DOI: 10.1111/1471-0528.12052 www.bjog.

org

Epidemiology

Pre-pregnancy body mass index, weight change during pregnancy, and risk of intellectual disability in children
JR Mann,a SW McDermott,a J Hardin,b C Pan,b Z Zhanga
University of South Carolina School of Medicine, Columbia, SC, USA b University of South Carolina Arnold School of Public Health, Columbia, SC, USA Correspondence: Dr J Mann, University of South Carolina School of Medicine, 3209 Colonial Drive, Columbia, SC 29203, USA. Email joshua.mann@sc.edu Accepted 27 September 2012. Published Online 27 November 2012.
a

Objective This study investigated pre-pregnancy body mass index

Main outcome measures Identied as having ID in special

(BMI) and weight change in pregnancy as potential risk factors for intellectual disability (ID) in children.
Design Retrospective cohort study. Setting South Carolina, USA. Population A total of 78 675 motherchild pairs, insured by the South Carolina Medicaid programme, born in the period 20042007. Methods We analysed South Carolina Medicaid data, linked to data from both the South Carolina Department of Education (DOE) and the South Carolina Department of Disabilities and Special Needs (DDSN). Maternal pre-pregnancy BMI and weight change during pregnancy were obtained from birth certicates. ID cases were identied from the three sources listed above. We used generalised estimating equation logistic regression models to model the odds of ID in children.

education, DDSN, or Medicaid billing records.

Results The risk of ID was greater in children of women with prepregnancy obesity, and the risk was greatest in children born to women with morbid obesity (OR 1.52, 95% CI 1.301.77 for ID of any severity; OR 1.73, 95% CI 1.232.45 for severe ID). Gestational weight change (gain or loss) was not signicantly associated with odds of ID. Conclusions Pre-pregnancy obesity may be a modiable

risk factor for ID in children, although further study is needed to evaluate whether the association meets criteria for causation.
Keywords Body mass index, intellectual disability, obesity, pregnancy, weight gain.

Please cite this paper as: Mann J, McDermott S, Hardin J, Pan C, Zhang Z. Pre-pregnancy body mass index, weight change during pregnancy, and risk of intellectual disability in children. BJOG 2013;120:309319.

Introduction
Intellectual disability (ID) is a developmental disability characterised by signicant limitations both in intellectual functioning and in adaptive behavior, which covers a many everyday social and practical living skills, with onset before 18 years of age.1 Limitation in intellectual ability corresponds to an intelligence quotient (IQ) of <70, described as mild (IQ 5570), moderate (IQ 4055), or severe to profound (IQ of <40).2 The prevalence of ID in the general population is estimated to be approximately 1%, and among those with ID 85% are characterised as having mild ID.3,4 The causes of ID are extensive, and include disorders that substantially affect brain development and functioning.

According to the timing of the insult, causes can be classied as prenatal, perinatal, and postnatal, or acquired during childhood. Causes of ID can also be classied as genetic or non-genetic. Genetic causes include chromosomal abnormalities (e.g. trisomy 21 and other trisomies), inherited genetic traits (e.g. fragile X syndrome), and single gene disorders (e.g. PraderWilli syndrome).5,6 Important non-genetic causes include brain trauma, congenital infection, meningitis and encephalitis, environmental toxins or teratogens, radiation, and extreme childhood deprivation.7 The cause of ID in particular cases is often unknown,6,8 and the proportion of cases with unknown cause is generally highest in mild ID.9 Increasing maternal age, decreasing maternal education, multiple gestation, male

