Carbohydrate intolerance is the medical complication that most often complicates pregnancy. The most common type is gestational diabetes (GDM) (2-32%). Unlike GDM, Type-1-diabetes is present before pregnancy, and is much less frequent (0.2-1%), and much more serious. Moreover, Type-1diabetes is not related to maternal age or obesity, as GDM (1).

Cognitive and psychomotor impairments, as well as lower intelligence quotient scores, have been observed in infants exposed to maternal diabetes, and these effects may persist into adolescence (2). Maternal hyperglycemia is thought disrupt fetal brain development through pathways involving neuroinflammation, oxidative stress, nutrients and hormone delivery, and epigenetic modifications. Optimal glycemic control during pregnancy is associated with reduced incidence and severity of these complications (3).

Epigenetics refers to heritable changes in gene function that occur without altering the underlying DNA sequence. During fetal development, epigenetic processes are crucial. They orchestrate tissue-specific gene expression, cellular differentiation, and overall developmental programming in response to both genetic predispositions and external conditions, including the intrauterine metabolic environment (4).

Accumulating evidence suggests that GDM triggers epigenetic changes in fetal DNA associated with an increased risk for metabolic and cardiovascular diseases, and neurologic disorders, in childhood and adult life. These epigenetic modifications have been identified in multiple tissues, including placenta, cord blood, and amniocytes (5).

To the best of our knowledge, the relationship between the neurodevelopment of infants exposed to maternal Type-1 diabetes (IMT1-diabetes) and changes in fetal DNA methylation has not yet been investigated. The only study conducted has exclusively assessed changes related to cardiovascular and metabolic diseases in offspring (6). Epigenetic marks could potentially serve as biomarkers for early intervention strategies in newborns at high risk for neurological disorders.

Our aim was to determine if the neurodevelopmental outcomes of offspring from mothers with Type-1 diabetes are associated with intrauterine epigenetic changes in fetal DNA. Given that, no previous studies have explored this specific association, we designed this pilot study as a hypothesis-generating analysis.

This is a prospective, hypothesis-generating pilot case-control study that included 10 IMT1-diabetes and 10 infants of healthy mothers (IHM) recruited at the University Hospital of Canary Islands, Spain, between June 2021 and January 2024. Pregnant women were matched 1:1 using a nearest neighbor based on pre-pregnancy BMI, stratified according to the World Health Organization (WHO) categories, and race/ethnicity. This case-control design was fundamental for establishing a physiological baseline to isolate maternal T1D-specific effects from standard population variations.

Inclusion criteria were: Singleton gestation, absence of maternal pathology, mode of delivery (vaginal or elective cesarean section under regional anesthesia), absence of medical or obstetrics complications and of toxic habits (tobacco, drug abuse, other medication than insulin), and gestational-age >37 weeks. Exclusion criteria: Birthweight of IHM <10^th or >90^th percentile, according to customized birthweight curves (7), congenital malformations, chromosomal abnormalities and admission to neonatal unit for special care. Normal glucose tolerance of healthy mothers was ensured according to the NDDG criteria (8). HbA1c-levels were determined in mothers with type1-diabetes throughout the pregnancy.

This study was conducted in accordance with the Declaration of Helsinki and was approved by the Clinical Ethics Committee of the Canary Islands University Hospital Complex, Spain (CHUC-201817). All mothers signed a written consent forms.

Maternal characteristics and perinatal outcomes are shown in Table 1. The mean glycated hemoglobin values were 6.9% ± 1.2 SDs; 6.5% ± 1.3 SDs and 6.6% ± 1.0 SDs, in the first, second and third trimester, respectively. Non obstetric or perinatal complications were recorded.

This hypothesis-generating pilot study provides the first evidence of an association between neurodevelopmental alterations in offspring of mothers with Type 1 Diabetes and epigenetic changes detected in umbilical cord blood at birth. Children in the IMT1-Diabetes group scored significantly lower across the cognitive, language, and motor domains of the Bayley-III Scales. Importantly, we found that methylation values within DMRs annotated to ten crucial genes for neurodevelopment and brain function correlated significantly with these domain scores. The enrichment analysis confirmed that DMR-containing genes were significantly overrepresented in key neurological pathways, such as, Synaptogenesis, Neurogenesis Vocal, and Observational learning and Imitative learning. The largest methylation differences were concentrated in the neurodevelopmental genes MYT1L, NRXN1, and SHANK3. Both, NRXN1 and SHANK3, were enriched across all identified neurodevelopmental pathways, and, notably, NRXN1 and MYT1L showed significant correlation with the Bayley-III language domain score.

