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Long‐term follow‐up of children with in utero exposure to sulfonylurea medications

Abstract Background Offspring born to mothers with gestational diabetes mellitus (GDM) are more likely to have negative neurodevelopmental health outcomes, early obesity, type 2 diabetes, and metabolic syndrome in childhood, adolescence, and adulthood. Standard of care management for GDM and type 2 diabetes mellitus during pregnancy is insulin, but oral sulfonylurea use is increasing, and these medications cross the placenta. Literature on treatment with sulfonylureas for maternal GDM has focused on maternal glycemic control and neonatal outcomes. Studies that have evaluated the long‐term outcomes of children exposed to sulfonylureas in utero are limited. Objective This study evaluated anthropometric and neurodevelopmental outcomes of 55 children (ages 5–10) born to mothers with diabetes during pregnancy treated with sulfonylurea or insulin. Methods and Results A group of 25 sulfonylurea‐exposed and 30 insulin‐exposed participants were age‐ and sex‐matched between groups. No significant differences were identified in z‐scores for body mass index (BMI), waist circumference, skinfold measurements, and body fat or rates of overweight/obese BMI between groups. On performance‐based cognitive assessment, the sulfonylurea‐exposed group had significantly lower scores on inhibition (p = 0.043). Conclusion In summary, children with in utero sulfonylurea exposure had similar physical measurements compared to children with insulin exposure and lower performance on a measure of executive function (inhibition), which is associated with adverse health outcomes.

style modifications, continued hyperglycemia warrants initiation of medical treatment. Though insulin is the only United States Food and Drug Administration-approved treatment for diabetes in pregnancy, sulfonylurea use has increased worldwide after data supporting adequate control in some women and absence of complications in their neonates. 13,18,19 Sulfonylurea use improves maternal satisfaction and adherence but has risks of maternal hypoglycemia, and the medications are known to cross the placenta and alter placental GLUT1 expression. [20][21][22] In utero exposure to sulfonylureas has been associated with increased incidence of neonatal hypoglycemia and large-for-gestational age (LGA) neonates as compared to insulin exposed. However, newer data indicate less concern for LGA, yet consistent higher rates of neonatal hypoglycemia among newborns exposed to sulfonylureas. 13,20,23,24 In addition to effects of GDM on NDH, neonatal hypoglycemia is associated with impaired neurological development in children, including delayed cognitive development as compared to normoglycemic neonates. 25 Importantly, poor NDH has been associated with adverse health outcomes, including obesity, perhaps due to impact on self-regulatory behavior. [26][27][28] The objective of this pilot study was to evaluate long-term effects of in utero sulfonylurea exposure by investigating the anthropometric and neurodevelopmental outcomes of 5-to 10-year-old children whose mothers were treated with sulfonylurea as compared to insulin.

| RESEARCH DESIGN AND METHODS
Children, ages 5-10 years old, who were born full-term to mothers with a diagnosis of GDM or T2DM treated with the oral sulfonylurea glyburide or glipizide for at least 4 weeks during gestation or insulin injections were recruited. Eligible participants were identified by the Northwestern Medicine Enterprise Data Warehouse of labor and delivery records, using search terms of: GDM, T2DM, insulin, sulfonylurea, glyburide, and glipizide. Children born to mothers treated with diabetes medications other than sulfonylurea or insulin, such as metformin, beyond the first prenatal visit were excluded. During the study visit, mothers provided written informed consent for review of their pregnancy medical record and for their child to participate and completed questionnaires. The study protocol was approved by the institutional review boards at Northwestern University and Lurie Children's Hospital of Chicago.
Children underwent anthropometric data collection, including height, blood pressure, skinfolds: triceps, subscapular, and suprailiac (Harpenden calipers), and air displacement plethysmography (BOD POD; Cosmed) for weight and body fat percentage. In children older than 9 years, a pubertal assessment was performed by a pediatric endocrinologist.
The child's BMI percentile for age, as well as weight category, was determined using the CDC database. Blood pressure percentiles were determined, 29 waist circumference z-scores were calculated using NHANES III LMS tables calculator, 30  Analysis included paired t-tests, chi-square test, and Analysis of variance (ANOVA) to identify differences in demographics, physical outcomes, and neuropsychological outcomes between groups. Table 1 displays the demographic data, as well as neonatal data, for the two study groups. Fifty-five children, 25 with in utero sulfonylurea exposure and 30 with mothers treated with insulin, participated in the study with a mean age of 7 years 8 months. There were five sets of siblings; children were from 49 unique mothers, 23 in the sulfonylurea group and 26 in the insulin group. There were similar numbers of mothers with GDM and T2DM in each group. The children in the sulfonylurea group had in utero exposure to sulfonylurea for a mean of 14.8 weeks (SD 9.5 weeks), with a range of 3-30.3 weeks and a median of 10.5 weeks (excluding missing data from two prenatal records). Race and age of the mothers were different between groups. The insulin group was 40% white as compared to the sulfonylurea group with 4% (p = 0.006), and the mean age at delivery was 33.6 years (SD 4.9) in the insulin group as compared to 28.2 years (SD 5.0) in the sulfonylurea group (p < 0.001). Children in the sulfonylurea group had lower median family income of $58,100 (SD $21,300) based on residential zip code as compared to the insulin group (mean $104,000, SD $57,200) (p < 0.001). More mothers in insulin group had education beyond high school (93.3%) compared to mothers in the sulfonylurea group (52%), yet this difference did not reach statistical significance (p = 0.077).

