Exposure to Maternal Diabetes during Pregnancy Is Associated with Aggravated Short-Term Neonatal and Neurological Outcomes following Perinatal Hypoxic–Ischemic Encephalopathy

Abstract

Objective Infants of diabetic mothers (IDM) are at higher risk of perinatal morbidities and glycemic instability, but the impact of maternal diabetes on neonatal and neurological short-term outcomes of neonates with hypoxic–ischemic encephalopathy (HIE) remains poorly described. Our objective was to determine the impact of maternal diabetes on neonatal and neurological short-term outcomes following neonatal HIE.

Study Design This was a retrospective single-center study including 102 term neonates with HIE who received therapeutic hypothermia (TH) treatment between 2013 and 2020. Multiple regression analysis was used to assess the relationship between the presence of maternal diabetes and short-term outcomes.

Results Neonates with HIE and maternal diabetes exposure had a significantly lower gestational age at birth (38.6 vs. 39.7 weeks of gestation, p = 0.005) and a significantly higher mean birth weight (3,588 ± 752 vs. 3,214 ± 514 g, p = 0.012). IDM with HIE were ventilated for longer duration (8 vs. 4 days, p = 0.0047) and had a longer neonatal intensive care unit (NICU) stay (18 vs. 11 days, p = 0.0483) as well as took longer time to reach full oral feed (15 vs. 7 days, p = 0.0432) compared with neonates of nondiabetic mother. Maternal diabetes was also associated with an increased risk of death or abnormal neurological examination at discharge in neonates with HIE (odds ratio: 6.41 [1.54–26.32]).

Conclusion In neonates with HIE, maternal diabetes is associated with an increased risk of death or short-term neonatal morbidities, such as longer duration of ventilation, prolonged neonatal stay, greater need for tube feeding, and being discharged with an abnormal neurological examination. Strategies to prevent, reduce, or better control maternal diabetes during pregnancy should be prioritized to minimize complications after perinatal asphyxia.

Key Points

• Maternal DB is associated with unfavorable outcomes.

• IDM have longer ventilatory support and tube feeding.

• IDM have higher risk of abnormal neurological examination.

Keywords

hypoxic–ischemic encephalopathy - maternal diabetes - asphyxia - neonatal outcomes - neurological examinations

