Maternal pregestational diabetes as an factor in the genesis of congenital malformations of the fetus

Cover Page


Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access

Abstract

This review article summarizes the results of modern clinical studies performed domestically or abroad, which provide information on maternal pregestational diabetes (type 1 or 2) shaping a spectrum of congenital malformations of the fetus. Advances in the treatment of diabetes mellitus have reduced the risk of fetal congenital malformations in pregnant women with the disease, but an increase in its incidence among women of childbearing age indicates that this cause of congenital malformations is becoming more relevant every year. This review article presents four diabetes-mediated pathways for the genesis of fetal congenital malformations: those associated with metabolic imbalance or oxidative stress, genetically mediated and caused by insufficient inhibition of apoptosis. Thus, based on clinical studies and meta-analysis over the past ten years, it has been demonstrated that women with pregestational diabetes mellitus are at the highest risk of developing fetal congenital malformations. Achievement of diabetes compensation and physiological nutritional status in such patients determines the favorable course of all stages of pregnancy.

Full Text

Restricted Access

About the authors

Nodari D. Shengelia

Center for Family Planning and Reproduction

Email: nod802210@yandex.ru
ORCID iD: 0000-0003-0677-494X
SPIN-code: 7495-9480

MD

Russian Federation, 3 Mendeleevskaya Line, Saint Petersburg, 199034

Olesya N. Bespalova

The Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott

Email: shiggerra@mail.ru
ORCID iD: 0000-0002-6542-5953
SPIN-code: 4732-8089
Scopus Author ID: 57189999252
ResearcherId: D-3880-2018

MD, Dr. Sci. (Med.)

Russian Federation, 3 Mendeleevskaya Line, Saint Petersburg, 199034

Margarita O. Shengelia

The Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott

Author for correspondence.
Email: bakleicheva@gmail.com
ORCID iD: 0000-0002-0103-8583
SPIN-code: 7831-2698
Scopus Author ID: 57203248029
ResearcherId: AGN-5365-2022

MD

Russian Federation, 3 Mendeleevskaya Line, Saint Petersburg, 199034

References

  1. Holmes LB, Driscoll SG, Atkins L. Etiologic heterogeneity of neural-tube defects. N Engl J Med. 1976;294(7):365−369. doi: 10.1056/NEJM197602122940704
  2. Gabbe SG. Pregnancy in women with diabetes mellitus. The beginning. Clin Perinatol. 1993;20(3):507−515.
  3. Hod M, Jovanovic L, Di Renzo GC, de Leiva A, editors. Textbook of diabetes and pregnancy. 2nd edition. London: Informa Healthcare; 2008.
  4. Freinkel N. Banting lecture 1980. Of pregnancy and progeny. Diabetes. 1980;29(12):1023−1035. doi: 10.2337/diab.29.12.1023
  5. Fahed AC, Gelb BD, Seidman JG, Seidman CE. Genetics of congenital heart disease: the glass half empty. Circ Res. 2013;112(4):707−720. [Corrected and republished from: Circ Res. 2013;112(12):e182]. doi: 10.1161/CIRCRESAHA.112.300853
  6. Kappen C, Kruger C, MacGowan J, Salbaum JM. Maternal diet modulates the risk for neural tube defects in a mouse model of diabetic pregnancy. Reprod Toxicol. 2011;31(1):41−49. doi: 10.1016/j.reprotox.2010.09.002
  7. Salbaum JM, Kappen C. Diabetic embryopathy: a role for the epigenome? Birth Defects Res A Clin Mol Teratol. 2011;91(8):770−780. doi: 10.1002/bdra.20807
  8. Wang L, Lin S, Yi D, et al. Apoptosis, expression of PAX3 and P53, and caspase signal in fetuses with neural tube defects. Birth Defects Res. 2017;109(19):1596−1604. doi: 10.1002/bdr2.1094
  9. Lin S, Ren A, Wang L, et al. Aberrant methylation of Pax3 gene and neural tube defects in association with exposure to polycyclic aromatic hydrocarbons. Clin Epigenetics. 2019;11(1):13. doi: 10.1186/s13148-019-0611-7
  10. Pani L, Horal M, Loeken MR. Rescue of neural tube defects in Pax-3-deficient embryos by p53 loss of function: implications for Pax-3-dependent development and tumorigenesis. Genes Dev. 2002;16(6):676−680. doi: 10.1101/gad.969302
  11. Bennett GD, An J, Craig JC, et al. Neurulation abnormalities secondary to altered gene expression in neural tube defect susceptible Splotch embryos. Teratology. 1998;57(1):17−29. doi: 10.1002/(SICI)1096-9926(199801)57:1<17::AID-TERA4>3.0.CO;2-4
  12. Floris I, Descamps B, Vardeu A, et al. Gestational diabetes mellitus impairs fetal endothelial cell functions through a mechanism involving microRNA-101 and histone methyltransferase enhancer of zester homolog-2. Arterioscler Thromb Vasc Biol. 2015;35(3):664−674. doi: 10.1161/ATVBAHA.114.304730
  13. Zabihi S, Loeken MR. Understanding diabetic teratogenesis: where are we now and where are we going? Birth Defects Res A Clin Mol Teratol. 2010;88(10):779−790. doi: 10.1002/bdra.20704
  14. Agha MM, Glazier RH, Moineddin R, Booth G. Congenital abnormalities in newborns of women with pregestational diabetes: A time-trend analysis, 1994 to 2009. Birth Defects Res A Clin Mol Teratol. 2016;106(10):831−839. doi: 10.1002/bdra.23548
  15. 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(4):636−644. doi: 10.1007/s00125-017-4206-6
  16. Liu S, Rouleau J, León JA, et al. Canadian perinatal surveillance system. Impact of pre-pregnancy diabetes mellitus on congenital anomalies, Canada, 2002−2012. Health Promot Chronic Dis Prev Can. 2015;35(5):79−84. doi: 10.24095/hpcdp.35.5.01
  17. Parimi M, Nitsch D. A systematic review and meta-analysis of diabetes during pregnancy and congenital genitourinary abnormalities. Kidney Int Rep. 2020;5(5):678−693. doi: 10.1016/j.ekir.2020.02.1027
  18. Minakova E, Warner BB. Maternal immune activation, central nervous system development and behavioral phenotypes. Birth Defects Res. 2018;110(20):1539−1550. doi: 10.1002/bdr2.1416.
  19. Kappen C, Salbaum JM. Gene expression in teratogenic exposures: a new approach to understanding individual risk. Reprod Toxicol. 2014;45:94−104. doi: 10.1016/j.reprotox.2013.12.008
  20. HAPO Study Cooperative Research Group; Metzger BE, Lowe LP, et al. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med. 2008;358(19):1991−2002. doi: 10.1056/NEJMoa0707943
  21. 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(6):2965. doi: 10.3390/ijms22062965
  22. Wahabi H, Fayed A, Esmaeil S, et al. Prevalence and complications of pregestational and gestational diabetes in Saudi women: analysis from Riyadh mother and baby cohort study (RAHMA). Biomed Res Int. 2017;2017:6878263.
  23. Ornoy A, Reece EA, Pavlinkova G, et al. Effect of maternal diabetes on the embryo, fetus, and children: congenital anomalies, genetic and epigenetic changes and developmental outcomes. Birth Defects Res C Embryo Today. 2015;105(1):53−72. doi: 10.1002/bdrc.21090
  24. Liu S, Evans J, MacFarlane AJ, et al. Association of maternal risk factors with the recent rise of neural tube defects in Canada. Paediatr Perinat Epidemiol. 2019;33(2):145−153. doi: 10.1111/ppe.12543
  25. Nakano H, Fajardo VM, Nakano A. The role of glucose in physiological and pathological heart formation. Dev Biol. 2021;475:222−233. doi: 10.1016/j.ydbio.2021.01.020
  26. Corrigan N, Brazil DP, McAuliffe F. Fetal cardiac effects of maternal hyperglycemia during pregnancy. Birth Defects Res A Clin Mol Teratol. 2009;85(6):523−530. doi: 10.1002/bdra.20567
  27. Burns JS, Manda G. Metabolic pathways of the warburg effect in health and disease: perspectives of choice, chain or chance. Int J Mol Sci. 2017;18(12):2755. doi: 10.3390/ijms18122755