| RESULTS
Other demographic characteristics were similar.
Physical and neurodevelopmental outcomes of the two study groups are displayed in Table 2. Across the two groups, childhood characteristics were similar except more children of mothers treated with insulin required learning services, evaluated by survey where mothers reported whether their child at any time received schoolbased learning services (speech, occupational, and/or physical therapy). Learning services were received by 60% of children with insulin exposure as compared to 20.8% with sulfonylurea exposure (p = 0.018). With regard to physical outcomes, the groups did not differ in BMI, percentages of overweight or obese category, blood pressure, skinfold measurements, waist circumference, and body fat percent. T-scores were used for analyses (M = 50, SD = 10). T-scores at or above 65 are considered clinically significant and scores between 60 and 64 are interpreted as "mildly elevated." BMI, evaluated by z-score, was not different, with mean z-score of 0.75 (SD 1.26) for sulfonylurea-exposed as compared to mean of 0.55 (SD However, the average blood pressure and percentile did not differ between groups, with average blood pressures of 99/61 in sulfonylurea-exposed children as compared to 103/64 in the insulinexposed group. Mean body fat percentage was similar in sulfonylureaexposed children 21.9% (SD = 12.2) as compared to 20.7% (SD = 11.1) in children in the insulin group.
From review of delivery records, it was determined that the children with in utero sulfonylurea exposure had larger birth weight.
The mean neonatal weight in the sulfonylurea group was 3.65 kg (SD 0.53), with 40% categorized as LGA, as compared to mean of 3.29 kg (SD 0.46) and 3.3% LGA in the insulin group (p = 0.009 and p = 0.003, respectively). Notably, there were more small-for-gestational age neonates in the insulin-exposed group (N = 6 vs. N = 1 in sulfonylureaexposed group), though this difference was not statistically significant.
For the neuropsychological assessment, children underwent performance-based cognitive testing. Not all participants were able to complete all tasks, thus group numbers differed for each measure as indicated in Table 2. Sulfonylurea-exposed children had lower scores on an assessment of inhibition (NEPSY-II) with mean score of 8.1 (SD 3.6) compared to the insulin-exposed group with mean 10.6 (SD 4.2) (p = 0.043). The sulfonylurea-exposed group performed in the low average range and the insulin-exposed group performed in the average range on inhibition. No clinically or statistically significant differences were observed on the BRIEF-2, 32 a parent-report measure of executive function. Results from the BRIEF-2 indicated that both groups had average scores that fell in a normal (nonelevated) range.

| DISCUSSION
This study of children with in utero exposure to sulfonylureas as compared to insulin demonstrated differences in the neurodevelopmental outcome of executive function (inhibition), but no significant differences in anthropometric outcomes. To our knowledge, this is the first report of long-term outcomes in children with in utero sulfonylurea exposure. These findings are preliminary, yet important to consider when treating diabetes during pregnancy with sulfonylurea medication. Poor childhood NDH, especially poor inhibition, is associated with excess weight gain and other lifestyle risk behaviors, including medication adherence and risky behaviors. 27 In the present study, in which all children were exposed to mothers with diabetes, similar rates of overweight/obesity and adiposity in the children exposed to either sulfonylurea or insulin were documented. Sulfonylurea exposure has been associated with increased birthweight and LGA incidence, although rigorous glucose control has been demonstrated to reduce these outcomes. 13,20,23,24 While the increased LGA incidence in this cohort may represent inferior glucose control of mothers treated with sulfonylurea, there was no sufficient data on maternal glucose control to study this association. A number of studies have documented increased incidence of neonatal hypoglycemia among children exposed to sulfonylurea, 13,20 and while more children with sulfonylurea exposure in this study experienced neonatal hypoglycemia, the difference was not statistically significant.
Performance on an inhibition task was lower for the sulfonylurea-exposed group compared to the insulin-exposed group. While inhibition was reduced on a performance-based measurement, the BRIEF-2 parent-report questionnaire did not indicate executive function impairments in daily life activities. These questionnaires were completed from maternal perspective, without input from a variety of sources, particularly school. Moreover, the study was not powered to analyze neonatal hypoglycemia as an etiology of differences in the NDH outcomes.
This study is limited by retrospective design, demographic differences, and sample size. The retrospective design of the study increases confounding prenatal variables, including blood glucose control throughout pregnancy. Another limitation was the variable length of sulfonylurea treatment in the mothers, ranging from 3 to 30 weeks, with a median of 10.5 weeks. Most mothers who were treated with sulfonylurea received prenatal care at a Federally Qualified Health Center, lived in poorer neighborhoods, and many speak exclusively Spanish. These factors may affect cognitive development and outcomes on neurodevelopmental testing. 33 Whether RODENSTEIN ET AL. -491