What is the Relationship between Folic Acid and Birth Defects - Research Paper Example

What is the Relationship between Folic Acid and Birth Defects? Introduction Folic acid is one of the many nutrients essential for maintaining proper health. It belongs to the water-soluble B vitamin family and is also known as Vitamin B9 or pteroylglutamic acid. The human body cannot synthesise folic acid within itself, thus, the daily requirement of the vitamin needs to be met through the diet and/or vitamin supplements. Folic acid is found naturally in some foods such as green leafy vegetables, nuts, dairy products, meat, and eggs. According to studies, it has been seen that almost 80% of folic acid is bioavailable when ingested. The RDA for an average adult is 400 mcg, while for pregnant and lactating women the required dosage increases to almost 600 mcg. One of the many major health concerns of society today is the prevalence of birth defects, especially neural tube defects. Birth defects, or congenital malformations, are defined as either structural or functional abnormalities or both, which may prevent the infant from leading a normal life (Hammouda et al, 2013). Each year, around the world, almost 300,000 babies are born with neural birth defects, and close to 3000 such babies are born in the U.S. In Europe almost 2%-3% of live births have some form of birth defects (Taruscio et al, 2011). Several experimental and observational studies have pointed out that fortification of food with folic acid has the ability to help prevent such birth defects. It has been recommended by some researchers that intake of 400 µg of folic acid before conception and during pregnancy could help reduce risk of defects in the fetus (Honein et al, 2001). It has been seen that periconceptional use of folic acid helps to reduce the occurrence of neural tube defects such as anencephaly and spina bifida by at least 50% (Canfield et al, 2005). Therefore it is essential to understand the role of folic acid during pregnancy for the prevention of birth defects. Literature Review Most studies on folic acid have focused on the efficacy of the vitamin in reducing birth defects. This has encouraged several governments across the globe to implement folic acid fortification in their respective countries as well. Canfield et al. assessed the effect of grain fortification with folic acid in the United States on the incidence of birth defects other than neural birth defects alone (Canfield et al., 2005). The authors assessed the post-fortification incidence of the following birth defects: spina bifida, anencephaly, common truncus, palate cleft, tetralogy of Fallot, reduction in limbs, pyloric stenosis, genitourinary defects, and Down syndrome. The methodology for investigation included accumulation of data about birth defect incidence and prevalence between the years 1995-1996 and 1999-2000 from the health registries of 23 different states. Information from health registries included both pre-fortification and post-fortification data. The two time periods were selected because fortification of grain with folic acid was at a maximum in the United States after 1996. For their analysis, the authors stratified the data based on the race/ethnicity of the mother. The researchers found a statistically significant decrease in the following birth defects: cleft palate (12%), pyloric stenosis (5%), great artery dispositions (12%), upper limb reduction defects (11%), and ornphalocele (21%). Among Hispanics, the especially common truncus and upper limb reduction defects were seen to have been reduced. Therefore, the researchers concluded that fortification of grain did provide a modest benefit for protection against birth defects. The study by Canfield et al. is strong in that the researchers used a large sample size. However, I believe that data from before 1995 should have also been included as that would have provided insight regarding birth defect incidence rates before fortification. Data from just a single year may not provide a complete picture of the change in birth defect incidence as a result of folic acid fortification. I do feel that the methodology and the analysis technique adopted was impressive, and that the researchers provided enough evidence about the change brought about by folic acid fortification. A similar study investigated the effects of folic acid fortification in Canada, and established that maternal intake of folic acid had the potential to reduce the risk of developing spina bifida (De Wals et al., 2008). In Canada, cereal fortification with folic acid has been mandatory since 1998. The researchers collected data on live births between 1993-2002 and examined the association between folic acid intake and births with neural tube defects. The results showed that in 1.9 million births only 2446 births had neural tube defects. The study by De Wals et al. helped to prove that the incidence of neural tube defects could be drastically reduced if mandatory fortification is introduced. However, even