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Vitamin A and D intake in pregnancy, infant supplementation, and asthma development: the Norwegian Mother and...


Vitamin A and D intake in pregnancy, infant supplementation, and asthma development: the Norwegian Mother and Child Cohort .5.6 Oystein Karilstad Kristin Holvik Nicolai A Land-BlixMargareta Haugen 1.7 Christian M Page. Per NdPer M Ueland. Stephanie JLondon Siri E Haberg.and Wenche Nysad Division of Mental and Physical Health. 2Department of Expount and Risk Assesort and Oate fr Ftlay and Health, Norwegian Intitute of Public Health, Oslo, Norway. ●Department of Nunung and Health Prometne akMet-ab Metropdaan Usoruty. Odo, Norway, ,Modical R earch Council Integrative Epademiology Unit. University of Brisa L Briad United KingdE 6Dqubeal of Rpulace Health Sciences, Bristol Mekal School, Bmi- tol, Usited Kingplom: Division of Pediaric and Adolescess Medicine, Departmens of Pediatrics Oslo eiversity Hospital Olo Norway. Department of Community Medlicine, University of Oso Osdo, Norway: Department of Clinical Science, Usiverity of Berpon, Bergen Norway: Laboratory of Clini cal Biochemisay. Haukeland University lio pital. Berpen, Norway, and : Epidemiology Branch, Nabond ๒titate of Eminonmental Health Sciences, NIH. Department of Health and Human ServicesReseach Triangle Park, NC ABSTRACT Background: Weslem diets may provide excess vitamin A, which and Child Cobort is potentially toxic and could adversely affect respiratory health and counteract benefits from vitamin D Objective: The aim of this study was to examine child asthma at age 7 y in relation to maternal intake of vitamins A and D during pregAsthma is currently among the top 5 chronic conditions con- nancy, infant supplementation with these vitamins, and their potential tributing to the global burden of disease in children aged 5-14 y interaction Desian: We studied 61.676 school-age children (bum during 2002 ส。ase the sucepth lity to asthma (2) and dietary exposures in 2007) from the Norwegian Mother and Child Cohont with data on utcro and infancy could play a role, in particular for childhood matemal total (food and supplement) nutrient intake in prenancy onset of the disease (3) (food-frequency quesdionnaire validated agaist biomarkers) and inFa-soluble vitamins have a broad range of effects related to fant supplement use at age 6 mo(n·54.142 duldren). Linkage with anto uda poperties (4) ait une fiction (5), and hing devel. the Norwegian Prescription Database enabled near-complete followopment (6) in partcuar, vitamin D has attracted much interest up (end of second quarter in 2015) for dispensed medications to clas- because of widesprcad deficiency in Westem populations (7) sify asthma. We used log-binoenial regression to calculate adjusted RRs .aRRs) for asthma with 95% Cls. Results: Asthma increased according to maternal intake of to- tal vitamin A [retinol activity equivalents (RAEs3] in the highest RecanAaHNanunNMeof Emin amental Health Scien esice tract 22031 RAEsd) compared with the lowest ($779 RAEd) quin- NOI-ES-75558) and NIBUNaional Initule of Neurological Disorders tile (aRR: 1.21; 95% CI: 1.05, 1.40) and decreased for total vitamin and Stokeipat Dos. 1 UOI NS 047537-ol and 2 U01 NS 04753746AD. D inte highest ( 리 3.6 Ag/d) compared with the lowest (S3Spg/d) Thn·ork wa ako supp rted by Norweg n Rotach Gemigrant no quintile (aRR: 0.51; 95% Cl: 0.67, 097) during pregnacy. No as- sociation was observed for maternal intake in the highest quintiles of both nutrients(aRR. 0. 99, 95% Cl: 083, 1.18) and idant supple- mentation with vitamin D or cod liver oal. Conclusions: Excess vitamin A (223 times the recommended in- tale) dring pregnancy was associated with increased risk, whereas .Suppknau, ite online posang of he article and from the vitamin D intake close to recommendations was associated with a re- same lak the eine tNe of contents duced risk of asthanan school-age children. No assocation for high AAde comequekwe··CLPie-mat ehnline-louise parethaw intakes of both nutrients suggests antagonistic effects of vitamins A Ariatioes ed FO. food-equncy quetionnasc Mola No- and D. This trial was registared at hp NCTO3197233. Am J Clin Nutr 2018:107:789-798 prescriptions, Norwepian Prescription Database, Norwegian Mother INTRODUCTION (1) Unfavorable changes in diet have been hypothesized to in- The Norwepian Mother nd Child Coon Saady is supported by the Nowe to-gin Minisy of Heakh and Cae Seevices and the Mnistey of Educatin and 221097, to w%)and by te tram ral Rexach hyram of the NIH. Na- tional ๒eMe of Eminnestal Health Sciences (201 ES49019, 10 SIL). The funders of the stuly had no roke in study design, data collection, data analysis and inapectation, witing of the port or the decision to suhaut the articke for pulication Supplemttal Fig aid Supplemental Tiles 1-8 are available from the as wepian Mother and Child Colbont Study NorPD. Norwegian Prescription Rexeived June 13, 2017. Accepied for publication January I7.2018 Fine pulished online April 20 2018 doi: htoo/0 1093/ajcn Keywords: food-frequency questionnaire, dictary supplements, women, infants, vitamin A, vitamin D, pediatric asthma Ani/ Ca Nrtr 2018; 107: 789-798 in the public domain in the US Printed in USA © 2018 American Society for ,ettim Thi work B wenen by (a) US Government employee(s) and is 789
790 PARR ET AL Studies that used Mendelian randomization do not support th for 212 mo from age 6y in 61.676bom 2002-3007 ofwhom genetically lowered 25-hydroxyvatamin D is a risk factor for 89% (n = 55.142, had data oantal ฉpplentnt use 6 mo. asthma (8), However, randomized trials 9, 10) and a meta Weused a random suhsample of 2244 iths from 2002-2008 so analysás of binh coho studies (11) sugpest that paenatal vitacompare maternal dictary intake with plasma concesrations of min D supplementation above the regular dose (9. IOL and higher fat-soluble vitami at 18 tegatotal wack maternal circulating 25-hydroxyvitamin D (11), may reduce the suscepibility lo asthma in the offspring, although follow-up of children to school age is not yet available in the trials Vitamin A deficiency poses apublic health problem in partsf The MoBa stady has been approved by the Norwegian Data the world, but westemized diets may peovide excess vitamin A Inspectorate (reference 01/4325) and the Regional Commitee (12-14) from increasing intakes of animal products and fortified for Medical Research Ethics (refererence S-97045, $-95) A foods and the use of dietary supplcmens Hagh dictary vitamin of the participants gave writien informed consent at the time of A has been associated with increased asthma severity in a marine enrollment The cament study was approvod by the Regional model (15) but human studies are limited by potential toxic Committice for Medical Research Ethics o SouthEasit Norway. effects and a lack of feasible biomarkers for assessing adequate or subtoxic status (16). Observational studies, rather than trials, are therefore important to examine unintended health effects of vitamin A excess at the population level. Previous observational Taa』( food and supplement) nument澀kes dang pregancy studies of vitamin A and asthma have mainly focused on the were esimated from the HQ, which queried about intake since antioxidant properties of carotenoids (3) and have not incladed becoming pregnant. The FFQ has been validated agaiest a4d retinol, the most potent form of vitamin A. Vitamin A supplemen- weighed food diary and with selected binders (25, 26). T> tation trials have been conducted in areas with endemic deficiency tal vitamin A <sum of total retinol and tial β-car tene) was ex- (17, 18) where the effects on respiratory outcomes could differ pressed as daily setinol activity equivalents (RAEs) per day by from those แ1 well-Dounshed populations due to differences in usang te conversion factors1 μ.etal drum áct or supple- baseline vitamin A status <19). Few studies, to our knowledge, ments) 12 ㎍ ßanlene from det 2 ㎍ ßanene feom have examined the risk of child asthma in relation to prenatal con- supplements to account for differences housaldlay d27). To- centrations of vitamin A, including retinol, outside of deficient tal vitamin D (micrograms per day) incladed vitamin D from populatie s (20, 21 er the importance of prenatal compared with foods and vunns D: and D, fecen獾pplements. Nutrient mule early postnatal exposure. Furthemore, high vitamin A intake was calculated by using the Norwepian Food Compesition Ta could potentially counteract the beneficial effects of itamin D, ble (28) and a compiled database od dietary supplements, mainly due to competition foe the nuclear tetinoid X receptor (22) Dictary esposure assessment and biomarker comparisons Our objective was to investigate the association of maternal and 25-hydrosyvitamin D: and D, were mcasuned at Bevital AS intakes of vitamins A and D during pregnancy, infant exposure laboratories in Bergon, Norway (www.bevitalmok in a singk to dietary supplements containing these nutrients, and potential nonfasting venous blood sample drawn at 18 wk of