Recurrent Pregnancy Loss Related to MTHFR Polymorphism

by Emily Cerda
Maryland University of Integrative Health
Summer 2015

 

General Definition & Who is Affected

 

Recurrent pregnancy loss (RPL), is defined as two or more miscarriages prior to 20 weeks from the last menstrual cycle, and affects an estimated 3-5% of couples trying to start a family (American Society for Reproductive Medicine, n.d.; Rajcan-Separovic et al., 2010). RPL is just one component of impaired fecundity, which is described as difficulty conceiving or bringing a pregnancy to term, and is unrelated to infertility (Macaluso et al., 2008).

 

This video by Natalie Burger, M.D. of the Texas Fertility Center (2015) gives a good overview of RPL, including its prevalence, causative factors, and the potential for evaluation:

 

There is some debate in classifying RPL at the second or third lost pregnancy, which skews the statistics about the population affected. It has been shown that after two lost pregnancies there is a 30% chance of subsequent pregnancy loss, whereas after 3 lost pregnancies there is a 33% chance of future miscarriages (Ford & Schust, 2009). These percentages suggest that testing for etiologies leading to RPL should be pursued after a second consecutive lost pregnancy (Ford & Schust, 2009).

Many different factors have been implicated in the development of RPL, but the focus here will be on how genetic mutations affect the methylenetetrahydrofolate reductase (MTHFR) enzyme to play a part in the pathogenesis of this condition. These mutations are called single nucleotide polymorphisms (SNPs), or genetic substitution defects affecting the MTHFR gene, that result in a reduction in MTHFR enzyme levels or activity (Mtiraoui et al., 2006).

 

Prevalence of MTHFR polymorphism varies widely between ethnicity and locations, with high occurrence in Italians and Hispanics, about 14% of Britain affected, and 10-14% of Canadians and Americans testing positive for the most serious form of this mutation (Liew & Gupta, 2015).

 

Pathogenesis

 

RPL is an outcome caused by MTHFR polymorphism in some individuals, so discussion of the pathogenesis of this condition will focus on the onset of MTHFR enzyme dysfunction. Individuals can inherit a gene for this polymorphism from one parent, making them heterozygous for the condition, or they can inherit a gene from both parents, making them homozygous for the condition (Liew & Gupta, 2015). To complicate this imbalance, there is more than one location along the MTHFR gene that can be affected, commonly referred to as C677T and A1298C (Mtiraoui et al., 2006). First, watch this very simple video from Dr. Stephen Smith (2012) about MTHFR polymorphism and how the different genotypes affect the methylation pathway, which we will learn about shortly:

 

Since the C677T and A1298C SNPs are the most common, and because compound heterozygousity for these polymorphisms equates to homozygousity in pathophysiological terms, this page will be written with a compound heterozygous (C667T/ A1298C) patient in mind.

 

Please watch the presentation (Cerda, 2015a) for an explanation of MTHFR function, the methylation and trans-sulphuration pathways, and the mechanisms and downstream ramifications of MTHFR dysfunction:

 

Self Check #1: What are the three major effects of MTHFR polymorphism? What pathways are involved?

 

Pathophysiology

 

The association between the MTHFR polymorphism and RPL is still being researched, but three main mechanisms are suspected. Elevated serum homocysteine (hyperhomocysteinemia), directly linked with MTHFR mutation, plays a part in two mechanisms suspected to influence RPL.

 

Moderate hyperhomocysteinemia causes thrombophilia, a tendency toward clotting within blood vessels, and increased arterial stiffness (Macovei et al., 2015; Wu et al., 2012). Homocysteine is known to induce oxidative stress and inflammation while reducing the activity of nitric oxide (a vasodilator). Elevated homocysteine is also responsible for increased aggregation of platelets, the constituents of the blood that are responsible for forming clots (Macovei et al., 2015). In short, arteries become stiff and lose flexibility as inflammation and the risk of developing blood clots increases. While research clearly links MTHFR with thrombophilia, data are inconsistent in linking MTHFR with pregnancy complications related to clotting. Preeclampsia, placental abruption, intrauterine growth restriction, intrauterine fetal demise and still birth are all outcomes associated with thrombosis yet inconclusively tied to MTHFR (Macovei et al., 2015).

