Abstract
Conotruncal cardiac defects are partially prevented by maternal folic acid supplementation. However, the biochemical mechanism is unknown. Maternal autoantibodies to folate receptors, previously associated with increased risk for neural tube defects, also may account for this effect. This study aimed to examine the titers of folate receptor-blocking autoantibodies in mothers of children with conotruncal congenital heart defects and to compare them with those in the general population. Serum samples were obtained from 22 women whose pregnancies were complicated by conotruncal congenital heart malformations. Groups of samples were analyzed for autoantibodies against [3H] folic acid-labeled folate receptors, quantitative amounts of immunoglobulin G (IgG) and IgM autoantibodies to the folate receptor, and for ability to block-bind folic acid to receptors. No elevated levels of antibodies binding to [3H] folic acid-labeled folate receptors were found. No difference was found in antifolate receptor alpha-IgG or IgM median levels between cases (261 vs. 240 μg/mL) and control subjects (773 vs. 924 μg/mL). There was no increased blocking of folic acid binding between cases [0.69 ng/mL; 95 % confidence interval (CI), 0.006–0.01] and control subjects (0.69 ng/mL; 95 % CI, 0.003–0.013). Although epidemiologic evidence suggests that periconceptual folic acid may prevent many conotruncal congenital heart defects, the current study suggests that this effect is unlikely to be explained by the presence of maternal autoantibodies to folate receptor. These data suggest that a strategy of screening women for such autoantibodies will not identify a high-risk group of women to target for supplemental folic acid to prevent congenital heart defects.
Similar content being viewed by others
References
Antony AC, Hansen DK (2000) Hypothesis: folate-responsive neural tube defects and folate neurocristopathies. Teratology 62:42–50
Botto LD, Khoury MJ, Mulinare J, Erickson JD (1996) Periconceptional multivitamin use and the occurrence of conotruncal heart defects: results from a population-based, case-control study. Pediatrics 98:911–917
Boyles AL, Ballard JL, Gorman EB, McConnaughey DR, Cabrera RM, Wilcox AJ, Lie RT, Finnell RH (2011) Association between inhibited binding of folic acid to folate receptor alpha in maternal serum and folate-related birth defects in Norway. Hum Reprod 26:2232–2238
Burgoon JM, Selhub J, Nadeau M, Sadler TW (2002) Investigation of the effects of folate deficiency on embryonic development through the establishment of a folate-deficient mouse model. Teratology 65:219–227
Cabrera RM, Shaw GM, Ballard JL, Carmichael SL, Yang W, Lammer EJ, Finnell RH (2008) Autoantibodies to folate receptor during pregnancy and neural tube defect risk. J Reprod Immunol 79:85–92
da Costa MP, Sequeira JM, Rothenberg SP, Weedon J (2003) Antibodies to folate receptors impair embryogenesis and fetal development in the rat. Birth Defects Res A Clinc Mol Teratol 67:837–847
De Marco P, Moroni A, Merello E et al (2000) Folate pathway gene alterations in patients with neural tube defects. Am J Med Genet 95:216–223
Hernandez-Diaz S, Werler MM, Walker AM, Mitchell AA (2000) Folic acid antagonists during pregnancy and the risk of birth defects. New Engl J Med 343:1608–1614
Hobbs CA, Celeves MA, Zhao W (2006) Maternal homocysteine and congenital heart defects. J Am Coll Cardiol 47:683–685
Kapusta L, Haagmans ML, Steegers EA et al (1999) Congenital heart defects and maternal derangement of homocysteine metabolism. J Pedatr 135:773–774
Molloy AM, Quadros EV, Sequira JM, Troendle JF, Scott JM, Kirke PN et al (2009) Lack of association between folate-receptor autoantibodies and neural tube defects. N Engl J Med 361:152–160
Posey DL (1996) Is mutation MTHFR a risk factor for neural tube defects? Lancet 347:686–687
Rosenquist TH, Ratashak SA, Selhub J (1996) Homocysteine induces congenital defects of the heart and neural tube: effect of folic acid. Proc Natl Acad Sci USA 93:15227–15232
Rothenberg SP, da Costa MP, Sequeira JM et al (2004) Autoantibodies against folate receptors in women with a pregnancy complicated by a neural tube defect. N Engl J Med 350:134–142
Scanlon KS, Ferencz C, Loffredo CA, Wilson PD, Correa Villasenor A, Khoury MJ et al (1998) Preconceptional folate intake and malformations of the cardiac outflow tract. Epidemiology 9:95–98
Shaw GM, O’Malley CD, Wasserman CR, Tolarova MM, Lammer EJ (1995) Maternal periconceptional use of multivitamins and reduced risk for conotruncal heart defects and limb deficiencies among offspring. Am J Med Genet 59:536–545
Solanky N, Requena Jimenez A, D’Souza SW, Sibley CP, Glazier JD (2010) Expression of folate transporters in human placenta and implications for homocysteine metabolism. Placenta 31:134–143
Wenstrom KD, Johanning GL, Johnston KE, DuBard M (2001) Association of the C677T methylene tetrahydro-folate reductase mutation and elevated homocysteine levels with congenital cardiac malformations. Am J Obstet Gynecol 184:806–812
Zhu H, Wlodarczyk BJ, Scott M, Yu W, Merriweather M et al (2007) Cardiovascular abnormalities in Folr1 knockout mice and folate rescue. Birth Defects Res A Clin Mol Teratol 79:257–268
Acknowledgments
The authors thank Stephen Rothenberg, Richard Finnell, and Ana Palacios for assistance with assay methodology and for sample analysis.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lewandowski, L.B., Sanghavi, D. Lack of Association Between Folate Receptor Autoantibodies and Conotruncal Congenital Heart Defects. Pediatr Cardiol 34, 512–517 (2013). https://doi.org/10.1007/s00246-012-0485-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00246-012-0485-3