gestation. nutrient interaction, with current asthma at school age when the The frequency of infant supplement use (sever, sometimes, diagnosis is moee reliable than at earlier ages Norway oflers daily) was assessed from a fellow-ap questionnaire mailed advantages for the study of high intakes of vitamin A during 6 mo of ape. We analyzed the use of the following sapplement pregnancy because of a generally high intake from food sources categories containing vitam A or D or bode vita D cely in addition to the widespread use of cod liver oil as a dietary (lsquid oil-based formula), cod lver oil maltivitamins, and any vitamin D supplement, excleding livitamins. The lamS egory included vitamin D only, cod liver eil and less commen sapplements (fish oil with added vitamin D, liquid vitamin A and vitamin D Sormula, vitamin D with fucride, and other vitamin D The study included participants in the Norwegian Mother and Child Cohort Study (MoBa), a population-hased pregmancy co hort (births dring 1999-2009) administered by the Norwegian We examined unnt asthma inchilien ~7yofagedfned Institute of Public Health (23, 24). Women were recruited naas having22pharmacy dispensations of asthma medication in the tionwide (41% participation) at ~ 18 wk of gestation when a pre- NoPD within a 12-mo interval, the fint prescrption being dis- natal screening is offered to all pregnant women. For the cur pensed between ages 6 and 7y. Noncases were all children who rent study we linked MoBa file version 9 (115,398 children and did not meet these criteria. Asthma medications were inhaled P 95,248 mothers) with the Medical Birth Registry of Norway agonists, inhaled glucoconicoids, combination inhalers with p (hereafter referred to as the birth registry) and the Norwegian apaists and glucocorticoids, or ledtrenereceptratagoi Prescription Database NorPD), with follow-up to the end of the second quarter of 2015. The curent study was repistered at Outcome measures of childrens asthma gov as NCTO3197233. Eligiblechildeen Figure 1) had available data on maternal dietary intake in preg- nancy from a validated food-frequency questionnaire (FFO) ad-the birth registry (maternal age at delivery, parity, region of de ministered ~20 gestational weeks and prescription follow up livery. Bode of delivery. childs sex buth wash and gestational Potential co funders and co vanaks wae bood on data from
VITAMINSA ANDD AND ASTHNEA DEVELOPMENT 791 Noe-live births n 371 Multiple birt (-3,139 Loss to later child death (-230 Loss to enigration or unknow vital status -677 -1,437) Ne sspelement data ( 836 having maternal haslne dts and FFQ om g6y -20,121 sitamin intake and child m ned n 61676 No folo-p at age 6 monds -6534) with maternal FFO and plain bomurk data (n-2244 ash(-55,142) age) or MoBa questionnaires compkesed at approximately gesta North) as a proxy for btitude of nesidence, and season of deliv tional weeks 18 (inclusion), 20 (FFO), and 30 and when the childy anuary Manch, April-June, Jaly-September, or October was aged 6 mo. December). Malernal histories of asthma and allergic disorders Because cod liver oil and other omega-3 pplements con- esep rate variables) were defined as ever reports at week 18 of tribute to the intake of vitamins A and D im many MoBa women asthma or hay fever, atopic dermatitis, animal hair allergies, or (13), we also evaluated malemal mtakes of (ter nutrients pro- าber alerg es. vided by these sapplements, including vitamin E (preservative,Mamy clinical practice guidelines recommend the use of di- ntioudant) and lingdaan 1-3 fatty ac ds (EPA. doos pa- day suppleme識ndulag multivitamins. to ensure adequate tacnoic acid, and DHA) In addition, we incladed vitamin C as mtentsapply to low-birth-weight or premabure infants (31). To a measure od fruit and vegetable intake (29) folate intake (30 adjust for child frailty, wich could be related to both supple and total energy intake. In sensitivity analyses, we aso eval ment use (therapestic or montherapeutic)and later asthma suscep- uated maternal rinc intake (3) and birth year to control for a ibility, we included low birth weight (2500 g), premature birth potential cobort effect. To assess potential confounding by UV gestatioeal age <37 wk), and postnatal exposures in the first exposure in the analysis of vitamin D intake, we included leisere- 6 mo to full breastfeeding (number of months), respiratory tract time physical ativay (a 1. 2-4, or 5 tame/wk) and solar, metus㈤ayes), and maternal smokmg (aa sca etime, of ium use (o, 1-3, or 26 total times) in pregnancy, peographical daily) in the main analysis. In sensitiviry analyses, we addision- region of delivery within Norway (South and East. West. Mid. ally incladed childs sex birth season cesarean delivery (no or
792 PARR ET AL yes), and use of paracetamol or acetaminophen (no or yes) and all spline term combinations from restricted cubie spline models with4 knots We also assessed the potcntial influence of unmea- sared confounding by using a recently published framework de- velopel by Ding and VanderWeele (33). The significance level was 5% or all tests. The analyses were conducted in Stata 14.0 antibiotics (no or yes) in the first 6 mo. Statistical analysis We examined associations of maternal vitamin A and D intake (SuaCop LP during pregnancy (exposuses) and infant supplement use (espo- sures) with childrens asthma (outcome) by using log binomial regression. We cakulaod RRs with 95% as cm the basis of to- RESULTS bust cluster variance estimation and controlled for potential con- founding by multivariable adjustment. The NorPD linkage am abled near-complete follow-up for asthma. Parcipant selection is shown in Figure I, and sekected partic shown in Table I (moihers) and Table 2 children) Characteristies were similar for the main study sam- ple.thtsubsample withquestionnai爬follow- p at 6 mo, and the inagea pantcharacteristics are Our regression models were based on a directed acyclic graph for the hypothesized causal relations (Supplemental Figure I) omarke According to the graph, the effects of matemal intake and infant supplementation on childrens asthma can be estimatiod indepen- dently when potentaal confounding faclors and modalonCharacteristics of mothers and children justed for. In the analysisof maternal intake (model I, vitamins A and D were mutsally adjusted for (Spearman comelation of 053 continuous data), and we additionally adjusted for total intakes of other nutrients (vitamin E: sam of the n-3 fatty acids EPA do- cosapentaenoic acid, and DHA: vitamin C and folate) andenargy during pregnancy. maternal prenatal factors(age at delivery. par- ity. prepregnancy BMI. education, history of asthma and atopy and smoking in pregnancy), and birth woight and prematurity as potential medialors In the analysis of infant supplementation (model 2), we mutually adjusted for the different supplements given and included all model 1 factors and postnatal child factons (months of full breastfeeding, child respiratory tract infections in the first 6 mo, and matcrnal smoking since birth) Missing val- ues in individual anariates were < 5% (Supplemental Table 1) and handled by maltiple imputation by using chained oquations (10 imputations )For 06% of the main study sample with miss ing questionnaire follow-up at age 6 mo (6534 of 61,6761 we assessed the effect of imputing the infant supplement exposure data before perferming multivariatle adjustments when potential confounding factors and modialors are ad- Associations between matenal characteristies and dsetary in take in pregnancy in- 61,676) ware generally in the same di- rection for vitamins A and D. High intakes were associated with older age, higher education, primipanity, lower BMI, less smok- dpplement use (Table I Sapplementation with cod liver oil at age 6 mo was related to high matemal intakes of both vitamins A and D (Table Dand was higher in chldren with positive heakh indicaaors (bnh weight 22500 g. tem birth, hreastfeeding 26 mo, and no respiratory ract infoctions or postmatal maternal smoking) (Table 2). The use of mulivitamins (percentage) was much higher among low birth weight(45%)and premature (31%) children, indicating therapeu- tic use accoeding to clinical practice guidelines (31), and was as- sociated with shorter beeastfeeding and mose postnatal matermal Maternal intakes of vitamis A and D and child asthma All of the matemal nutricnt intake variables were includodas The prevalence of current asthma at age 7 y. based on prescrip- quantiles so account for a potential nonlinear association aih in registry data, was 4.1%く2546 of 61,676). Children bom to childrens ashna. We toted for linearity by induding thc qīn- w0ณาส dic highest comparod with the lowest quintile of total tile values (ondinal scale) as a continuous variable. To eamine vmin A ntake during pregnancy had a slightly higher preva the potential interaction between vitamins A and D in the mother, ktor of asthma (4.9% compared with 4.1%), and the adjusted we created a binary variable for high (highest quintile) com ured RR was 20% higher (Table 3). We observed the lowest preva- with