Accumulating evidence suggests that maternal diabetes affects the maturation of the developing CNS through various mechanisms. One of the most important factors influencing the developing fetal brain is considered to be diabetes-induced iron deficiency. Several clinical studies have highlighted that maternal diabetes leads to abnormal serum iron profiles in offspring, and this effect is highly correlated with maternal glucose levels (75–77). Gestational diabetes constitutes a state of fetal hypoxia with decreased oxygen supply, resulting in lactic acidosis, which, in turn, drives increased erythropoiesis and higher iron demands (78). Iron is well-known as a key transport mediator important for the proper oxygenation and function of all tissues in the human body, including the brain. The intrauterine period, especially the first trimester of gestation when organogenesis occurs, is a critical time window with high iron demands to adequately support the developing fetal brain, overall organogenesis, and the metabolically active placenta. Thus, iron deficiency can account for severe developmental deficits. Monoamine neurotransmitters like dopamine, norepinephrine, and serotonin, which are crucial for proper psychomotor function, require iron hydroxylases for synthesis. Alterations in the levels of these critical neuromodulators have been observed in states of iron deficiency, potentially leading to neurobehavioral consequences (79). Furthermore, experimental studies have shown that depleted fetal iron reserves may alter neuronal differentiation in the hippocampus, interfere with proper Brain-derived neurotrophic Factor (BDNF) function, and induce changes in dendritic cell architecture in animal brains. There also appears to be an association between iron deficiency and dysregulation in the expression of genes critical for brain function, neurobehavior, and synaptic plasticity (80, 81).

To date, there is limited clinical research investigating the extent of iron deficiency in diabetic pregnancies and its impact on future neurodevelopment. In the study by Sidappa et al., iron-deficient newborns of diabetic mothers exhibited weakened auditory recognition memory, which was already present at birth, as evidenced by the recording of Evoked-Related Potentials (ERPs). ERPs are brain responses to external sensory, motor, and cognitive stimuli that reflect coordinated neuronal activity. These same newborns were evaluated at 12 months of age using the Bayley Scales of Infant Development, which revealed defective motor performance (26). Similarly, in their study, Riggins et al. demonstrated that 3 to 4-year-old infants of diabetic mothers demonstrated specific deficits in recall memory that were proportional to the degree of prenatal iron deficiency (82). Therefore, the negative effects of depleted prenatal iron stores may persist beyond the neonatal period into childhood, potentially leading to significant developmental consequences.

All types of diabetes during pregnancy have been linked to disturbances in maternal lipid metabolism, consequently leading to compromised placental transfer of essential lipids in the developing fetus (83). Docosahexaenoic acid (DHA), an omega-3 fatty acid, is pivotal for the structure of neural tissue and retina, mitochondrial membranes, cerebral cortex, and the proper function of the brain. Animal studies have suggested that omega-3 fatty acid deficiency results in depleted DHA levels in the cerebral cortex, leading to learning disabilities (84). On the contrary, human studies have shown that DHA supplementation during pregnancy resulted in enhanced performance in problem-solving or sustained attention during infancy (85, 86).

As DHA cannot be synthesized by either the fetus or the placenta, the mother represents the primary supply of DHA to the fetus. In pregnancies complicated by diabetes, DHA transfer to the fetal circulation is impaired, leading to severe deficiencies that can, in turn, impair fetal neurocircuitry. Several mechanisms have been suggested to mediate the diminished placental transfer of DHA in pregnancies complicated by diabetes. Namely, peroxisome proliferator-activated receptor (PPAR)-alpha, a nuclear receptor responsible for genes related to fatty acid oxidation and transport, has been observed to be downregulated in the placenta of diabetic pregnancies compared to normal pregnancies (87).

