Discussion
Maternal supplementation with 1000 IU cholecalciferol daily from 14
weeks’ gestation until delivery resulted in a reduced odds of infant
atopic eczema at age 12 months. The effects of supplementation, however,
were non-significant at ages 24 and 48 months. Interaction terms between
supplementation during pregnancy and breastfeeding duration were not
statistically significant, but sensitivity analysis showed that the
protective effect of maternal cholecalciferol supplementation on
infantile eczema was only significant in offspring breastfed for more
than one month.
Current evidence relating to maternal vitamin D status and its effect on
offspring atopic eczema is inconsistent, and evidence from
supplementation trials is sparse. A U-shaped association between
maternal vitamin D supply and status and offspring atopic eczema is
biologically plausible, whereby both low and high intakes and 25(OH)D
insufficiency and high 25(OH)D concentrations might be associated with
increased risk of atopic eczema (see below for discussion of potential
mechanisms).6 We would note that mothers with serum
25(OH)D levels above 100 mmol/L at baseline were excluded from MAVIDOS,
but found no evidence for an increased risk of atopic eczema with 1000
IU/d cholecalciferol supplementation. A reduced risk of wheeze and
eczema has been reported in children of mothers consumed 174 IU/d or
more of dietary vitamin D during pregnancy15, and
infants with cord blood 25(OH)D levels ≥ 75 nmol/L were found to have a
lower risk of eczema in infancy when compared to those with cord blood
levels of < 50 nmol/L.16 There are also
reports of no association between maternal or cord serum 25(OH)D
concentrations and atopic eczema.17 Others studies
have reported no clear associations between maternal vitamin D status in
late pregnancy and asthma, wheeze or skin sensitisation at age 1, 3 or 6
years.18
In the VDAART randomised controlled trial in women at high risk of
having children with asthma, the prevalence of offspring asthma at age 6
years was similar in those whose mothers received antenatal
supplementation with 4400 vs 400 IU/d vitamin D, as were the secondary
outcomes of eczema and total IgE levels; a between-group reduction in
asthma and recurrent wheeze was, however, suggested at early time points
through the age of 3 years.7, 19 Our study examined
the effect of gestational supplementation on offspring eczema at ages
from 12 to 48 months, also finding an effect at early age, 12 months. We
found no effect on eczema in the past year at ages 24 and 48 months
suggesting that other, post-natal influences might become important at
older ages in affecting the risk of atopic eczema beyond infancy.
Conceivably, supplementation during the postnatal period may be needed
for a sustained effect. There is evidence supportive of postnatal
vitamin D supplementation, with a meta-analysis of 11 intervention
studies in children with atopic eczema reporting a reduction in eczema
severity.20
Vitamin D has immunomodulatory effects on innate and adaptive
responses.21 The vast majority of cells of the
adaptive immune system express the vitamin D receptor and CYP27B1,
enabling the production of the active metabolite 1,25(OH)2 D, thought to
act predominantly in an auto-and paracrine fashion. Evidence fromin vitro and in vivo studies22 has
demonstrated that vitamin D supplementation inhibits expression of Th2
response cytokines, the predominant immune response seen acutely in
atopic eczema and other allergic disease. 23Vitamin D
deficiency in utero and early life has been linked with increased
Th2 lymphocytes and reduced T regulatory cells and interleukin IL-10,
leading to macrophage and dendritic cells producing pro-inflammatory
cytokines.24 However, contrary to this, there is
evidence that 1,25(OH)2 D promotes Th2 responses, with inhibition of
IFN-γ and promotion of IL-4, IL-5, and IL-10
production.25 Skin barrier function is important in
the pathogenesis of atopic eczema; vitamin D and its metabolites can
impact this through involvement in the synthesis of proteins such as
filaggrin, and through stratum corneum formation, keratinocyte formation
and differentiation and production and the regulation of skin
antimicrobial peptides. 26
Our data suggest that the effect of vitamin D supplementation on
offspring eczema risk may be seen soon after pregnancy, but weaken as
children grow older, where other risk factors can be influential. We
speculate that during infancy there may be a role of breast milk vitamin
D content. Evidence from MAVIDOS has demonstrated an increase in
maternal serum levels with 1000 IU/d cholecalciferol
supplementation,12 but in line with the Southampton
Women’s Survey observational study,18 our data showed
no association between maternal serum 25(OH)D in late pregnancy and
offspring atopic eczema. Previous studies have shown that gestational
vitamin D supplementation increases breast milk vitamin D
content,8, 9 and in MAVIDOS the vitamin D content of
breast milk is likely to have been higher in the supplemented group,
influenced by mobilisation from maternal fat and muscle tissue. This may
explain our finding of a protective effect only in children that were
breastfed for more than 1 month. Heterogeneity in the aetiology and
pathogenesis of atopic eczema in early childhood is increasingly
recognised,27 and an alternative possibility is that
vitamin D supplementation may only have an effect on particular atopic
eczema phenotypes.
In MAVIDOS, examination of genetic variants in genes related to the
vitamin D pathway has shown that rs12785878 (DHCR7) was associated with
baseline 25(OH)D, likely influencing cutaneous synthesis; achieved
25(OH)D status following supplementation was associated with rs10741657
(CYP2R1, which determines the efficiency of vitamin D to 25(OH)D
conversion), whereas rs12785878 and rs6013897 (CYP24A1) were
not.10 There were weak trends for higher ORs of atopic
eczema with rs10741657 (CYP2R1) at ages 12 and 24 months but no
associations for other SNPs examined. In a case-control study of Chinese
children, rs4674343 on CYP27A1 (27-hydroxylase, an enzyme converting the
pre-vitamin D3 metabolite lumisterol into further downstream metabolites
with biological activity in skin cells28) was reported
to be protective against atopic eczema and CYP2R1 and VDR haplotypes
also influenced atopic eczema risk and eosinophil
count.29
A strength of this study is analysis of data from a placebo‐controlled,
double‐blind, randomised trial. Atopic eczema was not the primary
outcome in MAVIDOS, but the data collected enabled ascertainment of
offspring atopic eczema using the UKWPDC well-recognised criteria for
the diagnosis of atopic eczema. Furthermore, these criteria were
determined by trained research nurses who examined the offspring. While
some participants were taking vitamin D in addition to the
intervention/placebo provided, supplement use at interview did not
differ between the intervention and placebo groups. A limitation of this
study is that cord blood and offspring 25(OH)D levels were not measured,
precluding examination of these in relation to atopic eczema. Possible
effects of UVB and any interaction with supplementation could not be
investigated because no UVB exposure data were available. Our study
population did not include many women who were not white and we could
not include participants with baseline 25(OH)D concentrations of less
than 25 nmol/L as a result of stipulations made during the ethics
approval process; these reduce the generalisability of our findings.
In conclusion, in a randomised controlled trial maternal supplementation
with 1000 IU/d cholecalciferol from 14 weeks’ gestation to delivery led
to a reduced incidence of atopic eczema in the first year of life. Many
international and national guidelines recommend 400-600 IU/d (10-15
micrograms) cholecalciferol throughout pregnancy, with the strongest
evidence for the prevention of neonatal hypocalcaemia and emerging
evidence for effects on other health outcomes affecting skeletal,
respiratory and immune systems.30 The current findings
inform understanding of the early life influences on infantile eczema
and support recommendations for routine vitamin D supplementation during
pregnancy.