Abstract
Purpose:
Investigation of the incidence and distribution of congenital structural cardiac malformations among the offspring of mothers with diabetes type 1 and of the influence of periconceptional glycemic control.
Methods:
Multicenter retrospective clinical study, literature review, and meta-analysis. The incidence and pattern of congenital heart disease in the own study population and in the literature on the offspring of type 1 diabetic mothers were compared with the incidence and spectrum of the various cardiovascular defects in the offspring of nondiabetic mothers as registered by EUROCAT Northern Netherlands. Medical records were, in addition, reviewed for HbA1c during the 1st trimester.
Results:
The distribution of congenital heart anomalies in the own diabetic study population was in accordance with the distribution encountered in the literature. This distribution differed considerably from that in the nondiabetic population. Approximately half the cardiovascular defects were conotruncal anomalies. The authors’ study demonstrated a remarkable increase in the likelihood of visceral heterotaxia and variants of single ventricle among these patients. As expected, elevated HbA1c values during the 1st trimester were associated with offspring fetal cardiovascular defects.
Conclusion:
This study shows an increased likelihood of specific heart anomalies, namely transposition of the great arteries, persistent truncus arteriosus, visceral heterotaxia and single ventricle, among offspring of diabetic mothers. This suggests a profound teratogenic effect at a very early stage in cardiogenesis. The study emphasizes the frequency with which the offspring of diabetes-complicated pregnancies suffer from complex forms of congenital heart disease. Pregnancies with poor 1st-trimester glycemic control are more prone to the presence of fetal heart disease.
Zusammenfassung
Ziel:
Untersuchung von Inzidenz und Verteilung angeborener Herzfehlbildungen bei Kindern von Müttern mit Diabetes mellitus Typ 1 sowie des Einflusses der Glucosewerte der Mutter in der Konzeptionsphase.
Methodik:
Retrospektive, klinische Multicenterstudie, Literaturübersicht und Metaanalyse. Die Inzidenz und Art der Herzfehlbildungen bei Kindern von Müttern mit Typ-1-Diabetes in der eigenen Patientengruppe und in der Literatur wurden mit der Inzidenz und Art verschiedener kardiovaskulärer Defekte bei Nachkommen nichtdiabetischer, via EUROCAT Northern Netherlands registrierter Mütter verglichen. Zudem wurden die HbA1C-Werte im 1. Schwangerschaftstrimester analysiert.
Ergebnisse:
Die Rate angeborener Herzfehlbildungen in der eigenen diabetischen Studienpopulation war vergleichbar mit jener in der Literatur. Die Häufigkeit unterschied sich deutlich von der nichtdiabetischen Gruppe. Ungefähr die Hälfte der verschiedenen kardiovaskulären Defekte waren konotrunkale Fehlbildungen. Die Studie der Autoren zeigte eine bemerkenswerte Zunahme der Wahrscheinlichkeit für viszerale Heterotaxie und Variationen eines singulären Ventrikels in dieser Patientengruppe. Erwartungsgemäß korrelierten erhöhte HbA1c-Werte im 1. Schwangerschaftstrimester mit erhöhter Inzidenz für verschiedene kardiovaskuläre Defekte.
Schlussfolgerung:
Diese Studie zeigt ein erhöhtes Risiko für spezifische Herzfehlbildungen, nämlich Transposition der großen Arterien, persistierender Truncus
Similar content being viewed by others
References
Ylinen K, Aula P, Stenman U, et al. Risk of minor and major fetal malformations in diabetics with haemoglobin A1c values in early pregnancy. Br Med J 1984;289:345–6.
Molsted-Pedersen L, Tygstrup I, Pedersen J. Congenital malformations in newborn infants of diabetic women. Lancet 1964;1:1124–6.
Kucera J. Rate and type of congenital anomalies among offspring of diabetic women. J Reprod Med 1971;7:73–82.
