Maternal Vitamin D Supplementation During Pregnancy

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Br Med Bull. Author manuscript; available in PMC 2018 June 15.
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Br Med Bull. 2018 June 01; 126(1): 57–77. doi:10.1093/bmb/ldy010.
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Maternal Vitamin D Supplementation during Pregnancy

Dr Elizabeth M Curtis1, Dr Rebecca J Moon1,2, Prof Nicholas C Harvey1,3, and Prof Cyrus
Cooper1,3,4
1MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, SO16 6YD, UK
2Paediatric
Endocrinology, Southampton University Hospitals NHS Foundation Trust,
Southampton, SO16 6YD, UK
3NIHR Southampton Biomedical Research Centre, University of Southampton and University
Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton, SO16 6YD, UK
4NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, OX3 7LD, UK
Structured Abstract
Introduction—Maternal vitamin D status in pregnancy has been linked to many health outcomes
in mother and offspring. A wealth of observational studies have reported on both obstetric
outcomes and complications, including preeclampsia, gestational diabetes, mode and timing of
delivery. Many fetal and childhood outcomes are also linked to vitamin D status, including
measures of fetal size, body composition and skeletal mineralisation, in addition to later childhood
outcomes, such as asthma.
Sources of Data—Synthesis of systematic and narrative reviews.

Areas of Agreement and Controversy—The findings are generally inconsistent in most

areas, and, at present, there is a lack of data from high quality intervention studies to confirm a
causal role for vitamin D in these outcomes. In most areas, the evidence tends towards maternal
vitamin D being of overall benefit, but often does not reach statistical significance in meta-
analyses.
Growing Points and Areas timely for developing research—The most conclusive
evidence is in the role of maternal vitamin D supplementation in the prevention of neonatal
hypocalcaemia; as a consequence the UK department of health recommends that pregnant women
take 400 IU vitamin D daily. High-quality randomised placebo controlled trials, such as the UK-
based MAVIDOS trial, will inform the potential efficacy and safety of vitamin D supplementation
in pregnancy across a variety of outcomes.
Corresponding author: Prof Cyrus Cooper, MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK,
cc@mrc.soton.ac.uk.
Disclosures:
EMC and RM have no disclosures. NH has no disclosures directly related to this work, and has received consultancy, lecture fees and
honoraria from Alliance for Better Bone Health, AMGEN, MSD, Eli Lilly, Servier, Shire, UCB, Consilient Healthcare and Internis
Pharma; CC has no disclosures directly related to this work, and has received consultancy, lecture fees and honoraria from AMGEN,
GSK, Alliance for Better Bone Health, MSD, Eli Lilly, Pfizer, Novartis, Servier, Medtronic and Roche.
Curtis et al. Page 2
Keywords
vitamin D; pregnancy; offspring; obstetric; bone; epidemiology
Introduction
The classical role of vitamin D is in calcium and phosphate homeostasis, and it is widely
known that that severe vitamin D deficiency (VDD) can result in rickets, osteomalacia and
neonatal hypocalcaemia. Clinically, neonatal hypocalcaemia can result in seizures, and has
been associated with softening and thinning of the skull (craniotabes) 4, and rarely, dilated
cardiomyopathy 5. However, there is increasing evidence to suggest that VDD in pregnancy
is associated with wide ranging clinical outcomes, including obstetric complications,
preterm birth, and adverse offspring outcomes affecting the skeletal, immune, and
respiratory systems6. As a result, a number of national and international guidelines
recommend vitamin D supplementation during pregnancy or offer guidance on defining
deficiency and sufficiency (Table 1), though there is considerable debate regarding the
thresholds for vitamin D deficiency and sufficiency. Most recommend between 400 and 600
IU (10-15 micrograms) cholecalciferol daily throughout pregnancy, although this is not
currently supported by the World Health Organisation (WHO)7. It is important to mention
that the Endocrine Society recommends a safe upper limit for 25(OH)D intake in pregnancy
of 10,000 IU/day for individuals over the age of 19 years at risk of vitamin D deficiency,
though their recommendations for those not at risk remain at 600IU/day8.
Here, we review the evidence basis for antenatal vitamin D supplementation to prevent
obstetric complications, and the influence of vitamin D on fetal growth, with a focus on
skeletal development.
Vitamin D in pregnancy: physiology and epidemiology

Vitamin D can be obtained through two pathways: via the diet or via endogenous synthesis.
In the diet, it can be obtained as ergocalciferol (vitamin D2) from plant sources, or
cholecalciferol (vitamin D3) from animal sources. However, the majority is formed
endogenously within the skin from the action of ultraviolet B radiation to convert 7-
dehydrocholesterol to pre-vitamin D3. The main circulating form, 25-hydroxyvitamin D
[25(OH)D], is produced through hydroxylation of pre-vitamin D in the liver. It is found
either bound to vitamin D binding protein (VDP), albumin, or in the free form, and acts as a
reservoir for conversion to the active metabolite, 1,25-dihydroxyvitamin D [1,25(OH)2D]),
primarily in the renal proximal tubular cells, but also within bone, the parathyroid gland and,
in pregnancy, the placenta. The production of 1,25(OH)2D is regulated in response to serum
calcium and has a short half-life of 4-6 hours. Hepatic 25-hydroxylation, conversely, is not
physiologically regulated and 25(OH)D has a half-life of approximately 2-3 weeks19. Serum
25(OH)D is consequently considered the best marker of vitamin D status20.
The main role of circulating 1,25(OH)2D is in calcium and phosphate homeostasis, which
occurs in conjunction with parathyroid hormone (PTH). Low serum ionised Ca2+ stimulates
PTH release, increasing renal calcium reabsorption in the distal tubule of the kidney,

decreasing proximal tubule phosphate reabsorption, and increasing 1,25(OH)2D synthesis.

