maternal glycemia during pregnancy and childhood adiposity

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Maternal Glycemia During Pregnancy and ChildhoodAdiposity in the Hyperglycaemia and Adverse PregnancyOutcome Follow-Up StudyDOI:10.1007/s00125-018-4809-6

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Citation for published version (APA):Clayton, P., & et al. (2019). Maternal Glycemia During Pregnancy and Childhood Adiposity in the Hyperglycaemiaand Adverse Pregnancy Outcome Follow-Up Study. Diabetologia, 62(4), 598-610. https://doi.org/10.1007/s00125-018-4809-6

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https://doi.org/10.1007/s00125-018-4809-6

https://doi.org/10.1007/s00125-018-4809-6

Maternal Glycemia During Pregnancy and Childhood Adiposity in the Hyperglycaemia and Adverse Pregnancy Outcome Follow-Up Study

HAPO Follow-Up Study Cooperative Research Group1

Running Title: Maternal glycaemia and risk of childhood adiposity

Abstract Word Count: 313

Main Text Word Count: 3934

Corresponding Author:

Boyd E Metzger

Northwestern University Feinberg School of Medicine

Endocrinology

300 E Superior

Suite 12-703

Chicago, IL 60611

Phone: 312-503-7979

Fax: 312-503-0037

[email protected]

1Members of the HAPO Follow-Up Study Cooperative Research Group are listed at the end of the manuscript.

mailto:[email protected]

Writing Group

William L Lowe, Jr, 1

Lynn P Lowe, 1

Alan Kuang, 1

Patrick M Catalano, 2

Michael Nodzenski, 1

Octavious Talbot, 1

WH Tam, 3

David A Sacks, 4

David McCance, 5

Barbara Linder, 6

Yael Lebenthal, 7

Jean M Lawrence, 4

Michele Lashley, 8

Jami L Josefson, 1,9

Jill Hamilton, 10

Chaicharn Deerochanawong, 11

Peter Clayton, 12

Wendy J Brickman, 1,9

Alan R Dyer, 1

Denise M Scholtens, 1

Boyd E Metzger, 1

The Writing Group takes responsibility for the content of this article.

1Northwestern University Feinberg School of Medicine, Chicago, IL, USA

2MetroHealth Medical Center/Case Western Reserve University, Cleveland, OH, USA

3The Chinese University of Hong Kong/Prince of Wales Hospital, Hong Kong, China

4Kaiser Permanente Southern California, Pasadena, CA, USA

5Royal Victoria Hospital, Belfast, United Kingdom

6NIDDK, National Institutes of Health, Bethesda, MD, USA

7Schneider Children’s Medical Center of Israel, Petah-Tiqva, Israel and Sackler Faculty of

Medicine, Tel Aviv University, Israel

8Queen Elizabeth Hospital/School of Clinical Medicine and Research, University of the West

Indies, Barbados, West Indies

9Ann and Robert H Lurie Children’s Hospital, Chicago, IL, USA

10The Hospital for Sick Children, University of Toronto, Ontario, Canada

11Rajavithi Hospital, Bangkok, Thailand

12Royal Manchester Children’s Hospital, Manchester University Hospitals NHS Foundation

Trust, Manchester Academic Healthy Sciences Centre/School of Medical Sciences, Faculty of

Biology, Medicine & Health, University of Manchester, Manchester, United Kingdom

ABSTRACT

Aims/hypothesis Maternal type 2 diabetes during pregnancy and gestational diabetes are

associated with childhood adiposity; however, associations of lower maternal glucose levels

during pregnancy with childhood adiposity, independent of maternal BMI, remain less clear.

The objective was to examine associations of maternal glycemia during pregnancy with

childhood adiposity in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) cohort.

Methods: The HAPO Study was an observational epidemiological international multi-ethnic

investigation that established strong associations of glucose levels during pregnancy with

multiple adverse perinatal outcomes. The HAPO Follow-Up Study (FUS) included 4832 children

from 10 HAPO centers whose mothers had a 75-g oral glucose tolerance test (OGTT) at ~28

weeks gestation 10-14 years earlier, with glucose values blinded to participants and clinical

caregivers.

The primary outcome was child adiposity, including overweight/obesity and obesity according to

sex- and age-specific cutoffs based on the International Obesity Task Force criteria as well as

sum of skinfolds, waist circumference, and percent body fat by air displacement

plethysmography >85th percentiles. Primary predictors were maternal OGTT and HbA1c values

during pregnancy.

Results: Fully adjusted models which included maternal BMI at pregnancy OGTT indicated

positive associations between maternal glucose predictors and child adiposity outcomes. For

one SD differences in pregnancy glucose and HbA1c measures, odds ratios (ORs) for each child

adiposity outcome ranged 1.05-1.16 for maternal fasting glucose, 1.11-1.19 for 1 h glucose,

1.09-1.21 for 2 h glucose and 1.12-1.21 for HbA1c. Associations were significant, except for

overweight/obesity and waist circumference > 85th percentile for fasting glucose. Linearity was

confirmed in all adjusted models. Exploratory sex-specific analyses indicated generally

consistent associations for boys and girls.

Conclusions/interpretation: Exposure to higher levels of glucose in utero is independently

associated with childhood adiposity including overweight/obesity, obesity, skinfold thickness,

percent body fat and waist circumference. Glucose levels less than those diagnostic of diabetes

are associated with greater childhood adiposity which may have implications for long-term

metabolic health.

Tweet:

Maternal glucose during pregnancy is associated with child adiposity along the continuum

Keywords:

Adiposity

Childhood obesity

Glucose

Pregnancy

Abbreviations:

BMI – body mass index

GDM – gestational diabetes mellitus

HAPO –Hyperglycaemia and Adverse Pregnancy Outcome Study

HAPO FUS – HAPO Follow-Up Study

IADPSG – International Association of Diabetes in Pregnancy Study Groups

IOTF – International Obesity Task Force

OGTT – oral glucose tolerance test

Research in context:

What is already known about this subject?

• Diabetes during pregnancy and gestational diabetes are associated with childhood adiposity

• Associations of maternal glucose with childhood adiposity are often complicated by maternal

adiposity and have generally been attenuated after adjusting for maternal BMI in prior

studies

What is the key question?

• Are maternal glucose levels during pregnancy across the continuum of glucose levels,

including levels less than those diagnostic of GDM, associated with measures of childhood

adiposity and obesity independent of maternal BMI?

What are the new findings?

• Maternal glucose levels across the continuum at ~28 weeks gestation were associated with

dichotomous childhood adiposity outcomes, including obesity, percent body fat > 85th

percentile, and sum of skinfolds > 85th percentile after adjustment for maternal BMI during

pregnancy.

• Positive linear associations of maternal fasting, 1 h and 2 h glucose levels and HbA1c at ~28

weeks gestation with child percent fat, waist circumference and sum of skinfolds were

observed in a fully adjusted model that included maternal BMI during pregnancy, except for

child waist circumference and maternal fasting glucose.

• With a few exceptions, associations of maternal glycaemia and HbA1c during pregnancy with

childhood adiposity outcomes were generally consistent in boys and girls.

How might this impact clinical practice in the foreseeable future?

• The findings could have implications for glucose treatment targets in mothers with pre-

existing or gestational diabetes and inform approaches to the monitoring of glucose levels

during pregnancy in mothers with other risk factors for higher offspring adiposity, e.g.,

maternal obesity.

INTRODUCTION

The intrauterine environment impacts fetal development with maternal glucose and adiposity

having independent associations with newborn adiposity [1-5]. Although both type 2 diabetes

mellitus during pregnancy and gestational diabetes mellitus (GDM) are associated with

childhood adiposity, women with these conditions are more likely to be overweight or obese.

Thus, the independent relationship between maternal hyperglycaemia and childhood adiposity

is less clear. Previous studies of maternal glucose levels during pregnancy and childhood

obesity have generally focused on women with preexisting diabetes (type 1 or type 2 diabetes)

or GDM and were often confounded by or did not account for diabetes treatment or maternal

body mass index (BMI) [6-13]. Studies of the association of maternal glucose across a

spectrum of glucose values with childhood adiposity outcomes have not been reported.

The Hyperglycaemia and Adverse Pregnancy Outcome (HAPO) Study recruited a large,

multinational, racially and ethnically diverse cohort of women and showed that glucose levels

during pregnancy, below those diagnostic of diabetes, were associated with adverse newborn

outcomes and that these associations were continuous across increasing levels of glucose [4].

The HAPO Follow-Up Study (FUS) offered a unique opportunity to examine associations of

maternal glycaemia during pregnancy with childhood adiposity, not confounded by treatment of

maternal glucose. We recently reported that, while GDM based on IADPSG criteria [14, 15] was

not associated with an increase in childhood overweight/obesity, it was associated with a higher

risk of obesity and other measures of adiposity, including sum of skinfolds, percent body fat and

waist circumference >85th percentile, in children ages 10-14 years from the HAPO FUS cohort

[16]. The objective of the analyses reported herein was to assess whether in utero exposure to

levels of maternal glucose across the continuous spectrum of glucose values, including values

less than those diagnostic of GDM based on IADPSG criteria, is also associated with adiposity,

including overweight/obesity, obesity, and other anthropometric measures in children from the

HAPO FUS cohort.

METHODS

HAPO Study methods have been described [4, 17, 18]. Briefly, eligible women underwent a 75-

g oral glucose tolerance test (OGTT) at 24-32 weeks’ gestation. Fasting, 1 h, and 2 h plasma

glucose, and hemoglobin A1c (HbA1c) were measured. Maternal height, weight, and blood

pressure were measured at the time of the pregnancy OGTT using standard procedures and

calibrated equipment. Demographic data including race/ethnicity were collected via

questionnaire and parity by medical record abstraction. OGTT results remained blinded to

caregivers and participants unless fasting glucose > 5.8 mmol/l and/or 2 h glucose > 11.1

mmol/l, or if either measure was < 2.5 mmol/l [4, 17, 18]. Data from unblinded women were not

included in HAPO analyses.

Participants

HAPO FUS participants were recruited during 2013-2016 from 10 of 15 original HAPO field

centers that demonstrated feasibility for this study. Eligibility criteria included: having remained

blinded to OGTT results during HAPO, gestational age at delivery > 37 weeks and no major

neonatal malformations or fetal/neonatal death. This yielded 15,812 eligible mother-child pairs

(ESM Table 1). A target sample size of 7000 was specified, with 300 mother-child pairs to be

recruited at Chicago and Cleveland and 800 at each of the other eight field centers [16].

Multiple attempts were made to contact all eligible participants through various means approved

by local IRBs. Screening questionnaires were completed by 9322 eligible mothers over the

phone to ascertain willingness to participate and confirm eligibility. From these, 4834 children

completed all or part of the HAPO FUS visit, which represented 69.1% of the recruitment goal of

7000 mother-child pairs (Figure 1). Data from two children were excluded, one due to

inadequate fasting and one for inability to complete the protocol due to autism spectrum

disorder, leaving 4832 children for analyses. Of these, 4821 had at least one physical

measurement, while 4775 had BMI measurements and were analyzed for overweight/obesity

outcomes.

The HAPO FUS Protocol was approved by each center’s IRB. All mothers gave written

informed consent for their child’s participation and their children provided assent where

required. The study was overseen by an external Observational Study Monitoring Board.

Study Visit

During the HAPO FUS visit, height was measured twice with shoes removed to the nearest 0.5

cm with a stadiometer and a third time if results differed by >1.0 cm. Weight was measured

twice on a calibrated scale to the nearest 0.1 kg and a third time if results differed by >0.5 kg.

Waist circumference was measured twice at the iliac crest to the nearest 0.1 cm and a third time

if results differed by >1.0 cm. Skinfolds were measured (triceps, subscapular, suprailiac) twice

with calibrated calipers (Harpenden, London, UK) to the nearest 0.1 mm and a third time if

results differed by >1.0 mm. Means of the two measurements, or the two closest

measurements if three measurements were made, were used for analysis. Percent fat was

measured by air displacement plethysmography using a BOD POD (Cosmed, Rome, Italy).

Tanner staging was performed by trained individuals using breast/areolar development for girls

and testicular volume (Prader orchidometer) for boys. Mothers provided girl’s menstrual status

via questionnaire.

Outcomes

Child adiposity was the primary outcome, including (i) child overweight/obesity according to age-

and sex-specific cutoffs based on International Obesity Task Force (IOTF) criteria (Asian-

specific cutoffs were used for self-reported Asian children, and international cutoffs for all other

children[19]); (ii) IOTF-defined obesity only; and (iii) percent body fat (BOD POD), waist

circumference and sum of skinfolds >85th percentiles according to quantile regression adjusted

for sex, age and field center. BMI, BMI z-score[19], percent body fat, waist circumference and

sum of skinfolds were also assessed as continuous outcomes.

Predictors

The primary predictors were continuous values of fasting, 1 h , 2 h glucose and HbA1c from the

original HAPO OGTT during pregnancy. Continuous predictors were scaled by their standard

deviations (SDs) as estimated in original HAPO data.

Additionally, to confirm graded associations, these continuous variables were divided into

discrete categorical variables with five categories for each measure. The fifth and highest

category for each measure corresponded to IADPSG diagnostic thresholds for GDM. The

lowest three categories for fasting, 1 h and 2 h glucose were the same as those used for

analyses of glucose levels during the original HAPO Study. The fourth category included values

between the third and fifth categories. For the HbA1c values, the lowest three categories were

used during the original HAPO Study, and the fourth and fifth categories combined smaller

categories used for original analyses of HbA1c in HAPO. Categories were defined as follows:

fasting glucose < 4.2, 4.2-4.4, 4.5-4.7, 4.8-5.0, >5.1 mmol/l; 1 h glucose <5.8, 5.9-7.3, 7.4-8.6,

8.7-9.9, >10.0 mmol/l; 2 h glucose <5.0, 5.1-6.0, 6.1-6.9, 7.0-8.4, >8.5 mmol/l; HbA1c <25, 26-

28, 29-31, 32-36, >37 mmol/mol (<4.4, 4.5-4.7, 4.8-5.0, 5.1-5.4, >5.5%).

