A C TA Obstetricia et Gynecologica

AOGS REVIE W A R T I C L E

The impact of vitamin D in pregnancy on extraskeletal health in children: a systematic review

HENRIK T. CHRISTESEN1,2 , CLAES ELVANDER1 , RONALD F. LAMONT3,4 & JAN S. JRGENSEN2,3
Hans Christian Andersen Childrens Hospital and 3 Department of Obstetrics and Gynaecology, Odense University Hospital, Odense, 2 Clinical Institute, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark, and 4 Division of Surgery, University College, London, UK
1

Key words Child health, fetal health, health care policy, neonatology, pregnancy, vitamin D Correspondence Henrik Thybo Christesen, Hans Christian Andersen Childrens Hospital, Odense University Hospital, Snder Boulevard 29, 5000 Odense C, Denmark. E-mail: henrik.christesen@ouh.regionsyddanmark.dk Conict of interest The authors have stated explicitly that there are no conicts of interest in connection with this article. Please cite this article as: Christesen HT, Elvander C, Lamont RF, Jrgensen JS. The impact of vitamin D in pregnancy on extraskeletal health in children: a systematic review. Acta Obstet Gynecol Scand 2012;91:13681380. Received: 16 February 2012 Accepted: 28 August 2012 DOI: 10.1111/aogs.12006

Abstract The impact of maternal vitamin D status in pregnancy on the extraskeletal health of the offspring has become a hot topic with a potential for cost-benecial prevention. The objective of this study was to systematically review the level I and II evidence. PubMed, Embase and Cochrane databases were searched using the MeSH terms vitamin D AND pregnancy until 1 January 2012. The search was limited to randomized controlled trials (evidence level I) and observational studies (evidence level II) in humans and in the English language. Papers reporting on vitamin D supplementation in combination with other supplements, or not reporting on 25OHD or outcomes of the offspring were excluded. Six randomized controlled trials and 24 observational studies were nally included. In randomized controlled studies, vitamin D supplementation resulted in increased birthweight in one study, but showed no effect in ve other studies. In cohort and casecontrol studies, higher vitamin D intake, or higher 25OHD, was associated with increased birthweight in large studies only, and modied by vitamin D receptor polymorphisms and by race (U-shaped in Caucasians in one unconrmed study). The risks of HIV mother-tochild transmission, rhinitis symptoms and eczema were lower. Data were conicting on the effect on respiratory infections and wheezing, whereas U-shaped associations to inhalant allergen-specic IgE at ve years and to schizophrenia were reported in unconrmed studies. The risk of type 1 diabetes at 15 years was lower or unchanged. It is concluded that observational studies suggest an effect of vitamin D on several outcomes. U-Shaped associations warrant caution.
Abbreviations: 1,25(OH)2 D, 1,25-dihydroxylated vitamin D; 25OHD, 25hydroxylated vitamin D2+3 ; MeSH, Medical Subject Headings; RCT, randomized controlled trial; SGA, small for gestational age; T1D, type 1 diabetes.

Introduction
Vitamin D sufciency of the fetus depends solely on the supply of maternal 25-hydroxylated vitamin D2+3 (25OHD) across the placenta. Maternal 25OHD stores depend on exposure to sunlight (ultraviolet B radiation promotes dermal D3 synthesis), animal foods such as oily sh and dairy products (D3 ), plants and vegetables (D2 ) and vitamin D supplementation. In the fetus, 25OHD is hydroxylated mainly in the kidneys to the biologically active form, 1,25(OH)2 D (1). Serum 25OHD has a half-life of two to three weeks, and maternal levels tend to be stable during pregnancy. 25-Hydroxylated

Key Message
Hypovitaminosis D in pregnancy may decrease birthweight and increase the risk of HIV mother-to-child transmission, respiratory infections, wheezing, rhinitis, eczema, type 1 diabetes and schizophrenia in the offspring, although evidence is conicting or sparse. UShaped associations warrant caution.

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Impact of vitamin D in pregnancy on children

Figure 1. Flow diagram of literature search.

vitamin D2+3 readily crosses the placenta, and maternal and neonatal hypovitaminosis D are strongly associated, albeit that cord 25OHD is usually lower than in maternal serum (16). Breastfed compared with bottle-fed infants are more prone to develop low vitamin D, depending on maternal serum 25OHD levels. Hypovitaminosis D is common in pregnancy and in neonates worldwide (211) and, when extreme, it may cause fetal death, infant hypocalcemic tetany and lifethreatening cardiomyopathy (12,13). In childhood, delayed bone ossication, abnormal tooth-enamel formation, rickets and delayed whole-body bone mineral content can be seen in nine-year-old children (9). The potential extraskeletal effects on the offspring of hypovitaminosis D during pregnancy have gathered much interest in recent years, as have the effects of hypovitaminosis D occurring later in childhood and in non-pregnant adults. The recommendations for vitamin D supplementation during pregnancy should take into account skeletal and extraskeletal effects on the offspring, as well as obstetric outcome (14). We performed an up-to-date systematic search for the evidence of extraskeletal effects in the offspring of women with low or high vitamin D levels during pregnancy.

ing the predetermined inclusion criteria. The full texts of all potentially relevant articles were retrieved for detailed review. We resolved disagreements by discussion until consensus was achieved. The systematic review identied 53 potentially suitable articles, which were screened using the titles and abstracts. No additional titles were found by searching without MeSH words in 2011, nor in the Cochrane Database. Forty-seven abstracts were excluded because of the criterion no randomization of exclusively vitamin D in pregnancy. For the remaining eight papers, the full-length texts were obtained. These studies were assessed for their methodological quality, which involved evaluation of study design, population size and statistical analysis. In addition to the RCTs (evidence level I), and using the same methodology, the full-length texts of relevant human cohort and casecontrol studies (evidence level II) were also obtained.

