The “long questionnaire” is the standard questionnaire sent
biennially to participants that asks about personal and physical characteristics,
reproductive history, family history, environmental and personal exposures,
physical activity, screening and other examination history, medication use,
use of supplements and certain dietary features, psychosocial history, and
A, P for interaction = .01; B, P for interaction = .49; C, P for interaction
<.001; and D, P for interaction = .51. NHS indicates
Nurses’ Health Study and BMI indicates body mass index. Error bars indicate
95% confidence intervals.
Forman JP, Rimm EB, Stampfer MJ, Curhan GC. Folate Intake and the Risk of Incident Hypertension Among US Women. JAMA. 2005;293(3):320-329. doi:10.1001/jama.293.3.320
Author Affiliations: Renal Division (Drs Forman
and Curhan), Channing Laboratory (Drs Forman, Rimm, Stampfer, and Curhan),
Department of Medicine, Brigham and Women’s Hospital and Harvard Medical
School and Departments of Epidemiology and Nutrition (Drs Forman, Rimm, Stampfer,
and Curhan), Harvard School of Public Health, Boston, Mass.
Context Folate has important beneficial effects on endothelial function, but
there is limited information about folate intake and risk of incident hypertension.
Objective To determine whether higher folate intake is associated with a lower
risk of incident hypertension.
Design, Setting, and Participants Two prospective cohort studies of 93 803 younger women aged 27
to 44 years in the Nurses’ Health Study II (1991-1999) and 62 260
older women aged 43 to 70 years in the Nurses’ Health Study I (1990-1998),
who did not have a history of hypertension. Baseline information on dietary
folate and supplemental folic acid intake was derived from semiquantitative
food frequency questionnaires and was updated every 4 years.
Main Outcome Measure Relative risk of incident self-reported hypertension during 8 years
Results We identified 7373 incident cases of hypertension in younger women and
12 347 cases in older women. After adjusting for multiple potential confounders,
younger women who consumed at least 1000 μg/d of total folate (dietary
plus supplemental) had a decreased risk of hypertension (relative risk [RR],
0.54; 95% confidence interval [CI], 0.45-0.66; P for
trend <.001) compared with those who consumed less than 200 μg/d. Younger
women’s absolute risk reduction (ARR) was approximately 8 cases per
1000 person-years (6.7 vs 14.8 cases). The multivariable RR for the same comparison
in older women was 0.82 (95% CI, 0.69-0.97; P for
trend = .05). Older women’s ARR was approximately 6 cases
per 1000 person-years (34.7 vs 40.4 cases). When the analysis was restricted
to women with low dietary folate intake (<200 μg/d), the multivariable
RR for younger women with total folate intake at least 800 μg/d compared
with less than 200 μg/d was 0.55 (95% CI, 0.32-0.94; P for trend = .03), and 0.61 (95% CI, 0.34-1.11; P for trend = .05) in the older cohort. Among women who did
not take folic acid–containing supplements, dietary folate intake of
400 μg/d or more was not significantly associated with risk of hypertension.
Conclusion Higher total folate intake was associated with a decreased risk of incident
hypertension, particularly in younger women.
Hypertension affects an estimated 65 million individuals in the United
States and many more worldwide.1,2 Because
the risk of hypertension increases with age, the prevalence is growing along
with the aging population. Hypertension is a potent independent risk factor
for cardiovascular disease3- 6 and
renal failure.7- 9 Therefore,
identifying risk factors for hypertension could lead to specific preventive
interventions that may favorably affect public health.
Folate may have beneficial effects on blood pressure by increasing nitric
oxide synthesis in endothelial cells,10,11 or
by reducing plasma homocysteine, which itself can cause endothelial cell injury.12- 16 Oral
folic acid supplementation improves endothelial function in vivo.17,18 Although there are no published studies
on the association between folate intake and risk of incident hypertension,
2 small randomized trials have demonstrated that high-dose folic acid supplementation
may lower systolic and diastolic blood pressure.19,20 Taken
together, these data suggest that a higher intake of folate may reduce an
individual’s risk of hypertension. We prospectively examined the association
between folate intake and risk of incident hypertension in 2 large studies
of younger and older women who were followed up for 8 years.