 

Elevated homocysteine is also known to impair chorionic villus vascularization, vital to the development of the fetus (Reus et al., 2013). The chorion lies between the mother and the fetus and develops new blood vessels through angiogenesis, the formation of new vessels from previously existing ones, as the fetus grows and requires more energy from the mother (Wu et al., 2012). To maintain normal fetal development, a good exchange through these vessels is necessary. Impaired vascularization in the development of the chorion is linked to hyperhomocysteinemia and results in embryonic death and miscarriage (Wu et al., 2012).

 

Independent of homocysteine, the MTHFR polymorphism also results in reduced folate metabolism, vital to fetal development. Neural tube defects (NTDs) result in pregnancies associated with low folate nutriture, but the degree of severity between MTHFR mutation and NTDs is variable in different ethnic populations (Kirke et al., 2004; Johanning et al., 2000). Red blood cell folate metabolism is a suspected cause of RPL linked to MTHFR (Wu et al., 2012).

 

Also of interest is the paternal link between the MTHFR genotype and RPL. Govindaiah et al.(2009) found that women were at 2.37 times greater risk for RPL if their partners were positive for MTHFR 677T mutation. High homocysteine levels in the males are suspected to play a part in DNA damage that leads to RPL, but this mechanism has yet to be researched (Wu et al., 2012).

 

Role of Diet in MTHFR polymorphism

 

Diet can play a large part in managing the effects of MTHFR polymorphism, which may in turn decrease the chances of RPL. This video by Cerda (2015b) discusses the nutrients involved in managing this condition, including food sources and how the metabolism of these vitamins fit into the mechanisms of the methylation and trans-sulphuration pathways affected by MTHFR dysfunction:

 

Self-Check #2: Why would a bioactive form of both folate and B12 be important for individuals with MTHFR genotype?

 

Integration

Again, since mutated MTHFR can be a mechanism causing RPL, this section will focus on how the effects of MTHFR enzyme dysfunction integrates with other material covered in our Pathophysiology course. Poorly controlled MTHFR polymorphism resulting in hyperhomocysteinemia can lead to a multitude of problems in the body, a handful of which are outlined below.

 

Inflammation & Arteriosclerosis

High homocysteine levels inhibit nitric oxide (NO), a powerful vasodilator, causing myriad cardiovascular problems including vascular inflammation and arteriosclerosis (Lentz, 2005). The mechanism by which homocysteine reduces the bioavailability of NO is not entirely clear, though it is thought to be linked to increased oxidative stress (Lentz, 2005). Glutathione is a product of the trans-sulphuration pathway and a potent antioxidant, but its antioxidant activity cannot keep up with the oxidative stress induced by hyperhomocysteinemia. As reactive oxygen species (ROS) promote oxidative stress in the presence of homocysteine, NO synthase is inhibited from triggering NO to relax smooth muscles and subsequently dilate vessels (Lieberman & Marks, 2013). Lentz (2005) suggests that this limiting of NO availability leads to endothelial dysfunction and damage, causing inflammation and arteriosclerosis.

 

Thrombosis

It is also thought that homocysteine directly activates thrombins, causing clotting in the already inflamed vascular spaces under conditions of hyperhomocysteinemia (Lentz, 2005). Saczi et al. (2006) report an increased risk of both hemorrhagic and ischemic stroke related to both the C667T and A1298C genotypes, likely from clotting that either causes an aneurysm (hemorrhagic) or a blockage (ischemic) in hardened, inflamed vessels. In a small number of case studies, Altomare et al. (2007) found that administering the anticoagulant heparin to pregnant women with MTHFR polymorphism resulted in positive pregnancy outcomes. In spite of this success, this treatment is still unproven in larger studies and need for such measures depends upon the individual’s nutritional status.

 

Cancer

MTHFR and high homocysteine levels are also known to cause elevated risks of certain cancers when folate status is low, but some studies show that MTHFR may exhibit a protective effect against the development of cancer when folate is sufficient (Liew & Gupta, 2015). A combination of factors contribute to this pathophysiology, including reduced methylation, reduced bioactive folate status from MTHFR mutation and inhibition of NO by homocysteine. NO functions as a cytotoxin against tumor cells (Lieberman & Marks, 2013) and decreased folate and methylation lead to improper DNA synthesis and repair (Liew & Gupta, 2015).