Results
Randomized controlled trials of vitamin D
Among the eight RCTs retrieved, one was considered to be preliminary, with data included in later analysis, and another RCT reported no data on the offspring (15,16). The remaining six RCTs (1722) are presented in Table 1. Only the two most recent RCTs (21,22) had a dened primary outcome parameter (25OHD at delivery) and a sample size that met a statistical power calculation. Only one RCT showed any direct effect on extraskeletal neonatal clinical outcome. In Northern India, administration of two large doses of 600,000 IU vitamin D in the third trimester to 100 pregnant women compared with 100 pregnant women without supplementation was associated with highly signicant increases in birthweight of 190 g. Birth length, head circumference, mid-arm circumference and skin-fold thicknesses were also increased (20). The study did not use placebo and had no data on serum 25OHD levels. In the non-supplemented group, symptoms of maternal vitamin D deciency were more frequent, cord calcium was lower and cord alkaline phosphatase was higher, suggesting widespread hypovitaminosis D. In the other RCTs, no effect was seen on birthweight (17,18,21,22), birth length or head circumference (17). Other extraskeletal outcomes were not reported. In the earliest study on Asians in London (1980), the neonates of the mothers given 1000 IU D2 /day had a smaller fontanelle area (4.1 cm2 vs. placebo, 6.1 cm2 ), suggesting improved skeletal health (17). In addition, symptomatic hypocalcaemia appeared in the placebo group only, and cord 25OHD levels were higher with higher doses of vitamin D. In ve RCTS, the cord 25OHD values were between 18% and 45% (mean 36%) lower than maternal serum 25OHD at delivery (1719,21,22). Although 83.9% of the mothers in the

Material and methods

A search in PubMed and Embase was performed using the Medical Subject Headings (MeSH) terms vitamin D AND pregnancy for randomized controlled trials (RCTs) in humans, in English, without date limits up to 1 January 2012 (Figure 1). An additional search was performed for vitamin D AND (pregnancy OR pregnant) for the last year to include possible new articles not yet MeSH indexed. Another search was done in the Cochrane Database. Identied clinical studies were included for screening after removal of duplicates. Inclusion criteria were English-written RCTs exclusively on vitamin D in pregnancy with outcomes of the offspring. Three authors (H.T.C., C.E. and R.F.L.) independently screened titles and abstracts of all studies identied by the search strategy and assessed the studies for inclusion usC 2012 The Authors Acta Obstetricia et Gynecologica Scandinavica

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No. of participants Intervention, vitamin D (i) 1000 IU D2 /day during third trimester vs. (ii) placebo control Similar in age, height, parity, % of vegetarians, county of origin, basal p-25OHD, season Baseline parameters Outcome Results 126 Statistics 77 P-1,25(OH)2 D (cord) No data P-25OHD (cord) Gestational age Birthweight Birth length Birth head circumference Fontanelle area Symptomatic hypocalcemia (n) P-25OHD (cord) p < 0.001 n.s. n.s. n.s. n.s. p < 0.05 p < 0.01 n.s. p < 0.001 n.s. 40 No data Term birthweight S-25OHD (cord) S-1,25(OH)2 D (cord) Birthweight Birth length Birth head circumference (i) 137.9 vs. (ii) 10.2 nmol/L (i) 39+1 vs. (ii) 39+3 weeks (i) 3157 vs. (ii) 3034 g (i) 49.7 vs. (ii) 49.5 cm (i) 34.5 vs. (ii) 34.3 cm (i) 4.1 vs. (ii) 6.1 cm2 (i) 0 vs. (ii) 5 (i) 18.2 vs. (ii) 15.7 nmol/L (ii) 15.7 vs. (iii) 5.3 nmol/L (i) 42.6 vs. (ii) 46.1 vs. (iii) 47.0 pmol/L (i) 3370 vs. (ii) 3210 vs. (iii) 3460 g (i) 45 vs. (ii) 17.5 nmol/L (i) 98.8 vs. (ii) 153.4 pmol/L (i) 2990 vs. (ii) 2800 g (i) 50.06 vs. (ii) 48.45 cm (i) 33.99 vs. (ii) 33.41 cm n.s. p < 0.0005 p < 0.05 p < 0.001 p < 0.001 p < 0.001 200 Similar in age, height, weight, parity 180 (i) 1000 IU vitamin D/day during third trimester vs. (ii) 200,000 IU vitamin D single dose at 7th month vs. (iii) control (no placebo) (i) 1000 IU D3 /day during third trimester vs. (ii) control (no placebo) (i) two doses of 600,000 IU vitamin D at 7th and 8th month of gestation vs. (ii) no supplementation (no placebo) (i) 200,000 IU D3 single dose, week 27 vs. (ii) 800 IU D2 /day from week 27 vs. (iii) control (no placebo) Similar in calcium, 25OHD, ethnicity P-25OHD at delivery (cord) (i) 4000 IU D3 /day from week 12 vs. (ii) 2000 IU D3 /day from week 12 vs. (iii) 400 IU D3 /day from week 12 Gestational age Birthweight Birthweight <10th percentile S-25OHD (cord) S-25OHD (cord) >50 nmol/L Gestational age (weeks) Birthweight (g) Similar in race/ethnicity, age, educational and employment status, health rating, % of planned pregnancy, body mass index, season at entry, p-25OHD, p-1,25(OH)2 D 350 (i) 25 vs. (iii) 17 nmol/L (ii) 26 vs. (iii) 17 nmol/L n.a. n.a. (i) 13 vs. (ii) 15 vs. (iii) 17% (i) 66.3 vs. (ii) 57.0 nmol/L (ii) 57.0 vs. (iii) 45.5 nmol/L (i) 78.6 vs. (ii) 58.2 vs. (iii) 39.7% (i) 39.1 (ii) 38.8 (iii) 38.6 (i) 3286.6, (ii) 3360.1, (iii) 3221.8 p < 0.001 p < 0.001 n.s. n.s. p = 0.7 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.17 p = 0.9

Table 1. Randomized controlled trials on vitamin D and offspring outcome.