Miodovnik M, Mimouni F, Dignan PS, et al. Major malformations in infants of IDDM women. Vasculopathy and early first-trimester poor glycemic control. Diabetes Care 1988;11:713–8.
Casson IF, Clarke CA, Howard CV, et al. Outcomes of pregnancy in insulin dependent diabetic women: results of a five year population cohort study. Br Med J 1997;315:275–8.
Kitzmiller JL, Cloherty JP, Younger MD, et al. Diabetic pregnancy and perinatal morbidity. Am J Obstet Gynecol 1978;131:560–80.
Gabbe SG. Congenital malformations in infants of diabetic mothers. Obstet Gynecol Surv 1977;32:125–32.
Pedersen J, Molsted-Pedersen LM. Congenital malformations: the possible role of diabetes care outside pregnancy. Ciba Found Symp 1978;63:265–71.
Meyer BA, Palmer SM. Pregestational diabetes. Semin Perinatol 1990;14:12–23.
Fuhrmann K, Reiher H, Semmler K, et al. Prevention of congenital malformations in infants of insulin-dependent diabetic mothers. Diabetes Care 1983;6:219–23.
Rosenn B, Miodovnik M, Combs CA, et al. Glycemic thresholds for spontaneous abortion and congenital malformations in insulin-dependent diabetes mellitus. Obstet Gynecol 1994;84:515–20.
Lowy C, Beard RW, Goldschmidt J. The UK diabetic pregnancy survey. Acta Endocrinol Suppl (Copenh) 1986;277:86–9.
Becerra JE, Khoury MJ, Cordero JF, Erickson JD. Diabetes mellitus during pregnancy and the risks for specific birth defects: a population-based case-control study. Pediatrics 1990;85:1–9.
Kitzmiller JL, Gavin LA, Gin GD, et al. Preconception care of diabetes. Glycemic control prevents congenital anomalies. JAMA 1991;265:731–6.
Mills JL, Baker L, Goldman AS. Malformations in infants of diabetic mothers occur before the seventh gestational week. Implications for treatment. Diabetes 1979;28:292–3.
Verheijen PM, Lisowski LA, Stoutenbeek P, et al. Prenatal diagnosis of congenital heart disease affects preoperative acidosis in the newborn patient. J Thorac Cardiovasc Surg 2001;121:798–803.
Mills JL, Knopp RH, Simpson JL, et al. Lack of relation of increased malformation rates in infants of diabetic mothers to glycemic control during organogenesis. N Engl J Med 1988;318:671–6.
Gladman G, McCrindle BW, Boutin C, Smallhorn JF. Fetal echocardiographic screening of diabetic pregnancies for congenital heart disease. Am J Perinatol 1997;14:59–62.
Shields LE, Gan EA, Murphy HF, et al. The prognostic value of hemoglobin A1c in predicting fetal heart disease in diabetic pregnancies. Obstet Gynecol 1993;159:352–6.
Rowland TW, Hubbell JP, Nadas AS. Congenital heart disease in infants of diabetic mothers. J Pediatr 1973;83:815–20.
Ramos-Arroyo MA, Rodriguez-Pinilla E, Cordero JF. Maternal diabetes: the risk for specific birth defects. Eur J Epidemiol 1992;8:503–8.
Ferencz C, Rubin JD, McCarter RJ, Clark EB. Maternal diabetes and cardiovascular malformations: predominance of double outlet right ventricle and truncus arteriosus. Teratology 1990;41:319–26.
Brown ZA, Mills JL, Metzger BE, et al. Early sonographic evaluation for fetal growth delay and congenital malformations in pregnancies complicated by insulin-requiring diabetes. National Institute of Child Health and Human Development Diabetes in Early Pregnancy Study. Diabetes Care 1992;15:613–9.
Greene MF, Hare JW, Cloherty JP, et al. First-trimester hemoglobin A1 and risk for major malformation and spontaneous abortion in diabetic pregnancy. Teratology 1989;39:225–31.