Statistical Analyses

HAPO FUS data were summarized using frequencies and counts for categorical variables and

means and SDs for continuous variables. Summary statistics from pregnancy were also

compared for eligible children who did and did not participate in HAPO FUS, including field-

center summaries weighted by the proportion of the total eligible at each field center.

Histograms and boxplots were examined to determine the shape of distributions and to identify

potential outlying observations. Multiple logistic regression was used for dichotomous outcomes;

results are reported as odds ratios (ORs) with 95% confidence intervals (CIs). Multiple linear

regression was used for continuous outcomes; results are reported as regression coefficients

(beta estimates) with 95% CIs. Multiple models were considered for all outcomes, with variables

identified according to study design, known potential confounders and adjustments used in

HAPO analyses [4, 16]. Covariate adjustments were examined as follows: Model 1: field center,

sex, child’s age at follow-up. Since IOTF definitions are sex- and age-specific, Model 1 for IOTF

outcomes included field center adjustment only. For percent body fat, waist circumference and

sum of skinfolds >85th percentiles, logistic regression Model 1 was unadjusted since 85th

percentiles included age, sex, and field center in their definition. Model 2: Model 1 + child’s

pubertal status (Tanner stage 1, 2/3, 4/5) with sex-by-Tanner stage interaction; Model 3: Model

2 + maternal variables at pregnancy OGTT [age, height, family history of diabetes in first degree

relatives, mean arterial pressure, parity (0, 1+), smoking (yes/no), alcohol (yes/no), gestational

age]; Model 4: Model 3 + maternal BMI at pregnancy OGTT. Exploratory analyses were also

conducted to evaluate differences in associations according to sex and race/ethnicity, using field

center as a proxy for race/ethnicity. Statistical interaction terms between continuous maternal

glucose and HbA1c with sex and field center were reviewed, and group-specific model

parameter estimates were compared. Multiple imputation under a ‘missing at random’

assumption[20, 21] using the mice R package[22] was used for imputation of all missing data,

with Tanner stage being the primary source of missingness, and incorporated sex steroid

measurements (ESM Methods). Logistic regression model fit was measured by C-statistics and

confirmed by Hosmer-Lemeshow goodness-of-fit tests[23]. Linear regression model fit was

assessed by scatterplots of residuals vs fitted values, histograms and qqplots of residuals, and

DFbeta statistics. Adjusted R2 values were used to gauge variability explained in linear models.

Quadratic terms and restricted cubic splines estimated with the rms R package[24] were used to

assess linearity between the continuous predictor and the log odds of the outcome for logistic

regression models and continuous outcomes for linear regression models. All analyses were

conducted in R (3.4.1)[25].

RESULTS

Participants

Characteristics of participating children during HAPO FUS and their mothers during HAPO are

shown in Table 1. The mean age of the children at follow-up was 11.4 years. The mean age at

the time of the HAPO OGTT and frequency of GDM according to IADPSG criteria [14] among

mothers of offspring who did not participate (unable to contact or declined) were 29.1 years and

16.9%, respectively, compared to 30.0 years and 14.9% among mothers of offspring who

participated. Mean maternal BMI, HbA1c, fasting, 1 h, and 2 h glucose during the HAPO OGTT

and race/ethnicity were similar between groups who did and did not participate (summaries

weighted to reflect full eligible population, ESM Table 1).

Model Diagnostics

Hosmer-Lemeshow p-values for logistic regression models with continuous maternal glucose

and HbA1c predictors ranged 0.06-0.99 for all outcomes, indicating reasonable model fit. C-

statistics for logistic regression models with continuous maternal glucose and HbA1c predictors

ranged 0.54-0.77 and R2 values ranged 0.04-0.35 for continuous maternal glucose and HbA1c

predictors with continuous outcomes. Both C-statistics and R2 values increased across Models

1-4, suggesting improved fit for additional covariate adjustments (Tables 2 and 3). Co-linearity

was not a concern with pairwise correlations ranging from 0-0.20 for model covariates. Visual

inspection of residual plots confirmed linear modeling assumptions and DFbeta statistics

indicated no observations of undue influence. Quadratic terms and restricted cubic spline

modeling indicated no significant departure from linearity for all analyses of continuous maternal

glucose and HbA1c predictors with p-values ranging from 0.29-0.98.

Continuous Measures of Maternal Glycaemia and Childhood Adiposity

Initial analyses examined the association of maternal glucose across the continuum with

dichotomous child adiposity outcomes. ORs for each dichotomous child adiposity outcome

were estimated for one SD differences in maternal fasting, 1 h and 2 h glucose, and HbA1c

during pregnancy (Table 2). In Models 1-3, positive associations for each child adiposity

outcome were observed for higher levels of each glucose measure and HbA1c. ORs were

attenuated after adjusting for maternal BMI during pregnancy (Model 4), but the results

remained significant for all measures with the exception of overweight/obesity and waist

circumference > 85th percentile for fasting glucose as a predictor. Linearity for the continuous

maternal glucose and HbA1c predictors was confirmed as described above.

Linear associations of continuous child BMI z-score, percent fat, waist circumference and sum

of skinfolds with maternal fasting, 1 h and 2 h glucose, and HbA1c during pregnancy were also

evaluated (Table 3). In Models 1-3, positive associations for each continuous child adiposity

outcome were observed for one SD differences in each maternal glucose measure and HbA1c.

Associations were again attenuated after adjusting for maternal BMI during pregnancy (Model

4). For child BMI z-score, associations with maternal fasting, 1 h and 2 h glucose were not

significant after adjustment for maternal BMI during pregnancy. Associations between child

percent fat and maternal HbA1c and child waist circumference and maternal fasting glucose

were also not significant in the fully adjusted Model 4. However, all other associations between

continuous maternal glucose levels and HbA1c and continuous child adiposity outcomes were

positive and statistically significant. As described above, linearity of all observed associations

was confirmed.

Maternal Glucose Categories and Childhood Adiposity

To complement the above analyses, analyses of childhood adiposity across categories of

maternal glucose levels during the HAPO OGTT and HbA1c at the time of the OGTT were also

conducted. Frequencies of childhood adiposity outcomes, including overweight/obesity, obesity

and percent fat, waist circumference, and sum of skinfolds > 85th percentiles, were higher

across increasing categories of maternal glucose levels and HbA1c (ESM Figure 1, ESM Table

2). Adjusted associations of childhood adiposity outcomes across maternal glucose and HbA1c

categories were examined next. Although adjustment for maternal BMI during pregnancy

(Model 4) attenuated the associations, ORs for child overweight/obesity, obesity, and percent

body fat, waist circumference and sum of skinfolds >85th percentiles increased across higher

categories of maternal glucose levels and HbA1c in all models (ESM Figure 2, ESM Tables 3-7).

This confirmed higher risk of each outcome with increasing levels of maternal glucose and

HbA1c (ESM Figure 2, ESM Tables 3-7).

To confirm a gradation of outcome means across maternal glucose categories, means of

continuous childhood adiposity measures, including BMI z-score, percent fat, waist

circumference and sum of skinfolds, by categories of maternal fasting, 1 h, and 2 h glucose and

HbA1c during pregnancy were also determined (ESM Figure 3, ESM Table 8). In general,

means were greater for higher levels of maternal glucose. Adjusted mean differences for each

child adiposity outcome across increasing categories of maternal glucose relative to the lowest

category of maternal glucose were also determined (ESM Tables 9-12). In Models 1-3,

adjusted mean differences for child BMI z-score, percent body fat, waist circumference and sum

of skinfolds across categories of maternal fasting, 1 h and 2 h glucose and HbA1c, relative to the

lowest category for each measure, confirmed higher means for each continuous child outcome

across higher categories of maternal glucose and HbA1c. Adjustment for maternal BMI during

pregnancy (Model 4) attenuated the adjusted mean differences of percent fat, waist

circumference, and sum of skinfolds, but they were still generally higher across categories of

maternal glucose and HbA1c (ESM Tables 9-12). For child BMI z-score, differences were no

longer evident across categories of fasting, 1 h and 2 h glucose but were still present for

categories of HbA1c.

Analyses to explore sex- and field center-specific associations

While HAPO FUS was not intentionally powered to evaluate differences in associations

according to subgroups, exploratory analyses were performed to evaluate sex- and

race/ethnicity-specific associations using field center as a proxy for race/ethnicity. Statistical

interactions between sex and 2 h glucose yielded p<0.05 for percent fat > 85th percentile and

percent fat as a continuous outcome, which reflected stronger associations for these outcomes

in boys than girls (Tables 4-5). The statistical interaction between fasting glucose and sex was

also significant for obesity, reflecting a higher OR estimate for girls than boys (Table 4). All other

sex-specific analyses and statistical interaction terms confirmed generally consistent

associations for boys and girls. No significant differences in associations across field centers

were observed.

DISCUSSION

We recently reported that, while GDM based on IADPSG criteria was not associated with an

increase in overweight/obesity, it was associated with a higher risk of obesity and measures of

adiposity >85th percentile in children from the HAPO FUS cohort [16]. The present study now

demonstrates that the positive association between maternal glucose levels during pregnancy

and measures of child adiposity in HAPO FUS children ages 10-14 years is present across the

spectrum of maternal glucose levels during pregnancy. This was demonstrated in a number of

ways. First, except for the association of overweight/obesity and waist circumference >85th

percentile with fasting glucose, the risk for each of the child adiposity outcomes was significantly

higher for each one SD difference in maternal fasting, 1 h, or 2 h glucose levels as well as

HbA1c. Second, other than the absence of an association between maternal glucose and child

BMI z-score, the continuous childhood adiposity outcomes were in general significantly higher

for each one SD difference in continuous maternal glucose and HbA1c predictors, even after

adjustment for maternal BMI during pregnancy. In addition, the linearity of the observed

associations was confirmed. Finally, complementary studies examining the prevalence of child

adiposity outcomes (overweight/obesity, obesity, and sum of skinfolds, waist circumference, and

percent body fat >85th percentiles) and means of continuous measures of child adiposity (BMI z-

score, percent fat, sum of skinfolds and waist circumference) across increasing categories of

maternal glucose, generally confirmed the relationships described above. Thus, the present

study demonstrates that the link between maternal glucose levels and child adiposity outcomes

extends across the spectrum of maternal glucose levels, including for glucose levels below the

diagnostic threshold for IADPSG GDM.

The original HAPO Study demonstrated continuous and graded associations between maternal

glucose levels during pregnancy and newborn adiposity outcomes [4]. Recent smaller studies

of children ages 5-10 years reported positive associations between maternal glucose levels

during pregnancy and measures of adiposity [26, 27]. The HAPO FUS now demonstrates the

novel finding that the continuous and graded association between maternal glucose levels and

offspring adiposity is also observed in a multi-ethnic cohort during adolescence. Whether these

relationships will continue into adulthood is yet to be determined and will require ongoing

surveillance of this well phenotyped at-risk population. However, previous studies have

demonstrated associations of childhood obesity with higher risk for obesity as well as other

cardiometabolic diseases as an adult [28-33], suggesting that these children with greater

childhood adiposity are at risk for poor metabolic outcomes as adults.

Previous studies that examined the association of maternal glycaemia during pregnancy with

adiposity in childhood typically compared offspring of mothers without GDM to offspring of

mothers with GDM [9, 10, 34-37]. In many cases, the associations were confounded by

treatment for GDM. In contrast, HAPO mothers were not treated and remained blinded to their

glucose levels during the pregnancy. Those with glucose levels during the HAPO pregnancy

OGTT that exceeded levels for unblinding were treated according to local practice and excluded

from HAPO Study analyses. Thus, the present study was not confounded by treatment.

Moreover, the relationships of glucose levels less than those diagnostic of GDM with childhood

adiposity outcomes seen in the present study demonstrated that the relationships between

maternal glucose and measures of child adiposity were largely continuous without evidence for

a threshold effect. These findings may have implications for target glucose levels in women

with GDM, including in clinical trials designed to examine the effect of GDM treatment on

childhood adiposity outcomes, and also inform approaches to the monitoring of women with

other independent risk factors for higher childhood adiposity, e.g., obesity.

In previous studies, associations between maternal glycaemia, typically GDM, during pregnancy

and measures of child adiposity were attenuated after adjustment for maternal BMI prior to or

during pregnancy [9, 10, 35, 36]. In the present study, the associations of maternal glucose

levels with risk for the 5 different child adiposity outcomes were also attenuated by adjustment

for maternal BMI during pregnancy but remained significant, with the exception of the

associations of maternal fasting glucose with risk for overweight/obesity and waist

circumference >85th percentile. These data are consistent with an independent association of

maternal glucose with measures of child adiposity. Whether this relationship is due solely to

maternal glucose or other metabolites related to maternal glycaemia has not been determined.

While transplacental transfer of glucose undoubtedly contributes to fetal growth, it has been

suggested that lipids, including triacylglycerol and non-esterified fatty acids, are important

contributors to excess fetal growth and fat accretion [38]. Indeed, in previous metabolomics

studies performed in the HAPO cohort, we demonstrated associations of maternal 1 h glucose

levels with maternal serum levels of triacylglycerol, non-esterified fatty acids, β-hydroxybutyrate,

and several amino acids [39]. This is consistent with the hypothesis proposed by Freinkel and

colleagues that the association of GDM with newborn and childhood outcomes is mediated

through the transplacental transfer of mixed nutrients [40].

Differences in adiposity in girls vs. boys have been previously reported. At birth, percent body

fat is higher in girls compared to boys [41], and sex-specific associations of maternal glycaemia

with childhood adiposity have been described. In the present study, associations of maternal

glycaemia with measures of child adiposity were generally consistent for boys and girls,

although stronger associations of maternal 2-hr glucose with percent fat was observed in boys,

while the OR estimate for obesity with higher levels of maternal fasting glucose was higher in

girls vs. boys. When considered together, other studies have also reported inconsistent

associations. For example, at age ~8 years, GDM was associated with higher fat mass in boys

but not girls, while lesser degrees of maternal hyperglycemia were associated with higher fat

mass in girls only [42]. In an Indian cohort at age ~9.5 years, higher adiposity was observed in

girl but not boy offspring of mothers with GDM [43]. Similarly, among HAPO participants from

Hong Kong, maternal glucose levels during the HAPO OGTT were associated with

overweight/obesity and adiposity in girls but not boys [26]. Thus, consistent sex-specific effects

of GDM and maternal glycaemia on measures of child adiposity have not been observed.