Study (reference no.)

Participants, location

Impact of vitamin D in pregnancy on children

Brooke et al. 1980 (17)

Asians, London, UK

Mallet et al. 1986 (18)

Northwest France

Acta Obstetricia et Gynecologica Scandinavica

Delvin et al. 1986 (19)

Lyon, France

Marya et al. 1988 (20)

Northern India

Yu et al. 2009 (21)

Four ethnic groups, London, UK

Hollis et al. 2011 (22)

Hispanic, white, black, Charleston, SC, USA

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Note: 25OHD conversion factor 2.5 from nanograms per milliliter and 1,25(OH)2 D conversion factor 2.6 from picograms per milliliter. Abbreviations: 1,25(OH)2 D, 1,25 dihydroxylated vitamin D; 25OHD, 25-hydroxylated vitamin D; n.a., not available; n.s., not signicant; p, plasma; and s, serum. Erratum for conversion in ref. 22 considered. Gestational age written as such in ref. 22.

H.T. Christesen et al.

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Impact of vitamin D in pregnancy on children

highest supplementation dose of 4000 IU/day had a serum level of 25OHD >80 nmol/L at delivery, only 78.6% of cord 25OHD levels were >50 nmol/L (22). In one study, cord 1,25(OH)2 D levels were highest in the non-supplemented group, probably reecting a lower calcium level, which enhances 1- hydroxylation (18).

Other studies
The search for cohort and casecontrol studies retrieved 24 papers on vitamin D in pregnancy and extraskeletal health of the offspring. Birthweight Several studies have examined the relation between maternal vitamin D status and birthweight or small for gestational age (SGA), with conicting results. No effects were seen in several relatively small observational studies (n = 100559; Table 2; 10,2326). In contrast, in a study of 971 pregnancies, maternal (but not cord) serum levels of 25OHD <25 nmol/L were associated with a birthweight that was lower by 151 g (3). Adjustment for the vitamin D receptor polymorphism FokI in 354 of the neonates revealed an association between 25OHD <28 nmol/L and birthweight, suggesting the importance of vitamin D receptor polymorphisms of the offspring (27). In an intermediate-sized cohort (n = 1194), no effect on birthweight from total vitamin D intake during pregnancy was detected (28). In a large cohort (n = 2251), maternal total vitamin D intake <5 g/day were associated with lower birthweight (29). In another large study (n = 3730), serum levels of 25OHD <30 nmol/L were associated with a 64 g lower birthweight and almost double the risk of SGA (30). Bodnar et al. (31) showed a U-shaped relation between serum 25OHD and the odds of SGA among white women, the lowest odds occurring between 60 and 75 nmol/L, but no association among black women. The minor allele of the maternal vitamin D receptor polymorphism, rs11168292, almost doubled the odds of SGA in white women with 25OHD <37.5 nmol/L, but no vitamin D receptor polymorphism was found to affect the association between 25OHD >75 nmol/L, and increased odds of SGA and vitamin D receptor polymorphisms did not alter the absent association in black women. The impact of maternal vitamin D deciency on the outcome of premature neonates is unknown. Childhood infections In a study on HIV-infected women (32), serum levels of 25OHD <80 nmol/L at 1227 weeks of gestation was associated with a 49% increased risk of mother-to-child transmission of HIV or neonatal death at birth, and a 50% increased risk of HIV mother-to-child transmission at six weeks of age (Table 3). At follow-up, live-borne children of mothers with
C 2012 The Authors Acta Obstetricia et Gynecologica Scandinavica

low vitamin D levels had a 61% increased risk of dying within 24 months, and mothers with low 25OHD levels in pregnancy showed progression of HIV disease (33). In a small casecontrol study, neonates below one month of age with acute lower respiratory tract infection and their mothers both had lower 25OHD values than control mothers and infants, with an odds ratio of 4.25 (unadjusted) for 25OHD <25 nmol/L (34). Likewise, umbilical cord levels of 25OHD <25 nmol/L were associated with twofold odds of respiratory infections by three months of age (35). In contrast, a UK study reported that by nine months of age, late-pregnancy 25OHD levels >75 nmol/L, compared with levels <30 nmol/L, were associated with approximately vefold increased odds of mother-reported physician-diagnosed pneumonia or bronchiolitis and almost twofold odds of mother-reported bouts of diarrhea. This did not apply to reported chest infections, bronchitis, overall respiratory infections or ear infections (24). Multiple regression analysis was not performed. Wheezing and asthma in childhood In ve prospective cohort studies (28,3538), estimated vitamin D intake during pregnancy was inversely associated with the odds of developing wheeze in the offspring (Table 3). In 1194 three-year-old children of mothers with an estimated vitamin D intake >659 IU/day during pregnancy, odds were 62% lower for recurrent wheeze, compared with mothers with a daily intake <446 IU. An increase of 100 IU vitamin D/day was associated with a 20% reduced odds of recurrent wheeze at three years of age (28). In a study of 823 infants, cord-blood 25OHD was inversely associated with the odds of parental-reported wheezing by 15 months, three and ve years of age (adjusted, p < 0.05), but not with doctor-diagnosed asthma by ve years (35). In 1120 ve-year-old children in Scotland, the adjusted odds ratio of persistent wheeze was 67% lower when their mothers had a vitamin D intake in pregnancy in the lowest, compared with the highest quintile. No association was seen in smaller subgroups to atopic sensitization or exhaled nitric oxide; however, bronchodilator response decreased with decreasing pregnancy vitamin D intake (36). In ve-year-old Finnish children with a genetically increased risk for type 1 diabetes (T1D), maternal vitamin D intake was inversely related to the risk of asthma, dened as persistent, physiciandiagnosed wheezing or medication during last 12 months (parental reported; 37). In Japan, maternal dietary vitamin D intake 172 IU/day during pregnancy was associated with 36% reduced odds of parental-reported wheeze in the children aged 1624 months (38). On the contrary, children of mothers with 25OHD >75 nmol/L in late pregnancy had an increased odds of parentally reported asthma at nine years, suggesting a

