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~ 1
Periconceptional Vitamin
Supplementation and
Neural Tube Defects
Very early in pregnancy, the developing embryo is susceptible to mal-
formations from a varieUr of causes. Animal studies suggest that these
causes may include certain maternal nutrient deficiencies or excesses if
they occur during embryogenesis (i.e., during the first 2 months of gesta-
tion). The implications of this for human nutrition are uncertain. Evidence
that excessive intake of vitamin A may be teratogenic (i.e., may cause
birth defects) is covered in Chapter 17. This chapter considers evidence
relating to periconceptional micronutrient status and supplementation to
neural tube defects. The periconceptional period is a term that lacks a tight
definition. The subcommittee suggests that it be used to denote a period
from 1 to 3 months before conception to week 6 of gestation. The critical
period for the formation of the neural tube is from 17 to 30 days gestation.
NEURAL TUBE DEFECTS
Neural tube defects such as spine bifida have been linked by several
investigators to periconceptional nutrient intake. The seriousness and the
frequency with which neural tube defects occur warrant careful considera-
tion of evidence from studies that address nutrition-related approaches for
reducing their incidence.
Occurrence
Despite a recent decline in the occurrence rate, 2,500 to 3,000 in-
fants are born with neural tube defects in the United States each year. It is
412
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PERICONCEPIIONAL VITAMIN SUPPLEMENTATION
413
estimated that 30,000 living Americans have spine bifida. Many other cases
of neural tube defects are aborted, stillborn, or die early in life. The
magnitude of the problem on a worldwide basis is estimated at 300,000 to
400,000 births per year.
Occurrence rates for neural tube defects vary widely according to
geographic area, socioeconomic status, and ethnic background. Rates are
relatively low in the United States, the highest rates being found in the
Southeast and lowest rates in the West. In each area, rates are much
lower for blacks than for whites. Marked changes in the occurrence rate
of neural tube defects have been observed; the rate peaked in the middle
of this century and has progressively declined over the past 40 years in
North America and Western Europe. The risk of a recurrent neural tube
defect, i.e., more than one affected child born to the same parents, is much
greater than the risk of occurrence. Recurrence rates have been estimated
to be as high as 2 to 10%, compared with an occurrence rate of <0.04%
in a low-risk area. However, the absolute number of first occurrences to
parents greatly exceeds that of recurrent events.
Possible Causes
Neural tube defects result from genetic-environmental interactions.
The genetic component, which probably involves several genes, is complex
and not well understood. The sum of epidemiologic and other evidence
indicates a strong environmental component. The nature of the envi-
ronmental factors, especially the supposed role of micronutrient nutrition
and metabolism, has become the focus of intense scientific interest and
debate. ~ reduce the risk of neural tube defects, periconceptional vi-
tamin supplementation has been recommended, especially for all women
who have had a previous pregnancy complicated by a neural tube defect
(International Conference on Prepregnancy Nutrition, 1987) but also for
all pregnant women (Holmes, 1988; International Conference on Prepreg-
nancy Nutrition, 1987~. However, most researchers have been cautious
about overinterpreting their data.
Evidence of Effects of Nutrients
The subcommittee examined evidence from studies in animal models
and in humans addressing the possible value of folate and multivitamin
supplementation commencing prior to conception. The human studies
reported to date have involved laboratory assays, supplementation studies,
and case-control studies, but no randomized controlled clinical trials.
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414
Studies in Animal Models
DIETARY INTAKE AND NUTRIENT SUPPLEMENTS
Animal models provide some support for the hypothesis that vitamin
deficiencies may be one etiologic factor in the multifactorial etiology of
human neural tube defects (Kalter and Warkany, 1959~. However, folate
deficiency produced neural tube defects in rats only when folate antagonists
were given (Nelson et al., 1955~.
The therapeutic use of the anticonvulsant drug valproic acid during
pregnancy is associated with a 20-fold excess risk of neural tube defects
(Lammer et al., 1987~. A similar teratogenic effect of valproic acid has been
demonstrated in mice ([Lots et al., 1987~. When folinic acid, the metaboli-
cally active form of folio acid, is administered, the rate of valproate-induced
neural tube defects is reduced. A recent preliminary report indicates that
valproate impairs the activity of the enzyme glutamate formyltransferase
(EC 2.1.2.6), which catalyzes the conversion of tetrahydrofolate to folinic
acid (Weaner and Nau, 1989~. These observations indicate that neural tube
defects can result from disturbed folate metabolism.