This study has several strengths. HAPO was a blinded observational study in which pregnant

women and their clinical caregivers were not made aware of their glucose values. Thus,

treatment is not a factor in this study of childhood outcomes. The large number and racial/ethnic

diversity of participants included in the HAPO FUS make the findings broadly applicable. In

addition to determining pubertal status of the children, this prospective study also used

standardized procedures to characterize childhood adiposity via multiple methods, with

generally consistent results across different measures. Finally, the HAPO FUS addressed

limitations of previous studies that examined the association of GDM with childhood adiposity,

including lack of complete data on glucose values in pregnancy, maternal BMI and child

measures of age-adjusted BMI [6-13].

There are some limitations. The proportion of participants who met IADPSG GDM criteria and

participated in the HAPO FUS (weighted estimate 14.9%) is lower than the frequency in all

eligible participants (16.2%). In addition, we used maternal BMI at the pregnancy OGTT and not

pre-gestational BMI, since objectively measured pre-pregnancy weight was not available in

HAPO. The HAPO FUS also did not have detailed paternal data or data related to postnatal

lifestyle variables that impact childhood adiposity. By design, participants with fasting and/or 2 h

OGTT glucose values during pregnancy that were above predefined thresholds were unblinded

during HAPO and excluded from the HAPO FUS. This subgroup (1.8% of the HAPO cohort) is

likely to have included children at highest risk of overweight/obesity and therefore the reported

associations may be underestimates. Finally, the number of mother-child pairs recruited was

69.1% of the target, although the maternal characteristics during pregnancy for children who did

and did not participate were similar.

In summary, the HAPO FUS provides new evidence for a continuous relationship between

maternal glucose levels during pregnancy and childhood adiposity outcomes that is independent

of maternal BMI. Since obese children are at high risk of obesity and related metabolic

disorders as adults [28, 29], this has important public health implications and may have

implications for treatment targets in mothers with pre-existing or gestational diabetes.

Acknowledgements: The HAPO FUS investigators are grateful for all mothers and children

who participated in HAPO and HAPO Follow-Up Studies. Study data were collected and

managed using REDCap electronic data capture tools hosted at Northwestern University

Feinberg School of Medicine (FSM). REDCap is supported at FSM by the Northwestern

University Clinical and Translational Science (NUCATS) Institute. The content is solely the

responsibility of the authors and does not necessarily represent the official views of the National

Institutes of Health.

Data availability: Data will be made available by the authors upon request.

Funding: The HAPO Follow-Up Study is funded by grant 1U01DK094830 from the National

Institute of Diabetes and Digestive and Kidney Diseases and the Eunice Kennedy Shriver

National Institute of Child Health and Human Development. Research reported in this

publication was supported, in part, by the National Institutes of Health’s National Center for

Advancing Translational Sciences, grant UL1TR001422. Dr. Linder (NIH) was a participating

member of the study Steering Committee and the Writing Group for this manuscript because of

the cooperative funding agreement. She was involved in the design of the study but not the

conduct of the study; she was not involved in the collection, management, and analysis of the

data; and she was involved in the preparation, review, and approval of the manuscript and the

decision to submit the manuscript for publication.

Duality of interest: All authors declare that there is no duality of interest associated with their

contribution to this manuscript.

Contribution statement: BEM and DMS had full access to all of the data in the study and take

responsibility for the integrity of the data and the accuracy of the data analysis. BEM, WLL,

DMS, LPL, PMC, ARD, and BL contributed to the study concept and design. All authors

contributed to the acquisition, analysis or interpretation of data. DMS, AK, MN and OT

performed the statistical analyses. All authors critically revised the final paper for important

intellectual content and approved the final version.

References

[1] Metzger BE (2007) Long-term outcomes in mothers diagnosed with gestational diabetes

mellitus and their offspring. Clin Obstet Gynecol 50: 972-979

[2] Pettitt DJ, Baird HR, Aleck KA, Bennett PH, Knowler WC (1983) Excessive obesity in

offspring of Pima Indian women with diabetes during pregnancy. N Engl J Med 308: 242-245

[3] Silverman BL, Rizzo TA, Cho NH, Metzger BE (1998) Long-term effects of the

intrauterine environment. The Northwestern University Diabetes in Pregnancy Center. Diabetes

Care 21 Suppl 2: B142-149

[4] Metzger BE, Lowe LP, Dyer AR, et al. (2008) Hyperglycemia and adverse pregnancy

outcomes. N Engl J Med 358: 1991-2002

[5] (2010) Hyperglycaemia and Adverse Pregnancy Outcome (HAPO) Study: associations

with maternal body mass index. BJOG 117: 575-584

[6] Tam WH, Ma RC, Yang X, et al. (2008) Glucose intolerance and cardiometabolic risk in

children exposed to maternal gestational diabetes mellitus in utero. Pediatrics 122: 1229-1234

[7] Catalano PM, Farrell K, Thomas A, et al. (2009) Perinatal risk factors for childhood

obesity and metabolic dysregulation. Am J Clin Nutr 90: 1303-1313

[8] Pirkola J, Pouta A, Bloigu A, et al. (2010) Risks of overweight and abdominal obesity at

age 16 years associated with prenatal exposures to maternal prepregnancy overweight and

gestational diabetes mellitus. Diabetes Care 33: 1115-1121

[9] Philipps LH, Santhakumaran S, Gale C, et al. (2011) The diabetic pregnancy and

offspring BMI in childhood: a systematic review and meta-analysis. Diabetologia 54: 1957-1966

[10] Kim SY, England JL, Sharma JA, Njoroge T (2011) Gestational diabetes mellitus and

risk of childhood overweight and obesity in offspring: a systematic review. Exp Diabetes Res

2011: 541308

[11] Kim SY, Sharma AJ, Callaghan WM (2012) Gestational diabetes and childhood obesity:

what is the link? Curr Opin Obstet Gynecol 24: 376-381

[12] Donovan LE, Cundy T (2015) Does exposure to hyperglycaemia in utero increase the

risk of obesity and diabetes in the offspring? A critical reappraisal. Diabet Med 32: 295-304

[13] Grunnet LG, Hansen S, Hjort L, et al. (2017) Adiposity, Dysmetabolic Traits, and Earlier

Onset of Female Puberty in Adolescent Offspring of Women With Gestational Diabetes Mellitus:

A Clinical Study Within the Danish National Birth Cohort. Diabetes Care 40: 1746-1755

[14] (2010) International association of diabetes and pregnancy groups recommendations on

the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 33: 676-682

[15] (2014) Diagnostic criteria and classification of hyperglycaemia first detected in

pregnancy: a World Health Organization Guideline. Diabetes Res Clin Pract 103: 341-363

[16] Lowe WL, Jr., Scholtens DM, Lowe LP, et al. (2018) Association of Gestational Diabetes

With Maternal Disorders of Glucose Metabolism and Childhood Adiposity. JAMA 320: 1005-

1016

[17] (2002) The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. Int J

Gynaecol Obstet 78: 69-77

[18] Nesbitt GS, Smye M, Sheridan B, Lappin TR, Trimble ER (2006) Integration of local and

central laboratory functions in a worldwide multicentre study: Experience from the

Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. Clin Trials 3: 397-407

[19] Cole TJ, Lobstein T (2012) Extended international (IOTF) body mass index cut-offs for

thinness, overweight and obesity. Pediatric obesity 7: 284-294

[20] White IR, Daniel R, Royston P (2010) Avoiding bias due to perfect prediction in multiple

imputation of incomplete categorical variables. Comput Stat Data Anal 54: 2267-2275

[21] Rubin DB (1987) Multiple imputation for nonresponse in surveys. Wiley, New York

[22] Van Buuren S, Groothuis-Oudshoorn K (2011) Multivariate imputation by chained

equations in R. Journal of Statistical Software 45: 1-67

[23] Hosmer DW, Lemeshow S (2013) Applied Logistic Regression. Wiley, New York

[24] Harrell Jr. FE (2018) rms: Regression Modeling Strategies. R package version 51-2

[25] Team RC (2016) A Language and Environment for Statistical Computing. R Foundation

for Statistical Computing, Vienna, Austria

[26] Tam WH, Ma RCW, Ozaki R, et al. (2017) In Utero Exposure to Maternal Hyperglycemia

Increases Childhood Cardiometabolic Risk in Offspring. Diabetes Care 40: 679-686

[27] Landon MB, Mele L, Varner MW, et al. (2018) The relationship of maternal glycemia to

childhood obesity and metabolic dysfunction(double dagger). J Matern Fetal Neonatal Med: 1-9

[28] Simmonds M, Llewellyn A, Owen CG, Woolacott N (2016) Predicting adult obesity from

childhood obesity: a systematic review and meta-analysis. Obes Rev 17: 95-107

[29] Whitaker RC, Wright JA, Pepe MS, Seidel KD, Dietz WH (1997) Predicting obesity in

young adulthood from childhood and parental obesity. N Engl J Med 337: 869-873

[30] Kelsey MM, Zaepfel A, Bjornstad P, Nadeau KJ (2014) Age-related consequences of

childhood obesity. Gerontology 60: 222-228

[31] Liang Y, Hou D, Zhao X, et al. (2015) Childhood obesity affects adult metabolic

syndrome and diabetes. Endocrine 50: 87-92

[32] Maffeis C, Tato L (2001) Long-term effects of childhood obesity on morbidity and

mortality. Horm Res 55 Suppl 1: 42-45

[33] Reilly JJ, Kelly J (2011) Long-term impact of overweight and obesity in childhood and

adolescence on morbidity and premature mortality in adulthood: systematic review. Int J Obes

(Lond) 35: 891-898

[34] Hillier TA, Pedula KL, Schmidt MM, Mullen JA, Charles MA, Pettitt DJ (2007) Childhood

obesity and metabolic imprinting: the ongoing effects of maternal hyperglycemia. Diabetes Care

30: 2287-2292

[35] Kubo A, Ferrara A, Windham GC, et al. (2014) Maternal hyperglycemia during

pregnancy predicts adiposity of the offspring. Diabetes Care 37: 2996-3002

[36] Zhao P, Liu E, Qiao Y, et al. (2016) Maternal gestational diabetes and childhood obesity

at age 9-11: results of a multinational study. Diabetologia 59: 2339-2348

[37] Patel S, Fraser A, Davey Smith G, et al. (2012) Associations of gestational diabetes,

existing diabetes, and glycosuria with offspring obesity and cardiometabolic outcomes. Diabetes

Care 35: 63-71

[38] Barbour LA, Hernandez TL (2018) Maternal Non-glycemic Contributors to Fetal Growth

in Obesity and Gestational Diabetes: Spotlight on Lipids. Curr Diab Rep 18: 37

[39] Jacob S, Nodzenski M, Reisetter AC, et al. (2017) Targeted Metabolomics

Demonstrates Distinct and Overlapping Maternal Metabolites Associated With BMI, Glucose,

and Insulin Sensitivity During Pregnancy Across Four Ancestry Groups. Diabetes Care 40: 911-

919

[40] Freinkel N (1980) Banting Lecture 1980. Of pregnancy and progeny. Diabetes 29: 1023-

1035

[41] Hawkes CP, Hourihane JO, Kenny LC, Irvine AD, Kiely M, Murray DM (2011) Gender-

and gestational age-specific body fat percentage at birth. Pediatrics 128: e645-651

[42] Regnault N, Gillman MW, Rifas-Shiman SL, Eggleston E, Oken E (2013) Sex-specific

associations of gestational glucose tolerance with childhood body composition. Diabetes Care

36: 3045-3053

[43] Krishnaveni GV, Veena SR, Hill JC, Kehoe S, Karat SC, Fall CH (2010) Intrauterine

exposure to maternal diabetes is associated with higher adiposity and insulin resistance and

clustering of cardiovascular risk markers in Indian children. Diabetes Care 33: 402-404

Table 1. Characteristics of Mothers during HAPO Pregnancy OGTT and their Children at Follow-

Up

Characteristics - Mothers

During HAPO Pregnancy

N=4832

Mean (SD)

Age at OGTT (yrs) 29.9 (5.7)

Gestational Age at OGTT (wks) 27.7 (1.7)

Height (cm) 161.8 (6.8)

Weight (kg) 72.0 (14.2)

Body Mass Index (BMI) (kg/m2) 27.5 (4.9)

Mean Arterial Pressure (mmHg) 80.5 (8.0)

Fasting Glucose (mmol/l) 4.5 (0.4)

1 h Glucose (mmol/l) 7.4 (1.7)

2 h Glucose (mmol/l) 6.1 (1.3)

HbA1c (mmol/l) 29.0 (4.5)

HbA1c (%) 4.8 (0.4)

N (%)

Race/Ethnicity

White, Non-Hispanic, n (%) 2287 (47.3)

Hispanic, n (%) 507 (10.5)

Black, Non-Hispanic, n (%) 775 (16.0)

Asian, n (%) 1176 (24.3)

Other, n (%) 87 (1.8)

Any Prenatal Smoking, n (%) 245 (5.1)

Any Prenatal Alcohol Use, n (%) 406 (8.4)

Parity (any prior delivery > 20 weeks),

n (%)

2485 (51.4)

Family History of Diabetes, n (%) 1077 (22.3)

Characteristics - Children Mean (SD)

At Follow-Up

Age (yrs) 11.4 (1.2)

Height (cm) 148.6 (10.2)

Weight (kg) 43.2 (13.3)

N (%)

Sex – Female, n (%) 2367 (49.0)

Tanner Stage - Girls

1, n (%) 381 (19.0)

2/3, n (%) 853 (42.5)