The younger cohort (Nurses’ Health Study II [NHS II]) was assembled
in 1989 when 116 671 female registered nurses aged 25 to 42 years returned
an initial questionnaire.21 The older cohort
(Nurses’ Health Study I, [NHS I]) was assembled in 1976 when 121 700
female nurses aged 30 to 55 years returned a mailed questionnaire.22 Subsequent questionnaires have been mailed every
2 years to update information on health-related behavior and medical events.
Detailed dietary information was collected every 4 years using a semiquantitative
food frequency questionnaire.23 The assembly
of the 2 populations for the purpose of this study is outlined in Figure 1. Each cohort was followed up for 8 years
(1991 to 1999 in NHS II and 1990 to 1998 in NHS I). The institutional review
board at Brigham and Women’s Hospital reviewed and approved this study,
including that participants provided implied consent by virtue of returning
The semiquantitative food frequency questionnaire asks about commonly
used portion sizes of various foods and prompts participants to record frequency
of consumption during the previous year, with 9 possible response categories
ranging from less than once per month to 6 or more times per day; this questionnaire
has been validated in these as well as several other cohorts.23 Nutrient
intakes were calculated by multiplying the frequency of consumption by the
nutrient content of the specified portion. Nutrient contents of food were
obtained from the Harvard University food consumption database, which was
derived from US Department of Agriculture sources, manufacturers, and published
reports. Information on folate-containing supplements was also collected.
The validity of the food frequency questionnaire for measurement of folate
intake has been previously demonstrated; the deattenuated correlation between
the questionnaire and 4 one-week dietary records was 0.77 for total folate
intake,24 and the correlation between the questionnaire
and measured serum folate was 0.63.23 Values
for total folate intake (food source plus supplement source), food source
folate, and supplemental folic acid were derived. Participants returned food
frequency questionnaires every 4 years during the period of follow-up (1991
and 1995 in NHS II and 1990 and 1994 in NHS I), and total folate intake was
updated after 4 years. Because dietary information in both cohorts was collected
prior to 1998, data on the folate content of foods reflected values before
mandated fortification of the nation’s food supply.
Age, body mass index (BMI; calculated as weight in kilograms divided
by height in meters squared), smoking status, and physical activity (metabolic
equivalent tasks) were ascertained on the 1991 (NHS II) and 1990 (NHS I) questionnaires
and updated after 4 years. Self-reported weight and physical activity have
been validated in these cohorts by direct weight measurement (r, 0.97) and activity diaries (r, 0.79). Intakes
of alcohol, caffeine, sodium, potassium, magnesium, calcium, protein, fiber,
methionine, vitamin B6, vitamin B12, and vitamin D were
ascertained and updated from the food frequency questionnaires. For these
dietary covariates, prior validation studies have shown correlations with
dietary records ranging from 0.56 for vitamin B12 to 0.90 for alcohol
intake. Detailed information on analgesic use was available in NHS II from
the 1995 questionnaire and in NHS I from the 1990 questionnaire. Information
on the use of oral contraceptives was obtained in NHS II from questionnaires
in 1991 and 1995. Information on family history of hypertension was available
on the 1989 (NHS II) and 1992 (NHS I) questionnaires. Participants reported
their blood pressure in 1989 (NHS II) and 1990 (NHS I) in 1 of 9 systolic
categories (<105 mm Hg, 105-114 mm Hg, 115-124 mm Hg, 125-134 mm Hg, 135-144
mm Hg, 145-154 mm Hg, 155-164 mm Hg, 165-174 mm Hg, and ≥175 mm Hg) and
in 1 of 7 diastolic categories (<65 mm Hg, 65-74 mm Hg, 75-84 mm Hg, 85-89
mm Hg, 90-94 mm Hg, 95-104 mm Hg, and ≥105 mm Hg). A participant’s
blood pressure was defined as the middle systolic and middle diastolic values
of the reported categories. Participants self-classified their race; classification
options were defined by the investigators.
