Association between dietary vitamin C intake and migraine in adults: A cross-sectional study of the National Health and Nutrition Examination Survey

doi:10.21203/rs.3.rs-3995906/v1

Objective:This study aim to evaluate the association between dietary vitamin C intake and the risk of migraine in adult individuals.

Methods: This cross-sectional study utilized data from the National Health and Nutrition Examination Survey (NHANES) conducted between 1999 and 2004. Logistic regression models, restricted cubic spline (RCS) regression, and stratified analyses were employed to assess the association between dietary vitamin C intake and migraine.

Results: This study included 4101 participants, of whom 702 (17.12%) experienced migraine. The study revealed an inverse association between dietary vitamin C intake and migraine risk (OR=0.89, 95% CI: 0.83-0.96, P=0.002) after adjusting for all covariates. When vitamin C intake was categorized, the adjusted OR (95% CI) for migraine risk in Q 4 (highest vitamin C intake ) was 0.64 (95% CI: 0.49-0.84, P=0.001) compared with Q1 (lowest vitamin C intake). The RCS regression showed a linear inverse relationship between dietary vitamin C intake and migraine risk (P for non-linearity=0.449). The findings remained consistent, and no significant interactions were found among different groups.

Conclusion: Dietary vitamin C intake was independently associated with migraine, and a linear negative relationship was found betweenvitamin C intake and the risk of migraine.

vitamin C

migraine

logistic regression

restricted cubic spline regression

cross-sectional study

Migraine, a common neurovascular disease, is associated with severe headache, emotional disorders (e.g., anxiety and depression), and nervous system dysfunction (e.g., nausea, vomiting, photophobia, and phonophobia) [1, 2]. It is estimated that migraine affects 15–18% of the worldwide population, resulting in a significant burden on individuals, families, health care systems, and societies [3]. Multiple factors, including genetics, environment, behavior, and nutrition, play a role in the development of migraines [4]. Previous studies have highlighted the potential of certain dietary nutrients to effectively alleviate migraine episodes [5, 6]. Vitamin C, as an antioxidant, can effectively reduce the risk of complex regional pain syndrome (CRPS) and can also be used as a preventive measure against migraines [7]. In a randomized sham-controlled pilot study, vitamin C combined with N-acetylcysteine and vitamin E reduced headaches and migraines in adult migraineurs [8]. In addition, based on an uncontrolled preliminary study, the combination of pine bark extract, vitamin C, and vitamin E may have potential benefits in reducing the frequency and severity of migraines [9]. However, the evidence of the relationship between dietary vitamin C intake and the prevalence of migraine is limited, necessitating further studies to validate this association. Therefore, we conducted a cross-sectional study to evaluate the association between dietary vitamin C intake and the risk of migraine in adults based on the National Health and Nutrition Examination Survey (NHANES).

Study population

This cross-sectional study was conducted using the NHANES data from 1999 to 2004. These cycles were included in this study due to the availability of questionnaire data related to migraine or severe headache. We excluded individuals under 20 years old, pregnant females, and those with missing data on migraine (or severe headache), dietary vitamin C intake, or covariates from the study. The NHANES project received approval from the Institutional Review Board of the National Center for Health Statistics, and participants provided informed consent. Thus, no further Institutional Review Board approval was required for this secondary analysis.

Migraine classification

Information on headache was obtained form the questionnaire data. Migraine was identified from the selfreport question “did you experience severe headache or migraines during the past 3 months?” Those who answered “yes” were categorized as having migraines.

Dietary vitamin C intake

Dietary vitamin C intake data were gathered using a 24-hour dietary recall method performed by trained interviewers. This survey collects detailed information on all food and drink consumed within a 24-hour period, serving as a retrospective assessment of dietary intake. The Food Intake Analysis System (FIAS) and United States Department of Agriculture (USDA) survey nutrient database were used to encode and convert dietary data into total nutrient intake. Participants were categorized into four groups based on their vitamin C intake.

Covariates

In this study, demographic covariates, lifestyle covariates, laboratory tests and physical examinations, physical activity, dietary covariates, and comorbidities were assessed based on previous studies and clinical practice. Demographic covariates included age, gender, race/ethnicity, marital status, family income, and education level. Lifestyle covariates comprised smoking status and drinking status. Laboratory tests and physical examinations focused on C-reactive protein (CRP) and body mass index (BMI). Physical activity was evaluated as well. Dietary covariates encompassed energy, proteins, carbohydrates, and fat. Lastly, comorbidities included diabetes, hypertension, hypercholesterolemia, stroke, and coronary heart disease. Variables description and coding were shown in Supplementary Table 1.

