time of the first major ultrasound examination at 1013 weeks of gestation if they were: resident in thestudy areas,416 years of age and without communi-cation handicaps. The cohort enrolled 1606 mothersand a random subgroup of 612 children performedthe neuropsychological test at around 18 months ofage. After excluding multiple pregnancies, pretermbirths, subjects with missing information on maternalBMI, infants with basic pathologies (pervasive devel-opmental disorder and hydrocephalus) and tests ofuncertain validity, a total of 412 mother-child pairs

were included in the analysis (Table 1).

Maternal and paternal overweight andobesity

Maternal height was measured and pre-pregnancy

weight reported by the mother at the first trimestervisit; these were used to calculate pre-pregnancy BMI(kg/m2). Reported pre-pregnancy weight was highlycorrelated with measured weight at 12 weeks of preg-nancy in INMA (r 0.96; P < 0.0001). Paternal weightand height were reported by the mother at the firsttrimester visit and used to calculate paternal BMI.Maternal and paternal BMI were grouped accordingto the World Health Organization categories for under-

weight (


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childrens birthweight, gestational age and gender wasobtained from clinical records. Data on nursery attend-ance, main childminder, childs weight and height, ma-ternal employment status after birth and breastfeedingduration were collected when infants were around 14and 9 months old in INMA and RHEA, respectively(Supplementary Table 1, available as Supplementary

data at IJE online). Childrens BMI-for-age z-scoreswere calculated and children with BMI z-scores51.035, corresponding to the 85th percentile, were clas-sified as overweight.27 All questionnaires were con-ducted face to face by trained interviewers.

In INMA, 25-OH vitamin D3 was determined in thefirst trimester plasma using a high-performance liquidchromatography assay (BioRAD kit28). First-trimesterserum thyroid-stimulating hormone (TSH) was deter-mined using a solid-phase, time-resolved sandwichfluoroimmunoassay (AutoDELFIA, PerkinElmer Lifeand analytical Sciences, Wallac Oy, Turku, Finland)using a lanthanide metal europium (Eu) label.First-trimester serum C-reactive protein (CRP), a sensi-

tive marker for systemic inflammation,2 was deter-mined by turbidimetric assay using a Hitachi modularanalyser system (Roche Modular DPP, Hitachi Ltd,Tokyo, Japan) (this last measure was only available inthe Gipuzkoa and Sabadell regions). Total PCBs (118,153, 138, 180) were also measured in maternalfirst-trimester serum in Gipuzkoa, Sabadell andValencia using a 96-well solid-phase extraction discplate procedure gas chromatograph as described else-

where.29 Total Hg was measured in cord blood in allINMA regions by thermal decomposition, amalgam-ation and atomic absorption spectrometry usinga single-purpose LECO AMA-254 analyzer.30 In RHEA,TSH was measured in first-trimester maternal serum bythe IMMULITE 2000 immunoassay system (SiemensHealthcare Diagnostics, IL, USA).

Statistical analysis

Multiple imputation of missing values for the covari-ates was performed using chained equations where 25completed datasets were generated, separately forINMA and RHEA cohorts, and analysed using thestandard combination rules for multiple imput-ations.31 Complete case analyses were also conductedfor all models.

Multivariate linear regression models were used toassess the association between maternal pre-

pregnancy overweight and obesity, and infant cogni-tive and psychomotor development scores. First, allmodels were adjusted for childs gender, as well asfor INMA regions (Model 1). In a second model, aset of primary socioeconomic variables were included:maternal and paternal education, maternal country ofbirth and maternal and paternal social class (INMAonly) (Model 2). In a third model, other potentialconfounders were included: maternal and paternalage, breastfeeding duration, maternal smoking, ma-ternal employment status during pregnancy and

after birth, parity, nursery attendance and main child-minder (Model 3). These variables were selected apriori from the literature based on their potential toconfound the association between maternal pre-pregnancy BMI and child cognitive development.5,79

A fourth model included paternal BMI categories(Model 4). Standardized effect size (Cohens d) was

calculated dividing theb coefficients by one SD (mag-nitude of effect size: 0.20 small, 0.50moderate,0.80 large).32 We repeated Model 3 using BMI ascontinuous measure. We also repeated Models 13using paternal rather than maternal overweight andobesity as the main exposure of interest.

