Reserch Articles Mternl Diet nd Risk of Childhood Acute Lympholstic Leukemi Mrilyn L. Kwn, PhD Christopher D. Jensen, PhD, MPH Gldys Block, PhD Mrk L. Hudes, PhD c Lis W. Chu, PhD c Ptrici A. Buffler, PhD, MPH SYNOPSIS Ojective. Intruterine environmentl fctors, including mternl diet, my ply n etiologic role in cute lympholstic leukemi (ALL), common childhood cncer. Expnding on previous findings from phse 1 of the Northern Cliforni Childhood Leukemi Study (NCCLS), popultion-sed cse-control study, we sought to further elucidte nd replicte the reltionships etween mternl diet nd ALL risk. Methods. We mtched 282 cse-control sets of children (205 pirs nd 77 triplets) from phses 1 nd 2 of the NCCLS on sex, dte of irth, mother s rce, Hispnic rcil/ethnic sttus, nd county of residence t irth. We used n interviewer-dministered food frequency questionnire to otin informtion on mternl dietry intke in the 12 months prior to pregnncy. Results. Risk of ALL ws inversely ssocited with mternl consumption of vegetle (djusted odds rtio [AOR] 5 0.65, 95% confidence intervl [CI] 0.50, 0.84); protein sources (AOR50.55, 95% CI 0.32, 0.96); fruit (AOR50.81, 95% CI 0.65, 1.00); nd legume food groups (AOR50.75, 95% CI 0.59, 0.95). The risk reduction ws strongest for consumption of the protein sources nd vegetle food groups, independent of the child s diet up to ge 2 yers, nd consistent cross phses 1 nd 2 of dt collection for vegetle consumption. Conclusions. These dt suggest tht it my e prudent for women to consume diet rich in vegetles nd dequte in protein prior to nd during pregnncy s possile mens of reducing childhood ALL risk in their offspring. Kiser Permnente, Division of Reserch, Oklnd, CA University of Cliforni, School of Pulic Helth, Berkeley, CA c University of Cliforni, Deprtment of Nutritionl Sciences nd Toxicology, Berkeley, CA c Cncer Prevention Fellowship Progrm, Office of Preventive Oncology, Ntionl Cncer Institute, Ntionl Institutes of Helth, Bethesd, MD Address correspondence to: Mrilyn Kwn, PhD, Kiser Permnente, Division of Reserch, 2000 Brodwy, Oklnd, CA 94612; tel. 510-891-3521; fx 510-891-3106; e-mil <Mrilyn.L.Kwn@kp.org>. 2009 Assocition of Schools of Pulic Helth 503
504 Reserch Articles Childhood leukemi is the primry cuse of cncerrelted mortlity of children in the United Sttes. 1 Of children with leukemi, 78% re dignosed with cute lympholstic leukemi (ALL), the etiology of which is lrgely unknown. 2,3 However, s summrized y Mi et l., 4 oservtions on clonl mrkers in leukemic cells from monozygotic twins concordnt for leukemi, nd evlution of neontl lood spots for clonotypic fusion gene sequences hve provided compelling evidence tht sustntil portion of childhood ALLs originte in utero, nd tht chromosome trnsloctions re very erly or inititing events. 4 These findings underscore the need to exmine potentil risk fctors in the fetl environment, such s mternl diet. In previous report of 138 cse-control pirs from phse 1 of the Northern Cliforni Childhood Leukemi Study (NCCLS), mternl consumption of the vegetle nd protein sources food groups ws inversely ssocited with offspring ALL. 5 Expnding on this reserch, we undertook comprehensive nlysis of 282 cse-control sets from phses 1 nd 2 of the NCCLS to further elucidte nd replicte the reltionships etween mternl diet nd ALL risk. Our nlyses lso took into ccount the potentil confounding effect of the child s erly diet, which hs recently een reported to e ssocited with childhood cute leukemi risk. 6 We hypothesized tht mternl diet is ssocited with offspring risk of ALL, independent of the child s erly diet, nd tht oserved reltionships would e consistent cross phse 1 nd 2 dt. METHODS Study popultion The NCCLS is mtched cse-control study, nd the nlysis presented in this rticle consisted of dt collected from August 19, 1995, to Novemer 30, 1999 (phse 1), nd from Decemer 1, 1999, to Novemer 30, 2002 (phse 2). We identified incident leukemi cses on the sis of Interntionl Clssifiction of Diseses for Oncology, Third Edition criteri, 7 using rpid cse-scertinment procedure from peditric hospitls in the northern nd centrl Cliforni study region. During phse 1, the study re encompssed seven peditric hospitls in 17 counties in the greter Sn Frncisco-Oklnd By re. During phse 2, the study re expnded to encompss nine peditric hospitls nd 35 counties including the Centrl Vlley of Cliforni. Comprison with the sttewide Cliforni Cncer Registry for 2000 showed tht the NCCLS protocol identified 95% of eligile cses mong residents in the five-county Sn Frncisco-Oklnd metropolitn sttisticl re nd 76% of eligile cses in the other 30 counties of the study re. We considered cse sujects to e eligile if they were younger thn 15 yers of ge, hd no prior cncer dignosis, lived within the study region, nd hd prents who spoke either English or Spnish. The University of Cliforni Committee for the Protection of Humn Sujects, the Cliforni Helth nd Humn Services Agency Committee for the Protection of Humn Sujects, nd the Institutionl Review Bords of the prticipting hospitls pproved the study. We otined written informed consent from prents of ll prticipting children. After identifying ech cse, we selected control sujects from irth certifictes through the Cliforni Office of Vitl Records, nd mtched the control sujects 1:1 (phse 1) or 1:2 (phse 2) to the cse sujects on dte of irth, sex, Hispnic sttus (if either prent ws Hispnic, then we considered the child Hispnic), mternl rce/ethnicity, nd mternl county of residence t irth (phse 1 only; mtching on mternl county of residence t irth ws not continued in phse 2 ecuse of concerns regrding overmtching on potentil environmentl exposures relted to leukemi risk). For the 7% of cse children not orn in Cliforni, we selected controls from the cse child s county of residence t dignosis. Out-ofstte cse children were comprle to cse children orn in Cliforni on ge, sex, Hispnic sttus, nd mternl rce. For ech cse suject, we identified four or more potentil control sujects from the Cliforni irth registry nd then rndomized the control sujects for selection. If the first-choice control suject could not e locted, ws ineligile, or refused to prticipte, we then contcted the next rndomly ordered control suject until n eligile control suject greed to prticipte. 