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Participants 100 mothers and neonates 559 mothers and neonates 466 mothers and neonates 374 mothers and neonates 2832 weeks of gestation Birthweight (g) 25OHD 32 weeks of gestation Birthweight (g) log(25OHD) 30 weeks of gestation Birthweight (g) 25OHD Delivery Birthweight (g) Univariate, n.s. Adjusted regression, n.s. Univariate, n.s. Determinant Time of determination Association Statistics (95% CI in parentheses) 374 mothers and neonates 221 mothers and neonates 971 mothers and neonates 254 mothers and neonates 25OHD <28 vs. 28 nmol/L 2832 weeks of gestation Total VD intake, quartiles Total VD intake <5 vs. 5 g/day Total VD intake, quintiles During pregnancy <28 weeks gestation <28 weeks gestation Birthweight (g) SGA (%) 25OHD 3032 weeks of gestation 25OHD <28 vs. 28 nmol/L log2(25OHD) 25OHD <37.5 nmol/L 2832 weeks of gestation 18.7 weeks of gestation Birthweight (g) Birthweight (g) Birthweight (g) Adjusted, 153 g (348 to 45) Adjusted, 31 (25 to 112) g Adjusted OR 0.91 (0.31 2.62) Adjusted regression, +151 g (50250) Adjusted regression, p = 0.02 1194 mothers and children 2251 mothers and neonates 2251 mothers and neonates 3730 mothers and neonates 3730 mothers and neonates 273 white mothers and neonates white mothers and neonates (numbers n.a.) 273 white mothers and neonates 139 black mothers and neonates 139 black mothers and neonates Birthweight (g), by offspring VDR SNP FokI Birthweight (z-score) Birthweight (g) Birthweight (g) Univariate, test for trend, n.s. Adjusted, test for trend, p = 0.027 Adjusted, test for trend, p = 0.043 64 g (107.1 to 20.9) Adjusted OR 1.9 (1.42.7) 25OHD <30 vs. 50 nmol/L 25OHD <30 vs. 50 nmol/L 25OHD <37.5 vs. 6075 nmol/L 25OHD <37.5 vs. 6075 nmol/L 25OHD >75 vs. 6075 nmol/L 25OHD <37.5 vs. 6075 nmol/L 25OHD >75 vs. 6075 nmol/L After 12 weeks of gestation After 12 weeks of gestation <22 weeks of gestation <22 weeks of gestation <22 weeks of gestation <22 weeks of gestation <22 weeks of gestation SGA (<10th p) SGA (<10th p), by maternal VDR SNP SGA (<10th p) SGA (<10th p) SGA (<10th p) Adjusted OR 7.5 (1.831.9) Adjusted OR 14.0 (2.773.0) Adjusted OR 2.1 (1.23.8) Adjusted OR 1.5 (0.63.5) Adjusted OR 2.2 (0.59.0)

Table 2. Cohort and casecontrol studies on effect of vitamin D on birthweight.

Article (reference no.)

Location

Kayseri, Turkey

Mysore, South India

Akcasus et al. 2006 (23) Farrant et al. 2009 (10) Gale et al. 2008 (24) Morley et al. 2006 (25)

Southampton, UK

Melbourne, Victoria, Australia

Impact of vitamin D in pregnancy on children

Acta Obstetricia et Gynecologica Scandinavica

Shand et al. 2010 (26) Bowyer et al. 2009 (3) Morley et al. 2009 (27)

Vancouver, Canada

Sydney, NSW, Australia Melbourne, Victoria, Australia

Massachusetts, USA

Camargo et al. 2007 (28) Scholl et al. 2009 (29)

New Jersey, USA

Leffelaar et al. 2010 (30)

Amsterdam, The Netherlands

Bodnar et al. 2010 (31)

Pittsburgh, Pennsylvania, USA

H.T. Christesen et al.

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Note: 25OHD conversion factor 2.5 from nanograms per milliliter. Vitamin D intake (food and/or supplemental) was estimated by questionnaires. Abbreviations: 25OHD, 25-hydroxylated vitamin D; CI, condence interval; n.a., not available; n.s., not signicant; OR, odds ratio; p, percentile; SGA, small for gestational age; VD, vitamin D; VDR SNP FokI, vitamin D receptor start codon single nucleotide polymorphism.

Table 3. Cohort and casecontrol studies on effect of vitamin D on infections, wheezing and allergy in children.

Outcome Dar es Salaam, Tanzania 884 mothers and neonates 884 mothers and neonates 25OHD <80 vs. 80 nmol/L 25OHD <80 vs. 80 nmol/L 1227 weeks of gestation 1227 weeks of gestation HIV mother-to-child infected or dead at birth HIV mother-to-child transmission at six weeks of age

Article (reference. no.) Location Participants Determinant Time of determination Association Adjusted RR 1.49 (1.072.09) Adjusted RR 1.50 (1.022.20) Adjusted RR 1.61 (1.262.07)

Statistics (95% CI in parentheses)

H.T. Christesen et al.

