The impact of vitamin D in pregnancy on extraskeletal

AOGS REVIEW ARTICLE

The impact of vitamin D in pregnancy on extraskeletalhealth in children: a systematic reviewHENRIK T. CHRISTESEN1,2, CLAES ELVANDER1, RONALD F. LAMONT3,4 & JAN S. JØRGENSEN2,3

1Hans Christian Andersen Children’s Hospital and 3Department of Obstetrics and Gynaecology, Odense University Hospital,Odense, 2Clinical Institute, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark, and 4Division ofSurgery, University College, London, UK

Key wordsChild health, fetal health, health care policy,neonatology, pregnancy, vitamin D

CorrespondenceHenrik Thybo Christesen, Hans ChristianAndersen Children’s Hospital, OdenseUniversity Hospital, Sønder Boulevard 29, 5000Odense C, Denmark. E-mail:[email protected]

Conflict of interestThe authors have stated explicitly that thereare no conflicts of interest in connection withthis article.

Please cite this article as: Christesen HT,Elvander C, Lamont RF, Jørgensen JS. Theimpact of vitamin D in pregnancy onextraskeletal health in children: a systematicreview. Acta Obstet Gynecol Scand2012;91:1368–1380.

Received: 16 February 2012Accepted: 28 August 2012

DOI: 10.1111/aogs.12006

Abstract

The impact of maternal vitamin D status in pregnancy on the extraskeletal healthof the offspring has become a “hot topic” with a potential for cost-beneficial pre-vention. The objective of this study was to systematically review the level I and IIevidence. PubMed, Embase and Cochrane databases were searched using the MeSHterms “vitamin D” AND “pregnancy” until 1 January 2012. The search was limitedto randomized controlled trials (evidence level I) and observational studies (evi-dence level II) in humans and in the English language. Papers reporting on vitaminD supplementation in combination with other supplements, or not reporting on25OHD or outcomes of the offspring were excluded. Six randomized controlledtrials and 24 observational studies were finally included. In randomized controlledstudies, vitamin D supplementation resulted in increased birthweight in one study,but showed no effect in five other studies. In cohort and case–control studies, highervitamin D intake, or higher 25OHD, was associated with increased birthweight inlarge studies only, and modified by vitamin D receptor polymorphisms and by race(U-shaped in Caucasians in one unconfirmed study). The risks of HIV mother-to-child transmission, rhinitis symptoms and eczema were lower. Data were conflictingon the effect on respiratory infections and wheezing, whereas U-shaped associationsto inhalant allergen-specific IgE at five years and to schizophrenia were reported inunconfirmed 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 severaloutcomes. U-Shaped associations warrant caution.

Abbreviations: 1,25(OH)2D, 1,25-dihydroxylated vitamin D; 25OHD, 25-hydroxylated vitamin D2+3; MeSH, Medical Subject Headings; RCT, randomizedcontrolled trial; SGA, small for gestational age; T1D, type 1 diabetes.

Introduction

Vitamin D sufficiency of the fetus depends solely on thesupply of maternal 25-hydroxylated vitamin D2+3 (25OHD)across the placenta. Maternal 25OHD stores depend on expo-sure to sunlight (ultraviolet B radiation promotes dermal D3

synthesis), animal foods such as oily fish and dairy products(D3), plants and vegetables (D2) and vitamin D supplemen-tation. In the fetus, 25OHD is hydroxylated mainly in the kid-neys to the biologically active form, 1,25(OH)2D (1). Serum25OHD has a half-life of two to three weeks, and maternallevels tend to be stable during pregnancy. 25-Hydroxylated

Key Message

Hypovitaminosis D in pregnancy may decrease birth-weight and increase the risk of HIV mother-to-childtransmission, respiratory infections, wheezing, rhinitis,eczema, type 1 diabetes and schizophrenia in the off-spring, although evidence is conflicting or sparse. U-Shaped associations warrant caution.

1368C© 2012 The Authors

Acta Obstetricia et Gynecologica Scandinavica C© 2012 Nordic Federation of Societies of Obstetrics and Gynecology 91 (2012) 1368–1380

A C TA Obstetricia et Gynecologica

H.T. Christesen et al. Impact of vitamin D in pregnancy on children

Figure 1. Flow diagram of literature search.

vitamin D2+3 readily crosses the placenta, and maternal andneonatal hypovitaminosis D are strongly associated, albeitthat cord 25OHD is usually lower than in maternal serum(1–6). Breastfed compared with bottle-fed infants are moreprone to develop low vitamin D, depending on maternalserum 25OHD levels. Hypovitaminosis D is common in preg-nancy and in neonates worldwide (2–11) and, when extreme,it may cause fetal death, infant hypocalcemic tetany and life-threatening cardiomyopathy (12,13). In childhood, delayedbone ossification, abnormal tooth-enamel formation, ricketsand delayed whole-body bone mineral content can be seenin nine-year-old children (9). The potential extraskeletal ef-fects on the offspring of hypovitaminosis D during pregnancyhave gathered much interest in recent years, as have the ef-fects of hypovitaminosis D occurring later in childhood andin non-pregnant adults. The recommendations for vitamin Dsupplementation during pregnancy should take into accountskeletal and extraskeletal effects on the offspring, as well asobstetric outcome (14). We performed an up-to-date sys-tematic search for the evidence of extraskeletal effects in theoffspring of women with low or high vitamin D levels duringpregnancy.

Material and methods

A search in PubMed and Embase was performed using theMedical Subject Headings (MeSH) terms “vitamin D” AND“pregnancy” for randomized controlled trials (RCTs) in hu-mans, in English, without date limits up to 1 January 2012(Figure 1). An additional search was performed for “vita-min D” AND “(pregnancy OR pregnant)” for the last yearto include possible new articles not yet MeSH indexed. An-other search was done in the Cochrane Database. Identifiedclinical studies were included for screening after removal ofduplicates. Inclusion criteria were English-written RCTs ex-clusively on vitamin D in pregnancy with outcomes of theoffspring. Three authors (H.T.C., C.E. and R.F.L.) indepen-dently screened titles and abstracts of all studies identified bythe search strategy and assessed the studies for inclusion us-

ing the predetermined inclusion criteria. The full texts of allpotentially relevant articles were retrieved for detailed review.We resolved disagreements by discussion until consensus wasachieved.