4/5, n (%) 774 (38.5)

Tanner Stage - Boys

1, n (%) 565 (36.0)

2/3, n (%) 726 (46.2)

4/5, n (%) 279 (17.8)

Table 2. Associations of Continuous Measures of Maternal Glucose and HbA1c During Pregnancy with Dichotomous Adiposity Outcomes among Children at Follow-up

Predictor Model 1 Model 2 Model 3 Model 4

OR (95% CI) p-valuea C-statistic OR (95% CI) p-valuea C-

statistic OR (95% CI) p-valuea C-statistic OR (95% CI) p-valuea C-

statistic IOTF Overweight/Obesity Fasting glucose 1.27 (1.19-1.36) <0.001*** 0.64 1.26 (1.18-1.35) <0.001*** 0.67 1.22 (1.13-1.31) <0.001*** 0.70 1.05 (0.98-1.14) 0.19 0.74

1-h glucose !.22 (1.14-1.30) <0.001*** 0.64 1.21 (1.13-1.29) <0.001*** 0.67 1.18 (1.10-1.27) <0.001*** 0.69 1.11 (1.03-1.19) 0.006** 0.74

2-h glucose 1.17 (1.10-1.25) <0.001*** 0.64 1.18 (1.10-1.26) <0.001*** 0.67 1.15 (1.07-1.23) <0.001*** 0.69 1.09 (1.01-1.17) 0.019** 0.74

HbA1c 1.23 (1.15-1.33) <0.001*** 0.64 1.25 (1.16-1.35) <0.001*** 0.67 1.24 (1.15-1.34) <0.001*** 0.69 1.12 (1.04-1.22) 0.004** 0.74 IOTF Obesity Fasting glucose 1.40 (1.28-1.54) <0.001*** 0.69 1.40 (1.27-1.53) <0.001*** 0.71 1.34 (1.21-1.48) <0.001*** 0.74 1.16 (1.05-1.29) 0.005** 0.77

1-h glucose 1.24 (1.13-1.36) <0.001*** 0.68 1.23 (1.12-1.35) <0.001** 0.70 1.20 (1.08-1.32) <0.001*** 0.73 1.13 (1.01-1.25) 0.025* 0.77

2-h glucose 1.28 (1.17-1.40) <0.001*** 0.68 1.29 (1.18-1.41) <0.001*** 0.71 1.25 (1.14-1.38) <0.001*** 0.71 1.21 (1.09-1.34) <0.001*** 0.78

HbA1c 1.37 (1.23-1.52) <0.001*** 0.69 1.37 (1.23-1.52) <0.001*** 0.71 1.36 (1.22-1.52) <0.001*** 0.74 1.21 (1.08-1.35) <0.001*** 0.77 BOD POD % Fat > 85th Percentilea Fasting glucose 1.35 (1.25-1.47) <0.001*** 0.54 1.34 (1.24-1.46) <0.001*** 0.62 1.29 (1.18-1.41) <0.001*** 0.65 1.15 (1.05-1.26) 0.002** 0.68

1-h glucose 1.27 (1.17-1.38) <0.001*** 0.55 1.25 (1.15-1.36) <0.001*** 0.62 1.23 (1.13-1.34) <0.001*** 0.65 1.18 (1.08-1.29) <0.001*** 0.69

2-h glucose 1.20 (1.10-1.29) <0.001*** 0.54 1.20 (1.11-1.30) <0.001*** 0.61 1.19 (1.09-1.29) <0.001*** 0.64 1.15 (1.06-1.26) 0.001** 0.69

HbA1c 1.25 (1.14-1.36) <0.001*** 0.52 1.25 (1.14-1.37) <0.001*** 0.61 1.23 (1.12-1.35) <0.001*** 0.64 1.14 (1.03-1.25) 0.009** 0.68 Waist Circumference > 85th Percentilea Fasting glucose 1.34 (1.23-1.45) <0.001*** 0.54 1.31 (1.21-1.42) <0.001*** 0.61 1.25 (1.14-1.36) <0.001*** 0.65 1.09 (0.99-1.19) 0.067 0.69

1-h glucose 1.22 (1.13-1.32) <0.001*** 0.55 1.22 (1.12-1.32) <0.001*** 0.60 1.21 (1.11-1.32) <0.001*** 0.64 1.15 (1.05-1.26) 0.002** 0.69

2-h glucose 1.20 (1.10-1.29) <0.001*** 0.53 1.21 (1.12-1.31) <0.001*** 0.60 1.20 (1.11-1.31) <0.001*** 0.64 1.17 (1.07-1.27) 0.003** 0.69

HbA1c 1.23 (1.13-1.34) <0.001*** 0.52 1.27 (1.16-1.38) <0.001*** 0.60 1.26 (1.15-1.38) <0.001*** 0.65 1.15 (1.05-1.27) 0.004** 0.69 Sum of Skinfolds > 85th Percentilea Fasting glucose 1.36 (1.25-1.47) <0.001*** 0.54 1.34 (1.23-1.45) <0.001*** 0.61 1.30 (1.19-1.41) <0.001*** 0.64 1.16 (1.06-1.27) 0.001** 0.67

1-h glucose 1.25 (1.16-1.36) <0.001*** 0.55 1.26 (1.16-1.37) <0.001*** 0.60 1.24 (1.14-1.35) <0.001*** 0.64 1.19 (1.09-1.30) <0.001*** 0.68

2-h glucose 1.23 (1.14-1.33) <0.001*** 0.54 1.25 (1.15-1.36) <0.001*** 0.60 1.24 (1.14-1.35) <0.001*** 0.63 1.21 (1.11-1.31) <0.001*** 0.68

HbA1c 1.25 (1.15-1.37) <0.001*** 0.52 1.26 (1.15-1.38) <0.001*** 0.59 1.24 (1.13-1.36) <0.001*** 0.63 1.15 (1.05-1.26) 0.004** 0.67 a, 85th percentiles were determined using quantile regression adjusted for age, sex, and field center.

ap value from logistic regression model; * p<0.05, ** p<0.01, *** p<0.001

IOTF = International Obesity Task Force

Odds ratios for the dichotomous outcomes are for the continuous predictors higher by 1 standard deviation estimated in the original HAPO data: Fasting glucose – 0.4 mmol/l; 1 h glucose – 1.7 mmol/l; 2 h glucose – 1.3 mmol/l; HbA1c – 5.0 mmol/mol (0.45 %). Model 1: Adjusted for field center for IOTF overweight/obesity and IOTF obesity outcomes, unadjusted for BOD POD % fat, waist circumference and sum of skinfolds >85th percentile outcomes; Model 2: Model 1+ child pubertal status (Tanner Stage 1, 2/3, 4/5, sex x Tanner stage interaction), Model 3: Model 2 + maternal variables during pregnancy OGTT (age, height, any family history of diabetes, mean arterial pressure, parity (0, 1+), smoking (yes/no), alcohol (yes/no), gestational age). Model 4: Model 3 + maternal BMI during pregnancy.

Table 3. Associations of Continuous Measures of Maternal Glucose and HbA1c During Pregnancy with Continuous Adiposity Outcomes among Children at Follow-up

Predictor Model 1 Model 2 Model 3 Model 4

Beta (95% CI) p-valuea Adjusted R2 Beta (95% CI) p-valuea Adjusted

R2 Beta (95% CI) p-valuea Adjusted R2 Beta (95% CI) p-valuea Adjusted

R2 BMI z-score Fasting glucose 0.14 (0.10-0.18) <0.001*** 0.07 0.13 (0.09-0.16) <0.001*** 0.13 0.10 (0.06-0.14) <0.001*** 0.15 -0.001 (-0.04-

0.04) 0.96 0.22

1-h glucose 0.10 (0.06-0.14) <0.001*** 0.07 0.09 (0.06-0.12) <0.001*** 0.14 0.07 (0.03-0.10) <0.001*** 0.14 0.02 (-0.01-0.05) 0.26 0.22

2-h glucose 0.08 (0.04-0.11) <0.001*** 0.07 0.08 (0.04-0.11) <0.001*** 0.12 0.05 (0.02-0.09) 0.003** 0.14 0.02 (-0.02-0.05) 0.38 0.22

HbA1c 0.13 (0.09-0.16) <0.001*** 0.07 0.14 (0.10-0.18) <0.001*** 0.21) 0.13 (0.09-0.16) <0.001*** 0.22 0.06 (0.02-0.10) 0.001** 0.29 BOD POD % Fat Fasting glucose 1.35 (1.04-1.66) <0.001*** 0.08 1.29 (0.99-1.59) <0.001*** 0.13 1.09 (0.78-1.40) <0.001*** 0.14 0.46 (0.14-0.77) 0.004** 0.18

1-h glucose 1.11 (0.81-1.41) <0.001*** 0.08 1.05 (0.75-1.34) <0.001*** 0.12 0.93 (0.63-1.24) <0.001*** 0.14 0.62 (0.32-0.92) <0.001*** 0.18

2-h glucose 0.87 (0.57-1.17) <0.001*** 0.08 0.86 (0.57-1.16) <0.001*** 0.12 0.75 (0.45-1.05) <0.001*** 0.14 0.50 (0.20-0.80) <0.001*** 0.18

HbA1c 0.66 (0.34-0.99) <0.001*** 0.08 0.81 (0.49-1.13) <0.001*** 0.19 0.68 (0.36-1.01) <0.001*** 0.21 0.25 (-0.07-0.58) 0.13 0.25 Waist circumference (cm) Fasting glucose 1.50 (1.15-1.85) <0.001*** 0.10 1.35 (1.02-1.67) <0.001*** 0.21 1.09 (0.75-1.43) <0.001*** 0.22 0.24 (-0.09-0.28) 0.16 0.28

1-h glucose 1.07 (0.73-1.41) <0.001*** 0.09 0.99 (0.68-1.31) <0.001*** 0.20 0.86 (0.53-1.19) <0.001*** 0.22 0.45 (0.13-0.76) 0.006** 0.28

2-h glucose 0.98 (0.64-1.32) <0.001*** 0.09 0.91 (0.59-1.22) <0.001*** 0.20 0.78 (0.46-1.11) <0.001*** 0.22 0.46 (0.14-0.77) 0.005** 0.28

HbA1c 0.51 (0.15-0.88) 0.005 0.09 1.07 (0.73-1.41) <0.001*** 0.28 0.96 (0.61-1.31) <0.001*** 0.30 0.39 (0.05-0.74) 0.025* 0.35 Sum of Skinfolds (mm) Fasting glucose 2.71 (2.05-3.35) <0.001*** 0.05 2.70 (2.06-3.34) <0.001*** 0.09 2.32 (1.67-2.99) <0.001*** 0.10 0.98 (0.31-1.65) 0.004** 0.14

1-h glucose 1.89 (1.26-2.52) <0.001*** 0.04 1.91 (1.29-2.53) <0.001*** 0.08 1.62 (0.97-2.26) <0.001*** 0.10 0.95 (0.31-1.58) 0.003** 0.15

2-h glucose 1.66 (1.03-2.29) <0.001*** 0.04 1.76 (1.14-2.38) <0.001*** 0.08 1.48 (0.84-2.13) <0.001*** 0.10 0.95 (0.32-1.58) 0.003** 0.15

HbA1c 1.61 (0.94-2.29) <0.001*** 0.04 1.96 (1.29-2.64) <0.001*** 0.17 1.74 (1.04-2.43) <0.001*** 0.18 0.83 (0.14-1.51) 0.018** 0.22 IOTF = International Obesity Task Force

ap value from linear regression model; * p<0.05, ** p<0.01, *** p<0.001

Beta estimates represent change in each continuous outcome for the continuous predictors higher by 1 standard deviation estimated in the original HAPO data: Fasting glucose – 0.4 mmol/l; 1 h glucose – 1.7 mmol/l; 2 h glucose – 1.3 mmol/l; HbA1c – 5.0 mmol/mol (0.45 %). Model 1: Adjusted for field center for IOTF overweight/obesity and IOTF obesity outcomes, unadjusted for BOD POD % fat, waist circumference and sum of skinfolds >85th percentile outcomes; Model 2: Model 1 + child pubertal status (Tanner Stage 1, 2/3, 4/5, sex x Tanner stage interaction), Model 3: Model 2 + maternal variables during pregnancy OGTT (age, height, any family history of diabetes, mean arterial pressure, parity (0, 1+), smoking (yes/no), alcohol (yes/no), gestational age). Model 4: Model 3 + maternal BMI during pregnancy.