low (all lower qmtiles) intakes of each vitamin d 4 ma- lene of asthma (3.6%) in the second quantile of total vitamin tually exclasive exposure categories for the following comA780-1102 RAEvd) in which intake was close to, or slightly tions low viamin A and low vitamin D, high vitamin A and lw ahove, the public recommendation for pregnant women ef vitamin D, high vitamin D and low vitamin A, and high vitamin RAEid in Nondic countrics (34), which is similar to other na- A and high vitamin D. To acount for multiple supplement use in bunal recommendations (35). Relative lo the second quintile, the children, we created 6 mutually exclusive categories for daily or adjusted RR of asthma was 32% higher (95% CI: 1.15, 1.51) in sometimes compared with never use of the followingh vitman the highest quantile. The effect of total vitamin A (retinol and β. D only; 2)cod liver oil only;3)multivitamin only:4)any vitamin carotene)was only marginally stronger than for total retinol. Total D sapplement inclading cod liver oil, combinod with a miD-canotene showed a weak, but positive association with asthma tamin: 5) maltiple vitamin D supplements (eg- vitamin Donly aer adjustment for total retinol The adjusted RR foe the high combined with a fish-oil supplement containing vitamin DK and Cx(>4007pgdaumpurod with the kwest (s1 360,pd) quin- ble of β carotene was I.I l (95% CI: 0.98. I.27) (Supplemental In sensitivity analyses, we added more covariates to our main Table 21. The Spearman comelation between total retinol and to- multivariable regression models, as described in Results, and we tal -canoene (continuous datal was 0.12. A high intake of vita performed propensity score matching as an ahernative method of min A from food was not associated with asthma when the study controlling for posential confounding (32). We tested for i sample was restricted to nonusers of retinol-containing supple- plicative interaction between maternal intakes of vtamn A and mrss (712 cases; m-16,924). The adjusted RR was 05 (95% vitamin D taking potential ถ0nlinearity intacoust by incluing 0.81. I 36) for the highe42 1462 RAENU) compared with 6) none of the categories (reference).
VITAMINSA ANDDANDASTHMA DEVELOPMENT 793 TABLE Vitamin Dy o1 (5779 RAEd 12,331 023031 RAE 0542 136 pg 12.378 Maternal age at. delivery. % 25-30y 01 38.7 89.2 197 Manal cluation. % Less tun Nigh school High school 4y of olle 95 10.7 270 y of college 201 185-249 50-299 57.8 250 49 203 67.9 195 25.9 Saoppeldl in prn Maonal history ofadina, % yes Macrnal history ofalipy, % yes Cod lnver oil 31S Oher n-3supplement Polic acid Cod liver 97 75.7 Child suppkan uea6mo(m-55,142. % yes Vaamin D dros 61.676 Q.quinike: RAE, stinol activity ogaivalet the lowest (97 RAEsd) quintile of food vitamin A ntake (e mohan the standard daily dose of 250 ug, or commbine multi-S sults not shown). ple supplements. However, food retinol contributed most to total A high intake of vitamin D during pregnancy was associa with less-freqarnt asthma (3.9% compared with 4.4% for the highest compared with the kwe quintilek, and the adgsled RR was-20% lower in the highest compared with the lowest qui tile Table 3). we observed no adverse effect of high vitanan A, or a protective effect of vitamin D.kr intakes in the highest quintiles of both nutrients (Table 4) vitmin A (Supplemental Table 3). The main food sources were sandwich meats, indudagliver spread.fortified margarine, and dary pecdads. In Norway. dairy products are not fortified with rcitol-4at milk is frihed with low ameusts of vitamin D, bui food ke of vitamin D vaned linke, and the use of supple- mcntal viani. D.7Vi overall compared with 99% in the highest quintikk) was an important coetributor to total vitamin D intake Supplemrntal Table 4 Food and supplement contributions to maternal intake o total vitamins A and D The use of supplements containing rctinol, inclading cod liver n the biomarker subsampke in-2244), matemal plasma oil. was cornmon (73% overall conpared with 86% in the high- vdan= D, coecentration increased across each quantile of total est quintile). The median intake of suapplemental retinol among vitamin D intake (medians: 68,72. 74,75, and 82 nmolVL for users was 300 Pgid in the third through fith quintiles of to- the first through the fifth quintile, respectively. see Supplemental tal vitamin A intale, indicating that many pregnant women talkle Table The overall plasma-diet Spearman correlation
794 PARR ET AL TABLE 27 2500-4S0 4901 1.223 2424 227 Preterm binh 291 Yes 1536 westtion 219 228 Mooths of fall beeastfeoling 132 21.295 89 57.3 Respirabony wact infoctioms in the firsl 6 mo 922 10 92 Yes, hospitali Posmatal matemall smking in the 5.680 218 55.1 continuous) for vitamin D varied with the season of Hlood (see Supplemental Table 3), ao as especied, due to its strict draw, from 0.15 in summer to 032 in winter. Asseciations homeostatic control with indicators of UV exposure were in Supplemental Table 5 plasma vitamin D increased with leisure-time physical activity and tanning bed une in pregnancy and from Nort to South for geographical region of delivery The Daily infant supplemenutoe wi血vu in Donly orcod liver macmi plasma retinol concentration (mediat: 164 μη1L oil was na assoaaed.ith n kofathmaat school age. Daly IQR; L46-L83 μη。VL) vaned little with vitamm A make use of mltvítamns was assaaed with al high RR after the expected direction Infant supplementation and child asthma TABLE D intake in peegmany Quistiles of intule Total vitamin A (RAEd Prevalence, % oene 02(780-102 3 (1103-1479) 04(14802030 05c200 Parend 06/12 33 78/12 39 312 345 313 813 08 (0.93,13 21 1.05.140 o1 (535) 0206-5.7 85/1248 90(0791 89 (.77, 15 40 04(87-35 QS(2135) 031 67.097) and prematurity no oryes). Misning values in covariates were haled by uiple impution1nhinedqt
VITAMINS A ANDDANDASTHMA DEVELOPMENT Cosdunod elect of bal vlanin A and vi ann D make-pregnancy and RR estimules e95% as) for current asthma aR age 7 y Total vtamin A (RA 128(1.15,1.43 087(076,0 21 L.08, 136) 086(073, 100 99 0.83,1.18 61676 RRs ane from a log binoemial negnession model A high intake coresponds to the highest quineilke (05) and low intake to all lower quiniles 01-04)is Tale 3.Q.quinike: RAE, enol activy equivalent rel eference ๒c㎕ energy inuke (continuousk the flowing maternal or yesi history of atopy (no or yes), and smok ing in pregnincy ino, quit or yes Adjusted for materal total intake of vitamins A or D(al adjudment vitamis Evitamin C. folate and sum of n-3 fary acids al in qeintiles) and pengal factors: age at delivery 60e_ws), p nay (AL or sh. edaatiou.les&an high 4hol. and the following medialerx bhrth weight (2500, 2500-4500 or 24500g and peematurity (no or yes) Missing values in covarates were handled by mbiple imputatic10p by using chained equations multivariable adjustment Table 5). However, there was no in control for a potential cohont effect Supplemental Table 6. The creased risk for any (daily or sometimes) use of mukivitamins in results from the nonlinear analysis of multiplicative interaction infants who were given an additional vitamin D containing sup were not significant (P-interaction from 059 to 094 in the multivariable model). Coafounder adjustment by multivariable regression and propensity score matching gave similar results Supplemental Table 7). From our main model (Table 3)% We estimated the direct effect of maternal intake not mediated Results on matcrnal intake (Table 3) were robust to a range through low bith weight and peematurity, however, the toal of sensitivity analyses including additional adjustment for total efect not adjusting for these medialos, was similar (results no inc intake. proxy variables for UV exposure during pregnancy shown).Resulks on infamt supplement use (Table 5) were little leisure-time physical activity. tanning bed use, and geographicall ected by additional adjustment for indicators of chil frailty region of delivery) in the vitamin D analysis, or birth year to or asthma susceptibility (childs sex, Hirth season, delivery by Maternal and child sensitivity analyses Infant s pglement use inthe first 6 mo and crude and bhiled RR e maes (95% Cls) forcameM adala at age 7 ya 0360.77. 0%, 086.0.77.097) 0.91 40si, i02) 92 00.84, LOD092(084, 10097(087, 1.9 0.84, 116 10240.87,19 105(089, 1.23 698 0.77, 19) 1.47 (1.25, 1.72) 97(0.78,12 0ss(071, 10 1.45(1.24, 1.70, 1.19(1.01, 1.41) Cod lner eil enly 95 (0.83, L)097(085, 1.10 119(098, 143 0944026, 1.15) 02(083, 1.26 Any vitamin D supplement and i 1 03.084. I 27) 093 (0.76 13)0990.81, 12 61,676 ref, neference RRs were from a log bisomial ngression model Sample incladed participans with a tollow-upquesionnaise at 6 moinm$5,142 RRs wetthon. kng binonsal regresana model Analyas nl ded all eligiNe children (n 61,676) with chald suppkmmt uie npkdfor 10.6% of Tnlan supplements vtamin only, ood liver oiL muluvitamins) were mutually adjunted for wih alditional adjustments foe matenal soul intake of AD.E and Colate; sum of s-3 faty acikds (all in quintles and sotal energy (oosisuous the folowing atenall prenatal facton: age at delivery following postnatal child factos:irth weight(2500 2500 4500, or 24500 gk prematurity (so or yesl moets of fall becastlceding 1 to 4,410 6or wese handied by muiple impuatin10 by using chained oquation