Sensitivity analyses were performed to assess the ro-bustness of our results (all based on Model 3). Weassessed the role of the following possible intermediatefactors: vitamin D, dietary folate intake, folate supple-mentation, TSH, CRP, PCBs and total Hg, gestational

weight gain, birthweight, gestational age and childsBMI after birth, by including them separately inModel 3 and evaluating if they changed the coeffi-

cients for maternal obesity. Further, we excluded ma-ternal and paternal social class covariates from theINMA models to assess the potential residual con-founding due to socioeconomic factors in RHEA.Finally, we excluded mothers who did not live withthe father to evaluate the validity of maternal reportof paternal BMI. All statistical analyses were conducted

with Stata 12.0 statistical software (Stata Corporation,College Station, TX, USA).

ResultsThe percentage of overweight and obese mothers was

18% and 8%, respectively, in INMA and 20% and 11%,respectively, in RHEA (Table 2). The percentage ofoverweight and obese fathers was higher: 44% and12%, respectively, in INMA and 47% and 25%, re-spectively, in RHEA (Supplementary Table 4, availableasSupplementary data at IJE online). The prevalenceof maternal overweight and obesity was higher inlower educational levels (INMA and RHEA) andlower social classes (INMA) (Table 2). Paternal obes-ity was more prevalent in lower educational andsocial class categories in INMA, but in RHEA there

was little difference between paternal educationallevels (Supplementary Table 4, available asSupplementary data at IJE online). In both cohorts,

younger and older mothers were more likely to beoverweight, whereas younger mothers were morelikely to be obese (Table 2). Paternal overweight wasmore prevalent in older fathers in INMA but in

younger fathers in RHEA; the prevalence of obesefathers was relatively similar between age categoriesin both cohorts. Smokers and mothers who breastfedless were more likely to be obese. Confounding pat-terns were similar between overweight and obesemothers; only obesity was more strongly associated

with lower educational levels than overweight.

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Table 2 Percentage of overweight and obese mothers by covariate categories

Characteristics

INMA RHEA

TotalN

Overweightn (%)

Obesen (%) P-valuea

TotalN

Overweightn (%)

Obesen (%) P-valuea

N 1967 361 (18.4) 150 (7.6) 412 82 (19.9) 44 (10.7)

Childs gender 0.404 0.225

Female 986 18.5 6.5 201 16.9 12.4

Male 980 18.4 8.8 211 22.8 9.0

Missing (%) 1 (0.1) 0

Maternal age 0.074 0.068


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In both cohorts, cognitive development scores werehigher among females, firstborns, children whosemothers were not the main childminder, and mothers

who worked either during pregnancy or after birth.

In INMA, children with higher psychomotor develop-ment scores were more likely to not attend nurseryschool, to have shorter breastfeeding duration, to havesiblings and to have younger parents. In RHEA,

Table 2 Continued

Characteristics

INMA RHEA

TotalN

Overweightn (%)

Obesen (%) P-valuea

TotalN

Overweightn (%)

Obesen (%) P-valuea

N 1967 361 (18.4) 150 (7.6) 412 82 (19.9) 44 (10.7)

Parity 0.006 0.249

0 1124 16.4 6.5 181 17.1 8.8

1 841 21.1 9.2 219 20.6 12.8

Missing (%) 2 (0.1) 12 (2.9)

Maternal smoking 0.369 0.126

Never smoke 896 18.8 7.5 237 17.7 11.0

Quit early pregnancy 730 16.6 7.5 92 28.3 6.5

During pregnancy 315 21.0 8.9 82 17.1 14.6

Missing (%) 26 (1.3) 1 (0.2)

Maternal employment statusduring pregnancy


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psychomotor development scores were higher amongchildren who were breastfed longer, whose parentshad higher educational levels, whose mothers wereolder and those whose mothers worked during preg-nancy or after birth (Supplementary Table 5, availableas Supplementary data at IJE online).

