Folic Acid

 Risk Factor: A*
 Class: VITAMINS

Read about Folic Acid in "Herbs And Mind Enhancing Foods Drugs" section

Contents of this page:

Fetal Risk Summary
Breast Feeding Summary
References
Questions and Answers

Fetal Risk Summary

Folic acid, a water-soluble B complex vitamin, is essential for nucleoprotein synthesis and the maintenance of normal erythropoiesis (1). The National Academy of Sciences' recommended dietary allowance (RDA) for folic acid in pregnancy is 0.4 mg (1). However, a recommended dietary intake of 0.5 mg/day has been proposed that would meet the needs of women with poor folate stores, those with essentially no other dietary folate, and those with multiple pregnancies (2).

Rapid transfer of folic acid to the fetus occurs in pregnancy (3,4 and 5). One investigation found that the placenta stores folic acid and transfer occurs only after placental tissue vitamin receptors are saturated (6). Results compatible with this hypothesis were measured in a 1975 study using radiolabeled folate in women undergoing 2nd trimester abortions (7).

Folic acid deficiency is common during pregnancy (8,9,10 and 11). If not supplemented, maternal serum and red blood cell (RBC) folate values decline during pregnancy (8,12,13,14,15 and 16). Even with vitamin supplements, however, maternal folate hypovitaminemia may result (8). This depletion is thought to result from preferential uptake of folic acid by the fetal circulation such that at birth, newborn levels are significantly higher than maternal levels (8,15,16,17 and 18). At term, mean serum folate in 174 mothers was 5.6 ng/mL (range 1.57.6 ng/mL) whereas in their newborns it was 18 ng/mL (range 5.566.0 ng/mL) (8). In an earlier study, similar serum values were measured with RBC folate decreasing from 157 ng/mL at 15 weeks' gestation to 118 ng/mL at 38 weeks (12). Folic acid supplementation prevented the decrease in both serum and RBC folate. Although supplementation is common during pregnancy in some countries, not all authorities believe this is necessary for the entire population (19, 20). The main controversy is whether all women should receive supplements because of the cost involved in identifying those at risk (19), or whether supplements should be given only to those in whom a clear indication has been established (20).

The most common complication of maternal folic acid deficiency is megaloblastic anemia (9,21,22,23,24,25,26,27,28,29 and 30). Pancytopenia secondary to folate deficiency has also been reported during pregnancy (31). The three main factors involved in the pathogenesis of megaloblastic anemia of pregnancy are depletion of maternal folic acid stores by the fetus, inadequate maternal intake of the vitamin, and faulty absorption (27). Multiple pregnancy, hemorrhage, and hemolytic anemia hasten the decline of maternal levels (13,27). A 1969 study used 1-mg daily supplements to produce a uniformly satisfactory hematologic response in these conditions (29). In anemia associated with b-thalassemia minor, 5 mg/day of folic acid were significantly better than 0.25 mg/day in increasing predelivery hemoglobin concentrations in both nulliparous and multiparous Chinese women (32). Patients with iron deficiency, chronic blood loss, and parasitic infestation were excluded.

The proposed effects on the mother and fetus resulting from folate deficiency, not all of which appear to be related to the vitamin, can be summarized as follows: Fetal anomalies (neural tube defects; other defects) Placental abruption Pregnancy-induced hypertension Abortions Placenta previa Low birth weight Premature delivery Several investigations have suggested a relationship between folic acid deficiency and neural tube defects (NTDs). (Studies conducted with multiple vitamin products and not specifically with folic acid are described under Vitamins, Multiple.) In a randomized double blind trial to prevent recurrences of NTDs, 44 women took 4 mg/day of folic acid from before conception through early pregnancy (33). There were no recurrences in this group. A placebo group of 51 women plus 16 noncompliant patients from the treated group had four and two recurrences, respectively. The difference between the supplemented and nonsupplemented patients was significant (p=0.04). Other researchers reported significantly lower RBC folate levels in mothers of infants with NTDs than in mothers of normal infants, but not all in the affected group had low serum folate (34). In a subsequent report by these investigators, very low vitamin B12 concentrations were found, suggesting that the primary deficiency may have been due to this latter vitamin with resulting depletion of RBC and tissue folate (35). A large retrospective study found a protective effect with folate administration during pregnancy, leading to a conclusion that deficiency of this vitamin may be teratogenic (36).