AT&T 2:33 PM moodle-2018-2019v2.calstatela.edu nom the Danish
(typically 200-250 ug) and vitamin D (typically the recom intake close to recommendations was associated with a reduced mended dose of 10㎍), and cod Iner oal also contains vitamun nsk of asthma at school age but tot when mamul =ake of v E and n-3 fatty acids. A potential explanation for this difference tamin A was high. Thus, be balatce od vtima A ะtamin D is that liquid multivitamins for children contain water-miscible or intake during pregnancy could be of importance to asthma sas- emulsified petimi, which could be more sonic thaaretinol in oil. ๙ptility in the offspring. A high make ofdi tary nol com- based solutions such as cod liver oil (40) lnierestingly, a Swedish hined with a low ntake of vitam= D is som Weltm study found an increased risk of asthma and allergy in infants populaions (12) in which child asthma is common supplememied with vitamins A and D in wate based bat not ol based formula (43). In our study, the lack of association between Theau ngoshdiseaeak1m←WNadar serempu any multivitamin use and the risk of asthma in indants who were for the ly oonnCoK,NAL B given an additional supplemen conmaining vitamin D could beanMatoenbed to the data anC.LPwscript andhad explained by an antagoeistie efect fmin D on retinel. How- ever, it is also possibNe that these infants had a lower intake of to alternating use of a vtamin D supplement. Other vitamins or minerals in a multivitamin formala, potentially folic acid could is always of concem in observational stadies, but Ding and Van derWeeles (33) framework provides some reassurance that even a modest RR o .2 is relatively robust to usmeasared confound ing. Last, we did not assess the potential influence of vitamin A and D exposures at other time points, such as during lactation or has been associated with atopy and a T-helper 2 (Th2) dominated cytokine peofile. Vitamin A exerts many of its effects through retisoic acid-mediated gene tramscription, and retinoic acid may Hn YY.Fone E Hopi F.eC Die and have a Th2 cell-promoting effect (44) Although vitamin A is mainly stored in the liver, excess vitamin A also accumulates in the lung (15), where retinoid metabolises may caase asma- like symptoms (45), In the rat lung, vitamin A sapplementation an une stress (46, which also may impair lung function. We found no in- asthma The effect of β-carceme was weaker hat inthe same di. 襄Manwaki D, Pamiwr L Stad M. Mdat MF. FanuB M. rection as retinol. However, many aspects related to the matemal- fetal transfer of retinoids and carotenoids, their metabolism in the developing tissues, and homeostatic control in the face of exces sive matemal dictary vitamin A intake are still poorly understoodwes BL Boescylie K Slin &, Vsing NH Biprsaotie E 47).Our results suggest that litt ke, if amy, of the effects of vitamin A and D imake during pregnancy on child asthma were modiated through low birth weight or prematurity. We found some inds- cation that the adverse effects associated with excess vitamin A Da-从Gmy va, L Nail.. Mila E were mitigated by having a sufticient intake of vitamin D. This observation is in line with mechanistic stadies in mycloid cells. showed that vitamin D represses retinoic acid transcrip- tional activity, but the action is 2 way, which also explains how vitamin A can atlenuale vitamin D activity (22 11. Fong H. X-P, Pk K. wlb AK 000 BL angand H, Ca In this study, we found that a dict naturally high in vitamin A combined with the use of supplements comtaining retinol during pregnancy place women at risk of vitamin A ecess, which was children. We observed this effect for intakes that were 2 25 times level for retinol of 3000 upld during pregnancy (27). Vitamin D
All of the following questions are in relation to the following journal article which is available on Moodle: Parr CL, Magnus MC, Karlstad O, Holvik K, Lund-Blix NA, Jaugen M, et al. Vitamin A and D intake in pregnancy, infant supplementation and asthma development: the Norwegian Mother and Child Cohort. Am J Clin Nutr 2018:107:789-798. QUESTIONS 1. Describe why the authors conducted the study 2. Who are the participants of the study? 3. Where did the study take place? 4. Name the main disease and exposure for this study? 5. Look at Table 3. The authors list quintiles of maternal vitamin A intake. (NOTE: A quintile is chopping the data into 5 even groups once it has been ordered from lowest to highest. The first quintile [Q1] is the group of moms that had the lowest intake of vitamin A. Q2 is the group of moms that had the second lowest intake of vitamin A and so on. Q1 is used as the comparison group for all of the relative risks (RR) reported in the table). Cases refer to the number of asthma cases. Create a two by two table that can be used to calculate the relative risk comparing tisk of asthma for children at 7 years old between the moms that had the highest intake of vitamin A to the lowest intake of vitamin A during pregnancy. a. b. Use the Cases/total n column of table 3 in the journal article to fill in the numbers of your two by two table. Calculate the risk of asthma for the children with moms who had the greatest intake of vitamin A during pregnancy. Calculate the risk of asthma for the children with moms who had the lowest intake of vitamin A during pregnancy. Use the risk estimates you calculated in 5c and 5d to calculate the relative risk. (HINT: your relative risk should be equal to the Crude RR presented in table 3 of the journal article for Q5). d. e. f. State in your own words what the relative risk in Se means.
Vitamin A and D intake in pregnancy, infant supplementation, and asthma development: the Norwegian Mother and Child Cohort .5.6 Oystein Karilstad Kristin Holvik Nicolai A Land-BlixMargareta Haugen 1.7 Christian M Page. Per NdPer M Ueland. Stephanie JLondon Siri E Haberg.and Wenche Nysad Division of Mental and Physical Health. 2Department of Expount and Risk Assesort and Oate fr Ftlay and Health, Norwegian Intitute of Public Health, Oslo, Norway. ●Department of Nunung and Health Prometne akMet-ab Metropdaan Usoruty. Odo, Norway, ,Modical R earch Council Integrative Epademiology Unit. University of Brisa L Briad United KingdE 6Dqubeal of Rpulace Health Sciences, Bristol Mekal School, Bmi- tol, Usited Kingplom: Division of Pediaric and Adolescess Medicine, Departmens of Pediatrics Oslo eiversity Hospital Olo Norway. Department of Community Medlicine, University of Oso Osdo, Norway: Department of Clinical Science, Usiverity of Berpon, Bergen Norway: Laboratory of Clini cal Biochemisay. Haukeland University lio pital. Berpen, Norway, and : 'Epidemiology Branch, Nabond ๒titate of Eminonmental Health Sciences, NIH. Department of Health and Human ServicesReseach Triangle Park, NC ABSTRACT Background: Weslem diets may provide excess vitamin A, which and Child Cobort is potentially toxic and could adversely affect respiratory health and counteract benefits from vitamin D Objective: The aim of this study was to examine child asthma at age 7 y in relation to maternal intake of vitamins A and D during pregAsthma is currently among the top 5 chronic conditions con- nancy, infant supplementation with these vitamins, and their potential tributing to the global burden of disease in children aged 5-14 y interaction Desian: We studied 61.676 school-age children (bum during 2002 ส。ase the sucepth lity to asthma (2) and dietary exposures in 2007) from the Norwegian Mother and Child Cohont with data on utcro and infancy could play a role, in particular for childhood matemal total (food and supplement) nutrient intake in prenancy onset of the disease (3) (food-frequency quesdionnaire validated agaist biomarkers) and inFa-soluble vitamins have a broad range of effects related to fant supplement use at age 6 mo(n·54.142 duldren). Linkage with anto uda poperties (4) ait une fiction (5), and hing devel. the Norwegian Prescription Database enabled near-complete followopment (6) in partcuar, vitamin D has attracted much interest up (end of second quarter in 2015) for dispensed medications to clas- because of widesprcad deficiency in Westem populations (7) sify asthma. We used log-binoenial regression to calculate adjusted RRs .aRRs) for asthma with 95% Cls. Results: Asthma increased according to maternal intake of to- tal vitamin A [retinol activity equivalents (RAEs3] in the highest RecanAaHNanunNMeof Emin amental Health Scien esice tract 22031 RAEsd) compared with the lowest ($779 RAEd) quin- NOI-ES-75558) and NIBUNaional Initule of Neurological Disorders tile (aRR: 1.21; 95% CI: 1.05, 1.40) and decreased for total vitamin and Stokeipat Dos. 1 UOI NS 047537-ol and 2 U01 NS 04753746AD. D inte highest ( 리 3.6 Ag/d) compared with the lowest (S3Spg/d) Thn·ork wa ako supp rted by Norweg n Rotach Gemigrant no quintile (aRR: 0.51; 95% Cl: 0.67, 097) during pregnacy. No as- sociation was observed for maternal intake in the highest quintiles of both nutrients(aRR. 0. 