8 As of Decemer 1, 2002, we hd otined dt from 866 individuls, including 283 leukemi cse-control pirs mtched 1:1 nd 100 cse-control triplets mtched 1:2. The overll prticiption rte ws 86% for cses (83% in phse 1 nd 89% in phse 2) nd 56% for controls (49% in phse 1 nd 64% in phse 2). The resons for nonprticiption mong control sujects included refusl (26%) nd unle to contct (18%). We excluded totl of 190 prticipnts for the following resons: leukemi dignosis ws not ALL (n5127), there were no dietry dt (n54), cse or control respondent ws not the iologicl mother (n514), nd cse nd/or control food frequency questionnire (FFQ) contined questionle dt (i.e., more thn 10 foods were skipped, the mother consumed fewer thn two or more thn 17 solid foods per dy, or the energy estimte ws greter thn 4,500 kiloclories, n545). Therefore, the finl nlytic smple included
Mternl Diet nd Childhood Leukemi Risk 505 282 mtched cse-control sets of children comprising 205 cse-control pirs nd 77 cse-control triplets. Dt collection We otined mternl dietry intke y interview, using modified version of the Block FFQ. 9 11 The time frme covered ws the 12 months efore the index pregnncy. We chose this period rther thn diet during pregnncy ecuse it represents the prole stte of nutritionl dequcy t the time of conception nd during erly pregnncy. The FFQ contined 76 food items nd questions on vitmin supplement usge. Food items were selected y identifying the top popultion contriutors of ech nutrient mong white, Africn Americn, nd Hispnic popultions in the Third Ntionl Helth nd Nutrition Exmintion Survey (NHANES III) nd the Hispnic Helth nd Nutrition Exmintion Survey (HHANES). 12 14 Frequency of consumption ws reported in nine ctegories, rnging from never or less thn once per month to greter thn twice per dy. We otined portion size for ech food using three-dimensionl strct models. We selected 76 food items to e representtive of wide rnge of dietry fctors including totl clories, mcronutrients, fier, vitmins, minerls, nd other dietry fctors such s crotenoids nd phytoestrogens. In ddition, we included cured mets nd other foods to ddress prior hypotheses. The vitmin supplement questions sked out two types of multiple vitmins nd nine single vitmins, nd otined informtion on frequency nd durtion of vitmin use, s well s usul dily dose for vitmins C nd E. We developed Spnish version of the FFQ to include culturlly pproprite trnsltions of the English version nd dditionl foods importnt in the diets of the Ltin popultion. To identify these foods, we gin exmined NHANES III nd HHANES, 12 14 nd lso used informtion from focus groups of Ltins in the Sn Frncisco By re. This process resulted in the ddition of seven foods (evported/condensed milk, green peppers/chile rellenos, vocdos/gucmole, chili peppers, mole/sofrito suces, corn tortills, nd flour tortills). These items were dded only to the Spnish version of the FFQ. Bilingul interviewers dministered the questionnire. We used the BlockSys progrm 11 to clculte dietry nutrients from food y multiplying frequency of consumption of ech food y its nutrient content nd reported portion size, nd then summing over ll foods. We estimted nutrients otined from vitmin supplements y multiplying the frequency of consumption of ech type (multiple vitmins nd specific single vitmins) times the mount of the nutrient in typicl compositions of ech type. For vitmins E nd C, we otined the usul dily dose from sujects who took those vitmins. We clculted totl nutrient intke s the sum of nutrients from foods nd supplements, unless otherwise noted. We clculted frequency of consumption of food groups vegetles, fruits, diry foods, ens, protein sources, grins, lcoholic everges, nd group consisting of fts, oils, sweets, nd sncks y summing the reported frequency for ll foods in food group. Food groups corresponded to the food groups found in the U.S. Deprtment of Agriculture Food Guide Pyrmid, 15 nd their component foods re listed in the Figure. Mcro- nd micronutrient estimtes from Block questionnires hve een sujected to numerous vlidtion studies nd found to produce good point estimtes nd rnkings in reltion to vriety of reference dt. 16 18 Bunin et l. conducted vlidtion of retrospective ssessment of diet efore nd during pregnncy, nd found correltions of the Willett FFQ with reference dt to e similr to those otined for current diet. 19 We otined dietry dt on ech child from the iologicl mother or primry cregiver using selfdministered questionnire completed prior to the in-home interview in phse 1 nd fter the in-home interview in phse 2. 6 The iologicl mother provided the informtion in 95% of cses. The wording of the dietry questions did not differ etween the two phses of the study. The questionnire sked out the child s wening history nd the frequency of consumption of nine foods/food groups (hot dogs/lunch mets, eef/ hmurger, vegetles, ornges/nns, pples/ grpes, ornge juice, other fruit juice, milk, nd sod) nd vitmin supplements during the child s first nd second yers of life. Frequency of consumption ws reported in six ctegories, rnging from rrely or never to three or more times dy. In ddition, we ssessed whether the child consumed vitmins during the first two yers of life. To summrize food consumption during the first two yers of life, we creted new ctegories of rre/no consumption, occsionl consumption, nd regulr consumption sed on the originl ctegories. Sttisticl nlysis We used the Person chi-squre test to compre selected chrcteristics of cses nd controls. To ssess the ssocition etween mternl diet nd childhood ALL risk, we constructed conditionl logistic regression models. We considered odds rtios (ORs) representing dietry consumption on continuous scle to e sttisticlly significnt if the 95% confidence intervl (CI) excluded 1.00. Before running the sttisticl models, we used
506 Reserch Articles Figure. Foods/food groups represented on the food frequency questionnire, Northern Cliforni Childhood Leukemi Study, Berkeley, Cliforni, 1995 2002 Vegetle group String ens or pes Broccoli Tomtoes, tomto juice Spinch, cooked or rw Mustrd greens, turnip greens, collrds, kle Crrots, or mixed vegetles contining crrots Cole slw, cge Culiflower or russels sprouts Cooked green peppers, chile rellenos Chili peppers, hot chili suce Fruit group Bnns Apples, pplesuce Peches, pricots, cnned or dried Peches, pricots, fresh Cntloupe Mngoes or ppys Ornges or grpefruit, not including juice Protein sources group (USDA Food Guide Pyrmid definition) Hmurgers, cheeseurgers, eef urritos, tcos Beef, including rosts, steks, or eef in stir-fry or sndwiches Pork, including chops, rosts, or pork in stir-fry Fried chicken Chicken or turkey, rosted or roiled Fried fish or fish sndwich Other fish, roiled or ked Oysters Liver, including chicken livers Hot dogs, including turkey or chicken Hm, ologn, other lunch mets, regulr or mde with turkey Bens such s ked ens, kidney ens, or ens in chili, urritos, or soup Eggs, not including Egg Beters Susge or con Tofu, en curd Penuts, penut utter Grin group Rice or dishes mde with rice Spghetti, lsgn, or other pst with tomto suce Cheese dishes without tomto suce, such s mcroni nd cheese Pizz Fier cerels such s risin rn, grnol, or shredded whet Other cold cerels such s corn flkes or Cheerios Cooked cerels such s otmel, ot rn, or grits Bgels, English muffins, hmurger uns Biscuits, muffins Bred, including white, French, nd whole whet Corn red, corn muffins Corn tortills Flour tortills Alcohol group Beer Wine, wine coolers Liquor, mixed drinks Diry group Cheese or cheese spreds Whole milk or chocolte whole milk 2% milk or chocolte 2% milk Skim milk, 1% milk Yogurt, frozen yogurt Instnt rekfst milk shkes such s Crntion, or nutritionl energy drinks such s Sego, Ensure, or Boost Pizz Cheese dishes without tomto suce such s mcroni nd cheese Evported or condensed milk Bens group String ens or pes Bens such s ked ens, kidney ens, ens in chili, urritos, or soup Tofu, en curd Soy milk Penuts, penut utter Miscellneous (not in other groups) Te, regulr lck te or Chinese te, not herl tes Kool-Aid, Hi-C, or other drinks with dded vitmin C Glsses of wter Ornge juice or grpefruit juice Apple juice, grpe juice Sls, ketchup, tco suce Green sld French fries nd fried pottoes White pottoes, not fried, including oiled, ked, mshed Sweet pottoes, yms Met sustitutes mde from soy, such s soy urgers Chicken stew, chicken csserole, or stir-fry Beef or vegetle stew or pot pie Vegetle soups Suces such s mole nd sofrito Gucmole, vocdos Fts, oils, sweets, sncks group Mrgrine Butter Slty sncks, such s potto or corn chips, popcorn, nd crckers Sld dressing nd myonnise Ice crem Doughnuts, pstries, cookies, grnol rs Chocolte cndy, cndy rs Crem, hlf-nd-hlf, nondiry cremer Sugr, honey Includes 282 cse-control sets comprising 205 pirs nd 77 triplets Included on Spnish version of food frequency questionnire only USDA 5 U.S. Deprtment of Agriculture
Mternl Diet nd Childhood Leukemi Risk 507 log trnsformtion for vriles s needed to improve normlity nd reduce skewness. Potentil confounding vriles considered priori were irthweight of the index child, whether the child ws restfed (yes or no), mternl ge, mternl eduction (#high school grdute, some college, or college grdute), nd smoking during pregnncy (yes or no). However, we oserved no evidence of confounding for these covrites, s the chnge in OR when dding ech of these vriles to the min model ws not considered sustntil (greter thn 10%). We included totl energy consumption, the proportion of foods consumed s lrge or extr-lrge portion size, household income, nd mternl exposure to indoor insecticides during pregnncy 20 in the finl model ecuse these vriles explined significnt proportion of the vriility in the outcome nd, therefore, llowed for more sensitive test of the reltionship etween mternl diet nd ALL. We lso exmined the reltionship etween mternl diet nd ALL risk while controlling for the child s diet erly in life (intke of hot dogs/lunch mets, eef/hmurger, vegetles, ornges/nns, pples/grpes, ornge juice, other fruit juice, milk, sod, nd vitmin supplements; intke ws coded s rrely/none, occsionl, or regulr ). RESULTS The men ge t ALL dignosis ws 5.2 yers, 58% of cse children were ged 2 to 5 yers t time of dignosis, nd 53% were mle (Tle 1). Cse nd control children were similr with respect to irthweight, restfeeding, nd mternl smoking. In terms of rce, the study smple ws 87% white, 3% Africn Americn, nd 10% other. Ethniclly, pproximtely 38% of mothers descried themselves s Hispnic. Compred with mtched control sujects, cse children were orn to younger mothers (p50.06) with fewer yers of eduction (p50.13), nd cme from fmilies with