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All of the following questions are in relation to the following journal article which is available...


All of the following questions are in relation to the following journal article which is available on Moodle: Parr CL, Magnus
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790 PARR ET AL Studies that used Mendelian randomization do not support th for 212 mo from age 6y in 61.676bom 2002-3007 ofwh
VITAMINSA ANDD AND ASTHNEA DEVELOPMENT 791 Noe-live births n 371 Multiple birt (-3,139 Loss to later child death (-230 Loss t
792 PARR ET AL yes), and use of paracetamol or acetaminophen (no or yes) and all spline term combinations from restricted cub
VITAMINSA ANDDANDASTHMA DEVELOPMENT 793 TABLE Vitamin Dy o1 (5779 RAEd 12,331 023031 RAE 0542 136 pg 12.378 Maternal age at.
PARR ET AL TABLE Child hirh weighg 27 22.7 Pretierm birth 30.7 12 112 21.298 25.354 27.7 552 279 Respinaony wa infections in
VITAMINS A ANDD AND ASTHMA DEVELOPMENT 795 Cenhnedeflict of kud vitanan A, and vitanna D.atake .npregnancy and RR canin 85% C
PARR ET AL cesarean section, and antibiotics and paracetamol use) car the authors nbuted the association tothe high retinol c
VITAMINS A ANDD AND ASTHMA DEVELOPMENT (typically 200-250 ㎍) and vitamin D (typically the moon, intake close to recommmhions
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. State one hypothesis the author's proposed in the manuscript. 2. There is previous research that shows that adequate Vitamin A intake is required in early lung development. Babies' lungs begin to develop during the 2nd trimester of pregnancy (26 weeks). Draw a timeline that includes both the induction time and the latent period for childhood asthma (main exposure) at 7 years and maternal intake of vitamin A (main exposure). Looking back at table 3, is there any evidence that Vitamin A intake during pregnancy protects children from getting asthma? Use one statistic from the table to support your answer Draw the causal model proposed by the authors of this study in table 3. Using the data from Table 5, create a two by two table to calculate the relative risk comparing risk of asthma for children at 7 years old between infants that that had cod liver oil supplements daily during their first 6 months of life and those that had no cod liver oil supplementation. 3. 4. 5. Calculate the risk of asthma among the children who had cod liver oil supplements daily Calculate the risk of asthma among the children who did not have the cod liver oil supplements. Use the risk estimates in 5a and 5b to calculate the relative risk. (Note: the relative risk you calculate should be the same as the Crude RR for daily cod liver oil supplements in table 5). a. b. c. d. State, n one sentence, the meaning of the relative risk that you calculated in 5c. 6. Discuss how Bradford Hill's causal criteria for temporarily is met or not met in relation to this study
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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 vitamin D, ble (28) anda compiled daabase of dietry supplement廴,umly 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) 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 education, primiparity, lower BML, less smok- older age, higher 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
PARR ET AL TABLE Child hirh weighg 27 22.7 Pretierm birth 30.7 12 112 21.298 25.354 27.7 552 279 Respinaony wa infections in the 289 267 9.2 132 12.7 12 Postsatal malemal smking in the 45 680 210 21.6 75 11.3 n 55.14 (continuous) for vitamin D varied with the season of hlood (see Supplemental Table 3), also as expecied, due to its strict draw, from 0.15 in summer to 032 in winter Associations bomeostatic control. with indicators of UV (Supplemental Table 5): plasma vitamin D] ฮ reased with leisure-time physical activity and tanning bed use in pregnancy and from North to South for geographical region of delivery. TheDaily infant supplementation with vitamin Donly or cod liver maternal plasma retinol concentration (median: 1.64 umolL: was not associated with the risk of asthma at school age. Daily IOR: 1.46-1.83 μί0VL) varied little with vitanin A ide uKofmoltivitamins was asociated with a 19% higher RR after exposure were in the expected direction Infant supplementation and child asthma TARLE Crade R Ttal vitamin A RAE 01 (3779 02(780-1102 03(1103-1479) I (ref) 0.91030, 1.8, 0.99 (0.86 113 108 4093,124 094疸83, 106, 03 4091 116 1843.05.133 Total vitamin Dipgld Q1(s35) 0206-57) 03(38-86) Q4 7-135) 0%136) 91 (081.1.03 08 091, L 88 40.78,0.99 0.9040.79, L02) 89 (0.77, 1.03 096(0.82 112 0.81 0.67,097) high school, 24 y ofeellepelunnersay, or >4 y ofaleple erwtyh.pe uny BMI4gh㎡ 185. 185-249. 250-299. or 3OL history of asthma cno
VITAMINS A ANDD AND ASTHMA DEVELOPMENT 795 Cenhnedeflict of kud vitanan A, and vitanna D.atake .npregnancy and RR canin 85% Cls)foe cumens asema at age 7,. Total viamin ARAE High (2203 High (2203 Adjuted RR ow (135) Low (s135) High 136 High 13.6 16874190 5.2 1 28(1.15,143 087 0.76, 0.98) 1.10(096, 126, 1.21 1.08, 1.36) 0.86 073, 100 99083 1.18 219 4951 61676 RRs are from a log binonial egression model A high intake corepoeds to the highest quintile 05) and low imake to all kower quinailes Q1-04) in Table 3,Q,quink: RAE, wtinol activity quivalemef, reference Adjasiold for macrnal cal intake of vitamim Aor D(l adjustment vitumin E, vitamin C. folate, and sm of n-3 fatty acids (all in quinikes) and k tal energy intake (continuou坎the flowing makmal preutal factor apr at delivery (coatinous), y 'o, .. or 2), educan tless than high school. igh school 4 yeff collegeunverity,o4 yofcollepolaniversity).peepeegnancy BMIIs5, 18.5 249, 250-29.9o z 30 hisy of ashmu (n and prematurity (noor yes) 獢tung values incowanates were handled by mwkiple .mpunn (m- 10) by using duted equatse. meltivariable adjustment (Table 5). However, there was no in- control for a potential cohort effect (Supplemental Table 6). The creased risk for any (daily or sometimes) use of multivitamins in results from the nonlinear analysis of multiplicative interaction vitamin D-containing sup not significant (P-interaction from 0.59 t0 094 in the multivariable model) Confounder adjustment by multivariable regression and propensity scoee matching gave similar results Supplemental Table7). From our main model (Table 3, we estimated the disect effect of maternal intake not mediated Resulks on maternal intake (Table 3) were robust to a range through low birth weight and prematurity; however, the total of sensitivity analyses including additional adjustment for total effect, not adjusting for these mediators, was simalar (resalts not rine intake, proxy variables for UV exposere during pregsancy shown). Resuks on infant supplement use (Table 5) were lale deisure-time physical activity, tanning bed use, and geographical affected by additional adjustme for indicators of child frailty region of delivery) in the vitamin D analysis, or birth year to or asthma sascepibility (child's sex birth season, delivery by infants who were given an Maternal and child sensitivity analyses TABLE Intant supplemeat use i the fins16 me ad crude and advind RResamaks Ο5% Cb) for currenc adma at age 7 y, Crude RR Cod liver oi 211 579 721/18.198 l (ref) 036"O 77, 096) 036 40,77,097) 091のSI, i02> 92 (0.84, LOD092(084 10)07 087. 109 Daily Munin Donly Ne 02 4087, 119)05089, 123) 099 (084, 16 96(0.87, 1.06099 (0.90, 1.10)07 56 1.09 7512053 40 12129 095 (0.77, 119)707812) 080.71, 1.10 47 1.25, 172 1A5 (1.24 1.70 119(1.01. 14 $.9 109397 91624545 24/12978 l ref) Cod liver oil only Veanis D only 40 (1.16169 10008.123 093 (0.76 L13)099(081. 1.21 1394115 167).19 098 143) 103 4084. 