1,25(OH)2D then acts on the intestinal enterocytes to increase uptake of dietary calcium,
simultaneously enabling PTH induced mobilisation of calcium and phosphate from bone
mineral21.
During pregnancy, significant alterations to calcium and phosphate metabolism occur,

allowing the accretion of calcium within the fetal skeleton, particularly during the third
trimester22. It is quite remarkable that during pregnancy maternal serum ionised calcium
concentrations remain stable, whilst intestinal calcium absorption increases 23,24, and
additional calcium is mobilised from the maternal skeleton25. 1,25(OH)2D is likely have an
important role in these adaptations, as total 1,25(OH)2D increases during the second and
third trimesters23,26, though this could be reflected by increases in vitamin D binding
protein (DBP) in early pregnancy but not late pregnancy. Therefore, free 1,25(OH)2D is
increased in the third trimester relative to earlier in pregnancy24,27,28. The increase in
1,25(OH)2D appears not to be driven by PTH, which remains within the normal adult range
throughout pregnancy22, though may be influenced by PTH-related protein (PTHrP), which
is elevated in the maternal circulation from early pregnancy26. It is also important to
consider that the rise in free 1,25(OH)2D from early pregnancy (when the calcium
requirements of the developing fetus are minimal) may have another function, as serum
levels of 1,25 (OH)2D increase by approximately twofold during the first trimester 29.
Indeed there is evidence to suggest that 1,25(OH)2D may have a role in immune tolerance in
a pregnant woman, to prevent fetal rejection 30.
The effect of pregnancy on 25(OH)D however is less well understood: some studies show a
reduction through pregnancy27, whilst others demonstrate no significant differences in
25(OH)D pre-pregnancy, within each trimester and during lactation24. Maternal 25(OH)D in
pregnancy is an important consideration as the fetus is entirely dependent on the mother for
25(OH)D. 25(OH)D readily crosses the placenta, partly through the megalin-cubulin
endocytotic system31 and maternal and umbilical cord venous blood 25(OH)D are
moderately-highly correlated (r=0.44 to 0.89), although umbilical cord concentrations are
typically lower than that of maternal blood 32–35.
Biochemically low levels of 25(OH)D are highly prevalent in pregnant women, albeit using
various 25(OH)D thresholds for deficiency. Dark skin pigmentation and extensive skin
covering (for example for religious or cultural reasons) are the strongest risk factors for
vitamin D deficiency, though many Caucasian women are also deficient, particularly at
higher latitudes. In a cohort of predominantly Caucasian women in the United Kingdom
(UK), 31% had a serum 25(OH)D less than 50nmol/l, and 18% less than 25nmol/l36; whilst
in an ethnically more diverse UK population, 36% of women had a 25(OH)D <25nmol/l at
pregnancy booking37.
There is some evidence to suggest that the cutoffs of <25nmol/L as deficient and >50nmol/L
as sufficient may not be relevant to pregnancy. Uniquely in pregnancy, the conversion of
25(OH)D to 1,25(OH)2D may be optimised at a 25(OH)D concentration of around
100nmol/L38. In this study, pregnant women were supplemented with 400IU/d, 2000IU/d or
4000 IU/d, the Institute of Medicine39 recommended upper limit of intake in pregnancy, and

was found to be effective in achieving vitamin D sufficiency throughout pregnancy without

increased risk of toxicity in women or neonates.
Comparison of outcomes between trials is further complicated by the vast range of dosages
of vitamin D given (200IU daily to 4400IU daily, or bolus doses ranging from single doses
of 60,000IU to 35,000 IU per week3 40 41).
Randomised controlled trials have clearly demonstrated that vitamin D supplementation in

pregnancy can increase umbilical cord venous and neonatal serum 25(OH)D compared to
placebo, however the amount by which maternal serum 25(OH)D increases with
supplementation varies between individuals38,42–48. In the MAVIDOS trial of 1000 IU
cholecalciferol from 14 weeks gestation, factors significantly associated with the response to
supplementation (maternal 25(OH)D at 34 weeks gestation) were season of delivery,
baseline 25(OH)D at randomisation, and compliance with the medication (Figure 1)49.
Weight gain was negatively associated with 25(OH)D at 34 weeks, which is in agreement
with previous observational findings suggesting that greater weight gain in pregnancy is
associated with a reduction in 25(OH)D between early and late pregnancy50, implying that
those women who gain most weight during pregnancy may benefit from higher supplement
doses. Interestingly BMI at baseline was not an independent determinant of late pregnancy
25(OH)D in either the treatment or placebo group, despite obesity being associated with
biochemically low 25(OH)D levels51.
Consistent with findings in non-pregnant adults52, genetic factors play a role in the response
to vitamin D supplementation during pregnancy. Single nucleotide polymorphisms (SNPs)
in or near to genes in the vitamin D metabolism pathway appear to modify the response to
vitamin D supplementation in pregnancy. Different SNPs were found to be associated with
baseline 25(OH)D (rs12785878 in DHCR7, encoding 7-dehydrocholesterol reductase in the
skin), compared with 25(OH)D achieved post supplementation (SNPs in genes encoding 25-
hydroxylase and vitamin D binding protein) (Figure 2). Women with more “at risk” alleles
may therefore require higher supplement doses to achieve vitamin D repletion in pregnancy,
which may be of interest in the future era of personalised medicine2.
Vitamin D and obstetric complications

