Abstract
Background:
Maternal abnormal glucose tolerance during pregnancy may adversely affect offspring cognition and behaviour, but few prospective studies investigated this association at multiple points throughout childhood.
Objectives:
We hypothesized that maternal abnormal glucose tolerance is associated with child cognitive and behavioural outcomes in early and mid-childhood.
Methods:
We examined the associations of maternal abnormal glucose tolerance at 26–28 weeks of pregnancy with offspring cognitive and behavioural scores in 1,421 children in the Project Viva pre-birth cohort. In early (mean 3.3 years) and mid-childhood (mean 7.9 years), we measured child cognition using validated instruments, the Kaufman Brief Intelligence Test, Wide Range Assessment of Memory and Learning and the Wide Range Assessment of Visual Motor Abilities (WRAVMA); we assessed parent and teacher rated behavioural outcomes with the Strengths and Difficulties Questionnaire and the Behavioural Rating Inventory of Executive Function. We used linear regression models adjusted for potential confounders (maternal race/ethnicity, pre-pregnancy BMI, intelligence, age, parity, smoking status, education, and household income at enrolment, in addition to child’s sex and age at assessment).
Results:
Of 1421 mothers, 69 (4.9%) had gestational diabetes mellitus, 43 (3.0%) impaired glucose tolerance, 122 (8.6%) isolated hyperglycaemia, and 1187 (83.5%) normal glucose tolerance. Offspring born to women with gestational diabetes mellitus had lower total WRAVMA scores (−3.09 points; 95% CI −6.12, −0.05) in early childhood compared to offspring of women with normal glucose tolerance. None of the abnormal glucose tolerance categories during pregnancy were associated with any of the cognitive outcomes (verbal, nonverbal and visual motor scores) or behavioural measures in mid-childhood.
Conclusions:
Children born to mothers who had gestational diabetes mellitus had slightly lower scores on one cognitive test in early childhood. We found no evidence to support that maternal abnormal glucose tolerance was associated with cognitive or behavioural development in mid-childhood.
Keywords: Gestational Diabetes Mellitus, Maternal Abnormal Glucose Tolerance, Child Cognition, Child Behavioural Problems
Background
Maternal abnormal glucose tolerance is defined as hyperglycaemia diagnosed in the second or third trimester of pregnancy that was not overt diabetes prior to gestation.1 In 2015, approximately 20.9 million births worldwide were affected by gestational diabetes mellitus (GDM).2,3 In the US, GDM occurs in approximately 9% of women during pregnancy.4,5 Maternal abnormal glucose tolerance during pregnancy is associated with adverse maternal and offspring outcomes.6,7 For example, offspring exposure to hyperglycaemia during in utero development is associated with macrosomia and neonatal hypoglycemia,8 as well as risks for type 2 diabetes and metabolic syndrome.9–16 Exposure to maternal hyperglycaemia along the whole spectrum of glycemia, including levels lower than the clinical threshold used to diagnose GDM, has been associated with adverse outcomes in children. In prior reports from our Project Viva cohort, exposure to impaired glucose tolerance (IGT) was associated with an increase in foetal growth12, and the offspring of mothers with isolated hyperglycaemia (IH) presented a higher risk of eating in the absence of hunger in early adolescence and tended to show higher adiposity indices.16,17
Intrauterine exposure to abnormal glucose tolerance may adversely affect cognitive and behavioural development.18–20 Recent studies have explored the association of abnormal glucose tolerance with children cognition and behaviour, but data are relatively limited and findings are inconclusive, or conflicting.19,21,22 While the majority of studies in early childhood show that GDM is associated with lower offspring cognitive development,23–25 results in school-aged children are less clear. In a cohort study of 5,126 mother–child pairs, Fraser et al. found that children aged 8 years born to mothers with GDM had a lower verbal intelligence quotient (IQ) scores measured by the Wechsler Intelligence Scale for Children-Third Edition (WISC-III) than those born to controls.22 In contrast, in a study of 785 mother-child pairs, children (mean age 9.7 years) born to mothers with GDM had higher scores for learning, long-term retrieval/storage and verbal ability than those of non-GDM mothers.21 The studies used different instruments such as the Kaufman Assessment Battery for Children-Second Edition (KABC-II) or Kohs Block Design Test; this could contribute to inconsistency in results. Two systematic reviews19,26 found that the association of maternal diabetes during pregnancy with offspring development remains uncertain, and large prospective studies that address potential confounders are needed to assess whether there is an independent association. Many studies included in the these systematic reviews focused on preschool-aged children while few of them included follow-up into school age or beyond. Additionally, most studies19,21,22 focused on child cognition only, while behavioural development is rarely examined.20,27 Importantly, some studies reporting an association of abnormal glucose tolerance with child cognitive and behavioural problems failed to adjust for crucial confounders,19,23,28,29 notably maternal IQ.
In the present study, our goal was to examine the associations of abnormal glucose tolerance with several cognitive and behavioural outcomes in offspring measured in early and mid-childhood in a large prospective pre-birth cohort study. Specifically, we studied cognitive outcomes at two different ages to assess associations throughout childhood, including one test repeated over the two time periods.
