Fruit of the Womb
Fruit of the Womb

Folate Receptor Antibodies and Congenital Birth Defects

We have such great readers! The comment and questions below were shared with us by a physician who had a twin pregnancy in which both of her babies were lost early in third trimester with different major congenital birth defects - one involving the neural tube and one with a complex congenital heart abnormality. Both of these types of abnormalities have been found to be associated with folic acid deficiency and abnormalities of the folic acid-dependent metabolic pathways. She, herself, was found to have high titers of autoantibodies against the folic acid receptor which, perhaps, led to a relative deficiency in folic acid, resulting in her identical twin babies' disparate birth defects...

• 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
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