Laboratory Assays
The results of laboratory assays suggest that maternal folate status may
be abnormal in subjects whose offspring have neural tube defects. Smithells
et al. (1976) observed significantly lower levels of red cell folate and white
cell ascorbate during the first trimester in mothers who delivered an infant
with a neural tube defect. Similarly, Yates et al. (1987) reported that
mothers with an affected pregnancy had lower red cell folate levels than
those of controls. Moreover, red cell folate levels were lowest in the group
with three or more neural tube defect pregnancies. No differences were
found for serum folate or for other serum vitamin measurements. Molloy
et al. (1985) observed no difference in maternal serum folate or vitamin
BE levels between those with neural tube defect pregnancies and controls.
These observations suggest that a change in maternal folate metabolism
may be associated with neural tube defect pregnancies, but they do not
necessarily suggest that a low intake of folate was involved.
Epidemiologic Observations
Epidemiologic observations indicate that poor maternal nutrition could
be important in the etiology of neural tube defects (Laurence et al., 1980~.
These observations were not sufficiently detailed to indicate any specific
nutrient deficiency.
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PERICONCEPIIONAL VITAMIN SUPPLEMENTATION
Penconcep~nal Vitamin Supplementation Studies
415
In 1981, Laurence and colleagues reported the outcome of a folate
supplementation study (4 mg of folate per day) in South Wales. Subjects
and controls were women who had a previous neural tube defect pregnancy.
They reported a statistically significant higher incidence of recurrence rates
in the placebo group, but only after the folate group was adjusted for
noncompliers, as determined from blood analyses (Laurence et al., 1981~.
The study group was very small (N = 111) with a total of six neural tube
defects occurring in test and control groups combined.
Smithells et al. (1983) reported the combined results of studies on two
cohorts of women with previous neural tube defect pregnancies included
in the United Kingdom Multicenter llial. The trial was a nonrandomized
study of periconceptional multivitamin and mineral supplementation. The
recurrence rate among subjects receiving the multivitamin preparation was
0.7% (3 out of 454) in comparison with a recurrence rate for the nonsupple-
mented group of 4.8% (24 out of 519~. This apparent sevenfold protective
effect is extremely unlikely to be attributable to chance. However, bias in
this nonrandomized trial cannot be excluded (Wald and Polani, 1984), es-
pecially since predictors of neural tube defects are still poorly understood.
For example, willingness to collaborate in a study involving administration
of a capsule three times a day for several months or the initiative to consult
with a doctor prior to conception may be factors associated with a relatively
low risk of a recurrent neural tube defect. The marked and unexplained
decrease in the overall rate of recurrence during the study period has
added further to the complexities of interpreting the data. The confusion
and controversy associated with this study are a direct consequence of an
inadequate design that did not include appropriate controls. Although the
presumptive evidence for a beneficial effect of the multivitamin mineral
preparation is quite strong, Smithells and colleagues have stated that "fur-
ther studies are a prerequisite for policy decisions designed to reduce the
occurrence of neural tube defects" (Smithells et al., 1983~.
Case-Control and Cohort Studies of
Periconceptional Multivitamin Use
The results of three case-control studies and one cohort study of
multivitamin or folate supplements or dietary folate intake in relation to
the occurrence of neural tube defects were reported in 1988 and 1989.
In one of these studies (Mulinare et al., 1988), the use of a folio acid-
containing multivitamin during the periconceptional period was associated
with a reduced prevalence of neural tube defects as compared with the
prevalence among nonusers (0.9 compared with 3.3 per 1,000, respectively).
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416
DIETARY INTAKE AND NUTRIENT SUPPLEMENTS
The precise composition of the multivitamin preparations in this study were
not available; the mothers were interviewed between 2.5 and 16 years after
the relevant pregnancy. The investigators emphasized that they could not
exclude the possibility that a factor associated with the use of multivitamins
rather than the vitamin intake per se was the real determinant of the
observed decrease. Such factors might involve socioeconomic status, since
poor women and women with relatively few years of formal education are
not as likely to take multivitamins as their more advantaged counterparts
(Block et al., 1988; Koplan et al., 1986~.