Numerous observational studies report associations between 25(OH)D status in pregnancy
and a variety of obstetric complications, including gestational hypertension (GHT) and
preeclampsia (PET), gestational diabetes (GDM), and timing and mode of delivery.
However, the interpretation and comparison of these studies is limited by differences in the
study design (e.g. prospective cohort, case-control), the timing of 25(OH)D measurements,
ranging from first trimester to delivery, the definition used for both VDD and the pregnancy
or delivery outcome, and the confounding factors adjusted for.
Gestational hypertension & preeclampsia

Previous studies have suggested that maternal calcium status might be important in the
aetiology of PET, as calcium supplementation can reduce PET risk particularly in women
with low calcium intake53. This led to the interest in the role of calcitropic hormones,

including vitamin D, in the development of PET. In addition, studies in humans have

demonstrated an association between vitamin D insufficiency and endothelial dysfunction,
implying that vitamin D has a role in regulating the conductance and resistance of blood
vessels 54. This provides another mechanism by which vitamin D insufficiency could be
associated with PET; indeed a substudy of a RCT of vitamin D supplementation in
pregnancy demonstrated that supplementation influenced mRNA level gene transcription of
angiogenic factors (such as vascular endothelial growth factor, VEGF), in the human
placenta 55.
The outcomes of many observational studies reporting on GHT and pre-eclampsia are
conflicting, with some demonstrating an inverse association between maternal vitamin D
status and the risk of pre-eclampsia56–64 and others no association 58,65–72. In recent
years, there have been several published meta-analyses of the relationship between maternal
vitamin D status and PET risk, providing a variety of inconsistent results6,40,73–78. The
most recent systematic review and meta-analysis, published in the BMJ in 2017, showed that
vitamin D had no significant influence on the risk of GHT or pre-eclampsia41. In the UK
Health Technology Assessment meta-analysis (Harvey et al), again, no significant reduction
in the risk of PET with higher vitamin D status was noted (Figure 3)6. In contrast,
Aghajafari et al reported on 9 studies in another meta-analysis of vitamin D deficiency and
pregnancy outcomes, and showed a significant association between pre-eclampsia and
25(OH)D insufficiency compared with the comparison group, with a pooled odds ratio of
1.79 (95% CI 1.25, 2.58)75. However, this appeared subject to a particular analytical
approach as the increased risk of PET in VDD was only observed in studies in which blood
sampling was later than 16 weeks gestation and when VDD was defined as
25(OH)D<75nmol/l and not <50nmol/l75. Tabesh et al., analysing a larger number of studies
defining VDD as less than 50nmol/l, also demonstrated an increased risk of PET, which was
not found when deficiency was defined as less than 38nmol/l76. A recently updated
Cochrane review of vitamin D supplementation and maternal and infant health outcomes by
De-Regil et al included 15 trials, nine comparing the effects of vitamin D supplementation
versus no supplementation or a placebo, and six comparing the effects of vitamin D in
combination with calcium and no supplementation. Only two trials (n=219, combined) 79,80
were included in the pre-eclampsia analysis, which suggested overall that women who
received vitamin D supplements may have a lower risk of PET (though borderline), than
those receiving no intervention or placebo (Risk Ratio 0.52 (95% CI 0.25, 1.05)) 40.
However, a more recently published trial, VDAART, showed no significant differences in the
incidence of pre-eclampsia (as a secondary outcome) in a group of pregnant women
supplemented with cholecalciferol (n=440, given 4400 IU 25(OH)D daily, and the placebo
group, receiving 400 IU daily n=436) 81.
Gestational Diabetes
As in the case of PET, conflicting findings have been reported for 25(OH)D status in case-
control and prospective cohort studies of GDM risk, with some reporting lower78,82–87,
and others no difference in 25(OH)D88,89 during pregnancy in women with GDM.
Evidence suggests that vitamin D contributes to various factors associated with the
propensity to develop impaired glucose tolerance, such as insulin sensitivity, β-cell function,

and insulin secretion. Immune dysfunction, through inflammatory dysregulation (cytotoxic

T-lymphocyte activation), links vitamin D deficiency with compromised maternal-fetal
tolerance and increased risk of GDM90.
Three separate meta-analyses of published studies all concluded that women with GDM had
significantly lower mean 25(OH)D than normoglycaemic women75,77,91 with the mean
difference in 25(OH)D ranging from 3.9 to 7.4nmol/l. Furthermore, these meta-analyses

suggested that the risk of GDM was increased by 40-60% in women with VDD 75,77,91.
However, since their publication, a meta-analysis by Harvey et al including eight
observational studies 68,82,83,88,92–95 showed no overall relationship between maternal
25(OH)D status and risk of GDM. Similarly, in a Cochrane meta–analysis, two trials were
included 79,80 comparing vitamin D supplementation during pregnancy with no treatment/
placebo, and no significant difference in the risk of gestational diabetes was seen between
the two groups40. In the most recent meta-analysis by Roth et al, vitamin D was shown to
reduce the risk of gestational diabetes (risk ratio 0.61, 95%CI 0.34 to 0.83, 2643
participants) when all trials were included, but when only the trials meeting their strict
eligibility criteria were included, no effect was seen 41.
Caesarean Delivery
There is increasing interest in the role of maternal vitamin D status in relation to mode and
timing of delivery, as it has been suggested that vitamin D deficiency may reduce pelvic
muscle strength and control 96. However, again, findings are inconsistent. Several studies
which assessed 25(OH)D in early pregnancy (at the time of GDM screening) or at delivery,
reported an increased risk of Caesarean delivery in 25(OH)D deficient women 96–98, whilst
other studies measuring 25(OH)D in the first trimester demonstrated no increased risk68,70.
In trials of high dose 25(OH)D supplementation of 4000 IU daily versus 400 IU daily,
primary Caesarean section births (with or without labour, for a maternal or fetal indication)
were found to be significantly reduced in the high dose group 38. Harvey et al (describing
six observational studies), De Regil (including two trials), and Roth et al (including 16 trials)
found no overall evidence in meta analyses to support the use of vitamin D supplementation
to reduce rates of Caesarean section 6 40 41.
Preterm Delivery and Newborn Health

