Mechanisms of Neonatal Respiratory Distress Syndrome Associated with Gestational Diabetes Mellitus

doi:10.12280/gjfckx.20251147

Abstract

Abstract:

Gestational diabetes mellitus (GDM) is a common metabolic disease during pregnancy. It not only increases the risk of preeclampsia, postpartum hemorrhage, and type 2 diabetes mellitus in pregnant women, but also makes the offspring prone to adverse outcomes. Neonatal respiratory distress syndrome (NRDS) is common in infants of mothers with GDM. Studies have shown that the pathological mechanisms of NRDS in infants of GDM mothers involve multiple interrelated pathways: oxidative stress caused by maternal hyperglycemia, systemic inflammatory response, disruption of pulmonary surfactant synthesis, and changes in epigenetic modifications. This review summarizes the latest progress in the mechanisms of NRDS in infants of GDM mothers, aiming to reduce the incidence of NRDS and improve perinatal health outcomes.

Key words: Diabetes, gestational, Respiratory distress syndrome, newborn, Pulmonary surfactants, Oxidative stress, Insulin

ZHANG Xing-ying, YI Feng-xin, WANG Peng-yuan, HAO Wei. Mechanisms of Neonatal Respiratory Distress Syndrome Associated with Gestational Diabetes Mellitus[J]. Journal of International Obstetrics and Gynecology, 2026, 53(1): 98-102.