lower household incomes (p,0.001). The reltionships etween mternl consumption of food groups (times/dy) nd offspring ALL risk for comined phse 1 nd 2 dt re shown in Tle 2. We noted inverse reltionships etween mternl consumption nd childhood ALL risk for the vegetle (djusted OR [AOR] 5 0.65, 95% CI 0.50, 0.84), fruit nd vegetle (AOR50.64, 95% CI 0.48, 0.85), legume (AOR50.75, 95% CI 0.59, 0.95), nd protein sources food groups (AOR50.55, 95% CI 0.32, 0.96). Fruit consumption ws lso inversely ssocited with ALL, ut ws orderline sttisticlly significnt (AOR50.81, 95% CI 0.65, 1.00). We did not find consumption of cured mets, grins, nd diry products to e significntly relted to disese risk. When we included mternl consumption of the vegetle nd protein sources food groups together in the model, consumption of oth vegetles (AOR50.65, 95% CI 0.50, 0.84) nd protein sources (AOR50.57, 95% CI 0.32, 0.99) remined ssocited with sttisticlly significnt decresed risk of ALL. We lso exmined the reltionship etween mternl intke of either the vegetle or protein sources food group nd offspring ALL risk while controlling for ech of the childhood diet vriles individully. In ll models, mternl vegetle intke remined sttisticlly significnt (p,0.05), wheres mternl consumption of protein sources remined sttisticlly significnt when controlling for children s intke of eef/hmurger, hot dogs/lunch mets, ornges/ nns, pples/grpes, sod, ornge juice, nd vitmins, nd ws orderline sttisticlly significnt (0.05.p,0.09) when controlling for children s intke of vegetles, fruit juice, nd milk. In no cse did the childhood diet vriles rech significnce, lthough severl pproched significnce (p,0.10 for intke of vegetles, ornges/nns, nd ornge juice) (dt not shown). Additionlly, we exmined the mternl consumption of individul foods nd found tht six foods were inversely relted to offspring risk of ALL: crrots, cntloupe, ornges, green ens, other ens, nd eef (Tle 3). Regulr use of ny dietry supplement ws not ssocited with disese risk (AOR51.10, 95% CI 0.76, 1.60) (dt not shown). Among the mcronutrients (Tle 4) nd micronutrients (Tle 5), mternl consumption ws inversely ssocited with offspring ALL for fier from fruits nd vegetles (AOR50.52, 95% CI 0.31, 0.88), provitmin A crotenoids (AOR50.77, 95% CI 0.60, 0.98), lph-crotene (AOR50.78, 95% CI 0.65, 0.93), totl glutthione (AOR50.48, 95% CI 0.25, 0.90), nd reduced glutthione (AOR50.49, 95% CI 0.27, 0.90). We found orderline significnt inverse ssocitions for mternl consumption of et-crotene (AOR50.79, 95% CI 0.62, 1.01) nd lutein (AOR50.82, 95% CI 0.66, 1.01). The direction of the reltionships etween offspring ALL nd mternl consumption of food groups did not chnge when we exmined only cse-control sets for cse children ged 2 to 5 yers t dignosis (the pek incidence of childhood ALL) nd when we restricted the nlysis to 81 income-concordnt cse-control sets, lthough the mgnitude of the reltionships ws ttenuted somewht nd CIs were wider (dt not shown). The dt collected during phses 1 nd 2 of the
508 Reserch Articles NCCLS represented replictions of the study with independent smples nd virtully identicl methods. Mternl intke of the vegetle nd protein sources food groups, nd the dietry fctors clcium, vitmin A, provitmin A crotenoids, lph-crotene, totl glutthione, nd reduced glutthione were significntly relted to offspring disese risk in phse 1 nd/or phse 2 (Tle 6). Of these vriles, only consumption of the vegetle food group ws sttisticlly significnt in oth phse 1 nd 2 dt. Tle 1. Cse nd mtched-control mternl nd child chrcteristics, Northern Cliforni Childhood Leukemi Study, Berkeley, Cliforni, 1995 2002 Mtching vriles Cses (n5282) N (percent) Controls (n5359) N (percent) P-vlue Child s ge (in yers) c,2 2 5 6 10.10 Men (SD) Child s gender Femle Mle Child s ethnicity Hispnic Not Hispnic Mother s rce White Blck Other 34 (12.1) 164 (58.2) 61 (21.6) 23 (8.2) 5.2 (3.4) 133 (47.2) 149 (52.8) 108 (38.3) 174 (61.7) 244 (86.5) 9 (3.2) 29 (10.3) 41 (11.4) 214 (59.6) 72 (20.1) 32 (8.9) 5.2 (3.4) 176 (49.0) 183 (51.0) 138 (38.4) 221 (61.6) 312 (86.9) 11 (3.1) 36 (10.0) 0.970 0.640 0.970 0.990 Other vriles Mternl ge (in yers) t child s irth,20 20 24 25 29 30 34 $35 Men (SD) Mternl eduction #High school Some college College grdute Annul household income,$15,000 $15,000 $29,999 $30,000 $44,999 $45,000 $59,999 $60,000 $74,999 $$75,000 29 (10.3) 67 (23.8) 66 (23.4) 83 (29.4) 37 (13.1) 28.1 (6.1) 116 (41.1) 84 (29.8) 82 (29.1) 34 (12.1) 53 (18.8) 45 (16.0) 51 (18.1) 28 (9.9) 71 (25.2) 25 (7.0) 67 (18.7) 103 (28.7) 106 (29.5) 58 (16.2) 29.1 (6.0) 119 (33.2) 129 (35.9) 111 (30.9) 31 (8.6) 52 (14.5) 39 (10.9) 56 (15.6) 44 (12.3) 137 (38.2) Child ws restfed Yes 234 (83.0) 303 (84.4) Mternl smoking during pregnncy Yes 34 (12.1) 38 (10.6) 0.056 0.130,0.001 0.630 0.560 Includes 282 cse-control sets comprising 205 pirs nd 77 triplets Person Chi-squre test, two-sided c Age t dignosis for cses nd ge t the corresponding dte for controls SD 5 stndrd devition