The baseline and follow-up biennial questionnaires asked participants
to report whether a clinician had made a new diagnosis of hypertension during
the preceding 2 years, and were also asked whether they had undergone a physical
examination or screening examination. Self-reported hypertension was shown
to be highly reliable in the NHS I cohort. In a subset of women who reported
hypertension, medical record review confirmed a documented systolic and diastolic
blood pressure higher than 140 and 90 mm Hg, respectively, in 100% and higher
than 160 mm Hg and 95 mm Hg in 77%; additionally, self-reported hypertension
was predictive of subsequent cardiovascular events.25 A
participant was considered to have prevalent hypertension if she reported
this diagnosis on any questionnaire up to and including the 1991 (NHS II)
or 1990 (NHS I) questionnaires. Women with prevalent hypertension were excluded.
Cases included individuals who first reported hypertension on subsequent questionnaires
and whose year of diagnosis was after the return of the 1991 or 1990 questionnaires.
Total folate intake was categorized as less than 200 μg/d, 200 to
399 μg/d, 400 to 599 μg/d, 600 to 799 μg/d, 800 to 999 μg/d, and
1000 μg/d or more. Supplemental folic acid use was analyzed by categorizing
total folate intake as less than 200 μg/d, 200 to 399 μg/d, 400 to 599 μg/d,
600 to 799 μg/d, and 800 μg/d or more among those participants with
very low dietary folate intake (<200 μg/d). Dietary folate intake among
those who did not take folic acid–containing supplements was divided
into categories of less than 200 μg/d, 200 to 399 μg/d, and 400 μg/d
or more. In all analyses, the reference group was the lowest intake category.
Folate intake, as well as other dietary variables, was adjusted for total
For each participant, person-months of follow-up were counted from the
date of return of the first questionnaire to the date of return of the last
questionnaire and allocated according to exposure status. Person-time was
truncated when an event occurred. Women were censored at the date of death;
or, if they did not return a subsequent questionnaire, they were censored
at the date the subsequent questionnaire was mailed. Women who did not provide
dietary information at baseline (1991 or 1990) were analyzed during the last
4-year period if they provided dietary information in 1995 or 1994. Incidence
rates were computed by dividing the number of new cases of hypertension by
the number of person-years in the particular category of folate intake.
Multivariable relative risks (RRs) were calculated using Cox proportional
hazards regression and folate intake and other covariates were updated after
4 years. To adjust for potential confounding factors, multivariable models
were adjusted for variables that have been previously associated with incident
hypertension or that may affect the plasma homocysteine level (age [continuous],
BMI [6 categories], smoking status [past, current, never], physical activity
[quintiles], alcohol intake [6 categories], family history of hypertension
[yes/no], oral contraceptive use [NHS II only, yes/no], and intakes of sodium,
potassium, magnesium, calcium, protein, caffeine, fiber, methionine, vitamin
B6, vitamin B12, and vitamin D [quintiles]). We also
controlled for baseline systolic and diastolic blood pressure. Secondary analyses
additionally considered adjustment for race (5 categories); frequency of use
of aspirin, other nonsteroidal anti-inflammatory drugs, and acetaminophen
(days per month); and intakes of cholesterol, saturated fat, polyunsaturated
fat, vitamin C, beta carotene, and vegetable and animal protein separately
(quintiles).26- 28 To
address the possibility of residual confounding, we analyzed models with BMI
and physical activity as continuous variables. Multivariable tests for linear
trend were assessed using the median of each exposure category.
We also investigated whether age, BMI, or alcohol consumption modified
the relationship between folate intake and risk of hypertension. These analyses
were performed by creating interaction terms based on total folate intake
and age (≤35 years, 36-40 years, and >40 years in NHS II and <50 years,
50-60 years, and >60 years in NHS I), BMI (≥25 or <25), or alcohol consumption
(no alcohol vs any alcohol). The P value for interaction
was computed from the log likelihood ratio test comparing models with and
without the interaction terms.
For all RRs, we calculated 95% confidence intervals (CIs). All P values are 2-tailed. Statistical tests were performed
using SAS statistical software (version 8.2, SAS Institute Inc, Cary, NC).
During 646 167 person-years of follow-up, 7373 participants in
the younger cohort (NHS II) reported having hypertension (11.4 cases per 1000
person-years). At baseline, the cohort mean age was 36.0 years (median, 36.0
years; interquartile range [IQR], 33.0-40.0 years) and the mean BMI was 24.3
(median, 23.0; IQR, 21.0-26.2). Table 1 shows
baseline characteristics of women stratified by category of total folate intake
who were in the NHS II cohort in 1991. With increasing folate intake, we observed
lower BMIs and less cigarette, alcohol, and caffeine use. Higher folate intake
was also coupled with increased physical activity and higher consumption of
vitamin B6, vitamin B12, vitamin D, potassium, calcium,
magnesium, and fiber.
