the impact of vitamin d in pregnancy on extraskeletal
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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:henrik.christesen@ouh.regionsyddanmark.dk
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
Inte
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
P-25
OH
D(c
ord)
P-1,
25(O
H) 2
D(c
ord)
Term
birt
hwei
ght
(i)18
.2vs
.(ii)
15.7
nmol
/L(ii
)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
g
n.s.
p<
0.00
1n.
s.
n.s.
Del
vin
etal
.19
86(1
9)Ly
on,F
ranc
e40
(i)10
00IU
D3/d
aydu
ring
third
trim
este
rvs
.(ii)
cont
rol(
nopl
aceb
o)
No
data
S-25
OH
D(c
ord)
S-1,
25(O
H) 2
D(c
ord)
(i)45
vs.(
ii)17
.5nm
ol/L
(i)98
.8vs
.(ii)
153.
4pm
ol/L
p<
0.00
05p
<0.
05
Mar
yaet
al.
1988
(20)
Nor
ther
nIn
dia
200
(i)tw
odo
ses
of60
0,00
0IU
vita
min
Dat
7th
and
8th
mon
thof
gest
atio
nvs
.(ii)
nosu
pple
men
tatio
n(n
opl
aceb
o)
Sim
ilar
inag
e,he
ight
,wei
ght,
parit
yBi
rthw
eigh
tBi
rth
leng
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
(i)20
0,00
0IU
D3
sing
ledo
se,
wee
k27
vs.(
ii)80
0IU
D2/d
ayfr
omw
eek
27vs
.(iii
)con
trol
(no
plac
ebo)
Sim
ilar
inca
lciu
m,2
5OH
D,
ethn
icity
P-25
OH
Dat
deliv
ery
(cor
d)
Ges
tatio
nala
geBi
rthw
eigh
tBi
rthw
eigh
t<
10th
perc
entil
e
(i)25
vs.(
iii)1
7nm
ol/L
(ii)2
6vs
.(iii
)17
nmol
/Ln.
a.n.
a.(i)
13vs
.(ii)
15vs
.(iii
)17%
p<
0.00
1p
<0.
001
n.s.
n.s.
p=
0.7
Hol
liset
al.
2011
(22)
∗H
ispa
nic,
whi
te,
blac
k,C
harle
-st
on,S
C,U
SA
350
(i)40
00IU
D3/d
ayfr
omw
eek
12vs
.(ii)
2000
IUD
3/d
ayfr
omw
eek
12vs
.(iii
)400
IUD
3/d
ayfr
omw
eek
12
Sim
ilar
inra
ce/e
thni
city
,age
,ed
ucat
iona
land
empl
oym
ent
stat
us,h
ealth
ratin
g,%
ofpl
anne
dpr
egna
ncy,
body
mas
sin
dex,
seas
onat
entr
y,p-
25O
HD
,p-1
,25(
OH
) 2D
S-25
OH
D(c
ord)
S-25
OH
D(c
ord)
>50
nmol
/LG
esta
tiona
lage
(wee
ks)
Birt
hwei
ght
(g)
(i)66
.3vs
.(ii)
57.0
nmol
/L(ii
)57.
0vs
.(iii
)45.
5nm
ol/L
(i)78
.6vs
.(ii)
58.2
vs.(
iii)3
9.7%
(i)39
.1(ii
)38.
8∗∗
(iii)
38.6
(i)32
86.6
,(ii)
3360
.1,(
iii)3
221.
8
p<
0.00
01p
<0.
0001
p<
0.00
01p
=0.
17p
=0.
9
Not
e:25
OH
Dco
nver
sion
fact
or2.
5fr
omna
nogr
ams
per
mill
ilite
ran
d1,
25(O
H) 2
Dco
nver
sion
fact
or2.
6fr
ompi
cogr
ams
per
mill
ilite
r.A
bbre
viat
ions
:1,2
5(O
H) 2
D,1
,25
dihy
drox
ylat
edvi
tam
inD
;25O
HD
,25-
hydr
oxyl
ated
vita
min
D;n
.a.,
not
avai
labl
e;n.
s.,n
otsi
gnifi
cant
;p,p
lasm
a;an
ds,
seru
m.
∗ Err
atum
for
conv
ersi
onin
ref.
22co
nsid
ered
.∗∗G
esta
tiona
lage
writ
ten
assu
chin
ref.
22.
1370C© 2012 The Authors
Acta Obstetricia et Gynecologica Scandinavica C© 2012 Nordic Federation of Societies of Obstetrics and Gynecology 91 (2012) 1368–1380
H.T. Christesen et al. Impact of vitamin D in pregnancy on children
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
C© 2012 The AuthorsActa Obstetricia et Gynecologica Scandinavica C© 2012 Nordic Federation of Societies of Obstetrics and Gynecology 91 (2012) 1368–1380 1371
Impact of vitamin D in pregnancy on children H.T. Christesen et al.
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
.20
06(2
5)M
elbo
urne
,Vic
toria
,A
ustr
alia
374
mot
hers
and
neon
ates
374
mot
hers
and
neon
ates
25O
HD
<28
vs.
≥28
nmol
/Llo
g2(2
5OH
D)
28–3
2w
eeks
ofge
stat
ion
28–3
2w
eeks
ofge
stat
ion
Birt
hwei
ght
(g)
Birt
hwei
ght
(g)
Adj
uste
d,−1
53g
(−34
8to
45)
Adj
uste
d,31
(−25
to11
2)g
Shan
det
al.
2010
(26)
Vanc
ouve
r,C
anad
a22
1m
othe
rsan
dne
onat
es25
OH
D<
37.5
nmol
/L18
.7w
eeks
ofge
stat
ion
Birt
hwei
ght
(g)
Adj
uste
dO
R0.
91(0
.31
−2.
62)
Bow
yer
etal
.20
09(3
)Sy
dney
,NSW
,A
ustr
alia
971
mot
hers
and
neon
ates
25O
HD
30–3
2w
eeks
ofge
stat
ion
Birt
hwei
ght
(g)
Adj
uste
dre
gres
sion
,+1
51g
(50–
250)
Mor
ley
etal
.20
09(2
7)M
elbo
urne
,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
ke,q
uart
iles
Dur
ing
preg
nanc
yBi
rthw
eigh
t(z
-sco
re)
Uni
varia
te,t
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.
1372C© 2012 The Authors
Acta Obstetricia et Gynecologica Scandinavica C© 2012 Nordic Federation of Societies of Obstetrics and Gynecology 91 (2012) 1368–1380
H.T. Christesen et al. Impact of vitamin D in pregnancy on children
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.
C© 2012 The AuthorsActa Obstetricia et Gynecologica Scandinavica C© 2012 Nordic Federation of Societies of Obstetrics and Gynecology 91 (2012) 1368–1380 1373
Impact of vitamin D in pregnancy on children H.T. Christesen et al.
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
.
1374C© 2012 The Authors
Acta Obstetricia et Gynecologica Scandinavica C© 2012 Nordic Federation of Societies of Obstetrics and Gynecology 91 (2012) 1368–1380
H.T. Christesen et al. Impact of vitamin D in pregnancy on children
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,
C© 2012 The AuthorsActa Obstetricia et Gynecologica Scandinavica C© 2012 Nordic Federation of Societies of Obstetrics and Gynecology 91 (2012) 1368–1380 1375
Impact of vitamin D in pregnancy on children H.T. Christesen et al.
Tab
le4.
Coh
ort
and
case
–con
trol
stud
ies
onef
fect
ofvi
tam
inD
onty
pe1
diab
etes
,cer
ebra
lfun
ctio
nan
dm
etab
olic
synd
rom
em
arke
rsin
child
hood
.
Out
com
e
Art
icle
(ref
eren
ce.
no.)
Loca
tion
Part
icip
ants
Det
erm
inan
tTi
me
ofet
erm
inat
ion
Ass
ocia
tion
Stat
istic
s(9
5%C
Iin
pare
nthe
ses)
Type
1di
abet
esSt
ene
etal
.20
03(4
0)N
orw
ay54
5ca
ses,
1668
cont
rols
545
case
s,16
68co
ntro
ls
Cod
liver
oilv
s.no
cod
liver
oilo
rV
Dsu
pple
men
tatio
nV
Dsu
pple
men
tatio
nvs
.no
supp
lem
enta
tion
orco
dliv
eroi
l
Dur
ing
preg
nanc
y
Dur
ing
preg
nanc
y
Type
1di
abet
es<
15ye
ars
Type
1di
abet
es<
15ye
ars
Adj
uste
d,te
stfo
rtr
end
0.89
Adj
uste
d,te
stfo
rtr
end
0.94
Mar
jam
akie
tal
.20
10(4
1)Fi
nlan
d37
23m
othe
rsan
dch
ildre
n37
23m
othe
rsan
dch
ildre
n
Tota
lVD
inta
ke,q
uart
iles
Tota
lVD
inta
ke,q
uart
iles
8th
mon
thof
preg
nanc
y8t
hm
onth
ofpr
egna
ncy
Type
1di
abet
es<
4.3
year
s(m
ean)
Adv
ance
dβ
-cel
laut
oim
mun
ityor
type
1di
abet
esat
4.3
year
s,n
=55
Adj
uste
dH
R1.
08(0
.65–
1.79
)A
djus
ted
HR
1.26
(0.9
2–1.
73)
Fron
czak
etal
.20
03(4
2)C
olor
ado,
USA
222
mot
hers
and
child
ren
Tota
lVD
inta
ke,i
ncre
ase
+155
.6IU
/day
Third
trim
este
rβ
-Cel
laut
oant
ibod
ies
atfo
urye
ars,
n=
138
Adj
uste
dH
R03
7(0
.17–
0.78
)Br
ekke
etal
.20
07(4
3)So
uthe
ast
Swed
en86
94m
othe
rsan
dch
ildre
n77
66m
othe
rsan
dch
ildre
n
VD
supp
lem
enta
tion
vs.
none
VD
supp
lem
enta
tion
vs.
none
Dur
ing
preg
nanc
y
Dur
ing
preg
nanc
y
β-C
ella
utoa
ntib
odie
sat
one
year
,n
=77
4β
-Cel
laut
oant
ibod
ies
at2.
5ye
ars,
n=
676
Adj
uste
dO
R0.
71(0
.52–
0.9
6)A
djus
ted
OR
1.25
(0.9
0–1.
73)
Søre
nsen
etal
.20
12(4
4)N
orw
ay10
9ca
ses,
219
cont
rols
25O
HD
<55
vs.
>89
nmol
/LD
urin
gpr
egna
ncy
Type
1di
abet
es<
15ye
ars
Adj
uste
dO
R2.
38(1
.12–
5.07
)C
ereb
ralf
unct
ion
Gal
eet
al.2
008
(24)
Sout
ham
pton
,U
K17
8m
othe
rsan
dch
ildre
n17
7m
othe
rsan
dch
ildre
n17
7m
othe
rsan
dch
ildre
n
25O
HD
25O
HD
25O
HD
32w
eeks
ofge
stat
ion
32w
eeks
ofge
stat
ion
32w
eeks
ofge
stat
ion
Wec
hsle
rA
bbre
viat
edSc
ale
ofIn
telli
genc
e(W
ASI
)sco
reat
nine
year
sSt
reng
than
dD
ifficu
ltyQ
uest
ionn
aire
;pe
erpr
oble
ms
Stre
ngth
and
Diffi
culty
Que
stio
nnai
rein
clud
ing
hype
ract
ivity
Una
djus
ted
regr
essi
on,
n.s.
Una
djus
ted
regr
essi
on,
p=
0.03
8U
nadj
uste
dre
gres
sion
,n.
s.M
cGra
thet
al.
2010
(45)
Den
mar
k42
4ca
ses,
424
cont
rols
424
case
s,42
4co
ntro
ls42
4ca
ses,
424
cont
rols
424
case
s,42
4co
ntro
ls
25O
HD
<19
.7vs
.40
.5–5
0.9
nmol
/L25
OH
D19
.7–3
0.9
vs.
40.5
–50.
9nm
ol/L
25O
HD
31–4
0.4
vs.
40.5
–50.
9nm
ol/L
25O
HD
≥51
vs.
40.5
–50.
9nm
ol/L
Neo
nata
ldry
spot
Neo
nata
ldry
spot
Neo
nata
ldry
spot
Neo
nata
ldry
spot
Schi
zoph
reni
a<
27ye
ars
ofag
e
Schi
zoph
reni
a<
27ye
ars
ofag
e
Schi
zoph
reni
a<
27ye
ars
ofag
e
Schi
zoph
reni
a<
27ye
ars
ofag
e
Adj
uste
dRR
2.1
(1.3
–3.5
)A
djus
ted
RR2.
0(1
.3–3
.2)
Adj
uste
dRR
2.1
(1.3
–3.4
)A
djus
ted
RR1.
71(1
.04–
2.8)
Met
abol
icsy
ndro
me
mar
kers
Gal
eet
al.2
008
(24)
Sout
ham
pton
,U
K17
8m
othe
rsan
dch
ildre
n25
OH
D32
wee
ksof
gest
atio
nBo
dym
ass
inde
x,fa
t/le
anbo
dym
ass,
bloo
dpr
essu
re,p
ulse
wav
eve
loci
ty,
caro
tidin
tima
thic
knes
s,ca
rdia
cst
ruct
ure
atni
neye
ars
Una
djus
ted
regr
essi
on,
n.s.
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;
VD
,vita
min
D.
1376C© 2012 The Authors
Acta Obstetricia et Gynecologica Scandinavica C© 2012 Nordic Federation of Societies of Obstetrics and Gynecology 91 (2012) 1368–1380
H.T. Christesen et al. Impact of vitamin D in pregnancy on children
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
C© 2012 The AuthorsActa Obstetricia et Gynecologica Scandinavica C© 2012 Nordic Federation of Societies of Obstetrics and Gynecology 91 (2012) 1368–1380 1377
Impact of vitamin D in pregnancy on children H.T. Christesen et al.
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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