The Importance of Detecting Folate Receptor Autoantibodies in Pregnancy

Folate (vitamin B9) is essential for DNA synthesis, cell division, and proper fetal development during pregnancy. Maternal folate deficiency is associated with severe complications, including neural tube defects (NTDs), miscarriage, preeclampsia, and other developmental disorders. While folate supplementation is widely recommended, some women still experience folate deficiency-related complications despite adequate intake. Emerging research suggests that folate receptor autoantibodies (FRα-Ab) may impair folate transport to the fetus, leading to functional folate deficiency even when blood levels appear normal.

Detecting folate receptor autoantibodies (FRα-Ab) in pregnancy is crucial because these antibodies can block or disrupt folate uptake, increasing the risk of adverse pregnancy outcomes. Folate receptor autoantibodies may be detected via the FRAT^® test, which screens for both blocking and binding Fraas. Although not well known, or extensively studied, folate receptor autoantibodies clearly have a role in the mechanisms of pregnancy. There are distinct clinical implications, and the importance of early detection and management of FRα-Ab in pregnant women cannot be stressed enough.

Let’s begin analyzing this connection:

Folate receptor alpha (FRα) is a high-affinity cell receptor responsible for folate (vitamin B9) uptake, particularly in the placenta, brain, and developing fetus. This means that folate receptor alpha is a major receptor that readily brings Vitamin B9 (otherwise known as folate) into the cell. This is critical during pregnancy as at this specific time period/cycle there is extensive cell replication and proper folate transport is critical.

Autoantibodies against FRα (FRα-Ab), also known as folate receptor autoantibodies, however, can have a detrimental effect on folate receptor alpha when they are present. In essence, they block folate from being properly absorbed into the cells that critically need it. This blockage can have significant negative consequences in the placenta, and in the fetus as well, where folate receptor alpha is readily expressed. In other words, these cells may potentially be starved of proper folate (vitamin B9).

Distinctly, there are two types of folate receptor autoantibodies:

• Blocking antibodies – Prevent folate binding to the receptor.
• Binding antibodies – Attach to FRα but may not fully block folate uptake, though they can still impair transport.

Folate receptor autoantibodies can develop due to genetic predisposition, environmental triggers (e.g., infections, dietary factors), or molecular mimicry (where the immune system mistakenly attacks FRα).

Placental folate transport disruption – FRα is highly expressed in the placenta to supply folate to the fetus. Autoantibodies can reduce folate transfer, leading to fetal folate deficiency despite normal maternal serum folate levels. This is an important caveat – folate levels in the blood may seem normal. However, that may not be the same for folate in the cerebrospinal fluid, thereby creating a neurological folate deficiency. FRAT^® will detect the presence of folate receptor autoantibodies in these cases.

Neural tube defects (NTDs) – Historically, studies have shown a strong association between Fraas and NTDs (e.g., spina bifida, anencephaly).

Miscarriage and pregnancy loss – Folate is critical for early embryonic development, and impaired transport increases miscarriage risk. If one has had a prior miscarriage, it may be prudent to test for folate receptor autoantibodies via FRAT^®.

Preeclampsia and intrauterine growth restriction (IUGR) – Folate deficiency contributes to endothelial dysfunction and poor placental perfusion.

Keeping in mind that folate receptor autoantibodies can potentially disrupt folate transport, it is important to identify them as soon as possible. This is especially critical for those that may have high risk pregnancies, or have had miscarriages prior.

Not all women with folate deficiency respond to standard supplementation. Testing for Fraas can help identify those at risk of functional folate deficiency, allowing for targeted interventions.

In a past study, it was determined that p to 70% of NTD cases may be linked to FRAAs (study by Rothenberg et al., 2004). Although more studies are necessary, this provides for a good indication on how folate receptor autoantibodies affect pregnancy.

Even with folic acid supplementation, women with FRα-Ab may still have insufficient folate reaching the fetus.

Overall, folate plays such an important role in pregnancy – from the time of conception and until post-delivery. Folate deficiency is linked to endothelial dysfunction and oxidative stress as seen in preeclampsia. Additionally, inadequate folate affects placental and fetal growth that may relate to preterm birth & low birth weight.

Although much more research is necessary and needs to be undertaken in this specific area, there is some thought that autism spectrum disorder (ASD) & neurodevelopmental delays are related to possible folate deficiency and the presences of folate receptor autoantibodies during pregnancy. Folate is critical for brain development; impaired transport may increase ASD risk (Ramaekers et al.,)

This has become a very popular research area as continued discoveries may aid in the reduction of ASD. Some of the key research findings that are of great interest are:

• Rothenberg et al. (2004) – Found FRα-Ab in 75% of mothers with NTD-affected pregnancies vs. 10% controls.
• Ramaekers et al. (2007, 2013) – Linked FRα-Ab to cerebral folate deficiency (CFD) and autism.
• Molloy et al. (2009) – Showed FRα-Ab reduces folate uptake in placental cells.

While not yet routine, testing with FRAT^® may be recommended for:

• Women with a history of NTD-affected pregnancies.
• Unexplained recurrent miscarriages.
• Autism or developmental delays in previous children.
• Low serum folate but normal dietary intake.

As mentioned in the above, FRAT^® is not a routine practice in the field of pregnancy. Please consult your medical professional for further information and guidance. More research is needed to define clinically significant antibody levels, but this is a good start.

Preconception screening may help in identifying FRAAs before pregnancy and can potentially allow for early folate optimization. This is an area that needs to be pursued!

Detecting folate receptor autoantibodies (FRaas) in pregnancy is a critical yet underutilized strategy to prevent neural tube defects, miscarriage, preeclampsia, and neurodevelopmental disorders. Since standard folic acid may not be sufficient in FRAAs – positive women, early identification allows for personalized folate, possibly improving pregnancy outcomes. FRAAs testing via FRAT^® should be incorporated into prenatal care for high-risk women, particularly those with a history of NTDs, recurrent pregnancy loss, or unexplained folate deficiency. Further research and clinical guidelines are needed to optimize detection and treatment protocols. As with any medical issue, please consult your physician for further information.

• Rothenberg SP, et al. (2004). Autoantibodies against folate receptors in women with a pregnancy complicated by a neural tube defect. N Engl J Med.
• Ramaekers VT, et al. (2013). Folate receptor autoimmunity and cerebral folate deficiency in low-functioning autism. Mol Psychiatry.
• Molloy AM, et al. (2009). Maternal folate status and the risk of neural tube defects. Lancet.