Folate Receptor Antibodies and Congenital Birth Defects
Monday, March 17, 2008
Kenneth F. Trofatter, Jr., MD, PhD
• At Mon Mar 10, 07:41:00 PM 2008, Anonymous said…
Hi Dr. T:
Six months ago I lost a monozygotic dichorionic twin pregnancy in which one twin had a neural tube defect and the other had hypoplastic left heart syndrome. Since then, I learned that I have a high titer of folate receptor autoantibodies (Rothenberg, et al. NEJM, Jan 2004;350:134-142)
I had a few questions for you:
1. What, if any, experience do you have with folate receptor autoantibodies in pregnancy?
2. What is the safety and/or utility of low dose steroids (prednisone 5 mg) pre-conception and throughout pregnancy as treatment for such autoantibodies?
Thank you!
Dr. S
• At Fri Mar 14, 02:33:00 PM 2008, Kenneth F. Trofatter, Jr., MD, PhD said…
To Dr S Mar 10: As you correctly surmised, both the neural tube defect and the complex congenital heart defect in your twins might well have been the result of relative folate deficiency as a consequence of your folate receptor autoantibodies. Orofacial clefting in both animal models and humans has also been correlated with folate deficiency states. In 2003, da Costa and colleagues (Birth Defects Res A Clin Mol Teratol. 2003;67:837-47) demonstrated that serum containing folate receptor antibodies given to pregnant rats early in gestation had a dose-related effect on embryo viability and organogenesis. Folinic acid prevented teratogenicity resulting from smaller doses of antiserum, but not that caused by larger doses. Resorption of embryos with the larger doses of the antiserum was prevented by dexamethasone which appeared to reduce embryo damage by preventing immune-mediated cell lysis. In the article you cite by Rothenberg and colleagues (N Engl J Med. 2004;350:134-42) autoantibodies to folate receptors were found in 9 of 12 women who had had, or were carrying, babies with neural tube defects. Interestingly, these antibodies were also found in 2 of the 20 ‘control subjects’ who had babies that did not have neural tube defects.
Although I do not have a lot of experience with the management of individuals known to have antifolate receptor antibodies, my experience with autoimmune conditions associated with autoantibodies in general would lead me to suspect that low-dose prednisone alone is NOT the answer. My gut (and clinical experience) and the animal studies tell me that high dose folic acid and B-complex vitamin supplementation is the way to go and, if more is needed, either higher dose prednisone and/or high-dose intravenous immunoglobulin (IV Ig) should be considered. I have used prednisone for various reasons during pregnancy over the years and generally found it to be quite safe. There is a slightly increased risk for having a baby with facial clefting, but the primary complications I have seen are increased risk for gestational diabetes, premature rupture of membranes, and early delivery. Hypertensive disorders also occur frequently in women who require prednisone, but that may be more an effect of the underlying medical conditions being treated than the drug itself.
It is interesting that folate receptor antibodies can be found in ‘normal’ women. Digging into the literature, one finds that folate receptors are expressed in many body tissues, especially tissues of the central nervous system and the immune system, and in various malignancies. In fact, antifolate receptor therapy as an adjunct to treatment of conditions such as ovarian cancer have been considered. In a mouse model for systemic lupus erythematosus, it was found that depletion of folate-receptor positive macrophages decreased expression of the disease and prolonged the life of the animals (Varghese, et al., Mol Pharm. 2007;4:679-85). My point for telling you this is simple. Folate receptor antibodies may be a natural modulator of the immune response (and perhaps mediator of tumor suppression?!?) that in some individuals is out of whack, producing too much of these antibodies, resulting in the complications that our reader (and others) experienced in her pregnancy by causing a ‘relative folate deficiency’ during the critical stages of her babies’ development.
So, to our reader, thanks for reading and for the great questions and if you find out anything else, let me know! I am here to learn too!