During 321 822 person-years of follow-up in NHS I, 12 347
participants reported incident hypertension (38.4 cases/1000 person-years).
At baseline, the mean age of the cohort was 55.4 years (median, 55.0 years;
IQR, 49.0-62.0 years) and the mean BMI was 24.9 (median, 24.0; IQR, 21.9-26.8).
Baseline characteristics of the cohort by category of total folate intake
in 1990 appear in Table 2. Similar relationships
between folate category and the covariates were noted as in the younger cohort.
In the younger NHS II cohort, total folate intake was associated with
a decreased risk of hypertension (Table 3).
Women who consumed 1000 μg/d or more of total folate had a significant
46% reduction in the risk of incident hypertension after adjusting for multiple
confounders (multivariable RR, 0.54 [95% CI, 0.45-0.66]; P for trend <.001) compared with women who consumed less than 200 μg/d.
Younger women’s absolute risk reduction was approximately 8 per 1000
person-years (6.7 vs 14.8 cases). In the cohort of older women (NHS I), higher
total folate consumption was also associated with a decreased risk of incident
hypertension (Table 3).
Compared with women who consumed less than 200 μg/d of folate, those whose
average daily intake was 1000 μg or more had a multivariable RR of 0.82
(95% CI, 0.69-0.97; P for trend = .05).
Older women’s absolute risk reduction was approximately 6 cases per
1000 person-years (34.7 vs 40.4 cases). We also adjusted for baseline systolic
and diastolic blood pressure reported by participants in 1989 (NHS II) and
1990 (NHS I), and the results were not substantially altered. For example,
comparing women whose intake was 1000 μg/d or more with those whose intake
was less than 200 μg/d, the multivariable RR was 0.58 (95% CI, 0.47-0.70)
in younger women and 0.84 (95% CI, 0.70-1.00) in older women. After we controlled
for BMI and physical activity as continuous variables, the results did not
materially change. Furthermore, when analgesic use and race were included
in the multivariable models (<4% of the NHS II cohort and <2% of the
NHS I cohort indicated they were either black, Hispanic, or Asian), the results
were not substantially altered. When we additionally controlled for cholesterol,
saturated fat, polyunsaturated fat, vitamin C, beta carotene, and separate
variables for vegetable and animal protein, the results were essentially unchanged
(results available on request).
Because the US recommended daily allowance for folate is 400 μg,
we examined whether higher folate intake was still associated with a decreased
risk of hypertension when the upper limit of the reference category was changed
to the recommended daily allowance. Compared with younger women whose total
daily folate intake was less than 400 μg, those who consumed 1000 μg/d
or more of folate had a significant 40% reduction in the risk of incident
hypertension (multivariable RR, 0.60; 95% CI, 0.51-0.71). In the older cohort,
those who consumed 1000 μg/d or more had a multivariable RR of hypertension
of 0.87 (95% CI, 0.75-1.01) compared with participants whose intake was less
than 400 μg/d.
Finally, because a clinician’s diagnosis of hypertension would
require an office visit during the 8-year period of follow-up, the analyses
were repeated after limiting the populations to those who had at least 1 physical
or screening examination during the study period (88 795 women in NHS
II and 59 465 women in NHS I). Women who had at least 1 examination during
follow-up had slightly higher mean total folate intakes (483 vs 439 μg/d
in younger women and 430 vs 411 μg/d in older women; P<.001 for both comparisons). In these restricted populations, the
multivariable RR for incident hypertension comparing women who consumed 1000 μg/d
or more compared with less than 200 μg/d was 0.53 (95% CI, 0.43-0.65) in
the younger cohort and 0.82 (95% CI, 0.69-0.97) in the older cohort.
We examined the association between supplemental folic acid and the
risk of incident hypertension by restricting the populations to those women
whose dietary folate consumption was less than 200 μg/d. In this limited
population, women in the highest total folate categories derived most of their
folate from vitamin supplements.