Several investigators have reported on associations between low maternal vitamin D status
and preterm births74,98–100, with some presenting the hypothesis that systemic
inflammation, which is associated with a low 25(OH)D status, may accompany the events
leading to the initiation of preterm birth, including membrane rupture and uterine
contractions 101,102. It is therefore argued that vitamin D status in late pregnancy is a better
predictor of preterm birth than early pregnancy vitamin D status 103. Notwithstanding this,
many studies have concluded that maternal 25(OH)D status is not beneficially related to
preterm birth65,68,70,78,104–109. Comparisons between these studies are complicated by
the differing definitions of preterm, 25(OH)D deficiency, timing of measurement, and
ethnicities of populations between studies. For example, Bodnar et al observed that only
non-white mothers had an increased risk of preterm birth with low 25(OH)D at 26 weeks

gestation100, suggesting stratification of women by ethnicity in future intervention studies

might be necessary.
In a meta-analysis of three trials 43,79,80, De Regil et al found that women who received
vitamin D supplements during pregnancy had a lower risk of having a preterm birth than
those women receiving no intervention or placebo (3.3% versus 9.9%; average RR 0.36;
95% CI 0.14 to 0.93). The meta-analysis of 3757 participants from 13 trials by Roth et al, on
the other hand, showed no effect of vitamin D supplementation on risk of preterm birth 41.
Health of the newborn is often of interest in trials of vitamin D supplementation in

pregnancy. In one study of 4000 IU cholecalciferol versus placebo in pregnant Pakistani
women, vitamin D supplementation had no effect on maternal outcomes or birthweight or
size, but did have a beneficial effect on markers of newborn health, the Apgar score, at one
and 5 minutes post-delivery (for example, mean Apgar at one minute in the supplemented
group 7.10±0.66, versus placebo group 6.90±0.50, p=0.026) 110. In another randomised trial
based in India, where women in the intervention group were given 25(OH)D
supplementation according to baseline vitamin D status, a positive correlation was found
between maternal vitamin D status and the Apgar Score of babies (r=0.325, p<0.001) 79.
However, the most recent meta-analysis of 1997 individuals from 5 trials showed that there
was no reduction in risk of admission to the neonatal intensive care unit in the offspring of
mothers receiving vitamin D supplementation 41.
In all obstetric outcomes, it must be acknowledged that 25(OH)D status is primarily

determined by environmental factors. Therefore, confounding and reverse causality need to
be considered; in addition, differences in the covariates included in multivariate models
might explain the inconsistent findings. Examples include the observation that obese
individuals have lower 25(OH)D status, and a higher incidence of GDM, GHT, PET,
caesarean section and preterm delivery111,112. Similarly, African-American women are

more likely to require delivery by Caesarean section and to experience pre-eclampsia and
preterm labour 113. Therefore, whether these relatively rare obstetric outcomes can truly be
attributed to lower 25(OH)D and therefore could be prevented by vitamin D supplementation
must be established through carefully designed intervention studies with large numbers of
participants.
Neonatal Hypocalcaemia
Symptomatic neonatal hypocalcaemia is one of the fetal outcomes most reliably associated
with maternal VDD. It is rarely reported in infants of white mothers, and most commonly
occurs in infants of mothers with the most profound VDD, often from ethnic and cultural
groups at highest risk.
Several intervention studies assessing the effect of vitamin D supplementation on umbilical

cord and neonatal serum Ca2+ have been reported, though with inconsistent findings. Such
differences might reflect the variations in supplementation used; the majority of studies that
used high dose weekly or monthly oral supplementation reported positive effects of vitamin
D supplementation on umbilical venous cord blood Ca2+ 44,114–116, whereas the trials
using daily oral vitamin D supplementation tended to demonstrate a null effect

41,44,48,115,117–119. Nonetheless, vitamin D supplementation consistently reduced the

incidence of symptomatic hypocalcaemia in the three studies in which this outcome was
reported 116,117,119. Hence, though the evidence for measurable biochemical changes to
calcium homeostasis with antenatal vitamin D supplementation are variable, the clinical
outcome of symptomatic hypocalcaemia, which is perhaps more important, is more
consistent and justifies the routine use of antenatal vitamin D supplementation.
Vitamin D and Fetal Development