Evidence was published in 1989 that low dietary intake of folic acid is related to the occurrence of NTDs (37). In this Australian population-based case-control study, 77 mothers whose pregnancies involved an isolated NTD were compared to 77 mothers of infants with other defects (control group 1) and 154 mothers of normal infants (control group 2). Free folate intake was classified into four levels (in g/day): 8.079.8, 79.9115.4, 115.5180.5, and 180.61678.0. After adjustment for potential confounding variables, a statistically significant trend for protection against an NTD outcome was observed with increasing free folate intake in comparison to both control groups: p=0.02 for control group 1, and p< 0.001 for control group 2. The odds ratios for the highest intake compared to the control groups were 0.31 and 0.16, respectively. When total folate intake was examined, the trends were less: p=0.10 for control group 1 and p=0.03 for control group 2. In an accompanying editorial comment, criticism of the above study focused on the authors' estimation of dietary folate intake (38). The commentary cited evidence that nutrition tables are unreliable for the estimation of folate content, and that the only conclusion the study could claim was that dietary factors, but not necessarily folate, had a role in the etiology of NTDs.

A 1989 study conducted in California and Illinois examined three groups of patients to determine whether multivitamins had a protective effect against NTDs (39). The groups were composed of women who had a conceptus with an NTD (N=571) and two control groups: those who had a stillbirth or an infant with another defect (N=546) and women who had delivered a normal child (N = 573). In this study, NTDs included anencephaly, meningocele, myelomeningocele, encephalocele, rachischisis, iniencephaly, and lipomeningocele. The periconceptional use of multivitamins, both in terms of vitamin supplements only and when combined with fortified cereals, was then evaluated for each of the groups. The outcome of this study, after appropriate adjustment for potential confounding factors, revealed an odds ratio of 0.95 for NTD-supplemented mothers (i.e., those who received the RDA of vitamins or more) compared to unsupplemented mothers of abnormal infants, and an odds ratio of 1.00 when the NTD group was compared to unsupplemented mothers of normal infants. Only slight differences from these values occurred when the data were evaluated by considering vitamin supplements only (no fortified cereals) or vitamin supplements of any amount (i.e., less than the RDA). Similarly, examination of the data for an effect of folate supplementation on the occurrence of NTDs did not change the results. Thus, this study could not show that the use of either multivitamin or folate supplements reduced the frequency of NTDs. However, the investigators cautioned that their results could not exclude the possibility that vitamins might be of benefit in a high-risk population. Several reasons were proposed by the authors to explain why their results differed from those obtained in other studies: (a) recall bias, (b) a declining incidence of NTDs, (c) geographic differences such that a subset of vitamin-preventable NTDs did not occur in the areas of the current study, and (d) others had not considered the vitamins contained in fortified cereals (39). However, other researchers concluded that this study lead to a null result because: (a) the vitamin consumption history was obtained after delivery, (b) the history was obtained after the defect was identified, or (c) the study excluded those women taking vitamins after they knew they were pregnant (40).

In contrast to the above report, a Boston study published in 1989 found a significant effect of folic acid-containing multivitamins on the occurrence of NTDs (40). The study population comprised 22,715 women for whom complete information on vitamin consumption and pregnancy outcomes was available. Women were interviewed at the time of a maternal serum a-fetoprotein screen or an amniocentesis. Thus, in most cases, the interview was conducted before the results of the tests were known to either the patient or the interviewer. A total of 49 women had an NTD outcome (2.2/1000). Among these, three cases occurred in 107 women with a history of previous NTDs (28.0/1000), and two were in 489 women with a family history of NTDs in someone other than an offspring (4.1/1000). After excluding the 87 women whose family history of NTDs was unknown, the incidence of NTDs in the remaining women was 44 cases in 22,093 (2.0/1000). Among the 3,157 women who did not use a folic acid-containing multivitamin, 11 cases of NTDs occurred, a prevalence of 3.5/1000. For those using the preparation during the first 6 weeks of pregnancy, 10 cases occurred from a total of 10,713 women (prevalence 0.9/1000). Among mothers who used vitamins during the first 6 weeks that did not contain folic acid, the prevalence was three cases in 926, a ratio of 3.2/1000. When vitamin use was started in the 7th week of gestation, there were 25 cases of NTD from 7,795 mothers using the folic acid-multivitamin supplements (3.2/1000; prevalence ratio 0.92) and no cases in the 66 women who started consuming multivitamins without folate. This study, then, observed a markedly reduced risk of NTDs when folic acid-containing multivitamin preparations were consumed in the first 6 weeks of gestation.