Arabiat et al. (18) in 2024 utilized the Bayley Scales to demonstrate an association between maternal Diabetes and poorer mental and motor skill outcomes in children aged 12–24 months. We have previously observed abnormal neurodevelopment features in video-EEG recording of infants of mothers with GDM and Type 1 Diabetes (19), difficulties in establishing stable behavioral states (20) and lower memory and learning abilities, both in utero and after birth (21). Levels of glycosylated hemoglobin were associated with the observed neurodevelopmental alterations (19–21). In the present study, birth weight, and the rate of large-for-gestational-age newborns, were significantly higher in the IMT1-diabetes group, objectively confirming the provided effect of maternal hyperglycemia on intrauterine growth (22).

To date, the few existing studies examining the link between intrauterine DNA methylation changes and subsequent neurodevelopmental outcomes in children have focused exclusively on GDM, not Type 1 Diabetes. Recently (2025), Wang et al. (23) demonstrated in rodent models that high glucose exposure alters DNA methylation and gene expression in neural progenitor cells. These alterations affected pathways critical for neurogenesis, axon guidance, and synaptic development, which provides a plausible biological basis for the observed neurodevelopmental impairment and aligns with the findings of our study.

Severe overlaps were observed between genes with DMRs that we identified in cord blood samples of IMT1-Diabetes and those reported in prior epigenetic studies of placental samples of pregnant women with GDM: NRXN1 and PRDM16 overlapped with genes reported Wang et al. (24), but they did not find any enriched pathway accounting for 256 differentially methylated genes that identified. ABLIM1 and SASH1 overlapped with genes identified by Chen et al. (25). In addition, SHANK3 and GRIK4 were differentially methylated in both our cord blood cohort and the placental cohort studied by Lu et al. (26). None of these prior studies assessed the correlation between the identified methylation changes and the subsequent neurodevelopment of the children. Also, in placental samples (but not those from pregnancies complicated by diabetes), Diez-Ahijado et al. (27) in 2024 are the sole investigators to have reported an association between methylation levels in DMRs annotated to four neurological development genes and cognitive development in children. One of these, MECOM, was also identified in our analysis. However, the enrichment analysis of all DM genes they identified did not reveal associations with neurological development pathways, a finding that contrast with the clear demonstration achieved in our study.

Our analysis identified 28 genes with annotated DMRs in the IMT1-diabetes group that overlapped with genes associated with ASD, according with the SFARI database (15). A large 2024 epigenome-wide association meta-analysis by Schuurmans et al. (28) identified DNA methylation differences associated with ASD using polygenic scores on cord blood DNA, but reported no overlap of differentially methylated candidate genes for ASD, either within their cohorts or with other published studies. To date, no studies have linked epigenetic changes in cord blood DNA with a later ASD diagnosis in children exposed to maternal Type-1 Diabetes. Only Howe et al. (29) previously explored this possibility in children exposed to GDM, identifying methylation differences in OR2L13, a neurodevelopment-associated gene. Notably, OR2L13 was also identified in our analysis. Furthermore, five neurodevelopment-enriched genes from our analysis (CNTNAP2, GALNT, SLC4A10, KIRREL3, and MYT1L) coincided with the DM genes identified by Mordaunt et al. (30) in 2025 in the cord blood of females later diagnosed with ASD, all of which are included the SFARI database (15). In our study, KIRREL3 and MYT1L exhibited the largest methylation differences; and MYT1L correlated with the Bayley-III language domain score, and CNTNAP2 correlated with the motor domain score. As ASD is a neurodevelopmental disorder, the involvement of genes associated with brain development is expected.

Among the strengths of this work is it originality as the first prospective, hypothesis-generating pilot study to suggest that epigenetic changes identified in newborns exposed to maternal Type1 Diabetes are potentially linked to later neurodevelopmental outcomes in childhood. Furthermore, we used WGBS, the gold-standard technique for DNA methylation analysis, which covered over 3.34 million CpGs. This method provides a more complete and unbiased view of the methylome compared to array-based studies (such as the Illumina 450-BeadChip or EPIC array, which cover 400-752,000 CpG sites). The broader coverage explains why we identified a higher number of DM CpGs and DMRs than similar previous studies. The only exception was the Mordaunt et al. (30) study, with which we found the most overlap, likely because they also used a WGBS approach.

The primary limitation of this study is its small sample size, which may increase the risk of false-positive findings; consequently, the present results should be interpreted as exploratory. This work does not constitute a definitive epigenome-wide association study (EWAS), but rather serves to identify potential pathways for future research. Due to sample size constraints, several key factors—including cell-type heterogeneity, maternal glycemic control, socioeconomic status, and education level—were not incorporated into the regression models to avoid over-parameterization. Nevertheless, these findings provide a valuable foundation for future larger-scale research that should account for these variables alongside gene expression analysis. If confirmed, DNA methylation patterns in umbilical cord blood could serve as potential biomarkers for neurodevelopmental alterations, enabling targeted interventions for high-risk newborns.”

In conclusion, while further confirmation in much larger cohorts is needed, we provide the first results supporting the hypothesis that neurodevelopmental alterations observed in children born to mothers with Type 1 Diabetes are potentially linked to DNA methylation changes during intrauterine life, which can be identified at birth.