Children of obese mothers had lower cognitive de-velopment scores than those of normal weightmothers in INMA (3.37 points, 95% CI: 5.90,0.83) and RHEA (6.00 points, 95% CI: 10.75,1.24) in the unadjusted Model 1 (Table 3 andFigure 1). Adjustment for socioeconomic variables(Model 2) attenuated these coefficients, especially in

RHEA. After further adjustment (Model 3), the coef-ficient for maternal obesity was 2.69 (95% CI:5.27, 0.11) in INMA and 3.92 (95% CI: 8.60,0.76) in RHEA (Table 3). These associations corres-ponded to a Cohens d of 0.18 (95% CI: 0.35,0.01) in INMA and of0.26 (95% CI: 0.57, 0.05)in RHEA, indicating a small effect size. Maternalpre-pregnancy overweight was associated with a

very small reduction in cognitive scores in INMAbut not in RHEA (Table 3). In both cohorts weobserved decreasing cognitive scores with increasing

continuous BMI (INMA: 0.17 per kg/m2; 95%CI: 0.34, 0.01; RHEA: 0.26 per kg/m2; 95% CI:0.57, 0.06). When analysing very obese mothers(BMI 433 kg/m2) separately, these tended to showthe lowest cognitive scores compared with normal

weight mothers, particularly in INMA (4.12; 95%CI: 7.64, 0.61) (RHEA [3.97; 95% CI: 9.72,1.79]). Receptive communication scores in RHEA

yielded similar results to those shown for cognitivescores; expressive communication scores had no asso-ciation with obesity (data not shown).

Coefficients for psychomotor scores in INMA andfine, but not gross, motor scores in RHEA showed

small reductions in obese and overweight motherscompared to normal weight mothers (Table 3), and

we observed trends for declining scores with continu-ous BMI (INMA: 0.18; 95% CI: 0.34, 0.01; RHEAfine motor: 0.28; 95% CI: 0.60, 0.03; RHEA grossmotor: 0.07; 95% CI: 0.44, 0.29). Adjusting forpaternal BMI did not greatly influence the coefficientsfor cognitive or psychomotor development scores(Table 3 [Model 4] and Figures 1 and 2). Paternaloverweight and obesity were not associated withchild cognitive or psychomotor development in

Table 3 Association (b coefficient with 95% confidence interval) of maternal pre-pregnancy BMI with cognitive andpsychomotor development scores main analysis with multiple imputed dataa (cognitive: INMA N 1866, RHEAN 397;psychomotor: INMA N 1869, RHEA N 397)

CohortMaternal

BMI N

Model 1b Model 2c Model 3d Model 4e

b 95% CI b 95% CI b 95% CI b 95% CI

Cognitive development scores

INMA Normal 1360 ref ref ref ref

Overweight 359 1.14 2.87, 0.59 0.95 2.69, 0.79 0.88 2.63, 0.88 0.88 2.64, 0.88

Obese 147 3.37 5.90, 0.83 2.93 5.49, 0.36 2.69 5.27, 0.11 2.72 5.35, 0.10

RHEA Normal 271 ref ref ref ref

Overweight 82 0.17 3.86, 3.52 0.64 2.97, 4.25 1.34 2.32, 5.00 1.41 2.26, 5.08

Obese 44 6.00 10.75, 1.24 4.20 8.88, 0.49 3.92 8.60, 0.76 3.71 8.45, 1.02

Psychomotor development scores

INMA Normal 1363 ref ref ref ref

Overweight 358 1.36 3.11, 0.38 1.49 3.25, 0.27 1.61 3.38, 0.16 1.68 3.45, 0.10

Obese 148 1.51 4.06, 1.04 1.57 4.15, 1.01 1.85 4.45, 0.75 2.10 4.74, 0.54

RHEA,fine

motor

Normal 271 ref ref ref ref

Overweight 82

3.49

7.07, 0.09

2.60

6.18, 0.97

2.23

5.88, 1.42

1.94

5.59, 1.71Obese 44 2.97 7.58, 1.64 1.51 6.15, 3.13 1.67 6.33, 3.00 1.09 5.80, 3.62