Statistical analysis

All statistical analyses were conducted using the statistical software package R, version 3.4.3, and Free Statistics software, version 1.8. A two-sided P-value < 0.05 was considered as statistically significant. Continuous variables were represented by mean and standard deviation (SD) for normal distributions, or median and interquartile range (IQR) for skewed distributions. Categorical variables were described as counts and frequencies. The chi-square test compared categorical variables, the one-way ANOVA compared variables with normal distributions, and the Kruskal-Wallis test compared variables with skewed distributions. The multivariable logistic regression was applied to explore the association between vitamin C intake intake and migraine by calculating the odds ratio (OR) and 95% confidence interval (CI). Additionally, restricted cubic spline (RCS) regression was employed to assess the dose-response relationship between dietary vitamin C intake and migraine. Furthermore, Stratified analyses were performed according to gender, age (< 60 years versus ≥ 60 years), family income, marital status, drinking status, and smoking status. Interactions test across subgroups were evaluated using likelihood ratio test.

Basic characteristics of participants

Out of the NHANES 1999-2004 data, a total of 31,126 participants were obtained. Exclusions were made for 27,025 participants who were pregnant (968), participants aged below 20 years (15,659), and participants with missing data (10,398). Consequently, the present study encompassed 4,101 participants. The exclusion process was detailed in Figure 1. In the study, a total of 4,101 participants were included, among whom 702 (17.12%) reported experiencing migraine. The mean age of the participants was 52.98 ± 16.92, with 2,127 (51.87%) of them being men. It was observed that individuals who were men, younger, other race, better educated, married, had higher income, non-drinkers, and never smokers, tended to consume higher amounts of vitamin C. The basic characteristics of the participants were listed in Table 1.

