title: Effect of Two Different Multimicronutrient Supplements on Vitamin D Status in Women of Childbearing Age: A Randomized Trial 25-Hydroxyvitamin D in pregnancy and genome wide cord blood DNA methylation in two pregnancy cohorts (MoBa and ALSPAC) The Effects of Vitamin D Supplement on Prevention of Recurrence of Preeclampsia in Pregnant Women with a History of Preeclampsia Vitamin D: do we get enough? Vitamin D and Testosterone in Healthy Men: A Randomized Controlled Trial Effects of Vitamin D Supplementation on Semen Quality, Reproductive Hormones, and Live Birth Rate: A Randomized Clinical Trial Response to Antenatal Cholecalciferol Supplementation Is Associated With Common Vitamin D–Related Genetic Variants Effect of vitamin D3 supplementation in pregnancy on risk of pre-eclampsia - Randomized controlled trial. Maternal gestational vitamin D supplementation and offspring bone health (MAVIDOS): a multicentre, double-blind, randomised placebo-controlled trial. Hormonal Contraceptive Use Is Associated With Higher Total but Unaltered Free 25-Hydroxyvitamin D Serum Concentrations Vitamin D supplementation during pregnancy: double-blind, randomized clinical trial of safety and effectiveness. Nutrients, endpoints, and the problem of proof. Maternal vitamin D supplementation to improve the vitamin D status of breast-fed infants: a randomized controlled trial. Maternal vitamin D supplementation during pregnancy Maternal Serum and Breast Milk Vitamin D Levels: Findings from the Universiti Sains Malaysia Pregnancy Cohort Study Maternal Versus Infant Vitamin D Supplementation During Lactation: A Randomized Controlled Trial Vitamin D activity of breast milk in women randomly assigned to vitamin D3 supplementation during pregnancy. Effects of Maternal Vitamin D Supplementation on the Maternal and Infant Epigenome. The 2011 Report on Dietary Reference Intakes for Calcium and Vitamin D from the Institute of Medicine: What Clinicians Need to Know Effectiveness of Prenatal Vitamin D Deficiency Screening and Treatment Program: A Stratified Randomized Field Trial Estimation of the maternal vitamin D intake that maintains circulating 25-hydroxyvitamin D in late gestation at a concentration sufficient to keep umbilical cord sera ≥25–30 nmol/L: a dose-response, double-blind, randomized placebo-controlled trial in pregnant women at northern latitude Vitamin D and risk of pregnancy related hypertensive disorders: mendelian randomisation study Association of preconception serum 25-hydroxyvitamin D concentrations with livebirth and pregnancy loss: a prospective cohort study.
abstract: The German Nutrition Society raised in 2012 the recommended daily vitamin D intake from 200 to 800 international units ( IU ) to achieve 25-hydroxyvitamin D ( 25(OH)D ) levels of at least 50 nmol/L , even when endogenous vitamin D synthesis is minimal such as in winter . We aim ed to evaluate this recommendation in women of childbearing age . This is a single-center , r and omized , open trial conducted from 8 January to 9 May 2016 in Esslingen , Germany . We r and omized 201 apparently healthy women to receive for 8 weeks a daily multimicronutrient supplement containing either 200 IU ( n = 100 ) or 800 IU vitamin D3 ( n = 101 ) . Primary outcome measure was serum 25(OH)D.  196 participants completed the trial .  Increases in 25(OH)D ( median with interquartile range ) from baseline to study end were 13.2 ( 5.9 to 20.7 ) nmol/L in the 200 IU group , and 35.8 ( 18.2 to 52.8 ) nmol/L in the 800 IU group ( p < 0.001 for the between group difference ) . At study end , levels of ≥50 nmol/L were present in 70.4 % of the 200 IU group and in 99 % of the 800 IU group . Participants on hormonal contraceptives had higher baseline levels and a stronger increase in 25(OH)D. In conclusion , daily supplementation of 800 IU vitamin D3 during wintertime in Germany is sufficient to achieve a 25(OH)D level of at least 50 nmol/L in almost all women of childbearing age , whereas 200 IU are insufficient Highlights • Pregnancy vitamin D and cord blood DNA methylation compared in 1416 infants.• Associations tested in two large prospect i ve cohort studies , MoBa and ALSPAC.• Similarly for offspring health outcomes and vitamin D  , no convincing associations Introduction Preeclampsia is a pregnancy-specific syndrome . One of the hypotheses concerning the etiology of preeclampsia is vitamin D deficiency during pregnancy . Method and Material s The present study is a r and omized controlled clinical trial which aims to determine the effect of vitamin D supplement on reducing the probability of recurrent preeclampsia .  72 patients were placed in control group while 70 patients were r and omized to the intervention group . The intervention group received a 50000 IU pearl vitamin D3 once every two weeks . The control group was administered placebo . Vitamin D or placebo was given until the 36th week of pregnancy . Results The patients in intervention group have significantly lower ( P value = 0.036 ) probability of preeclampsia than patients in the control group . The risk of preeclampsia for the control group was 1.94 times higher than that for the intervention group ( 95 % CI 1.02 , 3.71 ) . Conclusion The intended intervention ( i.e. , prescription of vitamin D ) has a protective effect against recurrent preeclampsia .  