Among younger women whose dietary folate intake was less than 200 μg/d
(n = 14 249), a total folate intake of 800 μg/d or more
compared with less than 200 μg/d was associated with a multivariable RR
for hypertension of 0.55 (95% CI, 0.32-0.94; P for
trend = .03; Table 4). In
older women whose dietary folate intake was less than 200 μg/d (n = 9007),
the same comparison resulted in a nonsignificant 39% decrease in risk of hypertension
(multivariable RR, 0.61 [95% CI, 0.34-1.11]; P for
trend = .05; Table 4).
Finally, we did not find an independent association between multivitamin
use and risk of hypertension in NHS II (multivariable RR, 1.02; 95% CI, 0.98-1.07)
or in NHS I (multivariable RR, 1.03; 95% CI, 0.99-1.07) compared with women
who did not take multivitamins.
We investigated the association of dietary folate intake with risk of
incident hypertension by restricting our cohorts to those who did not report
taking any folic acid–containing supplements (60 441 women in NHS
II and 38 387 women in NHS I). Because the number of women who consumed
at least 600 μg/d of dietary folate was too small to obtain stable estimates,
we analyzed dietary folate in 3 categories with intake of at least 400 μg/d
as the highest category. In NHS II, the multivariable RR for women who did
not take folic acid–containing supplements and who consumed at least
400 μg/d of dietary folate compared with women whose dietary folate intake
was less than 200 μg/d was 0.87 (95% CI, 0.74-1.03; P for trend = .15; Table 5).
In the cohort of older women, the same comparison was also not significant
(multivariable RR, 0.96 [95% CI, 0.85-1.10]; P for
trend = .60; Table 5).
Although the federal mandate for fortification of the US food supply
with folic acid took effect in 1998, many manufacturers began fortification
in 1996 and 1997 in anticipation of this mandate.12 In
our analyses, we classified participants’ dietary folate intake in 1991
and 1995 (NHS II), and in 1990 and 1994 (NHS I). We suspected that participants’
actual dietary folate intake likely increased in 1996 or 1997 due to fortification.
We therefore repeated our analyses for each 4-year period. In younger women,
the RR of hypertension in the highest compared with lowest category of total
folate intake was 0.48 (95% CI, 0.36-0.64; P for
trend <.001) from 1991 to 1995 and 0.65 (95% CI, 0.50-0.85; P for trend = .02) from 1995 to 1999. This same comparison
in older women yielded RRs of 0.68 (95% CI, 0.52-0.89; P for trend = .01) from 1990 to 1994 and 0.93 (95% CI, 0.74-1.16; P for trend = .52) from 1994 to 1998.
We investigated whether the association between folate intake and the
risk of incident hypertension varied by age, BMI, or alcohol intake. The magnitude
of the inverse association was greater among participants in NHS II who were
35 years or younger and aged 36 to 40 years than in participants who were
older than 40 years (P for interaction = .01; Figure 2A). The interaction between folate intake
and age in NHS I (in which approximately 75% of the cohort were ≥50 y)
was not significant (P for interaction = .49; Figure 2B). When we stratified the younger cohort
into those with normal BMI (<25) and those with elevated BMI (≥25),
the inverse association between folate intake and incident hypertension was
greater in women with normal BMI compared with women with elevated BMI (P for interaction <.001; Figure 2C). We found no interaction between folate
intake and BMI among older women (P for interaction = .51; Figure 2D). The relationship between folate and
hypertension was not significantly modified by alcohol consumption (P for interaction = .09 in NHS II and P for interaction = .11 in NHS I).
Higher total folate intake was significantly associated with a reduced
risk of incident hypertension even after controlling for a large number of
covariates including dietary intake, physical activity, BMI, and family history.
The magnitude of the association was greater in younger women. Although plausible
biological mechanisms exist that would predict an inverse association between
folate and hypertension, to our knowledge this is the first prospective study
to report an association between folate intake and the risk of incident hypertension.