Table 1 Basic characteristics of the included participants

Variables	ln (vitamin C intake), mg					P-value
Variables	Total	Q1 (<3.424 )	Q2 (3.424-4.267 )	Q3 (4.268-4.932)	Q4 (>4.932)	P-value
No.	4101	1023	1027	1025	1026
Gender, n (%)						< 0.001
Male	2127 (51.87)	512 (50.05)	507 (49.37)	520 (50.73)	588 (57.31)
Female	1974 (48.13)	511 (49.95)	520 (50.63)	505 (49.27)	438 (42.69)
Age, Mean ± SD	52.98 ± 16.92	50.37 ± 16.57	52.55 ± 16.51	55.57 ± 17.25	53.41 ± 16.96	< 0.001
Race, n (%)						0.314
Mexican American	601 (14.65)	152 (14.86)	150 (14.61)	145 (14.15)	154 (15.01)
Other Hispanic	143 ( 3.49)	31 (3.03)	42 (4.09)	33 (3.22)	37 (3.61)
Non-Hispanic white	2608 (63.59)	639 (62.46)	663 (64.56)	664 (64.78)	642 (62.57)
Non-Hispanic black	606 (14.78)	173 (16.91)	141 (13.73)	147 (14.34)	145 (14.13)
Other race	143 ( 3.49)	28 (2.74)	31 (3.02)	36 (3.51)	48 (4.68)
Education, n (%)						< 0.001
Less than high school	711 (17.34)	223 (21.8)	169 (16.46)	171 (16.68)	148 (14.42)
High school diploma	906 (22.09)	261 (25.51)	205 (19.96)	241 (23.51)	199 (19.4)
More than high school	2484 (60.57)	539 (52.69)	653 (63.58)	613 (59.8)	679 (66.18)
Marital status, n (%)						0.034
Married	2649 (64.59)	621 (60.7)	673 (65.53)	694 (67.71)	661 (64.42)
Living with a partner	1279 (31.19)	348 (34.02)	312 (30.38)	298 (29.07)	321 (31.29)
Living alone	173 ( 4.22)	54 (5.28)	42 (4.09)	33 (3.22)	44 (4.29)
Family income, n (%)						< 0.001
Low (PIR ≤ 1.3)	648 (15.80)	203 (19.84)	164 (15.97)	141 (13.76)	140 (13.65)
Medium (PIR > 1.3 to 3.5)	1445 (35.24)	381 (37.24)	349 (33.98)	388 (37.85)	327 (31.87)
High (PIR > 3.5)	2008 (48.96)	439 (42.91)	514 (50.05)	496 (48.39)	559 (54.48)
BMI, Mean ± SD	28.26 ± 5.94	28.58 ± 6.07	28.74 ± 6.09	27.95 ± 5.43	27.75 ± 6.08	< 0.001
CRP, Median (IQR)	0.21 (0.08, 0.45)	0.23 (0.10, 0.48)	0.23 (0.09, 0.49)	0.20 (0.08, 0.41)	0.18 (0.07, 0.42)	< 0.001
Diabetes, n (%)						0.04
No	3686 (89.88)	917 (89.64)	923 (89.87)	903 (88.1)	943 (91.91)
Yes	415 (10.12)	106 (10.36)	104 (10.13)	122 (11.9)	83 (8.09)
Migraine, n (%)						< 0.001
No	3399 (82.88)	805 (78.69)	835 (81.3)	867 (84.59)	892 (86.94)
Yes	702 (17.12)	218 (21.31)	192 (18.7)	158 (15.41)	134 (13.06)
Physical activity, n (%)						0.841
Moderate activities	3434 (83.74)	852 (83.28)	854 (83.15)	865 (84.39)	863 (84.11)
Vigorous activities	667 (16.26)	171 (16.72)	173 (16.85)	160 (15.61)	163 (15.89)
Drinking status, n (%)						0.937
Non-drinker	1123 (27.38)	274 (26.78)	288 (28.04)	281 (27.41)	280 (27.29)
Drinker	2978 (72.62)	749 (73.22)	739 (71.96)	744 (72.59)	746 (72.71)
Smoking status, n (%)						< 0.001
Never smokers	2156 (52.57)	475 (46.43)	533 (51.9)	561 (54.73)	587 (57.21)
Current smokers	627 (15.29)	250 (24.44)	157 (15.29)	107 (10.44)	113 (11.01)
Former smokers	1318 (32.14)	298 (29.13)	337 (32.81)	357 (34.83)	326 (31.77)
Coronary heart disease, n (%)						0.099
No	3855 (94.00)	976 (95.41)	953 (92.79)	962 (93.85)	964 (93.96)
Yes	246 ( 6.00)	47 (4.59)	74 (7.21)	63 (6.15)	62 (6.04)
Stroke, n (%)						0.405
No	3975 (96.93)	988 (96.58)	991 (96.49)	1001 (97.66)	995 (96.98)
Yes	126 ( 3.07)	35 (3.42)	36 (3.51)	24 (2.34)	31 (3.02)
Hypertension, n (%)						0.405
No	2632 (64.18)	663 (64.81)	655 (63.78)	639 (62.34)	675 (65.79)
Yes	1469 (35.82)	360 (35.19)	372 (36.22)	386 (37.66)	351 (34.21)
Hypercholesterolaemia, n (%)						0.194
No	2470 (60.23)	633 (61.88)	596 (58.03)	607 (59.22)	634 (61.79)
Yes	1631 (39.77)	390 (38.12)	431 (41.97)	418 (40.78)	392 (38.21)
Energy, Mean ± SD	2125.14 ± 994.71	1809.18 ± 817.47	2084.32 ± 967.54	2132.89 ± 960.47	2473.28 ± 1100.06	< 0.001
Protein, Mean ± SD	81.50 ± 40.40	68.53 ± 32.90	79.78 ± 37.92	83.87 ± 39.22	93.80 ± 46.32	< 0.001
Carbohydrate, Mean ± SD	260.68 ± 128.32	210.44 ± 105.75	249.65 ± 119.34	262.22 ± 120.26	320.28 ± 140.75	< 0.001
Fat, Median (IQR)	71.03 (48.42, 102.47)	64.74 (44.44, 91.20)	71.43 (50.49, 101.98)	70.94 (47.36, 103.69)	77.70 (53.01, 111.91)	< 0.001

Abbreviations: PIR, poverty income ratio.

Association between dietary vitamin C intake and migraine

The univariate analysis showed that gender, age, marital status, race/ethnicity, family income, BMI, physical activity, drinking status, smoking status, and coronary heart disease are influential factors associated with the risk of migraine (Table 2). Dietary vitamin C intake was assessed both as continuous and categorical variables using multivariable logistic regression analysis. The study findings indicated a negative association between vitamin C intake and migraine after adjusting for all covariates (OR=0.89, 95%CI: 0.83-0.96, P=0.002). The association remained similar when categorizing vitamin C intake. After adjusting for all covariates, the ORs (95% CI) of Q2, Q3, and Q4 were 0.92 (95% CI: 0.73-1.16, P=0.485), 0.80 (95% CI: 0.63-1.03, P=0.082), and 0.64 (95% CI: 0.49-0.84, P=0.001) compared with Q1 (Table 3). Additionally, the RCS analysis discovered a linear negative relationship between dietary vitamin C intake and the risk of migraine (P for non-linearity=0.449) (Figure 2).

