Diabetes-Induced Birth Defects: What Do We Know? What Can We Do?
Diabetes and Pregnancy (CJ Homko, Section Editor)
First Online: 15 December 2011 DOI:
Cite this article as: Reece, E.A. Curr Diab Rep (2012) 12: 24. doi:10.1007/s11892-011-0251-6 Abstract
Birth defects are the leading cause of infant mortality in the United States, which has one of the highest infant mortality rates in the developed world. Many of these birth defects can be attributed to pre-existing, or pregestational, diabetes in pregnancy, which significantly increases a mother’s risk of having a child with a major birth defect. Strict preconceptional and early pregnancy glucose control, supplementation with multivitamins and fatty acids, and lower glycemic dietary management have been shown to reduce the incidence of birth defects in experimental and epidemiologic studies. However, because more than half of pregnancies are unplanned, these methods are not generalizable across the population. Thus, better interventions are urgently needed. Based on what we know about the molecular pathophysiology of diabetic embryopathy, our laboratory and others are developing interventions against to key molecular targets in this multifactorial disease process.
Keywords Antioxidant therapy Birth defects Fatty acid Folic acid Diabetic embryopathy Dietary supplementation Hyperglycemia Infant mortality Pregnancy Glucose control Molecular pathogenesis Preconception care Diabetes References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Save the Children. State of the World’s Mothers 2011. Champions for Children. Available at:
. Accessed 11-3-11.
Heron M, Tejada-Vera B. Deaths: leading causes for 2005. Natl Vital Stat Rep. 2009;58(8):1–97.
Birth Defects and Congenital Anomolies. Faststats. Available at:
. Accessed 11-2-11.
World Health Organization. Birth Defects. Report by the Secretariat. Available on-line at:
. Accessed 10-19-11
Fetita LS, Sobngwi E, Serradas P, et al. Consequences of fetal exposure to maternal diabetes in offspring. J Clin Endocrinol Metab. 2006;91:3718–24.
Potenza MA, Nacci C, Gagliardi S, Montagnani M. Cardiovascular complications in diabetes: lessons from animal models. Curr Med Chem. 2011;18:1806–19.
Eidem I, Stene LC, Henriksen T, et al. Congenital anomalies in newborns of women with type 1 diabetes: nationwide population-based study in Norway, 1999–2004. Acta Obstet Gynecol Scand. 2010;89:1403–11.
Biggio Jr JR, Chapman V, Neely C, et al. Fetal anomalies in obese women: the contribution of diabetes. Obstet Gynecol. 2010;115:290–6.
Correa A, Gilboa SM, Besser LM, et al. Diabetes mellitus and birth defects. Am J Obstet Gynecol. 2008;199:237.e1–9.
Reece EA, Homko CJ, Wu YK. Multifactorial basis of the syndrome of diabetic embryopathy. Teratology. 1996;54:171–82.
Reece EA, Pinter E, Homko C, et al. The yolk sac theory: closing the circle on why diabetes-associated malformations occur. J Soc Gynecol Investig. 1994;1:3–13.
Mironiuk M, Kietlińska Z, Jezierska-Kasprzyk K, Piekosz-Orzechowska B. A class of diabetes in mother, glycemic control in early pregnancy and occurrence of congenital malformations in newborn infants. Clin Exp Obstet Gynecol. 1997;24:193–7.
Reece EA, Gabrielli S, Abdalla M. The prevention of diabetes-associated birth defects. Semin Perinatol. 1988;12:292–301.
Hone J, Jovanovic L. Approach to the patient with diabetes during pregnancy. J Clin Endocrinol Metab. 2010;95:3578–85.
Homko CJ, Khandelwal M. Glucose monitoring and insulin therapy during pregnancy. Obstet Gynecol Clin North Am. 1996;23:47–74.
Reece EA, Homko CJ. Diabetes mellitus in pregnancy. What are the best treatment options? Drug Saf. 1998;18:209–20.
Kitzmiller JL, Gavin LA, Gin GD, et al. Preconception care of diabetes. Glycemic control prevents congenital anomalies. JAMA. 1991;265:731–6.
Fuhrmann K, Reiher H, Semmler K, Glöckner E. The effect of intensified conventional insulin therapy before and during pregnancy on the malformation rate in offspring of diabetic mothers. Exp Clin Endocrinol. 1984;83:173–7.
Finer LB, Henshaw SK. Disparities in rates of unintended pregnancy in the United States, 1994 and 2001. Perspect Sex Reprod Health. 2006;38:90–6.
HAPO Study Cooperative Research Group, Metzger BE, Lowe LP, et al. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med. 2008;358:1991–2002.
Dalewitz J, Khan N, Hershey CO. Barriers to control of blood glucose in diabetes mellitus. Am J Med Qual. 2000;15:16–25.
Hay LC, Wilmshurst EG, Fulcher G. Unrecognized hypo- and hyperglycemia in well-controlled patients with type 2 diabetes mellitus: the results of continuous glucose monitoring. Diabetes Technol Ther. 2003;5:19–26.