RHEA,grossmotor

Normal 271 ref ref ref ref

Overweight 82 2.01 2.15, 6.17 3.16 1.00, 7.32 3.49 0.69, 7.67 4.00 0.18, 8.18

Obese 44 2.88 8.24, 2.49 0.72 6.12, 4.67 0.40 5.75, 4.94 0.73 4.66, 6.12

Ref, reference population.aExcluding underweight mothers.bModel 1: adjusted for childs gender and region (only in INMA).cModel 2: model 1 plus maternal education, paternal education, maternal country of birth and maternal and paternal social class(only in INMA).dModel 3: model 2 plus maternal age, paternal age, breastfeeding duration, maternal smoking, maternal employment status duringpregnancy and after birth, parity, nursery attendance and main childminder.eModel 4: model 3 plus paternal BMI.

512 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
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INMA (Figures 1 and 2 and Supplementary Table 7,available as Supplementary data at IJE online). InRHEA, however, children of overweight and obesefathers had reduced fine and gross psychomotorscores (Figure 2andSupplementary Table 7, availableas Supplementary data at IJE online). Complete case

analyses yielded similar results for both maternal andpaternal models (Supplementary Tables 6 and 8,available as Supplementary data at IJE online).

Sensitivity analyses showed no changes in coeffi-cients for cognitive development associated withmaternal obesity after additionally adjusting for

Figure 2 Association of maternal and paternal pre-pregnancy obesity on child psychomotor development scores.aUnadjusted (Model 1 of Table 3 and Supplementary Table 7, available as Supplementary data at IJE online): modelincluding childs gender and region (only in INMA).bWith mutual adjustment (Model 4 ofTable 3and Supplementary Table 7, available asSupplementary dataat IJE online):

model including childs gender, region (only in INMA), maternal education, paternal education, maternal country of birth,maternal and paternal social class (only in INMA), maternal age, paternal age, breastfeeding duration, maternal smoking,maternal employment status during pregnancy and after birth, parity, nursery attendance, main childminder, and paternalBMI

Figure 1 Association of maternal and paternal pre-pregnancy obesity on child cognitive development scores.aUnadjusted (Model 1 of Table 3 and Supplementary Table 7, available as Supplementary data at IJE online): modelincluding childs gender and region (only in INMA).bWith mutual adjustment (Model 4 ofTable 3and Supplementary Table 7, available asSupplementary dataat IJE online):model including childs gender, region (only in INMA), maternal education, paternal education, maternal country of birth,maternal and paternal social class (only in INMA), maternal age, paternal age, breastfeeding duration, maternal smoking,maternal employment status during pregnancy and after birth, parity, nursery attendance, main childminder, and paternalBMI

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gestational weight gain, gestational age at birth orchild BMI z-score after birth. However, includingbirthweight in the model led to a substantial reduc-tion in the coefficient in INMA (from2.69 to 3.14)

(Table 4). Adjusting for dietary folate intake, folatesupplementation, circulating levels of vitamin D, ma-ternal TSH, total Hg and PCBs levels did not changethe cognitive development coefficient linked to obesity(Table 4). After excluding maternal and paternalsocial class from the INMA models, coefficientsslightly decreased, particularly in paternal BMImodels (mental: from 0.56 to 0.85; psychomotor:from 0.09 to 0.26) (Supplementary Table 9, availableas Supplementary data at IJE online). Excludingmothers who did not live with the father, the direc-tion of the associations remained similar to the mainanalyses (data not shown).

DiscussionMaternal pre-pregnancy obesity was associated witha reduction in childrens cognitive developmentscores at 12 years of age. This association was con-sistent in the Spanish and Greek cohorts, althoughthe smaller sample size of the latter resulted inlower statistical power. Maternal pre-pregnancy over-

weight was associated with reduced cognitive devel-opment scores only in INMA. In both cohorts there

was evidence of a dose-response with continuousBMI. Associations between maternal overweight andobesity and infant psychomotor scores were weakerand less consistent between the two cohorts.