Publikationsverlauf

Eingereicht: 30. August 2022

Angenommen: 24. Februar 2023

Accepted Manuscript online:
14. März 2023

Artikel online veröffentlicht:
18. April 2023

• References

• 1 Rossi AC, Prefumo F. Antepartum and intrapartum risk factors for neonatal hypoxic-ischemic encephalopathy: a systematic review with meta-analysis. Curr Opin Obstet Gynecol 2019; 31 (06) 410-417
• 2 Fatemi A, Wilson MA, Johnston MV. Hypoxic-ischemic encephalopathy in the term infant. Clin Perinatol 2009; 36 (04) 835-858, vii
• 3 Azzopardi D, Strohm B, Marlow N. et al; TOBY Study Group. Effects of hypothermia for perinatal asphyxia on childhood outcomes. N Engl J Med 2014; 371 (02) 140-149
• 4 Shankaran S. Therapeutic hypothermia for neonatal encephalopathy. Curr Opin Pediatr 2015; 27 (02) 152-157
• 5 Lemyre B, Chau V. Hypothermia for newborns with hypoxic-ischemic encephalopathy. Paediatr Child Health 2018; 23 (04) 285-291
• 6 Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 2013; 2013 (01) CD003311
• 7 Tarvonen M, Hovi P, Sainio S, Vuorela P, Andersson S, Teramo K. Intrapartal cardiotocographic patterns and hypoxia-related perinatal outcomes in pregnancies complicated by gestational diabetes mellitus. Acta Diabetol 2021; 58 (11) 1563-1573
• 8 Persson M, Norman M, Hanson U. Obstetric and perinatal outcomes in type 1 diabetic pregnancies: a large, population-based study. Diabetes Care 2009; 32 (11) 2005-2009
• 9 Persson M, Johansson S, Villamor E, Cnattingius S. Maternal overweight and obesity and risks of severe birth-asphyxia-related complications in term infants: a population-based cohort study in Sweden. PLoS Med 2014; 11 (05) e1001648
• 10 Beta J, Khan N, Fiolna M, Khalil A, Ramadan G, Akolekar R. Maternal and neonatal complications of fetal macrosomia: cohort study. Ultrasound Obstet Gynecol 2019; 54 (03) 319-325
• 11 Barrois M, Patkai J, Delorme P, Chollat C, Goffinet F, Le Ray C. Factors associated with neonatal hypoxic ischemic encephalopathy in infants with an umbilical artery pH less than 7.00. Eur J Obstet Gynecol Reprod Biol 2019; 236: 69-74
• 12 Bilous RW, Jacklin PB, Maresh MJ, Sacks DA. Resolving the gestational diabetes diagnosis conundrum: the need for a randomized controlled trial of treatment. Diabetes Care 2021; 44 (04) 858-864
• 13 Cnattingius S, Lindam A, Persson M. Risks of asphyxia-related neonatal complications in offspring of mothers with type 1 or type 2 diabetes: the impact of maternal overweight and obesity. Diabetologia 2017; 60 (07) 1244-1251
• 14 Cnattingius S, Villamor E, Johansson S. et al. Maternal obesity and risk of preterm delivery. JAMA 2013; 309 (22) 2362-2370
• 15 Voormolen DN, de Wit L, van Rijn BB. et al. Neonatal hypoglycemia following diet-controlled and insulin-treated gestational diabetes mellitus. Diabetes Care 2018; 41 (07) 1385-1390
• 16 Feig DS, Berger H, Donovan L. et al; Diabetes Canada Clinical Practice Guidelines Expert Committee. Diabetes and pregnancy. Can J Diabetes 2018; 42 (suppl 1): S255-S282
• 17 Pintaudi B, Fresa R, Dalfrà M. et al; STRONG Study Collaborators. The risk stratification of adverse neonatal outcomes in women with gestational diabetes (STRONG) study. Acta Diabetol 2018; 55 (12) 1261-1273
• 18 Tam EWY, Haeusslein LA, Bonifacio SL. et al. Hypoglycemia is associated with increased risk for brain injury and adverse neurodevelopmental outcome in neonates at risk for encephalopathy. J Pediatr 2012; 161 (01) 88-93
• 19 Nadeem M, Murray DM, Boylan GB, Dempsey EM, Ryan CA. Early blood glucose profile and neurodevelopmental outcome at two years in neonatal hypoxic-ischaemic encephalopathy. BMC Pediatr 2011; 11: 10
• 20 Basu SK, Kaiser JR, Guffey D, Minard CG, Guillet R, Gunn AJ. CoolCap Study Group. Hypoglycaemia and hyperglycaemia are associated with unfavourable outcome in infants with hypoxic ischaemic encephalopathy: a post hoc analysis of the CoolCap Study. Arch Dis Child Fetal Neonatal Ed 2016; 101 (02) F149-F155
• 21 Salhab WA, Wyckoff MH, Laptook AR, Perlman JM. Initial hypoglycemia and neonatal brain injury in term infants with severe fetal acidemia. Pediatrics 2004; 114 (02) 361-366
• 22 Parmentier CEJ, de Vries LS, van der Aa NE. et al. Hypoglycemia in infants with hypoxic-ischemic encephalopathy is associated with additional brain injury and worse neurodevelopmental outcome. J Pediatr 2022; 245: 30-38.e1
• 23 Montaldo P, Caredda E, Pugliese U. et al. Continuous glucose monitoring profile during therapeutic hypothermia in encephalopathic infants with unfavorable outcome. Pediatr Res 2020; 88 (02) 218-224
• 24 Spies EE, Lababidi SL, McBride MC. Early hyperglycemia is associated with poor gross motor outcome in asphyxiated term newborns. Pediatr Neurol 2014; 50 (06) 586-590
• 25 Shah R, Harding J, Brown J, McKinlay C. Neonatal glycaemia and neurodevelopmental outcomes: a systematic review and meta-analysis. Neonatology 2019; 115 (02) 116-126
• 26 Bonifacio SL, Hutson S. The term newborn: evaluation for hypoxic-ischemic encephalopathy. Clin Perinatol 2021; 48 (03) 681-695