Methods
Cohort
Project Viva is a prospective pre-birth cohort designed to investigate maternal and child health. From 1999 to 2002, we recruited women during their initial prenatal visit at eight participating obstetric offices at Atrius Harvard Vanguard Medical Associates, a multispecialty group practice in Eastern Massachusetts. The eligibility criteria were a singleton pregnancy, ≤22 weeks’ gestation at the time of enrolment, and the ability to answer questions in English. We have previously published details of the enrolment and follow-up of this cohort.30 Project Viva is registered on clinicaltrials.gov as NCT02820402. The institutional review board of Harvard Pilgrim Health Care approved this study protocol. All mothers provided written informed consent and children provided verbal assent.
Of 2,128 live births in Project Viva, we excluded the following from the present analysis: 16 children whose mothers had pre-gestational type 1 or type 2 diabetes mellitus, 45 mothers who had missing or incomplete records on glucose tolerance testing during pregnancy, and 646 children who had no cognitive and behavioural outcome data in early or mid-childhood (Figure 1). This left 1,421 mother-child pairs in the analysis sample (each analysis varied from 869 to 1,216 based on the availability of outcome data). Compared with the 1,421 included mothers, the 646 excluded mothers were younger (31.2 vs. 32.1 years), less educated (57% vs. 69% college graduates), had higher rates of smoking during pregnancy (17% vs. 11%), and had lower household incomes (53% vs. 60% >$70,000/year). Compared with the included mothers, the excluded mothers were less likely to have a normal glucose tolerance status (80% vs. 83%) and slightly more likely to have GDM (7% vs. 5%) (eTable 1). In eTable 2, we present glucose tolerance status and outcome distributions among participants with early childhood outcomes only, mid-childhood outcomes only, and both early and mid-childhood outcomes. The percentage of mothers with GDM was slightly higher among those with mid-childhood outcomes only (8%) vs. early childhood outcomes only (5%), or both early and mid-childhood outcomes (4%).
Figure 1.
Participants flow chart
Exposure
Maternal glucose tolerance testing
At 26–28 weeks of gestation, clinicians routinely screened all women for gestational diabetes mellitus (GDM) with a non-fasting 50g 1h oral glucose challenge test (GCT). If this test result was ≥140 mg/dl, the participant was referred for a 3h fasting 100g oral glucose tolerance test (OGTT). According to Carpenter-Coustan criteria,31 abnormal results are a blood glucose >95 mg/dl at baseline, >180 mg/dl at 1h, >155mg/dl at 2h, or >140 mg/dl at 3h. We categorized women with two or more abnormal glucose levels on the 3h-OGTT as having GDM, as recommended by the American Diabetes Association.32,33 We categorized those with one abnormal value on the 3h-OGTT as having gestational impaired glucose tolerance (IGT), those with an abnormal GCT but a normal OGTT as having isolated hyperglycaemia (IH), and those with normal GCT as having normal glucose tolerance (NGT), as previously done in Project Viva.12,16,17 Women who were diagnosed with GDM were typically followed by an endocrinologist and a nutritionist, instructed to check their finger stick blood sugars daily, and treated with diet, exercise, and in some cases insulin. Women with IGT or IH were generally clinically managed in the same way as women with normal glucose challenge test results.
Outcomes
Cognition
At an early childhood (mean age 3.3 years) research visit, Project Viva-trained research staff administered the Wide Range Assessment of Visual Motor Abilities test (WRAVMA).34 The WRAVMA test consists of three subtests: drawing (visual motor), pegboard (fine motor), and matching (visual spatial), which were analysed separately and combined to generate a total standard score.
At a mid-childhood (mean age 7.9 years) research visit, trained research staff administered cognitive tests: the Kaufman Brief Intelligence Test, Second Edition (KBIT-2),35,36 the Wide Range Assessment of Memory and Learning, second edition (WRAML2),37 and the drawing subtest of the WRAVMA,34 which are reliable, valid, and norms-based brief assessments of cognition for individuals aged 4–90 years with good internal consistency and test–retest reliability above 0.9.38 The KBIT-235 focuses on two distinct cognitive functions: verbal and nonverbal cognition. The verbal cognition test measures crystallized ability, which includes an individual’s vocabulary, depth, and breadth of general knowledge. The non-verbal cognition test includes a matrices subtest that measures fluid intelligence, which includes an individual’s ability to perceive relationships and complete visual analogies. The WRAML contains design memory and picture memory tests, which assesses visual memory. We summarized the two results (design memory and picture memory) for a total visual memory score. The WRAVMA drawing test, which we also conducted at an early childhood visit, assesses both fine motor skills and visuospatial perception. Scaled scores were standardized to mean=100, standard deviation (SD)=15 for the KBIT-2 and WRAVMA, and mean=10, SD=3 for WRAML2 design memory and picture memory sub-scores.34,37
Behavioural development
Behaviour problems
At the mid-childhood visit we asked mothers and classroom teachers to complete the Strengths and Difficulties Questionnaire (SDQ),39 a validated 25-item questionnaire that includes 5 sub-scales: prosocial, hyperactivity, emotional, conduct problem, and peer relationship problems. It is a valid and reliable measure of behaviour problems among children aged 4–16 with good internal consistency above 0.7. Possible scores range from 0 to 40 points. Higher SDQ scores indicate higher levels of behavioural problems, except for prosocial behaviours in which a higher score is favourable.
Assessment of executive function
To assess behavioural components of executive function, mothers and teachers completed the Behavioural Rating Inventory of Executive Function (BRIEF),40,41 a validated 86-item questionnaire with internal consistency and test-retest reliability all above 0.8, designed to assess executive function behaviours in children and adolescents aged 5–18 years with 8-subscales. We calculated 3 indices after scoring completed BRIEF questionnaires based on published guidelines: (1) the Behavioural Regulation Index (BRI) indicates the ability to shift cognitive set and modulate emotions and behaviour through appropriate inhibitory control, (2) the Metacognition Index (MI) reflects the child’s ability to initiate, plan, organize, and sustain future-oriented problem-solving in working memory, and (3) the Overall Global Executive Composite score (GEC), which combines the MI and BRI. Scores are standardized to a mean of 50, and higher scores represent poorer executive function.
Covariates
We obtained information on parent, household, and child characteristics by using a combination of self-administered questionnaires and interviews. At enrolment, mothers reported their pre-pregnancy weight and height, age, education, race/ethnicity, smoking during pregnancy, parity, and household income. During the mid-childhood follow-up visits, we measured maternal general IQ using the KBIT-2. We obtained child sex and date of birth from hospital records to calculate child age at each research visit.
Statistical Analysis
In the present study, we defined our main exposure as categories of maternal abnormal glucose tolerance during pregnancy (GDM, IGT, IH) compared to NGT. We also investigated glucose as a continuous exposure variable using maternal serum glucose level measured 1h after the non-fasting 50g-GCT: we use 1h-glucose (per IQR=34 mg/dl) as continuous variable.
The main early childhood cognitive outcome was WRAVMA scores. The main mid-childhood cognitive outcomes were KBIT-2 (verbal and nonverbal scores), WRAVMA drawing, and WRAML2 total visual memory scores. In mid-childhood we also examined parent and teacher-rated behavioural problems (SDQ total difficulties) and executive function (BRIEF Global Executive Composite score). Although some outcome scores had skewed distributions, model residuals were approximately normal and so we included them in their native, untransformed form to improve interpretability.
We used multivariable linear regression analyses to assess the associations of maternal abnormal glucose tolerance during pregnancy with child outcomes. We established three linear regression models. Model 1 was an unadjusted model that estimated mean differences in cognition scores and behaviour scores according to maternal abnormal glucose tolerance categories, with NGT as the reference category. For Model 2, we adjusted for maternal race/ethnicity, pre-pregnancy BMI, age, parity, smoking status, education, and household income at enrolment, in addition to child’s sex and age, which were associated with the outcomes or exposures or were considered important potential confounders based on previous literature.42,43 Finally, in Model 3 we additionally adjusted for maternal general IQ. We assessed potential effect modification by examining models stratified by sex and computed sex by abnormal glucose tolerance interaction p-values.
Sensitivity analysis
In a sensitivity analysis, we dichotomized the exposure as any abnormal glucose (GDM, IGT, or IH) vs. normal glucose.
Missing data
To minimize the loss of information and potential bias by missing data, we used chained equations to perform multiple imputation (MI) for all 2,128 mother-child pairs in Project Viva. We then limited the analysis to the 1,421 included participants with data available on exposures and outcomes. We included all exposures, outcomes, and covariates in the PROC MI model to generate 50 complete datasets. We used the fully conditional specification method (“FCS”) and the regression predictive mean matching method (“REGPMM”) to make the minimum to maximum of the imputed data equal to the minimum to maximum of the observed data. For categorical variables (e.g. race/ethnicity) we used dichotomous dummy variables. We combined multivariable modelling estimates by using PROC MIANALYZE in SAS version 9.4 (SAS Institute, Cary, NC). We used imputed values for covariates only (not for exposures and outcomes). In eTable 3, we presented the number of participants with non-missing values for each covariate before imputation. The sample size varied from 1,075 to 1,421.
Ethics approval
The institutional review board of Harvard Pilgrim Health Care approved this study protocol.
Results
We presented the characteristics of 1,421 included mother–child pairs at early and mid-childhood in Table 1. Among the mothers, the mean (SD) age at enrolment was 32.1 (5.2) years and mean (SD) pre-pregnancy BMI was 24.7 (5.2) kg/m2. The percentage of mothers with a college degree was 68.6%. Over half of the women (69.2%) were white and 60.4% reported household income >$70,000. Based on clinical oral glucose tolerance testing, 234 (16.5%) women were classified with some degree of maternal abnormal glucose tolerance: 69 (4.9%) had GDM, 43 (3.0%) had IGT, and 122 (8.6%) had IH. Women with abnormal glucose tolerance (IH, IGT, and GDM) were older and had higher pre-pregnancy BMI than women with NGT.
Table 1.