Many clinical studies have demonstrated that supplemental folic acid
improves endothelial function in vivo.17,18,29- 31 In
addition, 2 small randomized trials have shown reductions in blood pressure
with folic acid supplementation. In the first study, 130 participants were
randomized to high-dose folic acid (5 mg/d) and pyridoxine (250 mg/d) or placebo
and followed up for 2 years or less.19 Significant
decrements in systolic blood pressure (by 3.7 mm Hg) and diastolic blood pressure
(by 1.9 mm Hg) were noted with supplementation but not with placebo.19 The participants in this trial were relatively young
(mean age, 45 years) and only 12% had a history of hypertension at baseline.
Because vitamin B6 was coadministered to the treatment group, the
effect seen could not be completely ascribed to folate intake, and the authors
concluded that a reduction in homocysteine accounted for the decrease in blood
pressure. However, a recent prospective cohort study did not find an association
between baseline level of homocysteine and subsequent risk of hypertension.32 Other data indicate that folic acid improves endothelial
function in the acute setting before any change in plasma homocysteine.17,18 In the second small randomized trial,
24 long-term smokers with endothelial dysfunction were randomized to 5 mg/d
of folic acid or placebo for 4 weeks. Not only did endothelial function improve
after treatment with folic acid but the mean systolic and diastolic blood
pressure decreased significantly from 121 mm Hg and 71 mm Hg, respectively,
to 113 mm Hg and 67 mm Hg; no change in blood pressure was noted in the placebo
group.20 As in the other trial, the participants
were young (mean age, 38 years) and none had a history of hypertension at
Although there are no previous reports that higher folate intake is
associated with reduced risk of incident hypertension, diets that are high
in folate are associated with improvements in blood pressure. Margetts et
al33 showed that a vegetarian diet reduced
systolic blood pressure by 5 mm Hg in participants with mild hypertension.
Higher intakes of calcium, magnesium, potassium, and fiber have been associated
with decreased risk of hypertension in observational studies,34,35 and
both observational and randomized trials suggest that a diet high in fruits
and vegetables lowers blood pressure.36,37 These
foods are also high in folate. Notably, trials in which individual supplements
of calcium, magnesium, potassium, or fiber were administered have not uniformly
supported these associations, suggesting that some other active ingredient
in food or a combination of nutrients may be necessary to reduce blood pressure.38- 43
In our cohorts of 93 803 younger women and 62 260 older women
followed up for 8 years, total folate intake remained significantly associated
with a decreased risk of hypertension after controlling for dietary factors
such as intakes of calcium, magnesium, potassium, and fiber, as well as other
covariates. This inverse association was robust even after changing the upper
limit of the reference group from 200 μg/d to 400 μg/d, which is the
target fortification level.44
Total folate intake is a combination of both food source (dietary) folate
andsupplemental folic acid. We observed a statistically significant association
between supplemental folic acid and a reduction in the risk of hypertension;
however, the relationship between dietary folate and hypertension was not
significant. Several explanations may account for these findings. First, the
range of dietary folate intake was limited and relatively few participants
consumed very high quantities of dietary folate. The larger variability when
supplements were analyzed allowed us to examine higher consumption of folate
(eg, ≥800 μg/d)—lower dietary folate intake limited the contrast
between the highest and lowest categories. Furthermore, an association between
folate and hypertension may not be linear, thus precluding any inferences
from being drawn when the variability of intake is so limited. A second explanation
may stem from the increased bioavailability of supplemental folic acid, which
has twice the bioavailability as naturally occurring folate from foods.45 Finally, ongoing supplementation of the food supply
during 1996 and 1997 may have led to misclassification of dietary folate intake
during the second half of the 8-year follow-up period. Some participants classified
into the reference group of less than 200 μg/d in 1995 or 1994 may well
have changed groups during the latter part of the last 4 years of follow-up.
This type of misclassification would tend to obscure any association. Indeed,
the magnitude of the inverse association between total folate intake and incident
hypertension was greater during the first than the second 4 years of follow-up.
The magnitude of the inverse association between folate intake and hypertension
was more pronounced in younger compared with older women. Similar observations
have been made in these cohorts when other exposures, such as the association
between nonnarcotic analgesic use and hypertension, have been examined.46,47 Participant age significantly modified
the association between folate intake and incident hypertension, with the
greatest reduction in those younger than 35 years for whom consumption of
at least 1000 μg/d of total folate was associated with one third the risk
of developing hypertension compared with those consuming less than 200 μg/d.