127) 0076 1.15 Any vitamin D sapplemest and wkivitami 2831.26) RiRs were from a log binomial egression model. Sample ined participants with a elliow-up quessionnaine at 6 mo (n 55142 RRs wer, from a log binonial regresion model Analysis included all eligible chiam u"-61,676) sith child suppkment impuind for 106% of thc sanplc ณม.aing follow-up at age 6 tan Masang values were hailed by multiple imputam cm 10, by uung chained cquan. .Infant supplements cviumin D cely, ood kver oil tHIrvitami) were mutually adjusted with oMibonal abilikib fof malemal ๒tal imake of vitamamA,D,E,and C: folate; sumofa-3lay ands (an an quinsink and total energy icosiuouak the Solong malou』peenatal Eatorkage at delivery (kg/m": < 18.5, 18.5-34 9, 250-299.骡と30k history of a thma <m»or yes), hiuay of apy (mor yes), and mimgsn pregun yino, qua, yesk and the following posm㈤alchild factoes: birth weight 2500, 2500 4500.0 450gs,prematurity (nDaryes), t of full breadcoding 0. Ito<4.4k> <6, or 26 moL child respuratory rat inlections un first 6 mono or yes), and matemal smoking sanoe hu油(nww. soetetimes. or daa'y i Misang values coanals sere handled by wakiple imputation(m109 by using chained oations
PARR ET AL cesarean section, and antibiotics and paracetamol use) car the authors nbuted the association tothe high retinol content of exclusion of 5.5%伎399 of 6.,676) of premature or low-birth Norwegian cod liver oil an the time(l000㎍/5 mL bdere 1999), weight children (Supplemental Table 8. Maternal and child combined with a traditional diet rich in vitamin A. Thus, the risk risk estimates were also unaffected by the esclusion of 39% of of adverse effects of vitamin A appears to be greater in Western controls (11,828 of 59,130) who had been dispensed any asthma populations whoconsume supplementalretinol in the face of high medication by the age of 8 y (see Supplemental Tables 6 and 8 food retinol intake Ding and VandkrWeek's (33) approach for assessing the poA hgh intake of vitamin D from our FFQ was reflocted in tential inflaence of unmeasured confounding showed that to higher maternal circulating 25-hydroxyvitamin D, which has completely explain an RR of 1.2 (as we observed for a high been associated with a lower risk of asthma in a recent meta maternal intake of total vitamin A and for infant supplemen- analysis of birth cohort stadies (11) including a case-cohort study tation with multivitamins, it would take an unmeasured con, in youngส MoBachildren (37). The findings of this review and founder with a strength 1.7, which is stronger than what we our current study are in koeping with recent reports from 2 tri- observed for all of our measared confounders, except for matemal als of prenatal vitamin D supplementation, which sugpest an in verse association hetween prenatal exposure to vitamin D and child asthma (38)·Our results suggested th.at the protective ef. fect of high vitamin D intake was aticnuated among those with vitamin A intake in the highest quintile. Likewise, there was no In this large population-hased pregnancy cobort study, a high adverse effect of high vitamin A intake when vitamin D intakae maternal intake of vitamin A during pregnancy was associated w high Other studies sagporta"tinol and vitamin D may with more asthma and a high intake of vitamin D was associated have antagonisic effects that affect health outcomes. A large, with kss asthma in childron at age 7 y, independent of infant sup nested, case-control shodty of coloretal cancer found that the pro- plement use in the finst 6 mo. The RR for inmake in the highest tective effect of high circulating vitamin D dupeared in sub compared with the lowest quintile was ~20% higher for vitamin jects with a hagh retinol intake (100 SigldH 39k however, vi- A and 20% lower for vitamin D ln agreement with the hypothesis tamin D may also reduce toxicity from retinol. In a review of hat vitamin A may antagonize actions of vitamin D, we observed case-repoets of vitamin A toxicity, the median dose of retinol as- no protective effect of vitamin D when the intake of vitamin A sociated with toxicity was higher in cases who had also taken asthma DISCUSSION was high and likewise no adverse effect of high vitamin A in the vitamin D (40) face of high vitamin D. We found no protective effect of infant supplementation