Mternl Diet nd Childhood Leukemi Risk 509 Tle 2. Associtions etween frequency of mternl consumption of food groups nd risk of ALL mong offspring, Northern Cliforni Childhood Leukemi Study, Berkeley, Cliforni, 1995 2002 Food group Smple medin times/dy (25th, 75th percentile) AOR (95% CI) Vegetles c 0.6 (0.4, 1.0) 0.65 (0.50, 0.84) Fruit d 0.6 (0.3, 1.0) 0.81 (0.65, 1.00) Fruit nd vegetles 1.3 (0.8, 2.0) 0.64 (0.48, 0.85) Grin products 2.6 (2.0, 3.3) 1.20 (0.70, 2.05) Diry products 2.1 (1.3, 3.0) 1.06 (0.83, 1.35) Legumes 0.5 (0.3, 0.8) 0.75 (0.59, 0.95) Protein sources 1.8 (1.3, 2.5) 0.55 (0.32, 0.96) Cured met 0.3 (0.1, 0.5) 0.91 (0.78, 1.05) Includes 282 cse-control sets comprising 205 pirs nd 77 triplets Seprte models for ech food group s continuous vrile with odds rtios nd 95% CIs clculted using log-trnsformed vlues of consumption; djusted for totl energy intke, household income, indoor insecticide exposure during pregnncy, nd proportion of foods reported s lrge or extr-lrge portion size c Grden vegetles only (excludes sld, pottoes, soup, nd stew) d Fruit only (excludes fruit juice) ALL 5 cute lympholstic leukemi AOR 5 djusted odds rtio CI 5 confidence intervl DISCUSSION In the comined phse 1 nd 2 dt from the NCCLS, the lrgest cse-control study to dte on mternl diet nd childhood ALL, we found tht intke of the vegetle, fruit, legume, nd protein sources food groups in the 12 months efore the index pregnncy (nd y inference during erly pregnncy) ws inversely ssocited with offspring disese risk when djusted for household income, mternl totl energy intke, proportion of foods reported s lrge or extr-lrge portion size, nd mternl exposure to indoor insecticides during pregnncy. The inverse reltionships were strongest for intke of the protein sources nd vegetle food groups, suggesting tht two distinct mternl dietry ptterns re independently nd inversely ssocited with offspring ALL risk. Mternl vegetle nd protein sources intke remined significnt nd orderline sttisticlly significnt, respectively, fter further djustment for the child s diet erly in life. In no cse did erly childhood intke of foods/food groups or vitmin supplements rech significnce, lthough intke of vegetles, ornges/nns, nd ornge juice pproched sttisticl significnce. Thus, childhood diet my contriute to reduced risk of ALL s previously reported, 6 ut the stronger effect ppers to e due to mternl diet. When exmining the diet-disese reltionship in the comined dt t the level of individul foods, mternl consumption of foods in the fruit nd vegetle food groups (i.e., crrots, cntloupe, nd ornges) nd the protein sources food group (i.e., green ens, ens, nd eef) ws inversely ssocited with offspring ALL risk. At the nutrient level, consumption of provitmin A crotenoids (found in fruits nd vegetles) nd reduced glutthione (found in protein-contining foods) ws inversely relted to ALL risk. The study findings my hve etiologic relevnce in light of evidence tht the inititing genetic event in the development of leukemi frequently occurs in utero. 4 Fetl exposure to ioctive compounds in vegetles, fruit, nd protein foods such s vitmins nd minerls, fier, peptides nd mino cids, nd other fctors my contriute to the ility of these foods to reduce cncer risk. 21 27 Using virtully identicl dt collection methods nd independent smples from phses 1 nd 2 of the NCCLS to exmine the reproduciility of our findings, we found tht mternl intke of the vegetles food group nd its relted component, provitmin A crotenoids, ws sttisticlly or orderline-sttisticlly ssocited with decresed offspring ALL risk in oth phses of the study. Thus, the inverse diet-disese reltionship ppers to e strongest for mternl consumption of the vegetle food group. Our results re generlly in greement with those Tle 3. Associtions etween mternl consumption of individul foods nd risk of ALL mong offspring, Northern Cliforni Childhood Leukemi Study, Berkeley, Cliforni, 1995 2002 Individul foods (times/dy) AOR (95% CI) Ornges 0.87 (0.77, 0.99) Cntloupe 0.87 (0.76, 0.98) Green ens 0.85 (0.74, 0.98) Bens 0.86 (0.74, 0.99) Crrots 0.82 (0.71, 0.96) Beef 0.82 (0.69, 0.98) Fier cerels 1.12 (1.07, 1.26) Includes 282 cse-control sets comprising 205 pirs nd 77 triplets Seprte models for ech food group s continuous vrile with odds rtios nd 95% CIs clculted using log-trnsformed vlues of consumption; djusted for totl energy intke, household income, indoor insecticide exposure during pregnncy, nd proportion of foods reported s lrge or extr-lrge portion size ALL 5 cute lympholstic leukemi AOR 5 djusted odds rtio CI 5 confidence intervl
510 Reserch Articles of recently pulished cse-control study of mternl diet nd offspring ALL in Greece involving 131 csecontrol sets. 28 In this study, investigtors reported tht mternl consumption of the vegetle nd fruit food groups ws inversely ssocited with risk of childhood ALL, which is generlly consistent with our findings from comined phse 1 nd 2 dt. While consumption of fish nd sefood s food group ws lso reportedly ssocited with reduced risk of disese, consumption of mets nd met products ws relted to moderte increse in disese risk, 28 in contrst to our findings. We oserved no evidence of incresed offspring ALL risk ssocited with mternl consumption of cured mets s food group or individul cured mets, which is consistent with previous reports. 29,30 We lso found no evidence of significnt risk reduction ssocited with mternl prepregnncy use of dietry supplements. This is in contrst to previous reports where vitmins A nd D from cod liver oil 31 nd mternl use of folic cid supplements with or without iron 32 hve een reported to e ssocited with reduced risk of childhood ALL. Strengths of our study included the use of popultion-sed irth certificte controls tht hve een shown to e representtive of the source popultion. 