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sex, preterm birth, maternal infection, and pre-eclampsia have been identied as risk factors for ID of unknown cause.9,10 Obesity (body mass index, BMI > 30) and overweight (BMI 2529.9) are growing problems in the USA. According to the most recent National Health and Nutrition Examination Survey (NHANES) data for the year 2007 2008, 33.8% of American adults are obese and another 34.2% are overweight; 5.7% of American adults have morbid obesity (BMI > 40). The same data also revealed that over one-third of women aged 2039 years in the USA are obese.11,12 Even women with normal pre-pregnancy BMI can be at risk of excessive weight gain during pregnancy. Some weight gain is recommended for all women (11.3415.88 kg for women of normal weight at baseline, and less for women who are overweight or obese, according to the 2009 Institute of Medicine, IOM, guidelines).13 However, approximately 4060% of women experience gestational weight gain that exceeds the current IOM recommendations.14,15 Pre-pregnancy obesity and excessive weight gain is associated with a wide range of adverse pregnancy outcomes in the mother and child, such as increased risk of pre-eclampsia, gestational diabetes, stillbirth, perinatal death, fetal macrosomia, and delivery by caesarean section.16 19 Furthermore, maternal pre-pregnancy obesity is associated with an increased risk of having a child with a range of structural birth defects, including neural tube defects, spina bida, and cardiovascular anomalies.2025 Few studies have investigated the relationship of maternal pre-pregnancy obesity with childrens ID or other neurodevelopmental disabilities. Dodds et al.26 reported that a maternal pre-pregnancy weight of 90 kg (approximately 200 lb) or greater, and a pregnancy weight gain of 18 kg (approximately 40 lb) or greater were each signicantly associated with a risk of autism. Heikura et al.27 followed two cohorts of Finnish children born in 1966 (n = 12 058) and 19851986 (n = 9432). Prepregnancy maternal obesity was found to be associated with an increased risk of child ID (OR 2.9) only in the 19851986 cohort. Low pre-pregnancy BMI (<20) was associated with ID (OR 2.1) in the 1966 birth cohort, but obesity was not signicant.27 The discrepancy in results between the two birth cohorts renders the studys ndings inconclusive. Another study in the USA found that children of women who had pre-pregnancy obesity had signicantly lower general cognitive scores (b = 4.7, P = 0.001) and nonverbal development scores (b = 5.6, P = 0.003), as compared with children of mothers of normal weight.28 No association was present between maternal weight gain during pregnancy and any of the cognitive (IQ), verbal, or nonverbal scores. The study was limited by its restriction to African American children from low-income families and a sample size of only 355.

Analysing data from two cohorts of children, one British and one Dutch, totalling approximately 7500 children, Brion et al.29 reported a signicant association between maternal overweight/obesity and reduced odds of being in a higher quintile for IQ (adjusted OR 0.84, P = 0.03). However, on the basis of a lack of consistent associations between maternal overweight/obesity and measures of specic aspects of cognitive ability, the authors concluded that the results were probably the result of unmeasured confounding factors. Most recently, researchers in California conducted a case control study that included 517 children with autism spectrum disorders, 172 children with another developmental disability, and 315 controls.30 They found that maternal obesity was signicantly associated with both autism spectrum disorders (OR 1.61) and developmental disability (OR 2.35). This study did not assess the impact of weight gain during pregnancy. These studies indicate that there may be an association between maternal weight and ID in children, but additional studies are needed, especially well-powered studies that assess both pre-pregnancy BMI and weight change during pregnancy.

Methods
We conducted a retrospective cohort study to investigate pre-pregnancy BMI and maternal weight gain during pregnancy as potential risk factors for ID in their children. Our a priori hypotheses were that pre-pregnancy obesity and high levels of weight gain would be associated with increased odds of ID. We obtained data for children from South Carolina Medicaid billing records and birth certicates for pregnancies and births that occurred during the period 20042007 (Medicaid purchases health services for low-income pregnant women and children), linked to data from the South Carolina Department of Education (DOE) and Department of Disabilities and Special Needs (DDSN). These linked data are available through the South Carolina Ofce of Research and Statistics (ORS), which maintains administrative data for state agencies at the individual level. At rst contact with a state entity (often at birth, when the birth certicate is completed), each individual who has contact with one or more agencies of the State government is assigned a unique identication number. This universal cross-agency identication number permits linkage of individual data across different types of services. It also permits linkage of data for mothers and their children, through birth certicate records. For this study, a maternal match was identied for 94.1% of the babies who were part of the Medicaid birth cohort for the years of interest. The study protocol was reviewed by all of the agencies from whom data were requested and the University of South

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Carolina Institutional Review Board, which granted exempt status.

ID but not meeting the criteria for number of diagnoses or diagnosing clinicians.

