Volume 1 | Issue 2 | Year 2022

Neurological Abnormalities in Infants of Mothers with Diabetes Mellitus

Vinayak Mishra1, Nalinikanta Panigrahi2, Anil Rao3, Akhil Maheshwari4, Thierry AGM Huisman5

1Department of Pediatrics, Grant Medical College and Sir JJ Group of Hospitals, Mumbai, Maharashtra, India

2Department of Neonatology, Rainbow Children’s Hospital, Hyderabad, Telangana, India

3Department of Radiology, University of Illinois at Chicago, Chicago, United States of America

4Global Newborn Society, Clarksville, Maryland, United States of America

5Department of Radiology, Baylor College of Medicine, Houston, United States of America

Corresponding Author: Vinayak Mishra, Department of Pediatrics, Grant Medical College and Sir JJ Group of Hospitals, Mumbai, Maharashtra, India, Phone: +91 8828079692, e-mail:

How to cite this article: Mishra V, Panigrahi N, Rao A, et al. Neurological Abnormalities in Infants of Mothers with Diabetes Mellitus. Newborn 2022;1(2):238–244.

Source of support: Nil

Conflict of interest: None


Fetal anomalies, neurocognitive disorders, and perinatal mortality rates are higher in infants of diabetic mothers (IDMs) than in infants of mothers without diabetes. The pathology of these defects is significantly influenced by maternal glucose control and the onset of diabetes during pregnancy. Maternal hyperglycemia, abnormal inflammatory response, and fetal oxidative stress contribute to the pathogenesis of neurological deficits in IDMs. Pregestational diabetes mellitus (PGDM) have a higher incidence of congenital neurologic structural anomalies than gestational diabetes mellitus (GDM). The assessment of neurodevelopmental impairment in IDMs is confounded by perinatal factors, including birth asphyxia, acute and chronic metabolic insults, and iron deficiency. The incidence of these defects tends to reduce with appropriate antenatal care and maternal glycemic control. We discuss the structural neurologic malformations, cognitive disorders, motor deficits, and psychosocial disorders in the offspring of diabetic mothers.

Keywords: Anencephaly, Attention-deficit hyperactivity disorder, Autism spectrum disorder, Caudal regression syndrome, Cognitive impairment, Encephalocele, Fetal pathology, Infants of diabetic mothers, Myelomeningocele, Neural tube defect, Neurodevelopmental delay, Neurodevelopmental impairment, Oxidative stress, Schizophrenia.



The World Health Organization (WHO) defines diabetes mellitus (DM) as “a chronic disease that appears when the pancreas does not produce enough insulin or when the body does not effectively use the insulin it produces.” There are two types of diabetes in pregnant mothers, depending on the onset time: PGDM, onset before pregnancy; GDM, onset between 24 and 28 weeks of pregnancy. Several studies have demonstrated that fetal anomalies, neurobehavioral abnormalities, and perinatal mortality rates are higher in IDMs than infants of mothers without diabetes.1,2 Maternal glycemic control during pregnancy has been shown to affect the pathogenesis of these morbidities.3,4

Timely diagnosis and adequate control of maternal diabetes during pregnancy could decrease the rates of cognitive and intellectual impairment, motor disorders, and psychosocial disorders.5 Yamamoto et al., in their meta-analysis, demonstrated that there is adequate evidence to indicate that maternal PGDM leads to adverse cognitive and neurobehavioral outcomes in children.6 Ornoy et al. showed that school-age children born to mothers with DM during pregnancy had some degree of impairment in their motor function and attention span, which was worse in the case of poor maternal glycemic control.7,8 The neurological sequelae in terms of cognition, motor function, and psychosocial development have been discussed in separate sections later. In this review, we cover the effects of maternal DM on the neurological development of the offspring. We aim to discuss the short-term and long-term neurodevelopmental impairments in IDMs.