Vitamin D supplementation therapy in pregnancy could help in reducing the incidence of gestational hypertension/preeclampsia . Registration This study has been registered in Iranian Registry of Clinical Trials ( I RCT ) site with ID number I RCT 2017010131695N1 Summary On September 29 , 2011 , acknowledged experts in the field of vitamin D , mainly European , were brought together in order to discuss the recent scientific advances in relation to vitamin D : the current requirements and associations with various health outcomes . In this article , the discussion s result ing from the meeting are summarized . Introduction Several groups at risk for developing vitamin D insufficiency have been identified . Accordingly , review s indicate that a significant percentage of the population worldwide have serum 25-hydroxyvitamin D levels below 50 nmol/l . In addition to the role of vitamin D in bone health , recent studies suggest that it may play a pivotal role in other systems , e.g. , the cardiovascular system , pancreas , muscle , immune system and brain . Most evidence , however , is obtained from observational studies and yet inconclusive . Methods To exchange and broaden knowledge on the requirements for vitamin D and its effect on various health outcomes , a workshop entitled “ Vitamin D Expert Meeting : Do we get enough ? ” , was organized . Results Despite low vitamin D levels worldwide , consensus on the definition of deficiency is not yet reached . In order to define cut-off points for vitamin D whilst taking into account extraskeletal health effects , r and omized controlled trials in these fields are warranted . The experts do emphasize that there is evidence to suggest an important role for vitamin D in the maintenance of optimal bone health at all ages and that vitamin D supplementation , in most studies co-administered with calcium , reduces fracture risk in the senior population . Conclusion To reach a serum 25-hydroxyvitamin D level of 50 nmol/l older adults aged ≥65 years are therefore recommended to meet a mean daily vitamin D intake of 20 μg ( 800 IU ) , which is best achieved with a supplement Context : Available evidence shows an association of vitamin D with and rogen levels in men . However , results from preliminary r and omized controlled trials ( RCTs ) are conflicting . Objective : To evaluate whether vitamin D supplementation increases total testosterone ( TT ) levels in healthy men . Design : The Graz Vitamin D&TT‐ RCT is a single‐center , double‐blind , r and omized , placebo‐controlled trial conducted between December 2012 and January 2017 . Setting : Endocrine outpatient clinic at the Medical University of Graz , Austria . Participants : Ninety‐eight healthy men with TT levels ≥10.4 nmol/L and 25‐hydroxyvitamin D [ 25(OH)D ] levels < 75 nmol/L completed the study . Intervention : Subjects were r and omly assigned to receive 20,000 IU/wk of vitamin D3 ( n = 50 ) or placebo ( n = 50 ) for 12 weeks . Main Outcome Measures : Primary outcome was TT measured using mass spectrometry . Secondary outcomes were free testosterone , sex hormone‐binding globulin , estradiol , follicle‐stimulating hormone , and luteinizing hormone levels ; free and rogen index ; metabolic characteristics ; and body composition . Results : In healthy men [ mean values ± st and ard deviation : age , 39 years ( ±13 years ) ; 25(OH)D level , 53.3 nmol/L ( ±18.3 nmol/L ) ; TT , 19.1 nmol/L ( ±5.6 nmol/l ) ] , no significant treatment effect on TT was found ; however , there were significant effects on quantitative insulin sensitivity check index ( QUICKI ) and a trend toward decreased Matsuda index . In the treatment group , median ( interquartile range ) changes for TT , QUICKI , and Matsuda index were 0.5 nmol/L ( −0.63 to 0.63 nmol/L ; P = 0.497 ) , −0.02 ( −0.04 to 0.01 ; P = 0.034 ) , and −0.9 ( −3.2 to 0.8 ; P = 0.051 ) , respectively . Conclusion : Vitamin D treatment had no effect on TT levels in middle‐aged healthy men with normal baseline TT , but it significantly decreased QUICKI . Additional studies investigating vitamin D effects on TT and insulin sensitivity in healthy men are required Context Results of animal models and cross-sectional cohort studies have suggested a beneficial role for vitamin D in male reproduction . Objective Determine the effect of vitamin D and calcium supplementation on semen quality in infertile men with serum 25-hydroxyvitamin-D ( 25OHD ) levels ≤50 nmol/L. Design A single-center , triple-blinded , r and omized clinical trial . Participants A total of 1427 infertile men were screened to include 330 ; 1002 men did not meet inclusion criteria and 95 did not wish to participate . Intervention The active group received cholecalciferol 300,000 IU initially , then 1400 IU cholecalciferol and 500 mg of calcium daily for 150 days ; the other group received placebo .  Results Serum concentrations of 25OHD and 1,25-dihydroxyvitamin D3 were significantly higher in men in the treatment group compared with the placebo group . Vitamin D supplementation was not associated with changes in semen parameters , although spontaneous pregnancies tended to be higher in couples in which the man was in the treatment group [ 7.3 % vs 2.4 % , Δ5.0 % ( -0.6 % ; 10.5 % ) ] . Vitamin D treatment in a subgroup of oligozoospermic men increased the chance for a live birth compared with placebo [ 35.6 % vs 18.3 % , Δ17.3 % ( 1.6 % ; 32.9 % ) ] . Moreover , serum inhibin B levels were higher in men deficient in vitamin D who were r and omly assigned to receive high-dose vitamin D [ 193 pg/mL vs 143 pg/mL , Δ49 pg/mL ( 8 ; 91 pg/mL ) ] ; however , the increase in sperm concentration was not significantly higher than in the placebo group ( P = 0.07 ) . Conclusion High-dose vitamin D supplementation did not improve semen quality in vitamin D-insufficient infertile men . The positive impact of vitamin D supplementation on live birth rate and serum inhibin B in oligozoospermic and vitamin D-deficient men may be of clinical importance and warrant verification by others Context : Single-nucleotide polymorphisms ( SNPs ) in genes related to vitamin D metabolism have been associated with serum 25-hydroxyvitamin D [ 25(OH)D ] concentration , but these relationships have not been examined following antenatal cholecalciferol supplementation . Objective : To determine whether SNPs in DHCR7 , CYP2R1 , CYP24A1 , and GC are associated with the response to gestational cholecalciferol supplementation . Design : Within-r and omization group analysis of the Maternal Vitamin D Osteoporosis Study trial of antenatal cholecalciferol supplementation . Setting : Hospital antenatal clinics . Participants : In total , 682 women of white ethnicity ( 351 placebo , 331 cholecalciferol ) were included . SNPs at rs12785878 ( DHCR7 ) , rs10741657 ( CYP2R1 ) , rs6013897 ( CYP24A1 ) , and rs2282679 ( GC ) were genotyped . Interventions : 1000 IU/d cholecalciferol from 14 weeks of gestation until delivery . Main Outcome Measure : 25(OH)D at r and omization and 34 weeks of gestation were measured in a single batch ( Liaison ; Diasorin , Dartford , UK ) . Associations between 25(OH)D and the SNPs were assessed by linear regression using an additive model [ β represents the change in 25(OH)D per additional common allele ] . Results : Only rs12785878 ( DHCR7 ) was associated with baseline 25(OH)D [ β = 3.1 nmol/L ; 95 % confidence interval ( CI ) , 1.0 to 5.2 nmol/L ; P < 0.004 ] . In contrast , rs10741657 ( CYP2R1 ) ( β = −5.2 nmol/L ; 95 % CI , −8.2 to −2.2 nmol/L ; P = 0.001 ) and rs2282679 ( GC ) ( β = 4.2 nmol/L ; 95 % CI , 0.9 to 7.5 nmol/L ; P = 0.01 ) were associated with achieved 25(OH)D status following supplementation , whereas rs12785878 and rs6013897 ( CYP24A1 ) were not . Conclusions : Genetic variation in DHCR7 , which encodes 7-dehyrocholesterol reductase in the epidermal vitamin D bio synthesis pathway , appears to modify baseline 25(OH)D. In contrast , the response to antenatal cholecalciferol supplementation was associated with SNPs in CYP2R1 , which may alter 25-hydroxylase activity , and GC , which may affect vitamin D binding protein synthesis or metabolite affinity BACKGROUND Vitamin D plays pivotal role in decidualization and implantation of the placenta . Recent research es have shown that low level of vitamin D3 " 25-hydroxyvitamin D ( 25[OH]D ) " in serum is a risk factor for pre-eclampsia . Latest evidence supports role of vitamin D3 deficiency treatment in reducing the risk of pre-eclampsia . The aim of this study is to determine the effect of antenatal supplementation of vitamin D3 on the risk of pre-eclampsia and to explore the dose effect in attaining the vitamin D3 normal level . METHOD An open labelled r and omized controlled study was conducted on 179 pregnant women presenting in King Fahad Medical City antenatal clinic from Oct 2012-Oct 2015 . Patients with age less than 20 years or more than 40 years , pregnancy with fetal anomalies , history of hypertension , pre-eclampsia , recurrent miscarriage , chronic renal or hepatic disease and malignancy were excluded from the study .  Serum 25[OH]D was analysed during the first trimester ( between 6 and 12 weeks of pregnancy ) . Patients with vitamin D3 deficiency ( serum levels < 25 nmol/L ) were included in the study and r and omized for vitamin D3 supplementation 400 IU ( Group 1 ) versus 4000 IU ( Group 2 ) . Both groups were compared for the prevalence of pre-eclampsia and dose effect on vitamin D level . RESULTS Of 179 gravidae enrolled , 164 completed the trial .  Mean maternal 25[OH]D was significantly increased in group 2 from 16.3 ± 5 nmol/mL to 72.3 ± 30.9 nmol/mL compared with group 1 from 17.5 ± 6.7 nmol/mL to 35.3 ± 20.7 nmol/mL ( p > 0.0001 ) . The relative risk reduction ( RRR ) for attaining ≥75 nmol/L before delivery was significantly higher ( RRR 93.2 [ CI 79 - 98 ] when treated with 4000 IU . The total incidence of pre-eclampsia in the study population was 4.3 % . In comparison to group 1 , the group 2 reported fewer pre-eclampsia events during the study period ( 8.6 % versus 1.2 % ; p < 0.05 ) . The total number of IUGRs was lesser in the group 2 ( 9.6 % ) versus group 1 ( 22.2 % ) ; p = 0.027 . However , other obstetric outcomes were comparable between both groups . CONCLUSION Vitamin D supplementation in the deficient group reduces the risk of pre-eclampsia and IUGR in a dose dependant manner . However larger clinical trials are essential to investigate optimum dosage of vitamin D3 in this group BACKGROUND Maternal vitamin D status has been associated with bone mass of offspring in many , but not all , observational studies . However , maternal vitamin D repletion during pregnancy has not yet been proven to improve offspring bone mass in a r and omised controlled trial . We aim ed to assess whether neonates born to mothers supplemented with vitamin D during pregnancy have greater whole-body bone mineral content ( BMC ) at birth than those of mothers who had not received supplementation . METHODS The Maternal Vitamin D Osteoporosis Study ( MAVIDOS ) was a multicentre , double-blind , r and omised , placebo-controlled trial that recruited pregnant women from three study sites in the UK ( Southampton , Oxford , and Sheffield ) . Eligible participants were older than 18 years , with a singleton pregnancy , gestation of less than 17 weeks , and a serum 25-hydroxyvitamin D ( 25[OH]D ) concentration of 25 - 100 nmol/L at 10 - 17 weeks ' gestation . P'articipants were r and omly assigned ( 1:1 ) , in r and omly permuted blocks of ten , to either cholecalciferol 1000 IU/day or matched placebo , taken orally , from 14 weeks ' gestation ( or as soon as possible before 17 weeks ' gestation if recruited later ) until delivery . Participants and the research team were masked to treatment allocation . The primary outcome was neonatal whole-body BMC , assessed within 2 weeks of birth by dual-energy x-ray absorptiometry ( DXA ) , analysed in all r and omly assigned neonates who had a usable DXA scan . Safety outcomes were assessed in all r and omly assigned participants . This trial is registered with the International St and ard R and omised Controlled Trial registry , IS RCT N 82927713 , and the European Clinical Trials Data base , EudraCT 2007 - 001716 - 23 . FINDINGS Between Oct 10 , 2008 , and Feb 11 , 2014 , we r and omly assigned 569 pregnant women to placebo  and 565 to cholecalciferol 1000 IU/day . 