Paternal BMI was not associated with infant cognitiveor psychomotor development in INMA; however, inRHEA, paternal obesity was more strongly associated

with infant fine and gross motor scores than was ma-ternal obesity.

Comparing maternal and paternal weight status, weobserved substantially stronger associations for mater-nal than paternal obesity with cognitive scores, espe-cially in the INMA cohort. In the INMA cohort, bothmaternal and paternal BMI were strongly and consist-ently associated with socioeconomic factors suggest-ing that, at least in this cohort, paternal BMI wasa good indicator for a common social environment.In RHEA, however, paternal BMI was less strongly

and consistently associated with education and wewere not able to adjust for social class, so here thepaternal adjustment is less likely to account for acommon social environment. In both cohortsthough, associations with maternal obesity wererobust to adjustment for paternal BMI, both usingmultiple imputation and complete case analyses.Overall, these results suggest that, for cognitive devel-opment, a maternal mechanism (be it a direct intra-uterine or an indirect mechanism) is more likely to beresponsible for these findings than an indirect effect

Table 4 Cognitive development scores for obese mothers (Model 3): intermediate factors (b coefficient with 95% confi-dence interval)

Characteristics

INMAb RHEAb

N b 95% CI N b 95% CI

Obese mothersa 147 2.69 5.27, 0.11 44 3.92 8.60, 0.76

Intermediate factors

Gestational weight gain 147 2.72 5.34, 0.11 44 3.68 8.39, 1.03

Childs birthweight 147 3.14 5.72, 0.57 44 4.23 8.91, 0.45

Childs gestational age 147 2.82 5.39, 0.26 44 3.99 8.68, 0.70

Childs BMI after birth 147 2.62 5.20, 0.04 44 4.01 8.72, 0.70

Dietary folate intake 147 2.65 5.23, 0.06 44 3.82 8.52, 0.89

Folate supplementation 147 2.69 5.28, 0.11 44 3.96 8.64, 0.73

Vitamin D (maternal plasma) 147 2.59 5.17, 0.02

TSH (maternal serum)d 147 2.84 5.54, 0.15 44 4.03 8.73, 0.67

Total Hg (cord blood) 147 2.67 5.25, 0.09

Sub-sample

CRP (maternal serum)c 64 3.55 4.30, 2.80

PCBs (cord blood)d 98 3.18 6.37, 0.02

TSH, thyroid-stimulating hormone; Hg, mercury; CRP, C-reactive protein; PCBs, polychlorinated biphenyls.aCompared with normal weight mothers (INMA: 1360; RHEA: 271).bModel 3: adjusted for childs gender, region (only in INMA), maternal education, paternal education, maternal country of birth,maternal and paternal social class (only in INMA), maternal age, paternal age, breastfeeding duration, maternal smoking, maternalemployment status during pregnancy and after birth, parity, nursery attendance and main childminder.cCRP only available in INMA: Gipuzkoa and Sabadell (Model 3 for obese mothers: 3.47; 95%CI: 7.27, 0.34).dPCBs available in INMA, Gipuzkoa, Sabadell and Valencia (Model 3 for obese mothers: 3.24; 95%CI: 6.12, 0.37).

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through factors that act in the shared family andsocioeconomic context (socioeconomic class, smoking,exercise patterns) or paternal factors (genetics).

Adjustment for paternal BMI is unlikely to adjustfor indirect factors that are mainly determined bythe mother: even though we adjusted for maternalemployment status, main childminder and nursery at-

tendance during the first year of life, residual con-founding by postnatal factors, such as diet andother factors related to postnatal care, cannot beruled out. It should also be noted that confoundingstructures for some variables were somewhat differentin the two cohorts: in RHEA, maternal BMI was lessassociated with maternal employment status, breast-feeding and nursery attendance than in INMA. Thesimilarity in the main results for cognitive develop-ment in these two cohorts with different confoundingstructures adds some support to a causal effect ofmaternal BMI on child cognition. Paternal BMI wasreported by the mothers and thus was probably esti-mated with more error than maternal BMI; this mayhave resulted in attenuated associations with paternalBMI. However, after excluding those women who didnot live with the father, results did not change. Also,the cohorts did not collect information on some otherpotential confounders, such as parental intelligence,mental health and home environment. To further ad-dress the confounding issues and establish causalityof the observed association with more certainty, largerstudies could use genetic variants that are reliablyassociated with maternal adiposity as instrumental

variables (i.e. Mendelian randomization studies ormultivariate twin design33,34).

