VITAMINS, MULTIPLE
Drugs in Pregnancy and Lactation.Name: VITAMINS, MULTIPLE
Class: Vitamins
Risk Factor: A*
Fetal Risk Summary
Vitamins are essential for human life. Preparations containing multiple vitamins (multivitamins) are routinely given to pregnant women. A typical product will contain the vitamins A, D, E, and C, plus the B complex vitamins thiamine (B1), riboflavin (B2), niacin (B3), pantothenic acid (B5), pyridoxine (B6), B12, and folic acid. Miscellaneous substances that may be included are iron, calcium, and other minerals. The practice of supplementation during pregnancy with multivitamins varies from country to country but is common in the United States. The National Academy of Sciences' recommended dietary allowance (RDA) for pregnant women, as of 1989, is as follows (1): Vitamin A
The role of vitamins in the prevention of certain congenital defects continues to be a major area of controversy. Two different classes of anomalies, cleft lip and/or palate (CLP) and neural tube defects (NTDs), have been the focus of numerous investigations with multivitamins. An investigation into a third class of anomalies, limb-reduction defects, has also appeared. The following sections will summarize the published work on these topics.
Animal research in the 1930s and 1940s had shown that both deficiencies and excesses of selected vitamins could result in fetal anomalies, but it was not until two papers in 1958 (2,3) that attention was turned to humans. These investigations examined the role of environmental factors, in particular the B complex vitamins, as agents for preventing the recurrence of CLP. In that same year, a study was published that involved 87 women who had previously given birth to infants with CLP (4). Although the series was too small to draw statistical conclusions, 48 women given no vitamin supplements had 78 pregnancies, resulting in 4 infants with CLP. The treated group, composed of 39 women, received multivitamins plus injectable B complex vitamins during the 1st trimester. This group had 59 pregnancies with none of the infants having CLP. A similar study found a CLP incidence of 1.9% (3 of 156) in treated pregnancies compared with 5.7% (22 of 383) in controls (5). The difference was not statistically significant. However, other researchers, in a 1964 survey, found no evidence that vitamins offered protection against CLP (6). Also in 1964, research was published involving 594 pregnant women who had previously given birth to an infant with CLP (7). This work was further expanded, and the total group involving 645 pregnancies was presented in a 1976 paper (8). Of the total group, 417 women were not given supplements during pregnancy, and they gave birth to 20 infants (4.8%) with CLP. In the treated group, 228 women were given B complex vitamins plus vitamin C before or during the 1st trimester. From this latter group, 7 infants (3.1%) with CLP resulted. Although suggestive of a positive effect, the difference between the two groups was not significant. Another investigator found only one instance of CLP in his group of 85 supplemented pregnancies (9). These patients were given daily multivitamins plus 10 mg of folic acid. In 206 pregnancies in women not given supplements in which the infants or fetuses were examined, 15 instances of CLP resulted. The difference between the two groups was significant (p=0.023). In contrast, one author suggested that the vitamin A in the supplements caused a cleft palate in his patient (10). However, the conclusion of this report has been disputed (11). Thus, the published studies involving the role of multivitamins in the prevention of CLP are inconclusive. No decisive benefit (or risk) of multivitamin supplementation has emerged from any of the studies.
The second part of the controversy surrounding multivitamins and the prevention of congenital defects involves their role in preventing NTDs. (Three excellent reviews on the pathophysiology and various other aspects of NTDs, including discussions on the role that multivitamins might play in the cause and prevention of these defects, have been recently published [12,13 and 14].) In a series of articles from 1976 to 1983, British investigators examined the effect of multivitamin supplements on a group of women who had previously given birth to one or more children with NTDs (15,16,17,18 and 19). For the purpose of their study, they defined NTDs to include anencephaly, encephalocele, cranial meningocele, iniencephaly, myelocele, myelomeningocele, and meningocele but excluded isolated hydrocephalus and spina bifida occulta (17). In their initial publication, they found that, in six mothers who had given birth to infants with NTDs, there were lower 1st-trimester levels of serum folate, red blood cell folate, white blood cell vitamin C, and riboflavin saturation index (15). The differences between the case mothers and the controls were significant for red blood cell folate (p<0.001) and white blood cell vitamin C (p<0.05). Serum vitamin A levels were comparable with those of controls. Based on this experience, a multicenter study was launched to compare mothers receiving full supplements with control patients not receiving supplements (16,17,18 and 19). The supplemented group received a multivitamin-iron-calcium preparation from 28 days before conception to the date of the second missed menstrual period, which is after the time of neural tube closure. The daily vitamin supplement provided: Vitamin A 4000 IU Nicotinamide
A 1980 report found that women receiving well-balanced diets had a lower incidence and recurrence rate of infants with NTDs than did women receiving poor diets (20). Although multivitamin supplements were not studied, it was assumed that those patients who consumed adequate diets also consumed more vitamins from their food compared with those with poor diets. This study, then, added credibility to the thesis that good nutrition can prevent some NTDs. Other researchers, using Smithells' protocol, observed that fully supplemented mothers (N=83) had no recurrences whereas an unsupplemented group (N=141) had four recurrences of NTDs (21,22). Interestingly, a short report that appeared 6 years before Smithells' work found that both vitamins and iron were consumed more by mothers who gave birth to infants with anencephalus and spina bifida (23).