Characteristics of Project Viva participants overall and according to glucose tolerance categories
| Glucose tolerance categories | |||||
|---|---|---|---|---|---|
| Overall | Normal | Isolated hyperglycaemia | Impaired glucose tolerance | Gestational diabetes mellitus | |
| N=1421 | N=1187 (83.5%) | N=122 (8.6%) | N=43 (3.0%) | N=69 (4.9%) | |
| Maternal characteristics | |||||
| Age at enrolment, years, mean (SD) | 32.1 (5.2) | 31.9 (5.3) | 33.7 (4.6) | 32.8 (4.6) | 33.2 (4.1) |
| Pre-pregnancy BMI, kg/m2, mean (SD) | 24.7 (5.2) | 24.5 (5.2) | 25.1 (4.9) | 25.8 (4.4) | 27.5 (5.9) |
| 1h-glucose after GCT, mg/dl, mean (SD) | 113.6 (26.7) | 104.9 (17.8) | 154.1 (15.7) | 156.9 (15.6) | 167.3 (21.1) |
| IQ (KBIT-2 composite), points, mean (SD) | 106.5 (15.0) | 106.5 (14.6) | 109.5 (17.7) | 104.7 (14.1) | 102.0 (16.8) |
| Nulliparous, N (%) | 675 (47.5) | 573 (48.3) | 53 (43.4) | 16 (37.2) | 33 (47.8) |
| Education >= college degree, N (%) | 974 (68.6) | 813 (68.5) | 92 (75.4) | 25 (58.1) | 44 (63.8) |
| Race/ethnicity, N (%) | |||||
| . Black | 206 (14.5) | 174 (14.7) | 10 (8.2) | 8 (18.6) | 14 (20.3) |
| . Hispanic | 97 (6.8) | 76 (6.4) | 11 (9.0) | 4 (9.3) | 6 (8.7) |
| . White | 983 (69.2) | 824 (69.4) | 94 (77.0) | 26 (60.5) | 39 (56.5) |
| . Other | 135 (9.5) | 113 (9.6) | 7 (5.7) | 5 (11.6) | 10 (14.5) |
| Smoking status, N (%) | |||||
| . Never | 989 (69.6) | 830 (69.9) | 82 (67.2) | 32 (74.4) | 46 (66.1) |
| . Former | 281 (19.7) | 228 (19.2) | 32 (26.2) | 6 (14.0) | 14 (20.6) |
| . During pregnancy | 151 (10.6) | 129 (10.9) | 8 (6.6) | 5 (11.6) | 9 (13.3) |
| Household income >$70,000/year, N (%) | 859 (60.4) | 720 (60.6) | 75 (61.7) | 22 (51.7) | 41 (59.9) |
| Child characteristics | |||||
| Female, N (%) | 694 (48.8) | 579 (48.8) | 69 (56.6) | 16 (37.2) | 30 (43.5) |
| Early childhood | |||||
| Child age early childhood visit, years, mean (SD) | 3.3 (0.4) | 3.3 (0.4) | 3.3 (0.4) | 3.2 (0.3) | 3.3 (0.4) |
| Cognition scores, points, median (Q1 – Q3) | |||||
| Total WRAVMA standardized score | 103.0 (95.0–110.0) | 103.0 (95.0–110.0) | 105.0 (98.0–112.0) | 100.5 (95.0–108.0) | 97.0 (89.0–106.0) |
| WRAVMA drawing | 97.0 (89.0–105.0) | 97.0 (89.0–105.0) | 97.0 (95.0–105.0) | 97.0 (97.0–105.0) | 97.0 (89.0–105.0) |
| WRAVMA pegboard | 99.0 (92.0–105.0) | 99.0 (92.0–105.0) | 102.0 (95.0–105.0) | 99.0 (92.0–105.0) | 93.5 (84.0–102.0) |
| WRAVMA matching | 109.0 (98.0–119.0) | 109.0 (98.0–119.0) | 112.0 (105.0–119.0) | 103.5 (95.0–116.0) | 105.0 (92.0–113.0) |
| Mid-childhood | |||||
| Child age mid-childhood visit, years, mean (SD) | 7.9 (0.8) | 7.9 (0.8) | 7.8 (0.7) | 7.7 (0.7) | 8.0 (0.8) |
| Cognition scores, points, median (Q1 – Q3) | |||||
| KBIT-2 verbal test | 113.0 (102.0–123.0) | 113.0 (103.0–122.0) | 115.5 (104.0–126.0) | 112.0 (100.0–122.0) | 112.0 (98.0–124.0) |
| KBIT-2 nonverbal test | 108.0 (94.0–118.0) | 108.0 (95.0–118.0) | 108.0 (91.5–119.0) | 110.0 (98.5–121.5) | 108.0 (88.0–119.0) |
| WRAML2 visual memory standard score | 17.0 (14.0–20.0) | 17.0 (14.0–20.0) | 18.0 (15.0–21.0) | 16.5 (14.0–19.0) | 16.0 (14.0–19.0) |
| WRAVMA drawing standard score | 91.0 (80.0–104.0) | 91.0 (80.0–104.0) | 97.0 (80.0–107.0) | 88.0 (80.5–104.5) | 87.0 (84.0–99.0) |
| Behaviour problems or Executive function scores, points, median (Q1 – Q3) | |||||
| Parent-rated scores, points, median (Q1 – Q3) | |||||
| BRIEF Global Executive Composite | 48.0 (42.0–54.0) | 48.0 (42.0–54.0) | 47.5 (41.0–53.5) | 45.0 (41.0–51.0) | 49.0 (41.0–55.0) |
| Behavior Regulation Index score | 47.0 (42.0–53.0) | 47.0 (42.0–53.0) | 47.0 (42.0–54.0) | 45.5 (39.0–52.0) | 49.0 (40.5–54.0) |
| BRIEF Metacognition Index | 48.0 (42.0–53.0) | 48.0 (42.0–53.0) | 46.0 (42.0–53.0) | 45.5 (40.0–49.0) | 49.0 (41.0–55.0) |
| SDQ Total Difficulties | 6.0 (3.0–9.0) | 6.0 (3.0–9.0) | 5.0 (3.0–10.0) | 5.0 (4.0–8.0) | 6.0 (3.0–10.0) |
| Teacher-rated scores, points, median (Q1 – Q3) | |||||
| BRIEF Global Executive Composite | 48.0 (43.0–57.0) | 48.0 (43.0–57.0) | 45.0 (42.5–53.0) | 50.0 (45.0–54.0) | 51.0 (44.5–58.0) |
| Behavior Regulation Index score | 48.0 (44.0–55.0) | 47.5 (44.0–55.0) | 46.0 (43.0–55.0) | 48.0 (43.0–54.0) | 49.0 (44.0–55.5) |
| BRIEF Metacognition Index | 48.0 (43.0–57.0) | 48.0 (43.0–57.0) | 45.0 (42.0–51.5) | 49.0 (44.0–56.0) | 50.0 (44.0–60.0) |
| SDQ Total Difficulties | 5.0 (2.0–10.0) | 5.0 (2.0–10.0) | 4.0 (1.0–9.0) | 5.0 (1.0–8.0) | 7.0 (2.0–11.0) |
GCT, Glucose Challenge Test; IQ, Intelligence Quotient; BMI, Body Mass Index; BRIEF, Behavioral Rating Inventory of Executive Function; SDQ, Strengths and Difficulties Questionnaire; WRAML2, Wide Range Assessment of Memory and Learning, 2nd Edition; WRAVMA, Wide Range Assessment of Visual Motor Abilities; KBIT-2, Kaufman Brief Intelligence Test, 2nd Edition; Q, Quartile.