Table 4. Sex-Specific Fully Adjusted Associations of Continuous Measures of Maternal Glucose and HbA1c During Pregnancy with Dichotomous Adiposity Outcomes among Children at Follow-up

Predictor Boys Girls Interaction term p-valued OR (95% CI) p-valueb C-statistic OR (95% CI) p-valuec C-statistic

IOTF Overweight/Obesity Fasting glucose 1.05 (0.96-1.17) 0.33 0.73 1.04 (0.93-1.16) 0.48 0.76 0.82 1-h glucose 1.10 (1.00-1.22) 0.06 0.73 1.10 (0.99-1.23) 0.08 0.76 0.98 2-h glucose 1.14 (1.03-1.26) 0.01* 0.73 1.03 (0.93-1.15) 0.55 0.76 0.12 HbA1c 1.10 (0.99-1.23) 0.07 0.73 1.14 (1.02-1.27) 0.03* 0.76 0.74 IOTF Obesity Fasting glucose 1.07 (0.93-1.24) 0.34 0.76 1.26 (1.08-1.47) 0.003** 0.81 0.03Ɨ 1-h glucose 1.14 (0.99-1.32) 0.06 0.76 1.12 (0.96-1.30) 0.16 0.80 0.66 2-h glucose 1.31 (1.14-1.50) <0.001*** 0.77 1.14 (0.98-1.32) 0.10 0.80 0.08 HbA1c 1.21 (1.04-1.42) 0.02* 0.77 1.18 (0.99-1.40) 0.62 0.80 0.98 BOD % Fat > 85% Percentilea Fasting glucose 1.12 (0.99-1.28) 0.07 0.66 1.18 (1.03-1.34) 0.01* 0.72 0.36 1-h glucose 1.18 (1.05-1.33) 0.01* 0.67 1.19 (1.05-1.36) 0.01* 0.72 0.77 2-h glucose 1.23 (1.09-1.39) <0.001*** 0.67 1.08 (0.95-1.22) 0.24 0.72 0.04 Ɨ HbA1c 1.22 (1.07-1.39) 0.003** 0.67 1.03 (0.90-1.19) 0.63 0.71 0.12 Waist Circumference > 85th Percentilea Fasting glucose 1.08 (0.95-1.22) 0.25 0.65 1.11 (0.97-1.27) 0.13 0.73 0.39 1-h glucose 1.12 (0.99-1.27) 0.06 0.66 1.20 (1.05-1.36) 0.01* 0.74 0.79 2-h glucose 1.20 (1.06-1.35) 0.003** 0.66 1.14 (1.00-1.29) 0.04* 0.73 0.29 HbA1c 1.21 (1.06-1.37) 0.005** 0.66 1.08 (0.94-1.25) 0.27 0.73 0.24 Sum of Skinfolds > 85th Percentilea Fasting glucose 1.07 (0.95-1.22) 0.27 0.65 1.26 (1.11-1.43) <0.001*** 0.70 0.07 1-h glucose 1.14 (1.01-1.29) 0.03* 0.65 1.26 (1.11-1.43) <0.001*** 0.70 0.41 2-h glucose 1.19 (1.06-1.35) 0.004** 0.66 1.23 (1.09-1.39) 0.001** 0.70 0.96 HbA1c 1.19 (1.04-1.35) 0.009** 0.65 1.10 (0.96-1.27) 0.17 0.69 0.63 IOTF = International Obesity Task Force

Odds ratios for the dichotomous outcomes are for the continuous predictors higher by 1 standard deviation estimated in the original HAPO data: Fasting glucose – 0.4 mmol/l; 1 h glucose – 1.7 mmol/l; 2 h glucose – 1.3 mmol/l; HbA1c – 5.0 mmol/mol (0.45 %). Models are adjusted for field center for IOTF overweight/obesity and IOTF obesity outcomes, child pubertal status (Tanner Stage 1, 2/3, 4/5), maternal variables during pregnancy OGTT (age, height, any family history of diabetes, mean arterial pressure, parity (0, 1+), smoking (yes/no), alcohol (yes/no), gestational age, maternal BMI during pregnancy.

a, 85th percentiles were determined using quantile regression adjusted for age, sex, and field center.

b p value from regression model for boys only; * p<0.05, ** p<0.01

c p-value from regression model for girls only; * p<0.05, ** p<0.01

d p-value for sex x maternal predictor interaction term from regression model including boys and girls; ** p<0.01

Table 5. Sex-Specific Fully Adjusted Associations of Continuous Measures of Maternal Glucose and A1c During Pregnancy with Continuous Adiposity Outcomes among Children at Follow-up

Predictor Boys Girls Interaction term p-valuec Beta (95% CI) p-valuea Adjusted R2 Beta (95% CI) p-valueb Adjusted R2

BMI z-score Fasting glucose -0.005 (-0.06-0.05) 0.84 0.17 0.007 (-0.04-0.06) 0.77 0.31 0.92 1-h glucose 0.02 (-0.03-0.07) 0.46 0.17 0.01 (-0.03-0.06) 0.56 0.31 0.46 2-h glucose 0.02 (-0.03-0.07) 0.45 0.17 0.02 (-0.03-0.06) 0.44 0.31 0.35 HbA1c 0.03 (-0.02-0.09) 0.22 0.23 0.04 (-0.009-0.09) 0.10 0.37 0.61 BOD POD % Fat Fasting glucose 0.37 (-0.10-0.83) 0.12 0.16 0.53 (0.11-0.94) 0.01* 0.23 0.51 1-h glucose 0.73 (0.29-1.17) 0.001** 0.16 0.49 (0.09-0.89) 0.02* 0.23 0.08 2-h glucose 0.69 (0.25-1.14) 0.002** 0.16 0.31 (-0.09-0.70) 0.13 0.23 0.005** HbA1c 0.33 (-0.15-0.80) 0.18 0.23 0.15 (-0.28-0.59) 0.49 0.29 0.52 Waist circumference (cm) Fasting glucose 0.12 (-0.37-0.60) 0.63 0.22 0.35 (-0.10-0.81) 0.13 0.35 0.85 1-h glucose 0.43 (-0.03-0.89) 0.07 0.23 0.44 (0.0002-0.87) 0.05 0.35 0.28 2-h glucose 0.51 (0.04-0.97) 0.03* 0.23 0.39 (-0.04-0.82) 0.07 0.35 0.11 HbA1c 0.41 (-0.08-0.90) 0.10 0.30 0.37 (-0.10-0.85) 0.13 0.41 0.79 Sum of Skinfolds (mm) Fasting glucose 0.60 (-0.39-1.59) 0.24 0.12 1.36 (0.48-2.24) 0.002** 0.18 0.53 1-h glucose 0.89 (-0.05-1.83) 0.06 0.12 0.97 (0.13-1.81) 0.02* 0.18 0.34 2-h glucose 0.98 (0.03-1.93) 0.04* 0.12 0.92 (0.09-1.76) 0.03* 0.18 0.14 HbA1c 1.09 (0.09-2.10) 0.03* 0.20 0.51 (-0.42-1.43) 0.28 0.25 0.42 Beta estimates represent change in each continuous outcome for the continuous predictors higher by 1 standard deviation estimated in the original HAPO data: Fasting glucose – 0.4 mmol/l; 1 h glucose – 1.7 mmol/l; 2 h glucose – 1.3 mmol/l; HbA1c – 5.0 mmol/mol (0.45 %). Models are adjusted for field center, child pubertal status (Tanner Stage 1, 2/3, 4/5), maternal variables during pregnancy OGTT (age, height, any family history of diabetes, mean arterial pressure, parity (0, 1+), smoking (yes/no), alcohol (yes/no), gestational age, maternal BMI during pregnancy.

a p value from regression model for boys only; * p<0.05, ** p<0.01

b p-value from regression model for girls only; * p<0.05, ** p<0.01

c p-value for sex x maternal predictor interaction term from regression model including boys and girls; ** p<0.01

FIGURE LEGENDS

Figure 1 Flowchart describing enrollment for HAPO FUS.

HAPO Follow-Up Study Cooperative Research Group

Field Center Principal Investigators and Study Staff:

Bangkok C Deerochanawong, T Tanaphonpoonsuk (Rajavithi Hospital), S Binratkaew U

Chotigeat, W Manyam, (Queen Sirikit National Institute of Child Health)

Barbados M Forde, A Greenidge, K Neblett, PM Lashley, D Walcott (Queen Elizabeth

Hospital/School of Clinical Medicine and Research, University of the West Indies, Barbados)

Belfast K Corry, L Francis, J Irwin, A Langan, DR McCance, M Mousavi, (Belfast Health and

Social Care Trust), IS Young (Queen’s University Belfast)

Bellflower J Gutierrez, J Jimenez, JM Lawrence, DA Sacks, HS Takhar, E Tanton (Kaiser

Permanente Southern California)

Chicago WJ Brickman, J Howard, JL Josefson, L Miller, R Steuer (Ann and Robert H Lurie

Children’s Hospital/Northwestern University Feinberg School of Medicine)

Cleveland J Bjaloncik, PM Catalano, A Davis, K Koontz, L Presley, S Smith, A Tyhulski

(MetroHealth Medical Center/Case Western Reserve University)

Hong Kong A Li, RC Ma, R Ozaki, WH Tam, M Wong, C Yuen (The Chinese University of

Hong Kong/Prince of Wales Hospital)

Manchester PE Clayton, A Khan, A Vyas (Royal Manchester Children’s Hospital, Manchester

University Hospitals NHS Foundation Trust, Manchester Academic Healthy Sciences

Centre/School of Medical Sciences, Faculty of Biology, Medicine & Health, University of

Manchester), M Maresh (St. Mary’s Hospital, Central Manchester University Hospitals NHS

Foundation Trust, Manchester Academic Health Sciences Centre)

Petah-Tiqva H Benzaquen, N Glickman, A Hamou, O Hermon, O Horesh, Y Keren, , S Shalitin

(Schneider Children’s Medical Center of Israel), Y Lebenthal (Jesse Z and Sara Lea Shafer

Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider

Children’s Medical Center of Israel, Sackler Faculty of Medicine, Tel Aviv University)

Toronto K Cordeiro, J Hamilton, HY Nguyen, S Steele (The Hospital for Sick Children,

University of Toronto)

Coordinating Centers: F Chen, AR Dyer, W Huang, A Kuang, M Jimenez, LP Lowe, WL

Lowe, Jr, BE Metzger, M Nodzenski, A Reisetter, D Scholtens, P Yim (Northwestern University

Feinberg School of Medicine)

Consultants: D Dunger, A Thomas

NIDDK: M Horlick, B Linder, A Unalp-Arida

NICHD: G Grave

15,812 eligible for HAPO FUS

9322 contacted

6490 unable to contact

4834HAPO FUS visits

4488 declinedparticipation

4832 physicalmeasurementsand/or glucoseoutcome data

2 excluded(non-fastingor unable to complete visitdue to autism)

4821 at least one physical measurement

11 glucose outcome data only

4775 with calculated BMI

HAPO‐FUS‐Paper‐Mat‐Gluc‐Child‐Adiposity‐Supp‐Tables‐08‐07‐18

Electronic Supplementary Material (ESM)

ESM Methods

Multiple Imputation for Missing Tanner Stage

The HAPO Follow-Up Study visit protocol specified evaluation of Tanner Stage 1, 2/3 or 4/5 by trained

medical study staff according to breast/areolar development or by asking about menstruation for girls and

measurement of testicular volume using a Prader orchidometer for boys. For girls, 2008 trained

assessments were completed and 381 (19.0%), 852 (42.5%) and 774 (38.5%) were Stage 1, 2/3 and 4/5,

respectively. For boys, 1570 trained assessments were completed and 565 (36.0%), 726 (46.2%) and

279 (17.8%) were Stage 1, 2/3 and 4/5, respectively. Due to refusal of either the HAPO child or the

HAPO child’s mother, trained assessments were not collected for 359/2367 (15.2%) of girls and 895/2465

(36.3%) of boys. For all HAPO FUS child participants for whom a back-up blood sample was available,

serum hormone-binding globulin (SHBG) was measured using an immunofluorometric assay. In addition,

testosterone was measured for boys and estradiol was measured for girls. Testosterone and estradiol

levels were measured by the Brigham Research Assay Core Laboratory using liquid chromatography (LC)

tandem mass spectrometry (MS) at the Brigham and Women’s Hospital [1-2]. The testosterone LC-

MS/MS assay has a sensitivity of 0.5 ng/mL and estradiol LC-MS/MS assay 1 pg/mL. SHBG and

testosterone were successfully measured in 2199 (89.2%) and 2230 (90.5%) of 2465 boys, respectively.

SHBG and estradiol were successfully measured in 2090 (88.3%) and 2131 (90.0%) of 2367 girls,

respectively.

Statistical models including adjustment for trained assessment of Tanner stage were performed using

multiple imputation. All variables to be used for statistical analyses as well as sex steroid measurements

were identified, and then 25 rounds of multiple imputation were performed to impute all missing

observations across all variables. Imputations were performed separately for boys and girls. Missing

data assumptions ‘missing at random’ and ‘missing not at random’ were both explored. Estimated

associations varied little for these assumptions, hence results were reported under the simpler ‘missing at

random’ assumption.

HAPO‐FUS‐Paper‐Mat‐Gluc‐Child‐Adiposity‐Supp‐Tables‐08‐07‐18

[1] Jasuja GK, Travison TG, Davda M, Murabito JM, Basaria S, Zhang A, Kushnir MM, Rockwood AL, Meikle W, Pencina MJ, Coviello A, Rose AJ, D’Agostino R, Ramachandran SV, Bhasin S. (2013) Age trends in estradiol and estrone levels measured using liquid chromatography tandem mass spectrometry in community-dwelling men of the Framingham Heart Study. The Journals of Gerontology: Series A. 68(6): 733-740.

[2] Bhasin S, Pencina M, Jasuja GK, Travison TG, Coviello A, Orwoll E, Wang PY, Nielson C, Wu F, Tajar A, Labrie F, Vesper H, Zhang A, Ulloor J, Singh R, D’Agostino R, Vasan RS. (2011) Reference ranges for testosterone in men generated using liquid chromatography tandem mass spectrometry in a community-based sample of healthy nonobese young men in the Framingham Heart Study and applied to three geographically distinct cohorts. Journal of Clinical Endocrinology and Metabolism. 96(8):2430-2439.