Vaddiraju S, Burgess DJ, Tomazos I, et al. Technologies for continuous glucose monitoring: current problems and future promises. J Diabetes Sci Technol. 2010;4:1540–62.
Wilson RD, Johnson JA, Wyatt P, et al. Pre-conceptional vitamin/folic acid supplementation 2007: the use of folic acid in combination with a multivitamin supplement for the prevention of neural tube defects and other congenital anomalies. J Obstet Gynaecol Can. 2007;29:1003–26.
Bánhidy F, Dakhlaoui A, Puhó EH, Czeizel AA. Is there a reduction of congenital abnormalities in the offspring of diabetic pregnant women after folic acid supplementation? A population-based case–control study. Congenit Anom (Kyoto). 2011;51:80–6.
Correa A, Botto L, Liu Y, Mulinare J, Erickson JD. Do multivitamin supplements attenuate the risk for diabetes-associated birth defects? Pediatrics. 2003;111:1146–51.
Wallach JB, Rey MJ. A socioeconomic analysis of obesity and diabetes in New York City. Prev Chronic Dis. 2009;6:A108.
Waller K. Prepregnancy obesity as a risk factor for structural birth defects. Arch Pediatr Adolesc Med. 2007;161:745–50.
Carmichael SL, Yang W, Feldkamp ML, et al. Reduced risks of neural tube defects and orofacial clefts with higher diet quality. Arch Pediatr Adolesc Med. 2011; Oct 3. [Epub ahead of print]
Stotland NE, Gilbert P, Bogetz A, et al. Preventing excessive weight gain in pregnancy: how do prenatal care providers approach counseling? J Womens Health (Larchmt). 2010;19:807–14.
Jay M, Gillespie C, Ark T, et al. Do internists, pediatricians, and psychiatrists feel competent in obesity care? Using a needs assessment to drive curriculum design. J Gen Intern Med. 2008;23:1066–70.
Chang MW, Nitzke S, Guilford E, et al. Motivators and barriers to healthful eating and physical activity among low-income overweight and obese mothers. J Am Diet Assoc. 2008;108:1023–8.
Reece EA, Homko CJ. Prepregnancy care and the prevention of fetal malformations in the pregnancy complicated by diabetes. Clin Obstet Gynecol. 2007;50:990–7.
Piomelli D. Arachidonic acid in cell signalling. Austin: Chapmam and Hall; 1996.
Jawerbaum A, Gonzalez E. The role of alterations in arachidonic acid metabolism and nitric oxide homeostasis in rat models of diabetes during early pregnancy. Curr Pharm Des. 2005;11:1327–42.
Wiznitzer A, Furman B, Mazor M, Reece EA. The role of prostanoids in the development of diabetic embryopathy. Semin Reprod Endocrinol. 1999;17:175–81.
Chang HY, Locker J, Lu R, Schuster VL. Failure of postnatal ductus arteriosus closure in prostaglandin transporter-deficient mice. Circulation. 2010;121:529–36.
Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414:813–20.
Kukuljan M, Vergara L, Stojilkovic SS. Modulation of the kinetics of inositol 1,4,5-trisphosphate-induced [Ca2+]i oscillations by calcium entry in pituitary gonadotrophs. Biophys J. 1997;72:698–707.
Larner J. D-chiro-inositol—its functional role in insulin action and its deficit in insulin resistance. Int J Exp Diabetes Res. 2002;3:47–60.
Gerasimenko JV, Flowerdew SE, Voronina SG, et al. Bile acids induce Ca2+ release from both the endoplasmic reticulum and acidic intracellular calcium stores through activation of inositol trisphosphate receptors and ryanodine receptors. J Biol Chem. 2006;281:40154–63.
Rapiejko PJ, Northup JK, Evans T, et al. G-proteins of fat-cells. Role in hormonal regulation of intracellular inositol 1,4,5-trisphosphate. Biochem J. 1986;240:35–40.
Shen X, Xiao H, Ranallo R, et al. Modulation of ATP-dependent chromatin-remodeling complexes by inositol polyphosphates. Science. 2003;299:112–4.
Steger DJ, Haswell ES, Miller AL, et al. Regulation of chromatin remodelling by inositol polyphosphates. Science. 2003;299:114–6.
Pinter E, Reece EA, Leranth CZ, Garcia-Segura M, Hobbins JC, Mahoney MJ, et al. Arachidonic acid prevents hyperglycemia-associated yolk sac damage and embryopathy. Am J Obstet Gynecol. 1986;155:691–702.
Wiznitzer A, Ayalon N, Hershkovitz R, et al. Am J Obstet Gynecol. 1999;180:188–93.
James AM, Murphy MP. How mitochondrial damage affects cell function. J Biomed Sci. 2002;9:475–87.
Nishikawa T, Edelstein D, Du XL, et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature. 2000;404:787–90.
Hagay ZJ, Weiss Y, Zusman I, et al. Prevention of diabetes-associated embryopathy by overexpression of the free radical scavenger copper zinc superoxide dismutase in transgenic mouse embryos. AJOG. 1995;173:1036–41.
Mao LM, Liu XY, Zhang GC, et al. Phosphorylation of group I metabotropic glutamate receptors (mGluR1/5) in vitro and in vivo. Neuropharmacology. 2008;55:403–8.