Table 2 Association of covariates and migraine risk

Variable	OR (95%CI)	P-value
Gender, n (%)
Male	1 (Ref)
Female	2.13 (1.80-2.52)	<0.001
Age (year)	0.97 (0.96-0.97)	<0.001
Race/ethnicity, n (%)
Mexican American	1 (Ref)
Other Hispanic	1.26 (0.82-1.95)	0.291
Non-Hispanic White	0.74 (0.59-0.93)	0.010
Non-Hispanic Black	0.95 (0.71-1.26)	0.718
Other Race	1.08 (0.69-1.69)	0.752
Education, n (%)
Less than high school	1 (Ref)
High school diploma	1.00 (0.77-1.28)	0.970
More than high school	0.88 (0.70-1.09)	0.233
Marital status, n (%)
Married	1 (Ref)
Living with a partner	1.08 (0.91-1.29)	0.374
Living alone	1.58 (1.09-2.27)	0.015
PIR, n (%)
Low (PIR ≤ 1.3)	1 (Ref)
Medium (PIR > 1.3 to 3.5)	0.86 (0.68-1.08)	0.188
High (PIR > 3.5)	0.63 (0.50-0.79)	<0.001
BMI (kg/m2)	1.02 (1.01-1.04)	<0.001
CRP (mg/dl)	1.07 (0.98-1.16)	0.140
Diabetes, n (%)
No	1 (Ref)
Yes	0.94 (0.72-1.24)	0.676
Physical activity, n (%)
Moderate activities	1 (Ref)
Vigorous activities	1.30 (1.05-1.6)	0.014
Drinking status, n (%)
No	1 (Ref)
Yes	0.70 (0.59-0.83)	<0.001
Smoking status, n (%)
Never smokers	1 (Ref)
Current smokers	1.19 (0.96-1.49)	0.113
Former smokers	0.62 (0.51-0.75)	<0.001
Coronary heart disease, n (%)
No	1 (Ref)
Yes	0.53 (0.35-0.81)	0.003
Stroke, n (%)
No	1 (Ref)
Yes	1.14 (0.73-1.80)	0.559
Hypertension, n (%)
No	1 (Ref)
Yes	0.94 (0.79-1.11)	0.465
Hypercholesterolaemia, n (%)
No	1 (Ref)
Yes	0.99 (0.84-1.17)	0.920
Energy (kcal)	1.00 (1.00-1.00)	0.389
Protein (g)	1.00 (1.00-1.00)	0.100
Carbohydrate (g)	1.00 (1.00-1.00)	0.731
Fat (g)	1.00 (1.00-1.00)	0.752

Abbreviations: CI, confidence interval; OR, odds ratio.

Table 3 Association between dietary vitamin C intake and the risk of migraine

Dietary vitamin C intake (mg)	Event (%)	Non-adjusted Model		Model 1		Model 2		Model 3
Dietary vitamin C intake (mg)	Event (%)	OR (95%CI)	P-value	OR (95%CI)	P-value	OR (95%CI)	P-value	OR (95%CI)	P-value
ln (vitamin C)	704 (17.1)	0.86 (0.8-0.91)	<0.001	0.90 (0.84-0.96)	0.002	0.90 (0.84-0.97)	0.003	0.89 (0.83-0.96)	0.002
Quartiles, ln (vitamin C)
Q1 (<3.424)	218 (21.3)	1 (Ref)		1 (Ref)		1 (Ref)		1 (Ref)
Q2 (3.424-4.267)	192 (18.7)	0.85 (0.68-1.05)	0.139	0.94 (0.75-1.18)	0.606	0.92 (0.73-1.16)	0.496	0.92 (0.73-1.16)	0.485
Q3 (4.268-4.932)	158 (15.4)	0.67 (0.54-0.84)	0.001	0.81 (0.64-1.02)	0.072	0.82 (0.65-1.04)	0.105	0.80 (0.63-1.03)	0.082
Q4 ( >4.932)	134 (13.1)	0.55 (0.44-0.70)	<0.001	0.66 (0.52-0.84)	0.001	0.67 (0.52-0.85)	0.001	0.64 (0.49-0.84)	0.001
Trend test			<0.001		<0.001		0.001		0.001

Abbreviations: CI, confidence interval; OR, odds ratio; ln (vitamin C), vitamin C intake values were natural logarithmised.

