Recurrent Pregnancy Loss (RPL) Workup Shows MTHFR: What Next?

Question:

Dear Dr. Ramirez,

I am 31 years old and have had 3 chemical pregnancies in the past 12 months. They have run a slew of genetic testing and a RPL (recurrent pregnancy loss) workup and all has come back normal with exception to the MTHFR test. I have tested positive for 1 copy of the MTHFR mutation. The nurse told me that because I was considered heterozygous that this was not a big deal. They prescribed me with a high dosage of Folic Acid. She said that it was likely not contributing to the repeat losses. I have been reading online and while the homozygous mutations seem to be more serious, there seem to be mixed reviews on whether this can contribute to early miscarriage.

Do you prescribe Lovenox or Heparin in this type of situation (only 1 copy?) Should I be concerned about this and demand that they treat it somehow? It doesn't seem like they are planning on doing anything besides the folic acid.

Also, given that this test has come back as it did, is there any other testing that you would reccommend that may be related to this? I am a little frustrated because this test was not originaly included in the work up and I had heard about it from online research and specifically requested it.

I just want to make sure that I am not missing anything.

Thank you,

D. from Boston

Answer:

Hello D. from the U.S. (Massachusetts),

The treatment for MTHFR (Methylenetetrahydrofolate reductase), is increased Folic acid (for more information MTHFR.net). But with your history of recurrent pregnancy loss or RPL, I usually will add the following to my patients, although there is not clear research backing it up if you are immunologically negative:

1. Low dose aspirin 81 mg starting with the start of the cycle

2. Low dose heparin 2000 units bid starting with the start of the cycle (you can substitute lovenox but it is more expensive).

3. Medrol 16 mg starting with the beginning of the cycle until ovulation then decrease to 8 mg

4. Increase progesterone supplementation of either Crinone 8% per day or Endometrin 100 mg three times per day starting after ovulation.

This cocktail has been shown to be effective in recurrent miscarriages (see Reproductive Immunology Associates for further information regarding immunological causes of miscarriage). My presumption is that you have had immunological testing, specifically antiphospholipid antibodies?

I hope this helps!

Good Luck,

Dr. Edward J. Ramirez, M.D., FACOG
Executive Medical Director
The Fertility and Gynecology Center
Monterey Bay IVF Program
www.montereybayivf.com
Monterey, California, U.S.A

Will Removing Blocked Fallopian Tube Help This Patient Conceive?

Question:

Hi again Dr Ramirez, it's K. in NY.

I have written in the past about my multiple miscarriages/chemical pregnancies. I tested positive for the MTHFR mutation this past fall. I had a miscarriage at 9 weeks in August, which you believed was most likely due to a virus I contracted. I have followed up with a new specialist recently, and received some new information today.

First of all, my right tube is definitely blocked (although most of my miscarriages/chemical pregnancies resulted from ovulating on the right) We are led to believe that I most likely had a few early ectopic pregnancies. The specialist today suggested that I undergo surgery to remove the right tube completely. I am not sure how I feel about this, as surgery for any procedure is risky. Do you feel that having the tube removed would increase my odds of becoming pregnant? I am willing to do it if it makes sense, but hate to do it "just because". I am not sure if research supports this practice or if it doesn't really make a difference in the long run.

The second piece to this scenario is that my husband was diagnosed with a translocation between chromosomes 11 and 13 (46xy,t(11;13)(q21;14)). IVF (in vitro fertilization) was suggested to us, but we do not have the money for this and it is not an option unfortunately. Our Dr prefers to remove the tube and discuss fertility meds and other options after that point. While it explains many of our losses, I am curious if you have any other treatment suggestions. We have two healthy children that we had no difficulty conceiving. I have taken femara multiple times (pregnancy x1) and progesterone. We have not tried IUI, but were wondering if it would be of any benefit. I am just confused with all of this new information as to how to proceed conservatively. I am willing to take meds and try IUI, but I would rather not have surgery at this time unless there is a strong link between increased fertility and tube removal. Also, if we continue with meds and u/s, is there a point in being aggressive on months where I ovulate on the right?

