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VOLUME 1 , ISSUE 2 ( April-June, 2022 ) > List of Articles


Neurological Abnormalities in Infants of Mothers with Diabetes Mellitus

Vinayak Mishra, Nalinikanta Panigrahi, Anil Rao, Thierry AGM Huisman

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

Citation Information : Mishra V, Panigrahi N, Rao A, Huisman TA. Neurological Abnormalities in Infants of Mothers with Diabetes Mellitus. 2022; 1 (2):238-244.

DOI: 10.5005/jp-journals-11002-0033

License: CC BY-NC 4.0

Published Online: 05-07-2022

Copyright Statement:  Copyright © 2022; The Author(s).


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.

  1. Moore LL, Bradlee ML, Singer MR, et al. Chromosomal anomalies among the offspring of women with gestational diabetes. Am J Epidemiol 2002;155(8):719–724. DOI: 10.1093/aje/155.8.719.
  2. Mathiesen ER, Ringholm L, Damm P. Stillbirth in diabetic pregnancies. Best Pract Res Clin Obstet Gynaecol 2011;25(1):105–111. DOI: 10.1016/j.bpobgyn.2010.11.001.
  3. Michael Weindling A. Offspring of diabetic pregnancy: short-term outcomes. Semin Fetal Neonatal Med 2009;14(2):111–118. DOI: 10.1016/j.siny.2008.11.007.
  4. Zhao J, Hakvoort TBM, Ruijter JM, et al. Maternal diabetes causes developmental delay and death in early-somite mouse embryos. Sci Rep 2017;7(1):11714. DOI: 10.1038/s41598-017-11696-x.
  5. Márquez-Valadez B, Valle-Bautista R, García-López G, et al. Maternal diabetes and fetal programming toward neurological diseases: beyond neural tube defects. Front Endocrinol 2018;9:664. DOI: 10.3389/fendo.2018.00664.
  6. Yamamoto JM, Benham JL, Dewey D, et al. Neurocognitive and behavioural outcomes in offspring exposed to maternal pre-existing diabetes: a systematic review and meta-analysis. Diabetologia 2019;62(9):1561–1574. DOI: 10.1007/s00125-019-4923-0.
  7. Ornoy A, Ratzon N, Greenbaum C, et al. Neurobehaviour of school age children born to diabetic mothers. Arch Dis Child Fetal Neonatal Ed 1998;79(2):F94–F99. DOI: 10.1136/fn.79.2.f94.
  8. Ornoy A, Ratzon N, Greenbaum C, et al. School-age children born to diabetic mothers and to mothers with gestational diabetes exhibit a high rate of inattention and fine and gross motor impairment. J Pediatr Endocrinol Metab JPEM 2001;14(Suppl 1):681–689. DOI: 10.1515/jpem.2001.14.s1.681.
  9. Jadhav A, Khaire A, Joshi S. Exploring the role of oxidative stress, fatty acids and neurotrophins in gestational diabetes mellitus. Growth Factors Chur Switz 2020;38(3–4):226–234. DOI: 10.1080/08977194.2021.1895143.
  10. Abell SK, De Courten B, Boyle JA, et al. Inflammatory and other biomarkers: role in pathophysiology and prediction of gestational diabetes mellitus. Int J Mol Sci 2015;16(6):13442–13473. DOI: 10.3390/ijms160613442.
  11. Challis JR, Lockwood CJ, Myatt L, et al. Inflammation and pregnancy. Reprod Sci Thousand Oaks Calif 2009;16(2):206–215. DOI: 10.1177/1933719108329095.
  12. Gomes CP, Torloni MR, Gueuvoghlanian-Silva BY, et al. Cytokine levels in gestational diabetes mellitus: a systematic review of the literature. Am J Reprod Immunol N Y N 1989 2013;69(6):545–557. DOI: 10.1111/aji.12088.
  13. Lappas M, Hiden U, Desoye G, et al. The role of oxidative stress in the pathophysiology of gestational diabetes mellitus. Antioxid Redox Signal 2011;15(12):3061–3100. DOI: 10.1089/ars.2010.3765.
  14. Cernea S, Dobreanu M. Diabetes and beta cell function: from mechanisms to evaluation and clinical implications. Biochem Med 2013;23(3):266–280. DOI: 10.11613/BM.2013.033.