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Infections

Metha et al. 2009 (32)

Metha et al. 2010 (33) Istanbul, Turkey Wellington, New Zealand Southampton, UK 882 children 25 cases; 15 controls Neonates, age <30 days Delivery (umbilical cord) 32 weeks of gestation

884 mothers and neonates

25OHD <80 vs. 80 nmol/L 1227 weeks of gestation

Karatekin et al. 2009 (34) Camargo et al. 2011 (35) Gale et al. 2008 (24) 32 weeks of gestation 32 weeks of gestation 466 mothers and neonates 466 mothers and neonates 466 mothers and neonates

25OHD <25 vs. 25 nmol/L 25OHD <25 vs. 75 nmol/L 25OHD >75 vs. <30 nmol/L 25OHD >75 vs. <30 nmol/L 25OHD >75 vs. <30 nmol/L

Unadjusted OR 4.25 (1.0617.1) Adjusted OR 2.04 (1.133.67) Unadjusted OR 4.80 (1.0122.73) Unadjusted OR 1.87 (1.013.46) n.s.

Camargo et al. 2007 (28)

Massachusetts, USA

During pregnancy During pregnancy Delivery (umbilical cord) Delivery (umbilical cord)

Wheezing, asthma, allergy Wellington, New Zealand 823 children

Camargo et al. 2011 (35)

1194 mothers and children 1194 mothers and children 823 children

Total VD intake >658 vs. <446 IU/day Total VD intake, per +100 IU/day 25OHD <25 vs. 75 nmol/L 25OHD <25 vs. 75 nmol/L Total VD intake, >188 vs. <93 IU/day Total VD intake, quintiles Total VD intake, quintiles Total VD intake, quintiles

Adjusted OR 0.38 (0.220.65) Adjusted OR 0.80 (0.720.90) Adjusted OR 2.15 (1.393.33) Adjusted OR 0.94 (0.531.64) Adjusted OR 0.33 (0.110.98) Adjusted, test for trend, p = 0.036 n.s. n.s. 2032 weeks of gestation 2032 weeks of gestation 2032 weeks of gestation 2032 weeks of gestation

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Devereux et al. 2007 (36)

Aberdeen, UK

1120 mothers and children 238 mothers and children 700 mothers and children 167 mothers and children

Death <24 months postpartum among live-borns Lower respiratory tract infections <30 days Respiratory infections less than three months of age Pneumonia or bronchiolitis less than nine months of age Diarrhoea less than nine months of age Overall respiratory or ear infections less than nine months Recurrent wheeze at three years Recurrent wheeze at three years Wheeze or whistling in the chest, ever, up to ve years Asthma at ve years, doctor diagnosed plus inhaler use or wheeze in last year Persistent wheeze at two and ve years Bronchodilator response at ve years Atopic sensitization at ve years Exhaled nitric oxide at ve years

Impact of vitamin D in pregnancy on children

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Location Multicenter, Finland Osaka, Japan 1669 mothers and children 763 mothers and children Total VD intake, quartiles 8th month of pregnancy During pregnancy Asthma last 12 months, at ve years Wheezing or whisting in the chest last 12 months, at 1624 months of age Asthma at nine years Current medication prescribed for asthma at nine years Participants Determinant Time of determination Association Statistics (95% CI in parentheses) Adjusted HR 0.80 (0.640.99) Adjusted OR 0.64 (0.430.97) Southampton, UK 32 weeks of gestation 178 mothers and children 178 mothers and children VD intake by food, 172.4 vs. <172.4 IU/day (25th quartile cut off) 25OHD >75 vs. <30 nmol/L 25OHD >75 vs. <30 nmol/L 32 weeks of gestation Unadjusted OR 5.40 (1.0926.65) Unadjusted OR 4.66 (0.9323.30) Arizona, USA 25OHD 194 children Delivery (umbilical cord) Adjusted regression, n.s. 208 children 208 children 172 children 25OHD 100 vs. 5074.9 nmol/L 25OHD <50 vs. 5074.9 nmol/L 25OHD 100 vs. 5074.9 nmol/L Delivery (umbilical cord) Delivery (umbilical cord) Delivery (umbilical cord) Adjusted OR 3.6 (1.210.5) Adjusted OR 2.8 (1.26.6) Adjusted OR 3.4 (1.011.4) Multicenter, Finland Arizona, USA 25OHD 100 vs. 5074.9 nmol/L Total VD intake, quartiles 1669 mothers and children 192 children Total VD intake, quartiles 8th month of pregnancy Delivery (umbilical cord) 8th month of pregnancy During pregnancy Asthma at ve years, doctor diagnosed plus symptoms or medication in last year Six inhalant-allergen-specic IgE up to ve years Six inhalant-allergen-specic IgE up to ve years Positive skin-prick test for one or more of 17 aeroallergens, at ve years Allergic rhinitis at ve years Adjusted HR 0.84 (0.720.98) Adjusted OR 2.4 (0.87.3) Allergic rhinitis by ve years, doctor diagnosed plus symptoms in last year Atopic dermatitis ever, at ve years Itchy rash up to 1624 months of age Adjusted HR 0.94 (0.831.07) Adjusted OR 0.63 (0.410.98) Multicenter, Finland Osaka, Japan 1669 mothers and children 763 mothers and children Southampton, UK 440 mothers and children VD intake by food, 172.4 vs. <172.4 IU/day (25th quartile cut off) 25OHD >75 vs. <30 nmol/L 32 weeks of gestation Atopic eczema at nine months of age Unadjusted OR 1.62 (0.673.89)

Outcome

Article (reference. no.)