• 27 Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch Neurol 1976; 33 (10) 696-705
• 28 The Royal College of Physicians and Surgeons of Canada, Neonatal-Perinatal Medicine Competencies. . 2021 version 1.0. available. Accessed March 23, 2023 at: https://www.royalcollege.ca/rcsite/documents/ibd/pediatrics_examformat_e
• 29 Amiel-Tison C. Update of the Amiel-Tison neurologic assessment for the term neonate or at 40 weeks corrected age. Pediatr Neurol 2002; 27 (03) 196-212
• 30 Piper MC, Pinnell LE, Darrah J, Maguire T, Byrne PJ. Construction and validation of the Alberta Infant Motor Scale (AIMS). Can J Public Health 1992; 83 (suppl 2): S46-S50
• 31 Darrah J, Piper M, Watt MJ. Assessment of gross motor skills of at-risk infants: predictive validity of the Alberta Infant Motor Scale. Dev Med Child Neurol 1998; 40 (07) 485-491
• 32 Richardson DK, Gray JE, McCormick MC, Workman K, Goldmann DA. Score for Neonatal Acute Physiology: a physiologic severity index for neonatal intensive care. Pediatrics 1993; 91 (03) 617-623
• 33 Harsha SS, Archana BR. SNAPPE-II (score for neonatal acute physiology with perinatal extension-II) in predicting mortality and morbidity in NICU. J Clin Diagn Res 2015; 9 (10) SC10-SC12
• 34 Ornoy A, Becker M, Weinstein-Fudim L, Ergaz Z. Diabetes during pregnancy: a maternal disease complicating the course of pregnancy with long-term deleterious effects on the offspring. a clinical review. Int J Mol Sci 2021; 22 (06) 1-38
• 35 Billionnet C, Mitanchez D, Weill A. et al. Gestational diabetes and adverse perinatal outcomes from 716,152 births in France in 2012. Diabetologia 2017; 60 (04) 636-644
• 36 Mitanchez D, Yzydorczyk C, Simeoni U. What neonatal complications should the pediatrician be aware of in case of maternal gestational diabetes?. World J Diabetes 2015; 6 (05) 734-743
• 37 Khalak R, Horgan M. Association of maternal obesity and neonatal hypoxic ischemic encephalopathy. J Perinatol 2020; 40 (01) 174-175
• 38 Aslam HM, Saleem S, Afzal R. et al. “Risk factors of birth asphyxia”. Ital J Pediatr 2014; 40: 94
• 39 Feng R, Liu L, Zhang YY, Yuan ZS, Gao L, Zuo CT. Unsatisfactory glucose management and adverse pregnancy outcomes of gestational diabetes mellitus in the real world of clinical practice: a retrospective study. Chin Med J (Engl) 2018; 131 (09) 1079-1085
• 40 Battarbee AN, Venkatesh KK, Aliaga S, Boggess KA. The association of pregestational and gestational diabetes with severe neonatal morbidity and mortality. J Perinatol 2020; 40 (02) 232-239
• 41 Rashid FB, Khatoon H, Hasnat MA, Amin R, Azad AK. Perinatal complications in diabetes mellitus with pregnancy: comparison between gestational diabetes mellitus (GDM) and diabetes mellitus prior to pregnancy. Mymensingh Med J 2017; 26 (01) 124-130
• 42 Perea V, Bertran B, Bellart J. et al. Impaired awareness of hypoglycaemia: a new risk factor for adverse pregnancy outcomes in type 1 diabetes. Diabetes Metab Res Rev 2019; 35 (07) e3176
• 43 Zeng X, Ren H, Zhu Y. et al. Gp91 phox (NOX 2) in activated microglia exacerbates neuronal damage induced by oxygen glucose deprivation and hyperglycemia in an in vitro model. Cell Physiol Biochem 2018; 50: 721-733
• 44 Zhang T, He MT, Zhang XP, Jing L, Zhang JZ. Uncoupling protein 2 deficiency enhances NLRP3 inflammasome activation following hyperglycemia-induced exacerbation of cerebral ischemia and reperfusion damage in vitro and in vivo. Neurochem Res 2021; 46 (06) 1359-1371
• 45 Li Y, Wang W, Zhang D. Maternal diabetes mellitus and risk of neonatal respiratory distress syndrome: a meta-analysis. Acta Diabetol 2019; 56 (07) 729-740
• 46 Yildiz Atar H, Baatz JE, Ryan RM. Molecular mechanisms of maternal diabetes effects on fetal and neonatal surfactant. Children (Basel) 2021; 8 (04) 281
• 47 Simard MN, Lambert J, Lachance C, Audibert F, Gosselin J. Interexaminer reliability of Amiel-Tison neurological assessments. Pediatr Neurol 2009; 41 (05) 347-352
• 48 Paro-Panjan D, Neubauer D, Kodric J, Bratanic B. Amiel-Tison Neurological Assessment at term age: clinical application, correlation with other methods, and outcome at 12 to 15 months. Dev Med Child Neurol 2005; 47 (01) 19-26
• 49 Paro-Panjan D, Sustersic B, Neubauer D. Comparison of two methods of neurologic assessment in infants. Pediatr Neurol 2005; 33 (05) 317-324
• 50 Chen HY, Ho YJ, Chou HC. et al. The role of transforming growth factor-beta in retinal ganglion cells with hyperglycemia and oxidative stress. Int J Mol Sci 2020; 21 (18) 1-21
• 51 Ornoy A, Wolf A, Ratzon N, Greenbaum C, Dulitzky M. Neurodevelopmental outcome at early school age of children born to mothers with gestational diabetes. Arch Dis Child Fetal Neonatal Ed 1999; 81 (01) F10-F14
• 52 Chen S, Zhao S, Dalman C, Karlsson H, Gardner R. Association of maternal diabetes with neurodevelopmental disorders: autism spectrum disorders, attention-deficit/hyperactivity disorder and intellectual disability. Int J Epidemiol 2021; 50 (02) 459-474