though most studies have shown the same results as those achieved by De Wals and Canfield, a study conducted by Mosley et al. concluded that folic acid supplementation during pregnancy reduced only those cases of neural tube defects that were sensitive to folic acid concentration (Mosley et al., 2008). There have many claims that alongside reducing neural tube defects such as spina bifida, supplementation of folic acid could also reduce other birth defects such as facial clefts, palate clefts, and heart defects. This claim has been researched by Wehby et al. who assessed the effect of high dose folic acid supplementation on the recurrence of oral cleft (Wehby et al., 2013). Oral clefts are thought to be caused by both genetic and environmental factors. The study was a double-blinded randomized clinical trial. The subjects consisted of women between the ages of 16-45 years who had non-syndromic or isolated oral clefts, and had at least one natural child who also had a non-syndromic or isolated oral cleft. The objective of this study was to see if the intake of additional folic acid could prevent oral cleft in children born to mothers who themselves had oral clefts, and/or had already given birth to a child with the birth defect. According to the research design, each of the subjects were randomly assigned to either take 0.4 mg or 4 mg of folic acid supplementation. The serum and folate level of each pregnant woman was periodically evaluated, and after delivery each case was inspected in-person. The outcomes were then compared based on the dosage of folic acid supplementation that the women received during their pregnancy. The results showed that the recurrence rates of oral cleft among the women receiving different folic acid dosages were significantly different from one another. The rate of cleft lip with palate recurrence was seen to be 2.9% in the 0.4 mg group and only 0.8% in the 4 mg group. It was thereby concluded that high dose folic acid supplementation can reduce the recurrence of oral clefts when compared to historic recurrence rates. The result also confirmed the fact that a high dosage of folic acid would not harm the fetus in any way. However, while the study confirms that a high intake of folic acid has no detrimental effects on the developing fetus, I personally feel that the researchers should not have used such high levels without knowing the possible ill-effects of that dosage during pregnancy. The effects of folic acid supplementation was also studied by Li et al. who concluded that mothers who supplemented folic acid for prolonged periods had reduced the risk of giving birth to babies with isolated cases of congenital heart defects. In their hospital based study, Li et al. analyzed 352 cases and 422 controls. The case mothers took tablets containing about 0.4mg of folic acid. The results showed that in comparison to mothers who did not intake folic acid supplementation, those who did, gave birth to babies with lower number of isolated cases of heart defects. Therefore, it could be concluded that folic acid could also reduce the risk of congenital heart defects (Li et al., 2013). Some researchers have also believed that the health of the mother also plays a role in development of birth defects. An experimental study conducted by Boyles et al. proved that even though the development of neural tube defects depends on both maternal antibodies and folic acid supplementation, the development of facial clefts did not depend on those factors (Boyles et al, 2011). The researchers conducted the nested case-control study within the Norwegian Mother and Child Cohort study group. This particular registry has data for almost 110,000 pregnancies between 1998-2008. The researchers included data from mothers from all neural tube defect (NTD) and oral facial cleft cases, which included almost 63182 births. The researchers randomly selected subjects and controls and also collected plasma samples from 17 weeks gestation. Ultimately the subject pool included: 11 cases of NTD, 72 cases of cleft lip (with or without cleft palate), 27 cases of cleft palate only, and 221 control mothers. Variables considered for analysis included: maternal age, smoking habit, and usage of periconceptional folic acid supplementation, gravidity and consumption of milk. Under laboratory settings the binding of folate receptor to folic acid was measured in each of the samples by measuring activity of the IgM and IgG antibodies. The serum analysis showed that with an increase in binding inhibition, the risk for NTD also increased. The results however also showed that an increase in the binding inhibition did not have any impact on cases of facial clefts. This study highlights the fact that fortification alone is not enough for protecting against congenital malformations because maternal antibodies play an important role in allowing binding between the folate receptor and folic acid. This study however is lacking due to its sample size sample size. Even though the results provide substantial