Erkkola et al. 2009 (37) Miyake et al. 2010 (38)

Impact of vitamin D in pregnancy on children

Gale et al. 2008 (24)

Acta Obstetricia et Gynecologica Scandinavica

Rothers et al. 2011 (39)

Allergic rhinitis

Erkkola et al. 2009 (37) Rothers et al. 2011 (39)

Eczema

Erkkola et al. 2009 (37) Miyake et al. 2010 (38)

Gale et al. 2008 (24)

H.T. Christesen et al.

C 2012 The Authors 2012 Nordic Federation of Societies of Obstetrics and Gynecology 91 (2012) 13681380

Note: 25OHD conversion factor 2.5 from nanograms per milliliter. Vitamin D intake (food and/or supplemental) was estimated by questionnaires. Abbreviations: 25OHD, 25-hydroxylated vitamin D; CI, condence interval; HR, hazard ratio; n.s., not signicant; OR, odds ratio; RR, relative risk; and VD, vitamin D. Parental reported. Modied UK working criteria.

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negative effect of high vitamin D in pregnancy for the risk of eczema and asthma in the offspring. However, the study did not adjust for confounders; the number of participants and the follow-up rate at nine years was low, and no signicant effect was detected on the odds of currently taking prescribed medications for asthma (24). Rothers et al. (39) recently found increased odds of inhalant-allergen-specic IgE in ve-year-old children whose cord 25OHD was either 100 or <50 nmol/L, compared with 5074.9 nmol/L. In addition, cord 25OHD 100 nmol/L was associated with a positive skin-prick test for aero-allergens by ve years. No association was detected for doctor-diagnosed asthma. Allergic rhinitis and atopic dermatitis/eczema In the ve-year-old Finnish children with a genetically increased risk for T1D, maternal vitamin D intake was also inversely related to the risk of allergic rhinitis, dened as sneezing, nasal congestion or rhinitis without respiratory infections, accompanied by eye itching and tearing (parental reported), but not to atopic eczema (Table 3; 37). In the smaller study of Rothers et al., no association between cord 25OHD and allergic rhinitis by ve years was seen (39). In Japan, maternal vitamin D intake by food 172 IU/day during pregnancy was associated with 37% reduced odds of parental-reported eczema in children aged 1624 months (38). No association was seen between 25OHD in pregnancy and atopic eczema in the offspring at nine months or nine years (unadjusted analysis; 24). Type 1 diabetes in childhood In a large casecontrol study, intake of cod liver oil (a potent source of vitamin D) or supplemental vitamin D during pregnancy was not associated with T1D below 15 years (Table 4; 40). Likewise, maternal vitamin D intake was not associated with T1D or advanced -cell autoimmunity in the mothers children with genetically increased risk of T1D up to four years (41). In contrast, maternal intake of dietary vitamin D (not supplementation) during pregnancy was associated with a reduced risk of islet antibodies in the four-year-old offspring (42). Vitamin D supplementation during pregnancy was associated with reduced odds of diabetes-related autoimmunity in the offspring at one year, but not at 2.5 years (43). In a recent Norwegian study, maternal serum levels of 25OHD during pregnancy were inversely correlated to offspring T1D up to 15 years of age (test for trend p = 0.031; 44). Cerebral function and diseases In nine-year-old children from Southampton, UK, no associations between late pregnancy 25OHD levels and cognitive function or psychological health were found (Table 4). The exception (in a univariate analysis) was an increase score in
C 2012 The Authors Acta Obstetricia et Gynecologica Scandinavica

peer problems with increasing (rather than decreasing) levels of pregnancy 25OHD (24). Using neonatal dried blood spots for the analysis of 25OHD in 428 Danish patients with schizophrenia up to 26 years of age and 428 matched control subjects, a U-shaped association between 25OHD and the risk of schizophrenia was observed. Compared with the fourth quintile (40.550.9 nmol/L), the three lowest quintiles had twice the risk of schizophrenia, but also the highest quintile (>50.9 nmol/L) had an increased risk by 71% (45). Cancer, adiposity and cardiovascular disease No associations between late-pregnancy serum 25OHD and body mass index, fat or lean body mass, blood pressure, pulse wave velocity, carotid intimal thickness or cardiac structure were found in nine-year-old children (Table 4; 24), and no data were found which related to childhood cancers/leukemia. The impact of in utero vitamin D status on adult cancer, adiposity, cardiovascular disease and aging is beyond the scope of this review.

Discussion
To date, evidence (level I data) concerning the impact of vitamin D in pregnancy on the extraskeletal health of offspring is sparse. In one RCT, increased birthweight, birth length and head circumference, but not gestational age, was seen when two large doses of 600,000 IU vitamin D were used vs. no supplementation (20). The frequency of vitamin D deciency symptoms was high in the non-supplemented group. Although not of high methodological quality, this study suggested that vitamin D in very high doses in populations with widespread severe vitamin D deciency may improve fetal growth. In ve other RCTs, vitamin D supplementation did not alter birthweight, birth length, head circumference or gestational age (when reported). These studies used lower doses (single or daily), or had a low frequency of vitamin D deciency (1719,21,22). We found a weak association between lower pregnancy 25OHD levels or vitamin D intake and lower birthweight in large observational studies (29,30), but not in smaller (10,2326) or intermediate-sized studies using estimated vitamin D intake (28), which is a weaker measure of maternal 25OHD status. A few days of shortening in the gestational age, detectable in some large studies, may be sufcient to contribute to lower birthweight (14). Although not detected in any of the RCTs, also when controlling for race (46), the U-shaped association between maternal 25OHD and SGA birthweight at levels <37.5 and >75 nmol/L in white women found in the study of Bodnar et al. (31) calls for further studies, including the impact of VRD polymorphisms (27). In summary, low maternal 25OHD levels in pregnancy may result in a race-dependent lowering of birthweight only detectable in large studies,