  15. Dhobale M. Neurotrophins: role in adverse pregnancy outcome. Int J Dev Neurosci 2014;37(1):8–14. DOI: 10.1016/j.ijdevneu.2014.06.005.
  16. Gardiner J, Barton D, Overall R, et al. Neurotrophic support and oxidative stress: converging effects in the normal and diseased nervous system. Neuroscientist 2009;15(1):47–61. DOI: 10.1177/1073858408325269.
  17. Meng M, Zhiling W, Hui Z, et al. Cellular levels of TrkB and MAPK in the neuroprotective role of BDNF for embryonic rat cortical neurons against hypoxia in vitro. Int J Dev Neurosci 2005;23(6):515–521. DOI: 10.1016/j.ijdevneu.2005.04.002.
  18. Parikh V, Evans DR, Khan MM, et al. Nerve growth factor in never-medicated first-episode psychotic and medicated chronic schizophrenic patients: possible implications for treatment outcome. Schizophr Res 2003;60(2):117–123. DOI: 10.1016/S0920-9964(02)00434-6.
  19. Briana DD, Malamitsi-Puchner A. Developmental origins of adult health and disease: the metabolic role of BDNF from early life to adulthood. Metab-Clin Exp 2018;81:45–51. DOI: 10.1016/j.metabol.2017.11.019.
  20. Su CH, Liu TY, Chen IT, et al. Correlations between serum BDNF levels and neurodevelopmental outcomes in infants of mothers with gestational diabetes. Pediatr Neonatol 2021;62(3):298–304. DOI: 10.1016/j.pedneo.2020.12.012.
  21. Eriksson UJ, Wentzel P. The status of diabetic embryopathy. Ups J Med Sci 2016;121(2):96–112. DOI: 10.3109/03009734.2016.1165317.
  22. Miller E, Hare JW, Cloherty JP, et al. Elevated maternal hemoglobin A1c in early pregnancy and major congenital anomalies in infants of diabetic mothers. N Engl J Med 1981;304(22):1331–1334. DOI: 10.1056/NEJM198105283042204.
  23. Ylinen K, Raivio K, Teramo K. Haemoglobin AIc predicts the perinatal outcome in insulin-dependent diabetic pregnancies. Br J Obstet Gynaecol 1981;88(10):961–967. DOI: 10.1111/j.1471-0528.1981.tb01681.x.
  24. Suhonen L, Hiilesmaa V, Teramo K. Glycaemic control during early pregnancy and fetal malformations in women with type I diabetes mellitus. Diabetologia 2000;43(1):79–82. DOI: 10.1007/s001250050010.
  25. Ornoy A. Embryonic oxidative stress as a mechanism of teratogenesis with special emphasis on diabetic embryopathy. Reprod Toxicol Elmsford N 2007;24(1):31–41. DOI: 10.1016/j.reprotox.2007.04.004.
  26. Gabbay-Benziv R, Reece EA, Wang F, et al. Birth defects in pregestational diabetes: defect range, glycemic threshold and pathogenesis. World J Diabetes 2015;6(3):481–488. DOI: 10.4239/wjd.v6.i3.481.
  27. Salbaum JM, Kappen C. Neural tube defect genes and maternal diabetes during pregnancy. Birth Defects Res A Clin Mol Teratol 2010;88(8):601–611. DOI: 10.1002/bdra.20680.
  28. Lupo PJ, Canfield MA, Chapa C, et al. Diabetes and obesity-related genes and the risk of neural tube defects in the national birth defects prevention study. Am J Epidemiol 2012;176(12):1101–1109. DOI: 10.1093/aje/kws190.
  29. Tinker SC, Gilboa SM, Moore CA, et al. Specific birth defects in pregnancies of women with diabetes: National Birth Defects Prevention Study, 1997–2011. Am J Obstet Gynecol 2020;222(2): 176.e1–176.e11. DOI: 10.1016/j.ajog.2019.08.028.
  30. Wu Y, Liu B, Sun Y, et al. Association of maternal prepregnancy diabetes and gestational diabetes mellitus with congenital anomalies of the newborn. Diabetes Care 2020;43(12):2983–2990. DOI: 10.2337/dc20-0261.
  31. Anderson JL, Waller DK, Canfield MA, et al. Maternal obesity, gestational diabetes, and central nervous system birth defects. Epidemiology 2005;16(1):87–92. Available from: [Accessed April 21, 2022].