370 ( 65 % ) neonates in the placebo group and 367 ( 65 % ) neonates in the cholecalciferol group had a usable DXA scan and were analysed for the primary endpoint . Neonatal whole-body BMC of infants born to mothers assigned to cholecalciferol 1000 IU/day did not significantly differ from that of infants born to mothers assigned to placebo ( 61·6 g [ 95 % CI 60·3 - 62·8 ] vs 60·5 g [ 59·3 - 61·7 ] , respectively ; p=0·21 ) . We noted no significant differences in safety outcomes , apart from a greater proportion of women in the placebo group with severe post-partum haemorrhage than those in the cholecalciferol group ( 96 [ 17 % ] of 569 mothers in the placebo group vs 65 [ 12 % ] of 565 mothers in the cholecalciferol group ; p=0·01 ) . No adverse events were deemed to be treatment related . INTERPRETATION Supplementation of women with cholecalciferol 1000 IU/day during pregnancy did not lead to increased offspring whole-body BMC  compared with placebo , but did show that 1000 IU of cholecalciferol daily is sufficient to ensure that most pregnant women are vitamin D replete , and it is safe . These findings support current approaches to vitamin D supplementation in pregnancy . Results of the ongoing MAVIDOS childhood follow-up study are awaited . FUNDING Arthritis Research UK , Medical Research Council , Bupa Foundation , and National Institute for Health Research Context Intake of hormonal contraceptives ( HC ) is associated with higher total 25-hydroxyvitamin D [ 25(OH)D ] concentrations , but the effect of HC on free 25(OH)D is unclear . Objective We investigated whether free 25(OH)D concentrations differ according to use of HC . Design This is a post hoc analysis of a r and omized open trial . Setting This study was conducted from 13 January to 9 May , 2016 , at a clinical research organization in Esslingen , Germany . Participants We included 201 apparently healthy women of childbearing age . Intervention Participants were r and omly assigned to receive a daily multimicronutrient supplement for 8 weeks ; the supplement contained 200 IU ( n = 100 ) or 800 IU ( n = 101 ) of vitamin D3 . Main Outcome Measures Primary outcome was the difference in free 25(OH)D between users and nonusers of  HC  . Results Overall , 176 participants [ median ( 25th to 75th percentiles ) age : 25 ( 22 to 29 ) years ] with available free 25(OH)D were included in the present analysis . At baseline , total 25(OH)D was significantly higher in users ( n = 110 ) than in nonusers ( n = 66 ) of HC [ 49.2 ( 33.4 to 63.4 ) vs 39.1 ( 23.8 to 52.5 ) nmol/L ; P < 0.001 ] , whereas there was no difference in free 25(OH)D [ 7.87 ( 6.50 to 10.11 ) vs 7.88 ( 6.35 to 10.12 ) pmol/L ; P = 0.923 ] . These results were confirmed after multimicronutrient supplementation and in subgroups according to treatment allocation . Conclusions Use of HC was associated with , on average , 26 % higher total 25(OH)D , whereas free 25(OH)D values did not differ according to use of HC . These findings are relevant for epidemiological studies , but the physiological implication s remain to be clarified The need , safety , and effectiveness of vitamin D supplementation during pregnancy remain controversial . In this r and omized , controlled trial , women with a singleton pregnancy at 12 to 16 weeks ' gestation received 400 , 2000 , or 4000 IU of vitamin D(3 ) per day until delivery . The primary outcome was maternal/neonatal circulating 25-hydroxyvitamin D [ 25(OH)D ] concentration at delivery , with secondary outcomes of a 25(OH)D concentration of 80 nmol/L or greater achieved and the 25(OH)D concentration required to achieve maximal 1,25-dihydroxyvitamin D(3 ) [ 1,25(OH)(2)D(3 ) ] production . Of the 494 women enrolled , 350 women continued until delivery : Mean 25(OH)D concentrations by group at delivery and 1 month before delivery were significantly different ( p < 0.0001 ) , and the percent who achieved sufficiency was significantly different by group , greatest in 4000-IU group ( p < 0.0001 ) . The relative risk ( RR ) for achieving a concentration of 80 nmol/L or greater within 1 month of delivery was significantly different between the 2000- and the 400-IU groups ( RR = 1.52 , 95 % CI 1.24 - 1.86 ) , the 4000- and the 400-IU groups ( RR = 1.60 , 95 % CI 1.32 - 1.95 ) but not between the 4000- and . 2000-IU groups ( RR = 1.06 , 95 % CI 0.93 - 1.19 ) . Circulating 25(OH)D had a direct influence on circulating 1,25(OH)(2)D(3 ) concentrations throughout pregnancy ( p < 0.0001 ) , with maximal production of 1,25(OH)(2)D(3 ) in all strata in the 4000-IU group . There were no differences between groups on any safety measure . Not a single adverse event was attributed to vitamin D supplementation or circulating 25(OH)D levels . It is concluded that vitamin D supplementation of 4000 IU/d for pregnant women is safe and most effective in achieving sufficiency in all women and their neonates regardless of race , whereas the current estimated average requirement is comparatively ineffective at achieving adequate circulating 25(OH)D concentrations , especially in African Americans The early days of nutritional science were a heady time . Working out the metabolic roles and many benefits of specific nutrients was both exciting and clearly important . In more recent times , emphasis has shifted somewhat from metabolism to policy . In a sense , this represents a major victory for nutrition . Less than a century ago , E. V. McCollum had to struggle with the prevailing notion that food was primarily fuel . The idea that not eating something could make one sick was considered laughable . Now , it is taken for granted that the quality of what we eat is at least as important as the quantity , an underst and ing that leads naturally to the determining of nutrient intake requirements . It is not surprising , therefore , that 7 of the last 14 Atwater lectures dealt more or less explicitly with the issue of requirements . This one will be no exception to that pattern . In my McCollum lecture of 5 y ago ( 1 ) , I called attention to what I perceived as a broadening of the way deficiency disease might be conceptualized . The original nutrient deficiency diseases were all of short latency and involved discrete body systems and dysfunctions . Rickets , pellagra , and beriberi are good cases in point . And , while the working science has progressed far beyond these beginnings , these short latency diseases have remained the implicit model for much of our thinking about nutritional deficiency and , to a substantial extent , our determination of nutrient intake requirements . For example , in the first of the dietary reference intake books , that for bone-related nutrients ( 2 ) , the intake requirement for vitamin D was explicitly pegged solely to the prevention of rickets/osteomalacia . As is evident on a moment ’s reflection , short latency was a prerequisite for the discovery of a connection between nutrient intake and disease . Had the outcome of an inadequate intake not been discrete and not been manifested promptly , it is doubtful that we ever would have recognized the connection between cause and effect ( i.e. nutrient intake and health or disease ) . But the science has gone far beyond that point , and it seems that there is no inherent reason why inadequate intake of the same nutrients involved in short-latency diseases could not be producing long latency deficiency disease as well . Moreover , as is now generally recognized , nutrients act through multiple mechanisms , and low intakes might be expected to lead to disorders quite distinct from the disease originally connected with the nutrient . Vitamin D is a good case in point . Total body inputs closer to those that must have prevailed during hominid evolution are associated with reduced risk of disorders as varied as Type I diabetes , hypertension , osteoporosis , various cancers , multiple sclerosis , and periodontal disease , to name only some ( 3–24 ) . ( For several of these disorders there is now what is referred to as ‘ ‘ level I evidence , ’’ i.e. r and omized controlled trials , confirming what had been found both in observational studies and in extensive bench and small animal studies . ) This broadened scheme is illustrated graphically in Figure 1 OBJECTIVE To determine whether a single monthly supplement is as effective as a daily maternal supplement in increasing breast milk vitamin D to achieve vitamin D sufficiency in their infants . PATIENTS AND METHODS Forty mothers with exclusively breast-fed infants were r and omized to receive oral cholecalciferol ( vitamin D3 ) 5000 IU/d for 28 days or 150,000 IU once . Maternal serum , breast milk , and urine were collected on days 0 , 1 , 3 , 7 , 14 , and 28 ; infant serum was obtained on days 0 and 28 . Enrollment occurred between January 7 , 2011 , and July 29 , 2011 . RESULTS In mothers given daily cholecalciferol , concentrations of serum and breast milk cholecalciferol attained steady levels of 18 and 8 ng/mL , respectively , from day 3 through 28 . In mothers given the single dose , serum and breast milk cholecalciferol peaked at 160 and 40 ng/mL , respectively , at day 1 before rapidly declining . Maternal milk and serum cholecalciferol concentrations were related ( r=0.87 ) . Infant mean serum 25-hydroxyvitamin D concentration increased from 17±13 to 39±6 ng/mL in the single-dose group and from 16±12 to 39±12 ng/mL in the daily-dose group ( P=.88 ) . All infants achieved serum 25-hydroxyvitamin D concentrations of more than 20 ng/mL. CONCLUSION Either single-dose or daily-dose cholecalciferol supplementation of mothers provided breast milk concentrations that result in vitamin D sufficiency in breast-fed infants . CLINICAL TRIAL REGISTRATION clinical trials.gov NCT01240265 Introduction Maternal vitamin D status in pregnancy has been linked to many health outcomes in mother and offspring . A wealth of observational studies have reported on both obstetric outcomes and complications , including pre-eclampsia , gestational diabetes , mode and timing of delivery . Many foetal and childhood outcomes are also linked to vitamin D status , including measures of foetal size , body composition and skeletal mineralization , in addition to later childhood outcomes , such as asthma . Sources of data Synthesis of systematic and narrative review s. Areas of agreement and controversy The findings are generally inconsistent in most areas , and , at present , there is a lack of data from high- quality intervention studies to confirm a causal role for vitamin D in these outcomes . In most areas , the evidence tends towards maternal vitamin D being of overall benefit , but often does not reach statistical significance in meta-analyses . Growing points and areas timely for developing research The most conclusive evidence is in the role of maternal vitamin D supplementation in the prevention of neonatal hypocalcaemia ; as a consequence the UK department of health recommends that pregnant women take 400 IU vitamin D daily . High- quality r and omized placebo-controlled trials , such as the UK-based MAVIDOS trial , will inform the potential efficacy and safety of vitamin D supplementation in pregnancy across a variety of outcomes Background Vitamin D deficiency has become a global health issue in pregnant women . This study aim ed to assess the adequacy of maternal vitamin D status by measuring maternal serum and breast milk 25-hydroxyvitamin D [ 25(OH)D ] levels and to determine the association between maternal serum and milk 25(OH)D levels . Methods Data was obtained from the Universiti Sains Malaysia Pregnancy Cohort Study . This study was conducted from April 2010 to December 2012 in the state of Kelantan , Malaysia . Blood sample s from pregnant women aged 19 to 40 years were drawn in the second and third trimesters of pregnancy , while breast milk sample s at delivery , 2 , 6 and 12 months postpartum were collected to analyze for 25(OH)D levels . A total of 102 pregnant women were included in the analysis . Results Vitamin D deficiency [ 25(OH)D < 50 nmol/L ] was detected in 60 % and 37 % of women in the second and third trimesters of pregnancy , respectively . There were 6 % and 23 % of women who reached normal level of vitamin D status in the second trimester and the third trimester , respectively . Multivitamin intakes during pregnancy were significantly associated with higher serum 25(OH)D levels in the second trimester ( β = 9.16 , p = 0.005 ) and the third trimester ( β = 13.65 , p = 0.003 ) . 