evidence, a larger data pool would also have made the results more concrete. The decision of the researchers to analyze the plasma samples from the 17th week of gestation was appropriate since it is during this time period that the neural tube closes in the fetus and neural defects emerge. A review published by De-Regil et al. also investigated the efficacy of folic acid supplementation in reducing various kinds of birth defects (De-Regil et al, 2010). The review included all experimental, randomized, and quasi-randomised studies from the Cochrane Pregnancy and Childbirth Group’s Trial Register, as well as other international clinical registries. The researchers used standard Cochrane criteria for evaluation of the data, and the results showed that intake of folate and other multivitamins had an effect on reducing the incidence of NTDs, but had little or no effect on other birth defects. In addition to reducing the risk of delivering babies with birth defects, it has been established that intake of folic acid could largely prevent preterm births. Li et al. conducted a study to investigate the efficacy of folic acid supplementation alone in reducing preterm births. The data for this cohort study was collected from a large population from two provinces in China-Kiangshu and Zhejiang. The subjects selected for the study included roughly 207,936 live births delivered between 24 weeks and 42 weeks gestation. The sub-types selected for categorizing preterm births included: iatrogenic preterm birth, preterm premature rupture of membranes, and spontaneous preterm delivery. The researchers used simple logistic regression analysis to determine the association between risk of preterm birth and folic acid supplementation. The results showed that of all the subjects analyzed, almost 51% took periconceptional folic acid while 47.9% did not take folic acid at all during any stage of their pregnancy. The regression analysis showed that the risk of preterm birth among folic acid users was less than that of non-users, showing almost 14% reduction in risk of preterm birth. Thus, the authors concluded that a regular intake of the recommended folic acid dosage alone when taken periconceptionally could help reduce the risk of spontaneous preterm births. The strength of this study is the large sample size and amount of data retrieved and analyzed. Some researchers believed that the recommendation for periconceptional usage of folic acid could result in an increased risk of miscarriage. However, according to a study conducted by Vila-Nova et al. in Brazil, it was proven that intake of folic acid did not increase chances of miscarriage at all (Vila-Nova et al, 2013). The birth of babies with birth defects has also been associated with maternal medical conditions, and it has been seen that mothers with diabetes mellitus specifically have a greater risk of delivering babies with congenital birth problems than those who do not suffer from any health condition. Correa et al. designed a study to investigate such cases in selected regions of Arkansas, Utah, Georgia, California, New Jersey, North Carolina, and Texas. These states were chosen because they were surveyed under the National Birth Defects Prevention Study between 1997 and 2004 (Correa et al, 2012). This population based, case-controlled, and multi-center study included 14,721 subject cases, and 5,437 controls. The researchers focused their study on detecting 18 types of heart defects, and 26 non-cardiac problems in infants. They also used pre-existing data regarding maternal usage of vitamins and other supplements, which included folic acid. From the data it was found that 0.5% of the control mothers suffered from diabetes mellitus, while 2.5% of the experimental cases had diabetes. It was also seen that diabetic mothers who used supplements with folic acid used it regularly for a period of three months. The results showed that mothers who had diabetes mellitus but did not supplement with folic acid were more likely to give birth to babies with birth defects as compared with those mothers who also suffered from the same medical problem but used folic acid supplementation (Correa et al, 2012). Thus, the study succeeded in proving that external supplementation of folic acid could decrease the negative effects of maternal medical conditions such as diabetes on the formation of a healthy fetus. I believe that the methodology for this particular study was appropriate as it involved multiple centres, and having a pre-existing data set to analyze seems more desirable. This not only allowed easy access to relevant information, but also allowed the researchers to study numerous cases together. However, it may be noted that the number of cases and controls obtained for the study were significantly different (recall 14,721 subject cases versus 5,437 control cases). The study may have been stronger had the authors attempted to set up a similar number of subjects in both groups. The worldwide recommended daily dosage of folic acid has been set at 