  32. Wender-Ożegowska E, Wróblewska K, Zawiejska A, et al. Threshold values of maternal blood glucose in early diabetic pregnancy–prediction of fetal malformations. Acta Obstet Gynecol Scand 2005;84(1):17–25. DOI: 10.1111/j.0001-6349.2005.00606.x.
  33. Garne E, Loane M, Dolk H, et al. Spectrum of congenital anomalies in pregnancies with pregestational diabetes. Birth Defects Res A Clin Mol Teratol 2012;94(3):134–140. DOI: 10.1002/bdra.22886.
  34. Caudal Regression Syndrome. NORD (National Organization for Rare Disorders). Available from: [Accessed April 21, 2022].
  35. Herrmann J, Brauer M, Scheer I, et al. Extrahepatic biliary atresia and caudal regression syndrome in an infant of a diabetic mother. J Pediatr Surg 2004;39(1):E20–E22. DOI: 10.1016/j.jpedsurg.2003.09.044.
  36. Al Kaissi A, Klaushofer K, Grill F. Caudal regression syndrome and popliteal webbing in connection with maternal diabetes mellitus: a case report and literature review. Cases J 2008;1(1):407. DOI: 10.1186/1757-1626-1-407.
  37. Kumar Y, Gupta N, Hooda K, et al. Caudal regression syndrome: a case series of a rare congenital anomaly. Pol J Radiol 2017;82:188–192. DOI: 10.12659/PJR.900971.
  38. Kanagasabai K, Bhat V, Pramod G, et al. Severe caudal regression syndrome with overlapping features of VACTERL complex: antenatal detection and follow up. BJR Case Rep 2017;3(2):20150356. DOI: 10.1259/bjrcr.20150356.
  39. Hami J, Kheradmand H, Haghir H. Gender differences and lateralization in the distribution pattern of insulin-like growth factor-1 receptor in developing rat hippocampus: an immunohistochemical study. Cell Mol Neurobiol 2014;34(2):215–226. DOI: 10.1007/s10571-013-0005-x.
  40. Hami J, Sadr-Nabavi A, Sankian M, et al. The effects of maternal diabetes on expression of insulin-like growth factor-1 and insulin receptors in male developing rat hippocampus. Brain Struct Funct 2013;218(1):73–84. DOI: 10.1007/s00429-011-0377-y.
  41. Delascio Lopes C, Sinigaglia-Coimbra R, Mazzola J, et al. Neurofunctional evaluation of young male offspring of rat dams with diabetes induced by streptozotocin. ISRN Endocrinol 2011;2011:e480656. DOI: 10.5402/2011/480656.
  42. He XJ, Dai RX, Tian CQ, et al. Neurodevelopmental outcome at 1 year in offspring of women with gestational diabetes mellitus. Gynecol Endocrinol Off J Int Soc Gynecol Endocrinol 2021;37(1):88–92. DOI: 10.1080/09513590.2020.1754785.
  43. Bolaños L, Matute E, Ramírez-Dueñas M de L, et al. Neuropsychological impairment in school-aged children born to mothers with gestational diabetes. J Child Neurol 2015;30(12):1616–1624. DOI: 10.1177/0883073815575574.
  44. Clausen TD, Mortensen EL, Schmidt L, et al. Cognitive function in adult offspring of women with gestational diabetes–the role of glucose and other factors. PLoS One 2013;8(6):e67107. DOI: 10.1371/journal.pone.0067107.
  45. Silverman BL, Rizzo TA, Cho NH, et al. Long-term effects of the intrauterine environment. The Northwestern University Diabetes in Pregnancy Center. Diabetes Care 1998;21(Suppl 2):B142–B149. PMID: 9704242.
  46. Razi EM, Ghafari S, Golalipour MJ. Effect of gestational diabetes on Purkinje and granule cells distribution of the rat cerebellum in 21 and 28 days of postnatal life. Basic Clin Neurosci 2015;6(1):6–13. PMID: 27504151.
  47. Yamano T, Shimada M, Fujizeki Y, et al. Quantitative synaptic changes on Purkinje cell dendritic spines of rats born from streptozotocin-induced diabetic mothers. Brain Dev 1986;8(3):269–273. DOI: 10.1016/S0387-7604(86)80080-8.
  48. Ratzon N, Greenbaum C, Dulitzky M, et al. Comparison of the motor development of school-age children born to mothers with and without diabetes mellitus. Phys Occup Ther Pediatr 2000;20(1):43–57. PMID: 11293914.