A 1989 preliminary report of a Hungarian controlled, double-blind study evaluated the effect on congenital defects and first occurrence of NTDs of periconceptional supplementation with a multivitamin combination containing 0.8 mg folic acid compared to a trace-element supplement (controls) (41). Women were randomized to the vitamin formulation or control 1 month before through 3 months after the last menstrual period. The differences in outcome between the groups (number of subjects 1,302) were not significant. Statistical significance was obtained, however, in the final report, published in 1992 (42) with an accompanying editorial (43), where pregnancy outcome was known in 2,104 vitamin-supplemented cases and 2,052 controls. Significantly more congenital malformations occurred in the control group (22.9 per 1000 vs. 13.3 per 1000, p=0.02), including six cases of NTDs in controls compared to none in those taking vitamins (p=0.029) (42). The rate of NTD occurrence in the control group corresponded to the expected rate in Hungary (41).

In 1991, the results of an 8-year study to examine the effects of folic acid supplementation, with or without other vitamins, on the recurrence rate of NTDs were published (44). This randomized, double-blind study conducted by the British Medical Research Council (MRC) was carried out at 33 medical centers in the United Kingdom, Australia, Canada, France, Hungary, Israel, and Russia. A total of 1,817 women, all of whom had had a previous pregnancy affected by an NTD (anencephaly, spina bifida cystica, or encephalocele), were enrolled in the study prior to conception and randomized to one of four treatment groups: folic acid (4 mg/day) (N=449), folic acid (4 mg/day) plus other vitamins (N=461), other vitamins (A, D, B1, B2, B6, C, and nicotinamide) (N=453), and no vitamins (placebo capsules containing ferrous sulfate and dicalcium phosphate) (N=454). Women with epilepsy were excluded, as were those with infants whose NTD was associated with genetic factors. Women who conceived were continued in the study until the 12th week of gestation. The study was terminated after 1,195 women had a completed pregnancy where the outcome could be classified as to either NTD or no NTD, because the preventive effect of folic acid was clear. Six NTDs were observed in the two folic acid groups (6/593; 10/1000) and 21 were observed in the nonfolic acid groups (21/602; 35/1000). Analysis of the data indicated that folic acid had prevented 72% of the NTD recurrences compared to other vitamins, which gave no protective effect. The benefit of folic acid was the same for anencephaly as for spina bifida and encephalocele. The study found no evidence that any other vitamin had a protective effect, nor did other vitamins enhance the effect of folic acid. Based on the results of the study, the MRC recommended that all women who have had a previous pregnancy outcome with an NTD should take folic acid supplements. The study could not determine, however, whether 4 mg/day of folic acid was required or whether a smaller dose, such as 0.36 mg, would have been equally efficacious. They speculated, however, that even small doses should have some preventive effect.

The Centers for Disease Control and Prevention (CDC) published interim recommendations for folic acid supplementation based on the MRC study, pending further research to determine the required dose, for women who have had an infant or fetus with an NTD (spina bifida, anencephaly, or encephalocele) (45): 4 mg/day of folic acid at least 4 weeks before conception through the first 3 months of pregnancy. This supplementation was not recommended for (a) women who have never had an infant or fetus with an NTD, (b) relatives of women who have had an infant or fetus with an NTD, (c) women who themselves have spina bifida, and (d) women who take valproic acid (45). Approximately 1 year later, the CDC, in conjunction with other American health agencies, published the recommendation that all women of childbearing age should consume 0.4 mg of folic acid per day either from the diet or from supplements (46). This recommendation included women who had had an NTD-affected pregnancy, unless they were planning to become pregnant. In that case, the CDC suggested that the 4-mg/day dose was still appropriate. Although the 0.4-mg dose may be as effective, the higher dose was based on a study designed to prevent NTDs, and the risks of an NTD-affected infant may be greater than the maternal risks from 4 mg/day of folic acid.