We are just looking for the best path to take and I am hoping that you have some input to help us make an informed decision. Obviously this journey gets more difficult with every diagnosis. Thank you for your time.

Answer:
Hello K. from the U.S.(New York),

So sorry about your secondary infetility problems. To begin, there are no studies to either validate or invalidate the recommendation to remove a nonfunctioning tube unless it is blocked at the fimbriated end (called a hydrosalpinx). In that case, it has been shown to decrease pregnancies via IVF and is thought to impair implantation. It is recomnended to remove or separate the tube from the uterus. However, your doctor's recommendation is not unreasonable. Considering that it is not predictable as to which tube the egg will go into, each month you have a 50/50 chance that the egg will get picked up by the wrong/damage tube, and therefore will not get pregnant. In addition, you are risking ectopic pregnancy should the sperm get through on that side. I think that removing the tube might give you a better chance at getting pregnant because that only leaves one tube where the egg can go, and it does not matter which side the egg is ovulated from. They all go into the culdesac where the tubes lie.

In terms of your husband's translocation, that certainly can be a cause for miscarriages, just as your postive MTHFR can be a cause. There are no real good solutions for his problem other than doing PGS (preimplatation genetic screening) in conjuction with IVF. You'll just have to take your chances. I am not sure that IUI will offer you any more than trying as you have been, but statistically it does give a slightly increased chance of pregnancy if 2-3 eggs are ovulated at a time. That's the only advantage.

Good Luck,

Dr. Edward J. Ramirez, M.D., FACOG
Executive Medical Director
The Fertility and Gynecology Center
Monterey Bay IVF Program
http://www.montereybayivf.com/
Monterey, California, U.S.A.

38 Year Old TTC'r With Factor V Lieden, MTHFR, High BMI, High FSH & Good Embryos Has Done 3 IVF Cycles: I'd Throw In The Kitchen Sink!

Question:

I am a 38 yo female in the Northeast US. I started menstruating when I was 10 yo and due to irregular (too frequent) and heavy periods, went on BCP's at age 15 thru 35 - after stopping BCP's, my periods are very regular. We started TTC 3 years ago, and after no success, initial tests showed my H had good sperm count but low motility. We started w/ an RE in Jan 09. For me, my problem areas are age, high BMI, hypothyroid (well controlled) and + for MTHFR (Methylenetetrahydrofolate reductase) & Factor 5 Leiden. No PCOS, no endometriosis, tubes are open, endometrial lining develops well, FSH 9.

We were advised to go right to IVF to increase our chances of conception. IVF#1 5/09 Lupron/Gonal F protocol - 13 retrieved, 7 fertilized, 3 day transfer of 3 embryos - all Grade 2 (8, 7, 6 cells), resulted in pregnancy that ended in m/c at 8 weeks due to triploidy. IVF#2 8/09 Lupron Flare protocol - 13 retrieved, 2 fertilized, 3 day transfer of 2 embryos - Grade 2 (6 & 5 cell) BFN. Dec 09 - had a d&c and a month of antibiotics & estrace to prepare for IVF. IVF #3 1/10 w/ acupuncture, Lupron/Gonal F/Menopur - 13 retrieved, 5 fertilized, 3 day transfer of 3 embryos - all Grade 1 (8 cells) another BFN. All IVF's had ISCI and last 2 w/Assisted Hatching and no embryos made it to freeze. My E2 levels were consistent for all 3 - always between 1900-2300. My meds are always prenatal vits, folgard, baby asa, and levoxyl (thyroid). Lovenox only during pregnancy. My RE says that my age is the problem & that although I respond well and fertilize well, my eggs are of poor quality and arrest several days after transfer. I have no more covered IVF's, but do have 6 IUI's. His recommendation was to try 4 IUI's and if I do not get pregnant, to move onto other options, like DE (donor eggs).

My questions:

1. Do you agree with this diagnosis? Would it be worth trying another IVF with another RE? I have been very happy w/ my experience w/ this group.

2. I've read about Natural Killer cells & antibodies & immunology treatments - my RE says the studies do not support this type of treatment and this will not help. Do you agree?