Suhonen L, Hiilesmaa V, Teramo K. Glycaemic control during early pregnancy and fetal malformations in women with type I diabetes mellitus. Diabetologia 2000;43:79–82.
Stubbs SM, Doddridge MC, John PN, et al. Haemoglobin A1 and congenital malformation. Diabet Med 1987;4:156–9.
Pedersen JF, Molsted-Pedersen L. Early fetal growth delay detected by ultrasound marks increased risk of congenital malformation in diabetic pregnancy. Br Med J (Clin Res Ed) 1981;283:269–71.
Small M, Cassidy L, Leiper JM, et al. Outcome of pregnancy in insulin-dependent (type 1) diabetic women between 1971 and 1984. Q J Med 1986;61:1159–61.
Khoury MJ, Becerra JE, Cordero JF, Erickson JD. Clinical-epidemiologic assessment of pattern of birth defects associated with human teratogens: application to diabetic embryopathy. Pediatrics 1989;84:658–65.
McFarland KF, Hemaya E. Neonatal mortality in infants of diabetic mothers. Diabetes Care 1985;8:333–6.
Mimouni F, Miodovnik M, Tsang RC, et al. Decreased maternal serum magnesium concentration and adverse fetal outcome in insulin-dependent diabetic women. Obstet Gynecol 1987;70:85–8.
Ballard JL, Holroyde J, Tsang RC, et al. High malformation rates and decreased mortality in infants of diabetic mothers managed after the first trimester of pregnancy (1956–1978). Am J Obstet Gynecol 1984;148:1111–8.
Cordero L, Treuer SH, Landon MB, Gabbe SG. Management of infants of diabetic mothers. Arch Pediatr Adolesc Med 1998;152:249–54.
Albert TJ, Landon MB, Wheller JJ, et al. Prenatal detection of fetal anomalies in pregnancies complicated by insulin-dependent diabetes mellitus. Am J Obstet Gynecol 1996;174:1424–8.
Aberg A, Westbom L, Kallen B. Congenital malformations among infants whose mothers had gestational diabetes or preexisting diabetes. Early Hum Dev 2001;61:85–95.
Centers for Disease Control. Contribution of birth defects to infants’ mortality — United States 1986. MMWR 1989;38:633–5.
Weatherall DJ, Ledingham JGG, Warrell DA. Oxford textbook of medicine, vol 1, 2nd edn. Oxford: Oxford University Press, 1987:985–6.
Hawthorne G, Robson S, Ryall EA, et al. Prospective population based survey of outcome of pregnancy in diabetic women: results of the Northern Diabetic Pregnancy Audit, 1994. BMJ 1997;315:279–81.
Evers IM, Bos AM, Aalders AL, et al. Zwangerschap bij vrouwen met diabetes mellitus type-1: nog steeds maternale en perinatale complicaties, ondanks goede bloedglucoseregulatie. Ned Tijdschr Geneeskd 2000;144:804–9.
Evers IM, de Valk HW, Visser GHA. A nationwide prospective study on the outcome of pregnancies in women with type 1 diabetes mellitus: do planned pregnancies result in better pregnancy outcome? Diabetologia 2001;44:Suppl 1:A42.
Hurwitz D, Irving IC. Diabetes and pregnancy. Am J Med Sci 1937;194:85–92.
Miller HC. Mortality in pregnancies complicated by diabetes. JAMA 1946;131:700.
Loffredo CA, Wilson PD, Ferencz C. Maternal diabetes: an independent risk factor for major cardiovascular malformations with increased mortality of affected infants. Teratology 2001;44:98–106.
Larsen WJ. Human embryology. New York: Churchill Livingstone, 1993:161–3.
Yasui H, Morishima M, Nakazawa M, et al. Developmental spectrum of cardiac outflow tract anomalies encompassing transposition of the great arteries and dextroposition of the aorta: pathogenic effect of extrinsic retinoic acid in the mouse embryo. Anat Rec 1999;254:253–60.
