DIFFERENCES IN VITAMIN B12, IRON, AND FOLATE STATUS AMONG WOMEN ACTIVELY TAKING ORAL CONTRACEPTIVES COMPARED TO THOSE NOT TAKING ORAL CONTRACEPTIVES

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1 DIFFERENCES IN VITAMIN B12, IRON, AND FOLATE STATUS AMONG WOMEN ACTIVELY TAKING ORAL CONTRACEPTIVES COMPARED TO THOSE NOT TAKING ORAL CONTRACEPTIVES IN WOMEN AGED 12 YEARS AND OLDER by Stephanie Send NHANES Data

2 BACKGROUND Since 1961, oral contraceptives (OCs) have been the leading form of birth control among premenopausal women 1 In addition to the risks for thromboembolisms and cardiovascular events, many nutrient deficiencies have been found to be associated with OC use 3 Folate, Vitamins B12, B6, B2, C, and E, zinc, magnesium, and selenium The hormone content in OCs has been decreased from original dosages to minimize these risk factors

3 BACKGROUND Many unplanned pregnancies occur while women are actively taking OCs due to skipping pills or inaccurate timing of pills In addition, many women become pregnant soon after discontinuing OC use It is important that women of childbearing age have adequate nutrient stores in order to provide the optimal environment for a developing fetus and reduce the risk for nutrient related birth defects

4 STUDY RATIONALE The literature is limited on the effects of OCs available on the market today in regards to nutrient status Additionally, iron is a nutrient of interest because previous studies has found that OC may have a protective effect on iron stores in premenopausal women 14

5 OBJECTIVES To determine the difference in Vitamin B12, folate, and iron levels in women actively taking oral contraceptives compared to those not taking oral contraceptives in women aged 12 years and older (NHANES ). To determine dietary supplement use in women aged 12 years and older actively taking oral contraceptives and if dietary supplement use has an impact of micronutrient status in this population (NHANES ).

6 METHODS: POPULATION SELECTION Sample: Women 12 years and older from NHANES cycles , , , Excluded those who had missing or incomplete data from the Reproductive Health Questionnaire, laboratory measurements, or dietary supplement information Final sample: 2,468 women " Those actively taking OCs: n=515 " Those not taking OCs: n=1,953

7 POPULATION SELECTION APPENDIXA. TotalSample: NHANESCycles2011C2012,2005C2006,2003C2004,2001C 2002 (n=41,265) & ReproductiveHealth Questionnaire ExcludeifReproductive HealthQuestionnairenot completedormissing data (n=37,711) 2011C2012 (n=888) 2005C2006 (n=922) 2003C2004 (n=833) 2001C2002 (n=911) Total (n=3,554) [Includes women12+ years]

8 LaboratoryandDietary Questionnaires ExcludeifIron,Folate, B12,orSupplementdata missing (n=1,086) 2011C2012 (n=745) 2005C2006 (n=846) 2003C2004 (n=789) 2001C2002 (n=88) Total (n=2,468) Yes,takingbirthcontrolpills (n=515) 38 No,notakingbirthcontrolpills (n=1,953)

9 METHODS: VARIABLES Demographic variables were used in describing the sample Age, BMI, race, education level, marital status, pregnancy status Serum iron (ug/dl), serum Vitamin B12 (pg/ml), and RBC folate (ng/dl) were used in determining micronutrient status Deficiency was defined as being below the reference range Serum iron <30 ug/dl Serum Vitamin B12 <200 pg/ml RBC folate <140 ng/dl

10 METHODS: DATA ANALYSIS Analysis was done using SPSS version 22 Frequencies [n, (%)] used for categorical variables and descriptive statistics (mean+sd) used for continuous variables for demographics Measurements of skew used in determining normality of data Frequencies [n, (%)] were used in determining prevalence of dietary supplement users and micronutrient deficiencies Non-parametric tests were used to determine differences in micronutrient status among groups (Mann Whitney U)

