Association of Maternal and Fetal MTHFR A1298C polymorphism with the risk of pregnancy loss A Study on an Indian Population and a Meta Analysis

The data of the present study clearly suggest that MTHFR A1298C polymorphism is a genetic risk factor for pregnancy loss, and it appears to be clinically important.

Rohini R. Nair, M.Sc., Anuradha Khanna, M.D., Rajender Singh, Ph.D., Kiran Singh, Ph.D.

Volume 99, Issue 5, Pages 1311-1318.e4, April 2013


To study the genetic association between methylenetetrahydrofolate reductase (MTHFR) A1298 polymorphism and recurrent pregnancy loss (RPL).

Prospective case-control study, a systematic review, and meta-analysis using electronic database up to July 27, 2012.

Meta-analysis of four studies on RPL and three studies on spontaneously aborted embryos, including the present study.

A total of 129 RPL patients and 202 healthy control women with successful pregnancy were analyzed including forty spontaneously aborted embryos and forty aborted embryos as controls. For meta-analysis 1,080 cases and 709 controls were included of RPL and 375 cases and 384 controls of spontaneously aborted embryos.

Blood was collected by peripheral venous punctures and spontaneously aborted embryos were collected by curettage or manual vacuum aspiration. Meta-analysis was done on the basis of heterogeneity of the studies.

Main Outcome Measure(s):
Genotyping was done by PCR-RFLP. DNA sequencing was used to ascertain PCR-RFLP results. Age adjusted odds ratios (ORs) were calculated by logistic regression analysis. Meta-analysis on this polymorphism was conducted to support our findings.

We found that presence of rare allele „C‟ and heterozygous and rare homozygous genotypes increased the risk of RPL significantly. No significant change in the fetal MTHFR A1298C genotype frequency was observed regardless of their chromosomal integrity. Meta-analysis of A1298C polymorphism on both RPL and in spontaneously aborted embryos showed significantly increased risk in the carriers of AC and CC genotypes.

The data of the present study clearly suggests that MTHFR A1298C polymorphism is a genetic risk factor for pregnancy loss.

  • Audrey Gaskins

    This is an interesting paper with presents original data on the association between MTHFR A1298C polymorphisms and risk of RPL and a meta-analysis. It was particularly helpful to see data on both the maternal genotype and the fetal genotype and risk of pregnancy loss; however I was surprised that the authors did not address a possible interaction between the two. For example, are mothers and fetuses who both have the CC genotype at a greater risk for pregnancy loss than mothers with a CC genotype but whose fetus has an AC genotype? It seems that the association between genotype and risk of pregnancy loss was greater in magnitude based on maternal genotype- could it be possible we are just seeing the increased risk of pregnancy loss due to fetal genotype because the fetal genotype is correlated with maternal genotype? While challenging to tease out, the answer to this question would lend insight into the mechanisms behind folate and pregnancy loss.

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