Dr T
Labels: congenital heart defects, folate metabolism, folate receptor antibodies, folic acid, neural tube defects
5 Comments:
At Thu Mar 20, 08:32:00 PM 2008,
ONE OUT OF SIX said…
Hi Dr. T - I had written to you a while back regarding recurrent pregnancy loss and inherited thrombophilias. Specifically - I have hetero Factor V and homo MTHFR .. I was asking what you thought of someone like me starting Lovenox right after ovulation.
Well - I am excited to report that I am pregnant! And my first beta (this past Tuesday, 3/18) at 15 days post ovulation was 173! Progesterone is over 40, estrogen is a little under 400. So far, so good!
My regimen for this cycle included follistim plus HCG trigger and progesterone suppositories after ovulation. I was also on (and am still on) a daily PNV, baby aspirin, foltex, and extra OTC folic acid supplement (bring my daily total to 3.8 grams), and a 1000 mg fish oil capsule.
I started 40mg injectable Lovenox the night after my IUI (which was also the day I ovulated.)
I go back for a second beta on Monday 3/24 at which point I'll be 21 days post ovulation. I am cautiously optimistic and feeling good ... I've had a good bit of cramping over the past few days but NO spotting or bleeding.
Thanks for your helpful advice a few months ago (you were supportive of me starting the low dose of Lovenox immediately after ovulation.)
I'm hoping I'm at the beginning of an exciting NEW journey! :-)
At Fri Mar 21, 06:22:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To one out of six: Great! We will all be pulling for you. Thanks for getting back to us and let us know how things turn out. Dr T
At Mon Mar 24, 07:28:00 PM 2008,
Anonymous said…
Dr. T, I did not realize you devoted a separate article to this. Thank you! I posted a follow-up question on the original ( MTHFR blog ) that should belong to this thread instead ( inquiring about folinic acid ). Please let me know if the question did not get to you and I'll repost.
Thanks again!
Dr. S
P.S. The first follow-up question ( from last week that I corrected & reposted earlier today ) did not contain correct dose of B12 - it should read 1mg.
At Wed Oct 22, 06:13:00 PM 2008,
Irish Lass said…
Hi Dr. T - I am 37 years old (will be 38 in March) and I had a baby girl in 1992 when I was 21 - didn't watch what I ate, didn't take pre-natals, didn't watch saccharin intake and although she weighed 5 lb, 4 oz when she was born, she is an otherwise healthy 16 year-old.
Last year, I was pregnant with another baby girl, but on 13 October, at 28 weeks, she just stopped kicking. We verified through ultrasound that she was gone, and I delivered her on 15 October. Needless to say, it was the most horrible time of our lives.
The doctors tested me and did an autopsy on Riley, and they came to the "closest but not 100%" conclusion that I "may" have antiphospholipid antibody syndrome.
My husband and I have remained faithful that the Lord has a plan - but we had a miscarriage at 12 weeks in June, which led to daily shots of Lovenox (40mg) when we became pregnant in July. Alas - a blighted ovum at 7 weeks at the end of August.
We took a break from trying and are eager and hopeful to start trying to concieve again in November. I have been taking a nightly dose of baby aspirin since we started trying at the beginning of this year. In reading quite a few of your posts, do you feel that I should start injecting myself again with Lovenox as soon as I am through ovulating, or as soon as I get a positive pregnancy test, or ??? I am otherwise perfectly healthy (although a bit of extra padding from the stress of losing Riley and am now losing some weight) and my OB has only suggested testing my progesterone levels once we get pregnant again. He and my MFM also tell me I just have an increased risk for miscarriage due to my age - other than that, it's making me crazy trying to find some answers.
I placed my first baby girl for adoption when she was 2 days old - and although she's in my life, she's not fully "mine", and my husband and are so SO desperate to have a baby.
Is there anything else you can suggest, or do we just need to keep trying?
Thank you.........
At Fri Oct 31, 05:20:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Irish Lass: Before I give an answer, can you tell me what tests you have had done to evaluate your losses and the results to date? Have you seen a specialist in Reproductive Endocrinology and Infertility yet? Dr T
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