Folate Receptor Autoantibodies and Miscarriages

Folate (vitamin B9) is one of the most critical nutrients required during pregnancy due to its essential roles in DNA synthesis, cell division, methylation processes, and fetal development. A deficiency in folate can lead to severe complications, including neural tube defects (NTDs), miscarriage, preterm birth, and placental dysfunction.

Folate has a significant role in DNA synthesis and cell division. In pregnancy, and immediately during conception, the embryo undergoes exponential cell division, requiring massive amounts of folate to synthesize DNA and RNA. Folate acts as a coenzyme in one-carbon metabolism, facilitating the production of purines and pyrimidines (building blocks of DNA). Without sufficient folate, cells cannot divide properly, leading to developmental delays or miscarriage.

Folate is also critical during placental development. The placenta forms early in pregnancy and relies on folate to grow and establish a functional blood supply to the fetus. Folate deficiency can cause poor trophoblast invasion (a key step in placental formation), leading to placental insufficiency, which is a major cause of miscarriage and preeclampsia.

The neural tube forms within the first 28 days of pregnancy, before many women even know they are pregnant. Because of this, folate is absolutely critical as this integral vitamin is required for proper neural tube closure. A deficiency increases the risk of Spina bifida (incomplete spinal cord development), Anencephaly (missing parts of the brain and skull, and Encephalocele (brain tissue protruding from the skull. Studies have shown that adequate folate intake before conception reduces NTD risk by 50-70% (CDC, 2022).

We also know that folate plays a major role in methylation and epigenetic regulation. Folate is a key player in methylation reactions, which regulate gene expression. As such, proper methylation ensures normal embryonic development, the silencing of harmful genes and the prevention of congenital abnormalities. Likewise, poor folate status during pregnancy is linked to increased risk of autism, ADHD, and metabolic disorders in offspring due to altered epigenetic programming.

Folate also plays a role in preventing miscarriages. It has a significant role in chromosomal stability & DNA Repair. Folate deficiency leads to uracil misincorporation into DNA, causing chromosomal breaks and increased mutation rates. This can result in lethal genetic errors, leading to early miscarriage.

Additionally, folate is connected to homocysteine regulation as folate helps convert homocysteine into methionine. High homocysteine levels, due to folate deficiency, cause blood vessel damage (endothelial dysfunction), increased clotting risk (thrombophilia) and poor placental blood flow, contributing to miscarriage.

Finally, folate supports regulatory T-cell function, preventing excessive inflammation that could harm the embryo.

Clearly, folate is very important during pregnancy. Because of this our food supply is fortified with folic acid (a synthetic form of folate) – to ensure healthy pregnancies and prevent neural tube defects.

Recurrent miscarriages affect approximately 1-2% of couples trying to conceive, and in many cases, the underlying cause remains unexplained. Emerging research suggests that folate receptor autoantibodies (FRAAs) may play a significant role in pregnancy loss by disrupting folate transport, leading to functional folate deficiency even in the presence of normal serum folate levels. As we identified previously, folate (vitamin B9) is essential for DNA synthesis, cell division, and proper fetal development. During pregnancy, folate requirements increase significantly to support rapid placental and embryonic growth. A deficiency in folate is linked to early pregnancy loss.

Folate is transported into cells via the reduced folate carrier (RFC) – a low-affinity, high-capacity transporter, and folate receptor-alpha (FRα) – a high-affinity receptor critical in tissues with high folate demand, such as the placenta and developing embryo.

FRAAs are autoantibodies that mistakenly target and bind to folate receptors, particularly FRα, blocking folate uptake. There are two types of these autoantibodies:

Blocking autoantibodies – Prevent folate binding to FRα.

Binding autoantibodies – Attach to FRα but may not fully block folate uptake.

These autoantibodies lead to functional folate deficiency, even if serum folate levels appear normal, because cellular uptake is impaired. In some cases FRAAs contribute to miscarriages through several pathways. Folate deficiency can lead to impaired embryonic development via perturbed dna synthesis and methylation. Additionally, folate deficiency due to FRAAs can lead to chromosomal instability and failed implantation.

Since FRα is highly expressed in placental trophoblasts. FRAAs can disrupt folate transport to the placenta, leading to poor vascularization and placental insufficiency, increasing miscarriage risk.

In other instances, folate deficiency elevates homocysteine, a known risk factor for thrombophilia and vascular damage, which can impair placental blood flow.

Because FRAAs indicate an autoimmune component, potentially triggering inflammatory responses, there is an indication that this can harm the developing embryo.

Several studies support the association:

• A 2016 study by Quadros et al. found that 56% of women with recurrent miscarriages had FRAAs, compared to 10% in controls.
• Research by Ramaekers et al. (2013) showed that FRAAs were prevalent in women with unexplained infertility and pregnancy loss.
• A 2020 meta-analysis confirmed that FRAAs are significantly higher in women with recurrent miscarriages compared to healthy controls.

Since serum folate levels may appear normal despite cellular deficiency, specialized testing is required. Folate receptor autoantibodies may be identified through the FRAT^® test. FRAT^® will screen for both blocking and binding autoantibodies. FRAT^® should be considered in cases of recurrent miscarriages, neural tube defects, or unexplained infertility.

As FRAAs block FRα-mediated uptake, bypassing this pathway with high-dose folinic acid (leucovorin) or 5-methyltetrahydrofolate (5-MTHF) can improve folate delivery via the RFC transporter. There are a few studies that indicate folinic acid may improve pregnancy outcomes in FRAA-positive women. Again, this subject matter needs to be discussed with a qualified physician. Please consult your medical professional for further information.

Folate receptor autoantibodies represent a significant but underdiagnosed cause of recurrent miscarriages. By impairing folate transport, FRAAs may lead to functional folate deficiency, placental dysfunction, and embryonic developmental failure. Testing for FRAAs via FRAT^® should be considered in women with unexplained pregnancy loss, and treatment with high-dose folinic acid or methylfolate may improve outcomes. Further research is essential to refine diagnostic and therapeutic approaches, offering hope for affected couples.

• Quadros EV et al. (2016). “Folate receptor autoantibodies are prevalent in subfertile women and associated with miscarriage.” Journal of Reproductive Immunology.
• Ramaekers VT et al. (2013). “Autoantibodies to folate receptors in the cerebral folate deficiency syndrome.” New England Journal of Medicine.
• Wang Y et al. (2020). “Association between folate receptor autoantibodies and recurrent miscarriage: A meta-analysis.” Fertility and Sterility.