Model 1 was adjusted for demographic characteristics, including age, gender, race/ethnicity, marital status, education level, and family income.

Model 2 was adjusted for smoking status, drinking status, BMI, physical activity, CRP, hypertension, hypercholesterolaemia, stroke, diabetes and coronary heart disease in addition to the variables from model 1.

Model 3 was was fully adjusted, including nutrients (energy, proteins, carbohydrates, and fat) and variables from model 2.

Adjustment factors included age, gender, race/ethnicity, marital status, education level, family income, smoking status, drinking status, BMI, physical activity, CRP, hypertension, hypercholesterolaemia, stroke, diabetes, coronary heart disease, energy, proteins, carbohydrates, and fat.

Stratified and interaction analyses

The results consistently showed a negative relationship between vitamin C intake and the risk of migraine in stratified analyses (Figure 3). There were no significant interactions observed in any of the subgroups (P>0.05).

This cross-sectional study demonstrated a negative relationship between dietary vitamin C intake and the risk of migraine. This association was stable in stratified analyses. Additionally, the RCS regression showed a linear negative relationship between dietary vitamin C intake and the risk of migraine. These findings was consisted with previous research that vitamin C may reduce the prevalence of migraine [8-10]. According to a randomized sham-controlled pilot study and an uncontrolled preliminary study, vitamin C combined with other antioxidants (e.g., vitamin E) can reduce the risk of migraine [8,9]. However, these studies did not analyze the individual impact of vitamin C on migraine. Additionally, they primarily concentrated on a small sample of migraine patients. To evaluate the independent association between vitamin C intake and the risk of migraine in the general population, we conducted a cross-sectional study using the NHANES data.

In our study, 4101 participants were included, of whom 702 (17.12%) reported experiencing migraines. The prevalence of migraines was comparable to that found in the American Migraine Prevalence and Prevention Study (17.4%) [11], suggesting the reliability of our migraine definition. We employed various models to account for different covariates in multivariable logistic regression analyses, and the results were robust among different models. Furthermore, the results remained consistent among different subgroups based on the stratified analyses. The OR for migraine progressively decreased in Q2, Q3, and Q4 compared to Q1, reflecting a statistically significant trend (P=0.001). The RCS regression confirmed this trend, showing a linear negative relationship.

The actual mechanism between vitamin C and migraine remains unclear, but it may be related to the anti-oxidation effects of the vitamin C [7]. Oxidative stress and brain oxygen accumulation contribute significantly to the development of migraine [12,13]. Consequently, vitamin C can effectively lower oxidation levels, safeguarding cells against oxidative stress, and diminishing the frequency and severity of migraine [7-9].

The current study has some limitations as well. First, the dietary data in our study were based on 24-h recalls, which may not represent the usual intake of participants. However, previous studies have demonstrated that 24-hour recalls offer more comprehensive information regarding the type and quantity of food compared to food frequency surveys, and the 24-h dietary recall interview in NHANES has been extensively evaluated [14-16]. Second, despite our effort to control for confounding variables by adjusting several relative covariates, the presence of residual confounding effects from unmeasured or unknown factors cannot be entirely ruled out. Third, the study participants were Americans; thereby, our findings may not be appropriate for generalizing to other populations. Lastly, our study is a cross-sectional study, which cannot establish a causal relationship between dietary vitamin C intake and the risk of migraine. Further studies using a cohort or prospective randomized controlled design will be essential to address this gap.

This study discovered a linear negative association between dietary vitamin C and the risk of migraine. These findings imply that vitamin C may be helpful in decreasing the prevalence of migraine.

Funding

No funding was received.

Availability of data and material

Data are available on the NHANES database.

Declarations

Acknowledgements

Not applicable.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

DZ and XL conceived the study and performed the data analysis. DZ drafted the manuscript. DZ and JW revised the manuscript. All authors have read and approved the final manuscript.

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No competing interests reported.

SupplementaryTable1.docx

Association between dietary vitamin C intake and migraine in adults: A cross-sectional study of the National Health and Nutrition Examination Survey

Status:

Version 1

Abstract

Figures

Introduction

Materials and Methods

Study population

Migraine classification

Dietary vitamin C intake

Covariates

Statistical analysis

Results

Discussion

Conclusion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1