Steinberg SF. Distinctive activation mechanisms and functions for protein kinase Cdelta. Biochem J. 2004;384:449–59.
Dempsey EC, Newton AC, Mochly-Rosen D, et al. Protein kinase C isozymes and the regulation of diverse cell responses. Am J Physiol Lung Cell Mol Physiol. 2000;279:L429–38.
Pearson G, Robinson F, Beers Gibson T, et al. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev. 2001;22:153–83.
Alnemri ES, Livingston DJ, Nicholson DW, et al. Human ICE/CED-3 protease nomenclature. Cell. 1996;87:171.
Fuentes-Prior P, Salvesen GS. The protein structures that shape caspase activity, specificity, activation and inhibition. Biochem J. 2004;384:201–32.
Koenen TB, Stienstra R, van Tits LJ, et al. Hyperglycemia activates caspase-1 and TXNIP-mediated IL-1beta transcription in human adipose tissue. Diabetes. 2011;60:517–24.
Kuan CY, Yang DD, Samanta Roy DR, et al. The Jnk1 and Jnk2 protein kinases are required for regional specific apoptosis during early brain development. Neuron. 1999;22:667–76.
• Zhao Z, Yang P, Eckert RL, Reece EA. Caspase-8: a key role in the pathogenesis of diabetic embryopathy. Birth Defects Res B DevReprodToxicol. 2009;86:72–7.
This study has had an important impact because it was the first to confirm the role of caspase-8 in diabetic embryopathy
Yang P, Zhao Z, Reece EA. Involvement of c-Jun N-terminal kinases activation in diabetic embryopathy. Biochem Biophys Res Commun. 2007;357:749–54.
• Zhao Z, Yang P, Eckert RL, Reece EA. Caspase-8: a key role in the pathogenesis of diabetic embryopathy. Birth Defects Res B Dev Reprod Toxicol. 2009;86:72–7.
This article has had a significant impact because it was the first to confirm the role of caspase-8 in the pathophysiology of diabetic embryopathy
Reece EA, Wu YK. Prevention of diabetic embryopathy in offspring of diabetic rats with use of a cocktail of deficient substrates and an antioxidant. Am J Obstet Gynecol. 1997;176:790–7.
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;31:41–9.
Pinter E, Reece EA, Leranth CZ, et al. Yolk sac failure in embryopathy due to hyperglycemia: ultrastructural analysis of yolk sac differentiation associated with embryopathy in rat conceptuses under hyperglycemic conditions. Teratology. 1986;33:73–84.
Reece EA, Wu YK, Wiznitzer A, et al. Dietary polyunsaturated fatty acid prevents malformations in offspring of diabetic rats. Am J Obstet Gynecol. 1996;175:818–23.
Reece EA, Wu YK, Zhao Z, Dhanasekaran D. Dietary vitamin and lipid therapy rescues aberrant signaling and apoptosis and prevents hyperglycemia-induced diabetic embryopathy in rats. Am J Obstet Gynecol. 2006;194:580–5.
Khandelwal M, Reece EA, Wu YK, Borenstein M. Dietary myo-inositol therapy in hyperglycemia-induced embryopathy. Teratology. 1998;57:79–84.
Wentzel P, Thunberg L, Eriksson UJ. Teratogenic effect of diabetic serum is prevented by supplementation of superoxide dismutase and N-acetylcysteine in rat embryo culture. Diabetologia. 1997;40:7–14.
• Li X, Weng H, Reece EA, Yang P. SOD1 overexpression in vivo blocks hyperglycemia-induced specific PKC isoforms: substrate activation and consequent lipid peroxidation in diabetic embryopathy. Am J Obstet Gynecol. 2011 Mar 5;[Epub ahead of print].
This article has had a significant impact because it not only confirmed the role of the PKC pathway in diabetic embryopathy, but it also demonstrated that this pre-apoptotic cascade could be blocked and is a modifiable drug target.
•• Cao Y, Zhao Z, Eckert RL, Reece EA. Protein kinase Cβ2 inhibition reduces hyperglycemia-induced neural tube defects through suppression of a caspase 8-triggered apoptotic pathway. Am J Obstet Gynecol. 2011;204:226.e1–5.
This paper demonstrated that not only can we reduce the risk of hyperglycemia-induced NTDs by inhibition of a specific PKC isoform, PKCβ2, but also that the mode of action is via suppression of the cellular apoptotic pathway. It further confirms that our approach to preventing diabetic embryopathies is justified and that there are multiple points in the pathophysiology of this disease that are potential therapeutic targets
Rothenberg SP. Increasing the dietary intake of folate: pros and cons. Semin Hematol. 1999;36:65–74.
Tessema J, Jefferds ME, Cogswell M, Carlton E. Motivators and barriers to prenatal supplement use among minority women in the United States. J Am Diet Assoc. 2009;109:102–8.
Reece EA. New developments in the prevention of diabetes-induced neural tube defects. Prenat Neonatal Med. 1996;1:97–9.
© Springer Science+Business Media, LLC 2011