The systematic review identified 53 potentially suitablearticles, which were screened using the titles and abstracts.No additional titles were found by searching without MeSHwords in 2011, nor in the Cochrane Database. Forty-sevenabstracts were excluded because of the criterion “no ran-domization of exclusively vitamin D in pregnancy.” For theremaining eight papers, the full-length texts were obtained.These studies were assessed for their methodological quality,which involved evaluation of study design, population sizeand statistical analysis.

In addition to the RCTs (evidence level I), and using thesame methodology, the full-length texts of relevant humancohort and case–control studies (evidence level II) were alsoobtained.

Results

Randomized controlled trials of vitamin D

Among the eight RCTs retrieved, one was considered to bepreliminary, with data included in later analysis, and anotherRCT reported no data on the offspring (15,16). The remain-ing six RCTs (17–22) are presented in Table 1. Only the twomost recent RCTs (21,22) had a defined primary outcomeparameter (25OHD at delivery) and a sample size that met astatistical power calculation. Only one RCT showed any directeffect on extraskeletal neonatal clinical outcome. In North-ern India, administration of two large doses of 600,000 IUvitamin D in the third trimester to 100 pregnant women com-pared with 100 pregnant women without supplementationwas associated with highly significant increases in birthweightof 190 g. Birth length, head circumference, mid-arm circum-ference and skin-fold thicknesses were also increased (20).The study did not use placebo and had no data on serum25OHD levels. In the non-supplemented group, symptomsof maternal vitamin D deficiency were more frequent, cordcalcium 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 lengthor head circumference (17). Other extraskeletal outcomeswere not reported.

In the earliest study on Asians in London (1980), theneonates of the mothers given 1000 IU D2/day had a smallerfontanelle area (4.1 cm2 vs. placebo, 6.1 cm2), suggestingimproved skeletal health (17). In addition, symptomatichypocalcaemia appeared in the placebo group only, and cord25OHD levels were higher with higher doses of vitamin D.

In five RCTS, the cord 25OHD values were between 18%and 45% (mean 36%) lower than maternal serum 25OHD atdelivery (17–19,21,22). Although 83.9% of the mothers in the

C© 2012 The AuthorsActa Obstetricia et Gynecologica Scandinavica C© 2012 Nordic Federation of Societies of Obstetrics and Gynecology 91 (2012) 1368–1380 1369

Impact of vitamin D in pregnancy on children H.T. Christesen et al.

Tab

le1.

Rand

omiz

edco

ntro

lled

tria

lson

vita

min

Dan

dof

fspr

ing

outc

ome.

Stud

yPa

rtic

ipan

ts,

No.

of(r

efer

ence

no.)

loca

tion

part

icip

ants

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rven

tion,

vita

min

DBa

selin

epa

ram

eter

sO

utco

me

Resu

ltsSt

atis

tics

Broo

keet

al.

1980

(17)

Asi

ans,

Lond

on,U

K12

6(i)

1000

IUD

2/d

aydu

ring

third

trim

este

rvs

.(ii)

plac

ebo

cont

rol

Sim

ilar

inag

e,he

ight

,par

ity,%

ofve

geta

rians

,co

unty

ofor

igin

,bas

alp-

25O

HD

,sea

son

P-25

OH

D(c

ord)

Ges

tatio

nala

geBi

rthw

eigh

tBi

rth

leng

thBi

rth

head

circ

umfe

renc

eFo

ntan

elle

area

Sym

ptom

atic

hypo

calc

emia

(n)

(i)13

7.9

vs.(

ii)10

.2nm

ol/L

(i)39

+1vs

.(ii)

39+3

wee

ks(i)

3157

vs.(

ii)30

34g

(i)49

.7vs

.(ii)

49.5

cm(i)

34.5

vs.(

ii)34

.3cm

(i)4.

1vs

.(ii)

6.1

cm2

(i)0

vs.(

ii)5

p<

0.00

1n.

s.n.

s.n.

s.n.

s.p

<0.

05p

<0.

01M

alle

tet

al.

1986

(18)

Nor

thw

est

Fran

ce77

(i)10

00IU

vita

min

D/d

aydu

ring

third

trim

este

rvs

.(ii)

200,

000

IUvi

tam

inD

sing

ledo

seat

7th

mon

thvs

.(iii

)con

trol

(no

plac

ebo)

No

data

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OH

D(c

ord)

P-1,

25(O

H) 2

D(c

ord)

Term

birt

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(i)18

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.(ii)

15.7

nmol

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)15.

7vs

.(iii

)5.3

nmol

/L(i)

42.6

vs.(

ii)46

.1vs

.(iii

)47

.0pm

ol/L

(i)33

70vs

.(ii)

3210

vs.(

iii)3

460

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0.00

1n.

s.

n.s.

Del

vin

etal

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86(1

9)Ly

on,F

ranc

e40

(i)10

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ring

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trim

este

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.(ii)

cont

rol(

nopl

aceb

o)

No

data

S-25

OH

D(c

ord)

S-1,

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H) 2

D(c

ord)

(i)45

vs.(

ii)17

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ol/L

(i)98

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.(ii)

153.

4pm

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p<

0.00

05p

<0.

05

Mar

yaet

al.

1988

(20)

Nor

ther

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dia

200

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ses

of60

0,00

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min

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7th

and

8th

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.(ii)

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ilar

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parit

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tBi

rth

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thBi

rth

head

circ

umfe

renc

e

(i)29

90vs

.(ii)

2800

g(i)

50.0

6vs

.(ii)

48.4

5cm

(i)33

.99

vs.(

ii)33

.41

cm

p<

0.00

1p

<0.

001

p<

0.00

1

Yuet

al.2

009

(21)

Four

ethn

icgr

oups

,Lo

ndon

,UK

180

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ledo

se,

wee

k27

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ii)80

0IU

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)con

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ethn

icity

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deliv

ery

(cor

d)

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tatio

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rthw

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t<

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e

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)17

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a.n.