Several studies have investigated the impact of dysregulated lipid metabolism in diabetic pregnancies and its effect on offspring neurodevelopment. The studies of Min et al. and Wijendran et al. demonstrated depleted levels of DHA in the cord blood of neonates of diabetic mothers compared to neonates of uncomplicated pregnancies (88, 89). A study by Zornoza-Moreno M et al. demonstrated that DHA levels were diminished in the cord blood of infants of diabetic mothers, and this reduction was further correlated with neurodevelopmental deficits at 6 months of age (90). Similarly, a recent prospective cohort study of 555 mother pairs provided evidence of impaired neurodevelopmental outcomes in infants of diabetic mothers during the first year of life, possibly mediated by alterations in lipid metabolism caused by maternal diabetes during gestation (91). The results of a recent meta-analysis of 24 observational studies confirmed that the cord blood of diabetic pregnancies has significantly lower levels of polyunsaturated fatty acids, potentially leading to severe neurocognitive sequelae for the exposed offspring (92).Taking these data into consideration, adequate supplementation of omega-3 fatty acids during pregnancy is mandatory, especially in cases of impaired lipid transfer to the fetus, such as maternal diabetes, in order to maintain sufficient distribution to both maternal and fetal circulation (93). Follow-up studies examining the long-term effects of omega-3 fatty acids on maternal and fetal metabolism will shed light on whether a higher intake of omega-3 fatty acids may benefit the future neurodevelopment of offspring in diabetic pregnancies.

Several animal studies have suggested that maternal diabetes can impact the process of synaptogenesis, which is crucial for establishing brain connectivity and function. In rats, it has been observed that maternal diabetes induction leads to changes in the physiology of synaptophysin, an integral membrane glycoprotein found on presynaptic vesicles of neurons. Synaptophysin serves as a marker for synaptic density and proper synaptogenesis and is involved in learning and memory processes (113). In an animal model study, researchers discovered a significant reduction in synaptophysin expression in the cerebral cortex of neonatal rats born to diabetic mothers during the critical two-week period of synaptogenesis in the developing CNS (114). These findings align with another study conducted by Vafaei-Nezhad et al., which identified decreased synaptophysin expression in hippocampal neurons of newborn rats born to diabetic mothers after 1 and 2 weeks postnatally (115). Jing et al. also observed a decrease in synaptophysin levels in neonatal rats of hyperglycemic mothers, alongside a noticeable delay in fetal dendritic development in the brain. This delay may be attributed to the dysregulation of insulin and insulin-like growth factor I expression, both of which play significant roles in brain development, dendritic branching, and myelination (116). Additionally, Hami J et al. reported a decline in insulin-like growth factor 1 receptor levels in the cerebellum of rats born to diabetic mothers, supporting the notion that maternal diabetes has detrimental effects on the motor and cognitive development of offspring (117).

Neurotrophins are a crucial family of peptides that play a significant role in developing the brain, peripheral, and central nervous systems. They are involved in neuronal growth, survival, and differentiation, possess antiapoptotic properties, and influence placental maturation. It has been proposed that neurotrophin levels may be downregulated in conditions characterized by increased oxidative stress. Cross-sectional studies have provided cumulative evidence showing that pregnancies complicated by diabetes exhibit higher levels of oxidative stress markers (such as 8-isoprostane and protein carbonyl) in both maternal and cord plasma. Consequently, an imbalance between oxidative stress and antioxidant defense mechanisms could potentially lead to altered neurotrophin levels in diabetic pregnancies. Omega-3 fatty acids are crucial in combating elevated ROS and maintaining normal neurotrophin levels. As mentioned earlier, impaired transfer of omega-3 fatty acids to the fetus has been observed in diabetic pregnancies, potentially resulting in deficiencies of these fatty acids and subsequent disturbances in neurotrophin regulation (118).

BDNF is a crucial neurotrophin that plays a role in neuronal differentiation, plasticity, and the establishment of synaptogenesis (119). Additionally, BDNF has been implicated as a mediator of glucose utilization and energy metabolism and has cytoprotective functions on pancreatic β cells. Decreased expression of BDNF has been observed in various neurodegenerative disorders characterized by neuronal loss, such as Parkinson’s and Alzheimer’s disease (120). Furthermore, low levels of BDNF have been reported in newborns who later developed ASD, suggesting its potential as a biomarker for neurodevelopmental disorders (121). In children with T1DM, particularly those with positive anti-GAD65 antibodies, lower serum BDNF levels and suboptimal neurocognitive performance have been observed (122). BDNF has also demonstrated neuroprotective effects against various adverse insults that threaten brain homeostasis, including cerebral ischemia, hypoglycemia, and GABAergic stimulations. Additionally, it enhances the action of neurotransmitters (123). Considering that gestational diabetes negatively impacts the neurobehavior of offspring and that adequate BDNF concentrations are crucial for optimal brain development, it is reasonable to assume that maternal diabetes may impair BDNF levels in offspring, leading to detrimental effects on their future neurocognition.