Siman CM, Gittenberger-De Groot AC, Wisse B, Eriksson UJ. Malformations in offspring of diabetic rats: morphometric analysis of neural crest-derived organs and effects of maternal vitamin E treatment. Teratology 2000;61:355–67.
Goldmuntz E, Clark BJ, Mitchell LE, et al. Frequency of 22q11 deletions in patients with conotruncal defects. J Am Coll Cardiol 1998;32:492–8.
Goldmuntz E, Bamford R, Karkera JD, et al. CFC1 mutations in patients with transposition of the great arteries and double-outlet right ventricle. Am J Hum Genet 2002;70:776–80.
Wilson TA, Blethen SL, Vallone A, et al. DiGeorge anomaly with renal agenesis in infants of mothers with diabetes. Am J Med Genet 1993;47:1078–82.
Kathiriya IS, Srivastava D. Left-right asymmetry and cardiac looping: implications for cardiac development and congenital heart disease. Am J Med Genet 2000;97:271–9.
Srivastava D. Genetic assembly of the heart: implications for congenital heart disease. Annu Rev Physiol 2001;63:451–69.
Slavotinek A, Hellen E, Gould S, et al. Three infants of diabetic mothers with malformations of left-right asymmetry — further evidence for the aetiological role of diabetes in this malformation spectrum. Clin Dysmorphol 1996;5:241–7.
Splitt M, Wright C, Sen D, Goodship J. Left-isomerism sequence and maternal type-1 diabetes. Lancet 1999;354:305–6.
Martinez-Frias ML. Heterotaxia as an outcome of maternal diabetes: an epidemiological study. Am J Med Genet 2001;99:142–6.
Kalter H. Case reports of malformations associated with maternal diabetes: history and critique. Clin Genet 1993;43:174–9.
Goto MP, Goldman AS. Diabetic embryopathy. Curr Opin Pediatr 1994;6:486–91.
McCarter RJ, Kessler II, Comstock GW. Is diabetes mellitus a teratogen or a coteratogen? Am J Epidemiol 1987;125:195–205.
Reece EA, Homko CJ, Wu YK. Multifactorial basis of the syndrome of diabetic embryopathy. Teratology 1996;54:171–82.
Miller E, Hare JW, Clotherty JP, et al. Elevated maternal hemoglobin A1c in early pregnancy and major congenital anomalies in infants of diabetic mothers. N Engl J Med 1981;304:1331–4.
Cederberg J, Siman CM, Eriksson UJ. Combined treatment with vitamin E and vitamin C decreases oxidative stress and improves fetal outcome in experimental diabetic pregnancy. Pediatr Res 2001;49:755–62.
Verheijen PM, Lisowski LA, Stoutenbeek P, et al. Lactacidosis in the neonate is minimized by prenatal detection of congenital heart disease. Ultrasound Obstet Gynecol 2002;19:552–5.
Bonnet D, Coltri A, Butera G, et al. Detection of transposition of the great arteries in fetuses reduces neonatal morbidity and mortality. Circulation 1999;99:916–8.
Tworetzky W, McElhinney DB, Reddy VM, et al. Improved surgical outcome after fetal diagnosis of hypoplastic left heart syndrome. Circulation 2001;103:1269–73.
Franklin O, Burch M, Manning N, et al. Prenatal diagnosis of coarctation of the aorta improves survival and reduces morbidity. Heart 2002;87:67–9.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lisowski, L.A., Verheijen, P.M., Copel, J.A. et al. Congenital Heart Disease in Pregnancies Complicated by Maternal Diabetes Mellitus. Herz 35, 19–26 (2010). https://doi.org/10.1007/s00059-010-3244-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00059-010-3244-3
Key Words:
- Congenital heart disease
- Periconceptional glycemic control
- Congenital structural cardiac malformations