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Location Norway 545 cases, 1668 controls 545 cases, 1668 controls Type 1 diabetes <4.3 years (mean) Type 1 diabetes <15 years Type 1 diabetes <15 years Participants Determinant Time of etermination Association Statistics (95% CI in parentheses) Adjusted, test for trend 0.89 Adjusted, test for trend 0.94 During pregnancy Cod liver oil vs. no cod liver oil or VD supplementation During pregnancy VD supplementation vs. no supplementation or cod liver oil Total VD intake, quartiles 8th month of pregnancy Total VD intake, quartiles 8th month of pregnancy Total VD intake, increase Third trimester +155.6 IU/day During pregnancy VD supplementation vs. none VD supplementation vs. During pregnancy none 25OHD <55 vs. During pregnancy >89 nmol/L 25OHD 32 weeks of gestation 25OHD 25OHD 25OHD <19.7 vs. 40.550.9 nmol/L 25OHD 19.730.9 vs. 40.550.9 nmol/L 25OHD 3140.4 vs. 40.550.9 nmol/L 25OHD 51 vs. 40.550.9 nmol/L 25OHD Adjusted HR 1.08 (0.651.79) Advanced -cell autoimmunity or type 1 Adjusted HR 1.26 (0.921.73) diabetes at 4.3 years, n = 55 -Cell autoantibodies at four years, Adjusted HR 037 n = 138 (0.170.78) Adjusted OR 0.71 -Cell autoantibodies at one year, (0.520 .96) n = 774 Adjusted OR 1.25 -Cell autoantibodies at 2.5 years, (0.901.73) n = 676 Type 1 diabetes <15 years Adjusted OR 2.38 (1.125.07) Unadjusted regression, Wechsler Abbreviated Scale of n.s. Intelligence (WASI) score at nine years Unadjusted regression, 32 weeks of gestation Strength and Difculty Questionnaire; p = 0.038 peer problems Unadjusted regression, 32 weeks of gestation Strength and Difculty Questionnaire n.s. including hyperactivity Neonatal dry spot Schizophrenia <27 years of age Adjusted RR 2.1 (1.33.5) Neonatal dry spot Schizophrenia <27 years of age Adjusted RR 2.0 (1.33.2) Neonatal dry spot Adjusted RR 2.1 Schizophrenia <27 years of age (1.33.4) Adjusted RR 1.71 Neonatal dry spot Schizophrenia <27 years of age (1.042.8) Unadjusted regression, 32 weeks of gestation Body mass index, fat/lean body mass, n.s. blood pressure, pulse wave velocity, carotid intima thickness, cardiac structure at nine years

Table 4. Cohort and casecontrol studies on effect of vitamin D on type 1 diabetes, cerebral function and metabolic syndrome markers in childhood.

Outcome

Article (reference. no.)

Type 1 diabetes

Stene et al. 2003 (40)

Impact of vitamin D in pregnancy on children

Acta Obstetricia et Gynecologica Scandinavica

Marjamaki et al. Finland 2010 (41)

Cerebral function

Metabolic syndrome markers

3723 mothers and children 3723 mothers and children Fronczak et al. Colorado, USA 222 mothers and 2003 (42) children Brekke et al. Southeast 8694 mothers and 2007 (43) Sweden children 7766 mothers and children Srensen et al. Norway 109 cases, 219 2012 (44) controls Gale et al. 2008 Southampton, 178 mothers and (24) UK children 177 mothers and children 177 mothers and children McGrath et al. Denmark 424 cases, 424 2010 (45) controls 424 cases, 424 controls 424 cases, 424 controls 424 cases, 424 controls Gale et al. 2008 Southampton, 178 mothers and (24) UK children

H.T. Christesen et al.

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Note: 25OHD conversion factor 2.5 from nanograms per milliliter. Vitamin D intake (food and/or supplemental) was estimated by questionnaires. Abbreviations: 25OHD, 25-hydroxylated vitamin D; CI, condence interval; HR, hazard ratio; n.s., not signicant; OR, odds ratio; RR, relative risk; VD, vitamin D.

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Impact of vitamin D in pregnancy on children

studies including a high number with severe vitamin D deciency, or race-dependent vitamin D receptor polymorphisms. A few studies show conicting associations between 25OHD in pregnancy and respiratory infections in infancy (24,34,35). Only those studies which used confounderadjusted analysis showed an inverse correlation with respiratory infections (35). Alarmingly, HIV mother-to-child transmission was inversely correlated with 25OHD levels of <80 nmol/L (32), suggesting potentially huge health and economic benets of vitamin D supplementation in pregnancy in such areas. The impact of vitamin D on the immune system is well documented, because 1,25(OH)2 vitamin D binds to vitamin D receptor in both innate and adaptive immune cell types, and activated vitamin D is a potent effector of proliferation, differentiation and complex regulation of immune function (4754). The paucity of available human data does not permit rm conclusions on the effect of vitamin D in pregnancy on infant infectious diseases. The impact of vitamin D during pregnancy on the risk of allergic conditions in the offspring remains controversial. Methodological problems should be taken into consideration. Wheezing, a non-specic nding, may not be asthma but due to respiratory infections and is often only reported parentally. Asthma, on the contrary, should be doctor diagnosed using some criteria of reversibility, but this is often not the case, especially in younger children who are unable to perform lung-function tests (55). A history of childhood eczema or parental asthma may strengthen the probability of an allergic asthma disease, but the diagnosis of asthma, allergic rhinitis or atopic dermatitis is usually not dependent on a positive allergy test. We identied ve cohorts, in which estimated vitamin D intake during pregnancy or serum 25OHD levels was inversely associated with the adjusted odds of developing wheeze in the offspring, whereas one study showed unadjusted increased odds for parentally reported asthma at nine years, but not for medications prescribed for asthma. No association between cord 25OHD levels and doctor-diagnosed asthma at ve years was found in two recent studies (35,39). A U-shaped association between cord 25OHD levels and the odds of inhalant-allergen-specic IgE at ve years together with the increased odds of a positive skin-prick test for aeroallergens in those with a cord 25OHD level of 100 nmol/L should raise concerns (39). High vitamin D supplementation in the rst year of life (recommended dose 2000 IU/day) has been associated with an increased risk of asthma, allergic rhinitis and atopy in adults (56). Inverse associations were found between vitamin D intake in pregnancy and parentally reported allergic rhinitis at ve years or itchy rash around 20 months (37,38), whereas doctor-diagnosed allergic rhinitis at ve years or atopic eczema was not associated with 25OHD in pregnancy in two relatively smaller studies (24,39). More studies are
C 2012 The Authors Acta Obstetricia et Gynecologica Scandinavica