Several unanswered questions have been raised by the findings of the MRC trial, in addition to the one involving dosage, including: (a) How long before conception is supplementation needed (47)? (b) What are the risks from supplementation (47,48 and 49)? (c) If there are risks, are they the same for 4 mg and 0.4 mg (47,48 and 49)? (d) Will the benefits of supplementation be the same for all ethnic groups, even in those with much lower prevalence rates of NTDs (47)? (e) Will the benefits be as great for women who are not at an increased risk for producing a child with an NTD (47)? (f) Can the required folic acid be obtained from food (47)? (g) Is one mechanism of folic acid's action in preventing NTDs related to the correction of genetic defects, such as inborn errors of homocysteine metabolism (50)? and (h) Is folic acid itself or its metabolite, 5-methyltetrahydrofolate (MTHF), the active form of the vitamin (48,49)? Two uncontrolled trials conducted in the United Kingdom during the MRC study described above provided additional evidence that folic acid supplementation is beneficial in preventing recurrences of NTDs (51, 52). Women at high-risk for recurrence, but who refused to be enrolled in the MRC trial, primarily out of fear of being placed in the placebo group, were treated with 4 mg/day of folic acid at least 1 month prior to conception through the 12th week of gestation (51). Of the 255 women supplemented, 234 achieved a pregnancy with 235 fetuses/infants (one set of twins). Two cases of NTDs were observed (spina bifida; encephalocele), a recurrence risk of 8.5/1000, approximately one-third the expected incidence of 30/1000 and nearly identical to the results in the MRC study. In the second trial, 208 high-risk women were treated similarly, but with a multivitamin preparation containing 0.36 mg of folic acid (52). Of the 194 who had delivered (14 were still pregnant), only one NTD was observed (an incidence of 5.2/1000), and that mother admitted poor compliance in taking the vitamins.

The results of three other studies, one conducted in 12 Irish hospitals beginning in 1981 (53), one in Spain between 1974 and 1990 (54), and one in the United States and Canada between 1988 through 1991 (55,56), indicated that folic acid may be protective at a much lower dosage (e.g., 0.3 mg/day or more) than used in the MRC trial. In the American/Canadian study, folic acid (the most commonly used daily dose was 0.4 mg) consumed 28 days before through 28 days after the last menstrual period decreased the risk for first occurrence of NTDs by approximately 60% (55). The investigators also found evidence that a relatively high dietary intake of folate reduced the risk of NTDs (55).

In a search for a possible mechanism of folic acid prevention of NTDs, several studies have compared the concentrations of folic acid in mothers who have produced a child with an NTD with control mothers with no history of NTDs in their infants (57,58,59 and 60). A brief 1991 report found no relation between NTDs and low folate levels in fetal blood, fetal red cells, or maternal blood, thus eliminating poor placental transfer of folic acid as a possible mechanism (57).

A study conducted in Dublin found no difference in serum folate or vitamin B12 levels in mothers whose pregnancies ended with an NTD infant or fetus when compared to 395 normal controls (58). The serum samples were obtained during a routine screening program for rubella antibody conducted in three Dublin hospitals. After testing, the samples were frozen and then later used for this study. One hundred sixteen cases of NTDs were identified during the study period, but serum was available for only 32 of the cases: 16 with anencephalus, 15 with spina bifida, and 1 with encephalocele. In half of the cases, serum was obtained between 913 weeks' gestation. The mean serum folate concentrations in the cases and controls were both 3.4 ng/mL, and levels of vitamin B12 were 297 and 277 pg/mL, respectively.