At early childhood, the mean (SD) age was 3.3 (0.4) years. Table 1 showed that offspring of mothers with GDM had lower median cognitive scores compared with those in the normal group for the total WRAVMA standardized score (97.0 vs. 103.0, overall range: 57.0–151.0), pegboard score (93.5 vs. 99.0, overall range: 60.0–155.0), and the matching score (105.0 vs. 109.0, overall range: 72.0–155.0) representing early childhood cognition. In mid-childhood at age of 7.9 (0.8) years, offspring of mothers with GDM, compared with those in the normal group, had slightly lower median scores for the KBIT-2 verbal scores (112.0 vs. 113.0, overall range: 44.0–147.0) and WRAVMA drawing standard scores (87.0 vs. 91.0, overall range: 45.0–155.0), as well as slightly higher (worse) BRIEF Global Executive Composite scores (parent report: 49.0 vs. 48.0, overall range: 30.0–88.0; teacher report: 51.0 vs. 48.0, overall range: 38.0–100.0) and teacher-rated SDQ Total Difficulties score (7.0 vs. 5.0, overall range: 0.0–31.0).
In Table 2, we presented the associations of maternal abnormal glucose tolerance categories (IH, IGT and GDM) with cognitive outcomes including total WRAVMA (drawing, pegboard and matching) in early childhood. In the adjusted Model 2, GDM exposure was associated with lower total WRAVMA standard scores (−3.28 points, 95% CI −6.32, −0.24). This association was attenuated with further adjustment for maternal IQ (−3.09 points, 95% CI −6.12, −0.05, Model 3), but confidence intervals continued to exclude the null. We observed similar patterns of association for the individual WRAVMA subscales in early childhood, but the effect sizes were reduced, and the confidence intervals included the null after adjusting for covariates. Given the small magnitude of difference between groups (< 6 points), the clinical meaning remains unclear as previous studies suggested that a difference of ≥ 6 points on child IQ score would be considered meaningful (for tool standardized to a mean of 100).44,45 For IH and IGT, we did not observe consistent associations with total WRAVMA and its subscales in early childhood. We did not find associations between maternal glucose post-GCT (using glucose values as continuous variable) and early childhood outcomes.
Table 2.
Associations of abnormal glucose tolerance during pregnancy with early childhood cognition
| Early childhood cognition | ||||
|---|---|---|---|---|
| Outcome | Total WRAVMA standardized score (drawing, pegboard, matching) | WRAVMA drawing | WRAVMA pegboard | WRAVMA matching |
| (N=1151) | (N=1216) | (N=1213) | (N=1172) | |
| Exposure | β (95% CI) | β (95% CI) | β (95% CI) | β (95% CI) |
| Normal glucose tolerance | 0.00 (reference) | 0.00 (reference) | 0.00 (reference) | 0.00 (reference) |
| Isolated hyperglycaemia | ||||
| Model 1 | 2.77 (0.47, 5.06) | 0.34 (−1.91, 2.59) | 2.47 (0.32, 4.63) | 3.37 (0.63, 6.11) |
| Model 2 | 1.86 (−0.33, 4.05) | −0.47 (−2.68, 1.73) | 1.90 (−0.24, 4.04) | 2.51 (−0.12, 5.15) |
| Model 3 | 1.74 (−0.45, 3.93) | −0.52 (−2.73, 1.68) | 1.86 (−0.28, 4.01) | 2.32 (−0.31, 4.95) |
| Impaired glucose tolerance | ||||
| Model 1 | −0.31 (−4.15, 3.54) | −1.14 (−4.78, 2.51) | −0.34 (−3.82, 3.15) | −1.44 (−6.06, 3.17) |
| Model 2 | 1.54 (−2.11, 5.20) | 0.47 (−3.10, 4.03) | 0.90 (−2.55, 4.35) | 0.56 (−3.86, 4.99) |
| Model 3 | 1.63 (−2.02, 5.28) | 0.51 (−3.05, 4.07) | 0.93 (−2.52, 4.39) | 0.68 (−3.72, 5.09) |
| Gestational diabetes mellitus | ||||
| Model 1 | −4.68 (−7.85,−1.52) | −3.79 (−6.90,−0.69) | −3.39 (−6.34,−0.44) | −4.02 (−7.78,−0.25) |
| Model 2 | −3.28 (−6.32,−0.24) | −3.00 (−6.05, 0.05) | −2.57 (−5.50, 0.36) | −2.47 (−6.11, 1.17) |