ESM Table 1. Characteristics of HAPO FUS Participants and Non-Participants

HAPO Maternal Characteristics Participants N=4832

Non-Participants N=10980

Participants N=4832

Non-Participants N=10980

Unweighted Summaries Weighted Summaries* Mean (SD) Mean (SD) Mean (SD) Mean (SD) Age at OGTT(yrs) 29.9 (5.7) 29.1 (5.7) 30.0 (5.1) 29.1 (5.3) Body Mass Index (BMI) 27.5 (4.9) 27.5 (5.1) 27.5 (4.6) 27.5 (4.7) Height (cm) 161.8 (6.8) 160.7 (7.3) 161.1 (6.2) 160.9 (6.3) Fasting Plasma Glucose (mmol/l) 4.5 (0.4) 4.5 (0.4) 4.5 (0.4) 4.5 (0.4) 1-hr Plasma Glucose (mmol/l) 7.4 (1.7) 7.5 (1.7) 7.5 (1.7) 7.5 (1.7) 2-hr Plasma Glucose (mmol/l) 6.1 (1.3) 6.2 (1.3) 6.2 (1.3) 6.2 (1.3) HbA1c (mmol/mol) [%] 29.0 (4.5) [4.8

(0.4)] 29.0 (4.5) [4.8 (0.4)] 29.0 (4.5) [4.8 (0.4)] 29.0 (4.5) [4.8 (0.4)]

N (%) N (%) (%) (%) GDM 683 (14.1) 1879 (17.1) (14.9) (16.9) Race/Ethnicity White, non-Hispanic 2287 (47.3) 4705 (42.9) (44.5) (44.1) Hispanic 507 (10.5) 1047 (9.5) (10.3) (9.6) Black, non-Hispanic 775 (16.0) 1551 (14.1) (14.8) (14.6) Asian 1176 (24.3) 3424 (31.2) (28.5) (29.3) Other 87 (1.8) 253 (2.3) (1.8) (2.3)

* Weighted summaries are weighted means and standard deviations or weighted percentages based on field-center-specific summary statistics with weights proportional to the total eligible population at the field center. **GDM=gestational diabetes mellitus defined by IADPSG criteria (1 or more glucose values from a 75g OGTT equals or exceeds FPG 5.1 mmol/l, 1-hr 10.0 mmol/l, 2-hr 8.5 mmol/l)

ESM Table 2. Frequencies of Child Adiposity at Follow-Up by Maternal Levels of Glucose and HbA1c During Pregnancy

IOTF Overweight/Obesity IOTF Obesity BOD POD % Fat

> 85th Percentile* Waist Circumference

> 85th Percentile* Sum of Skinfolds > 85th

Percentile* Glucose Levels % (n/Total N) % (n/Total N) % (n/Total N) % (n/Total N) % (n/Total N) FPG (mmol/l) < 4.2 26.0 (194/747) 7.2 (54/747) 10.1 (72/716) 10.7 (81/754) 11.1 (82/737) 4.2-4.4 28.3 (438/1550) 9.5 (147/1550) 13.6 (205/1511) 13.1 (204/1559) 13.0 (199/1533) 4.5-4.7 28.7 (378/1317) 12.1 (159/1317) 14.8 (191/1290) 15.1 (199/1321) 14.8 (192/1302) 4.8-5.0 33.6 (272/809) 11.7 (95/809) 18.0 (143/796) 18.1 (146/807) 17.7 (140/791) > 5.1 45.2 (159/352) 22.7 (80/352) 25.2 (87/345) 25.1 (88/351) 27.4 (93/340) 1-h PG (mmol/l) < 5.8 25.3 (226/894) 9.0 (80/894) 12.5 (109/872) 12.5 (113/901) 12.6 (112/888) 5.9-7.3 28.0 (436/1559) 9.6 (149/1559) 12.8 (194/1518) 13.2 (206/1566) 12.9 (198/1540) 7.4-8.6 29.8 (371/1244) 11.7 (146/1244) 14.9 (180/1211) 15.6 (195/1248) 15.4 (188/1221) 8.7-9.9 37.4 (273/730) 13.6 (99/730) 19.1 (137/716) 18.0 (131/730) 18.9 (135/714) > 10.0 38.8 (135/348) 17.5 (61/348) 22.9 (78/341) 21.0 (73/347) 21.5 (73/340) 2-h PG (mmol/l) < 5.0 25.6 (225/880) 7.2 (63/880) 11.3 (96/850) 11.1 (98/887) 11.1 (96/869) 5.1-6.0 29.6 (455/1540) 11.0 (169/1540) 14.9 (223/1500) 15.3 (237/1547) 15.1 (229/1518) 6.1-6.9 29.9 (367/1228) 10.8 (132/1228) 14.7 (176/1195) 14.4 (177/1233) 14.3 (174/1217) 7.0-8.4 33.3 (295/886) 14.0 (124/886) 17.4 (152/873) 17.8 (157/883) 17.5 (151/863) > 8.5 41.1 (99/241) 19.5 (47/241) 21.3 (51/240) 20.3 (49/242) 23.7 (56/236) HbA1c Levels (mmol/mol) [%]

< 25 [< 4.4] 24.8 (179/721) 6.7 (48/721) 11.5 (81/704) 11.4 (83/730) 12.2 (87/711) 26-28 [4.5-4.7] 26.9 (338/1257) 9.2 (115/1257) 13.2 (161/1217) 13.2 (167/1267) 12.9 (161/1245) 29-31 [4.8-5.0] 30.6 (511/1669) 12.4 (207/1669) 16.0 (261/1628) 16.0 (268/1671) 15.7 (258/1643) 32-36 [5.1-5.4] 36.4 (190/522) 14.0 (73/522) 16.6 (85/512) 17.3 (90/521) 17.6 (90/512) > 37 [> 5.5] 39.6 (80/202) 16.8 (34/202) 25.4 (50/197) 22.1 (44/199) 25.4 (49/193)

* 85th percentiles were determined using quantile regression adjusted for age, sex, and field center.


% is the proportion in the category with the adiposity outcome, n is the number in the category with the adiposity outcome, Total N is the total number in the category.

The lowest three categories for FPG, 1-h PG and 2-h PG were used for analyses of glucose levels during the original HAPO Study; the fourth category includes values up to the fifth category for each measure that correspond to IADPSG diagnostic thresholds for GDM. For HbA1c, the lowest three categories were used for analyses of HbA1c levels during the original HAPO Study, and the fourth and fifth categories combine smaller categories used for original analyses of HbA1c.

ESM Table 3. Frequencies and Odds Ratios of Child IOTF Overweight/Obesity at Follow-Up by Maternal Levels of Glucose and HbA1c During Pregnancy

IOTF Overweight/Obesity

% (n/Total N)

Model 1 OR (95% CI)

Model 2 OR (95% CI)

Model 3 OR (95% CI)

Model 4 OR (95% CI)

Glucose Levels FPG (mmol/l) < 4.2 26.0 (194/747) - - - - 4.2-4.4 28.3 (438/1550) 1.15 (0.94-1.41) 1.10 (0.90-1.35) 1.07 (0.87-1.32) 0.95 (0.77-1.18) 4.5-4.7 28.7 (378/1317) 1.18 (0.95-1.45) 1.13 (0.92-1.40) 1.08 (0.87-1.34) 0.87 (0.70-1.09) 4.8-5.0 33.6 (272/809) 1.50 (1.19-1.90) 1.45 (1.15-1.83) 1.33 (1.05-1.69) 0.95 (0.74-1.22) > 5.1 45.2 (159/352) 2.32 (1.75-3.07) 2.25 (1.69-2.98) 1.99 (1.48-2.67) 1.22 (0.90-1.66) 1-h PG (mmol/l) < 5.8 25.3 (226/894) - - - - 5.9-7.3 28.0 (436/1559) 1.19 (0.98-1.44) 1.23 (1.01-1.49) 1.21 (0.98-1.47) 1.09 (0.89-1.34) 7.4-8.6 29.8 (371/1244) 1.29 (1.05-1.33) 1.30 (1.06-1.60) 1.25 (1.02-1.55) 1.08 (0.87-1.34) 8.7-9.9 37.4 (273/730) 1.81 (1.45-2.26) 1.80 (1.44-2.25) 1.72 (1.36-2.17) 1.39 (1.09-1.77) > 10.0 38.8 (135/348) 1.76 (1.34-2.31) 1.78 (1.35-2.35) 1.68 (1.26-2.24) 1.38 (1.03-1.86) 2-h PG (mmol/l) < 5.0 25.6 (225/880) - - - - 5.1-6.0 29.6 (455/1540) 1.28 (1.06-1.55) 1.28 (1.05-1.55) 1.25 (1.02-1.52) 1.06 (0.87-1.31) 6.1-6.9 29.9 (367/1228) 1.27 (1.04-1.56) 1.27 (1.04-1.56) 1.23 (1.00-1.52) 1.02 (0.82-1.27) 7.0-8.4 33.3 (295/886) 1.49 (1.20-1.84) 1.48 (1.19-1.84) 1.40 (1.12-1.75) 1.18 (0.93-1.49) > 8.5 41.1 (99/241) 1.90 (1.40-2.59) 1.95 (1.43-2.67) 1.78 (1.28-2.46) 1.43 (1.03-2.00) HbA1c Levels (mmol/mol) [%]

< 25 [< 4.4] 24.8 (179/721) - - - - 26-28 [4.5-4.7] 26.9 (338/1257) 1.17 (0.95-1.46) 1.16 (0.93-1.44) 1.17 (0.94-1.46) 1.13 (0.90-1.42)

29-31 [4.8-5.0] 30.6 (511/1669) 1.36 (1.11-1.67) 1.38 (1.12-1.70) 1.36 (1.10-1.68) 1.16 (0.93-1.44) 32-36 [5.1-5.4] 36.4 (190/522) 1.79 (1.39-2.32) 1.78 (1.37-2.32) 1.74 (1.33-2.28) 1.34 (1.01-1.77) > 37 [> 5.5] 39.6 (80/202) 2.06 (1.47-2.89) 2.02 (1.44-2.84) 1.96 (1.38-2.79) 1.46 (1.01-2.10)





Odds ratios for the dichotomous outcomes are for each category relative to the lowest category. Model 1: Adjusted for field center for IOTF overweight/obesity and IOTF obesity outcomes, unadjusted for BOD POD % fat, waist circumference and sum of skinfolds >85th percentile outcomes; Model 2: Model 1+ + child pubertal status (Tanner Stage 1, 2/3, 4/5, sex x Tanner stage interaction), Model 3: Model 2 + maternal variables during pregnancy OGTT (age, height, any family history of diabetes, mean arterial pressure, parity (0, 1+), smoking (yes/no), alcohol (yes/no), gestational age). Model 4: Model 3 + maternal BMI during pregnancy.

ESM Table 4. Frequencies and Odds Ratios of Child IOTF Obesity at Follow-Up by Maternal Levels of Glucose and HbA1c During Pregnancy

IOTF Obesity % (n/Total N)

Model 1 OR (95% CI)

Model 2 OR (95% CI)

Model 3 OR (95% CI)

Model 4 OR (95% CI)

Glucose Levels FPG (mmol/l) < 4.2 7.2 (54/747) - - - - 4.2-4.4 9.5 (147/1550) 1.38 (1.00-1.93) 1.30 (0.94-1.81) 1.28 (0.92-1.78) 1.12 (0.80-1.57)

4.5-4.7 12.1 (159/1317) 1.82 (1.32-2.56) 1.74 (1.25-2.43) 1.66 (1.19-2.33) 1.36 (0.96-1.91)

4.8-5.0 11.7 (95/809) 1.77 (1.23-2.55) 1.67 (1.16-2.39) 1.55 (1.07-2.24) 1.19 (0.75-1.610

> 5.1 22.7 (80/352) 3.69 (2.51-5.47) 3.51 (2.37-5.19) 3.12 (2.08-4.67) 1.92 (1.26-2.92)

1-h PG (mmol/l) < 5.8 9.0 (80/894) - - - - 5.9-7.3 9.6 (149/1559) 1.11 (0.83-1.48) 1.17 (0.87-1.56) 1.15 (0.86-1.54) 1.02 (0.75-1.38) 7.4-8.6 11.7 (146/1244) 1.39 (1.04-1.88) 1.43 (1.06-1.93) 1.34 (0.99-1.82) 1.14 (0.83-1.56) 8.7-9.9 13.6 (99/730) 1.62 (1.17-2.24) 1.62 (1.17-2.24) 1.53 (1.09-2.15) 1.18 (0.83-1.68) > 10.0 17.5 (61/348) 1.96 (1.35-2.84) 2.02 (1.39-2.94) 1.85 (1.25-2.73) 1.54 (1.03-2.31) 2-h PG (mmol/l) < 5.0 7.2 (63/880) - - - - 5.1-6.0 11.0 (169/1540) 1.70 (1.26-2.32) 1.71 (1.26-2.33) 1.68 (1.23-2.28) 1.42 (1.03-1.95) 6.1-6.9 10.8 (132/1228) 1.60 (1.17-2.22) 1.60 (1.16-2.21) 1.55 (1.11-2.15) 1.28 (0.97-2.04) 7.0-8.4 14.0 (124/886) 2.15 (1.56-3.01) 2.17 (1.56-3.02) 2.05 (1.67-4.03) 1.74 (1.23-2.48) > 8.5 19.5 (47/241) 2.82 (1.84-4.28) 2.92 (1.91-4.45) 2.59 (1.67-4.03) 2.16 (1.38-3.39) HbA1c Levels (mmol/mol) [%]

< 25 [< 4.4] 6.7 (48/721) - - - - 26-28 [4.5-4.7] 9.2 (115/1257) 1.54 (1.08-2.22) 1.44 (1.00-2.07) 1.45 (1.01-2.09) 1.41 (0.97-2.04) 29-31 [4.8-5.0] 12.4 (207/1669) 2.09 (1.50-2.96) 1.96 (1.41-2.72) 1.94 (1.39-2.72) 1.64 (1.16-2.30) 32-36 [5.1-5.4] 14.0 (73/522) 2.42 (1.63-3.63) 2.22 (1.50-3.30) 2.16 (1.44-3.24) 1.56 (1.03-2.38) > 37 [> 5.5] 7.2 (63/880) 2.99 (1.83-4.86) 2.65 (1.65-4.27) 2.59 (1.58-4.24) 1.84 (1.11-3.07)

ESM Table 5. Frequencies and Odds Ratios of Child BOD POD % Fat >85th percentile at Follow-Up by Maternal Levels of Glucose and HbA1c During Pregnancy

BOD POD % Fat >85th percentile

% (n/Total N)

Model 1 OR (95% CI)

Model 2 OR (95% CI)

Model 3 OR (95% CI)

Model 4 OR (95% CI)


< 25 [< 4.4] 11.5 (81/704) - - - - 26-28 [4.5-4.7] 13.2 (161/1217) 1.17 (0.88-1.56) 1.15 (0.87-1.53) 1.14 (0.86-1.52) 1.11 (0.84-1.48) 29-31 [4.8-5.0] 16.0 (261/1628) 1.47 (1.13-1.93) 1.46 (1.12-1.91) 1.41 (1.07-1.85) 1.24 (0.95-1.63) 32-36 [5.1-5.4] 16.6 (85/512) 1.53 (1.10-2.13) 1.54 (1.11-2.14) 1.48 (1.06-2.06) 1.21 (0.86-1.69)

> 37 [> 5.5] 25.4 (50/197) 2.62 (1.75-3.88) 2.41 (1.62-3.59) 2.26 (1.51-3.40) 1.80 (1.18-2.73) * 85th percentiles were determined using quantile regression adjusted for age, sex, and field center.