The pathogenesis of the fetal morbidities in IDMs has been described scrupulously in several animal and human models. Inflammation and oxidative stress have significant implications for placental function and fetal well-being in GDM and PGDM.9 In a normal pregnancy, the T-cells have a predominant anti-inflammatory response favoring maternal-fetal immune interactions leading to normal fetal outcomes.10,11 However, conditions such as GDM are associated with an inflammatory response and disproportionate cytokine production that can lead to adverse maternal and fetal outcomes.12 In maternal DM, there is an increased production of reactive oxygen species and free radicals, which results in mitochondrial dysfunction.13,14 The decrease in cellular energy production due to mitochondrial dysfunction and oxidative stress could affect neurotrophin levels and impair fetal neurological development.9

Neurotrophins are peptides that influence neuronal growth and differentiation during fetal growth.15 Neurotrophins, including nerve growth factor (NGF), brain-derived neurotrophin, neurotrophin-3, and neurotrophin-4/5, regulate the growth and development of the fetal brain and nervous system.15 These peptides also safeguard the developing neurons by preventing apoptosis and promoting angiogenesis.15 The normal development of the nervous system depends on a positive feedback loop between antioxidant processes and neurotrophins.16 In maternal DM, increased oxidative stress decreases the levels of neurotrophins, thereby disturbing the positive feedback loop.16

Brain-derived neurotrophic factor (BDNF) and NGF are the most investigated neurotrophins. Animal models have demonstrated that BDNF plays a role in neuronal development and differentiation in the cerebral cortex and hippocampus.17 In addition, it may also protect fetal neurons by reducing apoptosis and promoting angiogenesis during hypoxic conditions.17 Similarly, NGF contributes to neuroplasticity during fetal brain development and influences neuronal survival.18 Briana et al. reported that the levels of BDNF and NGF were low in the cord blood of neonates born to mothers with GDM.19 Su et al. showed impairment in language development and low BDNF levels at 12 months of age in IDMs, indicating a correlation between BDNF levels and cognitive development.20 These alterations in neurotrophins in mothers with GDM and PGDM could lead to adverse neurodevelopmental and neurobehavioral outcomes in their offspring.


Infants of diabetic mothers have an increased incidence of congenital anomalies of the central nervous system, including microcephaly, cysts, hydrocephalus, NTDs, and caudal regression syndrome, compared to the general population. The incidence of congenital anomalies is not increased in the offspring of mothers with GDM. These anomalies are probably induced by chronic hyperglycemia, causing the build-up of advanced glycosylation end-products (AGE) and oxidative stress in early gestation.21 The risk of diabetic embryopathy rises if maternal glucose control, as estimated by glycosylated hemoglobin levels, is dysregulated in early gestation.2224

Increased oxidative and nitrosative stress in mothers with PGDM plays a role in diabetic embryopathy and abnormal placentation.25 The mechanism of this embryopathy is poorly understood; few animal studies showed that high oxidative stress in the embryo decreases cell proliferation and increases cell apoptosis.26 In addition, Salbaum et al.27 reported that maternal diabetes’ teratogenic effect is because it disturbs gene regulation and modifies the epigenome in the embryo. The effects of specific genetic variants associated with maternal glucose metabolism and NTD-related genes such as FT0, TCF7L2, and LEP may underline the molecular pathology of NTDs.28

Neural Tube Defects

The common anomalies of the central nervous system are due to the failure of neural tube closure, including anencephaly (Fig. 1), encephalocele (Fig. 2), and meningomyelocele (Fig. 3). Tinker et al. showed that, compared to offspring of non-diabetic mothers, the risk for holoprosencephaly increases around 13-fold; hydrocephalus, 8-fold; encephalocele, around 5-fold; and anencephaly, 3.5-fold in offspring of PGDM mothers.29 An extensive study of over 29 million mother-infant pairs in the United States demonstrated that even mothers with GDM had a higher risk of congenital malformations of the neonate, albeit less than PGDM.30 The likelihood of spina bifida was significantly around 2-fold in PGDM and around 1.25-fold in GDM.30 A Texas population-based study reported that the rate of NTDs such as anencephaly, spina bifida, and holoprosencephaly (Fig. 4) in IDMs was higher if maternal obesity was present.31

Figs 1A and B: Classic severe anencephaly with no skull and severe microcephaly, as seen on (A) Three-dimensional (3D) computed tomography (CT); (B) Matching T1- and T2-weighted magnetic resonance imaging (MRI). A small hypoplastic brain stem and cerebellum are visible, the entire supratentorial brain is lacking with some degenerative T2-hyperintense cysts