Case denition of intellectual disability

Children with ID were identied in the three data sources, updated to 31 December 2010. The rst source was the Medicaid le that includes the International Classication of Diseases, Ninth Revision (ICD9) diagnosis codes in clinical billing records. The ICD-9 codes for ID are 317 (mild), 318 (moderate, severe, or profound, depending on the specic fourth digit), and 319 (unspecied or unknown severity). The second source for identifying cases of ID was a data le from the DOE. Children in special education are placed in one of three categories: educable mentally handicapped (EMH, which corresponds to mild ID), trainable mentally handicapped (TMH, which corresponds to moderate to severe ID), and profoundly mentally handicapped (PMH, corresponding to profound ID). The nal source for identifying cases of ID was enrollment in ID support services from DDSN. Eligibility for special education and DDSN ID services requires formal psychological assessment, including IQ testing. However, because of the young age of the cohort, we anticipated that the majority of cases would come from Medicaid or DDSN, rather than the school system, as children frequently do not enroll in public school until 5 years of age. Medicaid diagnoses of ID are based on the ICD-9 codes entered by healthcare providers (including psychologists, therapists, and physicians), without corroborating information about these cases. To be conservative and minimise the risk of wrongly identifying children as cases of ID, we dened a case as a child who was either enrolled in special education in a South Carolina public school, enrolled in DDSN services for ID, or diagnosed with ID in the Medicaid billing data on at least ve different occasions. Children diagnosed with ID fewer than ve times and not conrmed in DOE or DDSN data were completely excluded from the analyses. We also created a variable that identied children who were diagnosed with moderate to profound ID in Medicaid billing data (ICD-9 code 318), were enrolled in TMH or PMH special education classes, or were receiving DDSN services (the last group was included because, according to personal communications with DDSN staff, a majority of DDSN clients have moderate to profound ID). We used this as a separate outcome in the modelling. For cases not conrmed in DDSN or DOE records but with a Medicaid diagnosis of ID (any severity and severe), we performed sensitivity testing based on the number of times diagnosed and/or number of different providers making a diagnosis of ID. We examined multiple cut-offs, the most restrictive being at least 25 separate diagnoses of ID or being diagnosed by at least ve different providers. For the sensitivity testing, we excluded children identied as having

Identication of independent variables and covariates

Pre-pregnancy BMI was calculated based on the prepregnancy height and weight measurements provided on the birth certicate: BMI (kg/m2) = (weight in kg)/(height in m)2. Weight gain or loss was calculated as the difference between the mothers weight at delivery and the prepregnancy weight as reported on the birth certicate. We controlled for a wide range of potential confounding factors using the birth certicate, Medicaid data, or both. Demographic information, obtained from birth certicates, included maternal age, race, ethnicity, and level of education. Information about maternal tobacco use, gonorrhea, chlamydia, syphilis, and intrapartum fever were also obtained from the birth certicate, as were the childs sex, gestational age (in completed weeks) at delivery, and birthweight. Women with hypertension and those with diabetes mellitus were identied based on a combination of ICD-9 codes and birth certicate information. Maternal epilepsy was identied using ICD-9 code 345 in the Medicaid data. We also obtained information about whether each mother had ever been reported as having ID, so that we could control for the presence of this potential confounding factor. We searched the Medicaid billing data for mothers and identied all those who had ever been diagnosed with ID of any severity. We also identied those who had received DDSN services for ID, and among those who could be identied in South Carolina public school records (41.1%), we identied those who were ever enrolled in special education in EMH, TMH, or PMH placements. We then created a dichotomous indicator variable for maternal ID, which was included as a covariate in all of the regression models.

Exclusions
We excluded mothers with pre-pregnancy BMIs >51.31 or <17.6. We also excluded mothers with heights >178 cm or <146 cm. These outliers were suspected to result from data entry errors. The cut-off points used were the corresponding rst and 99th percentiles for females aged 20 years and over from the NHANES for the US population in 20032006. The rst and 99th percentiles were not published, so we obtained cut-off values via personal communication with staff from the Centers for Disease Control and Prevention (CDC)/ National Center for Health Statistics.31 We also excluded women who gained or lost more than 45 kg during pregnancy, out of concern that these extreme values may have represented data entry errors. We excluded children who were not singleton births and those who were diagnosed with a known or likely cause of

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ID (whether ID was actually conrmed in the Medicaid, DOE, or DDSN records). The known/likely causes that were removed, based on birth certicate data, were trisomy 21, anencephaly, other brain anomalies, spina bida, suspected chromosomal abnormalities with chromosomal analyses pending, and meconium aspiration syndrome. Medicaid diagnoses excluded were PraderWilli syndrome, fragile X syndrome, fetal alcohol syndrome, congenital syphilis, congenital hypothyroidism, amino acid disorder, hydrocephalus, birth trauma, neonatal haemolytic disease, neonatal drug withdrawal, brain anomaly, traumatic brain injury, meningitis, encephalitis, congenital infections, neonatal infections, respiratory distress syndrome, birth asphyxia, and cardiac arrest. By excluding children with these known or likely causes of ID, we were able to evaluate maternal BMI and gestational weight gain or loss as potential risk factors for unexplained ID.
125,821 (100%) Medicaid children born in20042007

Intellectual disability cannot be diagnosed reliably in very young children. To ensure that children had a sufcient level of follow-up to be identied as having ID, we restricted analyses to children who met at least one of the following criteria:  enrollment in the South Carolina Medicaid programme until at least 3 years of age;  enrollment in the South Carolina public school system; or  identied as a case of ID in at least one of the three data sources. Figure 1 displays the number of children removed from the analyses for each category of exclusion. After exclusions, 62.53% of the observations from the original cohort were used for analysis. Among them, 3.96% were cases of ID.