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(22)

∗H

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2000

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ent

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dex,

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OH

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ord)

>50

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/LG

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(wee

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(g)

(i)66

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.(ii)

57.0

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/L(ii

)57.

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.(iii

)45.

5nm

ol/L

(i)78

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.(ii)

58.2

vs.(

iii)3

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(i)39

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)38.

8∗∗

(iii)

38.6

(i)32

86.6

,(ii)

3360

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iii)3

221.

8

p<

0.00

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0001

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0.00

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9

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Dco

nver

sion

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writ

ten

assu

chin

ref.

22.




highest supplementation dose of 4000 IU/day had a serumlevel of 25OHD >80 nmol/L at delivery, only 78.6% of cord25OHD levels were >50 nmol/L (22). In one study, cord1,25(OH)2D levels were highest in the non-supplementedgroup, probably reflecting a lower calcium level, which en-hances 1-α hydroxylation (18).

Other studies

The search for cohort and case–control studies retrieved 24papers on vitamin D in pregnancy and extraskeletal health ofthe offspring.

Birthweight

Several studies have examined the relation between mater-nal vitamin D status and birthweight or small for gestationalage (SGA), with conflicting results. No effects were seen inseveral relatively small observational studies (n = 100–559;Table 2; 10,23–26). In contrast, in a study of 971 pregnancies,maternal (but not cord) serum levels of 25OHD <25 nmol/Lwere associated with a birthweight that was lower by 151 g(3). Adjustment for the vitamin D receptor polymorphismFokI in 354 of the neonates revealed an association between25OHD <28 nmol/L and birthweight, suggesting the impor-tance of vitamin D receptor polymorphisms of the offspring(27).

In an intermediate-sized cohort (n = 1194), no effect onbirthweight from total vitamin D intake during pregnancywas detected (28). In a large cohort (n = 2251), maternaltotal vitamin D intake <5 μg/day were associated with lowerbirthweight (29). In another large study (n = 3730), serumlevels of 25OHD <30 nmol/L were associated with a 64 glower birthweight and almost double the risk of SGA (30).

Bodnar et al. (31) showed a U-shaped relation betweenserum 25OHD and the odds of SGA among white women,the lowest odds occurring between 60 and 75 nmol/L, butno association among black women. The minor allele of thematernal vitamin D receptor polymorphism, rs11168292, al-most doubled the odds of SGA in white women with 25OHD<37.5 nmol/L, but no vitamin D receptor polymorphism wasfound to affect the association between 25OHD >75 nmol/L,and increased odds of SGA and vitamin D receptor polymor-phisms did not alter the absent association in black women.The impact of maternal vitamin D deficiency on the outcomeof premature neonates is unknown.

Childhood infections

In a study on HIV-infected women (32), serum levels of25OHD <80 nmol/L at 12–27 weeks of gestation was associ-ated with a 49% increased risk of mother-to-child transmis-sion of HIV or neonatal death at birth, and a 50% increasedrisk of HIV mother-to-child transmission at six weeks of age(Table 3). At follow-up, live-borne children of mothers with

low vitamin D levels had a 61% increased risk of dying within24 months, and mothers with low 25OHD levels in pregnancyshowed progression of HIV disease (33).

In a small case–control study, neonates below one monthof age with acute lower respiratory tract infection and theirmothers both had lower 25OHD values than control moth-ers and infants, with an odds ratio of 4.25 (unadjusted) for25OHD <25 nmol/L (34). Likewise, umbilical cord levels of25OHD <25 nmol/L were associated with twofold odds ofrespiratory 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 withlevels <30 nmol/L, were associated with approximately five-fold increased odds of mother-reported physician-diagnosedpneumonia or bronchiolitis and almost twofold odds ofmother-reported bouts of diarrhea. This did not apply toreported chest infections, bronchitis, overall respiratory in-fections or ear infections (24). Multiple regression analysiswas not performed.

Wheezing and asthma in childhood

In five prospective cohort studies (28,35–38), estimated vi-tamin D intake during pregnancy was inversely associatedwith the odds of developing wheeze in the offspring (Ta-ble 3). In 1194 three-year-old children of mothers with anestimated vitamin D intake >659 IU/day during pregnancy,odds were 62% lower for recurrent wheeze, compared withmothers with a daily intake <446 IU. An increase of 100 IUvitamin D/day was associated with a 20% reduced odds ofrecurrent wheeze at three years of age (28).

In a study of 823 infants, cord-blood 25OHD was inverselyassociated with the odds of parental-reported wheezing by15 months, three and five years of age (adjusted, p < 0.05),but not with doctor-diagnosed asthma by five years (35). In1120 five-year-old children in Scotland, the adjusted oddsratio of persistent wheeze was 67% lower when their mothershad a vitamin D intake in pregnancy in the lowest, com-pared with the highest quintile. No association was seen insmaller subgroups to atopic sensitization or exhaled nitricoxide; however, bronchodilator response decreased with de-creasing pregnancy vitamin D intake (36). In five-year-oldFinnish children with a genetically increased risk for type 1diabetes (T1D), maternal vitamin D intake was inversely re-lated to the risk of asthma, defined as persistent, physician-diagnosed wheezing or medication during last 12 months(parental reported; 37). In Japan, maternal dietary vitamin Dintake ≥172 IU/day during pregnancy was associated with36% reduced odds of parental-reported wheeze in the chil-dren aged 16–24 months (38).

On the contrary, children of mothers with 25OHD>75 nmol/L in late pregnancy had an increased oddsof parentally reported asthma at nine years, suggesting a



Tab

le2.

Coh

ort

and

case

–con

trol

stud

ies

onef

fect

ofvi

tam

inD

onbi

rthw

eigh

t.