The fetus is dependent on the mother for accretion of approximately 30g of calcium to
enable skeletal development, and rickets has been reported in infants born to mothers with
VDD 120–122. As a result, a subclinical role for vitamin D and/or calcium in fetal growth
and bone development has been considered. Interestingly, maternal supplementation with
calcium alone does not appear to have beneficial effects on fetal bone mineral accrual123;
indeed a recent study has suggested detrimental effects of maternal calcium supplementation
on childhood growth in females in a Gambian population particularly accustomed to low
calcium intake 124.
A hypothesis is developing that vitamin D may have a role in the programming of fetal
development – that is, the prevailing in-utero environment modifies later phenotype, a
concept termed developmental plasticity 125. This hypothesis has been applied to
associations between maternal vitamin D status and offspring development in various
contexts, with studies and trials in various populations showing positive associations
between maternal 25(OH)D and birthweight, length and/or occipitofrontal head
circumference 126,33,127,128,129,130 and sometimes postnatal growth 131 126. However,
this is balanced by a greater number of studies with null findings 32,83,88,132–139.
Evidence generally supports only the lowest levels of 25(OH)D being associated with poorer
fetal growth outcomes 140, 127. A 2017 meta-analysis of 27 different neonatal outcomes
demonstrated vitamin D supplementation lead to an increase in birth weight and length at 1
year, a reduction in the risk of infants being small for gestational age, Risk Ratio 0.60 (95%
CI 0.40 to 0.90), and a reduction in the risk of asthma or wheeze by age 3 years, Risk Ratio
0.81 (95% CI 0.67 to 0.98) 41.
Mixed evidence is available for the influence of vitamin D status in pregnancy and other
fetal and childhood outcomes, including adiposity96,134 141 lean mass, and childhood
asthma81, however the most detailed evidence is in the realm of skeletal development,
which will be the focus for the latter part of this review.
Bone development
Observational studies
Some of the earliest data to suggest that vitamin D exposure might influence in utero bone
mineral accrual used season as a proxy marker of vitamin D status. Namgung et al observed
that in 71 Korean neonates, those born in summer months had 8% higher whole body bone
mineral content (BMC), measured by dual energy x-ray absorptiometry (DXA), after
adjustment for weight, than infants born in winter. In addition, in that cohort, neonatal

25(OH)D at delivery was positively correlated with whole body BMC 142. In contrast, the
same authors found that infants in the USA who were born in the summer had lower whole
body BMC than winter-born infants 143. The authors proposed that these differences reflect
the use of vitamin D supplementation in the two populations; the uptake of supplementation
is low throughout pregnancy in Korea but standard practice after the first trimester in the
USA, where differences in maternal 25(OH)D by season of birth were not observed 142.
This would suggest that early pregnancy 25(OH)D status is crucial to vitamin D
mineralisation, which is in contrast to several later studies with assessment of serum
25(OH)D. Data from the Southampton Women’s Survey mother-offspring cohort, in the UK,
suggest higher neonatal BMC amongst summer than winter births (Figure 4).
Subsequent studies have used measurements of maternal or cord blood 25(OH)D as the
exposure variable. In a Canadian study, 25(OH)D was measured in venous cord blood and
used to divide the infants into two groups using a cut point of 37.5 nmol/l. Whole body and
femur BMC relative to body weight were significantly lower in the 18 neonates with the
lower cord blood 25(OH)D, compared with 32 infants with a 25(OH)D above this cut point
144. Similarly, Viljakainen et al, using the mean of two maternal serum 25(OH)D
measurements from early pregnancy and 2 days postpartum as the assessment of maternal
vitamin D status, found neonatal tibial BMC and cross-sectional area measured by
peripheral quantitative computed tomography (pQCT) were 14% and 16% higher,
respectively, in infants born to mothers with 25(OH)D above the median for the cohort 145.
When a subset of these children were reassessed at 14 months of age, the difference in tibial
BMC was no longer present, but tibial CSA remained significantly higher in those born to
mothers with higher vitamin D status in pregnancy 146. Conversely, when 125 Gambian
mother–offspring pairs were studied, no significant relationships were observed between
maternal 25(OH)D at either 20 or 36 weeks of gestation and offspring whole body BMC or
bone area at 2, 13 or 52 weeks of age 136. However, in contrast to the other studies, none of
the mothers had a 25(OH)D below 50 nmol/l, consistent with the hypothesis that poorer
skeletal mineralisation might only occur in fetuses of mothers with the lowest 25(OH)D
levels.
There is some evidence to suggest that these relationships persist into childhood, although
study findings are less consistent than in the neonatal period. Positive relationships between
maternal 25(OH)D measured in late pregnancy and offspring whole body and lumbar spine
(LS) bone area, BMC and aBMD at 9 years of age in 198 mother-offspring pairs in the
Princess Anne Hospital Study (Southampton, UK) were reported by Javaid et al 139. It was
also noted that children born to women who consumed vitamin D containing supplements
had higher whole body BMC and bone area, but not areal BMD, supporting the evidence for
maternal vitamin D supplementation – this finding persisted after adjustment for
socioeconomic status. These findings were replicated in the Southampton Women’s Survey
(SWS), in which 1030 mother-offspring pairs had measurement of 25(OH)D at 34 weeks of
gestation and whole body less head (WBLH) and LS DXA at 6-7 years. WBLH BMC, bone
area, BMD and LS BMC were all significantly lower in children born to mothers with
25(OH)D < 25 nmol/l in late pregnancy, including after adjustment for maternal age,
ethnicity, height, pre-pregnancy BMI, smoking in late pregnancy, social class, maternal
educational attainment and duration of breast feeding 147.