25(OH)D levels in breast milk during the first year of lactation ranged from 1.01 to 1.26 nmol/L. Higher maternal serum 25(OH)D level in the second trimester of pregnancy was associated with an elevated level of 25(OH)D in breast milk at delivery ( β = 0.002 , p = 0.026 ) . Conclusions This study shows that high proportions of Malay pregnant women are at risk of vitamin D deficiency . Maternal vitamin D status in the second trimester of pregnancy was found to influence vitamin D level in breast milk at delivery OBJECTIVE : Compare effectiveness of maternal vitamin D3 supplementation with 6400 IU per day alone to maternal and infant supplementation with 400 IU per day . METHODS : Exclusively lactating women living in Charleston , SC , or Rochester , NY , at 4 to 6 weeks postpartum were r and omized to either 400 , 2400 , or 6400 IU vitamin D3/day for 6 months . Breastfeeding infants in 400 IU group received oral 400 IU vitamin D3/day ; infants in 2400 and 6400 IU groups received 0 IU/day ( placebo ) . Vitamin D deficiency was defined as 25-hydroxy-vitamin D ( 25(OH)D ) < 50 nmol/L. 2400 IU group ended in 2009 as greater infant deficiency occurred . Maternal serum vitamin D , 25(OH)D , calcium , and phosphorus concentrations and urinary calcium/creatinine ratios were measured at baseline then monthly , and infant blood parameters were measured at baseline and months 4 and 7 . RESULTS : Of the 334 mother-infant pairs in 400 IU and 6400 IU groups at enrollment , 216 ( 64.7 % ) were still breastfeeding at visit 1 ; 148 ( 44.3 % ) continued full breastfeeding to 4 months and 95 ( 28.4 % ) to 7 months . Vitamin D deficiency in breastfeeding infants was greatly affected by race . Compared with 400 IU vitamin D3 per day , 6400 IU/day safely and significantly increased maternal vitamin D and 25(OH)D from baseline ( P < .0001 ) . Compared with breastfeeding infant 25(OH)D in the 400 IU group receiving supplement , infants in the 6400 IU group whose mothers only received supplement did not differ . CONCLUSIONS : Maternal vitamin D supplementation with 6400 IU/day safely supplies breast milk with adequate vitamin D to satisfy her nursing infant ’s requirement and offers an alternate strategy to direct infant supplementation BACKGROUND Human milk is typically low in vitamin D activity ( VDA ) . Whether the vitamin D content of breast milk at birth can be increased by supplementing the mother during pregnancy has not been reported to the best of our knowledge . OBJECTIVE We examined the effect of vitamin D supplementation during pregnancy on breast-milk VDA in the first 2 mo of lactation . DESIGN Breast-milk sample s were obtained from women who were enrolled in a r and omized , double-blinded , placebo-controlled trial of vitamin D supplementation during pregnancy . Pregnant women were enrolled at 27 wk of gestation and r and omly assigned to the following 3 groups : a placebo group , a group who received one dosage of daily oral vitamin D3 ( 1000 IU ) , or a group who received 2 dosages of daily oral vitamin D3 ( 2000 IU ) . Serum 25-hydroxyvitamin D [ 25(OH)D ] was measured at enrollment , at 36 wk of gestation , and in cord blood at birth . Study participants who were breastfeeding were invited to provide breast-milk sample s for VDA measurement [ concentration of vitamin D2 , vitamin D3 , 25(OH)D2 , and 25(OH)D3 ] at 2 wk and 2 mo postpartum . A linear mixed model was used to compare breast-milk VDA between the 3 study groups . RESULTS A total of 75 women provided breast-milk sample s ( 44 women provided breast-milk sample s at both 2 wk and 2 mo postpartum ) . The mean ( 95 % CI ) VDA at age 2 wk was 52 IU/L ( 12 , 217 IU/L ) in the placebo group , 51 IU/L ( 17 , 151 IU/L ) in the 1000-IU group , and 74 IU/L ( 25 , 221 IU/L ) in the 2000-IU group ; and at age 2 mo , the mean ( 95 % CI ) VDA was 45 IU/L ( 16 , 124 IU/L ) , 43 IU/L ( 18 , 103 IU/L ) , and 58 IU/L ( 15 , 224 IU/L ) , respectively . There was no significant interaction in VDA between the sample - collection time and treatment ( P = 0.61 ) , but there was a difference between lower- and higher-dosage treatment groups ( P = 0.04 ) . CONCLUSION Maternal vitamin D supplementation during pregnancy of 2000 IU/d ( compared with 1000 IU/d and with a placebo ) results in a higher VDA of breast milk ≥2 mo postpartum . This trial was registered at the Australian New Zeal and Clinical Trials Registry as ACTRN12610000483055 INTRODUCTION Mothers and infants are at high risk for inadequate vitamin D status . Mechanisms by which vitamin D may affect maternal and infant DNA methylation are poorly understood . OBJECTIVE This study quantified the effects of vitamin D3 supplementation on DNA methylation in pregnant and lactating women and their breastfed infants . MATERIAL S AND METHODS In this r and omized controlled pilot study , pregnant women received vitamin D3 400 international units ( IU ) ( n = 6 ; control ) or 3,800 IU ( n = 7 ; intervention ) daily from late second trimester through 4 - 6 weeks postpartum . Epigenome-wide DNA methylation was quantified in leukocytes collected from mothers at birth and mother-infant dyads at 4 - 6 weeks postpartum . RESULTS At birth , intervention group mothers showed DNA methylation gain and loss at 76 and 89 cytosine-guanine ( CpG ) dinucleotides , respectively , compared to controls . Postpartum , methylation gain was noted at 200 and loss at 102 CpGs . Associated gene clusters showed strongest biologic relevance for cell migration/motility and cellular membrane function at birth and cadherin signaling and immune function at postpartum . Breastfed 4 - 6-week-old infants of intervention mothers showed DNA methylation gain and loss in 217 and 213 CpGs , respectively , compared to controls . Genes showing differential methylation mapped most strongly to collagen metabolic processes and regulation of apoptosis . CONCLUSIONS Maternal vitamin D supplementation during pregnancy and lactation alters DNA methylation in mothers and breastfed infants . Additional work is needed to fully eluci date the short- and long-term biologic effects of vitamin D supplementation at varying doses , which could hold important implication s for establishing clinical recommendations for prenatal and offspring health promotion This article summarizes the new 2011 report on dietary requirements for calcium and vitamin D from the Institute of Medicine ( IOM ) . An IOM Committee charged with determining the population needs for these nutrients in North America conducted a comprehensive review of the evidence for both skeletal and extraskeletal outcomes . The Committee concluded