needed, and the results of an RCT of 4400 vs. 400 IU of vitamin D in 870 pregnant women and their offspring for the primary prevention of asthma (Vitamin D Antenatal Asthma Reduction Trial; VDAART) are much anticipated. Recent data suggest an inverse association between low pregnancy 25OHD and T1D in the offspring (44). Postnatal supplementation of vitamin D (recommended dose 2000 IU) during the rst year of life was associated with markedly reduced odds of T1D with a median onset at 14 years (57). Stene et al. (40) showed no association of estimated vitamin D intake in pregnancy, but the odds of T1D were inversely associated with the intake of cod oil in the rst year of life. A window of programming of the immune system in the fetus and during early infancy which predisposes towards less autoimmunity in the presence of higher vitamin D levels is supported by experimental data, and an effect of vitamin D on the different pathways in the pathogenesis of T1D may exist (5860). The lack of association of pregnancy vitamin D intake and T1D in the offspring found by others (4143) may be due to an insufcient follow-up time of the offspring (2.54.3 years of age). Vitamin D deciency has also been associated with other autoimmune diseases, including Hashimotos thyreoiditis (61), inammatory bowel disease (62) and multiple sclerosis (63); however, data concerning the role of maternal vitamin D in pregnancy for their children are absent or sparse. An early effect of vitamin D on the fetus with respect to multiple sclerosis was recently suggested with the observation that maternal vitamin D intake in pregnancy was inversely associated with the risk of multiple sclerosis in their adult daughters (64). The role of vitamin D in the development of the fetal brain and later cerebral function in childhood has not been studied extensively in humans. In one study, levels of 25OHD in pregnancy were inversely correlated with peer problems at nine years, but not with cognitive score or hyperactivity (24). In animal studies, vitamin D has been demonstrated to play a role in normal brain development (65), and vitamin D deciency in pregnant rats inhibits brain development in offspring and induces characteristic and irreversible brain changes, which may mimic the clinical manifestation of schizophrenia (66,67). Like schizophrenia, autism is more prevalent in areas with poor ultraviolet B radiation, but only sparse data support an association between low vitamin D and the risk of autism (68). The suggested U-shaped association between neonatal 25OHD levels and schizophrenia up to the age of 26 years supports an effect of vitamin D (45), but the associated high 25OHD level may warrant caution with respect to the use of high-dose vitamin D supplementation in pregnancy. On the contrary, several papers provide support to suggest that the healthy 25OHD level for all ages is 75110 nmol/L or higher (69), also for lactating women (70), consistent with traditionally living native

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tribes in Africa, where the mean 25OHD in pregnancy was 139 nmol/L, in non-pregnant women 107 nmol/L and in umbilical cord 79 nmol/L, suggesting high healthy 25OHD levels in the evolutionary aspect of humans (71,72). In conclusion, the evidence concerning the effect of vitamin D in pregnancy on the outcome of the offspring is still sparse. Evidence from one RCT of lower quality and several observational studies suggests that low 25OHD in pregnancy may result in a race-dependent lowering of birthweight, inuenced by vitamin D receptor polymorphisms. A few observational studies suggest an impact on early childhood infections, of which reduced HIV mother-to child transmission with higher maternal 25OHD level is of special importance. An association to doctor-diagnosed asthma, allergic rhinitis or atopic eczema in childhood has not been reported, although weaker evidence may suggest some correlations. A U-shaped association between cord 25OHD and inhalantallergen-specic IgE and a direct association between regular vitamin D supplementation in the rst year of life (recommended dose 2000 IU) and adulthood asthma, allergic rhinitis and atopy warrant caution for high-dose supplementation, although the timing (prenatal/postnatal) may be of importance. As suggested by the inverse association between cord 25OHD or rst-year high-dose vitamin D supplementation and T1D, auto-immune diseases may be triggered in utero or during the rst year of life due to low vitamin D status. Finally, unconrmed observational studies suggest an inverse association with cerebral outcomes in pregnancy, peer problems at nine years and schizophrenia up to 26 years of age. Although the observational association studies have several limitations, the effect of vitamin D in pregnancy on various diseases in childhood is suspected and deserves further investigation for low but also for high levels of 25OHD. The low cost of vitamin D should encourage, rather than discourage, large-scale RCTs. Until such trials are performed, it is not possible to establish a target range of 25OHD levels in pregnancy for the future health of the offspring. A maternal serum 25OHD target range should take into consideration the one-third lowering of 25OHD between maternal and cord blood.

Funding
No specic funding. References
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