with vitamin D oely, or cod liver oil, on asthma at school age. Strengths and limitations of this study Total vitamin A intake in the highest quintile e 2031 RAEd Our study has several strengths We used a validated FFQ and in which we observed more froquent asthma, corresponds to few previous studies have estimated the total intake of vitamin 25 times the recommended intake for peegnant women of A from foods and supplements during pregnancy outside of de 800 RAEvd (34, 35). In comparison, the cutoff for the upper ficient populations (20 21) In addition, we had high statisical quintile of vitamin D (213.6 jagid), in which we observed less power (2546 cases) to study asthma, and the prescription reg- asthma was close to the Nordic ( 10 sp d) and US ' 15 μ. dnec- istry linkage enabled near-oomplete follow-up to school age. As in odser large, natioe wide, population-based studies, we were not able to classify asthma on the basis of clinical examination, and we cannot rule out some misclassification in our asthma outcome. We expect that any bias in our RR estimates would be in the di- Few other studies have assessed asthma development in rection of slight attenuation because the risk of ouscome misclas- school-age children in relation to pregnancy intake of vitamin A sification should be low and independent of matemal exposare nclading retinol, outside of populations at risk of deficiency. In a (nondiffcrential crror), Norway has universal health care and pre tudy from the Danish National Birth Cohont with half the sample scription coverage, so undiagnosed or untreated asthma should he size of the current study, the association of total vitamin A intake rae. In addition, in a validation study of the MoBa 7-y question- with the risk of asthma at age 7 y was only borderline significant naire items with regard to a되hna, we found that even a single (21), but the magnitude (8% higher risk per 100 0-pagid increase) dipeasang of asthma medication was very rre in the absence of is compatible with our finding of a 20% increased risk in the high- the matemal report of a doctor's diagnosis of asthma 441 ). A pre- est quantile A study from Finland of maternal antioxidant intake scription for asthma medication, requires a physacaan-sevaluataon. during peegnancy showed positive, but noesigniicant relationsand we reqaired 22 prescriptioas to increase the positive predio of total intake of carotenoids 4α and β) and retinol from food tive value of our asthma de nition (42) Furthermore, we would co,2% retinol supplement use was ignored) with child asthma at not expect high mu en.al intakes of vtamia A and vitamin D to be age 5 y (20).Our results support that intakes of B-carotene or food associated with asthma in opposite directions, if high intakes jus vitamin A alone (results shown in Sapplemental Table 2) are not reflected differences in health consciousness and health-seck ing mendatans fr pregant women. sufticient, or high enough, in most women to increase asthma bchavior isk. Furthemore, vitamin A supplementation trials conducted inA limitation of this study is that we did not have data on areas of Nepal with endemic deficiency reported better lung func. nutrient intake from supplements in infants, but we were able ion in children of supplemented mothers (17, 18). A prospective to compare different supplements Our results suggested more study in Norwegian adults reportod that daily intake of cod liver asthma among children who were given mukivitamins but nox co oil was associated with increased incidence of asthma (36). The liver oil. Both supplements provide similar doses of vitamin A