Children of overweight mothers showed a small re-

duction in cognitive development scores (only inINMA). In both cohorts however, we observeddecreasing cognitive scores with increasing continu-ous maternal BMI, with the greatest decreases in chil-dren of very obese mothers; therefore, it seemsprobable that there is an impact across the entireBMI range. Furthermore, in spite of the differencesobserved in educational levels between overweightand obese mothers, the reduction in cognitive scores

was stronger in obese than in overweight mothers inthe unadjusted model (Table 3, Model 1). This makesit unlikely that such differences in educational levels

were responsible for the non-significance of results inoverweight mothers.

Concerning psychomotor development, maternalBMI was associated with somewhat reduced scoresin INMA and RHEA. However, in RHEA, but notINMA, this association was stronger for paternal

than for maternal BMI. The inconsistencies observedbetween the cohorts with respect to paternal over-

weight and obesity make it difficult to assess whether

the weak associations observed between maternalBMI and psychomotor development are due tochance, indirect familial and paternal influences orother mechanisms.

Only six other studies have examined the associ-ation between maternal pre-pregnancy overweightand obesity and child cognitive development;5,8-12

two of them also assessed psychomotor develop-ment.5,10 Neggers et al.5 found that children of obesemothers had lower IQ and nonverbal scores at age5 years in a small (n 355) population with high

levels of obesity (44%) and low mean score for gen-eral IQ (82.1). A large US study (n 6850) showedthat children of obese mothers had lower mental de-

velopment scores at age 2 years.10 In both studies noassociation was observed with maternal overweight.Furthermore and consistently with our inconclusivefindings for psychomotor development, neither mater-nal obesity nor maternal overweight were associated

with childrens gross motor ability scores. In anothertwo studies, Heikura et al.9 and Tanda et al.11 reportedthat pre-pregnancy obesity, not overweight, was asso-ciated with offspring mild intellectual disability (IQ5070) at age 11 and lower Peabody individualachievement test (PIAT) at age 57 years, respectively.

An analysis within the Millenium Cohort Study(n 19 517) recently reported a significant decreasein cognitive scores with increasing continuous BMI(age 5: b0.075; age 7: b0.17).

12 Finally,Brion et al.8 found no consistent associations betweenmaternal overweight/obesity, as a combined variable,and maternal reports on child cognitive abilities at 30months to 8 years in two European cohorts (ALSPACand Generation R) with about 20% of overweight/obese mothers. There were no associations with pa-ternal BMI. In ALSPAC, however, a strong negativeassociation was observed between maternal over-

weight/obesity and general IQ assessed by a psycholo-gist at age 8 years. These findings reinforce the

potential importance of conducting standardized as-sessments by trained psychologists rather than mater-nal reports. These studies and our findings alsosuggest that it may be important to distinguish over-

weight and obese mothers and to evaluate associ-ations across the range of pre-pregnancy BMIs;combining these categories may obscure effects if as-sociations are observed only in a substantially smallersubset of mothers who are obese. Child age at testadministration may also explain some differences be-tween previous studies and ours. Children in ourstudy were younger, which may have the advantagethat they were less influenced by additional postnatalfactors such as schooling. However, the Bayley test

has shown low predictive value for later cognition35

and the associations reported here need to be fol-lowed up at older ages.