99, 95% Cl: 083, 1.18) and idant supple- mentation with vitamin D or cod liver oal. Conclusions: Excess vitamin A (223 times the recommended in- tale) dring pregnancy was associated with increased risk, whereas .Suppknau, ite online posang of he article and from the vitamin D intake close to recommendations was associated with a re- same lak the eine tNe of contents duced risk of asthanan school-age children. No assocation for high AAde" comequekwe··CLPie-mat ehnline-louise parethaw intakes of both nutrients suggests antagonistic effects of vitamins A Ariatioes ed FO. food-equncy quetionnasc Mola No- and D. This trial was registared at hp NCTO3197233. Am J Clin Nutr 2018:107:789-798 prescriptions, Norwepian Prescription Database, Norwegian Mother INTRODUCTION (1) Unfavorable changes in diet have been hypothesized to in- The Norwepian Mother nd Child Coon Saady is supported by the Nowe to-gin Minisy of Heakh and Cae Seevices and the Mnistey of Educatin and 221097, to w%)and by te tram ral Rexach hyram of the NIH. Na- tional ๒eMe of Eminnestal Health Sciences (201 ES49019, 10 SIL). The funders of the stuly had no roke in study design, data collection, data analysis and inapectation, witing of the port or the decision to suhaut the articke for pulication Supplemttal Fig aid Supplemental Tiles 1-8 are available from the as wepian Mother and Child Colbont Study NorPD. Norwegian Prescription Rexeived June 13, 2017. Accepied for publication January I7.2018 Fine pulished online April 20 2018 doi: htoo/0 1093/ajcn Keywords: food-frequency questionnaire, dictary supplements, women, infants, vitamin A, vitamin D, pediatric asthma Ani/ Ca" Nrtr 2018; 107: 789-798 in the public domain in the US Printed in USA © 2018 American Society for ,ettim Thi work B wenen by (a) US Government employee(s) and is 789
790 PARR ET AL Studies that used Mendelian randomization do not support th for 212 mo from age 6y in 61.676bom 2002-3007 ofwhom genetically lowered 25-hydroxyvatamin D is a risk factor for 89% (n = 55.142, had data oantal ฉpplentnt use 6 mo. asthma (8), However, randomized trials 9, 10) and a meta Weused a random suhsample of 2244 iths from 2002-2008 so analysás of binh coho studies (11) sugpest that paenatal vitacompare maternal dictary intake with plasma concesrations of min D supplementation above the regular dose (9. IOL and higher fat-soluble vitami at 18 tegatotal wack maternal circulating 25-hydroxyvitamin D (11), may reduce the suscepibility lo asthma in the offspring, although follow-up of children to school age is not yet available in the trials Vitamin A deficiency poses apublic health problem in partsf The MoBa stady has been approved by the Norwegian Data the world, but westemized diets may peovide excess vitamin A Inspectorate (reference 01/4325) and the Regional Commitee (12-14) from increasing intakes of animal products and fortified for Medical Research Ethics (refererence S-97045, $-95) A foods and the use of dietary supplcmens Hagh dictary vitamin of the participants gave writien informed consent at the time of A has been associated with increased asthma severity in a marine enrollment The cament study was approvod by the Regional model (15) but human studies are limited by potential toxic Committice for Medical Research Ethics o SouthEasit Norway. effects and a lack of feasible biomarkers for assessing adequate or subtoxic status (16). Observational studies, rather than trials, are therefore important to examine unintended health effects of vitamin A excess at the population level. Previous observational Taa』( food and supplement) nument澀kes dang pregancy studies of vitamin A and asthma have mainly focused on the were esimated from the HQ, which queried about intake since antioxidant properties of carotenoids (3) and have not incladed becoming pregnant. The FFQ has been validated agaiest a4d retinol, the most potent form of vitamin A. Vitamin A supplemen- weighed food diary and with selected binders (25, 26). T> tation trials have been conducted in areas with endemic deficiency tal vitamin A <sum of total retinol and tial β-car tene) was ex- (17, 18) where the effects on respiratory outcomes could differ pressed as daily setinol activity equivalents (RAEs) per day by from those แ1 well-Dounshed populations due to differences in usang te conversion factors1 μ.etal drum áct or supple- baseline vitamin A status <19). Few studies, to our knowledge, ments) 12 ㎍ ßanlene from det 2 ㎍ ßanene feom have examined the risk of child asthma in relation to prenatal con- supplements to account for differences housaldlay d27). To- centrations of vitamin A, including retinol, outside of deficient tal vitamin D (micrograms per day) incladed vitamin D from populatie s (20, 21 er the importance of prenatal compared with foods and vunns D: and D, fecen獾pplements. Nutrient mule early postnatal exposure. Furthemore, high vitamin A intake was calculated by using the Norwepian Food Compesition Ta could potentially counteract the beneficial effects of itamin D, ble (28) and a compiled database od dietary supplements, mainly due to competition foe the nuclear tetinoid X receptor (22) Dictary esposure assessment and biomarker comparisons Our objective was to investigate the association of maternal and 25-hydrosyvitamin D: and D, were mcasuned at Bevital AS intakes of vitamins A and D during pregnancy, infant exposure laboratories in Bergon, Norway (www.bevitalmok in a singk to dietary supplements containing these nutrients, and potential nonfasting venous blood sample drawn at 18 wk of gestation. nutrient interaction, with current asthma at school age when the The frequency of infant supplement use (sever, sometimes, diagnosis is moee reliable than at earlier ages Norway oflers daily) was assessed from a fellow-ap questionnaire mailed advantages for the study of high intakes of vitamin A during 6 mo of ape. We analyzed the use of the following sapplement pregnancy because of a generally high intake from food sources categories containing vitam A or D or bode vita D cely in addition to the widespread use of cod liver oil as a dietary (lsquid oil-based formula), cod lver oil maltivitamins, and any vitamin D supplement, excleding livitamins. The lamS egory included vitamin D only, cod liver eil and less commen sapplements (fish oil with added vitamin D, liquid vitamin A and vitamin D Sormula, vitamin D with fucride, and other vitamin D The study included participants in the Norwegian Mother and Child Cohort Study (MoBa), a population-hased pregmancy co hort (births dring 1999-2009) administered by the Norwegian We examined unnt asthma inchilien ~7yofagedfned Institute of Public Health (23, 24). Women were recruited naas having22pharmacy dispensations of asthma medication in the tionwide (41% participation) at ~ 18 wk of gestation when a pre- NoPD within a 12-mo interval, the fint prescrption being dis- natal screening is offered to all pregnant women. For the cur pensed between ages 6 and 7y. Noncases were all children who rent study we linked MoBa file version 9 (115,398 children and did not meet these criteria. Asthma medications were inhaled P 95,248 mothers) with the Medical Birth Registry of Norway agonists, inhaled glucoconicoids, combination inhalers with p (hereafter referred to as the birth registry) and the Norwegian apaists and glucocorticoids, or ledtrenereceptratagoi Prescription Database NorPD), with follow-up to the end of the second quarter of 2015. The curent study was repistered at Outcome measures of children's asthma gov as NCTO3197233. Eligiblechildeen Figure 1) had available data on maternal dietary intake in preg- nancy from a validated food-frequency questionnaire (FFO) ad-the birth registry (maternal age at delivery, parity, region of de ministered ~20 gestational weeks and prescription follow up livery. Bode of delivery. child's sex buth wash and gestational Potential co funders and co vanaks wae bood on data from