The current literature does not yet provide sufficient documentation on whether there is a connection between prenatal exposure to hyperglycemia and subsequent neurodevelopmental impairment through epigenetic modifications in gene expression. El Hajj et al. examined methylation levels of different genes in cord blood and placenta samples from the ODMs. They discovered significant alterations in genes previously associated with metabolism and obesity, implying that epigenetic changes might play a role in mediating the impact of maternal diabetes on the future development of metabolic disorders (130).

In neurodevelopment, only a limited number of experimental models have investigated the impact of maternal diabetes on gene dysregulation. In a recent study by Aviel Sheler et al., researchers observed behavioral abnormalities and impaired gene expression in the frontal cortex and striatum of male offspring from mothers with diabetes. The affected genes play a role in the proper formation of neuronal networks and, consequently, normal neurodevelopment (131). Another study identified the dysregulation of two genes encoding cytoplasmic proteins crucial for the process of apoptosis in the hippocampus of neonatal rats exposed to hyperglycemia. This group of rats also exhibited an increased expression of degenerating neurons. Dysregulation of programmed cell death has been proposed to be involved in various CNS pathologies, suggesting that the intrauterine hyperglycemic milieu may induce neuronal apoptosis dysregulation through epigenetic changes (132).

Similarly, Kandila et al. investigated the effects of hyperglycemia on DNA methylation in human neural progenitor cells and observed significant alterations in genes critical for neural tube development (133). Additionally, Zou et al. observed severe memory deficits in rats exposed to hyperglycemia and discovered epigenetic alterations in several genes associated with hippocampal synaptic plasticity (134). Finally, a novel study demonstrated the downregulation of genes expressed in the hippocampus of fetal mice exposed to GDM and alterations in hippocampal morphology. The differentially methylated genes are crucial in synaptogenesis, cognitive function, neuronal differentiation, neurotransmitter signaling, and dendritic development. Furthermore, significant changes in fetal brain metabolites associated with cognition and neurodevelopment, potentially attributed to DNA methylation changes, were noted (Graphical Abstract) (135).

Several studies have examined the impact of maternal diabetes on the attainment of infant motor milestones. Most studies support an association between diabetes during pregnancy and poorer motor performance in offspring. As early as 1969, Churchill et al. reported that children born to diabetic mothers with ketonuria during pregnancy showed impaired motor scores at 8 months and postural control at 12 months. The study findings were unaffected by maternal insulin treatment during pregnancy, while children born to mothers without ketonuria showed no difference in neurodevelopment compared to controls (18). Later, Ornoy et al. utilized the Bruininks-Oseretsky Motor Development Test, which assesses fine and gross motor development in children aged 4.5 to 14.5 years. Their results suggested that the ODMs, both with pre-gestational and gestational diabetes, exhibited lower motor scores than the control group, particularly when their mothers had higher glycosylated hemoglobin levels or severe acetonuria (141). In the Upstate Kids Study, a population-based birth cohort study, mothers with various underlying medical conditions recorded their children’s milestone achievements at ages up to 24 months. The results indicated that infants of diabetic mothers experienced a slight delay in sitting, walking alone, standing, and walking with assistance (23). In 2015, Torres-Espignola et al. conducted a prospective study involving 331 mothers, and their children were assessed using the Bayley III Scales of Infant and Toddler Development at 6 and 18 months of age. At 18 months, children of obese mothers and mothers with gestational diabetes exhibited lower scores in gross motor development (22). Consistent with other researchers, Lackovic et al. also confirmed impaired motor performance at 3 and 6 months of age in infants exposed to GDM (24). Furthermore, a recent longitudinal birth cohort study by Titmuss et al. investigated the effects of T2DM and GDM on offspring neurodevelopment at 16–60 months of age and reported defects in fine motor performance among offspring exposed to hyperglycemia (21). In a systematic review and meta-analysis conducted by Diana Arabiat et al., including 13 studies, maternal diabetes, especially when present before pregnancy or coexisting with other comorbidities such as hypertension and obesity, was found to harm the motor development of offspring (142).