Milunsky and colleagues (1989) reported that the use of folio acid-
containing multivitamins during the first 6 weeks of pregnancy was associ-
ated with a 73% reduction in the prevalence of neural tube defects. No
protective effect of multivitamins without folate was observed, nor was
there any apparent benefit of folate supplements started after 6 weeks of
gestation. Among women not taking folate supplements, the prevalence
of neural tube defects was lower among those with dietary folate intakes
exceeding 100 Friday than among those with lower intakes. (The estimated
mean daily folate intake of women aged 19 to 44 in the United States is
approximately 220 fig iSubar et al., 1989; USDA, 19853~. The cohort in this
study consisted of 23,500 women undergoing maternal serum a-fetoprotein
screening or amniocentesis at approximately week 16 of gestation, 49 of
whom had an affected fetus. Several biases are possible in the study. For
example, some of the subjects knew the results of their screening before
being interviewed. Furthermore, women who elected to take folate sup-
plements before week 6 of gestation may have had characteristics different
from those of women who did not take supplements or who started their
supplements later in gestation.
Bower and Stanley (1989) found a reduction in the occurrence of
neural tube defects with increasing dietary intake of free folate during the
first 6 weeks of pregnancy. Similar but weaker trends were seen when the
effect of total folate intake was examined. These investigators concluded
that dietary folate deficiency in early pregnancy is associated with the
occurrence of neural tube defects but that confirmation is required before
the issue of prevention can be addressed.
In a large population-based case-control study conducted in California
and Illinois, Mills et al. (1989) found no evidence of a protective effect
from the use of a multivitamin preparation during the periconceptional
period. Although these investigators attempted to minimize recall bias by
using two control groups (one consisting of mothers who had delivered
stillborn infants or infants with other abnormalities and one comprising
women who had given birth to normal infants), the possibility of recall
error or misclassification of multivitamin use cannot be discounted.
Although the results of these studies are not consistent, they do,
OCR for page 417
PERICONCEPTIONAL VITAMIN SUPPLEMENTATION
417
however, point clearly to the need for more definitive studies of maternal
vitamin intake, especially folate intake, in the periconceptional period.
Limitations of the Evidence
Data associating the periconceptional use of multivitamin or folate
preparations with protection against neural tube defects are inconsistent.
Although the findings of some key studies; e.g., the United Kingdom
Multicenter filial (nonrandomized) (Smithells et al., 1983), the Centers
for Disease Control case-control study (Mulinare et al., 1988), and the
Boston cohort study (Milunsly et al., 1989), were very unlikely to be due to
chance, factors other than periconceptional vitamin use cannot be excluded
as possible explanations for the results. For example, there is evidence that
the average diets consumed by women who take vitamin supplements have
a higher nutrient density than the diets of nonusers (Kurinij et al., 1986~.
Furthermore, dietary factors other than vitamins may provide protection.
In animal models, maternal zinc deficiency has produced lesions sim-
ilar to anencephaly (another type of neural tube defect) in humans, and
neural tube defects are produced more readily by zinc deficiencies than
by deficiency of any other micronutrient (Hurley, 1980~. Other evidence
from studies in humans suggests that maternal zinc deficiency is potentially
teratogenic, including neural tube defects as one of the adverse outcomes
(see the review by Hambidge et al., 1975~.
Well-designed randomized, prospective studies of periconceptional vi-
tamin supplementation are needed to examine the putative protection
against neural tube defects. I\vo major studies are in progress-one orga-
nized by the Medical Research Council in the United Kingdom and the
other in Hungary. Additional studies will be necessary.
Although the daily administration of a multivitamin preparation may
appear superficially to be simple, relatively inexpensive, safe, and possibly
beneficial, there are persuasive reasons for caution. The quantities of
vitamins in a standard multivitamin preparation are unlikely to be harmful,
but the possibility of side effects cannot be overlooked. For example,
inadvertent overuse of vitamins may damage the fetus. Furthermore, a
recommendation to take multivitamins during the periconceptional period
will divert attention from other factors that may be the true causative
factors of neural tube defects.
CONCLUSION
The subcommittee concluded that the scientific evidence does not
provide a sufficient basis for making recommendations concerning the
periconceptional use of vitamins and minerals for the prevention of neural
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418
DIETARY INTAKE AND NUTRIENT SUPPLEMENTS
tube defects. However, it recognizes the importance of the questions
that have been raised and the critical need for adequate, carefully designed
research to provide definitive answers as soon as possible. Meanwhile, since
one or more nutritional factors are likely to play a role in the etiology of
human neural tube defects, it would be desirable for women of childbearing
age to follow dietary guidelines. Guidelines that encourage increased
consumption of fruits, vegetables, whole grain breads and cereals, and
legumes all of which are good sources of folate and other micronutrients-
may be found in publications of both the public and private sector (e.g.,
ACS 1984; AHA [1988~; AICR [1985~; NCI [19873; NRC [19893; and
USDA/DHHS [19853~.
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Representative terms from entire chapter:
tube defects