Art

icle

(ref

eren

ceno

.)Lo

catio

nPa

rtic

ipan

tsD

eter

min

ant

Tim

eof

dete

rmin

atio

nA

ssoc

iatio

nSt

atis

tics

(95%

CIi

npa

rent

hese

s)

Akc

asus

etal

.20

06(2

3)K

ayse

ri,Tu

rkey

100

mot

hers

and

neon

ates

25O

HD

Del

iver

yBi

rthw

eigh

t(g

)U

niva

riate

,n.s

.

Farr

ant

etal

.20

09(1

0)M

ysor

e,So

uth

Indi

a55

9m

othe

rsan

dne

onat

eslo

g(25

OH

D)

30w

eeks

ofge

stat

ion

Birt

hwei

ght

(g)

Adj

uste

dre

gres

sion

,n.s

.

Gal

eet

al.2

008

(24)

Sout

ham

pton

,UK

466

mot

hers

and

neon

ates

25O

HD

32w

eeks

ofge

stat

ion

Birt

hwei

ght

(g)

Uni

varia

te,n

.s.

Mor

ley

etal

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06(2

5)M

elbo

urne

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toria

,A

ustr

alia

374

mot

hers

and

neon

ates

374

mot

hers

and

neon

ates

25O

HD

<28

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≥28

nmol

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28–3

2w

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ion

28–3

2w

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ofge

stat

ion

Birt

hwei

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(g)

Birt

hwei

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(g)

Adj

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d,−1

53g

(−34

8to

45)

Adj

uste

d,31

(−25

to11

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det

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2010

(26)

Vanc

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a22

1m

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dne

onat

es25

OH

D<

37.5

nmol

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ion

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hwei

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(g)

Adj

uste

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R0.

91(0

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−2.

62)

Bow

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etal

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09(3

)Sy

dney

,NSW

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ustr

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971

mot

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and

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30–3

2w

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ofge

stat

ion

Birt

hwei

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(g)

Adj

uste

dre

gres

sion

,+1

51g

(50–

250)

Mor

ley

etal

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09(2

7)M

elbo

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,Vic

toria

,A

ustr

alia

254

mot

hers

and

neon

ates

25O

HD

<28

vs.

≥28

nmol

/L28

–32

wee

ksof

gest

atio

nBi

rthw

eigh

t(g

),by

offs

prin

gV

DR

SNP

FokI

Adj

uste

dre

gres

sion

,p

=0.

02

Cam

argo

etal

.20

07(2

8)M

assa

chus

etts

,USA

1194

mot

hers

and

child

ren

Tota

lVD

inta

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uart

iles

Dur

ing

preg

nanc

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rthw

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t(z

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re)

Uni

varia

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est

for

tren

d,n.

s.Sc

holl

etal

.20

09(2

9)N

ewJe

rsey

,USA

2251

mot

hers

and

neon

ates

2251

mot

hers

and

neon

ates

Tota

lVD

inta

ke<

5vs

.≥5

μg/

day

Tota

lVD

inta

ke,q

uint

iles

<28

wee

ksge

stat

ion

<28

wee

ksge

stat

ion

Birt

hwei

ght

(g)

Birt

hwei

ght

(g)

Adj

uste

d,te

stfo

rtr

end,

p=

0.02

7A

djus

ted,

test

for

tren

d,p

=0.

043

Leff

elaa

ret

al.

2010

(30)

Am

ster

dam

,The

Net

herla

nds

3730

mot

hers

and

neon

ates

3730

mot

hers

and

neon

ates

25O

HD

<30

vs.

≥50

nmol

/L25

OH

D<

30vs

.≥5

0nm

ol/L

Aft

er12

wee

ksof

gest

atio

nA

fter

12w

eeks

ofge

stat

ion

Birt

hwei

ght

(g)

SGA

(%)

−64

g(−

107.

1to

−20.

9)A

djus

ted

OR

1.9

(1.4

–2.7

)

Bodn

aret

al.

2010

(31)

Pitt

sbur

gh,

Penn

sylv

ania

,USA

273

whi

tem

othe

rsan

dne

onat

esw

hite

mot

hers

and

neon

ates

(num

bers

n.a.

)27

3w

hite

mot

hers

and

neon

ates

139

blac

km

othe

rsan

dne

onat

es13

9bl

ack

mot

hers

and

neon

ates

25O

HD

<37

.5vs

.60

–75

nmol

/L25

OH

D<

37.5

vs.

60–7

5nm

ol/L

25O

HD

>75

vs.

60–7

5nm

ol/L

25O

HD

<37

.5vs

.60

–75

nmol

/L25

OH

D>

75vs

.60

–75

nmol

/L

<22

wee

ksof

gest

atio

n<

22w

eeks

ofge

stat

ion

<22

wee

ksof

gest

atio

n<

22w

eeks

ofge

stat

ion

<22

wee

ksof

gest

atio

n

SGA

(<10

thp)

SGA

(<10

thp)

,by

mat

erna

lVD

RSN

PSG

A(<

10th

p)SG

A(<

10th

p)SG

A(<

10th

p)

Adj

uste

dO

R7.

5(1

.8–3

1.9)

Adj

uste

dO

R14

.0(2

.7–7

3.0)

Adj

uste

dO

R2.

1(1

.2–3

.8)

Adj

uste

dO

R1.

5(0

.6–3

.5)

Adj

uste

dO

R2.

2(0

.5–9

.0)

Not

e:25

OH

Dco

nver

sion

fact

or2.

5fr

omna

nogr

ams

per

mill

ilite

r.V

itam

inD

inta

ke(f

ood

and/

orsu

pple

men

tal)

was

estim

ated

byqu

estio

nnai

res.

Abb

revi

atio

ns:2

5OH

D,2

5-hy

drox

ylat

edvi

tam

inD

;CI,

confi

denc

ein

terv

al;n

.a.,

not

avai

labl

e;n.

s.,n

otsi

gnifi

cant

;OR,

odds

ratio

;p,p

erce

ntile

;SG

A,s

mal

lfor

gest

atio

nala

ge;V

D,v

itam

inD

;VD

RSN

PFo

kI,v

itam

inD

rece

ptor

star

tco

don

sing

lenu

cleo

tide

poly

mor

phis

m.




Tab

le3.

Coh

ort

and

case

–con

trol

stud

ies

onef

fect

ofvi

tam

inD

onin

fect

ions

,whe

ezin

gan

dal

lerg

yin

child

ren.

Out

com

eA

rtic

le(r

efer

ence

.no

.)Lo

catio

nPa

rtic

ipan

tsD

eter

min

ant

Tim

eof

dete

rmin

atio

nA

ssoc

iatio

nSt

atis

tics

(95%

CIi

npa

rent

hese

s)

Infe

ctio

nsM

etha

etal

.200

9(3

2)D

ares

Sala

am,

Tanz

ania

884

mot

hers

and

neon

ates

884

mot

hers

and

neon

ates

25O

HD

<80

vs.

≥80

nmol

/L25

OH

D<

80vs

.≥8

0nm

ol/L

12–2

7w

eeks

ofge

stat

ion

12–2

7w

eeks

ofge

stat

ion

HIV

mot

her-

to-c

hild

infe

cted

orde

adat

birt

hH

IVm

othe

r-to

-chi

ldtr

ansm

issi

onat

six

wee

ksof

age

Adj

uste

dRR

1.49

(1.0

7–2.

09)

Adj

uste

dRR

1.50

(1.0

2–2.

20)

Adj

uste

dRR

1.61

(1.2

6–2.

07)

Met

haet

al.2

010

(33)

884

mot

hers

and

neon

ates

25O

HD

<80

vs.

≥80

nmol

/L12

–27

wee

ksof

gest

atio

nD

eath

<24

mon

ths

post

part

umam

ong

live-

born

sK

arat

ekin

etal

.20

09(3

4)Is

tanb

ul,T

urke

y25

case

s;15

cont

rols

25O

HD

<25

vs.

≥25

nmol

/LN

eona

tes,

age

<30

days

Low

erre

spira

tory

trac

tin

fect

ions

<30

days

Una

djus

ted

OR

4.25

(1.0

6–17

.1)

Cam

argo

etal

.20

11(3

5)W

ellin

gton

,New

Zeal

and

882

child

ren

25O

HD

<25

vs.

≥75

nmol

/LD

eliv

ery

(um

bilic

alco

rd)

Resp

irato

ryin

fect

ions

less

than

thre

em

onth

sof

age

Adj

uste

dO

R2.

04(1

.13–

3.67

)G

ale

etal

.200

8(2

4)So

utha

mpt

on,U

K46

6m

othe

rsan

dne

onat

es46

6m

othe

rsan

dne

onat

es46

6m

othe

rsan

dne

onat

es

25O

HD

>75

vs.

<30

nmol

/L25

OH

D>

75vs

.<

30nm

ol/L

25O

HD

>75

vs.

<30

nmol

/L

32w

eeks

ofge

stat

ion

32w

eeks

ofge

stat

ion

32w

eeks

ofge

stat

ion

Pneu

mon

iaor

bron

chio

litis

∗

less

than

nine

mon

ths

ofag

eD

iarr

hoea

∗le

ssth

anni

nem

onth

sof

age

Ove

rall

resp

irato

ryor

ear

infe

ctio

ns∗

less

than

nine

mon

ths

Una

djus

ted

OR

4.80

(1.0

1–22

.73)

Una

djus

ted

OR

1.87

(1.0

1–3.

46)

n.s.

Whe

ezin

g,as

thm

a,al

lerg

y

Cam

argo

etal

.20

07(2

8)M

assa

chus

etts

,U

SA11

94m

othe

rsan

dch

ildre

n11

94m

othe

rsan

dch

ildre

n

Tota

lVD

inta

ke>

658

vs.

<44

6IU

/day

Tota

lVD

inta

ke,p

er+1

00IU

/day

Dur

ing

preg

nanc

y

Dur

ing

preg

nanc

y

Recu

rren

tw

heez

e∗at

thre

eye

ars

Recu

rren

tw

heez

e∗at

thre

eye

ars

Adj

uste

dO

R0.

38(0

.22–

0.65

)A

djus

ted

OR

0.80

(0.7

2–0.

90)

Cam

argo

etal

.20

11(3

5)W

ellin

gton

,New

Zeal

and

823

child

ren

823

child

ren

25O

HD

<25

vs.

≥75

nmol

/L

25O

HD

<25

vs.

≥75

nmol

/L

Del

iver

y(u

mbi

lical

cord

)

Del

iver

y(u

mbi

lical

cord

)

Whe

eze

orw

hist

ling

inth

ech

est,

ever

,up

tofiv

eye

ars

Ast

hma

atfiv

eye

ars,

doct

ordi

agno

sed

plus

inha

ler

use

orw

heez

ein

last

year

Adj

uste

dO

R2.

15(1

.39–

3.33

)

Adj

uste

dO

R0.

94(0

.53–

1.64

)

Dev

ereu

xet

al.

2007

(36)

Abe

rdee

n,U

K11

20m

othe

rsan

dch

ildre

n23

8m

othe

rsan

dch

ildre

n70

0m

othe

rsan

dch

ildre

n16

7m

othe

rsan

dch

ildre

n

Tota

lVD

inta

ke,>

188

vs.

<93

IU/d

ayTo

talV

Din

take

,qui

ntile

s

Tota

lVD

inta

ke,q

uint

iles

Tota

lVD

inta

ke,q

uint

iles

20–3

2w

eeks

ofge

stat

ion

20–3

2w

eeks

ofge

stat

ion

20–3

2w

eeks

ofge

stat

ion

20–3

2w

eeks

ofge

stat

ion

Pers

iste

ntw

heez

e∗at

two

and

five

year

sBr

onch

odila

tor

resp

onse

atfiv

eye

ars

Ato

pic

sens

itiza

tion

atfiv

eye

ars

Exha

led

nitr

icox

ide

atfiv

eye

ars

Adj

uste

dO

R0.

33(0

.11–

0.98

)A

djus

ted,

test

for

tren

d,p

=0.

036

n.s.

n.s.



Tab

le3.

Con

tinue

d.

Out

com

eA

rtic

le(r

efer

ence

.no

.)Lo

catio

nPa

rtic

ipan

tsD

eter

min

ant

Tim

eof

dete

rmin

atio

nA

ssoc

iatio

nSt

atis

tics

(95%

CIi

npa

rent

hese

s)

Erkk

ola

etal

.200

9(3

7)M

ultic

ente

r,Fi

nlan

d16

69m

othe

rsan

dch

ildre

nTo

talV

Din

take

,qua

rtile

s8t

hm

onth

ofpr

egna

ncy

Ast

hma∗

last

12m

onth

s,at

five

year

sA

djus

ted

HR

0.80

(0.6

4–0.

99)

Miy

ake

etal

.201

0(3

8)O

saka

,Jap

an76

3m

othe

rsan

dch

ildre

nV

Din

take

byfo

od,

≥172

.4vs

.<

172.

4IU

/day

(25t

hqu

artil

ecu

tof

f)

Dur

ing

preg

nanc

yW

heez

ing

orw

hist

ing

inth

ech

est

last

12m

onth

s,at

16–2

4m

onth

sof

age

Adj

uste

dO

R0.

64(0

.43–

0.97

)

Gal

eet

al.2

008

(24)

Sout

ham

pton

,UK

178

mot

hers

and

child

ren

178

mot

hers

and

child

ren

25O

HD

>75

vs.

<30

nmol

/L25

OH

D>

75vs

.<

30nm

ol/L

32w

eeks

ofge

stat

ion

32w

eeks

ofge

stat

ion

Ast

hma∗

atni

neye

ars

Cur

rent

med

icat

ion

pres

crib

edfo

ras

thm

aat

nine

year

s

Una

djus

ted

OR

5.40

(1.0

9–26

.65)

Una

djus

ted

OR

4.66

(0.9

3–23

.30)

Roth

ers

etal

.20

11(3

9)A

rizon

a,U

SA19

4ch

ildre

n

208

child

ren

208

child

ren

172

child

ren

25O

HD

25O

HD

≥100

vs.

50–7

4.9

nmol

/L25

OH

D<

50vs

.50

–74.

9nm

ol/L

25O

HD

≥100

vs.

50–7

4.9

nmol

/L

Del

iver

y(u

mbi

lical

cord

)

Del

iver

y(u

mbi

lical

cord

)D

eliv

ery

(um

bilic

alco

rd)

Del

iver

y(u

mbi

lical

cord

)

Ast

hma

atfiv

eye

ars,

doct

ordi

agno

sed

plus

sym

ptom

sor

med

icat

ion

inla

stye

arSi

xin

hala

nt-a

llerg

en-s

peci

ficIg

Eup

tofiv

eye

ars

Six

inha

lant

-alle

rgen

-spe

cific

IgE

upto

five

year

sPo

sitiv

esk

in-p

rick

test

for

one

orm

ore

of17

aero

alle

rgen

s,at

five

year

s

Adj

uste

dre

gres

sion

,n.

s.

Adj

uste

dO

R3.

6(1

.2–1

0.5)

Adj

uste

dO

R2.

8(1

.2–6

.6)

Adj

uste

dO

R3.

4(1

.0–1

1.4)

Alle

rgic

rhin

itis

Erkk

ola

etal

.200

9(3

7)M

ultic

ente

r,Fi

nlan

d16

69m

othe

rsan

dch

ildre

nTo

talV

Din

take

,qua

rtile

s8t

hm

onth

ofpr

egna

ncy

Alle

rgic

rhin

itis∗

atfiv

eye

ars

Adj

uste

dH

R0.

84(0

.72–

0.98

)Ro

ther

set

al.

2011

(39)

Ariz

ona,

USA

192

child

ren

25O

HD

≥100

vs.

50–7

4.9

nmol

/LD

eliv

ery

(um

bilic

alco

rd)

Alle

rgic

rhin

itis

byfiv

eye

ars,

doct

ordi

agno

sed

plus

sym

ptom

sin

last

year

Adj

uste

dO

R2.

4(0

.8–7

.3)

Ecze

ma

Erkk

ola

etal

.200

9(3

7)M

ultic

ente

r,Fi

nlan

d16

69m

othe

rsan

dch

ildre

nTo

talV

Din

take

,qua

rtile

s8t

hm

onth

ofpr

egna

ncy

Ato

pic

derm

atiti

s∗ev

er,a

tfiv

eye

ars

Adj

uste

dH

R0.

94(0

.83–

1.07

)M

iyak

eet

al.2

010

(38)

Osa

ka,J

apan

763

mot

hers

and

child

ren

VD

inta

keby

food

,≥1

72.4

vs.

<17

2.4

IU/d

ay(2

5th

quar

tile

cut

off)

Dur

ing

preg

nanc

yItc

hyra

sh∗

upto

16–2

4m

onth

sof

age

Adj

uste

dO

R0.

63(0

.41–

0.98

)

Gal

eet

al.2

008

(24)

Sout

ham

pton

,UK

440

mot

hers

and

child

ren

25O

HD

>75

vs.

<30

nmol

/L32

wee

ksof

gest

atio

nA

topi

cec

zem

a†at

nine

mon

ths

ofag

eU

nadj

uste

dO

R1.

62(0

.67–

3.89

)

Not

e:25

OH

Dco

nver

sion

fact

or2.

5fr

omna

nogr

ams

per

mill

ilite

r.V

itam

inD

inta

ke(f

ood

and/

orsu

pple

men

tal)

was

estim

ated

byqu

estio

nnai

res.

Abb

revi

atio

ns:2

5OH

D,2

5-hy

drox

ylat

edvi

tam

inD

;CI,

confi

denc

ein

terv

al;H

R,ha

zard

ratio

;n.s

.,no

tsi

gnifi

cant

;OR,

odds

ratio

;RR,

rela

tive

risk;

and

VD

,vita

min

D.

∗ Par

enta

lrep

orte

d.† M

odifi

edU

Kw

orki

ngcr

iteria

.




negative effect of high vitamin D in pregnancy for the risk ofeczema and asthma in the offspring. However, the study didnot adjust for confounders; the number of participants andthe follow-up rate at nine years was low, and no significanteffect was detected on the odds of currently taking prescribedmedications for asthma (24).

Rothers et al. (39) recently found increased odds ofinhalant-allergen-specific IgE in five-year-old children whosecord 25OHD was either ≥100 or <50 nmol/L, compared with50–74.9 nmol/L. In addition, cord 25OHD ≥100 nmol/L wasassociated with a positive skin-prick test for aero-allergens byfive years. No association was detected for doctor-diagnosedasthma.

Allergic rhinitis and atopic dermatitis/eczema

In the five-year-old Finnish children with a genetically in-creased risk for T1D, maternal vitamin D intake was alsoinversely related to the risk of allergic rhinitis, defined assneezing, nasal congestion or rhinitis without respiratory in-fections, accompanied by eye itching and tearing (parentalreported), but not to atopic eczema (Table 3; 37).

In the smaller study of Rothers et al., no association be-tween cord 25OHD and allergic rhinitis by five years wasseen (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 aged16–24 months (38). No association was seen between 25OHDin pregnancy and atopic eczema in the offspring at ninemonths or nine years (unadjusted analysis; 24).

Type 1 diabetes in childhood

In a large case–control study, intake of cod liver oil (a potentsource of vitamin D) or supplemental vitamin D during preg-nancy was not associated with T1D below 15 years (Table 4;40). Likewise, maternal vitamin D intake was not associatedwith T1D or advanced β-cell autoimmunity in the mother’schildren with genetically increased risk of T1D up to fouryears (41). In contrast, maternal intake of dietary vitamin D(not supplementation) during pregnancy was associated witha reduced risk of islet antibodies in the four-year-old offspring(42). Vitamin D supplementation during pregnancy was as-sociated with reduced odds of diabetes-related autoimmunityin the offspring at one year, but not at 2.5 years (43). In arecent Norwegian study, maternal serum levels of 25OHDduring pregnancy were inversely correlated to offspring T1Dup 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 asso-ciations between late pregnancy 25OHD levels and cognitivefunction or psychological health were found (Table 4). Theexception (in a univariate analysis) was an increase score in

“peer problems” with increasing (rather than decreasing) lev-els of pregnancy 25OHD (24). Using neonatal dried bloodspots for the analysis of 25OHD in 428 Danish patients withschizophrenia up to 26 years of age and 428 matched con-trol subjects, a U-shaped association between 25OHD andthe risk of schizophrenia was observed. Compared with thefourth quintile (40.5–50.9 nmol/L), the three lowest quin-tiles had twice the risk of schizophrenia, but also the highestquintile (>50.9 nmol/L) had an increased risk by 71% (45).

Cancer, adiposity and cardiovascular disease

No associations between late-pregnancy serum 25OHD andbody mass index, fat or lean body mass, blood pressure, pulsewave velocity, carotid intimal thickness or cardiac struc-ture were found in nine-year-old children (Table 4; 24),and no data were found which related to childhood can-cers/leukemia. The impact of in utero vitamin D status onadult cancer, adiposity, cardiovascular disease and aging isbeyond the scope of this review.

Discussion

To date, evidence (level I data) concerning the impact of vi-tamin D in pregnancy on the extraskeletal health of offspringis sparse. In one RCT, increased birthweight, birth lengthand head circumference, but not gestational age, was seenwhen two large doses of 600,000 IU vitamin D were used vs.no supplementation (20). The frequency of vitamin D defi-ciency symptoms was high in the non-supplemented group.Although not of high methodological quality, this study sug-gested that vitamin D in very high doses in populations withwidespread severe vitamin D deficiency may improve fetalgrowth.

In five other RCTs, vitamin D supplementation did notalter birthweight, birth length, head circumference or gesta-tional age (when reported). These studies used lower doses(single or daily), or had a low frequency of vitamin D defi-ciency (17–19,21,22). We found a weak association betweenlower pregnancy 25OHD levels or vitamin D intake and lowerbirthweight in large observational studies (29,30), but not insmaller (10,23–26) or intermediate-sized studies using esti-mated vitamin D intake (28), which is a weaker measure ofmaternal 25OHD status. A few days of shortening in the gesta-tional age, detectable in some large studies, may be sufficientto contribute to lower birthweight (14).

Although not detected in any of the RCTs, also whencontrolling for race (46), the U-shaped association betweenmaternal 25OHD and SGA birthweight at levels <37.5 and>75 nmol/L in white women found in the study of Bod-nar et al. (31) calls for further studies, including the im-pact of VRD polymorphisms (27). In summary, low maternal25OHD levels in pregnancy may result in a race-dependentlowering of birthweight only detectable in large studies,



Tab

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studies including a high number with severe vitamin D de-ficiency, or race-dependent vitamin D receptor polymor-phisms.

A few studies show conflicting associations between25OHD in pregnancy and respiratory infections in in-fancy (24,34,35). Only those studies which used confounder-adjusted analysis showed an inverse correlation with res-piratory infections (35). Alarmingly, HIV mother-to-childtransmission was inversely correlated with 25OHD levels of<80 nmol/L (32), suggesting potentially huge health and eco-nomic benefits of vitamin D supplementation in pregnancyin such areas. The impact of vitamin D on the immune systemis well documented, because 1,25(OH)2 vitamin D binds tovitamin D receptor in both innate and adaptive immune celltypes, and activated vitamin D is a potent effector of prolif-eration, differentiation and complex regulation of immunefunction (47–54). The paucity of available human data doesnot permit firm conclusions on the effect of vitamin D inpregnancy on infant infectious diseases.

The impact of vitamin D during pregnancy on the riskof allergic conditions in the offspring remains controversial.Methodological problems should be taken into considera-tion. Wheezing, a non-specific finding, may not be asthmabut due to respiratory infections and is often only reportedparentally. Asthma, on the contrary, should be doctor diag-nosed using some criteria of reversibility, but this is often notthe case, especially in younger children who are unable to per-form lung-function tests (55). A history of childhood eczemaor parental asthma may strengthen the probability of an aller-gic asthma disease, but the diagnosis of asthma, allergic rhini-tis or atopic dermatitis is usually not dependent on a positiveallergy test. We identified five cohorts, in which estimatedvitamin D intake during pregnancy or serum 25OHD levelswas inversely associated with the adjusted odds of developingwheeze in the offspring, whereas one study showed unad-justed increased odds for parentally reported asthma at nineyears, but not for medications prescribed for asthma. No as-sociation between cord 25OHD levels and doctor-diagnosedasthma at five years was found in two recent studies (35,39).A U-shaped association between cord 25OHD levels and theodds of inhalant-allergen-specific IgE at five years togetherwith the increased odds of a positive skin-prick test for aero-allergens in those with a cord 25OHD level of ≥100 nmol/Lshould raise concerns (39).

High vitamin D supplementation in the first year of life(recommended dose 2000 IU/day) has been associated withan increased risk of asthma, allergic rhinitis and atopy inadults (56). Inverse associations were found between vita-min D intake in pregnancy and parentally reported allergicrhinitis at five years or itchy rash around 20 months (37,38),whereas doctor-diagnosed allergic rhinitis at five years oratopic eczema was not associated with 25OHD in pregnancyin two relatively smaller studies (24,39). More studies are

needed, and the results of an RCT of 4400 vs. 400 IU of vi-tamin D in 870 pregnant women and their offspring for theprimary prevention of asthma (Vitamin D Antenatal AsthmaReduction Trial; VDAART) are much anticipated.

Recent data suggest an inverse association between lowpregnancy 25OHD and T1D in the offspring (44). Postnatalsupplementation of vitamin D (recommended dose 2000 IU)during the first year of life was associated with markedly re-duced odds of T1D with a median onset at 14 years (57).Stene et al. (40) showed no association of estimated vita-min D intake in pregnancy, but the odds of T1D were in-versely associated with the intake of cod oil in the first yearof life. A window of programming of the immune system inthe fetus and during early infancy which predisposes towardsless autoimmunity in the presence of higher vitamin D levelsis supported by experimental data, and an effect of vitamin Don the different pathways in the pathogenesis of T1D may ex-ist (58–60). The lack of association of pregnancy vitamin Dintake and T1D in the offspring found by others (41–43)may be due to an insufficient follow-up time of the offspring(2.5–4.3 years of age).

Vitamin D deficiency has also been associated with otherautoimmune diseases, including Hashimoto’s thyreoiditis(61), inflammatory bowel disease (62) and multiple sclerosis(63); however, data concerning the role of maternal vita-min D in pregnancy for their children are absent or sparse.An early effect of vitamin D on the fetus with respect to mul-tiple sclerosis was recently suggested with the observationthat maternal vitamin D intake in pregnancy was inverselyassociated with the risk of multiple sclerosis in their adultdaughters (64).

The role of vitamin D in the development of the fetal brainand later cerebral function in childhood has not been stud-ied extensively in humans. In one study, levels of 25OHDin pregnancy were inversely correlated with peer problemsat nine years, but not with cognitive score or hyperactivity(24). In animal studies, vitamin D has been demonstratedto play a role in normal brain development (65), and vita-min D deficiency in pregnant rats inhibits brain develop-ment in offspring and induces characteristic and irreversiblebrain changes, which may mimic the clinical manifestationof schizophrenia (66,67). Like schizophrenia, autism is moreprevalent in areas with poor ultraviolet B radiation, but onlysparse data support an association between low vitamin Dand the risk of autism (68). The suggested U-shaped asso-ciation between neonatal 25OHD levels and schizophreniaup to the age of 26 years supports an effect of vitamin D(45), but the associated high 25OHD level may warrant cau-tion with respect to the use of high-dose vitamin D sup-plementation in pregnancy. On the contrary, several papersprovide support to suggest that the healthy 25OHD levelfor all ages is 75–110 nmol/L or higher (69), also for lactat-ing women (70), consistent with traditionally living native



tribes in Africa, where the mean 25OHD in pregnancy was139 nmol/L, in non-pregnant women 107 nmol/L and in um-bilical cord 79 nmol/L, suggesting high healthy 25OHD levelsin the evolutionary aspect of humans (71,72).

In conclusion, the evidence concerning the effect of vita-min D in pregnancy on the outcome of the offspring is stillsparse. Evidence from one RCT of lower quality and severalobservational studies suggests that low 25OHD in pregnancymay result in a race-dependent lowering of birthweight, in-fluenced by vitamin D receptor polymorphisms. A few obser-vational studies suggest an impact on early childhood infec-tions, of which reduced HIV mother-to child transmissionwith higher maternal 25OHD level is of special importance.An association to doctor-diagnosed asthma, allergic rhinitisor atopic eczema in childhood has not been reported, al-though weaker evidence may suggest some correlations. AU-shaped association between cord 25OHD and inhalant-allergen-specific IgE and a direct association between regularvitamin D supplementation in the first year of life (recom-mended dose 2000 IU) and adulthood asthma, allergic rhini-tis and atopy warrant caution for high-dose supplementation,although the timing (prenatal/postnatal) may be of impor-tance. As suggested by the inverse association between cord25OHD or first-year high-dose vitamin D supplementationand T1D, auto-immune diseases may be triggered in uteroor during the first year of life due to low vitamin D status.Finally, unconfirmed observational studies suggest an inverseassociation with cerebral outcomes in pregnancy, peer prob-lems at nine years and schizophrenia up to 26 years of age.Although the observational association studies have severallimitations, the effect of vitamin D in pregnancy on variousdiseases in childhood is suspected and deserves further in-vestigation for low but also for high levels of 25OHD. Thelow cost of vitamin D should encourage, rather than discour-age, large-scale RCTs. Until such trials are performed, it isnot possible to establish a target range of 25OHD levels inpregnancy for the future health of the offspring. A maternalserum 25OHD target range should take into considerationthe one-third lowering of 25OHD between maternal and cordblood.

Funding

No specific funding.

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The impact of vitamin D in pregnancy on extraskeletal

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