In this study we examined the impact of adjustingfor several plausible biological intermediates.However, none of the factors explored seemed toexplain the association between maternal obesityand child cognition. Obese mothers from ourstudy did not have elevated levels of TSH or lowerlevels of vitamin D compared with normal weightindividuals, as reported in other studies;15,16 this



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may explain why we did not observe a mediatingeffect. Though levels of CRP were higher in obesemothers (mean: 11.39 6.95 mg/l) compared with nor-mal weight mothers (mean: 5.65 7.27 mg/l), this in-dicator of systemic inflammation did not seem toexplain the association between maternal obesityand the reduction in cognitive scores. However, only

one inflammatory indicator was available and only ina sub-sample (n 894). The inclusion of additionalmarkers of inflammatory processes such as certaininterleukins, cytokines or hormones involved in theregulation of energy balance processes such as leptinhormone36 would be of great interest in determiningpossible mechanisms.

The strengths of this study lie in its prospectivedesign, its use of two independent cohorts for repli-cation, its adjustment for paternal BMI, and the qual-ity of neuropsychological tests: the BSID is recognisedinternationally as one of the most comprehensivetools to assess cognitive and psychomotor abilities ofchildren starting as young as 1 month old.25 Different

versions of the Bayley test were used, however, inINMA and RHEA, requiring caution in comparing re-sults between cohorts.

ConclusionsThis study in two Southern European birth cohorts

with moderately high obesity prevalence suggeststhat maternal pre-pregnancy obesity is associated

with reduced child cognitive development at earlyages; this association appears more likely to be dueto maternal than shared family and social mechan-

isms. Findings for psychomotor development wereinconclusive. Further research is needed to disentan-gle an intrauterine effect from other maternal con-founding factors, for example by using markers ofthe inflammatory processes or genetic variants thatare reliably associated with maternal adiposity.

Supplementary DataSupplementary data are available at IJE online.

Funding

This work was supported by grants from the SpanishMinistry of Health-Instituto de Salud Carlos III(Red INMA G03/176, CB06/02/0041, FIS-PI041436,FIS-PI081151, FIS-PI042018, FISPI09/02311, FIS-PI06/0867, FIS-PS09/00090, FIS-FEDER 03/1615, 04/1509,04/1112, 04/1931, 05/1079, 05/1052, 06/1213, 07/0314,09/02647); Generalitat de Catalunya (CIRIT 1999SGR00241); Conselleria de Sanitat Generalitat Valenciana;Universidad de Oviedo; Obra social Cajastur;Department of Health of the Basque Government(2005111093, 2009111069); the Provincial Governmentof Gipuzkoa (DFG06/004, DFG08/001); Fundacion RogerTorne (INMA Project); European project: EU FP7-2008-ENV-1.2.1.4 Envirogenomarkers; and the Greek

Ministry of Health (Program of Prevention of obesityand neurodevelopmental disorders in preschool children,in Heraklion district, Crete, Greece (2011-2014) (RHEAstudy). European projects: EU FP6-2003-Food-3-ANewGeneris, EU FP6. STREP Hiwate, EU FP7 ENV.2007.1.2.2.2. Project No 211250 Escape, EU FP7-HEALTH-2009 Proposal No 241604 CHICOS, EU FP7-ENV-2008 Proposal No 226285 ENRIECO (INMAProject and RHEA study). All these sources of fundinghave confirmed their agreement.

AcknowledgementsThe authors would particularly like to thank all the

cohort participants for their generous collaboration. Afull roster of the INMA Project Investigators can befound at http://www.proyectoinma.org/presentacion-inma/listado-investigadores/listado-investigadores.html .

Conflict of interest: None declared.

KEY MESSAGES

Maternal pre-pregnancy obesity may be associated with impaired infant neuropsychologicaldevelopment; however, there are few studies and it is unclear if reported associations are due tointrauterine mechanisms rather than to social factors or indirect pathways linked to maternal weight

status.

Using data from two birth cohorts with moderately high obesity prevalence, children of obesemothers had a reduction in cognitive development scores at 12 years of age.

This reduction in cognitive developmental scores appears more likely to be due to maternal thanshared family and social mechanisms.

Further research is needed to disentangle a direct intrauterine effect from other maternal confound-ing factors.

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