Compound Heterozygous MTHFR - now what?

I intended this information to be viewed by my friends and family about my personal history and background with MTHFR, but then it occurred to me that others with the condition may also stumble upon my blog when googling MTHFR so I should probably provide some helpful information to them as well! Feel free to ask questions, and I will definitely try to help answer if I can=).
(Here's my disclaimer though - I am NOT a doctor or healthcare professional qualified to diagnose or make any treatment recommendations. If you have questions or concerns regarding your diagnosis or treatment, please ask your heathcare provider. Thanks!)

Compound Heterozygous MTHFR – My Personal Background
After my last miscarriage in December 2009, I requested that some additional blood work be completed to make sure we weren’t missing any potential causes of miscarriage that could be treated ahead of time, prior to additional expensive fertility treatments. Under normal circumstances this recurrent miscarriage testing (or “habitual aborter” testing as it is commonly called) won’t be covered by insurance until after the female has had at least 3 documented miscarriages. As I have only had two miscarriages, and one was ectopic and may not be considered a “true” miscarriage to some practitioners, my RE (Reproductive Endocrinologist) refused to run any additional testing on me. As I was already paying out of pocket for the IVF cycles, paying the out of pocket cost on some blood work wasn’t a big deal to me. I talked to my OB about the testing and he agreed to have the blood work run. He said that he requests the blood work be completed after one miscarriage. He said especially in a situation where a patient is spending loads of money and is using IVF to get pregnant, it makes sense to do the testing just to make sure you have a clear picture of any potential problems. I love my OB!

So, the blood work came back at the end of December and it showed that I am “Compound Heterozygous” for the MTHFR gene mutation. My homocysteine level was within normal range (although on the high end of normal – this will be important later). Essentially what this means is I have one copy of the C677T gene mutation and one copy of the A1298C gene mutation, and it inhibits my body’s ability to properly metabolize folic acid, and may also be an inherited clotting disorder (depending on homocysteine levels in my blood). I got one copy of the mutations from each parent (so both parents were heterozygous for at least one MTHFR mutation in order for me to end up compound heterozygous).

All other blood work came back normal (Anti-Thrombin, Cardiolipin, Lupus, Plasminogen Activator Inhibitor, Factor V Leiden, and Protein C&S).

Now you may be wondering what this all means! Brilliant! Let me try to fill you in.

Different MTHFR Mutations
With MTHFR, there are two different genes identified for this mutation, and it's possible to be "heterozygous," "compound heterozygous," or "homozygous." According to the information I have found, the order of potential severity from most to least is:

1. C677T & C677T (Two C Copies - C677T Homozygous)
2. C677T & A1298C (One Copy of Each The C & A - Compound Heterozygous)
3. C677T (One C Copy - C677T Heterozygous)
4. A1298C & A1298C (Two A Copies - A1298C Homozygous)
5. A1298C (One A Copy - A1298C Heterozygous)

The heterozygous MTHFR mutation is relatively common in the general population. Approximately 44% of the population is heterozygous (having one copy of one of genes) and another approximate 12% are homozygous for the MTHFR mutation (two copies of either C677T or two copies of A1298A). Compound heterozygous and homozygous MTHFR have the highest incidences of being linked to implantation failure, late term miscarriages, specific birth defects and overall vascular health. (See also supporting study)

What does the MTHFR gene do?
Essentially the MTHFR gene takes the folate that you consume from food or vitamins, and breaks it down into a metabolized form that can be used by your cells to complete protein synthesis (the building blocks of DNA). More specifically, the gene MTHFR (Methylenetetrahydofolate Reductase) encodes the protein MTHFR. Its job is to convert one form of folate (5,10- Methylenetetrahydofolate) to another form of folate (5-Methyltetrahydrofolate). 5-Methyltetrahydrofolate is used to convert Homocysteine (a "bad" amino acid) to Methionine (a "good" amino acid). So, if MTHFR is not doing its job as well, homocysteine will not be converted to Methionine as efficiently and the homocysteine will be elevated in patient’s plasma. Elevated homocysteine has been associated with a variety of diseases (including but not limited to cardiovascular disease, stroke, Alzheimer's, recurrent miscarriage, etc.) and can also indicate a higher risk of DVT (deep vein thrombosis) or blood clots (hence MTHFR is considered an inherited clotting disorder in patients with elevated homocysteine levels).

