Maternal preexisting type 1, type 2, or gestational diabetes diagnosed relatively early in pregnancy are associated with increased risk for autism spectrum disorders (ASDs) in offspring.1,2 This study extends previous observations by examining the association between maternal hemoglobin A 1c (HbA 1c ) levels during pregnancy and risk of ASD in offspring.

Methods

This retrospective cohort study included singleton children born at 28 to 44 weeks’ gestation in Kaiser Permanente Southern California (KPSC) hospitals between January 1, 2012, and December 31, 2013. KPSC implemented HbA 1c screening in the early prenatal period for all pregnancies starting in 2012. Children who enrolled as KPSC health plan members at age 1 year were tracked through electronic medical records until the first of the following: (1) clinical diagnosis of ASD with at least 1 diagnostic code, (2) last date of continuous KPSC membership, (3) death, or (4) study end date of December 31, 2017. The KPSC institutional review board approved this study and provided waiver of participant consent.

The last HbA 1c level in the first 2 trimesters of pregnancy was obtained from the electronic laboratory database. HbA 1c was analyzed as a continuous variable and a categorical variable classified as less than 5.7%, 5.7% to 5.9%, 6.0% to 6.5%, and greater than 6.5%. Methods to identify ASD were previously described.1,2 Cox regression was used to estimate hazard ratios of ASD associated with HbA 1c exposure. Kaplan-Meier plots were used to display the crude cumulative incidences of ASD by the HbA 1c categories. Potential confounders listed in the Table footnote “a” were evaluated. Interaction with gestational age at HbA 1c testing was also assessed. SAS Enterprise Guide version 7.1 (SAS Institute Inc) was used for data analysis. A 2-sided P < .05 was considered significant.

Results

A total of 35 819 mother-infant pairs (51% boys) met the study criteria with complete HbA 1c and covariate information. The maternal mean (SD) age was 30.9 (5.6) years; the mean (SD) prepregnancy body mass index (calculated as weight in kilograms divided by height in meters squared) was 27.2 (6.4); and 51% were Hispanic, 24%, white, 7%, black, 14%, Asian/Pacific Islander, and 3%, other. The median gestational age at HbA 1c testing was 9.0 weeks (interquartile range, 6.7-11.4 weeks); 83% of the testing was in the first trimester. The median HbA 1c level was 5.4% (interquartile range, 5.2%-5.6%); 84.9% of pregnancies had HbA 1c levels less than 5.7%, 11.7% between 5.7% and 5.9%, 2.4% between 6.0% and 6.5%, and 1% greater than 6.5%. A total of 99% of women with HbA 1c levels greater than 6.5% had diabetes during pregnancy (Table footnote “c”).

Children were followed up for a median of 4.5 years (interquartile range, 4.0-5.0 years) after birth, during which time 707 (2.0%) had a clinical diagnosis of ASD. In the multivariable analysis, none of the potential confounders changed the model estimates by more than 10% except for maternal prepregnancy body mass index and race/ethnicity. After adjusting for these variables, the hazard ratio of ASD associated with each 1% increase of HbA 1c level was 1.12 (95% CI, 0.96-1.31; P = .15) for the continuous measure and 1.08 (95% CI, 0.87-1.35; P = .46) for HbA 1c level between 5.7% and 5.9%, 0.79 (95% CI, 0.48-1.28; P = .33) for HbA 1c level between 6.0% and 6.5%, and 1.79 (95% CI, 1.06-3.00; P = .03) for HbA 1c level greater than 6.5% relative to HbA 1c level less than 5.7% (Table; Figure). The risk associated with HbA 1c levels did not vary by gestational age at HbA 1c testing (P > .19 for interaction).

Discussion

In this study, there was no association between maternal HbA 1c levels during early pregnancy and ASD in offspring when HbA 1c levels were analyzed as a continuous variable or as a categorical measure if less than 6.5%. An association with HbA 1c levels greater than 6.5% was found but was based on only 15 affected children. These findings are consistent with previous observations and the preconception counseling recommendation to optimize glycemic control with HbA 1c levels greater than 6.5%.3

These results suggest that maternal glycemic control in early pregnancy may be important for ASD risk in offspring. Study limitations include the lack of information on maternal glycemic control throughout pregnancy, other prenatal and early life risk factors, paternal risk factors, and genetic factors as well as the relatively small sample size for pregnancies with HbA 1c levels greater than 6.5%.

Section Editor: Jody W. Zylke, MD, Deputy Editor.

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Accepted for Publication: May 30, 2019.

Corresponding Author: Anny H. Xiang, PhD, Department of Research & Evaluation, Kaiser Permanente Southern California, 100 S Los Robles Ave, Fifth Floor, Pasadena, CA 91101 (anny.h.xiang@kp.org).

Published Online: June 9, 2019. doi:10.1001/jama.2019.8584

Author Contributions: Dr Xiang and Ms Chow 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.

Concept and design: Xiang, Buchanan, Feldman.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Xiang.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Xiang, Chow, Getahun, Feldman.

Obtained funding: Xiang.

Administrative, technical, or material support: Xiang, Martinez, Page.

Supervision: Xiang.

Conflict of Interest Disclosures: None reported.

Funding/Support: This work was partially supported by Kaiser Permanente Southern California Direct Community Benefit funds.

Role of the Funder/Sponsor: The sponsor had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The opinions expressed are solely the responsibility of the authors and do not necessarily reflect the official views of the Kaiser Permanente Community Benefit Funds.

Meeting Presentation: This study was presented at the American Diabetes Association 79th Scientific Session; June 9, 2019; San Francisco, California.