Statistical modelling
Some of the women in our cohort gave birth to more than one baby during the study period. Results from multiple

3,815 Non-Singleton Births 3712 twins 90 triplets 4 quadruplets 6 quintuplets 3 missing 122,006 (96.97%)

7,650 BMI/Height Outliers

114,356 (90.89%) 17,986 Excluded Because of Medical Conditions 1,378 excluded based on birth certificate 16608 excluded based on Medicaid diagnoses 96,370 (76.59%) Children not diagnosed with a known cause of ID 15,532 Excluded Because of Inadequate Follow-Up duration and no Identification of ID 80,838 (64.25%) Enrolled in Medicaid until at least age 3; Enrolled in SC public schools; or Diagnosis with ID 449 Excluded for Having ID Identified Only in Medicaid, with Fewer than 5 Diagnoses 80,389 (63.89%) No diagnosis of ID; Diagnosed as ID at least 5 times; Receiving DDSN services for ID; or Enrolled in special education in a public school 1714 Excluded for weight change greater than 45kg during pregnancy 78675 (62.53%)

75,562 (96.04%) No ID

3,113 (3.96%) Confirmed ID

Figure 1. Study exclusions.

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pregnancies in the same woman violate the assumption of independence of observations for logistic regression models. To account for such correlated data, we estimated the population-averaged logistic regression generalised estimating equations (GEE) models, which appropriately analyse longitudinal/repeated measures and other correlated data, even when the response is discrete.32,33 We specied an exchangeable structure (all observations have the same pairwise correlation) to model the correlation between the babies born to the same mother. We anticipated that the assumption of a constant odds ratio across the range of some independent variables might not be reasonable. If so, the associations between the outcome and those predictors would not be linear in our logistic model. An approach that allows a nonlinear exposureresponse association is to use fractional polynomials.34 The fractional polynomials method gives a functional formula for the nonlinear term and produces useful exposureresponse plots.3537 The functional form for an independent variable X is dened as b1 X p1 b2 X p2 , with p1 and p2 taken from the set S = {2, 1, 0.5, 0, 0.5, 1, 2, 3}, where X0 = log(X). The best functional form for X is the one with the highest likelihood.

Table 1. Demographic and other characteristics (n = 78 675) No ID (n = 75 562)

Infant characteristics Sex Male 37 528 Female 38 034 Gestational age 38.59 (weeks) Birthweight (g) 3210.3 Maternal characteristics Mean age 23.71 Age category 1834 66352 <18 5831 >34 3374 Education <HS 28 638  HS 46 714 Race White 37 617 Black 36 761 Other 1092 Hispanic Yes 8294 No 66 998 Tobacco use Yes 13 874 No 61 646 Weight change (kg) 11.70 Pre-pregnancy BMI 27.55 Intellectual disability Yes 2392 No 73 170 Febrile at delivery No 74 890 Yes 672 Chlamydia during pregnancy No 70 927 Yes 4635 Gonorrhea during pregnancy No 74 730 Yes 832 Syphilis during pregnancy No 75 436 Yes 126 Epilepsy No 75 258 Yes 304 Diabetes No 66 198 Yes 9364 Hypertension No 64 669 Yes 10 893

ID (n = 3113)

P*

(49.67%) (50.33%) (1.52) (496.3) (5.29) (87.82%) (7.72%) (4.47%) (38.01%) (61.99%) (49.84%) (48.71%) (1.45%) (11.02%) (88.98%) (18.37%) (81.63%) (8.60) (6.74) (3.17%) (96.83%) (99.11%) (0.89%) (93.87%) (6.13%) (98.90%) (1.10%) (99.83%) (0.17%) (99.60%) (0.40%) (87.61%) (12.39%) (85.58%) (14.42%)

2141 (68.78%) 972 (31.22%) 38.30 (1.85) 3146.1 (572.2) 24.60 (5.65) 2705 (86.89%) 199 (6.39%) 209 (6.71%) 1312 (42.27%) 1792 (57.73%) 1626 (52.35%) 1443 (46.46%) 37 (1.19%) 389 (12.53%) 2715 (87.47%) 629 2483 11.24 28.14 (20.21%) (79.79%) (8.69) (7.11)

<0.0001 <0.0001 <0.0001 <0.0001 <0.0001

<0.0001

0.0164

0.0083

Results
Characteristics of the cohort
The demographic and other characteristics of the 78 675 motherchild pairs included in our analyses are summarised in Table 1. There were 3113 children identied with ID. Only three cases of ID were identied in DDSN or school data, and all three were also diagnosed in the Medicaid le. We compared the characteristics of children with ID against children without ID. As can be seen from Table 1, children with ID were more likely to be boys, had shorter gestational ages, and had lower birthweights. Maternal characteristics associated with an increased likelihood of child ID included older age, completion of <12 years of education, being white or Hispanic, smoking during pregnancy, higher pre-pregnancy BMI, less weight gain, intellectual disability, and epilepsy.