Maternal diabetes is increasingly recognized as a potential risk factor for developing common neurodevelopmental disorders, including ADHD, in offspring. ADHD is one of the most prevalent neurodevelopmental disorders characterized by a persistent pattern of inattention, hyperactivity, and/or impulsivity, which disrupts a child’s normal development in various domains. Children diagnosed with ADHD often exhibit poorer school performance, difficulties in socializing, and an increased risk for substance abuse and other mental disorders (143). Multiple studies have explored the association between ADHD and maternal diabetes during pregnancy, yielding conflicting results. Ornoy et al. suggested in their study that school-age children exposed to maternal pre-gestational diabetes exhibited increased soft neurological signs during neurological assessments, indicating a higher likelihood of attention-deficit and/or hyperactivity (141). A recent population cohort study demonstrated that the diagnosis of GDM between 27 and 30 weeks of gestation is associated with a higher risk of developing ADHD.

Furthermore, the study suggested that the odds of ADHD and other neurodevelopmental disorders are greater when coexisting intellectual disability is present (46). A retrospective birth cohort study by Xiang et al. in 2018 reported that the offspring of mothers with GDM who required antidiabetic medication to lower their glucose levels during pregnancy had a higher likelihood of developing ADHD than children not exposed to hyperglycemia. Conversely, it was noted that GDM that did not require antidiabetic therapy did not pose an increased risk for ADHD. Additionally, the study indicated that, compared to normal pregnancies, the offspring of women with T1DM had the greatest risk for ADHD, followed by those with T2DM and, finally, those with GDM. Thus, the severity of hyperglycemia during pregnancy constitutes an independent risk factor for the development of ADHD in the next generation. However, the study found no association between the timing of diabetes diagnosis during gestation and ADHD (40).

In a prospective study conducted in Singapore, researchers reported electrophysiological alterations in 6- and 18-month-old children exposed to diabetes during pregnancy, particularly in the left hemisphere responsible for attention processing. These findings further support the idea that maternal diabetes may strongly impact the development of ADHD. Additionally, these alterations in neuronal activity were found to be associated with maternal blood glucose levels (33). Nomura et al. observed that when GDM is combined with low family socioeconomic status, there is approximately a 14-fold increased risk of developing impaired social functioning and ADHD symptomatology (38). Consistent with other researchers, a retrospective study from China indicated an increased incidence of ADHD in children of diabetic mothers, especially in males and full-term infants. Notably, gestational and pre-gestational diabetes posed a 2.6-fold increased risk for future ADHD development compared to the control group (41). Recently, Perea et al. conducted a prospective study to assess the association between maternal weight gain in pregnancies complicated by GDM and the future development of ADHD in offspring. Interestingly, the results indicated a higher rate of ADHD in the ODMs whose mothers had a combination of pre-gestational obesity and extreme weight gain during pregnancy (39).

However, a study by Bytoft et al. examined the effects of maternal T1DM on adolescent offspring, and the results did not reveal a higher rate of attention problems in the adolescent population. Nevertheless, there was a tendency towards increased use of ADHD medication among adolescents exposed to diabetes (37). Furthermore, a recent systematic review and meta-analysis investigating the impact of maternal diabetes on the most prevalent neurodevelopmental disorders found no significant association between maternal diabetes and ADHD, while a strong association was observed with ASD (144).

To date, there has been a strong association between metabolic disturbances during the perinatal period and the development of ASD. ASD, also known as pervasive developmental disorders, is a group of disorders characterized by early-onset deficits in communication and social interaction and repetitive behavior patterns. ASD is considered a multifactorial disorder with genetic and environmental factors playing a role (145).

Only a limited number of clinical studies have investigated the potential impact of maternal diabetes on the memory function of offspring. In the early 2000s, Deregnier RA et al. assessed the recognition memory of infants born to mothers with both gestational and pre-gestational diabetes using ERPs and identified slight deficits in memory recognition (25). In 2003, Nelson et al. evaluated cross-modal (tactile to vision) memory in infants of diabetic mothers compared to control children. The children exposed to diabetes showed impaired recognition of palpated objects, despite having normal Bayley scores (136). A longitudinal study conducted by Adeline Jabeen et al. in 2015 examined the effect of maternal diabetes on 19 children assessed at the age of 10 years. The study did not find any memory impairment at this age; however, when assessing hippocampal volume in these children – a brain region essential for memory development – they observed that higher hippocampal volume was associated with slower performance on certain tasks, which was an intriguing finding not observed in control children (152). In summary, the current literature regarding the effect of maternal diabetes on offspring memory function is limited, and further research is needed to address this knowledge gap.