| Model 3 | −3.09 (−6.12,−0.05) | −2.91 (−5.97, 0.14) | −2.53 (−5.46, 0.41) | −2.25 (−5.88, 1.38) |
| 1h-glucose after GCT (per IQR=34 mg/dl) | ||||
| Model 1 | −0.50 (−1.34, 0.34) | −0.77 (−1.58, 0.05) | −0.30 (−1.08, 0.48) | −0.07 (−1.07, 0.93) |
| Model 2 | −0.24 (−1.05, 0.57) | −0.58 (−1.39, 0.23) | −0.15 (−0.94, 0.63) | 0.17 (−0.80, 1.14) |
| Model 3 | −0.21 (−1.02, 0.60) | −0.56 (−1.38, 0.25) | −0.14 (−0.93, 0.64) | 0.21 (−0.76, 1.17) |
Model 1 = Unadjusted
Model 2 = Adjusted for maternal race/ethnicity, pre-pregnancy BMI, age, parity, smoking status, education, and household income at enrolment, in addition to child’s sex and age at early childhood assessment
Model 3 = Model 2 + maternal IQ
GCT, Glucose Challenge Test; WRAVMA, Wide Range Assessment of Visual Motor Abilities; IQR, Interquartile Range; β, Coefficient; CI, Confidence Interval.
In mid-childhood, we did not find associations between exposure to maternal abnormal glucose tolerance categories and any of the cognition scores (verbal, nonverbal and visual motor) (Table 3). Specifically, we did not observe associations of maternal abnormal glucose tolerance with WRAVMA, KBIT-2, and WRAML-2 scores at mid-childhood. Moreover, we did not observe any clinically meaningful difference between exposure groups and the NGT group. In our continuous model using maternal glucose post-GCT, our estimates were close to the null (eTable 4).
Table 3.
Associations of abnormal glucose tolerance during pregnancy with mid-childhood cognition
| Outcome | KBIT-2 verbal test | KBIT-2 nonverbal test | WRAML2 visual memory | WRAVMA drawing |
|---|---|---|---|---|
| (n=1085) | (n=1095) | (n=1089) | (N=1085) | |
| Exposure | β (95% CI) | β (95% CI) | β (95% CI) | β (95% CI) |
| Normal glucose tolerance | 0.00 (reference) | 0.00 (reference) | 0.00 (reference) | 0.00 (reference) |
| Isolated hyperglycaemia | ||||
| Model 1 | 2.40 (−0.79, 5.58) | −1.38 (−4.95, 2.19) | 0.99 (0.06, 1.91) | 2.95 (−0.58, 6.48) |
| Model 2 | 0.33 (−2.44, 3.10) | −2.33 (−5.82, 1.16) | 0.77 (−0.15, 1.70) | 2.53 (−1.01, 6.06) |
| Model 3 | 0.16 (−2.54, 2.85) | −2.48 (−5.92, 0.97) | 0.76 (−0.17, 1.68) | 2.48 (−1.05, 6.02) |
| Impaired glucose tolerance | ||||
| Model 1 | 0.74 (−4.37, 5.85) | 1.44 (−4.21, 7.10) | −0.05 (−1.51, 1.42) | 0.53 (−5.03, 6.09) |
| Model 2 | 2.21 (−2.22, 6.63) | 2.79 (−2.71, 8.29) | 0.17 (−1.29, 1.63) | 1.41 (−4.14, 6.96) |
| Model 3 | 2.35 (−1.95, 6.65) | 2.72 (−2.71, 8.15) | 0.16 (−1.29, 1.62) | 1.39 (−4.16, 6.93) |
| Gestational diabetes mellitus | ||||
| Model 1 | −0.82 (−5.09, 3.45) | −0.86 (−5.66, 3.93) | 0.12 (−1.13, 1.38) | −1.09 (−5.81, 3.62) |
| Model 2 | 0.30 (−3.44, 4.04) | −0.33 (−5.04, 4.37) | 0.23 (−1.02, 1.49) | 0.20 (−4.55, 4.95) |
| Model 3 | 0.98 (−2.65, 4.62) | 0.24 (−4.42, 4.89) | 0.29 (−0.97, 1.54) | 0.39 (−4.36, 5.13) |
| 1h-glucose after GCT (per IQR=34 mg/dl) | ||||
| Model 1 | 1.03 (−0.11, 2.17) | −0.03 (−1.30, 1.24) | 0.14 (−0.19, 0.48) | −0.07 (−1.32, 1.19) |
| Model 2 | 0.69 (−0.31, 1.70) | −0.17 (−1.44, 1.09) | 0.15 (−0.19, 0.49) | 0.13 (−1.14, 1.41) |
| Model 3 | 0.81 (−0.17, 1.79) | −0.08 (−1.33, 1.17) | 0.16 (−0.18, 0.50) | 0.17 (−1.11, 1.44) |
Model 1 = Unadjusted
Model 2 = Adjusted for maternal race/ethnicity, pre-pregnancy BMI, age, parity, smoking status, education, and household income at enrolment, in addition to child’s sex and age at early childhood assessment
Model 3 = Model 2 + maternal IQ
KBIT-2, Kaufman Brief Intelligence Test, 2nd Edition; WRAML2, Wide Range Assessment of Memory and Learning, 2nd Edition; WRAVMA, Wide Range Assessment of Visual Motor Abilities; GCT, Glucose Challenge Test; IQR, Interquartile Range; β, Coefficient; CI, Confidence Interval.