0.0095 0.0040 <0.0001 <0.0001

270 (8.67%) 2843 (91.33%) 3080 (98.94%) 33 (1.06%) 2932 (94.19%) 181 (5.81%) 3073 (98.72%) 40 (1.28%) 3107 (99.81%) 6 (0.19%) 3084 (99.07%) 29 (0.93%) 2693 (86.51%) 420 (13.49%) 2590 (83.20%) 523 (16.80%)

0.3219

0.4659

0.3369

0.7284

<0.0001

Pre-pregnancy BMI and odds of intellectual disability

We investigated the relationship between maternal prepregnancy BMI and odds of child ID, controlling for baby characteristics of sex, gestational age, and birthweight, and maternal characteristics of race, ethnicity, education level, tobacco use, weight change during pregnancy, epilepsy, and ID. We modelled both child ID of any severity and moderate to profound ID (henceforth termed severe ID) as our responses. We investigated the effect of

0.0685

0.0002

For continuous variables, means (standard deviations) are reported, whereas for categorical variables, frequencies (percentages) are reported. *P values test the equivalence of means (Students t-test) for continuous variables and equivalence of proportions (chi-square test) for categorical variables.

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pre-pregnancy BMI both as a continuous variable and as a categorical variable using commonly used BMI classications. Degree of maternal weight gain, as a continuous variable, was the second key independent variable. Intuitively, we anticipated that the impact of antenatal weight change would be modied by prepregnancy BMI; that is, more weight gain would be benecial for women who were underweight at baseline but harmful for women who were overweight or obese before becoming pregnant. Because of this potential effect modication, we rst tested whether there was a signicant interaction between pre-pregnancy BMI and weight change. We found that there was not a signicant interaction between the two variables. When we estimated the models with pre-pregnancy BMI and weight change as continuous variables, only BMI was statistically signicant. For ID of any severity, each one-unit increase in pre-pregnancy BMI was associated with a 2% increase in the odds of ID (OR 1.02, 95% CI 1.011.02). For severe ID, the increase was slightly greater (OR 1.03, 95% CI 1.011.04).

The results of the models where pre-pregnancy BMI is categorised are presented in Table 2. BMI was classied as follows:  underweight (BMI < 18.5);  normal weight (BMI 18.524.99);  overweight (BMI 2529.99);  mild obesity (BMI 3034.99);  severe obesity (BMI 3539.99);  morbid obesity (BMI 40 or greater). Normal weight is the reference level. Being underweight was not associated with increased odds of child ID, whereas there was a trend towards increased odds of ID in children of women who were overweight but not obese. Maternal obesity was signicantly associated with risk of ID, and it appeared that a doseresponse relationship was present. The strongest association was for children of women who were morbidly obese, compared with those who were of ideal weight. The odds of ID of any severity in children born to women with morbid obesity were increased by over 50% (OR 1.52, 95% CI 1.301.77), and the odds of severe ID were increased by more than 80% (OR 1.83, 95% CI