VITAMINS A ANDD AND ASTHMA DEVELOPMENT (typically 200-250 ㎍) and vitamin D (typically the moon, intake close to recommmhions was associated with anodaced mended dose of IO μg), and cod liver oil also contains vtarman nsk of ath a at school age but xt when matสาน1 intake of vi- E and n-3 fatty acids. A potential explanation for this difference tamin A w high s, the blance of vitamin A and vitamin D is that liquid multivitamins for childrencontain waternichler intake during prepay could be of importance to asthma emulsified retinol, which could be more toxic than retinol in oil ceptibility is the offsgring A high intake of dietary retinol com based solutions such ascod liver oil (40). Interestingly, a Swedish bined wiカa low inke of uta D is sees in many westem study found an increased risk of asthma and allergy in infants populations (12) in wich child asthma is common applemented with vitamins A and D in water-based but not oil based formula (43). In our study, the lack of association between The au﹄īysdltos ผอฝ1.-WNandor wewong any multivitamin use and the risk of asthma in infants who were skirt,灬 lopata apaatttekakk given an additional supplement containing vitamin D could be and Mt:cbuedsothe data anyCLP ht and ic effect of vitamin D on retinol How mary nelit o the ialctand all authons cibued o the ever, ia is also possible that these infants had a lower intake od to alternating use of a vitamin D supplement. Other vitamins or minerals in a multivitamin fomula, potentially folic acid, could 80 Unmeasared confoundin REFERENCES is always of concern in observational stadies, bu Ding and Van- derWeele's (33) framework provides some reassurance that even a modest RR of .2 is relatively robust to unmeasared confound- ing. Last, we did not assess the potential inflacnce of vitamin A and D exposures at other time points, such as during lactation or has been associated with atopy and a Thelper 2(Th2) dominated cytokine peoile. Vitamin A exerts many of its effects through retinoie acid-mediated gene transcription, and retinoic acid mayHYY,Forno E HiFCdie IC Dict and aha an upc have a Th2 cel-promoting effoct (44) Although vitamin A is mainly stored in the liver, excess vitamin A also accumulates in the lungく15), where retnad metabolites may cause asthma- Shilahtu DR.AT Nrden LP. Tantsin KG Weiss ST like symptoms (45). In the rat lung. vitamin A supplementation with higher and intermediate doses increases markers of oxidative Cmn KD Dowling kG Siabakova Z Gonralca-Gross M stress (46), which also may impair lung function. We found no in- 逝thma The effect of β-carotcnc was wear but inthe samedi, 裏Mans aka D. Pano" L Stadl M. Mtha MF, Fanal M. fctal transfer of retinoids and carotenoids, their metaholism in the developing tissues, and homeostatic control in the face of exces ive maternal dietary vitamin A îmake are still poorly under tood (47), Our results suggest that little, if any,of the effects of vitamin A and Dimake during pregnancy on child asthma were mediated through low birth weight or prematurity. We found some indi cation that the adverse clects associatedwith excos vitamin A were mitigated by having a sufficient intake of vitamin D. This observation is in line with mechanistic studies in myeloid cells which showed that vitamin D sepresses retinoic acid transcrip- tional activity, tu"he action is 2 way, which also explains how 9. Om BL koukselnlVi g NH, Banant Da Lise-AA. Qǐy VL Liigo N. ㎐nhfield BI, MElih TF 11. Fong H. Xam P. Na K. wil, AK ด me, BL Begaand Cai nd In this study, we found that a diet natarally high in vitamin A combined with the use of sepplements containing retinol during pregnancy place women at risk of vitamin A excess, which was children We observed this cffoct for intakes that were2 25 times the recommended dose, whichis below the tolerable upper intake level for retinol of 3000 pgld during pregnancy (27). Vitamin D
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Answer 1 : Hypothesis :H1 : There will be significant association between child asthma and maternal intake of Vitamin A and Vitamin D

Answer 2 : SECONDARY PREVENTION PRIMARY 4ーPREVENTION-A>← PERIOD LATENT Years weeks o f Pregmey EXPOSURE DISEASE MANICESTATION INDUCTION Answer 3 : Second Quintile (Q2) of total Vitamin A (780-1102 RAEs/d) intake have observered lower prevelence of Asthma

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