ESM Table 6. Frequencies and Odds Ratios of Child Waist Circumference >85th percentile at Follow-Up by Maternal Levels of Glucose and HbA1c During Pregnancy

Waist Circumference >85th

percentile % (n/Total N)

Model 1 OR (95% CI)

Model 2 OR (95% CI)

Model 3 OR (95% CI)

Model 4 OR (95% CI)

Glucose Levels FPG (mmol/l) < 4.2 10.7 (81/754) - - - - 4.2-4.4 13.1 (204/1559) 1.25 (0.96-1.65) 1.17 (0.89-1.54) 1.13 (0.86-1.50) 1.01 (0.76-1.34) 4.5-4.7 15.1 (199/1321) 1.47 (1.12-1.95) 1.37 (1.04-1.81) 1.28 (0.96-1.70) 1.05 (0.79-1.40) 4.8-5.0 18.1 (146/807) 1.84 (1.37-2.47) 1.69 (1.26-2.26) 1.51 (1.12-2.05) 1.10 (0.81-1.51) > 5.1 25.1 (88/351) 2.78 (1.99-3.89) 2.58 (1.84-3.61) 2.17 (1.52-3.08) 1.36 (0.94-1.97) 1-h PG (mmol/l) < 5.8 12.5 (113/901) - - - - 5.9-7.3 13.2 (206/1566) 1.06 (0.83-1.35) 1.08 (0.84-1.38) 1.07 (0.84-1.38) 0.99 (0.77-1.28) 7.4-8.6 15.6 (195/1248) 1.29 (1.01-1.66) 1.33 (1.03-1.72) 1.31 (1.01-1.70) 1.18 (0.90-1.54) 8.7-9.9 18.0 (131/730) 1.53 (1.16-2.01) 1.54 (1.17-2.03) 1.53 (1.15-2.04) 1.28 (0.95-1.72) > 10.0 21.0 (73/347) 1.86 (1.34-2.57) 1.89 (1.36-2.63) 1.83 (1.30-2.58) 1.58 (1.11-2.24) 2-h PG (mmol/l) < 5.0 11.1 (98/887) - - - - 5.1-6.0 15.3 (237/1547) 1.46 (1.14-1.88) 1.45 (1.12-1.86) 1.44 (1.11-1.85) 1.27 (0.98-1.65) 6.1-6.9 14.4 (177/1233) 1.35 (1.04-1.76) 1.36 (1.04-1.77) 1.38 (1.05-1.80) 1.21 (0.92-1.60) 7.0-8.4 17.8 (157/883) 1.74 (1.33-2.29) 1.77 (1.35-2.33) 1.79 (1.34-2.37) 1.60 (1.20-2.14) > 8.5 20.3 (49/242) 2.04 (1.39-2.97) 2.07 (1.41-3.03) 1.98 (1.33-2.93) 1.68 (1.12-2.510 HbA1c Levels (mmol/mol) [%]

< 25 [< 4.4] 11.4 (83/730) - - - - 26-28 [4.5-4.7] 13.2 (167/1267) 1.18 (0.90-1.57) 1.18 (0.89-1.57) 1.18 (0.89-1.57) 1.14 (0.85-1.53) 29-31 [4.8-5.0] 16.0 (268/1671) 1.49 (1.15-1.95) 1.58 (1.20-2.03) 1.53 (1.17-2.00) 1.33 (1.02-1.75)

32-36 [5.1-5.4] 17.3 (90/521) 1.63 (1.18-2.25) 1.71 (1.24-2.37) 1.69 (1.21-2.36) 1.35 (0.95-1.90) > 37 [> 5.5] 22.1 (44/199) 2.21 (1.47-3.31) 2.28 (1.52-3.41) 2.21 (1.46-3.35) 1.69 (1.10-2.60)






ESM Table 7. Frequencies and Odds Ratios of Child Sum of Skinfolds >85th percentile at Follow-Up by Maternal Levels of Glucose and HbA1c During Pregnancy

Sum of Skinfolds >85th percentile

% (n/Total N)

Model 1 OR (95% CI)

Model 2 OR (95% CI)

Model 3 OR (95% CI)

Model 4 OR (95% CI)


< 25 [< 4.4] 12.2 (87/711) - - - - 26-28 [4.5-4.7] 12.9 (161/1245) 1.07 (0.81-1.41) 1.06 (0.81-1.40) 1.06 (0.80-1.40) 1.03 (0.78-1.36)

29-31 [4.8-5.0] 15.7 (258/1643) 1.34 (1.03-1.74) 1.34 (1.04-1.74) 1.30 (1.001-1.69) 1.15 (0.88-1.50) 32-36 [5.1-5.4] 17.6 (90/512) 1.53 (1.11-2.11) 1.56 (1.14-2.15) 1.51 (1.09-2.08) 1.24 (0.89-1.72) > 37 [> 5.5] 25.4 (49/193) 2.44 (1.64-3.61) 2.29 (1.53-3.41) 2.18 (1.45-3.28) 1.73 (1.14-2.64)






ESM Table 8. Mean (SD) of Continuous Measures of Child Adiposity at Follow-Up by Maternal Levels of Glucose and HbA1c During Pregnancy

BMI (kg/m2) BOD POD % Fat Waist Circumference (cm) Sum of Skinfolds (mm) Glucose Levels Mean (SD) Mean (SD) Mean (SD) Mean (SD) FPG (mmol/l) < 4.2 18.4 (3.7) 18.5 (9.8) 68.1 (10.5) 36.0 (18.9) 4.2-4.4 18.9 (4.1) 20.5 (10.1) 69.3 (11.3) 37.9 (20.8) 4.5-4.7 19.4 (4.6) 21.4 (10.6) 70.6 (12.3) 39.3 (21.5) 4.8-5.0 19.7 (4.3) 22.6 (10.3) 71.5 (12.2) 41.3 (21.9) > 5.1 21.0 (5.0) 25.3 (11.3) 75.2 (13.8) 46.3 (25.9) 1-h PG (mmol/l) < 5.8 19.0 (4.3) 20.1 (10.1) 69.7 (11.2) 37.1 (20.0) 5.9-7.3 19.1 (4.3) 20.3 (10.4) 69.6 (11.8) 37.5 (20.7) 7.4-8.6 19.3 (4.4) 21.4 (10.3) 70.3 (12.3) 39.7 (21.3) 8.7-9.9 19.7 (4.4) 22.6 (10.6) 71.4 (12.0) 42.5 (23.2) > 10.0 19.8 (4.4) 23.7 (11.3) 72.4 (12.5) 43.7 (23.4) 2-h PG (mmol/l) < 5.0 18.9 (4.0) 19.8 (9.9) 69.5 (11.1) 36.1 (18.5) 5.1-6.0 19.4 (4.4) 21.2 (10.5) 70.8 (12.0) 39.2 (21.6) 6.1-6.9 19.2 (4.3) 21.2 (10.2) 69.7 (11.9) 39.3 (21.6) 7.0-8.4 19.4 (4.5) 21.6 (10.8) 70.4 (12.4) 40.8 (22.8) > 8.5 20.0 (4.4) 23.8 (11.3) 72.8 (12.5) 44.6 (23.2) HbA1c Levels (mmol/mol) [%]

< 25 [< 4.4] 19.0 (4.0) 20.1 (10.3) 70.2 (11.0) 36.3 (18.8) 26-28 [4.5-4.7] 19.1 (4.1) 20.7 (10.0) 70.1 (11.3) 38.2 (20.7) 29-31 [4.8-5.0] 19.3 (4.4) 21.4 (10.6) 70.0 (12.4) 39.7 (21.9) 32-36 [5.1-5.4] 19.5 (4.3) 21.7 (10.6) 70.2 (12.2) 41.2 (21.5) > 37 [> 5.5] 19.7 (4.6) 23.3 (11.6) 71.8 (13.2) 44.9 (27.3)

ESM Table 9. Group Means and Adjusted Mean Differences for Child BMI z-scores at Follow-Up by Maternal Levels of Glucose and HbA1c During Pregnancy

BMI z-score Mean (SD)

Model 1 Adjusted Mean

Difference (95% CI)


Difference (95% CI)


Difference (95% CI)


Difference (95% CI)

Glucose Levels FPG (mmol/l) < 4.2 0.29 (1.18) - - - - 4.2-4.4 0.41 (1.21) 0.09 (-0.02-0.19) 0.06 (-0.04-0.16) 0.04 (-0.06-0.14) -0.03 (-0.13-0.07) 4.5-4.7 0.48 (1.28) 0.13 (0.02-0.24) 0.10 (-0.02-0.20) 0.06 (-0.05-0.17) -0.07 (-0.17-0.03) 4.8-5.0 0.60 (1.24) 0.22 (0.10-0.35) 0.19 (0.07-0.30) 0.13 (0.01-0.25) -0.09 (0.21-0.03) > 5.1 0.95 (1.26) 0.51 (0.36-0.67) 0.47 (0.32-0.62) 0.38 (0.23-0.53) 0.03 (-0.12-0.18) 1-h PG (mmol/l) < 5.8 0.40 (1.22) - - - - 5.9-7.3 0.41 (1.24) 0.05 (-0.05-0.15) 0.07 (-0.03-0.16) 0.05 (-0.04-0.15) -0.02 (-0.11-0.07) 7.4-8.6 0.49 (1.23) 0.14 (0.04-0.25) 0.14 (0.04-0.24) 0.11 (0.01-0.21) 0.01 (-0.09-0.10) 8.7-9.9 0.64 (1.25) 0.31 (0.19-0.42) 0.28 (0.17-0.40) 0.24 (0.12-0.35) 0.08 (-0.03-0.19) > 10.0 0.63 (1.32) 0.24 (0.09-0.39) 0.23 (0.08-0.37) 0.16 (0.02-0.33) 0.02 (-0.12-0.17) 2-h PG (mmol/l) < 5.0 0.37 (1.20) - - - - 5.1-6.0 0.51 (1.24) 0.17 (0.07-0.27) 0.15 (0.06-0.25) 0.14 (0.04-0.23) 0.03 (-0.06-0.13) 6.1-6.9 0.45 (1.23) 0.14 (0.04-0.25) 0.13 (0.03-0.23) 0.11 (0.01-0.21) -0.004 (-0.10-0.09) 7.0-8.4 0.51 (1.29) 0.22 (0.11-0.33) 0.20 (0.09-0.31) 0.15 (0.04-0.26) 0.04 (-0.07-0.14) > 8.5 0.72 (1.28) 0.40 (0.23-0.57) 0.39 (0.22-0.56) 0.31 (0.14-0.48) 0.16 (-0.003-0.32) HbA1c Levels (mmol/mol) [%]

< 25 [< 4.4] 0.32 (1.23) - - - - 26-28 [4.5-4.7] 0.39 (1.21) 0.08 (-0.03-0.19) 0.10 (-0.01-0.21) 0.10 (-0.003-0.21) 0.07 (-0.03-0.17)

29-31 [4.8-5.0] 0.52 (1.24) 0.22 (0.12-0.33) 0.26 (0.16-0.37) 0.25 (0.14-0.35) 0.13 (0.03-0.23) 32-36 [5.1-5.4] 0.62 (1.26) 0.37 (0.23-0.51) 0.39 (0.26-0.53) 0.36 (0.23-0.50) 0.18 (0.05-0.31) > 37 [> 5.5] 0.66 (1.29) 0.39 (0.20-0.58) 0.40 (0.22-0.58) 0.37 (0.19-0.55) 0.15 (-0.02-0.33)



Adjusted mean differences for the continuous outcomes are for each category relative to the lowest category. Model 1: Adjusted for field center for IOTF overweight/obesity and IOTF obesity outcomes, unadjusted for BOD POD % fat, waist circumference and sum of skinfolds >85th percentile outcomes; Model 2: Model 1+ + child pubertal status (Tanner Stage 1, 2/3, 4/5, sex x Tanner stage interaction), Model 3: Model 2 + maternal variables during pregnancy OGTT (age, height, any family history of diabetes, mean rterial pressure, parity (0, 1+), smoking (yes/no), alcohol (yes/no), gestational age). Model 4: Model 3 + maternal BMI during pregnancy.