The above investigations have generated a number of discussions, criticisms, and defenses (24,25,26,27,28,29,30,31,32,33,34, 35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53, 54,55,56 and 57). The primary criticism centered around the fact that the groups were not randomly assigned but were self-selected for supplementation or no supplementation. A follow-up study, in response to some of these objections, was published in 1986 (58). This study examined six factors that may have influenced the earlier results by increasing the risk of recurrence of NTDs: (a) two or more previous NTDs, (b) residence in Northern Ireland, (c) spontaneous abortions immediately before the studied pregnancy, (d) less than 12 months between studied pregnancy and abortion, (e) social class, and (f) therapeutic abortion immediately before the studied pregnancy. The relative risk was increased only for the first four factors, and only in those cases with two or more previous NTDs was the increase significant. In addition, none of the four factors would have predicted more than a 4% increase in the recurrence rate in unsupplemented mothers compared with those supplemented. The results indicated that none of these factors contributed significantly to the differential risk between supplemented and unsupplemented mothers, thus leading to the conclusion that the difference in recurrence rates was caused by the multivitamin (58).
Several recent studies examining the effect of multivitamins on NTDs have been published. A case-control, population-based study evaluated the association between periconceptional (3 months before and after conception) multivitamin use and the occurrence of NTDs (59). The case group involved either live-born or stillborn infants with anencephaly or spina bifida born during the years 1968–1980 in the Atlanta area. A total of 347 infants with NTDs were eligible for enrollment and became the case group, whereas 2,829 infants without birth defects served as controls. Multivitamin usage and other factors were ascertained by interview 2–16 years after the pregnancies. This long time interval might have induced a recall problem into the study, even though the authors did take steps to minimize any potential bias (59). A protective effect of periconceptional multivitamin usage against having an infant with an NTD was found in comparison with controls with an estimated relative risk for all NTDs of 0.41 (95% confidence interval [CI] 0.26–0.66), anencephaly 0.47 (95% CI 0.25–0.91), and spina bifida 0.37 (95% CI 0.19–0.70). The odds ratios for whites, but not for other races, were statistically significant. Except for anencephaly among whites (odds ratio [OR] 95% CI 0.35–1.34), similar results were obtained when infants with congenital defects other than NTDs were used as controls. Although the results indicated that periconceptional use of multivitamins did protect against NTDs, the authors could not determine whether the effect was related to vitamins or to some unknown characteristic of vitamin users (59). In commenting on this study, one investigator speculated that if the lack of a statistical effect observed in black women was confirmed, it may be related to a different genetic makeup of the population (60). In other words, the gene(s) that cause NTDs are responsive to periconceptional multivitamins only in whites (60).
Three brief letter communications examined the effects of gastric or intestinal bypass surgery, performed for obesity, on the incidence of NTDs (61,62 and 63). The first report appeared in 1986 and described three births with NTDs occurring in Maine (61). During the interval 1980–1984, 261 gastric bypass procedures were performed in Maine, but only 133 were in women under the age of 35. One woman delivered an anencephalic fetus 2 years after her surgery. A second suffered a spontaneous abortion at 16 weeks' gestation, 6 years after a gastrojejunostomy. Her serum a-fetoprotein level 10 days before the abortion was 4.8 times the median. She became pregnant again 2 years later and eventually delivered a stillborn infant in the 3rd trimester. The infant had a midthoracic meningomyelocele, iniencephaly, absence of diaphragms, and hypoplastic lungs. During this latter pregnancy, she had intermittent heavy alcohol intake. In the third case, a woman whose surgery had been done 7 years earlier had an anencephalic fetus associated with a lumbar rachischisis diagnosed at 6 months' gestation. In response to this report, investigators in Denmark and Sweden could find no cases of NTDs in 77 infants born after their mothers had bypass operations for obesity (62). However, the procedures in these cases involved intestinal bypass, not gastric. Low birth weight and growth retardation were increased in 64 live-born infants. Gastric bypass surgery is known to place recipients at risk for nutritional deficiencies, especially for iron, calcium, vitamin B12, and folate (61,63). In the third report, of a total of 908 women who underwent the procedure, 511 (57%) responded to a questionnaire (63). Of these, 87 (17%) had been pregnant at least once after the surgery. The 87 women had 73 pregnancies (more than 20 weeks' gestation) before the operation with no cases of NTDs. After the surgery, these women had 110 pregnancies with two cases of NTDs. This represented a 12-fold increase in the risk for NTDs compared with the general population (incidence 0.15%) (63). A third case of an infant with an NTD born from a mother who had undergone the operation was identified later, but the mother was not part of the original group. In each of the three cases, the birth of the infant with an NTD had occurred more than 4 years after the bypass surgery. Moreover, the three mothers had not consumed vitamin supplements as prescribed by their physicians. Because of these findings, the authors recommended pregnancy counseling for any woman who has undergone this procedure and who then desires to become pregnant (63).