11 Table&1.&Demographics&of&Participants&in&NHANES&2001>2002,&2003>2004,&2005>2006,&2011>2012& (n=2,468)& Variable AllSubjects (n=2,468) Yes,Oral Contraceptives (n=515) No,Oral Contraceptives (n=1,953) Age:(years) mean+sd BMI:(kg/m 2 ) mean+sd n=2, n= n=1, Race:n(%) MexicanAmerican OtherHispanic NonWHispanicWhite NonWHispanicBlack OtherRace/MultiWRacial 402(16.3%) 121(4.9%) 1,164(47.2%) 626(25.4%) 155(6.3%) 77(15.0%) 17(3.3%) 298(57.9%) 94(18.3%) 29(5.6%) 325(16.6%) 104(5.3%) 866(44.3%) 532(27.2%) 126(6.5%) EducationLevel12W19yrs:n(%) (n=309) 6 th Grade 7 th Grade 8 th Grade 9 th Grade 10 th Grade 11 th Grade 12 th Grade,NoDiploma HighSchoolGraduate GEDorEquivalent MorethanHighSchool Lessthan9 th Grade 1(0.0%) 4(0.2%) 14(0.6%) 40(1.6%) 47(1.9%) 57(2.3%) 12(0.5%) 71(2.9%) 6(0.2%) 50(2.0%) 7(0.3%) 0(0.0%) 4(0.8%) 8(1.6%) 15(2.9%) 17(3.3%) 20(3.9%) 3(0.6%) 39(7.6%) 1(0.2%) 26(5.0%) 3(0.9%) 1(0.1%) 0(0.0%) 6(0.3%) 25(1.3%) 30(1.5%) 37(1.9%) 9(0.5%) 32(1.6%) 5(0.3%) 24(1.2%) 4(0.2%) EducationLevel20+yrs:n(%)

12 Table&1.&Demographics&of&Participants&in&NHANES&2001>2002,&2003>2004,&2005>2006,&2011>2012& (n=2,468)& Variable AllSubjects (n=2,468) Age:(years) EducationLevel20+yrs:n(%) mean+sd (n=2,159) BMI:(kg/m Lessthan9 th 2 ) Grade mean+sd Race:n(%) 9W11 th Grade(NoDiploma) MexicanAmerican HighSchoolGraduate/GED OtherHispanic SomeCollegeorAA NonWHispanicWhite CollegeGraduateorAbove NonWHispanicBlack OtherRace/MultiWRacial MaritalStatus:n(%) Married (n=309) Widowed 6Divorced th Grade 7 Separated th Grade 8 NeverMarried th Grade 9 th Grade 10 LivingwithaPartner Grade 11 Refused/Missing th Grade 12 PregnancyStatus:n(%) th Grade,NoDiploma HighSchoolGraduate GEDorEquivalent Pregnant MorethanHighSchool NotPregnant Lessthan9 Uncertain th Grade EducationLevel20+yrs:n(%) Missing EducationLevel12W19yrs:n(%) (n=2,159) Lessthan9 th Grade 9W11 th Grade(NoDiploma) n=2,115 88(3.6%) (10.0%) 402(16.3%) 409(16.6%) 803(32.5%) 121(4.9%) 1,164(47.2%) 611(24.8%) 626(25.4%) 155(6.3%) 1,089(44.0%) 30(1.2%) 218(8.8%) 1(0.0%) 4(0.2%) 100(4.1%) 14(0.6%) 786(31.8%) 40(1.6%) 244(9.9%) 47(1.9%) 57(2.3%) 4(0.1%) 12(0.5%) 36(1.5%) 6(0.2%) 2,210(89.5%) 50(2.0%) 56(2.3%) 7(0.3%) 166(6.7%) 71(2.9%) 88(3.6%) 248(10.0%) Yes,Oral Contraceptives (n=515) n=445 10(1.9%) (4.1%) 52(10.1%) 77(15.0%) 147(28.5%) 17(3.3%) 298(57.9%) 149(28.9%) 94(18.3%) 29(5.6%) 157(30.5%) 2(0.4%) 21(4.1%) 0(0.0%) 4(0.8%) 17(3.3%) 8(1.6%) 262(50.9%) 15(2.9%) 54(10.5%) 17(3.3%) 20(3.9%) 2(0.4%) 3(0.6%) 39(7.6%) 6(1.2%) 1(0.2%) 490(95.1%) 26(5.0%) 5(1.0%) 3(0.9%) 14(2.7%) 10(1.9%) 21(4.1%) No,Oral Contraceptives (n=1,953) n=1,670 78(4.0%) (11.6%) 357(18.3%) 325(16.6%) 656(33.6%) 104(5.3%) 462(23.7%) 866(44.3%) 532(27.2%) 126(6.5%) 929(47.6%) 28(1.4%) 197(10.1%) 1(0.1%) 0(0.0%) 83(4.2%) 6(0.3%) 524(26.8%) 25(1.3%) 190(9.7%) 30(1.5%) 37(1.9%) 2(0.2%) 9(0.5%) 32(1.6%) 30(1.5%) 5(0.3%) 1,720(88.1%) 24(1.2%) 51(2.6%) 4(0.2%) 152(7.8%) 78(4.0%) 227(11.6%)

13 Figure 1. Mann Whitney U analysis indicates a significant difference in serum B12 (pg/ml) between active OC users (mdn 401.0, IQR: ) and non users (mdn 484.0, IQR ), U= , z = -9.92, p < 0.001, r=-.20

14 Figure 2. Mann-Whitney U analysis indicates a significant difference in serum iron between active OC users (mdn 87.0, IQR: ) and non users (mdn 68.0, IQR ), U= , z = -7.90, p < 0.001, r = -.16

15 Figure 3. Mann-Whitney U analysis indicates no significant difference in median RBC folate (ng/ ml) levels between active OC users (mdn 278.0, IQR ) and non users (mdn 289.0, IQR ) (p =0.267).