8 Mtching on rce nd Hispnic ethnicity reduced some of the ises tht cn e prolem in other recruitment designs. We otined the mternl dietry dt using previously vlidted FFQ, nd we designed the extensive food list to ssess wide rnge of food groups, foods, nd nutrients, thus enling us to control for totl energy intke. The child s diet questionnire, lthough not vlidted, ws composed of foods tht covered rod spectrum of typicl young child s diet such tht we were le to exmine its impct on the potentil ssocition etween mternl diet nd Tle 4. Associtions etween mternl consumption of mcronutrients nd risk of ALL mong offspring, Northern Cliforni Childhood Leukemi Study, Berkeley, Cliforni, 1995 2002 Mcronutrient (unit) Dily intke estimte: medin (25th, 75th percentile) AOR (95% CI) Energy (kcl) 1,990 (1,518, 2,582) 0.78 (0.35, 1.74) Protein (g) 75 (57, 101) 1.18 (0.35, 4.06) Energy from protein (percent) 15.6 (13.7, 17.5) 1.01 (0.93, 1.09 Totl ft (g) 87.7 (65.6, 115.6) 0.62 (0.16, 2.48) Energy from ft (percent) 40.5 (35.4, 44.9) 0.98 (0.95, 1.02) Sturted ft (g) 27.5 (20.3, 38.0) 1.32 (0.44, 3.99) Monounsturted ft (g) 32.1 (23.7, 43.2) 0.34 (0.09, 1.22) Polyunsturted ft (g) 19.0 (13.6, 24.9) 0.78 (0.37, 1.68) Cholesterol (mg) 254 (177, 349) 1.06 (0.51, 2.23) Omeg-3 ftty cids (mg) 1.61 (1.19, 2.08) 1.15 (0.50, 2.65) Crohydrte (g) 224 (169, 300) 1.69 (0.36, 8.01) Energy from crohydrtes (percent) 45.1 (40.8, 50.2) 1.01 (0.98, 1.05) Glycemic Index 55.9 (50.6, 59.4) 3.18 (0.51, 19.81) Glycemic lod 113 (83, 154) 2.43 (0.75, 7.87) Energy from sweets (percent) 8.00 (4.09, 14.5) 0.99 (0.96, 1.02) Energy from lcoholic everges (percent) 0.00 (0.00, 0.00) 1.06 (0.92, 1.22) Dietry fier, totl (g) 15.6 (11.2, 21.2) 0.49 (0.23, 1.04) Fier from ens (g) 2.08 (0.87, 4.37) 0.91 (0.73, 1.13) Fier from fruits/vegetles (g) 6.18 (0.87, 8.76) 0.52 (0.31, 0.88) Fier from grins (g) 5.79 (3.84, 8.58) 0.99 (0.60, 1.63) Includes 282 cse-control sets comprising 205 pirs nd 77 triplets Seprte models for ech nutrient s continuous vrile with odds rtios nd 95% CIs clculted using log-trnsformed vlues of consumption; djusted for totl energy intke, household income, indoor insecticide exposure during pregnncy, nd proportion of foods reported s lrge or extr-lrge portion size ALL 5 cute lympholstic leukemi AOR 5 djusted odds rtio CI 5 confidence intervl kcl 5 kiloclorie g 5 grm mg 5 milligrm
Mternl Diet nd Childhood Leukemi Risk 511 Tle 5. Associtions etween mternl consumption of micronutrients nd risk of ALL mong offspring, Northern Cliforni Childhood Leukemi Study, Berkeley, Cliforni, 1995 2002 Micronutrient (unit) Vitmins Dily intke estimte: medin (25th, 75th percentile) AOR (95% CI) Vitmin A (RE) c 1,204 (842, 1,789) 0.82 (0.62, 1.08) Retinol (mcg) 470 (307, 684) 1.17 (0.87, 1.58) Folte (dietry folte equivlents) c 640 (437, 963) 1.02 (0.71, 1.47) Thimin (mg) c 1.63 (1.21, 2.14) 1.18 (0.73, 1.89) Rioflvin (mg) c 1.93 (1.41, 2.57) 1.29 (0.83, 1.98) Nicin (mg) c 19.8 (14.3, 25.7) 1.05 (0.67, 1.64) Vitmin B6 (mg) c 1.85 (1.36, 2.50) 1.12 (0.73, 1.72) Vitmin B12 (mcg) c 5.34 (3.35, 8.66) 1.10 (0.82, 1.48) Pntothenic cid (mg) c 4.47 (3.37, 5.91) 1.31 (0.62, 2.77) Vitmin C (mg) c 123 (84, 185) 0.96 (0.74, 1.25) Vitmin D (mg) c 185 (114, 282) 1.13 (0.93, 1.36) Vitmin E (TE) c 10.00 (7.68, 12.90) 0.88 (0.70, 1.10) Gmm-tocopherol (mg) 20.5 (13.6, 29.3) 0.81 (0.54, 1.20) Minerls Clcium (mg) c 844 (612, 1,208) 1.36 (0.91, 2.03) Zinc (mg) c 10.40 (7.49, 14.00) 1.09 (0.78, 1.53) Iron (mg) c 14.2 (10.2, 18.7) 1.05 (0.77, 1.44) Mgnesium (mg) c 272 (203, 361) 1.21 (0.63, 2.34) Phosphorus (mg) 1,244 (911, 1,649) 1.65 (0.69, 3.91) Sodium (mg) 2,424 (1,888, 3,159) 0.86 (0.29, 2.56) Potssium (mg) 2,936 (2,249, 3,950) 1.08 (0.47, 2.50) Selenium (mcg) c 96.3 (74.0, 127.0) 0.68 (0.32, 1.44) Copper (mg) 1.06 (0.78, 1.38) 0.72 (0.32, 1.59) Mngnese (mcg) 2.83 (1.99, 3.96) 1.00 (0.66, 1.50) Other dietry fctors Provitmin A crotenoids (mcg) 3,930 (2,434, 6,431) 0.77 (0.60, 0.98) Alph-crotene (mcg) 572 (324, 1,111) 0.78 (0.65, 0.93) Bet-crotene (mcg) c 2,553 (1,549, 4,193) 0.79 (0.62, 1.01) Cryptoxnthin (mcg) 115.0 (52.6, 223.0) 0.97 (0.85, 1.09) Lutein (mcg) 1,023 (570, 1,773) 0.82 (0.66, 1.01) Lycopene (mcg) 4,797 (2,415, 8,420) 0.91 (0.76, 1.09) Didzein (mcg) (3 ctegories) 0.00 (0.00, 0.00) 1.19 (0.84, 1.69) Genistein (mcg) (3 ctegories) 0.00 (0.00, 0.00) 1.17 (0.82, 1.67) Glutthione, totl (mg) 47.1 (34.0, 64.7) 0.48 (0.25, 0.90) Glutthione, reduced (mg) 30.3 (21.8, 41.5) 0.49 (0.27, 0.90) Isoflvones (mg) 1.89 (0.95, 3.58) 1.11 (0.92, 1.33) Quercetin (mg) 5.56 (3.19, 9.67) 0.92 (0.77, 1.11) Includes 282 cse-control sets comprising 205 pirs nd 77 triplets Seprte models for ech nutrient s continuous vrile with odds rtios nd 95% CIs clculted using log-trnsformed vlues of consumption; djusted for totl energy intke, household income, indoor insecticide exposure during pregnncy, nd proportion of foods reported s lrge or extr-lrge portion size c Nutrient estimtes represent the sum of food nd supplement sources. Nutrient estimtes for vriles without footnote c reflect nutrients only from foods. ALL 5 cute lympholstic leukemi AOR 5 djusted odds rtio CI 5 confidence intervl RE 5 retinol equivlents mcg 5 microgrm mg 5 milligrm TE 5 lph-tocopherol equivlents
512 Reserch Articles Tle 6. Mternl food groups nd dietry fctors significntly ssocited with ALL mong offspring in either phse 1 or phse 2, Northern Cliforni Childhood Leukemi Study, Berkeley, Cliforni, 1995 2002 Dietry fctor Phse 1 AOR (95% CI) Phse 2 AOR (95% CI) Vegetles food group (times/dy) 0.53 (0.33, 0.85) 0.60 (0.42, 0.86) Protein sources food group (times/dy) 0.40 (0.18, 0.90) 0.69 (0.34, 1.42) Clcium (mg) 0.99 (0.48, 2.04) 1.73 (1.01, 2.94) Vitmin A (RE) 0.58 (0.32, 0.98) 0.87 (0.60, 1.27) Provitmin A crotenoids (mcg) 0.65 (0.42, 1.01) 0.73 (0.51, 1.03) Alph-crotene (mcg) 0.66 (0.49, 0.90) 0.81 (0.62, 1.05) Glutthione (mg) 0.48 (0.17, 1.32) 0.33 (0.14, 0.79) Glutthione, reduced (mg) 0.42 (0.16, 1.10) 0.44 (0.20, 0.99) Includes 138 cse-control sets from phse 1 nd 144 sets from phse 2 Seprte models for ech food group or dietry fctor s continuous vrile with odds rtios nd 95% CIs