 

Depression & Mental Health

Gilbody et al. (2006) demonstrate a link between MTHFR and depression, schizophrenia and bipolar disorder. NO acts as a neurotransmitter and inhibition of NO has been shown to lead to neurological problems (Lieberman & Marks, 2013). This may be a mechanism by which high homocysteine in MTHFR polymorphism results in these imbalances (Gilbody et al., 2006). Additionally, Liew & Gupta (2015) report that folate and vitamin B12 deficiencies are associated with the development of neurological and psychiatric disease and are significantly associated with Parkinson’s Disease and Alzheimer’s Disease in certain ethnic populations.

 

Big Picture

 

In my opinion, the outcome of RPL related to MTHFR polymorphism does make sense as an adaptive response when nutritional needs are not being met. Under conditions of poor folate and B12 status, inducing hyperhomocysteinemia, it makes sense for the body to terminate a pregnancy that will endanger both the fetus and the mother. The links between poor chorionic vascularization, low folate levels and fetal damage coupled with the mother’s tendency toward thrombotic events due to high serum homocysteine all point toward RPL as an adaptation that not only fails to support a damaged fetus, but also protects the health of the mother by sparing her a potentially dangerous delivery.

 

Contrary to my opinion, many researchers are hypothesizing that MTHFR mutation represented a selective advantage in certain populations (Ueland et al., 2001; Rosenberg et al., 2002). We’ve seen how low folic acid levels can increase the risk of many health complications for individuals with MTHFR, but it is also apparent that MTHFR can offer protection against colorectal cancer, prostate cancer and acute lymphatic leukemia when folic acid levels are regulated (Liew & Gupta, 2015; Rosenberg et al., 2002). Additionally, fetuses with MTHFR polymorphism demonstrate greater survivability compared to fetuses unaffected by these genotypes when maternal folic acid is optimal (Rosenberg et al., 2002). Ueland et al. (2001) predicts that MTHFR represents an adaptation promoting survival during times of nutritional deficit and that individuals with this genotype might have used limited dietary folate for DNA synthesis and repair. Such adaptive mechanisms would have given those with MTHFR greater chance for reproduction (DNA synthesis) and for healing after birth (DNA repair), and may be why MTHFR remains so prevalent across many varying cultures worldwide. This hypothesis could also explain why MTHFR affects the disease profiles of certain populations, but does not affect their morbidity or mortality rates (Ueland et al., 2001).

 

Optional Extras

This article by Kwak-Kim et al. (2009) discusses the mechanisms behind RPL, many of which focus on inflammation and thrombophilia.

 

This Huffington Post article by Bianca Garilli, N.D. (2014) covers the extent to which MTHFR polymorphism can show up clinically, and how personalized medicine is helping those with this genotype.

 

This video shows symptoms through the eyes of someone with MTHFR (Horn, 2011):

 

Here is an interesting paper by Janaki (2015) about lifestyle factors, including coffee consumption & elevated homocysteine.

 

This in an extensive blog written by someone who manages MTHFR mutation, with this specific page being about the author’s experience with folic acid supplementation (Have MTHFR?, n.d.).

 

Finally, if you’re interested in learning more about methylation problems and how MTHFR and homocysteine affects the brain, Dr. Andrew Rostenberg (Beyond MTHFR, 2014a-c) has an excellent three-video series on the topic:

 

Part I (15:59):

 

Part II (15:56):

 

Part III (15:22):

 

References

Altomare, I., Adler, A., & Aledort, L. M. (2007). The 5, 10 methylenetetrahydrofolate reductase C677T mutation and risk of fetal loss: a case series and review of the literature. Thromb J, 5, 17. Retrieved August 4, 2015 from http://www.biomedcentral.com/content/pdf/1477-9560-5-17.pdf

American Society for Reproductive Medicine (n.d.). ASRM Fact Sheet and Information Booklets: What is recurrent pregnancy loss (RPL)? Retrieved May 25, 2015, from http://www.asrm.org/FACTSHEET_What_is_recurrent_pregnancy_loss

Beyond MTHFR. (2014a). MTHFR and Homocysteine – Part I. Retrieved from https://www.youtube.com/watch?v=tfpXYU9UQlg

Beyond MTHFR. (2014b). MTHFR and Homocysteine – Part II. Retrieved from https://www.youtube.com/watch?v=VE90egM0-YY

Beyond MTHFR. (2014c). MTHFR and Homocysteine – Part III. Retrieved from https://www.youtube.com/watch?v=Dp8qPUkas7w