Figs 2A to D: Encephaloceles. (A) Sagittal and axial T2-weighted fetal MRI and matching; (B) Postnatal sagittal T2/T1-weighted and axial T2-weighted MRI show a large occipital encephalocele with herniation of large parts of the occipital and parietal lobes including part of the lateral ventricles; (C) Fronto-ethmoidal encephalocele. The T1-hyperintense structure in the brain corresponds to a lipoma and (D) Sagittal T1-weighted brain MRI and matching sagittal CT and 3D skull of a newborn child with a large occipital encephalocele with herniation of the brain and meninges through a focal skull defect which communicates with the foramen magnum

Figs 3A and B: (A) Fetal T2-weighted MRI with non-skin-covered cystic appearing lumbo-sacral meningomyelocele including an associated Arnold Chiari type-II malformation with a small posterior fossa and herniation of cerebellar tissue into the upper cervical spinal canal and supratentorial hydrocephalus; (B) Sagittal T1-weighted and axial T2-weighted postnatal MRI in a patient with Arnold Chiari type-II secondary to an open meningomyelocele with severe crowding of the posterior fossa. The infants received a ventriculoperitoneal shunt; decompressed supratentorial ventricles and malformed dysplastic corpus callosum are noted

Figs 4A and B: Holoprosencephaly. (A) 3D CT bone and soft tissue reconstruction of a neonate with near-complete alobar holoprosencephaly with matching characteristic facial features including a single central incisor, hypotelorism, and proboscis; (B) Sagittal T1-weighted and axial T2-weighted MRI of the same child show the classic non-dived or fused cerebral hemispheres and large monoventricle

Caudal Regression Syndrome

Caudal regression syndrome (Fig. 5) includes a group of anomalies of the lower spine, lower limbs, and genitourinary system, and it is strongly associated with maternal diabetes. The Welch and Alterman classification of congenital sacral malformations includes four subgroups (Table 1). Some reports suggest that this syndrome might be seen more than 200 times more frequently in IDMs than in infants of non-diabetic mothers.32 Garne et al.33 studied 18 population-based EUROCAT registries of congenital anomalies from 1990 to 2005 and found that the odds ratio for caudal regression syndrome was 26.4 (95% CI = 8.98–77.64) in IDMs.

Figs 5 to C: Lateral views in (A) Conventional X-ray; (B) Sagittal T1- and T2-weighted MRI images show classic caudal regression syndrome with blunt ending of the distal spinal cord, and absence of the conus medullaris and terminal ventricle with matching lack of the osseous spinal column and sacrum below $3 (deficient secondary neurulation) and (C) Axial T2-weighted MRI images show notable colonic constriction and functional urinary tract obstruction

Table 1: The Welch and Alterman classification of congenital sacral malformations
Type Description
I A non-familial type associated with maternal DM showing complete absence of the sacrum and lower vertebrae with congenital anomalies
II Agenesis of the distal sacral or coccygeal segments
III Hemisacral dysgenesis with presacral teratoma
IV Hemisacral dysgenesis with anterior meningocele

Lower spine malformations can lead to spinal cord abnormalities, thereby predisposing to neurological lower limb defects, abnormal bladder and bowel control, and flexion contractures of the knee and hip.34 In type I caudal regression syndrome, the spinal cord ends abruptly and bluntly, deforming the conus medullaris and cauda equina. Some case reports have shown that in IDMs, caudal regression syndrome can occur with additional malformations such as spinal-pelvic instability, hip dislocation, popliteal webbing, and extrahepatic biliary atresia.3537 Severe caudal regression syndrome can be associated with multisystem anomalies, including VACTERL complex (vertebral, anorectal, cardiac, renal, and limb defects).38


Cognitive Disorders

Cognition is evaluated in terms of intelligence, memory, and attention. These functions are essential for communication, learning, motor coordination, and problem-solving and are controlled by sophisticated coordination among the cerebral cortex, basal ganglia, amygdala, and hippocampus. Several animal models have demonstrated that maternal hyperglycemia adversely affects neurological development and synaptic plasticity in the hippocampus, as this process is regulated by receptors to insulin and insulin-like growth factors.3941 This hippocampal defect could lead to cognitive and behavioral abnormalities.