We did not find an association between maternal abnormal glucose tolerance categories during pregnancy and behavioural problems as reported by parent or teacher-rated SDQ total difficulties scores in mid-childhood for either total score (Table 4) or SDQ sub-scales (prosocial, hyperactivity, emotional, conduct problem and peer relationship problems – data shown in eTable 5 and eTable 6). Likewise, children exposed to maternal abnormal glucose tolerance have similar executive function scores (parent or teacher-rated BRIEF Global Executive Composite score) of controls. For continuous exposure to maternal hyperglycaemia post-GCT, the results were consistently null.
Table 4.
Associations of abnormal glucose tolerance during pregnancy with mid-childhood parent and teacher rated behaviour problems and executive function
| Outcome | Behaviour problems (SDQ Total Difficulties) | Executive function (BRIEF Global Executive Composite) | ||
|---|---|---|---|---|
| Parent rated | Teacher rated | Parent rated | Teacher rated | |
| (n=1174) | (n=892) | (n=1157) | (n=869) | |
| Exposure | β (95% CI) | β (95% CI) | β (95% CI) | β (95% CI) |
| Normal glucose tolerance | 0.00 (reference) | 0.00 (reference) | 0.00 (reference) | 0.00 (reference) |
| Isolated hyperglycaemia | ||||
| Model 1 | 0.03 (−0.96, 1.01) | −0.68 (−2.07, 0.72) | −0.32 (−2.24, 1.59) | −1.81 (−4.36, 0.73) |
| Model 2 | 0.38 (−0.57, 1.33) | −0.26 (−1.61, 1.08) | −0.16 (−2.08, 1.75) | −0.87 (−3.26, 1.52) |
| Model 3 | 0.39 (−0.57, 1.34) | −0.25 (−1.60, 1.09) | −0.19 (−2.11, 1.72) | −0.86 (−3.25, 1.53) |
| Impaired glucose tolerance | ||||
| Model 1 | −0.64 (−2.27, 0.99) | −0.87 (−2.98, 1.24) | −2.23 (−5.36, 0.90) | −1.19 (−5.03, 2.64) |
| Model 2 | −1.01 (−2.59, 0.57) | −1.40 (−3.43, 0.63) | −2.78 (−5.89, 0.34) | −0.79 (−4.40, 2.81) |
| Model 3 | −1.01 (−2.59, 0.57) | −1.40 (−3.43, 0.63) | −2.79 (−5.90, 0.33) | −0.79 (−4.40, 2.81) |
| Gestational diabetes mellitus | ||||
| Model 1 | 0.39 (−0.86, 1.65) | 0.77 (−1.17, 2.70) | 0.13 (−2.36, 2.61) | 1.28 (−2.24, 4.80) |
| Model 2 | 0.03 (−1.19, 1.25) | 0.32 (−1.58, 2.21) | −0.42 (−2.91, 2.06) | 0.14 (−3.20, 3.49) |
| Model 3 | 0.02 (−1.21, 1.24) | 0.30 (−1.59, 2.20) | −0.38 (−2.86, 2.11) | 0.13 (−3.22, 3.47) |
| Continuous glucose after GCT (per IQR=34 mg/dl) | ||||
| Model 1 | 0.02 (−0.33, 0.36) | 0.05 (−0.44, 0.54) | −0.20 (−0.88, 0.47) | −0.40 (−1.29, 0.49) |
| Model 2 | 0.04 (−0.30, 0.38) | −0.04 (−0.52, 0.45) | −0.25 (−0.93, 0.44) | −0.28 (−1.13, 0.58) |
| Model 3 | 0.04 (−0.30, 0.38) | −0.04 (−0.53, 0.45) | −0.24 (−0.93, 0.44) | −0.28 (−1.14, 0.58) |
Model 1 = Unadjusted
Model 2 = Adjusted for maternal race/ethnicity, pre-pregnancy BMI, age, parity, smoking status, education, and household income at enrolment, in addition to child’s sex and age at early childhood assessment
Model 3 = Model 2 + maternal IQ
BRIEF, Behavioral Rating Inventory of Executive Function; SDQ, Strengths and Difficulties Questionnaire; GCT, Glucose Challenge Test; IQR, Interquartile Range; β, Coefficient; CI, Confidence Interval
For all analyses, we tested potential effect modification by sex. There was no evidence of effect modification by sex, thus we presented only overall results.
Comment
Principal findings
The goal of this study was to examine the associations of maternal abnormal glucose tolerance during pregnancy (categorized as IH, IGT and GDM) with cognitive and behavioural outcomes in offspring in early and mid-childhood. GDM was associated with lower total WRAVMA scores in early childhood, but the difference between groups was small and may not be considered clinically meaningful.44,45 We did not find associations of maternal abnormal glucose tolerance in pregnancy with children’s cognitive (verbal, nonverbal and visual motor) and behavioural development (parent or teacher-rated behaviour and executive functioning problems) later in mid-childhood.