Table 2. Model results for ID and severe ID (pre-pregnancy BMI categorised) ID (3113 cases) OR (95% CI) Underweight Overweight Mild obesity Severe obesity Morbid obesity Maternal weight gain Female sex Gestational age Birthweight Education < 12 years Maternal race Black versus white Other versus white Hispanic ethnicity Tobacco use Maternal intellectual disability Maternal age <18 years >34 years Febrile at delivery Chlamydia during pregnancy Gonorrhea during pregnancy Syphilis during pregnancy Maternal epilepsy Maternal diabetes Maternal hypertension 1.08 (0.861.37) 1.09 (0.991.20) 1.18 (1.061.33) 1.26 (1.091.45) 1.52 (1.301.77) 1.000 (0.9991.001) 0.44 (0.400.47) Nonlinear Nonlinear 1.16 (1.061.26) 0.83 0.76 1.20 1.08 2.90 0.80 1.52 1.19 0.97 1.20 0.82 1.97 1.01 1.03 (0.760.90) (0.541.07) (1.061.37) (0.971.19) (2.523.34) (0.680.93) (1.301.76) (0.821.72) (0.831.14) (0.861.67) (0.332.05) (1.332.93) (0.901.13) (0.921.14) P 0.490 0.079 0.003 0.002 0.000 0.690 0.000 0.001 0.000 0.001 0.000 0.118 0.005 0.148 0.000 0.005 0.000 0.368 0.740 0.287 0.678 0.001 0.900 0.635 Severe ID (579 cases) OR (95% CI) 1.31 (0.79, 2.17) 1.25 (1.001.56) 1.35 (1.051.74) 1.70 (1.262.29) 1.83 (1.312.56) 1.001 (0.9991.003) 0.29 (0.240.36) Nonlinear 0.86 (0.780.95) 1.17 (0.971.40) 0.95 0.11 0.67 1.00 2.93 0.54 1.31 1.05 0.74 1.23 0.96 2.07 1.00 1.00 (0.791.16) (0.010.89) (0.470.96) (0.801.25) (2.173.96) (0.360.82) (0.911.89) (0.432.59) (0.501.09) (0.592.56) (0.146.66) (0.894.82) (0.781.28) (0.791.26) P 0.298 0.049 0.021 0.001 0.002 0.442 0.000 0.0051 0.004 0.107 0.634 0.039 0.029 0.993 0.000 0.004 0.144 0.915 0.130 0.576 0.964 0.091 0.980 0.982

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1.312.56). Again, weight change during pregnancy was not signicantly associated with odds of ID. Other signicant associations with ID can be seen in Table 2. Table 3 summarises the results of our sensitivity analyses, based on the number of times a child was diagnosed with ID, or the number of different providers making the diagnosis. For each model, the odds ratio was adjusted by the full list of covariates. In every model, for both ID of any severity and for severe ID, children born to obese women were signicantly more likely to have ID. The point estimates were consistently somewhat greater for severe ID than for ID of any severity, and they were also higher for women with severe or morbid

obesity (with BMIs of 35 or greater) than for those with mild obesity.

Discussion
To our knowledge, this is the largest study to investigate both pre-pregnancy BMI and gestational weight change as risk factors for ID in children. The key nding is that prepregnancy BMI is associated with signicantly increased odds of ID in the children. The association is signicant when controlling for a wide range of demographic and other characteristics. When we classied pre-pregnancy BMI by level of obesity, we found a marginally signicant association for being overweight, with an increase of the strength of the association for increasing levels of obesity. These ndings are important from a public health perspective given the recent, dramatic increase in the rates of obesity in the USA and other industrialised nations.38 We did not nd a signicant association between weight change (gain or loss) in pregnancy and odds of ID. This is consistent with the ndings of Neggers et al., who reported that pre-pregnancy obesity but not weight gain during pregnancy was associated with lower psychomotor development scores in 355 African-American children.28 Our study expands upon their nding by assessing diagnosed ID in a much larger sample that includes approximately 50% white children. One pathway by which maternal obesity could increase the risk of ID in the child is fetal/neonatal macrosomia, which is more likely in the context of maternal obesity and is associated with an increased risk of a number of adverse pregnancy and birth outcomes, including stillbirth, birth asphyxia, and neonatal mortality. However, macrosomia does not explain the observed association between prepregnancy obesity and ID in our study, as the association was present despite controlling for birthweight. Obesity in pregnancy has a number of metabolic and other effects, which could account for the association. These include insulin resistance/hyperinsulinaemia and systemic inammation, as well as epigenetic effects on fetal DNA.39 Obese pregnant women exhibit low-grade endotoxemia and increased systemic C-reactive protein and interleukin-6 concentrations, as well as increased gene expression for a number of pro-inammatory cytokines in adipose tissue,40 and they also exhibit increased macrophage accumulation and inammation in the placenta.41 Furthermore, there is evidence that prepubescent children of women who were obese during pregnancy were dramatically more likely to have detectable C-reactive protein levels than children of non-obese mothers, even after controlling for the childs BMI and other potential confounding factors.42 There is convincing evidence that intrauterine inammation and fetal systemic inammation are associated with an increased

Table 3. Adjusted odds ratios for BMI categories, sensitivity testing ID Case denition 2 Underweight 1.10 Overweight 1.10 Mild obesity 1.20 Severe 1.27 obesity Morbid 1.54 obesity Case denition 3 Underweight 1.07 Overweight 1.12 Mild obesity 1.20 Severe 1.27 obesity Morbid 1.55 obesity Case denition 4 Underweight 1.07 Overweight 1.14 Mild obesity 1.25 Severe 1.30 obesity Morbid 1.69 obesity Case denition 5 Underweight 0.95 Overweight 1.16 Mild obesity 1.23 Severe 1.29 obesity Morbid 1.76 obesity Severe ID