A study of school-age children demonstrated that those born to mothers with GDM performed poorly in verbal tasks and motor coordination compared to their peers; however, they did not have reduced cognitive ability.7,8,42 In another study of school-age children, the GDM group showed mild cognitive impairment and lower scores for general intelligence and working memory.43 In addition, 18–27-year-old adults born to women with GDM had lower cognitive test scores than their counterparts, and the scores were negatively correlated with maternal blood glucose levels.44 These observational studies suggest a causal influence of maternal hyperglycemia and insulin resistance on cognitive impairment in the offspring.

Motor Disorders

Abnormal maternal glucose metabolism is associated with impaired intellectual and psychomotor development in offspring during pregnancy.45 There was impairment of fine motor and gross motor control in school-age children of mothers with GDM.8 Experimental studies have shown a decrease in cerebellar size due to reduced density of Purkinje and granular cells in the cerebellar cortex in gestational diabetes rat offspring models.46,47 These findings suggest possible defects in cerebellar development in offspring of GDM mothers.

Ratzon et al. showed that offspring of diabetic mothers have poorer control in fine and gross motor functions when compared to children of mothers without DM.48 In addition, the motor control in children of diabetic mothers was negatively correlated to the severity of hyperglycemia assessed by glycosylated hemoglobin levels and acetonuria.48 A prospective cohort study in Iran reported that the risk of motor developmental delay in IDMs was 1.49 (95% CI = 0.98–1.87).49 A recent meta-analysis showed that children born to mothers with DM had delayed motor development when compared to children born to mothers without diabetes, and this impairment in motor development was worse in PGDM than GDM.50

Psychosocial Disorders

Maternal DM has been linked to multiple psychosocial disorders in the offspring, including ASD, ADHD, and schizophrenia (Table 2). As stated above, intrauterine hyperglycemia could reduce the size of the fetal cerebellum by reducing the density of Purkinje and granular cells.46,47 Autism spectrum disorder has also been associated with developmental cerebellar abnormalities, including cerebellar hypoplasia and a decrease in size.5153 The increased production of free radicals and oxidative stress, which are present in the cases of PGDM and GDM, have been shown to be associated with ASD and schizophrenia.5457

Table 2: Summary of neurologic anomalies and defects in IDMs
Category Abnormalities References
Congenital anomalies Neural tube defects—anencephaly, encephalocele, and spina bifida 25,26
Cognitive impairment Deficits in intelligence, memory, and verbal tasks 30–32
Motor disorders Delayed motor development, poor gross and fine motor control 36–38
Psychosocial disorders Autism spectrum disorder, attention-deficit hyperactivity disorder, and schizophrenia 46–52

A large prospective cohort study of 66,445 pregnancies reported a significantly higher risk of ASD in association with GDM (odds ratio = 1.76, 95% CI = 1.34–2.32, p <0.05).58 However, other studies have contested these findings and rendered this association as controversial.59,60 Similarly, the link between maternal DM and schizophrenia has also been a matter of debate.

In a case-control study, Hultman et al.61 noted increased risk of schizophrenia in offspring of mothers with GDM or PGDM but the association did not reach statistical significance. A meta-analysis showed a strong association between diabetes in pregnancy and schizophrenia; however, this was based on only two studies.62 A Swedish population-based study of 15,615 children born to mothers with type 1 DM showed a significantly higher risk of ADHD (hazard ratio = 1.35, 95% CI = 1.18–1.55).63 Xiang et al. demonstrated that the risk of ADHD was higher in PGDM and if the GDM required management with antidiabetic medications (Table 2).64


Our review shows that the pathogenesis of congenital malformations and neurodevelopmental impairment in offspring of mothers with DM is complex and poorly understood. The assessment of neurodevelopmental impairment in IDMs is confounded by perinatal factors, including birth asphyxia, acute and chronic metabolic insults, and iron deficiency. The incidence of these defects tends to reduce with appropriate antenatal care and maternal glycemic control.

There are multiple factors, including oxidative stress and inflammation and molecular mechanisms involving neurotrophins interfering with the development of the nervous system. Global research initiatives are needed to elucidate these mechanisms. The review also highlighted that PGDM and GDM are associated with an increased risk of multiple neurobehavioral disorders, including cognitive impairment, motor developmental delay, ASD, schizophrenia, and ADHD. Attention-deficit hyperactivity disorder has the most substantial evidence to support its association with maternal DM among psychiatric disorders.


Akhil Maheshwari


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