Strengths of the study
The strengths of our study include the prospective longitudinal design and the large population-based sample. We also used validated instruments to assess cognitive outcomes, and both teachers and parents completed multiple behavioural rating scales to account for different settings.
Limitations of the data
Women recruited into our study were generally well educated and from a single health system in Massachusetts; therefore, results may not be generalizable to other populations. Although the overall sample size was large, the number of pregnant women in each of the abnormal glucose tolerance groups may not have been sufficient enough to detect small associations. In addition, more severe insulin dependent GDM might potentially be associated with children’s cognition and behaviour; this would warrant the consideration of future studies. Some mother-child pairs were lost to follow-up before early or mid-childhood assessments. We observed some demographic differences between those with and without outcome data; this selection effect towards higher socioeconomic status might have reduced the variation in outcomes and contributed to the negative findings. We measured maternal glycaemia at 26–28 weeks during pregnancy only; additional measures of glycaemia at other time-points during pregnancy would have been informative and may have helped to observe “critical window” of exposure during pregnancy. We assessed many components of cognitive and behavioural problems at two points in time during childhood, yet only one test was repeated at the two times, limiting longitudinal assessment of outcomes measures.
Interpretation
Animal studies provided mechanistic evidence for the postulated association that maternal hyperglycaemia may affect the cognitive and behavioural development of offspring via in utero exposure to high or fluctuating concentrations of glucose.46,47 Our results regarding the association of GDM on the total WRAVMA score in early childhood are in line with these studies and confirm results from some epidemiologic human studies observing worst cognitive outcomes in early childhood.19 Differences in other cognitive tests at this age showed a consistent direction, but all were of small magnitude with unclear clinical meaningfulness.23–25
In our study, we followed children from early to mid-childhood. During this later period, cognition and executive functioning can be assessed more reliably and assessments are considered predictive of later school and occupational achievements.48 However, in older children, we did not observe associations between GDM and cognitive development. Importantly, only the WRAVMA drawing test was measured repeatedly in this study. In 2016, Adane et al. published a systematic review of 14 studies19, which concluded that there is good evidence for an association between GDM exposure and lower IQ scores in children under the age of 5 years, but that this relationship was less consistent in older children and adult offspring.19,49 For example, in a retrospective cohort49 of 271 individuals (including 153 in the GDM exposed group and 118 in the control group from background population) with 18 to 27-year-old offspring of women with diet-treated GDM and controls, there was no difference in global cognitive function scores.
There are potential explanations why an association observed in young children may be attenuated or disappear by mid-childhood. With older age, a child experiences more environmental influences that may compensate any cognitive problems occurring earlier in life. Adane et al. suggested that children learn compensatory behavioural mechanisms that help them overcome cognitive problems.19 Alternatively, different environmental factors in childhood may reduce the effect of exposure to abnormal glucose tolerance levels in utero.50 Another possible explanation is based on the heritability of cognitive development including attention and memory.51,52 Studies showed that the heritability of cognition depended on the developmental period (it increases from around 40% in early childhood to over 80% in elders), reflecting increasing active gene-environment correlation as positive feedback loops (e.g. brighter children seek more cognitive stimulation).53 Therefore, we postulate that as children get older, differences in cognition between children of mothers with and without GDM diminish and may largely disappear.
While previous studies mostly focused on associations between maternal diabetes and child’s cognition,54–56 few investigated behavioural problems.20,57 Our null findings are consistent for both cognition and behavioural problems in mid-childhood. We carefully measured aspects of children’s cognition and behaviour using validated instruments and included objective measures by using teachers’ reports. Our study did not support associations between maternal abnormal glucose tolerance and cognitive and behavioural problems in mid-childhood.
Conclusions
In this pre-birth cohort, we found that GDM tested at 26–28 weeks of gestation was associated with lower children’s cognition in early childhood, but only in one sub-scale of our evaluation and with a small effect size. We did not find evidence that maternal abnormal glucose tolerance in pregnancy was associated with child cognitive and behavioural development at mid-childhood, suggesting that early effects may attenuate. Maternal hyperglycaemia is thus unlikely to meaningfully affect cognitive development and behavioural performance after early childhood.
Supplementary Material
Social media quote.
Children born to mothers who had abnormal glucose tolerance in pregnancy were found to have slightly lower scores on one cognitive test in early childhood. We did not find evidence that maternal abnormal glucose tolerance in pregnancy was associated with child cognitive and behavioural development in mid-childhood.
Synopsis.
Study question
Is maternal abnormal glucose tolerance in pregnancy associated with offspring cognition and behaviour in early and mid-childhood?
What is already known
Current evidence suggests that exposure to maternal hyperglycaemia in pregnancy is associated with lower cognitive development in early childhood, but studies are contradictory concerning cognitive outcomes later in childhood. No study has repeatedly assessed a population in early and mid-childhood, and few studies have investigated child behavioural problems.
What this Study Adds
The study examines the associations of abnormal maternal glucose tolerance with child cognition and behaviour from early to mid-childhood and provides some evidence that maternal abnormal glucose tolerance (defined as gestational diabetes, impaired glucose tolerance, and isolated hyperglycaemia) is not associated with children’s cognition and behaviour past early childhood.
Acknowledgements:
We thank the participants and staff of Project Viva.
Funding source:
This study was supported by the National Institutes of Health (grant number R01 HD034568, and UH3OD023286).
Footnotes
Conflicts of Interest: The authors report no conflict of interest.
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