VITAMINSA ANDD AND ASTHNEA DEVELOPMENT 791 Noe-live births n 371 Multiple birt (-3,139 Loss to later child death (-230 Loss to enigration or unknow vital status -677 -1,437) Ne sspelement data ( 836 having maternal haslne dts and FFQ om g6y -20,121 sitamin intake and child m ned n 61676 No folo-p at age 6 monds -6534) with maternal FFO and plain bomurk data (n-2244 ash(-55,142) age) or MoBa questionnaires compkesed at approximately gesta North) as a proxy for btitude of nesidence, and season of deliv tional weeks 18 (inclusion), 20 (FFO), and 30 and when the childy anuary Manch, April-June, Jaly-September, or October was aged 6 mo. December). Malernal histories of asthma and allergic disorders Because cod liver oil and other omega-3 pplements con- esep rate variables) were defined as ever reports at week 18 of tribute to the intake of vitamins A and D im many MoBa women asthma or hay fever, atopic dermatitis, animal hair allergies, or (13), we also evaluated malemal mtakes of (ter nutrients pro- าber" alerg es. vided by these sapplements, including vitamin E (preservative,Mamy clinical practice guidelines recommend the use of di- ntioudant) and lingdaan 1-3 fatty ac ds (EPA. doos pa- day suppleme識ndulag multivitamins. to ensure adequate tacnoic acid, and DHA) In addition, we incladed vitamin C as mtentsapply to low-birth-weight or premabure infants (31). To a measure od fruit and vegetable intake (29) folate intake (30 adjust for child frailty, wich could be related to both supple and total energy intake. In sensitivity analyses, we aso eval ment use (therapestic or montherapeutic)and later asthma suscep- uated maternal rinc intake (3) and birth year to control for a ibility, we included low birth weight (2500 g), premature birth potential cobort effect. To assess potential confounding by UV gestatioeal age <37 wk), and postnatal exposures in the first exposure in the analysis of vitamin D intake, we included leisere- 6 mo to full breastfeeding (number of months), respiratory tract time physical ativay (a 1. 2-4, or 5 tame/wk) and solar, metus㈤ayes), and maternal smokmg (aa sca etime, of ium use (o, 1-3, or 26 total times) in pregnancy, peographical daily) in the main analysis. In sensitiviry analyses, we addision- region of delivery within Norway (South and East. West. Mid. ally incladed childs sex birth season cesarean delivery (no or
792 PARR ET AL yes), and use of paracetamol or acetaminophen (no or yes) and all spline term combinations from restricted cubie spline models with4 knots We also assessed the potcntial influence of unmea- sared confounding by using a recently published framework de- velopel by Ding and VanderWeele (33). The significance level was 5% or all tests. The analyses were conducted in Stata 14.0 antibiotics (no or yes) in the first 6 mo. Statistical analysis We examined associations of maternal vitamin A and D intake (SuaCop LP during pregnancy (exposuses) and infant supplement use (espo- sures) with children's asthma (outcome) by using log binomial regression. We cakulaod RRs with 95% as cm the basis of to- RESULTS bust cluster variance estimation and controlled for potential con- founding by multivariable adjustment. The NorPD linkage am abled near-complete follow-up for asthma. Parcipant selection is shown in Figure I, and sekected partic shown in Table I (moihers) and Table 2 children) Characteristies were similar for the main study sam- ple.thtsubsample withquestionnai爬follow- p at 6 mo, and the inagea pantcharacteristics are Our regression models were based on a directed acyclic graph for the hypothesized causal relations (Supplemental Figure I) omarke According to the graph, the effects of matemal intake and infant supplementation on children's asthma can be estimatiod indepen- dently when potentaal confounding faclors and modalonCharacteristics of mothers and children justed for. In the analysisof maternal intake (model I, vitamins A and D were mutsally adjusted for (Spearman comelation of 053 continuous data), and we additionally adjusted for total intakes of other nutrients (vitamin E: sam of the n-3 fatty acids EPA do- cosapentaenoic acid, and DHA: vitamin C and folate) andenargy during pregnancy. maternal prenatal factors(age at delivery. par- ity. prepregnancy BMI. education, history of asthma and atopy and smoking in pregnancy), and birth woight and prematurity as potential medialors In the analysis of infant supplementation (model 2), we mutually adjusted for the different supplements given and included all model 1 factors and postnatal child factons (months of full breastfeeding, child respiratory tract infections in the first 6 mo, and matcrnal smoking since birth) Missing val- ues in individual anariates were < 5% (Supplemental Table 1) and handled by maltiple imputation by using chained oquations (10 imputations )For 06% of the main study sample with miss ing questionnaire follow-up at age 6 mo (6534 of 61,6761 we assessed the effect of imputing the infant supplement exposure data before perferming multivariatle adjustments when potential confounding factors and modialors are ad- Associations between matenal characteristies and dsetary in take in pregnancy in- 61,676) ware generally in the same di- rection for vitamins A and D. High intakes were associated with older age, higher education, primipanity, lower BMI, less smok- dpplement use (Table I Sapplementation with cod liver oil at age 6 mo was related to high matemal intakes of both vitamins A and D (Table Dand was higher in chldren with positive heakh indicaaors (bnh weight 22500 g. tem birth, hreastfeeding 26 mo, and no respiratory ract infoctions or postmatal maternal smoking) (Table 2). The use of mulivitamins (percentage) was much higher among low birth weight(45%)and premature (31%) children, indicating therapeu- tic use accoeding to clinical practice guidelines (31), and was as- sociated with shorter beeastfeeding and mose postnatal matermal Maternal intakes of vitamis A and D and child asthma All of the matemal nutricnt intake variables were includodas The prevalence of current asthma at age 7 y. based on prescrip- quantiles so account for a potential nonlinear association aih in registry data, was 4.1%く2546 of 61,676). Children bom to children's ashna. We toted for linearity by induding thc qīn- w0ณาส dic highest comparod with the lowest quintile of total tile values (ondinal scale) as a continuous variable. To eamine vmin A ntake during pregnancy had a slightly higher preva the potential interaction between vitamins A and D in the mother, ktor of asthma (4.9% compared with 4.1%), and the adjusted we created a binary variable for high (highest quintile) com ured RR was 20% higher (Table 3). We observed the lowest preva- with low (all lower qmtiles) intakes of each vitamin d 4 ma- lene of asthma (3.6%) in the second quantile of total vitamin tually exclasive exposure categories for the following comA780-1102 RAEvd) in which intake was close to, or slightly tions low viamin A and low vitamin D, high vitamin A and lw ahove, the public recommendation for pregnant women ef vitamin D, high vitamin D and low vitamin A, and high vitamin RAEid in Nondic countrics (34), which is similar to other na- A and high vitamin D. To acount for multiple supplement use in bunal recommendations (35). Relative lo the second quintile, the children, we created 6 mutually exclusive categories for daily or adjusted RR of asthma was 32% higher (95% CI: 1.15, 1.51) in sometimes compared with never use of the followingh vitman the highest quantile. The effect of total vitamin A (retinol and β. D only; 2)cod liver oil only;3)multivitamin only:4)any vitamin carotene)was only marginally stronger than for total retinol. Total D sapplement inclading cod liver oil, combinod with a miD-canotene showed a weak, but positive association with asthma tamin: 5) maltiple vitamin D supplements (eg- vitamin Donly aer adjustment for total retinol The adjusted RR foe the high combined with a fish-oil supplement containing vitamin DK and Cx(>4007pgdaumpurod with the kwest (s1 360,pd) quin- ble of β carotene was I.I l (95% CI: 0.98. I.27) (Supplemental In sensitivity analyses, we added more covariates to our main Table 21. The Spearman comelation between total retinol and to- multivariable regression models, as described in Results, and we tal -canoene (continuous datal was 0.12. A high intake of vita performed propensity score matching as an ahernative method of min A from food was not associated with asthma when the study controlling for posential confounding (32). We tested for i sample was restricted to nonusers of retinol-containing supple- plicative interaction between maternal intakes of vtamn A and mrss (712 cases; m-16,924). The adjusted RR was 05 (95% vitamin D taking potential ถ0nlinearity intacoust by incluing 0.81. I 36) for the highe42 1462 RAENU) compared with 6) none of the categories (reference).
VITAMINSA ANDDANDASTHMA DEVELOPMENT 793 TABLE Vitamin Dy o1 (5779 RAEd 12,331 023031 RAE 0542 136 pg 12.378 Maternal age at. delivery. % 25-30y 01 38.7 89.2 197 Manal cluation. % Less tun Nigh school High school 4y of olle 95 10.7 270 y of college 201 185-249 50-299 57.8 250 49 203 67.9 195 25.9 Saoppeldl in prn Maonal history ofadina, % yes Macrnal history ofalipy, % yes Cod lnver oil 31S Oher n-3supplement Polic acid Cod liver 97 75.7 Child suppkan uea6mo(m-55,142. % yes Vaamin D dros 61.676 Q.quinike: RAE, stinol activity ogaivalet the lowest (97 RAEsd) quintile of food vitamin A ntake (e mohan the standard daily dose of 250 ug, or commbine multi-S sults not shown). ple supplements. However, food retinol contributed most to total A high intake of vitamin D during pregnancy was associa with less-freqarnt asthma (3.9% compared with 4.4% for the highest compared with the kwe quintilek, and the adgsled RR was-20% lower in the highest compared with the lowest qui tile Table 3). we observed no adverse effect of high vitanan A, or a protective effect of vitamin D.kr intakes in the highest quintiles of both nutrients (Table 4) vitmin A (Supplemental Table 3). The main food sources were sandwich meats, indudagliver spread.fortified margarine, and dary pecdads. In Norway. dairy products are not fortified with rcitol-4at milk is frihed with low ameusts of vitamin D, bui food ke of vitamin D vaned linke, and the use of supple- mcntal viani. D.7Vi overall compared with 99% in the highest quintikk) was an important coetributor to total vitamin D intake Supplemrntal Table 4 Food and supplement contributions to maternal intake o total vitamins A and D The use of supplements containing rctinol, inclading cod liver n the biomarker subsampke in-2244), matemal plasma oil. was cornmon (73% overall conpared with 86% in the high- vdan= D, coecentration increased across each quantile of total est quintile). The median intake of suapplemental retinol among vitamin D intake (medians: 68,72. 74,75, and 82 nmolVL for users was 300 Pgid in the third through fith quintiles of to- the first through the fifth quintile, respectively. see Supplemental tal vitamin A intale, indicating that many pregnant women talkle Table The overall plasma-diet Spearman correlation