that available scientific evidence supports a key role of calcium and vitamin D in skeletal health , consistent with a cause- and -effect relationship and providing a sound basis for determination of intake requirements . For extraskeletal outcomes , including cancer , cardiovascular disease , diabetes , and autoimmune disorders , the evidence was inconsistent , inconclusive as to causality , and insufficient to inform nutritional requirements . R and omized clinical trial evidence for extraskeletal outcomes was limited and generally uninformative . Based on bone health , Recommended Dietary Allowances ( RDAs ; covering requirements of ≥97.5 % of the population ) for calcium range from 700 to 1300 mg/d for life-stage groups at least 1 yr of age . For vitamin D , RDAs of 600 IU/d for ages 1–70 yr and 800 IU/d for ages 71 yr and older , corresponding to a serum 25-hydroxyvitamin D level of at least 20 ng/ml ( 50 nmol/liter ) , meet the requirements of at least 97.5 % of the population . RDAs for vitamin D were derived based on conditions of minimal sun exposure due to wide variability in vitamin D synthesis from ultraviolet light and the risks of skin cancer . Higher values were not consistently associated with greater benefit , and for some outcomes U-shaped associations were observed , with risks at both low and high levels . The Committee concluded that the prevalence of vitamin D inadequacy in North America has been overestimated . Urgent research and clinical priorities were identified , including re assessment of laboratory ranges for 25-hydroxyvitamin D , to avoid problems of both undertreatment and overtreatment Context Despite evidence on the association between hypovitaminosis D and adverse pregnancy outcomes and the positive impact of vitamin D supplementation , no evidence exists supporting a universal screening program in pregnancy as part of routine prenatal care . Objective We sought to determine the effectiveness of a prenatal screening program on optimizing 25-hydroxyvitamin D [ 25(OH)D ] levels and preventing pregnancy complications . Also , to identify a safe regimen , we compared several regimens in a subgroup of vitamin D-deficient pregnant women . Design Two cities of Masjed-Soleyman and Shushtar from Khuzestan province , Iran , were selected as the screening and nonscreening arms , respectively . Within the screening arm , a r and omized controlled trial was conducted on 800 pregnant women . Setting Health centers of Masjed-Soleyman and Shushtar cities . Patients or Participants Pregnant women aged 18 to 40 years . Intervention Women with moderate [ 25(OH)D , 10 to 20 ng/mL ] and severe [ 25(OH)D , < 10 ng/mL ] deficiency were r and omly divided into four subgroups and received vitamin D3 ( D3 ) until delivery . Main Outcome Measure Maternal concentration of 25(OH)D at delivery and rate of pregnancy complications . Results After supplementation , only 2 % of the women in the nonscreening site met the sufficiency level ( > 20 ng/mL ) vs 53 % of the women in the screening site . Adverse pregnancy outcomes , including preeclampsia , gestational diabetes mellitus , and preterm delivery , were decreased by 60 % , 50 % , and 40 % , respectively , in the screening site . A D3 injection in addition to monthly 50,000 IU maintenance therapy contributed the most to achievement of sufficient levels at delivery . Conclusions A prenatal vitamin D screening and treatment program is an effective approach in detecting deficient women , improving 25(OH)D levels , and decreasing pregnancy adverse outcomes ABSTRACT Background In the absence of dose-response data , Dietary Reference Values for vitamin D in nonpregnant adults are extended to pregnancy . Objective The aim was to estimate vitamin D intake needed to maintain maternal 25-hydroxyvitamin D [ 25(OH)D ] in late gestation at a concentration sufficient to prevent newborn 25(OH)D < 25–30 nmol/L , a threshold indicative of increased risk of nutritional rickets . Design We conducted a 3-arm , dose-response , double-blind , r and omized placebo-controlled trial in Cork , Irel and ( 51.9oN ) . A total of 144 white-skinned pregnant women were assigned to receive 0 , 10 ( 400 IU ) , or 20 ( 800 IU ) µg vitamin D3/d from ≤18 wk of gestation . Vitamin D metabolites at 14 , 24 , and 36 wk of gestation and in cord sera , including 25(OH)D3 , 3-epi-25(OH)D3 , 24,25(OH)2D3 , and 25(OH)D2 were quantified by liquid chromatography – t and em mass spectrometry . A curvilinear regression model predicted the total vitamin D intake ( from diet and antenatal supplements plus treatment dose ) that maintained maternal 25(OH)D in late gestation at a concentration sufficient to maintain cord 25(OH)D at ≥25–30 nmol/L. Results Mean ± SD baseline 25(OH)D was 54.9 ± 10.7 nmol/L. Total vitamin D intakes at the study endpoint ( 36 wk of gestation ) were 12.1 ± 8.0 , 21.9 ± 5.3 , and 33.7 ± 5.1 µg/d in the placebo and 10-µg and 20-µg vitamin D3 groups , respectively ; and 25(OH)D was 24.3 ± 5.8 and 29.2 ± 5.6 nmol/L higher in the 10- and 20-µg groups , respectively , compared with placebo ( P < 0.001 ) . For maternal 25(OH)D concentrations ≥50 nmol/L , 95 % of cord sera were ≥30 nmol/L and 99 % were > 25 nmol/L. The estimated vitamin D intake required to maintain serum 25(OH)D at ≥50 nmol/L in 97.5 % of women was 28.9 µg/d . Conclusions Thirty micrograms of vitamin D per day safely maintained serum 25(OH)D concentrations at ≥50 nmol/L in almost all white-skinned women during pregnancy at a northern latitude , which kept 25(OH)D at > 25 nmol/L in 99 % and ≥30 nmol/L in 95 % of umbilical cord sera . This trial was registered at www . clinical trials.gov as NCT02506439 Abstract Objective To use mendelian r and omisation to investigate whether 25-hydroxyvitamin D concentration has a causal effect on  gestational hypertension or pre-eclampsia .  