(0.871.38) (1.001.21) (1.071.34) (1.111.47) (1.321.80)

0.432 0.060 0.001 0.001 0.000

1.31 1.25 1.35 1.70

(0.792.17) (1.001.56) (1.051.74) (1.262.29)

0.298 0.049 0.021 0.001 0.002

1.73 (1.232.45)

(0.841.37) (1.011.24) (1.071.35) (1.091.47) (1.321.83)

0.571 0.030 0.003 0.002 0.000

1.26 1.21 1.38 1.73

(0.732.15) (0.961.53) (1.061.80) (1.262.36)

0.406 0.103 0.017 0.001 0.012

1.61 (1.112.33)

(0.821.39) (1.021.26) (1.111.42) (1.111.52) (1.422.00)

0.620 0.018 0.000 0.001 0.000

1.22 1.25 1.50 1.78

(0.672.22) (0.971.61) (1.121.99) (1.262.51)

0.518 0.091 0.006 0.001 0.001

1.90 (1.292.81)

(0.701.29) (1.031.30) (1.071.41) (1.081.54) (1.462.13)

0.749 0.016 0.004 0.005 0.000

1.40 1.21 1.54 1.63

(0.732.69) (0.901.63) (1.112.14) (1.082.47)

0.315 0.216 0.010 0.020 0.001

2.08 (1.333.24)

Case denitions: 2At least 5 Medicaid diagnoses or at least 2 different providers or DDSN or special education; 3At least 10 Medicaid diagnoses or at least 3 different providers or DDSN or special education; 4At least 15 Medicaid diagnoses or at least 4 different providers or DDSN or special eduction; 5At least 25 Medicaid diagnosis or at least 5 different providers or DDSN or special education.

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risk of brain injury leading to neurodevelopmental disability, such as cerebral palsy.43,44 It is possible that the potential effects of increased inammation in obese women, even in the absence of clinical signs or symptoms, is sufcient to signicantly alter brain development in some children. Other metabolic and/or epigenetic effects of obesity may also have an impact on fetal brain development, but currently there is not sufcient evidence to speculate on what those effects may be. Other characteristics accompanying obesity, such as differences in dietary intake and physical activity patterns, may also play a role. Finally, obesity is known to alter levels of steroid hormones, including those involved in oocyte maturation and ovulation, and obesity is a known risk factor for infertility.45 So it is possible that endocrine factors early in pregnancy play a role. This study does have a number of limitations. First, it is limited to Medicaid-funded births in South Carolina. Medicaid is a health insurance programme for low-income families and funds approximately half of the births in South Carolina. Findings in the South Carolina Medicaid population may not be fully generalizable to middle and upper income families, or to other geographic areas outside of the southern USA. A second limitation is our reliance on administrative data for the ascertainment of both independent and dependent variables. Pre-pregnancy and delivery height and weight have been recorded on South Carolina birth certicates since 2004. We relied upon this information for our analyses. Height and weight are recorded on birth certicates based on the mothers self-report, rather than on objective measurement. Therefore, they are subject to being misreported. Nevertheless, many recent studies have used birth certicate data for epidemiological studies related to maternal weight.4651 A large study of women with low incomes in Florida demonstrated that pre-pregnancy height and weight as recorded on birth certicates were generally reliable.52 In a smaller, clinic-based study, Wright et al. found that gestational weight gain recorded in birth certicates was within 4.5 kg for 48% of women, whereas 52% had weight gain either over- or under-reported by at least 4.5 kg.53 For the misreporting of BMI to have accounted for the ndings of this study, a systematic relationship between maternal misreporting and the odds of child ID would be needed. Rothman describes how non-differential misclassication can result in a bias away from the null if the exposure variable is continuous (like BMI).54 However, he further explains that changing to a dichotomous variable (such as obese versus not obese) generally alleviates this problem. In this case, the results of comparing each category of abnormal weight with women of normal weight resulted in the same ndings as the models with BMI as a continuous variable. In addition, our decision to remove women with extreme values for prepregnancy weight or weight gain from the analyses also