794 PARR ET AL TABLE 27 2500-4S0 4901 1.223 2424 227 Preterm binh 291 Yes 1536 westtion 219 228 Mooths of fall beeastfeoling 132 21.295 89 57.3 Respirabony wact infoctioms in the firsl 6 mo 922 10 92 Yes, hospitali Posmatal matemall smking in the 5.680 218 55.1 continuous) for vitamin D varied with the season of Hlood (see Supplemental Table 3), ao as especied, due to its strict draw, from 0.15 in summer to 032 in winter. Asseciations homeostatic control with indicators of UV exposure were in Supplemental Table 5 plasma vitamin D increased with leisure-time physical activity and tanning bed une in pregnancy and from Nort to South for geographical region of delivery The Daily infant supplemenutoe wi血vu in Donly orcod liver macmi plasma retinol concentration (mediat: 164 μη1L oil was na assoaaed.ith n kofathmaat school age. Daly IQR; L46-L83 μη。VL) vaned little with vitamm A make use of mltvítamns was assaaed with al high RR after the expected direction Infant supplementation and child asthma TABLE D intake in peegmany Quistiles of intule Total vitamin A (RAEd Prevalence, % oene 02(780-102 3 (1103-1479) 04(14802030 05c200 Parend 06/12 33 78/12 39 312 345 313 813 08 (0.93,13 21 1.05.140 o1 (535) 0206-5.7 85/1248 90(0791 89 (.77, 15 40 04(87-35 QS(2135) 031 67.097) and prematurity no oryes). Misning values in covariates were haled by uiple impution1nhinedqt
VITAMINS A ANDDANDASTHMA DEVELOPMENT Cosdunod elect of bal vlanin A and vi ann D make-pregnancy and RR estimules e95% as) for current asthma aR age 7 y Total vtamin A (RA 128(1.15,1.43 087(076,0 21 L.08, 136) 086(073, 100 99 0.83,1.18 61676 RRs ane from a log binoemial negnession model A high intake coresponds to the highest quineilke (05) and low intake to all lower quiniles 01-04)is Tale 3.Q.quinike: RAE, enol activy equivalent rel eference ๒c㎕ energy inuke (continuousk the flowing maternal or yesi history of atopy (no or yes), and smok ing in pregnincy ino, quit or yes Adjusted for materal total intake of vitamins A or D(al adjudment vitamis Evitamin C. folate and sum of n-3 fary acids al in qeintiles) and pengal factors: age at delivery 60e_ws), p nay (AL or sh. edaatiou.les&an high 4hol. and the following medialerx bhrth weight (2500, 2500-4500 or 24500g and peematurity (no or yes) Missing values in covarates were handled by mbiple imputatic10p by using chained equations multivariable adjustment Table 5). However, there was no in control for a potential cohont effect Supplemental Table 6. The creased risk for any (daily or sometimes) use of mukivitamins in results from the nonlinear analysis of multiplicative interaction infants who were given an additional vitamin D containing sup were not significant (P-interaction from 059 to 094 in the multivariable model). Coafounder adjustment by multivariable regression and propensity score matching gave similar results Supplemental Table 7). From our main model (Table 3)% We estimated the direct effect of maternal intake not mediated Results on matcrnal intake (Table 3) were robust to a range through low bith weight and peematurity, however, the toal of sensitivity analyses including additional adjustment for total efect not adjusting for these medialos, was similar (results no inc intake. proxy variables for UV exposure during pregnancy shown).Resulks on infamt supplement use (Table 5) were little leisure-time physical activity. tanning bed use, and geographicall ected by additional adjustment for indicators of chil frailty region of delivery) in the vitamin D analysis, or birth year to or asthma susceptibility (child's sex, Hirth season, delivery by Maternal and child sensitivity analyses Infant s pglement use inthe first 6 mo and crude and bhiled RR e maes (95% Cls) forcameM adala at age 7 ya 0360.77. 0%, 086.0.77.097) 0.91 40si, i02) 92 00.84, LOD092(084, 10097(087, 1.9 0.84, 116 10240.87,19 105(089, 1.23 698 0.77, 19) 1.47 (1.25, 1.72) 97(0.78,12 0ss(071, 10 1.45(1.24, 1.70, 1.19(1.01, 1.41) Cod lner eil enly 95 (0.83, L)097(085, 1.10 119(098, 143 0944026, 1.15) 02(083, 1.26 Any vitamin D supplement and i 1 03.084. I 27) 093 (0.76 13)0990.81, 12 61,676 ref, neference RRs were from a log bisomial ngression model Sample incladed participans with a tollow-upquesionnaise at 6 moinm$5,142 'RRs wetthon. kng binonsal regresana model Analyas nl ded all eligiNe children (n 61,676) with chald suppkmmt uie npkdfor 10.6% of Tnlan supplements vtamin only, ood liver oiL muluvitamins) were mutually adjunted for wih alditional adjustments foe matenal soul intake of AD.E and Colate; sum of s-3 faty acikds (all in quintles and sotal energy (oosisuous the folowing atenall prenatal facton: age at delivery following postnatal child factos:irth weight(2500 2500 4500, or 24500 gk prematurity (so or yesl moets of fall becastlceding 1 to 4,410 6or wese handied by muiple impuatin10 by using chained oquation
AT&T 2:33 PM moodle-2018-2019v2.calstatela.edu nom the Danish
(typically 200-250 ug) and vitamin D (typically the recom intake close to recommendations was associated with a reduced mended dose of 10㎍), and cod Iner oal also contains vitamun nsk of asthma at school age but tot when mamul =ake of v E and n-3 fatty acids. A potential explanation for this difference tamin A was high. Thus, be balatce od vtima A ะ'tamin D is that liquid multivitamins for children contain water-miscible or intake during pregnancy could be of importance to asthma sas- emulsified petimi, which could be more sonic thaaretinol in oil. ๙ptility in the offspring. A high make ofdi tary nol com- based solutions such as cod liver oil (40) lnierestingly, a Swedish hined with a low ntake of vitam= D is som Weltm study found an increased risk of asthma and allergy in infants populaions (12) in which child asthma is common supplememied with vitamins A and D in wate based bat not ol based formula (43). In our study, the lack of association between Theau ngoshdiseaeak1m←WNadar serempu any multivitamin use and the risk of asthma in indants who were for the ly oonnCoK,NAL B given an additional supplemen conmaining vitamin D could beanMatoenbed to the data anC.LPwscript andhad explained by an antagoeistie efect fmin D on retinel. How- ever, it is also possibNe that these infants had a lower intake of to alternating use of a vtamin D supplement. Other vitamins or minerals in a multivitamin formala, potentially folic acid could is always of concem in observational stadies, but Ding and Van derWeele's (33) framework provides some reassurance that even a modest RR o .2 is relatively robust to usmeasared confound ing. Last, we did not assess the potential influence of vitamin A and D exposures at other time points, such as during lactation or has been associated with atopy and a T-helper 2 (Th2) dominated cytokine peofile. Vitamin A exerts many of its effects through retisoic acid-mediated gene tramscription, and retinoic acid may Hn YY.Fone E Hopi F.eC Die and have a Th2 cell-promoting effect (44) Although vitamin A is mainly stored in the liver, excess vitamin A also accumulates in the lung (15), where retinoid metabolises may caase asma- like symptoms (45), In the rat lung, vitamin A sapplementation an une stress (46, which also may impair lung function. We found no in- asthma The effect of β-carceme was weaker hat inthe same di. 襄Manwaki D, Pamiwr L Stad M. Mdat MF. FanuB M. rection as retinol. However, many aspects related to the matemal- fetal transfer of retinoids and carotenoids, their metabolism in the developing tissues, and homeostatic control in the face of exces sive matemal dictary vitamin A intake are still poorly understoodwes BL Boescylie K Slin &, Vsing NH Biprsaotie E 47).Our results suggest that litt ke, if amy, of the effects of vitamin A and D imake during pregnancy on child asthma were modiated through low birth weight or prematurity. We found some inds- cation that the adverse effects associated with excess vitamin A Da-"从Gmy va, 'L Nail.. Mila E were mitigated by having a sufticient intake of vitamin D. This observation is in line with mechanistic stadies in mycloid cells. showed that
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Answer #1