Design One and two sample mendelian r and omisation analyses . Setting Two European pregnancy cohorts ( Avon Longitudinal Study of Parents and Children , and Generation R Study ) , and two case-control studies ( subgroup nested within the Norwegian Mother and Child Cohort Study , and the UK Genetics of Pre-eclampsia Study ) . Participants 7389 women in a one sample mendelian r and omisation analysis ( 751 with gestational hypertension and 135 with pre-eclampsia ) , and 3388 pre-eclampsia cases and 6059 controls in a two sample mendelian r and omisation analysis . Exposures Single nucleotide polymorphisms in genes associated with vitamin D synthesis ( rs10741657 and rs12785878 ) and metabolism ( rs6013897 and rs2282679 ) were used as instrumental variables . Main outcome measures Gestational hypertension and pre-eclampsia defined according to the International Society for the Study of Hypertension in Pregnancy . Results In the conventional multivariable analysis , the relative risk for pre-eclampsia was 1.03 ( 95 % confidence interval 1.00 to 1.07 ) per 10 % decrease in 25-hydroxyvitamin D level , and 2.04 ( 1.02 to 4.07 ) for 25-hydroxyvitamin D levels < 25 nmol/L compared with ≥75 nmol/L. No association was found for gestational hypertension . The one sample mendelian r and omisation analysis using the total genetic risk score as an instrument did not provide strong evidence of a linear effect of 25-hydroxyvitamin D on the risk of gestational hypertension or pre-eclampsia : odds ratio 0.90 ( 95 % confidence interval 0.78 to 1.03 ) and 1.19 ( 0.92 to 1.52 ) per 10 % decrease , respectively . The two sample mendelian r and omisation estimate gave an odds ratio for pre-eclampsia of 0.98 ( 0.89 to 1.07 ) per 10 % decrease in 25-hydroxyvitamin D level , an odds ratio of 0.96 ( 0.80 to 1.15 ) per unit increase in the log(odds ) of 25-hydroxyvitamin D level < 75 nmol/L , and an odds ratio of 0.93 ( 0.73 to 1.19 ) per unit increase in the log(odds ) of 25-hydroxyvitamin D levels < 50 nmol/L. Conclusions No strong evidence was found to support a causal effect of vitamin D status on gestational hypertension or pre-eclampsia . Future mendelian r and omisation studies with a larger number of women with pre-eclampsia or more genetic instruments that would increase the proportion of 25-hydroxyvitamin D levels explained by the instrument are needed BACKGROUND Vitamin D deficiency during pregnancy is associated with adverse pregnancy outcomes , although the association between preconception vitamin D concentrations and livebirth is unknown . We aim ed to assess the association between preconception vitamin D and pregnancy outcomes among women with proven fecundity . METHODS We did a secondary analysis of a prospect i ve cohort from the block-r and omised , double-blind , placebo-controlled EAGeR trial . Women aged 18 - 40 years with one to two previous pregnancy losses were recruited from June 15 , 2007 , to July 15 , 2011 , at four clinical sites in the USA and followed up for up to six menstrual cycles while attempting pregnancy and throughout pregnancy if they conceived . Serum 25-hydroxyvitamin D was measured at baseline ( preconception ) and 8 weeks of gestation . Outcomes of interest included clinical pregnancy , time to pregnancy , pregnancy loss , and livebirths . Risk ratios ( RRs ) and 95 % CIs for livebirths , pregnancy , and pregnancy loss were estimated with weighted log-binomial regression . To assess time to pregnancy , we used discrete time Cox proportional hazards models to calculate fecundability odds ratios ( FORs ) with 95 % CIs . EAGeR is registered with Clinical Trials.gov , number NCT00467363 . FINDINGS 1191 women had available data on preconception 25-hydroxyvitamin D concentrations . 555 ( 47 % ) women were classified as having sufficient concentrations ( ≥75 nmol/L ) and 636 ( 53 % ) as having insufficient concentrations ( < 75 nmol/L ) . Women with sufficient preconception 25-hydroxyvitamin D were more likely to achieve clinical pregnancy ( adjusted RR 1·10 [ 1·01 - 1·20 ] ) and livebirth ( 1·15 [ 95 % CI 1·02 - 1·29 ] ) than were women with insufficient concentrations . Among women who achieved pregnancy , sufficient preconception 25-hydroxyvitamin D , but not that at 8 weeks of gestation , was associated with reduced risk of pregnancy loss ( preconception RR per 25 nmol/L 0·88 [ 95 % CI 0·77 - 0·99 ] ; 8 weeks of gestation 0·98 [ 0·95 - 1·01 ] ) . No association was observed with fecundability in women with sufficient versus those with insufficient preconception 25-hydroxyvitamin D concentrations ( adjusted FOR 1·13 [ 95 % CI 0·95 - 1·34 ] ) . INTERPRETATION Sufficient preconception 25-hydroxyvitamin D ( ≥75 nmol/L ) was associated with increased likelihood of pregnancy and livebirth . Increased vitamin D concentrations before conception , but not in early pregnancy , were associated with reduced pregnancy loss . FUNDING National Institutes of Health and Doris Duke Charitable Foundation
target: Meta-analyses of r and omized controlled trials ( RCTs ) document that physiological vitamin D supplementation during pregnancy is safe and improves vitamin D and calcium status , thereby protecting skeletal health .
  Although certain RCTs and /or meta-analyses reported some other beneficial effects , it is still not clear whether vitamin D supplementation  improves fertility or decreases the risk of adverse pregnancy outcomes such as low birth weight , pre-eclampsia and neonatal mortality , or reduces wheeze/asthma in the infants .
background: Vitamin D deficiency is common and there exists a huge gap between recommended dietary vitamin D intakes and the poor vitamin D supply in the general population .
  While vitamin D is important for musculoskeletal health , there are accumulating data suggesting that vitamin D may also be important for fertility , pregnancy outcomes and lactation .
  Significant changes in vitamin D metabolism during pregnancy such as increased production of the " active vitamin D hormone " calcitriol support the important role of vitamin D in this setting .
  Observational studies show that vitamin D deficiency is a risk marker for reduced fertility and various adverse pregnancy outcomes and is associated with a low vitamin D content of breast milk .
  Nevertheless , vitamin D supplementation in pregnant women is frequently required to achieve a sufficient vitamin D status as recommended by nutritional vitamin D guidelines .