In another brief Reference, the final results of a British clinical trial were presented in 1989 (64). Women who resided in the Yorkshire region were enrolled in the study if: (a) they had one or more previous NTD infants, (b) they were not pregnant at the time of enrollment, and (c) they were considering another pregnancy. Mothers were requested to take the vitamin formulation described above for at least 4 weeks before conception and until they had missed two menstrual periods (i.e., same as previously). The results of the study included three reporting intervals: 1977–1980, 1981–1984, and 1985–1987. The 148 fully supplemented mothers (those who took vitamins as prescribed or only missed taking vitamins on 1 day) had 150 infants or fetuses, only 1 (0.7%) of whom had an NTD. In contrast, 315 unsupplemented mothers had 320 infants or fetuses among whom there were 18 (5.6%) cases of NTDs. The difference between the groups was significant (p=0.006). In addition, 37 partially supplemented (defined as mothers who took the prescribed vitamin for a shorter period of time than the fully supplemented group) women had 37 pregnancies with no cases of NTDs. The investigators concluded that the difference between the groups could not be attributed to declining NTD recurrence rates or to selection bias. Summarizing these and previously published results, only 1 NTD recurrence had been observed in 315 infants or fetuses born to 274 fully supplemented mothers, and no recurrences had been observed among 57 examined infants or fetuses born to 58 partially supplemented women (64).
A 1989 study conducted in California and Illinois examined three groups of patients to determine whether multivitamins had a protective effect against NTDs (65). 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 other 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 OR of 0.95 (95% CI 0.78–1.14) for NTD-supplemented mothers (i.e., those who received the RDA of vitamins or more) compared with unsupplemented mothers of abnormal infants, and an OR of 1.00 (95% CI 0.83–1.20) when the NTD group was compared with 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 were different than those obtained in the Atlanta study cited above: (a) recall bias, (b) a declining incidence of NTDs, (c) geographic differences such that a subset of vitamin-preventable NTDs was in the Atlanta region but not in the areas of the current study, and (d) the Atlanta study did not consider the vitamins contained in fortified cereals (65). However, others 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 (66).
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 (66). 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, 3 cases occurred in 107 women with a history of previous NTDs (28.0/1000), and 2 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 NTD 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). The prevalence ratio estimate for these two groups was 0.27 (95% CI 0.12–0.59). For mothers who used vitamins during the first 6 weeks that did not contain folic acid, the prevalence was 3 cases in 926, a ratio of 3.2. The ratio, when compared with that of nonusers, was 0.93 (95% CI 0.26–3.3). 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 (prevalence 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 recent investigation into a third class of anomalies, limb-reduction defects, was opened by a report that multivitamins may have caused this malformation in an otherwise healthy boy (52). The mother was taking the preparation because of a previous birth of a child with an NTD. A retrospective analysis of Finnish records, however, failed to show any association between 1st-trimester use of multivitamins and limb-reduction defects (67).
In summary, the use of multivitamins up to the RDA for pregnancy is recommended for the general good health of the mother and the fetus. There is no strong evidence to suggest that vitamin supplementation can prevent CLP. However, a body of evidence has accumulated that supplementation during the first few weeks of gestation, especially with folic acid, may reduce the risk of NTDs (see Folic Acid). The evidence appears particularly strong for the prevention of NTD recurrences in England. Additional studies will be needed to establish whether the protective effect includes only certain types of patients. Until that time, it seems prudent to recommend that folate-containing multivitamin preparations should be used immediately before and during at least the first few months of pregnancy. Women who have had gastric bypass surgery for obesity may be at increased risk for delivering offspring with NTDs, and pregnancy counseling to ensure adequate nutritional intake may be of benefit.
[* Risk factor varies for amounts exceeding RDA. See individual vitamins.]
Breast Feeding Summary
Vitamins are naturally present in breast milk (see individual vitamins). The recommended dietary allowance of vitamins and minerals during lactation (1st 6 months) are as follows (1): Vitamin A 1300 RE Vitamin D
References
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