Another trial found significantly lower RBC folate levels in pregnancies ending with an NTD (59). This Scottish study measured vitamin levels in 20 women under the age of 35 years who had a history of two or more NTD pregnancies. A control group of 20 women with no pregnancies ending in NTDs, but matched for age, obstetric history, and social class, was used for comparison. No significant differences between the two groups were found in assays for plasma or serum vitamin A, thiamine, riboflavin, pyridoxine, vitamin B12, folate, vitamin C, vitamin E, total protein, albumin, transferrin, copper, magnesium, zinc, and white cell vitamin C. RBC folate, however, was significantly lower in the case mothers than in controls, 178 vs 268 ng/mL (p=0.005), respectively, although both were within the normal range (106614 ng/mL). Moreover, a linear relationship was found between RBC folate and the number of NTD pregnancies. Women who had three or four such pregnancies also had the lowest concentrations of RBC folate (59). The dietary intake of folic acid was lower in the case mothers than in controls, but the difference was not statistically significant. Because the lower RBC folate levels could not be attributed entirely to dietary intake of folic acid, the authors speculated that one factor predisposing to the occurrence of NTDs may be an inherited disorder of folate metabolism (59).

A study conducted in Finland, and published in 1992, was similar in design and findings to the Dublin study described above (60). Serum samples from women who had delivered an infant with an NTD were analyzed and compared to samples from 178 matched controls. Cases of NTDs with known or suspected causes unrelated to vitamins were excluded. Maternal serum had been drawn during the first or second prenatal care appointment for reasons not related to the study, all within 8 weeks of neural tube closure, and kept frozen in a central laboratory. No statistical differences were found between case mothers and controls in serum levels of folate, vitamin B12, and retinol. After adjustment, the odds ratios for being a case mother were 1.00 for folate, 1.05 for vitamin B12, 0.99 for retinol. Several possible explanations have been offered as to why this study was unable to find differences between case and control mothers (61): (a) serum samples may not have been obtained early enough in pregnancy, (b) maternal serum vitamin concentrations may not be a good test of the folic acid deficiency necessary to cause NTDs, and (c), most likely, the group tested may not have been at risk to have a vitamin-sensitive NTD since the normal incidence of NTDs in the studied population is very low.

At least three publications have commented on the potential risks of high-dose folic acid supplementation (45,62,63). Megaloblastic anemia resulting from vitamin B12 deficiency may be masked by folic acid doses of 4 mg/day but still allow the neurologic damage of the deficiency to progress (45,62). Responding to this, a Canadian editorial recommended that a woman's vitamin B12 status be checked prior to commencing high-dose folic acid supplementation (62). A second risk identified concerned the inhibition of dihydropteridine reductase (DHPR), a key enzyme in the maintenance of tetrahydrobiopterin levels, by folic acid but not by 5-methyltetrahydrofolate (63). Children with an inherited deficiency of this enzyme have lowered levels of dopamine, noradrenaline, serotonin, and folates in the central nervous system, which results in gross neurologic damage and death if untreated, thus raising the potential that high-dose folic acid could cause damage to embryonic neural tissue.

Folic acid deficiency is a known experimental animal teratogen (64). In humans, the relationship between fetal defects other than NTDs and folate deficiency is less clear. Several reports have claimed an increase in congenital malformations associated with low levels of this vitamin (9,24,25 and 26,33,36,65,66), and one study observed a significant decrease in birth defects when a multivitamin-folic acid preparation was used before and during early gestation (see details above) (42). Other investigators have stated that maternal deficiency does not result in fetal anomalies (22,23,67,68,69,70,71,72 and 73). One study found the folate status of mothers giving birth to severely malformed fetuses to be no different from that of the general obstetric population and much better than that of mothers with overt megaloblastic anemia (67). Similar results were found in other series (71,72 and 73).

The strongest evidence for an association between folic acid and fetal defects comes from cases treated with drugs that either are folic acid antagonists or induce folic acid deficiency, although agreement with the latter is not universal (70,74,75). The folic acid antagonists, aminopterin and methotrexate, are known teratogens (see Aminopterin and Methotrexate). A very high incidence of defects resulted when aminopterin was used as an unsuccessful abortifacient in the 1st trimester. These antineoplastic agents may cause fetal injury by blocking the conversion of folic acid to tetrahydrofolic acid in both the fetus and the mother.