My homocysteine level was checked when the recurrent miscarriage blood work was completed (I was not pregnant at the time). My homocysteine level was within normal ranges at the time it was drawn (although it was on the high end of normal). I will likely request that my homocysteine level be drawn again once I become pregnant to ensure that everything is still normal=). In the meantime I have been switched from a “normal” prescription prenatal vitamin to a special prescription prenatal vitamin (Neevo) containing the metabolized form of folate that my body can actually use (5-MHTR). Additionally my OB has recommended that I start taking an 81 mg baby aspirin every day, and I will continue taking said baby aspirin all the way through pregnancy.

Is there any research? What are the treatments?
Some research has been completed on MTHFR, particularly by Dr. Alan Beer, a Reproductive Immunologist (RI) who passed away in 2006 (and his colleagues). Dr. Beer had a specific protocol that he used when treating ladies with homozygous or compound heterozygous MTHFR, particularly with elevated/abnormal homocysteine levels (although it doesn’t appear that elevated or abnormal homocysteine levels were required to use his treatment protocol during fertility treatments – I am currently trying to find the article of Dr. Beer’s that I read that shows this). I have joined a yahoo group with other ladies with MTHFR, endometriosis and other immune conditions, and being a member of the group has given me access to piles of research, information, and even some protocols used by patients of the Beer Center. From what I can gather, Dr. Beer would begin Lovenox (40mg/once a day) on cycle day 6 of a fertility cycle (particularly IVF) and would continue the Lovenox throughout the cycle. If pregnancy is confirmed, this dosage would probably be increased (Typically up to 40mg/twice a day, but potentially higher doses can be prescribed – up 60 mg/twice a day- dependent upon blood work results and homocysteine levels) and usage continues throughout pregnancy. Approximately two to four weeks prior to birth, the patient is usually converted to Heparin and continues to take an anti- coagulant for another 6 weeks postpartum.

Dr. Beer’s Center for Reproductive Immunology and Genetics website is a wonderful source of information and can be accessed here.  This is a specific link to information regarding inherited and acquired thrombophilias. You can go backwards through the site for more general information. This page speaks to MTHFR and other inherited an acquired clotting disorders.

Many doctors prescribe “Folgard” or “Metanx” to ladies with MTHFR gene mutations, which is a prescription vitamin supplement containing very high levels of folic acid, B12 and B6. To put these amounts into perspective, the average multivitamin contains 400 mcgs of Folic Acid , and most decent prenatals have 800mcg of Folic Acid (about 200% of the normal daily value). It is recommended to take 1 -2.2 mg Folgard or Metanx per mutation. Those that are compound heterozygous and those that are homozygous for the mutation are recommended to take nearly 4.5-5mg of Folic Acid/B vitamins (or 2 Folgard or Metanx) (12 times the average multi-vitamin and 6 times more than prenatals)!

However, recent research has indicated the importance of supplementing with 5-MTHF instead of the actual folic acid that is provided in both the Folgard and Metanx. 5-MTHF, is a bioactive form of folate. Although synthetic folic acid is the common form of "folate" used for supplementation and food fortification, it must be converted to 5-methyltetrahydrofolate (5-MTHF) by the intestines and liver to become biologically useful to cells.

The prenatal vitamin I am taking now, Neevo, contains 5-MTHF. I don’t know if it really is better or not, but that’s what my OB wanted me to do, so I’m running with it! It is also recommended that patients with MTHFR begin taking a low dose or “baby” aspirin (81 mgs) once a day, every day, for the rest of their lives.