  49. Alamolhoda SH, Ahmadi Doulabi M, Afraz F. The impact of gestational diabetes mellitus on motor development in 12-month-old children referred to Qazvin University of Medical Sciences, Iran. Int J Pediatr 2020;8(12):12575–12583. DOI: 10.22038/ijp.2020.48903.3927.
  50. Arabiat D, AL Jabery M, Kemp V, et al. Motor developmental outcomes in children exposed to maternal diabetes during pregnancy: a systematic review and meta-analysis. Int J Environ Res Public Health 2021;18(4):1699. DOI: 10.3390/ijerph18041699.
  51. Courchesne E. New evidence of cerebellar and brainstem hypoplasia in autistic infants, children and adolescents: the MR imaging study by Hashimoto and colleagues. J Autism Dev Disord 1995;25(1):19–22. DOI: 10.1007/BF02178164.
  52. Schmitz C, Rezaie P. The neuropathology of autism: where do we stand? Neuropathol Appl Neurobiol 2008;34(1):4–11. DOI: 10.1111/j.1365-2990.2007.00872.x.
  53. van Kooten IAJ, Palmen SJMC, von Cappeln P, et al. Neurons in the fusiform gyrus are fewer and smaller in autism. Brain 2008;131(4): 987–999. DOI: 10.1093/brain/awn033.
  54. Chauhan A, Chauhan V, Brown WT, et al. Oxidative stress in autism: Increased lipid peroxidation and reduced serum levels of ceruloplasmin and transferrin–the antioxidant proteins. Life Sci 2004;75(21):2539–2549. DOI: 10.1016/j.lfs.2004.04.038.
  55. Ming X, Stein TP, Brimacombe M, et al. Increased excretion of a lipid peroxidation biomarker in autism. Prostaglandins Leukot Essent Fatty Acids 2005;73(5):379–384. DOI: 10.1016/j.plefa.2005.06.002.
  56. Meyer U. Developmental neuroinflammation and schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2013;42:20–34. DOI: 10.1016/j.pnpbp.2011.11.003.
  57. Möller M, Swanepoel T, Harvey BH. Neurodevelopmental animal models reveal the convergent role of neurotransmitter systems, inflammation, and oxidative stress as biomarkers of schizophrenia: implications for novel drug development. ACS Chem Neurosci 2015;6(7):987–1016. DOI: 10.1021/cn5003368.
  58. Lyall K, Pauls DL, Spiegelman D, et al. Pregnancy complications and obstetric suboptimality in association with autism spectrum disorders in children of the nurses’ health study II. Autism Res 2012;5(1):21–30. DOI: 10.1002/aur.228.
  59. Burstyn I, Sithole F, Zwaigenbaum L. Autism spectrum disorders, maternal characteristics and obstetric complications among singletons born in Alberta, Canada. Chronic Dis Can 2010;30(4): 125–134. PMID: 20946713.
  60. Zhang X, Lv CC, Tian J, et al. Prenatal and perinatal risk factors for autism in China. J Autism Dev Disord 2010;40(11):1311–1321. DOI: 10.1007/s10803-010-0992-0.
  61. Hultman CM, Geddes J, Sparén P, et al. Prenatal and perinatal risk factors for schizophrenia, affective psychosis, and reactive psychosis of early onset: case-control study. BMJ 1999;318(7181):421–426. DOI: 10.1136/bmj.318.7181.421.
  62. Cannon M, Jones PB, Murray RM. Obstetric complications and schizophrenia: historical and meta-analytic review. Am J Psychiatry 2002;159(7):1080–1092. DOI: 10.1176/appi.ajp.159.7.1080.
  63. Ji J, Chen T, Sundquist J, et al. Type 1 diabetes in parents and risk of attention deficit/hyperactivity disorder in offspring: a population-based study in Sweden. Diabetes Care 2018;41(4):770–774. DOI: 10.2337/dc17-0592.
  64. Xiang AH, Wang X, Martinez MP, et al. Maternal gestational diabetes mellitus, type 1 diabetes, and type 2 diabetes during pregnancy and risk of ADHD in offspring. Diabetes Care 2018;41(12):2502–2508. DOI: 10.2337/dc18-0733.
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