Cerda, E. (2015a). What is MTHFR? Retrieved from https://www.youtube.com/watch?v=hbhxWVWLT5Q

Cerda, E. (2015b). MTHFR: Diet & Health. Retrieved from https://www.youtube.com/watch?v=4oowy9VKFmw

Ford, H., and Schust, D. (2009). Recurrent Pregnancy Loss: Etiology, Diagnosis, and Therapy. Reviews in Obstetrics and Gynecology 2.2 : 76–83. Print. Retrieved May 27, 2015 from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2709325/

Garilli, B. (2014). Personalized Medicine Takes on the MTHFR Gene. Huffington Post. Retrieved July 22, 2015, from http://www.huffingtonpost.com/bianca-garilli-nd/personalized-medicine-tak_b_6355982.html

Gilbody, S., Lewis, S., & Lightfoot, T. (2007). Methylenetetrahydrofolate Reductase (MTHFR) Genetic Polymorphisms and Psychiatric Disorders: A HuGE Review. American Journal of Epidemiology, 165(1), 1–13. http://doi.org/10.1093/aje/kwj347

Govindaiah, V., Naushad, S. M., Prabhakara, K., Krishna, P. C., & Devi, A. R. R. (2009). Association of parental hyperhomocysteinemia and C677T Methylene tetrahydrofolate reductase (MTHFR) polymorphism with recurrent pregnancy loss. Clinical biochemistry, 42(4), 380-386. Retrieved July 18, 2015 from http://www.researchgate.net/profile/Naushad_Shaik_Mohammad/publication/23708204_Association_of_parental_hyperhomocysteinemia_and_C677T_Methylene_tetrahydrofolate_reductase_(MTHFR)_polymorphism_with_recurrent_pregnancy_loss/links/0deec5162f1c8b47ee000000.pdf

Have MTHFR? How To Avoid Folic Acid In Food. (n.d.). Retrieved August 4, 2015, from http://mthfrliving.com/health-tips/mthfr-avoid-folic-acid-in-food/

Horn, J. (2011). Jamie Horn’s MTHFR Story. Retrieved from https://www.youtube.com/watch?v=6ZcC94kRB5E

Janaki, S. (2015). Coffee intake on homocysteine and CVD: review article. History, 16(65), 24-28. Retrieved from http://www.discovery.org.in/medicalscience/current_issue/v16/n65/A1.pdf

Johanning, G. L., Tamura, T., Johnston, K. E., & D WENSTROM, K. A. T. H. A. R. I. N. E. (2000). Comorbidity of 5, 10-methylenetetrahydrofolate reductase and methionine synthase gene polymorphisms and risk for neural tube defects. Journal of medical genetics, 37(12), 949-951. Retrieved June 6, 2015 from http://jmg.bmj.com/content/37/12/949.full

Kirke, P. N., Mills, J. L., Molloy, A. M., Brody, L. C., O’Leary, V. B., Daly, L., … Scott, J. M. (2004). Impact of the MTHFR C677T polymorphism on risk of neural tube defects: case-control study. BMJ : British Medical Journal, 328(7455), 1535–1536. http://doi.org/10.1136/bmj.38036.646030.EE

Kwak‐Kim, J., Yang, K. M., & Gilman‐Sachs, A. (2009). Recurrent pregnancy loss: a disease of inflammation and coagulation. Journal of Obstetrics and Gynaecology Research, 35(4), 609-622. Retrieved August 4, 2015 from http://www.tsrm.org.tr/konu/dosyalar/pdf/celiac.disease.and.recurrent.pregnancy.loss.2009.pdf

Lentz, S. R. (2005). Mechanisms of homocysteine-induced atherothrombosis. Journal of Thrombosis and Haemostasis, 3(8), 1646–1654. http://doi.org/10.1111/j.1538-7836.2005.01364.x

Lieberman, M. & Marks, A. (2013). Marks’ basic medical biochemistry: a clinical approach, 4th ed. Lippincott Williams & Wilkins: Baltimore, MD.