Speech and language development are crucial in a child’s acquisition of normal milestones. These skills are primarily developed during the early years of life when the infant’s brain is highly responsive to external environmental stimuli. Developmental pediatricians commonly use multiple screening tests to evaluate both receptive and expressive language abilities.

In a study by Sells et al. (36), it was reported that at the age of 3, infants of mothers with poor diabetic control showed a reduction in verbal performance. However, there were no differences in verbal performance between controls and infants of mothers with optimal glycemic control. Another study conducted in Quebec in 2008 compared language development between infants of diabetic mothers (IDMs) and controls. The findings indicated that gestational diabetes hindered normal language evolution, as IDMs had lower vocabulary and grammar acquisition scores at 18 and 30 months. This study also revealed that infants of mothers with higher education were less affected in their language development, suggesting that genetic predisposition may also play a role (35).

Krakowiak et al. (34) assessed children of mothers with metabolic conditions, including diabetes, using the Mullen Scales of Early Development. They reported that these children performed worse than other children in the domain of receptive language ability. A meta-analysis was conducted to investigate the association between diabetes and language impairment, although only a limited number of studies on this subject were identified. The results of the included studies showed high heterogeneity, but it was suggested that diabetes might diminish language performance in children (153).

Intellectual development encompasses the dynamic process through which a child develops their ability to think, acquire knowledge, and organize it effectively for appropriate interaction with the social environment. However, clinical studies investigating the relationship between diabetes during pregnancy and intellectual disability in offspring are limited in the literature.

Churchill et al. (18) were among the first researchers to explore the impact of maternal diabetes on the future development of the child. They reported that children born to diabetic mothers with ketonuria during pregnancy exhibited cognitive deficits at 4 years of age. Ornoy et al. later reported poorer verbal IQ performance in young school-age children of diabetic mothers than in age-matched controls (19). A population-based study conducted by Helen Leonard et al. noted that maternal diabetes and other maternal medical conditions negatively affected the intellectual development of offspring (27). In 2013, Mann et al. found that pre-existing diabetes before pregnancy had a more significant negative impact on intellectual development than diabetes that developed during gestation (31).

Fraser et al. conducted a study using data from a prospective pregnancy cohort, assessing children born to diabetic mothers in terms of their IQ and academic performance at different ages. The results showed lower verbal IQ scores in children born to mothers with diabetes and glucosuria when assessed at 8 years old using the Wechsler Intelligence Scale for Children. The strongest association was observed with diabetes that developed during pregnancy. At 16 years of age, children born to women with pre-existing diabetes, and to a lesser extent, GDM, achieved poorer grades in their educational assessments (30).

In a recent study, researchers examined the cognitive performance of 3 to 6-year-old children of women with gestational hyperglycemia in an urban African population. They found significantly lower cognitive scores in children of hyperglycemic mothers than in children of euglycemic women. However, no notable association was observed between gestational hyperglycemia and the motor performance of exposed children (32). Additionally, a recent birth cohort study, which included 2,162 pregnancies complicated by GDM, assessed offspring neurodevelopment up to 4 years of age. The study found that diabetes-exposed offspring, especially males, displayed notable defects in problem-solving skills (20).

In contrast, a study from India revealed that a relatively small number of ODMs exhibited better learning, long-term storage/retrieval, and verbal ability at ages 9-10 when assessed using Kaufman’s Assessment Battery for Children and other tests. These discrepancies in findings may be attributed to variations in the tests and methods used to evaluate the cognitive abilities of the participants (29).

A recent study by Tingting Xu et al. reported that children of mothers with abnormal glucose tolerance at 26-28 weeks of gestation did not show clinically significant differences in cognitive and behavioral outcomes compared to control children during mid-childhood. This suggests that the impact of maternal diabetes on child cognition diminishes over time. However, the study also found a slightly reduced total score in the Wide Range Assessment of Visual Motor Abilities, a test that assesses visual motor, fine motor, and visual-spatial performance in children, indicating an association between GDM and diminished performance in these areas during early childhood (154).

