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Rationalization of Taking Folic Acid in Pregnancy

Evidence-based medical information about the benefits of folic acid prescribing in pregnancy, states that not only to prevent neural tube closure defects but also to prevent other congenital diseases and also prematurity.

Folate (Vitamin B9) is a water-soluble vitamin that is classified as an essential nutrient needed for DNA replication and forming red blood cells. Moreover, folate is also a raw material for some enzyme reactions, including amino acid synthesis and vitamin metabolism.

The need for folate in pregnant women increases because folate is essential for fetal growth and development. Folate deficiency is associated with abnormalities in both the mother and fetus.

Folate and folic acid have different definitions. Folate or vitamin B9 is one of the 13 essential vitamins. Folate cannot be synthesized in the body and must be obtained from food or supplements. Naturally, folate is obtained from foods such as green vegetables, beans, egg yolks, liver, and citrus fruits. Meanwhile, folic acid is a synthetic form of folate which can be found in food supplements or fortified foods. However, in their daily use, the terms both are often equated. 



Folate and NTD (neural tube defect)

It has long been known that folate plays a role in neural tube closure. The role of folate in neural tube closure is by increasing cellular proliferation. Folate is an essential cofactor in epigenetic regulation of gene transcription that controls neural tube closure.

 Around the 4th to 6th week of gestation, a neural tube forms and then closes. This neural tube will then become the spinal cord, spine, brain, and skull. Neural tubes that fail to close will cause the spinal cord or brain to be expelled. This disorder is known as spina bifida and anencephaly. Therefore, the protective effect of folate on neural tubes is obtained since it is consumed before pregnancy occurs (preconception) until about 1 month of gestational age.

Increased levels of folic in the body (especially for women planning for pregnancy and those who are pregnant) can be done by folic acid supplementation or folic acid fortification into food.

Fortification of folic acid into food has become a national policy in several countries. In the United States, the addition of folic acid to wheat-derived products such as flour, cereals, and pasta has been implemented since January 1998. In 2009, the US Preventive Services Task Force (USPSTF) issued a recommendation that all women of reproductive age should consume acid supplements folate 0.4 to 0.8 mg daily, and these recommendations are still relevant today.

However, not all experts support the benefits of folate for neural tube closure. The majority of European countries choose not to implement a policy of folic acid fortification into food because of the side effects.

In the body, both folic and folic acid must be metabolized beforehand to become its active form. Because folic acid is a synthetic form of folate, its metabolism is slower than folate. Therefore, the addition of supplementation and/or fortification of folic acid will make more inactive folic acid (folic acid that has not been metabolized) that accumulates in the blood.

This condition is related to several side effects, such as the increased risk of cancer and the masking effect on pernicious anemia (vitamin B12 deficiency). This condition will get worse if folic acid fortification is added with folic acid supplementation.

A systematic review study from M.Visnawathan et al. stated that in the United States before 1998, folic acid was shown to have a protective effect against NTD. However, after 1998, when fortification of folic acid into food began to be applied, the effectiveness of folic acid supplementation became biased.

Other Benefits of Folic Acid

Preconception folic acid supplementation is not only beneficial for preventing NTD but also prevents congenital heart disease and cleft lip and palate. The mechanism by which folic acid prevents structural anomalies in the fetus is still unknown but may involve regulation of homocysteine ​​metabolism.

Giving folic acid supplements after the first month of pregnancy is no longer effective in preventing NTD, but it is still important to give because it still has benefits to other aspects of maternal and fetal health.

Folic acid plays a vital role in the formation of red blood cells (erythropoiesis). One of the factors needed for the process of forming red blood cells is the fulfillment of three nutrients: folate, cobalamin (vitamin B12), and iron. Therefore, besides giving folic acid supplements to pregnant women, WHO also recommends iron supplements. In conditions where folic acid supplements are not available, iron supplements should still be given.

Besides having a role in the formation of red blood cells, folic acid is also useful to reduce the risk of premature birth and small babies according to the Pregnancy Period.

Definition of Premature birth is the birth that occurs before 37 weeks of gestation, while the definition of small for gestational age is a baby with a birth weight less than the 10th percentile. Both of these conditions are associated with increased neonatal mortality and morbidity.

In an observational study, there was an association between shorter duration of pregnancy with lower serum folate levels and the absence of folic acid supplementation during pregnancy. In another study, a cohort study, supplementing preconception supplementation for 1 year was associated with a significant reduction in the incidence of preterm birth.

Recommendations for Folic Acid

In women of reproductive age, folate can be obtained from the consumption of foods rich in folate. However, folate obtained from food is not enough to increase serum folate levels, especially in women who are planning a pregnancy and are pregnant. One way to increase it is by giving folic acid supplements.

WHO recommends a 400 mg or 0.4 mg dose of the folic acid supplement daily. Also, the American Congress of Obstetricians and Gynecologists (ACOG) and the Royal College of Obstetricians and Gynecologists (RCOG) issued recommendations for folic acid supplementation.

ACOG recommends that women at low risk take folic acid supplements at a dose of 400μg / day, whereas for women at high risk, the dose becomes 4mg / day. According to ACOG, high-risk women are women with a history of NTD in a previous pregnancy.

Meanwhile, the RCOG recommendation is that all women of reproductive age consume 400μg / day of folic acid supplements from before pregnancy (preconception) until the 12th week of pregnancy, whereas for women at high risk, the dose becomes 5mg / day. According to the RCOG, high-risk women are women with a history of NTD in a previous pregnancy, with a history of NTD in their family/husband's family, in the treatment of epilepsy, with diabetes or celiac disease, with a BMI ≥30, or with sickle cell anemia or thalassemia.

Side Effects of Folic Acid

Although folic acid supplementation at supraphysiological levels shows many advantages for pregnant women and fetuses as discussed earlier, the potential risks of high doses of folic acid supplementation must also be considered. 

Although there are still pros and cons, the potential risk of high doses of folic acid, which is often discussed, is asthma / allergic diseases, cancer, and multiple pregnancies.

Indeed folate has benefits for the body, but the benefits of supplementation and fortification of high doses of folic acid are still controversial, as are the side effects. However, as long as the benefits are still considered more than the disadvantages, the supplementation and fortification of folic acid for women who will and are pregnant are continued.


References
1. H.N. Moussa, S.H. Nasab, Z.A. Haidar, S.C. Blackwell, dan B.M. Sibai, Future Science OA, 2016, 2(2). Tersedia pada https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5137972/pdf/fsoa-02-116.pdf
2. K.B. Domingo, et al., JAMA, 2017, 317(2), 183-89. http://jamanetwork.com/journals/jama/fullarticle/2596300
3. M. Viswanathan et al., JAMA, 2017, 317(2), 190-203. http://jamanetwork.com/journals/jama/fullarticle/2596299
4. J.A. Greenberg, S.J. Bell, Y. Guan, dan Y.H. Yu, Review in Obstetrics and Gynecology, 2011, 4(2): 52-9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3218540/pdf/RIOG004002_0052.pdf
5. World Health Organization. Guideline: Daily iron and folic acid supplementation in pregnant women. Geneva: WHO; 2012. https://www.ncbi.nlm.nih.gov/books/NBK132263/pdf/Bookshelf_NBK132263.pdf
6. V.A. Hodgetts, R.K. Morris, A. Francus, J. Gardosi, dan K.M. Ismail, BJOG, 2014. Tersedia pada https://www.rcog.org.uk/globalassets/documents/news/folic-acid-supplementation.pdf



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