References 42

[1]	American Diabetes Association Professional Practice Committee. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2022[J]. Diabetes Care, 2022, 45(Suppl 1):S17-S38. doi: 10.2337/dc22-S002.
[2]	Aziz F, Khan MF, Moiz A. Gestational diabetes mellitus, hypertension, and dyslipidemia as the risk factors of preeclampsia[J]. Sci Rep, 2024, 14(1):6182. doi: 10.1038/s41598-024-56790-z. pmid: 38486097
[3]	Lin D, Hu B, Xiu Y, et al. Risk factors for premature rupture of membranes in pregnant women: a systematic review and meta-analysis[J]. BMJ Open, 2024, 14(3):e077727. doi: 10.1136/bmjopen-2023-077727.
[4]	Liu Y, Wang M, Zhou J. Impact of Gestational Diabetes Mellitus on Neonatal Birth Outcomes[J]. Br J Hosp Med(Lond), 2024, 85(11):1-12. doi: 10.12968/hmed.2024.0410.
[5]	Zhu H, Wang Y, Yin H, et al. Risk factors associated with respiratory distress syndrome in late preterm infants[J]. Pak J Med Sci, 2024, 40(9):1947-1952. doi: 10.12669/pjms.40.9.9078. pmid: 39416628
[6]	Sweet DG, Carnielli VP, Greisen G, et al. European Consensus Guidelines on the Management of Respiratory Distress Syndrome: 2022 Update[J]. Neonatology, 2023, 120(1):3-23. doi: 10.1159/000528914.
[7]	Yang F, Liu H, Ding C. Gestational diabetes mellitus and risk of neonatal respiratory distress syndrome: a systematic review and meta-analysis[J]. Diabetol Metab Syndr, 2024, 16(1):294. doi: 10.1186/s13098-024-01539-x. pmid: 39639383
[8]	Zhang J, Mao C, Cao Q, et al. Influencing factors of glycemic control in singleton pregnancies complicated by gestational diabetes mellitus in western China: A retrospective study[J]. Medicine(Baltimore), 2024, 103(38):e39853. doi: 10.1097/MD.0000000000039853.
[9]	Han T, Jin XD, Yang JF, et al. Clinical Analysis of Fetal Lung Development Index and Pregnancy Outcome in Pregnant Women with Gestational Diabetes Mellitus with Satisfactory Blood Glucose Control[J]. Contrast Media Mol Imaging, 2022, 2022:5777804. doi: 10.1155/2022/5777804.
[10]	American Diabetes Association Professional Practice Committee. 8. Obesity and Weight Management for the Prevention and Treatment of Type 2 Diabetes: Standards of Medical Care in Diabetes-2022[J]. Diabetes Care, 2022, 45(Suppl 1):S113-S124. doi: 10.2337/dc22-S008.
[11]	Chen H, Tan Q, Lai S, et al. Association between glycated hemoglobin and the risk of neonatal respiratory distress syndrome in preterm premature rupture of membranes pregnancies[J]. Sci Rep, 2024, 14(1):27122. doi: 10.1038/s41598-024-78679-7.
[12]	Wang R, Zhang Y, Zeng H, et al. Correlation Between Blood Glucose Variability Indices Using Continuous Glucose Monitoring in Gestational Diabetes Patients and Abnormal Glucose Levels 42 Days Postpartum[J]. J Diabetes Res, 2025, 2025:1021066. doi: 10.1155/jdr/1021066.
[13]	Liu Q, Shu S, Zhao X, et al. Retrospective Analysis of the Correlation between Umbilical Blood Flow Index and Maternal and Fetal Outcomes in Pregnant Women with Gestational Diabetes[J]. Br J Hosp Med(Lond), 2025, 86(1):1-12. doi: 10.12968/hmed.2024.0582.
[14]	Erdoğan F, Şenkal E, Özer ÖF, et al. Oxidative stress in maternal milk and cord blood in gestational diabetes mellitus: a prospective study[J]. Sao Paulo Med J, 2022, 140(3):390-397. doi: 10.1590/1516-3180.2021.0209.R1.25082021. pmid: 35508001
[15]	Durga KD, Adhisivam B, Vidya G, et al. Oxidative stress and DNA damage in newborns born to mothers with hyperglycemia-a prospective cohort study[J]. J Matern Fetal Neonatal Med, 2018, 31(18):2396-2401. doi: 10.1080/14767058.2017.1344630.
[16]	Mishra R, Nawas AF, Mendelson CR. Role of NRF2 in immune modulator expression in developing lung[J]. FASEB J, 2021, 35(8):e21758. doi: 10.1096/fj.202100129RR.
[17]	董梦园, 吉玲, 刘萌萌, 等. 呼吸窘迫综合征早产儿发生支气管肺发育不良的危险因素分析[J]. 中国儿童保健杂志, 2021, 29(6):685-688. doi: 10.11852/zgetbjzz2020-2150.
[18]	He MY, Zhang P, Shi N, et al. Nrf2 Is Involved in Hyperglycemia-induced Abnormal Lung Development through both Antioxidation-Dependent and Antioxidation-Independent Activation[J]. Am J Respir Cell Mol Biol, 2023, 69(2):197-209. doi: 10.1165/rcmb.2022-0345OC.
[19]	Tamatam CM, Venkareddy LK, Ankireddy A, et al. Myeloid Nrf2 Protects against Neonatal Oxidant-Stress-Induced Lung Inflammation and Alveolar Simplification in Mice[J]. Antioxidants(Basel), 2024, 13(6):698. doi: 10.3390/antiox13060698.
[20]	Zhao ZW, Lin XX, Guo YZ, et al. Irisin alleviates hyperoxia-induced bronchopulmonary dysplasia through activation of Nrf2/HO-1 pathway[J]. Peptides, 2023, 170:171109. doi: 10.1016/j.peptides.2023.171109.