16 Figure 7. Among OC users, a Mann-Whitney U analysis indicates a significant difference in serum B12 (pg/ml) between dietary supplement users (mdn 421.0, IQR: ) and non users (mdn 367.0, IQR ), U= , z = -3.14, p = 0.002, r = -.06

17 Figure 8. Among OC users, a Mann-Whitney U analysis indicates a significant difference in RBC folate between dietary supplement users in those actively taking OCs (mdn 308.5, IQR: ) and non users (mdn 252.0, IQR ), U= , z = -6.16, p < 0.001, r = -.12

18 Figure 9. Mann-Whitney U analysis indicates no significant difference in median serum iron (ug/dl) levels between dietary supplement users (mdn 84.5, IQR ) and non users (mdn 87.0, IQR ) in those actively taking OCs (p= 0.834).

19 PREVALENCE OF NUTRIENT DEFICIENCIES NUTRIENT OF CONCERN ACTIVE OC USERS (n=515) NON USERS (n=1,953) VITAMIN B12 (<200 pg/ml) FOLATE (<140 ng/ml) IRON (<30 ug/dl) 2.9% 1.5% 2.5% 4.1% 5.2% 9.3%

20 DISCUSSION: Vitamin B12 Women taking OCs have significantly lower serum B12 levels than non users Consistent with findings of both Sutterlin et al in 2003 and Riedel et al in ,12 In addition, Riedel found that MMA and total homecysteine were not significantly different between OC users and non users, indicating that decreased serum levels could be a result of B12 redistribution rather than true deficiency 12 When adjusting for dietary supplement use, those taking dietary supplements had significantly higher serum B12 levels

21 DISCUSSION: Folate There is no significant difference in RBC folate levels between OC users and non users Mixed results in the literature regarding the effect that OC use has on folate status Sutterlin et al found no significant difference in mean serum folate levels between OC users and non users 4 Among OC users, those taking dietary supplements have significantly higher RBC folate levels Prevalence of folate deficiency was higher in OC non users than active OC users Likely due to the fact that many OC on the market today are supplemented with folate 16

22 DISCUSSION: Iron Women taking OCs have significantly higher serum levels of iron than non users Recent Tanzanian study found an inverse relationship between OC use and markers of iron deficiency 14 Protective effect found with greater than 13 months of OC use 14 Findings of current study likely due to the idea that women actively taking OCs lose less blood per menstrual cycle than non users Premenopausal women can lose up to 80 ml of blood per menstrual cycle, which is equal to 11 mg iron loss 15 There is approximately a 50% reduction in blood loss among OC users 15

23 DISCUSSION: Trends Across NHANES Cycles Serum B12 levels remain similar across cycles in OC users; increase in B12 levels among non users in the cycle Could be related to an increase in dietary supplement use Serum iron levels variable across cycles; overall upwards trend among OC users and downwards trend among non users Large increase in RBC folate levels from previous cycles to the cycle Similar trends seen in both OC users and non users Increase in RBC folate levels likely due to OC folate supplementation as well as increase in interest among premenopausal women

24 Figure 13. Serum B12 levels (pg/ml) across NHANES cycles by oral contraceptive use..

25 Figure 14. Serum iron levels (ug/dl) across NHANES cycles by oral contraceptive use..

26 Figure 15. RBC folate levels (ng/ml) across NHANES cycles by oral contraceptive use..

27 LIMITATIONS Multiple confounding variables not accounted for Dietary patterns, alcohol and tobacco use, medication use, past medical and surgical history, and established nutrient deficiencies prior to OC use OC brand, hormone dosage, duration of use, or compliance to OCs unknown Method in determining micronutrient status Would have been beneficial to use multiple biomarkers 5% of the study population was over the age of 50 Unequal sample size among OC users and non users

28 CONCLUSION Women who take OCs have significantly lower levels of Vitamin B12 Among those taking OCs, those also taking dietary supplements have higher levels of B12 and folate On the other hand, OC use may be beneficial for the preservation of iron stores in premenopausal women Women actively taking OCs need to be aware of potential nutritional deficiencies and the negative impact they may have if the woman becomes pregnant while taking OCs or soon after discontinuation Due to the small effect size of results, must consider if results are of clinical significance

29 RECOMMENDATIONS FOR FUTURE RESEARCH Use of multiple biomarkers in determining nutrient status Adjusting for confounding variables as previously mentioned Use of a larger sample size with less variation in age Stratify into age groups OCs available on the market are always changing; must stay up-to-date on research

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