3. I've had my first IUI on 3/31 and am awaiting a beta on 4/13. Do you think trying several IUI's is worth it or are the chances of success so low that I am wasting my time?

4. Is moving onto Donor Eggs my best next step?

Thank you so much for taking the time to read and reply. I really enjoy reading your answers on this site. A. from the U.S.A.

Answer:

Hello Alyssa from the U.S.,

1. In reviewing your history, out of three IVF cycles, you were successful with one (the first one), but in each, you stimulated well, had a good number of eggs retrieved and, except for the second cycle, had decent embryos. So that means that your ovaries are functioning well and stimulating well despite your high FSH level, and you seem to make good embryos. Of course, since embryos are rated only based on how they look, we cannot know if they are normal or not. Your first pregnancy was genetically abnormal and that is the "age factor" i.e. poor quality eggs leading to abnormal embryos. It is possible that the embryos in cycles #2 and 3 were genetically abnormal as well and that is the reason they did not implant. So, I agree that egg quality might be the issue, leading to imperfect embryos. That is the hurdle that you need to overcome and is totally based on your age. You may not necessarily need to change doctors, but it just may take more tries to become pregnant, since the majority of your eggs are not good quality and the goal is to get a good one.

However, pregnancy rates do vary by physician and protocols, and that could possibly make a difference. For instance, I do not use the Long (lupron) protocol or flare protocol. I use a combination (Ganerelix (antagonist) + Follistim + Menopur) protocol. That could possibly make a difference in your stimulation and the number of eggs retrieved, thereby increasing the chances of finding a good egg. Also, a lot of it is just luck of the draw, so to speak. Each cycle is unique and has the potential to yield a different outcome.

2. You have a +MTHFR and Factor V Leidin. That puts you at increased risk immunologically. For that reason, low dose aspirin, Medrol, and possibly Heparin or Lovenox, might make a difference and would be a good idea. I automatically place my failed patients on this protocol. My reasoning is that, despite the studies showing no value to this regimen, it is like stress reduction, acupuncture or any number of other adjuncts that have not been clinically proven in that, it doesn't hurt and it might help. The American Society of Reproductive Medicine does not advocate the use of immunological therapies, so your RE is correct. However, if you keep failing multiple times and that is something you want to try, then go for it. Basically I throw the kitchen sink in to try to overcome the failures. So, what's the harm?

3. If your IUI is positive, great. If negative, then you need to understand that you are doing them because you have the benefit and not because it is a better treatment. It is not. It certainly has a chance of working that is better than trying naturally, but that chance is not that good. At 38 yo, the chances are about 7-10% per cycle, which is much less than the 60+% with IVF per cycle. But, that doesn't mean it can't work. The goal would be to make sure that you are ovulating as least three eggs with each cycle. It should preferably be 5. Use injectables if you have to. It is the ovulation of multiple eggs that increases the pregnancy rate with IUI.

4. Donor eggs is certainly an option and an option that you will have until you are 50 years old. It certainly gives you the best chances of success because it eliminates the egg factor and reduces the risk of miscarriage. It's your ace in the pocket. Whether or not to proceed with it at this time is your personal decision. Because your ovaries stimulate well, there is still the opportunity for you to get pregnant with your own eggs. There should still be some good ones left inside. It will just be a matter of time. But, if you would rather not keep trying until you find that good egg, and increase your chances of success in the shortest time, then donor eggs would be the logical option. There was a report in the NY Times about a patient who is now the oldest patient to get pregnant successfully with her own eggs at age 49. She was very persistent and dedicated to being successful, and it took her two years of doing IVF.

I hope this helps, you have the potential to get that one good embryo & it may only be a matter of time and changing up the treatment protocol a bit. I find it heartening that you are willing to stay open to all possibilities, so I know you will succeed!

Good Luck,

Edward J. Ramirez, M.D., FACOG

Executive Medical Director

The Fertility and Gynecology Center

Monterey Bay IVF Program

www.montereybayivf.comMonterey, California, U.S.A.