clculted using log-trnsformed vlues of consumption; djusted for totl energy intke, household income, indoor insecticide exposure during pregnncy, nd proportion of foods reported s lrge or extr-lrge portion size ALL 5 cute lympholstic leukemi AOR 5 djusted odds rtio CI 5 confidence intervl mg 5 milligrm RE 5 retinol equivlents mcg 5 microgrm ALL risk. To our knowledge, this type of comprehensive dietry nlysis hs not een conducted efore in the childhood leukemi literture. In ddition, we otined nondietry dt, which llowed us to evlute nd control for other potentil confounding vriles. We were le to oserve the reltionships etween mternl diet nd offspring ALL risk for ll cses, s well s in the sugroup of cses where children were ged 2 to 5 yers t dignosis, therey incresing our confidence tht the findings re generlizle to the mjority of childhood ALL cses. Furthermore, the consistent findings of n inverse ssocition etween mternl vegetle consumption nd childhood ALL risk with independent smples from phses 1 nd 2 of the NCCLS support the vlidity of the findings, lthough roust repliction would involve different investigtors nd methods, nd different popultion. Limittions Severl limittions of these dt should e considered. Our dt collection focused on mternl diet in the 12 months efore the index pregnncy nd, therefore, my hve the gretest implictions for mternl nutritionl sttus immeditely efore nd during erly pregnncy. Recll is is concern in cse-control studies, nd lthough no widely known hypotheses exist out the possile role of mternl dietry fctors in childhood leukemi tht might led to recll is, generl hypotheses out helthy diet could hve led cse mothers to underreport their intke of perceived helthy foods such s vegetles nd fruits. However, it is difficult to imgine tht this would hold true for reported consumption of protein sources. Mesurement error is prolem in reserch requiring self-reports; however, dt collection methods did not differ etween cses nd controls in this study. Thus, misclssifiction from mesurement error would e expected to e nondifferentil nd would likely, lthough not lwys, is the results towrd the null. The prticiption rte of controls ws modest, nd controls tended to hve higher incomes nd more eduction thn cses; s result, selection is must e considered s fctor in interpreting our results. A selection tht fvored controls with higher income nd eduction might produce n inverse ssocition etween disese risk nd vegetle consumption, s higher socioeconomic sttus is ssocited with higher consumption of fruits nd vegetles. 33,34 However, it would e unlikely to result in n inverse ssocition with consumption of protein sources (mets nd legumes), which re less frequently consumed mong more ffluent or well-educted groups. 35 In ddition, such selection is should lso hve produced n pprently protective effect of dietry supplements, s the more ffluent nd well educted do tke more vitmin supplements. 36,37 However, we did not find n inverse ssocition with dietry supplement use. Also, to ccount for differences in socioeconomic sttus, we controlled for household income, mtched
Mternl Diet nd Childhood Leukemi Risk 513 on Hispnic ethnicity, nd repeted the nlysis in income-concordnt pirs, with no mteril chnge in our findings. Finlly, dietry fctors re often correlted with one nother. Thus, cution is wrrnted in directly ttriuting risk or enefit to ny prticulr food or nutrient. CONCLUSIONS Mternl intke of the vegetle, fruit, legume, nd protein sources food groups ws found to e inversely ssocited with offspring ALL risk. The ssocitions were strongest for consumption of protein sources nd vegetle food groups, nd their reltionships with disese risk were independent of one nother nd the child s diet erly in life. Although cuslity cnnot e inferred from this study, the dt suggest tht it my e prudent for women to consume diet rich in vegetles nd dequte in protein prior to nd during pregnncy s possile mens of reducing the risk of ALL in their offspring. This reserch ws supported y two U.S. Pulic Helth Service grnts, #R01ES09137 (Environmentl Exposures nd Childhood Leukemi) nd #P42ES04705 (Superfund, Moleculr Epidemiology of Childhood Leukemi), nd grnt from the Pul O Gormn Foundtion for Children with Leukemi. The uthors thnk Dr. Jim Feusner of Children s Hospitl & Reserch Center Oklnd; Dr. Gry Dhl of Lucile Pckrd Children s Hospitl in Plo Alto; Drs. Ktherine Mtthy nd Mignon Loh of the University of Cliforni, Sn Frncisco; Dr. Vond Crouse of Children s Hospitl Centrl Cliforni in Mder; Dr. Kenneth Leung of Kiser Permnente Sn Frncisco Medicl Center; Drs. Crolyn Russo nd Aln Wong of Kiser Permnente Snt Clr Medicl Center; Dr. Jonthn Ducore of the University of Cliforni, Dvis; nd Dr. Vincent Kiley of Kiser Permnente Scrmento Medicl Center for ssistnce with recruiting ptients. The uthors lso thnk Dr. Youqing Hu for nlytic ssistnce; Monique Does for supervising fieldwork nd interviews; Dr. Ctherine Metyer for dt mngement; nd ll of the University of Cliforni, Berkeley, s well s the study stff for their hrd work nd dediction. REFERENCES 1. Ries LAG, Smith MA, Gurney JG, Linet M, Tmr T, Young JL, et l., editors. Cncer incidence nd survivl mong children nd dolescents: United Sttes SEER progrm 1975 1995 [NIH puliction no. 99-4649]. Bethesd (MD): Ntionl Cncer Institute, SEER Progrm; 1999. 2. Buffler PA, Kwn ML, Reynolds P, Urym KY. Environmentl nd genetic risk fctors for childhood leukemi: pprising the evidence. Cncer Invest 2005;23:60-75. 3. Belson M, Kingsley B, Holmes A. Risk fctors for cute leukemi in children: review. Environ Helth Perspect 2007;115:138-45. 