In contrast, certain anticonvulsants, such as phenytoin and phenobarbital, induce maternal folic acid deficiency, possibly by impairing gastrointestinal absorption or increasing hepatic metabolism of the vitamin (70,74,75). Whether these agents also induce folic acid deficiency in the fetus is less certain, because the fetus seems to be efficient in drawing on available maternal stores of folic acid. Low maternal folate levels, however, have been proposed as a mechanism for the increased incidence of defects observed in infants exposed in utero to some anticonvulsants. In a 1984 article, investigators reported research on the relationship between folic acid, anticonvulsants, and fetal defects (74). In the retrospective part of this study, a group of 24 women who were treated with phenytoin and other anticonvulsants produced 66 infants, of whom 10 (15%) had major anomalies. Two of the mothers with affected infants had markedly low RBC folate concentrations. A second group of 22 epileptic women was then given supplements of daily folic acid, 2.55.0 mg, starting before conception in 26 pregnancies and within the first 40 days in 6 pregnancies. This group produced 33 newborns (32 pregnancies, 1 set of twins) with no defects, a significant difference from the group not receiving supplementation. Negative associations between anticonvulsant-induced folate deficiency and birth defects have also been reported (70,75). Investigators studied a group of epileptic women taking anticonvulsants and observed only two defects (2.9%) in pregnancies producing a live baby, a rate similar to that expected in a healthy population (70). Although folate levels were not measured in this retrospective survey, maternal folate deficiency was predicted by the authors, based on their current research with folic acid in patients taking anticonvulsants. Another group of researchers observed 20 infants (15%) with defects from 133 women taking anticonvulsants (75). No NTDs were found, but this defect is rare in Finland and an increase in the anomaly could have been missed (75). All of the women were given folate supplements of 0.11.0 mg/day (average 0.5 mg/day) from the 6th to 16th weeks of gestation until delivery. Folate levels were usually within the normal range (normals considered to be serum >1.8 ng/mL, RBC >203 ng/mL).

Whole embryo cultures of rats have been tested with valproic acid and folinic acid, a folic acid derivative (76). The anticonvulsant produced a dose-related increase in the incidence of NTDs that was not prevented by the addition of the vitamin. Experiments in embryonic mice, however, indicated that valproic acid-induced NTDs were related to interference with embryonic folate metabolism (77). Teratogenic doses of valproic acid caused a significant reduction in embryonic levels of formylated tetrahydrofolates and increased the levels of tetrahydrofolate by inhibition of the enzyme glutamate formyltransferase. The result of this inhibition would have serious consequences on embryonic development, including neural tube closure (77).

A review of teratogenic mechanisms involving folic acid and antiepileptic therapy was published in 1992 (78). Several studies conducted by the authors and others demonstrated that phenytoin, phenobarbital, and primidone, but not carbamazepine or valproic acid, significantly reduced serum and RBC levels of folate, and that polytherapy decreased these levels significantly more than monotherapy. Animal studies cited indicated that valproic acid disrupts folic acid metabolism, possibly by inhibiting key enzymes, rather than by lowering concentrations of the vitamin, whereas phenytoin may act on folic acid by both mechanisms (78). Data from a study conducted by the authors indicated that a significant association existed between low serum and RBC folate levels, especially <4 ng/mL, before or early in pregnancy in epileptic women and spontaneous abortions and the occurrence of congenital malformations (78). The reviewers concluded that folic acid supplementation may be effective in preventing some poor pregnancy outcomes in epileptic women.

Another 1992 report, based on the results of a 1990 workshop addressing the use of antiepileptic drugs during pregnancy, offered guidelines to counsel women with epilepsy who plan pregnancy or who are pregnant (79). Included among the guidelines was the recommendation that adequate folic acid be consumed daily, either from the diet or from supplements, to maintain normal serum and RBC levels of folate before and during the first months of pregnancy (i.e., during organogenesis). A specific folic acid dose was not recommended.

Several articles have proposed that maternal folic acid status is associated with placental abruption (25,26,28,66,80). In a review and analysis of 506 consecutive cases of abruptio placentae, defective folate metabolism was found as a predisposing factor in 97.5%. The authors theorized that folic acid deficiency early in pregnancy caused irreversible damage to the fetus, chorion, and decidua, leading to abruption, abortion, premature delivery, low birth weight, and fetal malformations. Other studies have discovered that 60% of their patients with abruption were folate deficient, but their numbers were too small for statistical analysis (81). In other series, no correlation was found between low levels of folic acid and this complication (16,69,82).

