European Heart Journal Advance Access originally published online on June 15, 2007
European Heart Journal 2007 28(16):2043; doi:10.1093/eurheartj/ehm235
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Non-optimal maturation of the oocyte, maternal MTHFR polymorphisms, periconceptional folate, and decrease of congenital heart defects
Department of Epidemiology and Biostatistics
Radboud University Nijmegen Medical Centre
PO Box 9101 6500 HB Nijmegen
The Netherlands
Tel: +31 24 3619132 fax: +31 24 3613505 E-mail address: p.jongbloet{at}epib.umcn.nl
The protective effect of periconceptional folate on congenital heart defects (CHDs) presented by Van Beynum et al. (2006)1 contributes to the governing folate paradigm. The researchers showed a quantitative trait effect between MTHFR 677 > CT heterozygosity and homozygosity (TT) and a modification by periconceptional folate supplementation. In addition, using the family-based transmission disequilibrium test (TDT), they identified this polymorphism in the mother as risk factor for CHDs in their progeny, independent of its presence in the foetus. Similar results were found in relation with cleft lip with or without cleft palate.2 Studies on the relation between MTHFR 677 > T polymorphism and congenital anomalies as a consequence of mildly elevated plasma homocysteine (Hcy)—presume an extensive reduction of migrating cardiac neural crest cells during early development.
The connection of a very broad spectrum of chromosomal aberrations,3 congenital anomalies, and constitutional diseases with MTHFR polymorphisms support the concept of non-optimal maturation of the oocyte as causal pathway into adverse progeny as suggested by Wynn and Wynn (1993), who moved the attention away from teratological disturbances during the early months of pregnancy into the maturation of the oocyte.4 In fact, deficiency of folate in rhesus monkeys is known to depress the concentration of oestradiol and progestagen and to slow down the replication of granulosa cells, being the principal cells in the ovarian follicle. This deficiency results in a reduction of the growth of the follicle and in delayed ovulation, as markers for retardation of embryonic growth and malformations. Therefore, they presume that folic acid is the prerequisite for optimum maturation of the oocyte and inherent favourable outcome.
Heterozygous and homozygous carriership of these polymorphisms implies increased plasma of total Hcy and, thus lower folate concentration threatening optimal maturation of the oocyte and embryonic development. Non-optimal maturation of the oocyte or over-ripeness of the egg in animal experiments and observations has been shown to be associated with a wide spectrum of chromosomal and developmental anomalies. It has also been presumed in a range of conditions in which the maturation of the oocyte is at stake, such as very premature and advanced reproductive age, postpartum restoration of the ovulatory pattern, seasonally bound transitional stages of it, etc.6 This is in line with the association between follicular fluid Hcy levels and detrimental effect on embryo quality in couples undergoing assisted reproductive techniques (ART), as well as with the greater risk for miscarriage, particularly when foetal chromosomal anomalies are present.3
Low folate concentrations connected with over-ripeness ovopathy, therefore, may play a role in the causal pathway of unfavourable pregnancy outcomes. This concept not only explains the broad spectrum of chromosomal aberrations, congenital anomalies, and constitutional diseases, but also their pleiotropic pattern and male preponderance,7 and finally, the analogy with the above-mentioned high-risk conception categories.
References
- Van Beynum IM, Kapusta L, den Heyer M, Vermeulen SHMM, Kouwenberg M, Daniels O, Blom HJ. Maternal MTHFR 677 > T is a risk factor for congenital heart defects: modification by periconceptional folate supplementation. Eur Heart J (2006) 27:981–987.
[Abstract/Free Full Text] - van Rooij IALM, Vermeij-Keers C, Kluijtmans LAJ, Ocke MC, Zielhuis GA, Goorhuis-Brouwer SM, van der Biezen J-J, Kuijpers-Jagtman A-M, Steegers-Theunissen RPM. Does the interaction between maternal folate intake and the methylenetetrafolate reductase polymorphisms affect the risk of cleft lip with or without cleft palate? Am J Epidemiol (2003) 157:583–591.
[Abstract/Free Full Text] - George L, Mills JL, Jhansson ALV, Nordmark A, Olander B, Grannath F, Cnattingius S. Plasma folate levels and risk of spontaneous abortion. JAMA (2002) 288:1867–1873.
[Abstract/Free Full Text] - Wynn M, Wynn A. No nation can rise above the level of women: new thoughts on maternal nutrition. In: The Carolyne Walker Lecture (1993) London: Carolyne Walker Trust. 1–39.
- Ebisch IMW, Peters WHM, Thomas CMG, Wetzels AMM, Peer PGM, Steegers-Theunissen RPM. Homocysteine, glutathione and related thiols affect fertility parameters in the (sub)fertiled couple. Hum Reprod (2006) 21:1725–1733.
[Abstract/Free Full Text] - Jongbloet PH. Prepregnancy care: background biological effects. In: Prepregnancy Care: A Manual for Practice—Chamberlain G, Lumey J, eds. (1986) John Wiley & Sons Ltd. 31–52.
- Jongbloet PH. Over-ripeness ovopathy: a challenging hypothesis for sex ratio modulation. Hum Reprod (2004) 19:769–774. 1036–1037.
[Abstract/Free Full Text]
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