4. Mi AT, Koechling J, Corett R, Metzler M, Wiemels JL, Greves M. Protrcted postntl nturl histories in childhood leukemi. Genes Chromosomes Cncer 2004;39:335-40. 5. Jensen CD, Block G, Buffler P, M X, Selvin S, Month S. Mternl dietry fctors in childhood cute lympholstic leukemi (United Sttes). Cncer Cuses Control 2004;15:559-70. 6. Kwn ML, Block G, Selvin S, Month S, Buffler PA. Food consumption y children nd the risk of childhood cute leukemi. Am J Epidemiol 2004;160:1098-107. 7. Fritz A, Percy C, Jck A, Shnmugrtnm K, Soin L, Prkin DM, et l., editors. Interntionl clssifiction of diseses for oncology. 3rd ed. Genev: World Helth Orgniztion; 2000. 8. M X, Buffler PA, Lyefsky M, Does MB, Reynolds P. Control selection strtegies in cse-control studies of childhood diseses. Am J Epidemiol 2004;159:915-21. 9. Block G, Hrtmn AM, Dresser CM, Crroll MD, Gnnon J, Grdner L. A dt-sed pproch to diet questionnire design nd testing. Am J Epidemiol 1986;124:453-69. 10. Block G, Hrtmn AM, Nughton D. A reduced dietry questionnire: development nd vlidtion. Epidemiology 1990;1:58-64. 11. NutritionQuest. Block dietry dt systems [cited 2008 Jn 30]. Aville from: URL: http://www.nutritionquest.com 12. Centers for Disese Control nd Prevention, Ntionl Center for Helth Sttistics (US). Third Ntionl Helth nd Nutrition Exmintion Survey, 1988 1994, NHANES III [CD-ROM Series 11, No. 2A]. Hyttsville (MD): NCHS; 1998. 13. The Hispnic Helth nd Nutrition Exmintion Survey. Nutr Rev 1991;49:156-8. 14. Block G, Norris JC, Mndel RM, DiSogr C. Sources of energy nd six nutrients in diets of low-income Hispnic-Americn women nd their children: quntittive dt from HHANES, 1982 1984. J Am Diet Assoc 1995;95:195-208. 15. Deprtment of Agriculture (US), Center for Nutrition Policy nd Promotion. The food guide pyrmid [Home nd Grden Bulletin Numer 252]. Wshington: USDA; 1992. 16. Block G, Thompson FE, Hrtmn AM, Lrkin FA, Guire KE. Comprison of two dietry questionnires vlidted ginst multiple dietry records collected during 1-yer period. J Am Diet Assoc 1992;92:686-93. 17. Block G, Woods M, Potosky A, Clifford C. Vlidtion of selfdministered diet history questionnire using multiple diet records. J Clin Epidemiol 1990;43:1327-35. 18. Mres-Perlmn JA, Klein BE, Klein R, Ritter LL, Fisher MR, Freudenheim JL. A diet history questionnire rnks nutrient intkes in middle-ged nd older men nd women similrly to multiple food records. J Nutr 1993;123:489-501. 19. Bunin GR, Gyllstrom ME, Brown JE, Khn EB, Kushi LH. Recll of diet during pst pregnncy. Am J Epidemiol 2001;154:1136-42. 20. M X, Buffler PA, Gunier RB, Dhl G, Smith MT, Reinier K, et l. Criticl windows of exposure to household pesticides nd risk of childhood leukemi. Environ Helth Perspect 2002;110:955-60. 21. Collins AR, Hrrington V, Drew J, Melvin R. Nutritionl modultion of DNA repir in humn intervention study. Crcinogenesis 2003;24:511-5. 22. Astley SB, Elliott RM, Archer DB, Southon S. Incresed cellulr crotenoid levels reduce the persistence of DNA single-strnd reks fter oxidtive chllenge. Nutr Cncer 2002;43:202-13. 23. Torergsen AC, Collins AR. Recovery of humn lymphocytes from oxidtive DNA dmge; the pprent enhncement of DNA repir y crotenoids is proly simply n ntioxidnt effect. Eur J Nutr 2000;39:80-5. 24. Fillion L, Collins A, Southon S. Bet-crotene enhnces the recovery of lymphocytes from oxidtive DNA dmge. Act Biochim Pol 1998;45:183-90. 25. Woltereek AP, Roggend R, vn Moorsel CJ, Bn RA, Koemn JH, Feron VJ, et l. Vitmin A nd et-crotene influence the level of enzo[]pyrene-induced DNA dducts nd DNA-repir ctivities in hmster trchel epithelium in orgn culture. Cncer Lett 1995;91:205-14. 26. Greenwld P, Clifford CK, Milner JA. Diet nd cncer prevention. Eur J Cncer 2001;37:948-65. 27. Meister A. Strtegies for incresing cellulr glutthione. In: Pcker L, Cdens E, editors. Biothiols in helth nd disese. New York: Mrcel Dekker, Inc.; 1995. p. 165-89. 28. Petridou E, Ntouvelis E, Dessypris N, Terzidis A, Trichopoulos D; the Childhood Hemtology-Oncology Group. Mternl diet nd cute lympholstic leukemi in young children. Cncer Epidemiol Biomrkers Prev 2005;14:1935-9. 29. Srsu S, Svitz DA. Cured nd roiled met consumption in reltion to childhood cncer: Denver, Colordo (United Sttes). Cncer Cuses Control 1994;5:141-8.
514 Reserch Articles 30. Ross JA, Potter JD, Remn GH, Pendergrss TW, Roison LL. Mternl exposure to potentil inhiitors of DNA topoisomerse II nd infnt leukemi (United Sttes): report from the Children s Cncer Group. Cncer Cuses Control 1996;7:581-90. 31. Shu XO, Go YT, Brinton LA, Linet MS, Tu JT, Zheng W, et l. A popultion-sed cse-control study of childhood leukemi in Shnghi. Cncer 1988;62:635-44. 32. Thompson JR, Gerld PF, Willoughy ML, Armstrong BK. Mternl folte supplementtion in pregnncy nd protection ginst cute lympholstic leukemi in childhood: cse-control study. Lncet 2001;358:1935-40. 33. Ptterson BH, Block G, Rosenerger WF, Pee D, Khle LL. Fruit nd vegetles in the Americn diet: dt from the NHANES II survey. Am J Pulic Helth 1990;80:1443-9. 34. Cliforni Deprtment of Helth Services. Cliforni dietry prctices survey: overll trends in helthy eting mong dults, 1989 1997, cll to ction, prt 2. Scrmento (CA): Cliforni Deprtment of Helth Services; 1999. 35. Ptterson BH, Block G. Food choices nd the cncer guidelines [pulished errtum ppers in Am J Pulic Helth 1988;78:620]. Am J Pulic Helth 1988;78:282-6. 36. Block G, Cox C, Mdns J, Schreier GB, Licitr L, Meli N. Vitmin supplement use, y demogrphic chrcteristics. Am J Epidemiol 1988;127:297-309. 37. Sur AF, Block G. Use of vitmin nd minerl supplements: demogrphics nd mounts of nutrients consumed. The 1987 Helth Interview Survey. Am J Epidemiol 1990;132:1091-101.