ESM Table 10. Group Means and Adjusted Mean Differences for Child BOD POD % Fat at Follow-Up by Maternal Levels of Glucose and HbA1c During Pregnancy

BOD POD % Fat Mean (SD)


Difference (95% CI)


Difference (95% CI)


Difference (95% CI)


Difference (95% CI)

Glucose Levels FPG (mmol/l) < 4.2 18.5 (9.8) - - - - 4.2-4.4 20.5 (10.1) 1.48 (0.58-2.38) 1.29 (0.42-2.15) 1.15 (0.29-2.01) 0.71 (-0.13-1.55) 4.5-4.7 21.4 (10.6) 1.89 (0.96-2.83) 1.69 (0.78-2.59) 1.42 (0.51-2.32) 0.57 (-0.31-1.46) 4.8-5.0 22.6 (10.3) 2.73 (1.69-3.78) 2.50 (1.49-3.51) 2.06 (1.05-3.09) 0.69 (-0.31-1.70) > 5.1 25.3 (11.3) 4.97 (3.65-6.28) 4.72 (3.43-6.00) 4.00 (2.71-5.30) 1.80 (0.50-3.09) 1-h PG (mmol/l) < 5.8 20.1 (10.1) - - - - 5.9-7.3 20.3 (10.4) 0.36 (-0.48-1.20) 0.49 (-0.32-1.30) 0.41 (-0.39-1.22) -0.04 (-0.82-0.75) 7.4-8.6 21.4 (10.3) 1.48 (0.60-2.36) 1.55 (0.69-2.40) 1.33 (0.47-2.19) 0.67 (-0.17-1.51) 8.7-9.9 22.6 (10.6) 2.66 (2.66-3.67) 2.54 (1.57-3.52) 2.29 (1.29-3.28) 1.29 (0.31-2.27) > 10.0 23.7 (11.3) 3.16 (1.89-4.43) 3.03 (1.79-4.26) 2.68 (1.42-3.93) 1.77 (0.54-3.00) 2-h PG (mmol/l) < 5.0 19.8 (9.9) - - - - 5.1-6.0 21.2 (10.5) 1.44 (0.59-2.29) 1.35 (0.53-2.18) 1.27 (0.45-2.09) 0.59 (-0.21-1.39) 6.1-6.9 21.2 (10.2) 1.53 (0.69-2.48) 1.47 (0.61-2.34) 1.38 (0.51-2.25) 0.63 (-0.22-1.48) 7.0-8.4 21.6 (10.8) 2.12 (1.15-3.08) 2.03 (1.09-2.97) 1.78 (0.83-2.74) 1.03 (0.10-1.96) > 8.5 23.8 (11.3) 3.97 (2.52-5.43) 3.95 (2.53-5.37) 3.48 (2.04-4.92) 2.46 (1.05-3.87) HbA1c Levels (mmol/mol) [%]

< 25 [< 4.4] 20.1 (10.3) - - - -

26-28 [4.5-4.7] 20.7 (10.0) 0.54 (-0.40-1.48) 0.57 (-0.33-1.48) 0.58 (-0.32-1.48) 0.36 (-0.52-1.24) 29-31 [4.8-5.0] 21.4 (10.6) 1.03 (0.13-1.93) 1.39 (0.51-2.28) 1.23 (0.34-2.12) 0.50 (-0.36-1.36) 32-36 [5.1-5.4] 21.7 (10.6) 1.56 (0.39-2.73) 1.93 (0.76-3.10) 1.64 (0.46-2.82) 0.47 (-0.36-1.62) > 37 [> 5.5] 23.3 (11.6) 2.97 (1.36-4.57) 3.02 (1.48-4.57) 2.67 (1.11-4.23) 1.25 (-0.28-2.78)



Adjusted mean differences for the continuous outcomes are for each category relative to the lowest category. Model 1: Adjusted for field center for IOTF overweight/obesity and IOTF obesity outcomes, unadjusted for BOD POD % fat, waist circumference and sum of skinfolds >85th percentile outcomes; Model 2: Model 1+ + child pubertal status (Tanner Stage 1, 2/3, 4/5, sex x Tanner stage interaction), Model 3: Model 2 + maternal variables during pregnancy OGTT (age, height, any family history of diabetes, mean arterial pressure, parity (0, 1+), smoking (yes/no), alcohol (yes/no), gestational age). Model 4: Model 3 + maternal BMI during pregnancy.

ESM Table 11. Group Means and Adjusted Mean Differences for Child Waist Circumference at Follow-Up by Maternal Levels of Glucose and HbA1c During Pregnancy

Waist

Circumference (cm)

Mean (SD)


Difference (95% CI)


Difference (95% CI)


Difference (95% CI)


Difference (95% CI)

Glucose Levels FPG (mmol/l) < 4.2 68.1 (10.5) - - - - 4.2-4.4 69.3 (11.3) 0.93 (-0.07-1.93) 0.72 (-0.21-1.66) 0.54 (-0.39-1.47) -0.04 (-0.94-0.85) 4.5-4.7 70.6 (12.3) 1.93 (0.89-2.97) 1.38 (0.41-2.36) 1.03 (0.05-2.00) -0.10 (-1.04-0.85) 4.8-5.0 71.5 (12.2) 2.42 (1.26-3.59) 2.00 (0.91-3.10) 1.46 (0.36-2.55) -0.37 (-1.44-0.71) > 5.1 75.2 (13.8) 5.53 (4.06-7.00) 5.14 (3.76-6.52) 4.22 (2.82-5.62) 1.28 (-0.09-2.66) 1-h PG (mmol/l) < 5.8 69.7 (11.2) - - - - 5.9-7.3 69.6 (11.8) 0.43 (-0.50-1.37) 0.64 (-0.24-1.52) 0.55 (-0.32-1.42) -0.05 (-0.88-0.79) 7.4-8.6 70.3 (12.3) 1.41 (0.42-2.39) 1.44 (0.52-2.37) 1.18 (0.25-2.11) 0.31 (-0.58-1.21) 8.7-9.9 71.4 (12.0) 2.73 (1.60-3.85) 2.63 (1.57-3.69) 2.33 (1.26-3.41) 1.02 (-0.02-2.06) > 10.0 72.4 (12.5) 3.21 (1.78-4.63) 3.08 (1.74-4.41) 2.66 (1.30-4.02) 1.46 (0.16-2.77) 2-h PG (mmol/l) < 5.0 69.5 (11.1) - - - - 5.1-6.0 70.8 (12.0) 1.82 (0.88-2.77) 1.54 (0.66-2.43) 1.43 (0.55-2.32) 0.54 (-0.31-1.39) 6.1-6.9 69.7 (11.9) 1.50 (0.51-2.49) 1.34 (0.41-2.28) 1.24 (0.30-2.17) 0.26 (-0.65-1.16) 7.0-8.4 70.4 (12.4) 2.57 (1.49-3.65) 2.24 (1.22-3.25) 1.97 (0.94-3.00) 0.98 (-0.01-1.97) > 8.5 72.8 (12.5) 4.70 (3.07-6.33) 4.36 (2.82-5.89) 3.83 (2.28-5.39) 2.49 (1.00-4.00) HbA1c Levels (mmol/mol) [%]

< 25 [< 4.4] 70.2 (11.0) - - - - 26-28 [4.5-4.7] 70.1 (11.3) 0.11 (-0.93-1.15) 0.43 (-0.56-1.41) 0.45 (-0.53-1.42) 0.16 (-0.77-1.10)

29-31 [4.8-5.0] 70.0 (12.4) 0.33 (-0.67-1.33) 1.57 (0.61-2.52) 1.42 (0.46-2.37) 0.46 (-0.45-1.38) 32-36 [5.1-5.4] 70.2 (12.2) 1.36 (0.05-2.67) 2.61 (1.35-3.87) 2.34 (1.07-3.61) 0.81 (-0.41-2.04) > 37 [> 5.5] 71.8 (13.2) 2.39 (0.59-4.18) 3.22 (1.53-4.91) 3.22 (1.53-4.91) 1.38 (-0.26-3.01)




ESM Table 12. Group Means and Adjusted Mean Differences for Child Sum of Skinfolds at Follow-Up by Maternal Levels of Glucose and HbA1c During Pregnancy

Sum of Skinfolds (mm)

Mean (SD)


Difference (95% CI)


Difference (95% CI)


Difference (95% CI)


Difference (95% CI)

Glucose Levels FPG (mmol/l) < 4.2 36.0 (18.9) - - - - 4.2-4.4 37.9 (20.8) 1.86 (-0.002-3.71) 1.47 (-0.36-3.30) 1.22 (-0.60-3.04) 0.29 (-1.49-2.07) 4.5-4.7 39.3 (21.5) 3.05 (1.11-4.98) 2.61 (0.70-4.52) 2.11 (0.19-4.03) 0.32 (-1.56-2.21) 4.8-5.0 41.3 (21.9) 4.97 (2.80-7.14) 4.41 (2.26-6.55) 3.59 (1.43-5.75) 0.68 (-1.46-2.82) > 5.1 46.3 (25.9) 9.68 (6.92-12.43) 10.00 (7.28-12.71) 8.69 (5.94-11.45) 4.00 (1.25-6.75) 1-h PG (mmol/l) < 5.8 37.1 (20.0) - - - - 5.9-7.3 37.5 (20.7) 0.24 (-1.50-1.98) 0.78 (-0.94-2.50) 0.59 (1.13-2.30) -0.38 (-2.05-1.29) 7.4-8.6 39.7 (21.3) 2.08 (0.25-3.91) 2.67 (0.86-4.48) 2.15 (0.32-3.97) 0.74 (-1.05-2.52) 8.7-9.9 42.5 (23.2) 4.66 (2.56-6.76) 4.74 (2.67-6.82) 4.09 (1.97-6.20) 1.94 (-0.13-4.02) > 10.0 43.7 (23.4) 5.51 (2.86-8.16) 5.79 (3.17-8.42) 4.93 (2.26-7.60) 2.98 (0.37-5.59) 2-h PG (mmol/l) < 5.0 36.1 (18.5) - - - - 5.1-6.0 39.2 (21.6) 3.05 (1.29-4.81) 2.97 (1.23-4.70) 2.77 (1.03-4.50) 1.32 (-0.38-3.01) 6.1-6.9 39.3 (21.6) 2.79 (0.93-4.64) 2.78 (0.95-4.62) 2.49 (0.64-4.34) 0.89 (-0.92-2.70) 7.0-8.4 40.8 (22.8) 4.17 (2.16-6.18) 4.30 (2.31-6.29) 3.68 (1.66-5.71) 2.07 (0.09-4.05) > 8.5 44.6 (23.2) 7.70 (4.65-10.75) 7.98 (4.98-10.99) 6.90 (3.85-9.95) 4.72 (1.74-7.70) HbA1c Levels (mmol/mol) [%]

< 25 [< 4.4] 36.3 (18.8) - - - - 26-28 [4.5-4.7] 38.2 (20.7) 1.83 (-0.11-3.77) 1.31 (-0.61-3.23) 1.32 (-0.59-3.22) 0.85 (-1.00-2.71) 29-31 [4.8-5.0] 39.7 (21.9) 2.61 (0.74-4.48) 2.80 (0.91-4.69) 2.48 (0.59-4.36) 0.92 (0.91-2.75)

32-36 [5.1-5.4] 41.2 (21.5) 3.95 (1.52-6.39) 4.39 (1.94-6.84) 3.82 (1.36-6.28) 1.33 (-1.09-3.75) > 37 [> 5.5] 44.9 (27.3) 7.92 (4.56-11.28) 8.12 (4.81-11.44) 7.49 (4.14-10.84) 4.48 (1.19-7.77)




ESM Figure 1

Frequencies of child a) overweight/obesity, b) obesity, c) percent bodyfat > 85th percentile, d) waist circumference > 85th percentile and e) sum of skinfolds > 85th percentile across categories of maternal fasting glucose (light orange lines), 1-h glucose (blue lines), 2-h glucose (red lines) and HbA1c (purple lines). Glucose categories are defined as follows: fasting plasma glucose level — category 1, less than 4.2 mmol per liter; category 2, 4.2 to 4.4 mmol per liter; category 3, 4.5 to 4.7 mmol per liter; category 4, 4.8 to 5.0 mmol per liter; category 5, 5.1 mmol per liter or more; 1-hour plasma glucose level — category 1, 5.8 mmol per liter or less; category 2, 5.9 to 7.3 mmol per liter; category 3, 7.4 to 8.6 mmol per liter; category 4, 8.7 to 9.9 mmol per liter; category 5, 10.0 mmol per liter or more; and 2-hr plasma glucose level — category 1, 5.0 mmol per liter or less; category 2, 5.1 to 6.0 mmol per liter; category 3, 6.1 to 6.9 mmol per liter; category 4, 7.0 to 8.4 mmol per liter; category 5, 8.5 mmol per liter or more. The key applies to all panels of the figure.

ESM Figure 2

Odds ratios and 95% confidence intervals in fully adjusted models including maternal BMI during pregnancy (Model 4) for child a) overweight/obesity, b) obesity, c) percent bodyfat > 85th percentile, d) waist circumference > 85th percentile and e) sum of skinfolds > 85th percentile for category 2 v. 1 (light orange lines), category 3 v. 1 (blue lines), category 4 v. 1 (red lines) and category 5 v. 1 (purple lines). Glucose categories are defined as follows: fasting plasma glucose level — category 1, less than 4.2 mmol per liter; category 2, 4.2 to 4.4 mmol per liter; category 3, 4.5 to 4.7 mmol per liter; category 4, 4.8 to 5.0 mmol per liter; category 5, 5.1 mmol per liter or more; 1-hour plasma glucose level — category 1, 5.8 mmol per liter or less; category 2, 5.9 to 7.3 mmol per liter; category 3, 7.4 to 8.6 mmol per liter; category 4, 8.7 to 9.9 mmol per liter; category 5, 10.0 mmol per liter or more; and 2-hr plasma glucose level — category 1, 5.0 mmol per liter or less; category 2, 5.1 to 6.0 mmol per liter; category 3, 6.1 to 6.9 mmol per liter; category 4, 7.0 to 8.4 mmol per liter; category 5, 8.5 mmol per liter or more. The key applies to all panels of the figure.

ESM Figure 3

Means of child a) BMI z-score, b) percent bodyfat, c) waist circumference and d) sum of skinfolds across categories of maternal fasting glucose (red lines), 1-h glucose (green lines), 2-h glucose (blue lines) and A1c (purple lines). Glucose categories are defined as follows: fasting plasma glucose level — category 1, less than 4.2 mmol per liter; category 2, 4.2 to 4.4 mmol per liter; category 3, 4.5 to 4.7 mmol per liter; category 4, 4.8 to 5.0 mmol per liter; category 5, 5.1 mmol per liter or more; 1-hour plasma glucose level — category 1, 5.8 mmol per liter or less; category 2, 5.9 to 7.3 mmol per liter; category 3, 7.4 to 8.6 mmol per liter; category 4, 8.7 to 9.9 mmol per liter; category 5, 10.0 mmol per liter or more; and 2-hr plasma glucose level — category 1, 5.0 mmol per liter or less; category 2, 5.1 to 6.0 mmol per liter; category 3, 6.1 to 6.9 mmol per liter; category 4, 7.0 to 8.4 mmol per liter; category 5, 8.5 mmol per liter or more. The key applies to all panels of the figure.

maternal glycemia during pregnancy and childhood adiposity

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