1. The study was conducted to assess the adverse effect of excess Vitamin A on respiratory health as it counteracts benefits from vitamin D. The study researched the child asthma at the age in relation to the intake of vitamins A and D during pregnancy by the mothers, infant supplementation with vitamins A and D, and their possible interaction. The research was conducted based on the background that asthma is one among the top 5 chronic conditions in children aged 5–14 y adding to the global burden of disease in children.

The hypothesis of unfavourable changes in dietary exposures in utero and infancy play a particular role in childhood-onset asthma.

2. Participants

61,676 school-age children from the Norwegian Mother and Child Cohort, they were born during 2002– 2007. The participants from Norwegian Mother and Child Cohort had all the data on maternal total nutrient intake in pregnancy and infant supplement use at age 6 mo (n = 54,142 children). The Norwegian Mother and Child Cohort the nutrition assessment questionnaire was validated against biomarkers to ensure reliability.

In the population-based pregnancy cohort study conducted by the Norwegian Institute of Public Health of Norwegian Mother and Child Cohort Study (MoBa) considered the births during 1999-2009.

For the present study, the researchers used the MoBa file version 9 (115,398 children and 95,248 mothers) with the Medical Birth Registry of Norway and the Norwegian Prescription Database (NorPD), and the follow up ended till the second quarter of 2015.

3. Where?

Women were recruited nationwide from Norway at ∼18 weeks of gestation a, done when a prenatal

screening is offered to all pregnant women.

4. Disease and exposure

The study assessed asthma in children at∼7 y of age. The cases were defined as having more than or equal to two pharmacy dispensations of asthma medication in the NorPD within a year and the dispensation of the first prescription must be between ages 6 and 7 y. The medications considered were inhaled β2- agonists, combination inhalers with β2- agonists and glucocorticoids, inhaled glucocorticoids, or leukotriene receptor antagonists.

The controls were the non-cases were all children who did not meet these criteria.

The selection of potential confounders and covariates were done based on data from the birth registry like parity, region of delivery , maternal age at delivery, mode of delivery, gender of child, birth weight, and gestational age or MoBa questionnaires completed at nearly 18, 20 and 30 weeks of gestational age (including 18 weeks) and the time the child is 6 months old.

Maternal intake of other nutrients was also evaluated like vitamin E and long-chain n–3 fatty acids (EPA, docosapentaenoic acid, and DHA) along with vitamin A and D as the cod liver oil and other omega-3 supplements are the main source of supplementation for most of the women.

The fruit and vegetable, folate, and total energy intake were measured by the Vitamin C intake. Maternal Zinc intake was monitored in sensitivity analyses.

Leisure time physical activity and solarium use in pregnancy, geographical

a region of delivery within Norway and season of delivery used to assess the cofounding influence of UV rays in analyzing the vitamin D intake.

The maternal histories of asthma and allergic disorders were assessed as ever reports and other allergies.

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