Liew, S. C., & Gupta, E. D. (2015). Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: epidemiology, metabolism and the associated diseases. European journal of medical genetics, 58(1), 1-10. Retrieved June 23, 2015 from

http://www.uni-medica.com/Private/Files/C677T%E4%B8%8E%E5%90%84%E7%A7%8D%E7%96%BE%E7%97%85%E8%AF%81%E6%8D%AE.pdf

Macaluso, M., Wright-Schnapp, T., Chandra, A., Johnson, R., Satterwhite, C., Pulver, A., Berman, S., Wang, R., Farr, S., Pollack, L. (2008). A Public Health Focus on Infertility Prevention, Detection, and Management-PAGE 2 – Reproductive Health. Center for Disease Control. Retrieved May 25, 2015, from http://www.cdc.gov/reproductivehealth/Infertility/Whitepaper-PG2.htm

Macovei, L., Gurzu, A., Alexandrescu, D. M., & Georgescu, C. A. (2015). Simultaneous tromboembolic events in a patient with heterozygous MTHFR mutation. International Archives of Medicine, 8. Retrieved July 6, 2015 from http://www.imed.pub/ojs/index.php/iam/article/download/1108/755

Mtiraoui, N., Zammiti, W., Ghazouani, L., Braham, N. J., Saidi, S., Finan, R. R., … Mahjoub, T. (2006). Methylenetetrahydrofolate reductase C677T and A1298C polymorphism and changes in homocysteine concentrations in women with idiopathic recurrent pregnancy losses. Reproduction, 131(2), 395–401. http://doi.org/10.1530/rep.1.00815

Rajcan-Separovic, E., Diego-Alvarez, D., Robinson, W. P., Tyson, C., Qiao, Y., Harvard, C., … Stephenson, M. D. (2010). Identification of copy number variants in miscarriages from couples with idiopathic recurrent pregnancy loss. Human Reproduction, 25(11), 2913–2922. http://doi.org/10.1093/humrep/deq202

Reus, A. D., Stephenson, M. D., van Dunné, F. M., Krijger, R. R. de, Joosten, M., Steegers, E. A. P., & Exalto, N. (2013). Chorionic villous vascularization related to phenotype and genotype in first trimester miscarriages in a recurrent pregnancy loss cohort. Human Reproduction, 28(4), 916–923. http://doi.org/10.1093/humrep/det025

Rosenberg, N., Murata, M., Ikeda, Y., Opare-Sem, O., Zivelin, A., Geffen, E., & Seligsohn, U. (2002). The Frequent 5,10-Methylenetetrahydrofolate Reductase C677T Polymorphism Is Associated with a Common Haplotype in Whites, Japanese, and Africans. The American Journal of Human Genetics, 70(3), 758–762. http://doi.org/10.1086/338932 Retrieved July 18, 2015 from http://www.sciencedirect.com/science/article/pii/S0002929707602778

Sazci, A., Ergul, E., Tuncer, N., Akpinar, G., & Kara, I. (2006). Methylenetetrahydrofolate reductase gene polymorphisms are associated with ischemic and hemorrhagic stroke: Dual effect of MTHFR polymorphisms C677T and A1298C. Brain Research Bulletin, 71(1–3), 45–50. http://doi.org/10.1016/j.brainresbull.2006.07.014 Retrieved August 4, 2015 from http://akademikpersonel.kocaeli.edu.tr/emel.ergul/sci/emel.ergul14.04.2010_10.04.55sci.pdf

Smith, S. (2012). MTHFR Heterozygous versus Homozygous. Youtube Video. Retrieved from https://www.youtube.com/watch?v=tBUCeulUoe0

Texas Fertility Center (2015). Learn about Recurrent Pregnancy Loss. Youtube Video. Retrieved from https://www.youtube.com/watch?v=efwXPXvV_M4

Ueland PM, Hustad S, Schneede J, Refsum H, Vollset SE. Biological and clinical implications of the MTHFR C677T polymorphism. Trends Pharmacol Sci. 2001; 22195-201. Retrieved June 8, 2015 from http://www.folk.uib.no/mfapu/Pages/papers%20pdf/2001/ueland_2001_tips_22-195.pdf

Wu, X., Zhao, L., Zhu, H., He, D., Tang, W., & Luo, Y. (2012). Association between the MTHFR C677T polymorphism and recurrent pregnancy loss: a meta-analysis. Genetic testing and molecular biomarkers, 16(7), 806-811. Retrieved June 12, 2015 from http://www.researchgate.net/profile/Wen-Ru_Tang/publication/221813369_Association_Between_the_MTHFR_C677T_Polymorphism_and_Recurrent_Pregnancy_Loss_A_Meta-Analysis/links/53f1da500cf2711e0c46089e.pdf

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