A relationship between folate deficiency and pregnancy-induced hypertension (PIH) is doubtful. In a study of women with megaloblastic anemia, 14% had PIH compared with the predicted incidence of 6% for that population (22). In another report, although 22 of 36 PIH patients had folate deficiency, the authors were unable to conclude that a positive association existed (66,81). Other investigators have also failed to find a relationship between low levels of the vitamin and PIH (23, 27). In one of these studies, the incidence of PIH in megaloblastic anemia was 12.2% compared with 14.0% in normoblastic anemia (27). A second group of investigators studied folate levels in 101 preeclamptic and 17 eclamptic women and compared them with 52 normal controls and 29 women with overt megaloblastic anemia (83). No correlation was found between levels of folic acid and the complications.

Several papers have associated folic acid deficiency with abortion (25,26,66,78,80,84,85 and 86). The cause of some abortions, as proposed by some, is faulty folate metabolism in early pregnancy, producing irreversible injury to the fetus and placenta (80). Others have been unable to detect any significant relationship between serum and RBC folate levels and abortion (12,68,87). In a series of 66 patients with early spontaneous abortions, the incidence of folate deficiency was the same as in those with uncomplicated pregnancies (87). These researchers did find a relationship between low folic acid levels and placenta previa. However, others found no evidence of an association between folate deficiency and either abortion or antepartum hemorrhage (12).

The relationship between prematurity, low birth weight, and folic acid levels has been investigated. In one study, significantly lower folate levels were measured in the blood of low-birth-weight neonates as compared with normal-weight infants (18). The incidences of both premature delivery and infants with birth weight less than 2500 g were increased in folate-deficient mothers in a 1960 report (22). These patients all had severe megaloblastic anemia and a poor standard of nutrition. In a later study of 510 infants from folate-deficient mothers, 276 (56%) weighed 2500 g or less compared with a predicted incidence of 8.6% (80). A study of women with uterine bleeding during pregnancy found a significant association between serum folate and low birth weight (85). Similarly, another study reported a significant relationship between folate levels at the end of the 2nd trimester and newborn birth weight (88). A 1992 report described the effects of supplementation with ferrous sulfate (325 mg/day) and folic acid (1 mg/day), beginning at the first prenatal visit, on infant birth weight (89). A significant association between low serum folate levels at 30 weeks' gestation and fetal growth retardation (defined as below the 15th percentile for gestational age) was discovered. Adjustment for psychosocial status, maternal race, body mass index, smoking history, history of a low-birth-weight infant, and infant gender did not change the results. In contrast, others have found no association between folic acid deficiency and prematurity (27,69,90,91) or between serum folate and birth weight (12,69,92,93).

Two reports have alluded to problems with high folic acid levels in the mother during pregnancy (94,95). An isolated case report described an anencephalic fetus whose mother was under psychiatric care (94). She had been treated with very high doses of folic acid and vitamins B1, B6, and C. The relationship between the vitamins and the defect is questionable. A 1984 study examined the effect of folic acid, zinc, and other nutrients on pregnancy outcome (95). Total complications of pregnancy (infection, bleeding, fetal distress, prematurity or death, PIH, and tissue fragility) were associated with high serum folate and low serum zinc levels. The explanation offered for these surprising findings was that folate inhibits intestinal absorption of zinc, which, they proposed, was responsible for the complications. This study also found an association between low folate and abortion.

In summary, folic acid deficiency during pregnancy is a common problem in undernourished women and in women not receiving supplements. The relationship between folic acid levels and various maternal or fetal complications is complex. Evidence has accumulated that interference with folic acid metabolism or folate deficiency induced by drugs such as anticonvulsants and some antineoplastics early in pregnancy results in congenital anomalies. Moreover, a substantial body of evidence is now available that non-drug-induced folic acid deficiency, or abnormal folate metabolism, is related to the occurrence of birth defects and some NTDs. Lack of the vitamin or its metabolites may also be responsible for some cases of spontaneous abortion and intrauterine growth retardation. For other complications, it is probable that a number of factors, of which folic acid deficiency may be one, contribute to poor pregnancy outcome. Thus, to ensure good maternal and fetal health, all pregnant women should receive sufficient dietary or supplementary folic acid to maintain normal maternal folate levels. The CDC and other U.S. health agencies recommend a daily consumption of 0.4 mg of folic acid, from either the diet or supplements or both, for all women of childbearing age before the onset of pregnancy (46,96).