Similarly, Zhu et al found a positive relationship between maternal 25(OH)D status at 18

weeks gestation and bone mass in young adulthood in the Raine cohort in Western Australia.
They showed, after adjustment for sex, age, height and body composition at age 20 years,
maternal height and pre-pregnancy weight, maternal age at delivery, parity, education,
ethnicity, smoking during pregnancy and season of maternal blood sampling, whole body
BMC and aBMD were 2.7% and 1.7% lower at 20 years of age in offspring of mothers with
25(OH)D < 50 nmol/l compared to those above this level 148.
In contrast, analyses using the UK Avon Longitudinal Study of Parents and Children
(ALSPAC) cohort study do not support these findings. Initially, using 6995 mother-offspring
pairs, Sayer et al reported a positive relationship between estimated maternal UVB exposure
in late pregnancy and offspring WBLH BMC, bone area and BMD at 9.9 years of age 149.
However, further analysis in a subset of 3960 of the children for whom maternal serum
25(OH)D measurement was available in the first (n=1035), second (n=879) or third
(n=2046) trimester did not reveal any significant associations between maternal 25(OH)D
and offspring bone mineralisation 150, though collinearity of the estimated maternal UVB
measurement with age at assessment might have confounded the relationships reported in
the initial study. More recently, the Netherlands Generation R cohort documented
inconsistent relationships between pregnancy 25(OH)D and offspring bone measures151.
Unfortunately the analytical models used make it difficult to conclusively compare these
analyses with previous studies152; however, these conflicting findings from 2 very large
cohorts demonstrate the limitations of the observational approach, and the clear necessity for
testing the hypothesis that maternal pregnancy supplementation with vitamin D will lead to
improved offspring bone mass in randomised controlled trial settings.
Intervention studies
In 1983, the first intervention study to assess the effect of antenatal vitamin D
supplementation on offspring bone mineralisation was published. Sixty-four women of

Asian ethnicity living in the UK participated in a non-randomised study; 19 received a daily
supplement containing 1000 IU vitamin D and calcium (of unknown strength) during the last
trimester, whereas 45 received no supplementation. There was no significant difference in
forearm BMC of the offspring at birth assessed using single photon absorptiometry 153;
however the study size, lack of randomisation and technology used limits the interpretation
of the findings.
Three more recently published studies of gestational vitamin D supplementation report on

postnatal bone outcomes, of which the largest is the Maternal Vitamin D Osteoporosis Study
(MAVIDOS). MAVIDOS is a randomised double-blind placebo-controlled trial of antenatal
vitamin D supplementation from 14 weeks of gestation until delivery conducted in three
centres in the UK, reporting a primary outcome of neonatal bone mass 154. 1134 women
with a baseline 25(OH)D between 25 and 100 nmol/l were randomised to 1000 IU/day
cholecalciferol or placebo; 965 remained in the study until delivery, and 736 infants
underwent DXA of the whole body and/or LS. Although there were no differences in whole
body or LS BMC, bone area or aBMD between the two groups overall, a significant
interaction was observed between season of birth and maternal randomisation group, as

shown in (p for interaction for BMC 0.04) 155. Thus, whole body BMC and BMD were
approximately 9% and 5% higher, respectively, in the children born in winter to mothers
randomised to cholecalciferol compared to those randomised to placebo. This effect size is
substantially larger than those observed between children with and without fractures 156,
and hence if persisting into later childhood is likely to be clinically relevant, particularly if it
has an impact on peak bone mass, as peak bone mass achieved is a strong predictor of
osteoporosis in later life 157.
Two smaller intervention studies from India and Iran have also assessed bone mass in infants
born to mothers randomised to vitamin D supplementation or placebo. Sahoo et al
randomised 300 women to three groups, which received 400 IU/day cholecalciferol daily
(“placebo”), 60 000 IU cholecalciferol every 4 weeks or 60 000 IU cholecalciferol every 8
weeks from the second trimester. All women also received daily calcium supplementation,
though relatively small numbers of women and children (17% of the original cohort)
underwent DXA at 12-16 months of age. The children in the placebo group were
significantly older at DXA scan and had higher measurements of whole body BMC and
BMD, but in multivariate analysis randomisation group was not a significant predictor of
BMC or BMD 158. Vaziri et al randomised 153 women to placebo or 2000 IU/day
cholecalciferol from 26-28 weeks until delivery, but only 25 infants (16% of the original
cohort) had DXA assessment. No significant difference in whole body BMC, BMD or bone
area was found 159, but as with the study by Sahoo et al, the small numbers included are
unlikely to have sufficient power to detect a difference in the outcomes studied.
Evidence from observational studies does therefore suggest that achieving higher levels of
serum 25(OH)D in pregnancy might have beneficial effects on offspring bone development,
but further high quality RCTs are required to assess this. Moreover, long-term follow up of
children born to participants of these trials is required. This will enable us to determine
whether any effects observed in the neonatal period, such as the effect of gestational vitamin
D supplementation on increased bone mineralisation in children born in winter, does persist
beyond the neonatal period and whether this can influence peak bone mass obtained.
Maternal pregnancy vitamin D status, epigenetics and developmental

plasticity
An individual’s skeletal health, most often described by measurement of BMD and BMC by
DXA, is only partly explained by genetic factors160 161 162, and there is increasing
evidence that some of the residual variance in both BMD and fracture risk in adulthood
might be explained by the influence of the environment on gene expression, both in utero
and in early life 163. Evidence is accumulating that this concept of developmental plasticity
may apply in the case of the actions of vitamin D in utero on the developing fetus directly, or
indirectly. It is widely recognised that genes effectively provide a library of information that
can be read (expressed) differently in different cells and tissues according to function and
need. Thus, in a single organism, although the genetic code contained in every somatic cell
is the same, the genes expressed will vary widely from organ to organ and even from cell to
cell, often in response to environmental cues 125 – so a single genotype can give rise to