What does this mean for me?
I have spoken with several RE’s, and so far, no one has suggested that I take lovonox during my upcoming IVF cycle or after a pregnancy is confirmed. I will check with my OB after we successfully achieve pregnancy again. Several other ladies with compound heterozygous MTHFR and seemingly normal homocysteine levels informed me that after they achieved pregnancy that their RE’s gave them the option to continue taking baby aspirin or switch to lovonox, but due to the risks of lovonox, they chose to stay on the baby aspirin. So far their pregnancies are progressing wonderfully! This is wonderful news! I would definitely give myself a daily shot or two of lovonox or heparin if it meant I would have a happy healthy baby (I will do nearly ANYTHING for a happy healthy baby!), but if it’s not necessary I have no desire to jab myself in the abdomen twice a day either!!

There is a lot more information out there online regarding MTHFR. A diagnosis of a MTHFR gene mutation and subsequent treatment still seems to be pretty controversial, and testing has only become common in the last 5-7 years or so. Some physicians recommend no “treatment” for the mutation, and others will treat with increased doses of folic acid (because extra folic acid “can’t hurt”). Some providers may recommend baby aspirin, and others may not. Still others may recommend lovonox or heparin during a fertility cycle and during pregnancy, while others will recommend against such treatments stating that they are unnecessary and offer more of a risk than a benefit. I’m quite sure that as more research on MTHFR is completed, we will get better treatment recommendations. If only we had the 10 years to wait for that research to be completed!

If you think your physician isn’t being aggressive enough with treatment, please don’t hesitate to seek out a second opinion or even see a reproductive immunologist or a genetic counselor. You are your #1 advocate!

*Update*
Just in case you may be curious what the recurrent miscarriage/habitual aborter workup will run you - my insurance was charged $1026 for all 9 tests. I have good insurance - I only had to pay about $40 out of pocket - but it still would have been worth it to me to have the testing done even if I would have had to pay the entire amount out of pocket. It really is worth asking your doctor about.

I wrote this post in January of 2010. Since that time I have had a successful twin pregnancy and gave birth to two beautiful little baby girls on October 13, 2010 as well as a successful singleton pregnancy and gave birth to a beautiful baby boy on June 12, 2012.   I took Neevo prenatal (with the metabolized form of folic acid) and baby aspirin throughout my entire pregnancy for both pregnancies. It CAN work. One of my fellow bloggers and commenters on this post also had a successful twin pregnancy and gave birth to her boy/girl twins a few weeks after I did. She is homozygous for the C677T mutation and was on lovonox injections and metanx (among other things for her other clotting conditions). My point being - with the right treatment - you very well may be able to have the baby you have always dreamed of. Please make sure to explore your options, push for the testing you believe that you need, and above all, don't give up!!

**Update 10/30/13**
Since my original posting, there have been several occurrences where people have been unable to ascertain Neevo due to manufacturing changes, or the copays have simply been too high for people to be able to afford it.  I have been taking Neevo DHA again for the last 18 months, and I want to take a moment to share with you a more cost effective option with you to get the Neevo you need if your insurance doesn't cover it:
The maker of Neevo is Pam Laboratories
If you click on the Neevo link on the Pam Laboratories site, then click on the "ordering information" tab you will see information about ordering Neevo through "Brand Direct Health".  I would highly encourage you check out this ordering option.  I just refilled my Neevo DHA prescription for 90 days (with GOOD federal insurance) through Hy-Vee, a local grocery store and one of the few places in town that carries Neevo, and my copay was still $150!  When I had called Brand Direct Health previously (a year+ ago) they had quoted me $114 for a 90 day supply, and they will ship it direct to your door! Your OB just needs to fax in the 90 day prescription.  I would highly encourage you to check this option out.  Neevo IS still available!

Also, for those of you who are reading this blog who are NOT trying to get pregnant, if you go to the Pam Laboratories website you will see that they are also the makers of Metanx AND Deplin... you can also order these products instead of the prenatal through Brand Direct Health for substantial savings.  Remember, MTHFR is a lifelong issue, that you will need to treat forever, not only when you are pregnant or lactating. 

God bless ladies, and Good Luck!
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