A Swedish cohort study conducted in 2007 evaluated the academic performance of 16-year-old adolescents and reported that children exposed to diabetes during gestation were more likely to experience difficulties in completing compulsory school and achieving lower school marks (28). Similarly, a recent national registry-based cohort study in Denmark, spanning from 1994 to 2001, assessed the academic performance of children born to diabetic mothers. The results indicated that adolescents born to diabetic mothers tended to achieve lower grades than other children, and a history of low birth weight appeared to exacerbate the negative impact of maternal diabetes on the offspring’s school performance (137). Finally, a retrospective cohort study from Denmark assessed the school performance of 3,474 children with intrauterine exposure to T1DM, revealing diminished school test marks in IDMs compared to the general population (155).

Although several studies have linked maternal diabetes to neurodevelopmental disorders such as ADHD and autism, less attention has been given to the association between exposure to high glucose levels and psychiatric disorders, which requires further investigation. Animal models have demonstrated that maternal diabetes, producing excessive pro-inflammatory cytokines that directly affect the CNS, may contribute to developing psychiatric disorders (49).

A recent population-based cohort study conducted in Finland investigated the relationship between various types of diabetes during gestation and future psychiatric disorders in offspring. The study’s results indicated that pre-pregnancy diabetes requiring insulin treatment, followed by T2DM and, to a lesser extent, GDM when combined with an elevated BMI, were associated with an increased risk of mood abnormalities and intellectual impairment in the offspring (43).Furthermore, it has been suggested that elevated peripheral insulin levels can worsen insulin resistance, which has also been linked to depressive phenotypes (156).

Schizophrenia, one of the most severe neuropsychiatric disorders, is believed to result from a complex interplay between genetic and environmental factors. Epidemiological evidence suggests that maternal diabetes may predispose individuals to the future development of schizophrenia (157). Multiple potential pathophysiological pathways have been proposed to explain the increased risk of schizophrenia in the ODMs. These include increased oxidative stress, mitochondrial modifications, altered lipid metabolism, elevated levels of inflammatory cytokines, structural brain abnormalities, and disrupted neurotransmitter metabolism, which has been observed in both the brains of the ODMs and schizophrenia patients (158).

In a recent population cohort study, researchers collected and analyzed data from the ODMs over 39 years, considering the possibility that mental health disorders may manifest later in life. The results revealed a higher risk of developing schizophrenia, behavioral disorders, anxiety, and decreased intellectual ability in this population (139). Another study indicated that 10-year-old children with a history of maternal diabetes during the early gestational period had a higher incidence of hallucinatory experiences (42). Previous research has also demonstrated that gestational diabetes during the first 11 weeks of gestation is associated with an increased risk of developing psychotic experiences during adolescence (159).

Another population-based cohort study conducted in Israel found that maternal diabetes poses a significant risk for the future development of ASD, eating disorders, and obstructive sleep apnea in offspring. Additionally, the study observed that children exposed to maternal hyperglycemia were more prone to developing mental health disorders at a younger age than unexposed children (15).

In a prospective study conducted in 2018, the impact of maternal diabetes and other metabolic complications during pregnancy on communication skills was examined. The study revealed an association between maternal diabetes and suboptimal communication, problem-solving, and socializing skills in the offspring (160).

A longitudinal birth cohort study by Krzeczkowski et al. demonstrated a strong link between maternal diabetes and behavioral and emotional problems in the offspring at 2 years old. Both internalizing and externalizing problems were observed, although these findings appeared to be influenced by confounding factors that could have been prevented, such as maternal diet, depressive symptoms, and socioeconomic status (138).

Furthermore, Kong et al., in their study, proposed that the combination of pre-gestational maternal diabetes and obesity during pregnancy increases the predisposition of children up to 11 years of age to a wide range of psychiatric disorders, including conduct disorders, emotional problems, and social function disorders. The study also reported an elevated prescription rate of psychotropic medication among this group of children (147).

The existing literature does not provide sufficient data to definitively determine whether intrauterine exposure to hyperglycemia predisposes individuals to future psychiatric disorders. Organizing large-scale, well-designed studies to obtain more robust evidence and draw clear conclusions on this matter is essential.