reduces the likelihood that erroneous weights accounted for the observed ndings. We believe it is highly unlikely that the ndings of this study were substantially impacted by the misreporting of BMI or gestational weight change. For the outcome of ID we relied on Medicaid diagnoses, public school records, and receipt of services from the South Carolina DDSN. The public school system and DDSN require a formal psychological assessment, with IQ and adaptive function testing, before a child is eligible for special education classes or ID-related services. We do not have information on the factors underlying a diagnosis of ID in the Medicaid billing records. The number of children enrolled in DDSN programmes for ID or in special education in public schools was exceedingly low. This is probably because of their young agesall were born from January 2004 through December 2007: therefore, the maximum age was 6 years. We were unable to go further back than 2004 in our cohort because that is when South Carolina birth certicates began including pre-pregnancy height and weight. To determine how many of the cases of ID identied using Medicaid records ultimately wind up enrolling in DDSN services or special education, we would need to follow up with the analyses in a few years, when all of the children have had an opportunity to enroll in school and have had time for their learning difculties to be identied. Meanwhile, our decision to limit cases to those identied in the public school or DDSN records, or diagnosed with ID on at least ve different occasions, minimises the likelihood of false-positive diagnoses of ID in our case group. In addition, we conducted extensive sensitivity testing based on the number of times diagnosed with ID and the number of providers making the diagnosis. The association between obesity and ID was robust to the sensitivity testing, even when requiring that a child be diagnosed with ID at least 25 times or by at least ve different healthcare providers in order to be considered a case. Such a robust nding indicates that the associations reported in this paper are highly unlikely to be attributable to misidentied ID. One of the greatest strengths of this study is the large sample size, which provides ample power for the analyses. Our cohort included almost 80 000 children after exclusions, over 3100 of whom were identied as having ID. Another strength is our analytic method, which allowed us to model and interpret nonlinear relationships between pre-pregnancy BMI and weight change during pregnancy and the outcome ID. This is vital, as we would not necessarily anticipate a linear relationship between BMI/weight change and odds of ID. Our consideration of weight change during pregnancy is also an important strength, as it would be reasonable (although apparently incorrect) to anticipate that gaining too much weight during pregnancy would be similarly associated with ID as having pre-pregnancy obesity. Finally,

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we controlled for a number of potentially important factors (including demographic characteristics, gestational age, birthweight, and diagnoses of epilepsy and ID in mothers), so we can be condent that the association between obesity and ID does not result from confounding by those factors. We are not aware of any studies of maternal obesity and child ID that have adjusted for such a broad range of covariates. And we excluded children with birth defects, chromosomal conditions, or other diagnoses known to be causes of ID, so our ndings are directly relevant for the approximately 50% of cases of ID that do not have known causes. The ndings regarding other factors associated with risk of ID (such as maternal ID and maternal epilepsy, lower gestational age, and birthweight) are consistent with what might be expected, which lends additional support to the general validity of ID diagnoses in the cohort. One notable exception is the higher rate of ID among white children compared with black children, as in the US ID is more prevalent among children from minority groups; on further examination, we found that before exclusions, ID was in fact more common among black children with ID, but that a larger number of ID cases were excluded from minority groups by the diagnosis of known causes of ID (data available from authors). Despite its strengths, this is an associational study and does not establish a causal relationship between maternal obesity and child ID. Two key factors in establishing causation are consistency/replication of ndings and the identication of one or more plausible mechanisms for causation.55 Additional epidemiological study in a variety of geographic and socio-economic groups is needed to test the consistency of the association, and to assess the generalisability of our ndings to the entire population of pregnant women and children. In addition, basic science and translational research are needed to provide a better understanding of the potential mechanism(s) whereby maternal obesity may impact fetal brain development, and (if the association is determined to be causal) to identify potential methods to reduce the effects of obesity on fetal brain development. Meanwhile, the observed link between pre-pregnancy obesity and risk of ID in offspring may be yet another impetus (in addition to the established associations between obesity and numerous other adverse health outcomes) to develop and implement effective approaches to counteract the obesity epidemic in the USA and other industrialised nations.

Acknowledgements
The authors would like to thank Heather Kirby and other staff at the South Carolina Ofce of Research and Statistics for making available the data used in this study.

Disclosure of interests
The authors have no interests to declare.

Contribution to authorship
JM, SM, and JH are co-investigators. CP performed the majority of the data analysis. ZZ assisted in the literature review and contributed substantially to the writing of the article. The contributions made by all authors to the article are consistent with co-authorship.

Details of ethics approval

The study was granted exempt status by the University of South Carolina Institutional Review Board.

Funding
This study was funded by the Health Resources and Services Administration, grant number R40MC21523 (to J.R.M., as principle investigator), Maternal Obesity, Excessive Weight Gain, Diabetes Mellitus, and Hypertension during Pregnancy and Risk of Neuro-developmental Disability in Children. &

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Conclusions
Pre-pregnancy obesity is associated with an increased risk of intellectual disability in children. If this nding is conrmed and determined to be causal, then efforts to reduce obesity in childbearing women have the potential to reduce the prevalence of ID in children.

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