An increased risk of adverse fetal outcome can be lowered by folic acid supplementation in at least two groups of women. (a) Women with a history of a fetus or infant with an NTD should receive supplementation with 4 mg/day of folic acid beginning 1 month (3 months have been recommended in England [97]) before conception and continuing through the 12th week of gestation (45,97,98). (b) Women receiving antiepileptic medications should receive sufficient folic acid from either the diet or supplementation or both to maintain normal serum and RBC levels of the vitamin beginning before conception through the period of organogenesis. (A specific dosage recommendation has not been located for women receiving anticonvulsants.) [*Risk Factor C if used in doses above the RDA.]

Breast Feeding Summary

Folic acid is actively excreted in human breast milk (99,100,101,102,103,104,105,106,107 and 108). Accumulation of folate in milk takes precedence over maternal folate needs (99). Levels of folic acid are relatively low in colostrum but as lactation proceeds, concentrations of the vitamin rise (100,101 and 102). Folate levels in newborns and breast-fed infants are consistently higher than those in mothers and normal adults (103, 104). In Japanese mothers, mean breast milk folate concentrations were 141.4 ng/mL, resulting in a total intake by the infant of 1425 g/kg/day (104). Much lower mean levels were measured in pooled human milk in an English study examining preterm (26 mothers, 2934 weeks) and term (35 mothers, 39 weeks or longer) patients (102). Preterm milk folate concentrations rose from 10.6 ng/mL (colostrum) to 30.5 ng/mL (16196 days), whereas term milk folate concentrations increased during the same period from 17.6 to 42.3 ng/mL.

Supplementation with folic acid is apparently not needed in mothers with good nutritional habits (102,103,104,105 and 106). Folic acid deficiency and megaloblastic anemia did not develop in women not receiving supplements even when lactation exceeded 1 year (102,103). In another study, maternal serum and red blood cell folate levels increased significantly after 1 mg of folic acid/day for 4 weeks, but milk folate levels remained unchanged (104). Investigators gave well-nourished lactating women a multivitamin preparation containing 0.8 mg of folic acid (105). At 6 months postpartum, milk concentrations of folate did not differ significantly from those of controls who were not receiving supplements. Other investigators measured more than adequate blood folate levels in American breast-fed infants during the 1st year of life (106). The mean milk concentration of folate consumed by these infants was 85 ng/mL.

In patients with poor nutrition, lactation may lead to severe maternal folic acid deficiency and megaloblastic anemia (99). For these patients, there is evidence that low folate levels, as part of the total nutritional status of the mother, are related to the length of the lactation period (102). In one study, lactating mothers with megaloblastic anemia were treated with 5 mg/day of folic acid for 3 days (101). Breast milk folate rose from 79 ng/mL to 1540 ng/mL 1 day after treatment began. The elevated levels were maintained for 3 weeks without further treatment. Nine lower- socioeconomic-status women were treated with multivitamins containing 0.8 mg of folic acid and were compared with seven untreated controls (107). Breast milk folate was significantly higher in the treated women. In another study of lactating women with low nutritional status, supplementation with folic acid, 0.210.0 mg/day, resulted in mean milk concentrations of 2.35.6 ng/mL (108). Milk concentrations were directly proportional to dietary intake.

Folic acid concentrations were determined in preterm and term milk in a study to determine the effect of storage time and temperature (109). Storage of milk in a freezer resulted in progressive decreases over 3 months such that the RDA of folate for infants could not be provided from milk stored for this length of time. Storage in a refrigerator for 24 hours did not affect folate levels.

The National Academy of Sciences' RDA for folic acid during lactation is 0.280 mg (1). If the lactating woman's diet adequately supplies this amount, maternal supplementation with folic acid is not needed. Maternal supplementation with the RDA for folic acid is recommended for those patients with inadequate nutritional intake. The American Academy of Pediatrics considers maternal consumption of folic acid to be compatible with breast feeding (110).

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