400µg. However, some researchers believe that long term intake of a lower dosage of folic acid 140 µg could increase maternal folate status, and could also have the same beneficial effect for preventing neural tube defects in pregnant women. Hursthouse et al. conducted a double blinded, placebo-controlled study in Dunedin, New Zealand (Hursthouse et al, 2011). The study lasted 40 weeks between 2008 and 2009, and included women of healthy and reproductive age between 18-40 years. Random selection was used to assign one of two supplementation groups to all the participants. One group received a daily intake of 140 µg and the other received 400 µg of folic acid supplementation. The methodology included measuring the baseline RBC folate concentrations at 6, 12, 29, and 40 weeks gestation. At the end of 40 weeks, the overall RBC folate concentration was measured in each of the subjects. It was seen that at the end of the trial there was no significant difference between the groups. The effect of 400µg of folic acid had the same effect as that of 140 µg of folic acid. This study provides evidence that the recommended dosage of folic acid could be lowered to achieve the same protection against birth defects. The socioeconomic status of an individual can greatly influence their health. Previous studies have established that cases of neural tube defects occur mostly among women hailing from a lower socioeconomic class. Rouhani et al. conducted a study to assess the effect socioeconomic background on the incidence of neural tube or other birth defects. The researchers hypothesized that socioeconomic status would not play any role in the birth of babies with birth defects by Spanish-Mediterranean women. 1740 subjects were selected of which 980 were experimental and 774 were controls. All data was collected from the Spanish Collaborative Study of Congenital Malformations, and data from 1998-2003 was analyzed. The results showed that the risk of NTD did not vary with socioeconomic class. The authors justified this result by noting that the population studied already consumed a folate-rich diet regardless of their socioeconomic status. This study highlights the fact that the risk of developing NTDs and other birth defects is similar across a population with equal access to folic acid or folate-rich foods. However, to verify if socioeconomic status is in fact negligible when considering birth-defect risk, it would be interesting to see if the same effect holds true in another population consuming a folate-rich diet. Unfortunately, there exists evidence that not all women across the world are receiving adequate amounts of folate. According to a study conducted by Garcia-Casal et al., pregnant women in Venezuela, another Spanish country, are still suffering from folic acid deficiency because they have reduced access to folate rich foods (Garcia-Casal et al, 2005). Therefore, this calls for the implementation of folic acid fortification and/or healthy pregnancy programs by governments of affected countries, in an effort to facilitate healthy pregnancies and the birth of healthy babies. Conclusion The intake of a proper diet including essential nutrients is crucial for a healthy pregnancy. Folic acid has been regarded as one of the most important micronutrients since it is known to prevent neural tube defects in the baby. In contrast to some research, there is evidence that even though intake of folic acid is beneficial in the prevention of NTD, it does not necessarily reduce the risk of other congenital malformations such as oral clefts In addition to folic acid, maternal antibodies also play an important role in the prevention of birth defects. However, this does not necessarily reduce the efficacy or the need for folic acid fortification of grains and other foods. Governments of affected countries need to introduce folic acid fortification in an effort to help facilitate healthy pregnancies. Lastly, I firmly believe that socioeconomic factors do have an influence on the quality and quantity of nutrition that a pregnant woman receives. Health agencies need to identify areas of the world where women lack access to fortified foods, and ensure that pregnant women receive adequate folic acid supplementation. Thus, it is evident that folic acid supplementation for women before conception, as well as during pregnancy, is necessary to prevent neural tube defects, and as well as to potentially reduce the risk of preterm births, and the development other birth defects. REFERENCES Boyles,A,L. Et al (2011). Association between inhibited binding of folic acid to folate receptor a in maternal serum and folate-related birth defects in Norway. Human Reproduction, 26 (8):p.2232-2238. Canfield, M.A. et al.(2005).Changes in the Birth prevalence of Selected Birth Defects after Grain Fotification with Folic Acid in the United States: Findings from a multi-state population based study. Birth Defects Research, 73: p.679-689. CorreaA. Et al (2012). 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