We observed a similarly pronounced reduction in the risk of hypertension among
younger women with a BMI of less than 25. Although the mechanisms for these
associations are unclear, we speculate that differences in the pathogenesis
of hypertension in younger compared with older and leaner compared with heavier
individuals may explain differences in folate sensitivity.
Our study has limitations and strengths that deserve mention. First,
current figures from the Framingham Offspring Study estimate that after US
fortification was completed in 1998, folic acid intake increased by an average
of 190 μg/d.48 Therefore, in the United
States today, there are probably few persons whose total folate intake falls
below 200 μg/d. Nevertheless, we still observed a decreased risk of hypertension
among women with high total folate intake compared with those who consumed
less than 400 μg/d. Second, we did not directly measure the participants’
blood pressure, and the diagnosis of hypertension was self-reported. However,
self-reported hypertension is highly reliable in these cohorts of health professionals.25 Third, we do not have information on which women
had blood pressure measurements during the follow-up period. Despite this,
when we limited our analysis to women who reported having physical or screening
examinations during the follow-up period, increasing the likelihood that their
blood pressure was measured, our findings were not altered. In addition, the
mean total folate intake was slightly higher among women who had physical
or screening examinations (483 vs 439 μg/d in younger women and 430 vs
411 μg/d in older women; P<.001 for both comparisons).
Thus, if women who visited their clinicians were more likely to be diagnosed
as having hypertension, then this difference in folate intake would have attenuated
our results. Fourth, we did not measure serum folate levels, raising the potential
for misclassification. Nevertheless, ascertainment of folate consumption from
our questionnaires has been validated in the past and correlates well with
dietary records and serum folate levels.23,24 Finally,
the possibility for residual confounding in any observational study cannot
be fully eliminated; however, we were able to adjust for multiple known and
suspected risk factors for hypertension, and we observed little difference
between the age-adjusted and multivariable models.
In conclusion, higher intake of folate is associated with a decreased
risk of incident hypertension, especially in younger women. Supplemental folic
acid appears to be independently associated with a reduction in risk, and
future trials should examine folic acid supplementation as a means of lowering
blood pressure and preventing hypertension in young women. These results may
have important public health implications in the United States, given the
ready availability and safety of folic acid supplementation and the clinical
importance of hypertension.
Corresponding Author: John P. Forman, MD,
Channing Laboratory Third Floor, 181 Longwood Ave, Boston, MA 02115 (firstname.lastname@example.org).
Author Contributions: Dr Forman had full access
to all of the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analysis.
Study concept and design: Forman, Curhan.
Acquisition of data: Stampfer, Curhan.
Analysis and interpretation of data: Forman,
Rimm, Stampfer, Curhan.
Drafting of the manuscript: Forman.
Critical revision of the manuscript for important
intellectual content: Forman, Rimm, Stampfer, Curhan.
Statistical analysis: Forman, Stampfer, Curhan.
Obtained funding: Forman, Curhan.
Administrative, technical, or material support:
Forman, Stampfer, Curhan.
Study supervision: Rimm, Curhan.
Financial Disclosure: The Nurses’ Health
Studies have received modest resources from the Alcoholic Beverage Medical
Research Foundation, the American Cancer Society, Amgen, the California Prune
Board, the US Centers for Disease Control and Prevention, the Ellison Medical
Foundation, the Florida Citrus Growers, the California Strawberry Commission,
the Glaucoma Medical Research Foundation, Hoffman-La Roche, Kellogg’s,
Lederle, the Massachusetts Department of Public Health, Mission Pharmacal,
the National Dairy Council, Rhone Poulenc Rorer, the Robert Wood Johnson Foundation,
Roche, GlaxoSmithKline, Ortho-McNeil, Sandoz, the US Department of Defense,
the US Department of Agriculture, the Wallace Genetics Fund, Wyeth-Ayerst,
Merck, Genzyme, TAP Pharmaceutical, Esai and Janssen Pharmaceutica, and private
Funding/Support: This study was funded by National
Institutes of Health grants HL78093, DK07791, DK52866, CA87969, and CA050385.
Role of the Sponsor: The National Institutes
of Health had no role in the collection, management, analysis, or intrepretation
of the data and had no role in the preparation, review, or approval of the