Periconceptional Use of Multivitamins and
the Occurrence of Anencephaly and Spina Bifida
In 1988, ÐÇ¿ÕÓéÀÖ¹ÙÍø completed the analysis of data collected in 1982 and
1983
from a population-based case-control study to evaluate the
association
between periconceptional multivitamin use* and the occurrence of
anencephaly or spina bifida (neural tube defects (NTDs)). Results
of
this study suggest that mothers who were periconceptional
multivitamin
users were at lower risk of having babies with NTDs than were
mothers
who did not use multivitamins (1).
In 1982 and 1983, the Atlanta Birth Defects Case-Control (ABDCC)
Study
obtained information from parents of babies with serious
malformations
identified through the Metropolitan Atlanta Congenital Defects
Program.
Information was gathered also from a randomly selected group of
parents
of babies without birth defects from the same area identified
through
birth certificates. Mothers were questioned about a variety of
maternal
exposures, including multivitamin use, through a telephone
interview
(2,3).
A total of 519 babies with NTDs and 4043 controls without birth
defects
were identified. The mothers of 347 NTD babies and 2829 matched
controls completed interviews, for an overall 70% participation
rate.
Participation was higher for white mothers (74%) than for mothers
of
other races (57%). To assess possible maternal recall bias, a
second
control group, comprising ABDCC mothers whose babies had serious
birth
defects other than NTDs (n=3665), was used.
In addition to the group of mothers defined as periconceptional
multivitamin users, mothers who used multivitamins were classified
into
two additional groups: 1) early postconceptional multivitamin users
(use during each of the first 3 months of pregnancy only) and 2)
late
postconceptional multivitamin users (use during the second and/or
third
months of pregnancy only). Mothers who said they used vitamins less
than 3 times a week and mothers who reported no periconceptional
vitamin use were considered nonusers of multivitamins. Fourteen
percent
of mothers reported periconceptional multivitamin use, 11% reported
early postconceptional multivitamin use, 28% reported late
postconceptional multivitamin use, 40% reported nonuse, 5% reported
other vitamin use, and 2% were unknown.
For mothers who were periconceptional multivitamin users, the risk
of
having babies with NTDs was lower than that for mothers who did not
use
multivitamins (odds ratio = 0.41, 95% CI = 0.26, 0.66) (Table 1).
For
mothers who were early or late postconceptional multivitamin users,
the
odds ratios were 0.75 and 0.86, respectively (Table 1). For
anencephaly
and spina bifida separately, odds ratios were less than 1.0, except
for
mothers of other races whose babies had anencephaly. These odds
ratios
for early and late postconceptional multivitamin use relative to no
multivitamin use were 1.80 and 1.28, respectively. Neither of these
associations was statistically significant.
When periconceptional multivitamin use among mothers of babies with
NTDs was compared with use among mothers of babies with all other
types
of major malformations, odds ratios were similar to those obtained
using controls without birth defects.
Reported by: Birth Defects and Genetic Diseases Br, Div of Birth
Defects and Developmental Disabilities, Center for Environmental
Health
and Injury Control, ÐÇ¿ÕÓéÀÖ¹ÙÍø.
Editorial Note
Editorial Note: Severe congenital malformations occur in 2%-4% of
all
infants born in the United States. The cause of most of these
defects
is unknown. NTDs are among the more common severe congenital
malformations. Approximately 3500 infants with anencephaly or spina
bifida (1 case per 1000 live births) are born each year in the
United
States. The etiologies of NTDs are usually unknown.
Women who previously have had NTD-affected infants are at increased
risk of having similarly affected infants in subsequent
pregnancies.
Periconceptional multivitamin use by these women had been reported
to
reduce this risk (4), but no studies similar to that reported here
had
been done among women who have not previously had an NTD-affected
infant.
The ÐÇ¿ÕÓéÀÖ¹ÙÍø study is the first population-based investigation of the
relationship between multivitamin use and birth defects in the
United
States. The findings suggest that women who have never had an
NTD-affected child and who use periconceptional multivitamins are
less
likely to have an infant with an NTD.
Methodologic concerns about case-control studies, such as the
representativeness of a sample, call into question the strength of
the
conclusions about a multivitamin effect. In this study,
periconceptional multivitamin users differed from nonusers in a
number
of demographic, health-related, and lifestyle characteristics.
These
include maternal age, education, alcohol use, and history of
stillbirths or fetal deaths before the index birth, use of
spermicides
before the index birth, smoking any time during the
periconceptional
period, and a maternal history of chronic illness. Adjusting the
data
for these factors did not change results. However, it is not known
whether the apparent protective effect of multivitamins for NTDs
results directly from multivitamin use or from other
characteristics of
women who use multivitamins.
Randomized clinical trials offer an opportunity to minimize the
inherent weaknesses, such as selection and recall bias, of
case-control
studies. Such clinical trials among mothers of NTD-affected
children in
the United Kingdom and Egypt are being conducted to assess the
effect
of multivitamin use on the recurrence of NTDs.
Recent laboratory data have increased interest in the mechanisms of
folate metabolism and its possible relationship to NTDs. Studies
have
been done measuring red cell folate in women who had a history of
two
or more NTD pregnancies. Compared to a control group, mothers with
an
NTD-affected pregnancy had lower red cell folate levels. These
studies
suggest that maternal metabolic factors are involved in the
etiology of
NTDs (5,6), indicating that the mechanisms relating to these
factors
should be explored further.
Evidence is insufficient to recommend periconceptional multivitamin
use
in the United States to prevent NTDs. The question of whether
multivitamin use affects the risk of NTDs can be answered best by
randomized clinical trials of proper design and size and through
clinical and biochemical studies.
References
Mulinare J, Cordero JF, Erickson JD, Berry RJ. Periconceptional
use
of multivitamins and the occurrence of neural tube defects. JAMA
1988;260:3141-5.
2.Erickson JD, Mulinare J, McClain PW, et al. Vietnam veterans'
risks
for fathering babies with birth defects. JAMA 1984;252:903-12.
3.ÐÇ¿ÕÓéÀÖ¹ÙÍø. Vietnam veterans' risks for fathering babies with birth
defects.
Atlanta: US Department of Health and Human Services, Public Health
Service, 1984.
4.Smithells RW, Nevin NC, Seller MJ, et al. Further experience of
vitamin supplementation for prevention of neural tube defect
recurrences. Lancet 1983;1:1027-31.
5.Yates JR, Ferguson-Smith MA, Shenkin A, Guzman-Rodriguez R, White
M,
Clark BJ. Is disordered folate metabolism the basis for the genetic
predisposition to neural tube defects? Clin Genet 1987;31:279-87.
6.Trotz M, Wegner C, Nau H. Valproic acid-induced neural tube
defects:
reduction by folinic acid in the mouse. Life Sci 1987;41:103-10.
*Periconceptional multivitamin use was defined as regular
multivitamin
or prenatal vitamin use during every month of a 6-month
periconceptional period (i.e., 3 months before conception through
the
first 3 months of pregnancy).
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