many different phenotypes. Various experimental studies have clearly demonstrated that
alterations to maternal dietary factors during pregnancy may lead to changes in offspring
phenotype and gene expression 164 165. These effects are likely to be underpinned by
epigenetic mechanisms, processes by which gene expression is modified but without
changes in the DNA code itself. Such epigenetic signals are essential in determining when
and where genes are expressed. An understanding of these epigenetic processes has the
potential to enable early intervention strategies to improve early development and later
health; consequently the study of epigenetic biomarkers is a rapidly advancing field 166.
Epigenetic mechanisms include DNA methylation, histone modification and non-coding
RNAs, the most widely studies of which is DNA methylation, the transfer of a methyl group
to a particular genomic location, usually at the 5’ carbon position of cytosine adjacent to a
guanine base, or CpG site. A CpG site can either be methylated or unmethylated in an
individual cell, however, across a whole tissue where genes in cells may be methylated or
unmethylated, a range of graded gene expression from 0% to 100% is possible 125.
Methylation at regions of the genome particularly rich in CpG sites, for example, at the 5’
end of genes in regions known as CpG islands, often near to the promoter of a gene, may
have important influences on that gene’s expression167, 125,168.
In terms of the links between maternal 25(OH)D status and offspring bone mass, there is
evidence that this association may be mediated partly through umbilical cord calcium
concentrations, and expression of a particular active placental calcium transporter was
positively associated with neonatal bone mass169, and with 1,25(OH)2-vitamin D implicated
in experimental studies170. There is increasing evidence that epigenetic mechanisms such as
DNA methylation may underlie such observations125,171. In the SWS, perinatal DNA
methylation at two loci of interest, CDKN2A, a key element in cell senescence172 and the
retinoid-X-receptor-A(RXRA) gene were inversely associated with childhood BMC
corrected for body size at four years 173 1. RXRA forms a heterodimer with the vitamin D
receptor and is essential in the nuclear action of 1,25(OH)2-vitamin D. Methylation at one

CpG site was related to an estimate of free 25(OH)D (figure 6). Further analyses are ongoing
to establish the influence of maternal 25(OH)D on methylation of RXRA in a randomised
controlled trial setting, MAVIDOS. In order to fully exploit these findings, it is essential to
establish whether these associations persist into older childhood, to refine the bone
phenotype, and to experimentally validate whether gestational supplementation with vitamin
D might alter DNA methylation.
In this section, we have mainly focussed on epigenetic mechanisms associating vitamin D

status in pregnancy with offspring bone health. Research is ongoing into the links between
maternal vitamin D and its influence on multiple developing body systems within the fetus,
for example immunity and allergy, as investigated in the VDAART trial174, and in maternal
health, such as vascular pregnancy complications 55.
Conclusions and knowledge gaps

Our understanding of the role of vitamin D during pregnancy and its role in maternal and
offspring health has improved considerably over the last decade, though there is still a great
deal of work to do. The UK Department of Health currently recommends routine antenatal

vitamin D supplementation with 400 IU cholecalciferol daily throughout pregnancy for all
women, independent of ethnicity and other risk factors for VDD 175. There is good
evidence to suggest that supplementation is important in reducing the risk of neonatal
hypocalcaemia and increasing neonatal 25(OH)D status. There is evidence to suggest that
certain maternal characteristics, including genetic factors, influence an individual’s response
to supplementation, though currently these are not usually taken into account when advising
on whether a higher level supplementation is necessary for particular individuals. Further

research into this and into the way in which vitamin D status tracks through pregnancy,
would aid in dosing recommendations. Avoidance of vitamin D toxicity by over-
supplementation, which could cause harm, is also important – the Institute of Medicine
suggests that toxic effects can occur above the threshold of 125nmol/L, and recommend
avoidance of intakes above 4000IU/day.
In terms of obstetric outcomes, there is mixed and conflicting evidence on the benefits of
vitamin D supplementation in pregnancy. As 25(OH)D status is primarily determined by
environmental factors, confounding and reverse causality need to be considered when
evaluating obstetric studies; in addition, differences in covariates included in multivariate
models might explain the inconsistent findings. Whether these relatively rare obstetric
outcomes can truly be attributed to lower 25(OH)D must be established through carefully
designed intervention studies.
There is some evidence to support a positive relationship between vitamin D status and
offspring birthweight and offspring bone mass, but conflicting evidence still exists.
Intervention studies point towards a role for vitamin D in these offspring health outcomes,
particularly in women who are deficient or borderline deficient in vitamin D. Research is
ongoing into the mechanism by which vitamin D may be important in developmental
programming of later diseases, such as osteoporosis. The programming hypothesis may
present a potential approach to targeting and reducing the burden of diseases with a
developmental origin across a population, rather than an individual level. Double-blinded
RCTs with a lengthy follow-up periods, such as MAVIDOS, are required to further establish
the associations between vitamin D status in pregnancy and offspring health. To guide future
policy, research should evaluate several important factors. These include whether serum
25(OH)D levels improve maternal and offspring outcomes in populations with different diets
or skin pigmentation, establish the timing of initiation of therapy and its most effective and
safe dosage, and inform whether critical periods in pregnancy exist in the role of vitamin D
and its impact on the future health of both mother and offspring. Experimental techniques,
including epigenetic analyses, will be important in clarifying these underlying mechanisms.
Acknowledgements
We would like to thank the Medical Research Council (UK), National Institute for Health Research, Wellcome
Trust, Arthritis Research UK, National Osteoporosis Society (UK) and International Osteoporosis Foundation for
supporting this work. The work was also supported by the European Union's Seventh Framework Programme
(FP7/2007-2013), projects EarlyNutrition and ODIN under grant agreements numbers 289346 and 613977 and the
BBSRC (HDHL-Biomarkers: ALPHABET; BB/P028179/1). Sections from a PhD transfer thesis by Dr E Curtis
and a PhD thesis by Dr R Moon were used in the writing of this review.