[21]	Vellers HL, Cho HY, Gladwell W, et al. NRF2 Alters Mitochondrial Gene Expression in Neonate Mice Exposed to Hyperoxia[J]. Antioxidants(Basel), 2022, 11(4):760. doi: 10.3390/antiox11040760.
[22]	Yang Y, Liu Y, Wang Y, et al. Regulation of SIRT1 and Its Roles in Inflammation[J]. Front Immunol, 2022, 13:831168. doi: 10.3389/fimmu.2022.831168.
[23]	Wang Y, Lei F, Lin Y, et al. Peroxisome proliferator-activated receptors as therapeutic target for cancer[J]. J Cell Mol Med, 2024, 28(5):e17931. doi: 10.1111/jcmm.17931.
[24]	He J, Fan F, Li J, et al. SIRT1 alleviates insulin resistance and respiratory distress in late preterm rats by activating QKI5-mediated PPARγ/PI3K/AKT pathway[J]. Cell Cycle, 2023, 22(21/22):2449-2466. doi: 10.1080/15384101.2023.2297567.
[25]	Le T, Dao XD, Nguyen DV, et al. Insulin signaling and its application[J]. Front Endocrinol(Lausanne), 2023, 14:1226655. doi: 10.3389/fendo.2023.1226655.
[26]	Kheirollahi V, Khadim A, Kiliaris G, et al. Transcriptional Profiling of Insulin-like Growth Factor Signaling Components in Embryonic Lung Development and Idiopathic Pulmonary Fibrosis[J]. Cells, 2022, 11(12):1973. doi: 10.3390/cells11121973.
[27]	Yang L, Zhang Z, Wang D, et al. Targeting mTOR Signaling in Type 2 Diabetes Mellitus and Diabetes Complications[J]. Curr Drug Targets, 2022, 23(7):692-710. doi: 10.2174/1389450123666220111115528. pmid: 35021971
[28]	Zhang K, Yao E, Chuang E, et al. mTORC1 signaling facilitates differential stem cell differentiation to shape the developing murine lung and is associated with mitochondrial capacity[J]. Nat Commun, 2022, 13(1):7252. doi: 10.1038/s41467-022-34763-y. pmid: 36433959
[29]	Bao J, Bao W, Song Y, et al. The dual role of mTOR signaling in lung development and adult lung diseases[J]. Cell Biosci, 2025, 15(1):103. doi: 10.1186/s13578-025-01428-4. pmid: 40676702
[30]	Luo Q, Chai X, Xin X, et al. Maternal hyperglycemia inhibits pulmonary vasculogenesis during mouse fetal lung development by promoting GβL Ubiquitination-dependent mammalian target of Rapamycin assembly[J]. Diabetol Metab Syndr, 2023, 15(1):49. doi: 10.1186/s13098-022-00974-y. pmid: 36927703
[31]	Ikeda H, Shiojima I, Oka T, et al. Increased Akt-mTOR signaling in lung epithelium is associated with respiratory distress syndrome in mice[J]. Mol Cell Biol, 2011, 31(5):1054-1065. doi: 10.1128/MCB.00732-10. pmid: 21189286
[32]	Jenkins KJ. Evaluation of Treatment Effect of Sirolimus on Pediatric Pulmonary Vein Stenosis Using a Neonatal Rat Model Induced by Bilateral Pulmonary Vein Banding[J]. JACC Basic Transl Sci, 2025, 10(7):101296. doi: 10.1016/j.jacbts.2025.04.010.
[33]	Hurtado-Sierra D, Ramos Garzón JX, Romero-Guevara SL, et al. Everolimus and sirolimus in the treatment of cardiac rhabdomyomas in neonates[J]. Pediatr Res, 2025 Apr 26. doi: 10.1038/s41390-025-04043-8.
[34]	Parsons A, Netsanet A, Seedorf G, et al. Understanding the role of placental pathophysiology in the development of bronchopulmonary dysplasia[J]. Am J Physiol Lung Cell Mol Physiol, 2022, 323(6):L651-L658. doi: 10.1152/ajplung.00204.2022.
[35]	Wang Y, Xiao T, Zhao C, et al. The Regulation of Exosome Generation and Function in Physiological and Pathological Processes[J]. Int J Mol Sci, 2023, 25(1):255. doi: 10.3390/ijms25010255.
[36]	Gurunathan S, Kang MH, Kim JH. Functions, A Comprehensive Review on Factors Influences Biogenesis, Therapeutic and Clinical Implications of Exosomes[J]. Int J Nanomedicine, 2021, 16:1281-1312. doi: 10.2147/IJN.S291956.
[37]	Chen P, Gu M, Wan S, et al. Gestational Diabetes Mellitus Impedes Fetal Lung Development Through Exosome-Dependent Crosstalk Between Trophoblasts and Lung Epithelial Cells[J]. Int J Nanomedicine, 2023, 18:641-657. doi: 10.2147/IJN.S396194.
[38]	Vladu IM, Clenciu D, Mitrea A, et al. Maternal and Fetal Metabolites in Gestational Diabetes Mellitus: A Narrative Review[J]. Metabolites, 2022, 12(5):383. doi: 10.3390/metabo12050383.
[39]	肖平娟, 邵庆亮. 妊娠期糖尿病对子代肺成熟度影响的代谢组学研究进展[J]. 中国儿童保健杂志, 2019, 27(6):617-619. doi: 10.11852/zgetbjzz2018-0623.
[40]	Cai X, Pan S, Li M, et al. Non-Targeted Metabolomics Analysis of Mother and Infant in Gestational Diabetes Mellitus and Neonatal Clinical Characterization[J]. Clin Lab, 2024 Jun 1, 70(6). doi: 10.7754/Clin.Lab.2023.230527.
[41]	Buck CO, McCollum S, Wang W, et al. Alterations in newborn metabolite patterns with preterm birth and diabetes in pregnancy[J]. Pediatr Res, 2025, 98(3):1023-1032. doi: 10.1038/s41390-025-03844-1.
[42]	Yin X, Yu T, Jiang D, et al. Metabolic profiles in gestational diabetes mellitus can reveal novel biomarkers for prediction of adverse neonatal outcomes[J]. Front Pediatr, 2024, 12:1432113. doi: 10.3389/fped.2024.1432113.