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2. Fig. 1. Balance of p53 activity upon Pax3 expression. Before differentiation, early embryonic cells are proliferative (self-renewing), have the potential to differentiate into many cell types (pluripotent), and fuel metabolism is predominantly anaerobic (glycolytic). After terminal differentiation, cells become non-proliferative (post-mitotic) and can no longer differentiate into other cell types (fixed cell type), and fuel metabolism is predominantly aerobic (oxidative). p53 activation promotes terminal cell differentiation. Pax3 may be required to balance p53 activity by maintaining the characteristics of undifferentiated cells until the developmental stage at which terminal differentiation should occur. In addition to neuroepithelium and neural crest, progenitor cells of other embryonic organs may contain other regulators of the phenotype of undifferentiated cells [10]

Download (136KB)
Indexing metadata
3. Fig. 2. Biochemical / molecular pathway in which maternal hyperglycemia can cause birth defects. Excessive glucose transported to the embryo is actively metabolized. The increased glycolytic flux stimulates the synthesis of glucosamine-6-phosphate, which inhibits the activity of glucose-6-phosphate dehydrogenase, which reduces the synthesis of nicotinamide adenine dinucleotide phosphate and subsequently reduces the synthesis of reduced glutathione. Also, active glucose uptake stimulates the diacylglycerol / protein kinase pathway, which is able to inhibit the synthesis of nicotinamide adenine dinucleotide phosphate and reduced glutathione. Increased glucose metabolism, including aerobic metabolism, increases oxygen consumption faster than it can be delivered, which stimulates superoxide production. The increased production of superoxide increases the production of hydrogen peroxide, which, due to the reduced availability of reduced glutathione, leads to an increase in the production of the hydroxyl radical rather than water. The resulting oxidative stress suppresses the expression of critical regulatory genes (such as Pax3) and promotes derepression of the cell cycle regulator (such as p53), leading to apoptosis. The loss of a critical mass of organ progenitor cells that are at the stage of active formation leads to the formation of congenital malformations of the fetus [27]. NADP+ — nicotinamide adenine dinucleotide phosphate; NADPH is reduced form of NADP+ Сигнальный путь мембранных фосфолипидов Membrane phospholipid signaling pathways

Download (284KB)
Indexing metadata
4. Fig. 3. Possible targets for the prevention of diabetic embryopathy. Maternal hyperglycemia leads to increased oxidative stress through the production of reactive oxygen species, partly produced by mitochondria. The reactive oxygen species produced cause membrane damage, which in turn activates programmed cell death through pro-apoptotic proteins. Upregulation of pro-apoptotic proteins leads to endoplasmic stress and cell death. Abnormal apoptosis causes malformations of the main organ systems of the developing fetus [23]

Download (216KB)
Indexing metadata

Copyright (c) 2022 Eсо-Vector


СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77 - 66759 от 08.08.2016 г. 
СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия Эл № 77 - 6389 от 15.07.2002 г.


This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies