Context Daily consumption of 400 µg of folic acid before conception and
during early pregnancy dramatically reduces the occurrence of neural tube
defects (NTDs). Before food fortification, however, only an estimated 29%
of US reproductive-aged women were taking a supplement containing 400 µg
of folic acid daily. The US Food and Drug Administration authorized addition
of folic acid to enriched grain products in March 1996, with compliance mandatory
by January 1998.
Objective To evaluate the impact of food fortification with folic acid on NTD
birth prevalence.
Design, Setting, and Population National study of birth certificate data for live births to women in
45 US states and Washington, DC, between January 1990 and December 1999.
Main Outcome Measure Birth certificate reports of spina bifida and anencephaly before fortification
(October 1995 through December 1996) compared with after mandatory fortification
(October 1998 through December 1999).
Results The birth prevalence of NTDs reported on birth certificates decreased
from 37.8 per 100 000 live births before fortification to 30.5 per 100 000
live births conceived after mandatory folic acid fortification, representing
a 19% decline (prevalence ratio [PR], 0.81; 95% confidence interval [CI],
0.75-0.87). During the same period, NTD birth prevalence declined from 53.4
per 100 000 to 46.5 per 100 000 (PR, 0.87; 95% CI, 0.64-1.18) for
women who received only third-trimester or no prenatal care.
Conclusions A 19% reduction in NTD birth prevalence occurred following folic acid
fortification of the US food supply. However, factors other than fortification
may have contributed to this decline.
Spina bifida and anencephaly, the most common neural tube defects (NTDs),
together affect approximately 4000 pregnancies resulting in 2500 to 3000 US
births annually.1,2 In randomized
controlled trials, folic acid supplementation before conception and during
the first trimester has been shown to reduce the recurrence of NTDs by 72%
(relative risk, 0.28; 95% CI, 0.12-0.71) in women with a previous NTD-affected
pregnancy,3 and in another randomized study,
supplementation reduced the occurrence of NTDs by 100% (95% CI, 0.0-0.63).4
In 1992, the US Public Health Service issued a recommendation that all
US reproductive-aged women who are capable of becoming pregnant should consume
400 µg of folic acid daily2,5;
however, a recent survey indicated that only 29% of US women were following
this recommendation in 1998.6 In a further
effort to reduce the occurrence of folate-preventable NTDs, the US Food and
Drug Administration (FDA) authorized the addition of folic acid to enriched
grain products in March 1996 and made compliance mandatory by January 1998.
The current level of fortification was expected to add approximately 100 µg
of folic acid to the daily diet of the average person and to result in approximately
50% of all reproductive-aged women receiving 400 µg of folate from all
sources.7-9 In
addition, other countries recently fortified their grain supplies on either
a voluntary or mandatory basis,10-12
and several more countries are considering folic acid fortification.13-16
Birth certificates are an important data source for monitoring national
NTD trends. They are completed for all US live births, and since 1989, they
include check boxes for selected congenital anomalies, including anencephaly
and spina bifida.17-19
The quality of data on birth defects from birth certificates is limited, 20-22 in particular, sensitivity
is low. Nonetheless, birth certificates represent a stable source of data
that can be used for monitoring approximately 4 million births per year. The
impact of universal folic acid fortification as a public health intervention
was assessed by evaluating birth certificate data on NTDs to determine its
effect on the US NTD birth prevalence.
Birth certificate information is routinely collected by state vital
statistics offices and compiled by the Centers for Disease Control and Prevention's
(CDC's) National Center for Health Statistics (NCHS). We evaluated the prevalence
of NTDs in births to US residents, specifically spina bifida and anencephaly,
reported on birth certificates from 45 states and Washington, DC, from January
1990 through December 1999. Residents of Connecticut, Maryland, New Mexico,
New York, and Oklahoma were excluded for the following reasons: New Mexico,
New York, and Oklahoma birth certificates did not report congenital anomalies
for 1 or more years during this period, and in Connecticut and Maryland, congenital
anomaly status was "not stated" for more than 25% of births during several
years between 1990 and 1999. To determine whether the overall sensitivity
of birth certificates to birth defects varied during this period, the percentage
of certificates noting 1 or more defects by year for 1990 through 1999 was
calculated. Any birth certificate that did not indicate an NTD but did indicate
at least 1 of 19 other congenital anomalies was included.18
Birth certificates with only "other" checked in the congenital anomaly list
were excluded. This analysis was conducted because a decline in the sensitivity
of birth certificates to other birth defects during this time period would
suggest that any observed decline in NTDs would need to be viewed more cautiously.
Folic acid fortification was first authorized in March 1996 and was
mandatory by January 1998.7 Information on
the estimated time from grain production to consumption or on the proportion
of the grain supply that was fortified before the mandatory deadline was not
obtainable. In at least some US regions, evidence of substantial folic acid
fortification was shown by increasing serum folate levels beginning in 199723,24 and continuing to increase through
1998.24 From this evidence, we assumed that
nearly all births from October 1998 through December 1999 (conceptions from
approximately January 24, 1998, to April 23, 1999) were exposed to folic acid
fortification periconceptionally. (The dates of conception are estimated assuming
a 38-week gestation because this is the mean gestation for NTD-affected pregnancies
reported on birth certificates.) The birth prevalence of NTDs from October
1995 through December 1996 (5 quarters of births before folic acid fortification)
was compared with the birth prevalence of NTDs from October 1998 through December
1999 (5 quarters of births conceived after mandatory folic acid fortification).
In addition, the postfortification NTD prevalence (October 1998 to December
1999 births) was compared with the mean prevalence from 1990 to 1996 as the
reference group to assess if any reduction in NTDs observed was dependent
on our choice of comparison group. Differences between these periods were
expressed as prevalence ratios (PRs) and 95% confidence intervals (CIs), which
were calculated using Epi Info (version 6; CDC, Atlanta, Ga). Furthermore,
these estimates were calculated for spina bifida and anencephaly birth prevalences
(defined as the number of infants whose birth certificates indicated that
they had either spina bifida or anencephaly, with the denominator as the total
number of live births during the same period).
To examine trends unaffected by changes in the use of prenatal diagnosis
or termination of affected pregnancies, the prevalence of NTDs among women
who began prenatal care in the third trimester or had no prenatal care at
all was evaluated. Although some states are increasing restrictions on and
decreasing access to pregnancy termination services,25
second-trimester elective terminations are legal in the United States. However,
in the practice of obstetrics in the United States today, third-trimester
terminations are rare, even with a prenatal diagnosis of an NTD.26
Therefore, affected pregnancies without obstetric oversight in the first 2
trimesters are unlikely to be terminated. As a result, the birth prevalence
of NTDs in women receiving only third-trimester or no prenatal care should
be relatively unaffected by changes or trends in the use of prenatal diagnosis
and termination. This group of women also may be less likely to be affected
by any changes in patterns of vitamin supplement use. The birth certificate
has a field to indicate what month prenatal care began. The trimester that
prenatal care began was dichotomized to "first or second trimester prenatal
care," meaning that the mother began prenatal care in the first 6 months of
pregnancy, and "third trimester/no prenatal care," meaning that the mother
either received no prenatal care or began prenatal care in the seventh month
of pregnancy or later. The percentage of women who received third-trimester
or no prenatal care decreased from 6.4% in 1989 to 3.9% in 1998,27
limiting the number of births for subgroup analysis to approximately 150 000
births in 1998.
The exponential weighted moving average (EWMA) method (using SAS; SAS
Institute, Cary, NC) was used to determine the timing of statistically significant
changes from a baseline mean, that is, the timing and occurrence of any statistically
significant changes during the entire 10-year period. This method sets a boundary
that is analogous to upper and lower confidence limits using the baseline
SD. The baseline mean and SD were based on the 1990 through 1996 data. Observed
values above and below the baseline mean increase the value of the EWMA statistic.
When the EWMA statistic is large enough to cross the boundary (an out-of-control
point), it means an increase or decrease beyond the limits of the model has
occurred. The EWMA statistic was reset to the 1990 to 1996 baseline mean after
each out-of-control point. The α level was set at .01, and the weight
was set at 0.075 to yield an average run length of 25 years, meaning that
only 1 false out-of-control signal should occur in every 25 years of data
analyzed.28 The EWMA method was used to detect
the timing of statistically significant shifts from the overall mean quarterly
spina bifida and anencephaly prevalence. Among women receiving third-trimester
only or no prenatal care, the total NTD birth prevalence was analyzed for
6-month intervals instead of quarters because of the limited numbers in this
subgroup. Also examined for ease of comparability was the total NTD prevalence
among all births by 6-month intervals.
The percentage of infants whose birth certificate indicated the presence
of at least 1 congenital anomaly other than an NTD was highest in 1990 and
was relatively stable from 1991 through 1999, with slight increases noted
in 1998 and 1999 (Table 1). Approximately
1% of all birth certificates indicated at least 1 congenital anomaly other
than an NTD.
A total of 1123 infants with spina bifida (26.2 per 100 000 births)
and 497 infants with anencephaly (11.6 per 100 000 births) were reported
on birth certificates from October 1995 through December 1996 (Table 2). The birth prevalence of spina bifida decreased to 20.2
per 100 000 births during October 1998 through December 1999, representing
a 23% decline (PR, 0.77; 95% CI, 0.70-0.84). The birth prevalence of anencephaly
declined 11% (PR, 0.89; 95% CI, 0.78-1.01), reaching a birth prevalence of
10.3 per 100 000 live births during October 1998 through December 1999.
The decline in total NTDs during October 1998 through December 1999 compared
with October 1995 through December 1996 was 19% (PR, 0.81; 95% CI, 0.75-0.87),
from 37.8 to 30.5 per 100 000 live births. The decline in spina bifida
and total NTDs was similar when the entire 7-year period from 1990 to 1996
was used as the referent group; however, the decline in the prevalence of
anencephaly was greater when this alternative comparison group was used.
The NTD birth prevalence for women who received third-trimester only
or no prenatal care was 53.4 per 100 000 from October 1995 through December
1996 and declined to 46.5 per 100 000 for October 1998 through December
1999 (PR, 0.87; 95% CI, 0.64-1.18). Comparing data from October 1998 through
December 1999 with the entire period from 1990 through 1996 yielded a similar
result (PR, 0.79; 95% CI, 0.62-1.00) (Table
2).
Among all women, data are presented by quarter of birth for spina bifida
and anencephaly separately (Figure 1).
Spina bifida prevalence has been declining since early 1997. The EWMA statistical
analysis demonstrated a statistically significant increase in spina bifida
prevalence in the fourth quarter of 1996, and statistically significant decreases
in spina bifida prevalence in the second quarter of 1992, the fourth quarter
of 1998, and the second and third quarters of 1999. Anencephaly prevalence
was higher in 1990 to 1991, declined from late 1991 through 1994, remained
relatively stable from 1995 to 1997, and showed a further slight decline in
1998 to 1999. For anencephaly, the EWMA analysis indicated 5 statistically
significant increases in 1990 to 1991 and 3 statistically significant decreases
from 1994 through 1997. There were also statistically significant decreases
in anencephaly in the first and fourth quarters of 1998 and the second and
fourth quarters of 1999.
Among women receiving third-trimester only or no prenatal care, data
are presented in 6-month intervals (Figure
2). While the data are unstable, the point estimates for the last
half of 1998 and all of 1999 are the 3 lowest points on the figure. A statistically
significant decline in total NTDs was detected by the EWMA analysis in the
second half of 1999 among women who received only third-trimester or no prenatal
care. For comparability purposes, total NTDs among all births also are presented
by 6-month intervals. The EWMA analysis for NTDs among all births showed 1
statistically significant increase (January to June 1991) and 3 statistically
significant decreases in the last 3 time periods (July to December 1998, January
to June 1999, and July to December 1999).
Data from US birth certificates indicate a 19% decline in the birth
prevalence of NTDs and a 23% decline in spina bifida prevalence among births
conceived after mandatory folic acid fortification (October 1998 through December
1999) compared with the NTD prevalence before folic acid fortification (October
1995 through December 1996). This decline was temporally associated with the
fortification of the grain supply with folic acid: the EWMA analysis indicated
that a statistically significant decline in spina bifida prevalence occurred
in the fourth quarter of 1998 and the second and third quarters of 1999. These
declines were observed despite no apparent decline in sensitivity of the birth
certificate during this time. Due to the public health importance of the NTD
declines observed in our study, a brief announcement was published on the
CDC's NCHS Web site in December 2000.29
The long-term downward trend in anencephaly prevalence that preceded
folic acid fortification makes it difficult to interpret the 11% decline following
fortification. In particular, the mean anencephaly prevalence from 1990 through
1996 was heavily influenced by the high prevalence observed in 1990 to 1991
and may have resulted from reporting differences in those years. The check
box format for reporting birth defects was introduced on the birth certificate
in 1989, and anencephaly was the first check box on the congenital anomaly
list. It is unclear why the EWMA analysis showed 5 statistically significant
increases and 2 statistically significant decreases in anencephaly prevalence
from 1990 to 1996, complicating the interpretation of the 4 significant decreases
observed in 1998 and 1999.
Among infants whose mothers received third-trimester or no prenatal
care, the magnitude of the decline in NTDs was similar when the entire period
from 1990 through 1996 was used as the reference group, but the decline was
not statistically significant when the 5 quarters just before fortification
were used as the reference group. There was a statistically significant decline
in this group during the last half of 1999 by the EWMA analysis. We expected
that the birth prevalence of NTDs in this subgroup would be unaffected by
changes in prenatal diagnosis or termination. While the NTD prevalence was
higher among women receiving third-trimester only or no prenatal care, the
trend was very similar to that for all births.
The 1999 National Health and Nutrition Examination Survey data documented
dramatic increases in serum and red blood cell (RBC) folate levels among reproductive-aged
women in the US population following folic acid fortification of enriched
grain products.30 This increase confirms the
findings of 2 earlier studies of selected US populations that noted increases
in serum folate levels beginning in 1997 that also may have been due to folic
acid food fortification.23,24
It is not known whether the increase in serum folate levels observed is sufficient
to maximize NTD prevention, 31 but measurements
of RBC folate levels taken early in pregnancy have shown a dose-response relation
to the risk for having an infant with an NTD, with the lowest risk among those
women with the highest RBC folate levels.32
The authors of a study conducted in Ireland predicted a decline in NTD
prevalence of a magnitude similar to that observed in our study if fortification
added 100 µg of folic acid to the average daily diet of reproductive-aged
women.33,34 Daly et al34 estimated that folic acid levels equivalent to the
current level of fortification in the United States would result in a 22%
reduction in the NTD risk. They also estimated that 200 µg would lead
to a 41% reduction, and 400 µg would lead to a 47% reduction in NTD
risk. Wald et al33 extended these analyses
and predicted 18%, 35%, and 53% reductions from 100, 200, and 400 µg,
respectively. These estimates of 22% and 18% bracket the 19% decline observed
in our study. However, recent data suggest that women may be getting more
folic acid from fortification than was originally projected.35
Despite these possibly higher levels of folic acid in fortified foods, we
may have observed only a 19% decline due to differences between the US population
and the Irish population on which these predictions were originally made or
due to differences in lab techniques for measuring RBC folate levels in the
Irish vs US studies.
A major concern is the validity of birth defect data from birth certificates.
The sensitivity of birth certificates is low for total birth defects, but
it is higher for defects that are usually diagnosed at birth. An evaluation
of 1989 birth certificate data on birth defects in Tennessee found that the
birth certificate had a 67% sensitivity to detect anencephaly and an 89% positive
predictive value.21 One study found that of
all 1989 and 1990 births in metropolitan Atlanta the sensitivity of the birth
certificates was 86% for anencephaly and 40% for spina bifida and the positive
predictive value was 100% for both defects.20
A recent unpublished evaluation that indicated a sensitivity for anencephaly
is closer to the Tennessee study than to the Atlanta study (written communication,
L. Miller, MD, September 16, 1999). However, despite their limited sensitivity,
the positive predictive value of NTDs reported on birth certificates is high.
The high positive predictive value indicates that trends in true NTD cases
are being observed rather than false positives.
If the sensitivity and specificity of birth certificates have remained
stable over time, then observed declines in NTDs reported on birth certificates
should represent actual declines in the birth prevalence of these defects.
The percentage of all birth certificates with 1 or more defects other than
NTDs remained relatively stable from 1991 through 1999 and even increased
slightly in 1998 and 1999. Therefore, a variation in reporting of all defects
on the birth certificate over time does not explain the decline observed in
NTDs after folic acid fortification. However, we cannot rule out the possibility
that subtle changes in the sensitivity of NTD reporting on birth certificates
have contributed to the observed trends.
Birth certificates are completed for live births only; any NTD-affected
pregnancies ending in induced or spontaneous abortions are not recorded. Any
observed changes in the birth prevalence of NTDs may actually be due to changing
patterns in the percentage of affected fetuses being born alive. There has
been some debate on the possible role of folic acid in increasing or decreasing
the likelihood of a spontaneous abortion of an NTD-affected pregnancy36-38; however, in the
absence of evidence to the contrary, we have assumed that the proportion of
NTD-affected pregnancies that are spontaneously aborted has not changed over
time.
The proportion of NTD-affected pregnancies that are electively terminated
may be influenced by many factors, including the proportion of pregnant women
receiving prenatal care, insurance reimbursement for prenatal diagnostic tests,
availability of termination services, and improvements in the prognosis of
the affected fetus. Termination is more likely to occur among pregnancies
affected by anencephaly than among pregnancies affected by spina bifida.39,40 Techniques, such as α-fetoprotein
screening and ultrasound, now are often used during the second trimester of
pregnancy to detect fetal defects. In concert with pregnancy termination,
these techniques have had a substantial impact on the prevalence of NTDs in
live births as measured by surveillance systems. Several recent studies show
that the percentage of NTD-affected pregnancies that were prenatally diagnosed
and terminated ranged from 39% to 48%.41-44
However, the Hawaii study,44 which included
cases from 1987 through 1996, suggested that the proportion of fetuses prenatally
diagnosed with NTDs and terminated has remained relatively stable during that
time, and no other evidence indicates that the percentage of affected pregnancies
that are terminated has changed since 1990 in the United States. Indeed, spina
bifida prevalence for 1990 to 1996 was relatively stable. It seems unlikely
that a substantial increase in use of prenatal diagnosis and termination of
pregnancies affected by an NTD occurred between 1996 and 1999.
The decline in NTDs observed among infants born to women who received
only third-trimester or no prenatal care was similar to that observed for
all women, but this was only statistically significant when the entire period
from 1990 to 1996 was used as the reference group. This may be due to the
limited number of women obtaining only third-trimester or no prenatal care.
Our analysis comparing postfortification with prefortification births only
had 40% power to detect a 20% decline in NTDs among women in this subgroup,
but the analysis did have more than 90% power to detect a 40% decline in NTDs
for these women. This difference in power means that is it unlikely that a
large decline occurred that was not detected in our analysis. It seems implausible
that increased use of prenatal diagnosis and termination caused the reduction
in NTDs among total live births because the declines in women receiving third-trimester
or no prenatal care were of similar magnitude to those observed among all
births. We will continue to monitor the birth prevalence of NTDs to further
evaluate the impact of folic acid fortification on the occurrence of NTDs.
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