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Figure 1.
Factors affecting response to 25(OH)D supplementation (1000 IU daily from 14 to 34
weeks) in the MAVIDOS trial. Adapted with permission from Moon et al 49.

Figure 2.
Associations between SNPs and change in 25(OH)D from 14 to 34 weeks of gestation
following supplementation with 1000 IU/d cholecalciferol. Shown as β and 95% CI. The
homozygous low-frequency allele was used as the reference group, with the β representing
the change in 25(OH)D (nmol/L) per common allele (additive model). Models were adjusted
for age, physical activity, smoking status, educational attainment, season of blood sampling,
compliance, and pregnancy weight gain. Adapted with permission from Moon et al, 2017 2

Figure 3.
Forest plot of the association between maternal vitamin D status and risk of pre-eclampsia
(observational studies (adjusted), ES, effect size). Reproduced with permission from Harvey
et al; Health Technology Assessment 2014 3

Figure 4.
Neonatal whole-body bone mineral content (BMC) of neonates born in the summer (June-
November) or winter (December-May) in the UK Southampton Women’s Survey. Data are
mean and 95% CI.

Figure 5.
Neonatal whole body bone mineral content (BMC), bone area and bone mineral density
(BMD) by intervention group and season of birth in the MAVIDOS trial. Data are shown as
mean and 95% confidence interval. Winter is December to February, spring is March to
May, summer is June to August and autumn is September to November.
Reproduced with permission from Cooper et al, 2016 2 and in accordance with a Creative
Commons Licence; https://creativecommons.org/licenses/by/4.0/; https://doi.org/10.1016/
S2213-8587(16)00044-9

Figure 6.
Percent DNA methylation at RXRA & offspring size corrected bone mineral content (a);
maternal 25(OH)D & RXRA DNA methylation (b). scBMC, size-corrected Bone Mineral
Content. Adapted with permission from Harvey et al, 20141

Guideline Countries Deficiency (nmol/l) Insufficiency (nmol/l) Sufficiency (nmol/l) Dietary

covered by recommendation
recommendation for vitamin D
intake in
pregnancy (IU)* -
RI +
Scientific Advisory UK <25 ≥25 400

Committee on
Nutrition (SACN)9
and UK
Department for
Health
Institute of USA and Canada < 30 30-50 ≥ 50 600
Medicine (IOM) 10
Endocrine Society Worldwide < 50 50-75 ≥ 75 600

Practice Guidelines
11
British Paediatric UK < 25 25-50 ≥ 50 Refers to SACN,

and Adolescent 400
Bone Group 12
Global Consensus Worldwide < 30 30-50 ≥ 50 600

Recommendations
on Prevention and
Management of
Nutritional Rickets
13
National UK < 30 30-50 ≥ 50 No recommendation

Osteoporosis
Society (UK) 14
Canadian Canada < 25 25-75 75-225 No recommendation

Paediatric Society
15
Working group of Australia and < 50 ≥ 50 No recommendation

the Australian and New Zealand At the end of winter
New Zealand Bone (level may need to be
and Mineral 10-20 nmol/l higher
Society, Endocrine at the end of
Society of Australia summer)
and Osteoporosis
Australia 16
NORDEN Nordic Nordic countries <30 ≥ 50 400

Nutrition
Recommendations
17
European Food EU countries < 50 ≥ 50 600

Safety Authority 18
* 400 IU cholecalciferol equivalent to 10 micrograms, +RI – Recommended Intake in low-risk individuals

Maternal Vitamin D Supplementation During Pregnancy

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Maternal Vitamin D Supplementation during Pregnancy

Sources of Data—Synthesis of systematic and narrative reviews.

Areas of Agreement and Controversy—The findings are generally inconsistent in most

Vitamin D in pregnancy: physiology and epidemiology

Br Med Bull. Author manuscript; available in PMC 2018 June 15.

decreasing proximal tubule phosphate reabsorption, and increasing 1,25(OH)2D synthesis.

During pregnancy, significant alterations to calcium and phosphate metabolism occur,

Br Med Bull. Author manuscript; available in PMC 2018 June 15.

was found to be effective in achieving vitamin D sufficiency throughout pregnancy without

Randomised controlled trials have clearly demonstrated that vitamin D supplementation in

Vitamin D and obstetric complications

Gestational hypertension & preeclampsia

Br Med Bull. Author manuscript; available in PMC 2018 June 15.

including vitamin D, in the development of PET. In addition, studies in humans have

Br Med Bull. Author manuscript; available in PMC 2018 June 15.

and insulin secretion. Immune dysfunction, through inflammatory dysregulation (cytotoxic

difference in 25(OH)D ranging from 3.9 to 7.4nmol/l. Furthermore, these meta-analyses

Preterm Delivery and Newborn Health

Br Med Bull. Author manuscript; available in PMC 2018 June 15.

gestation100, suggesting stratification of women by ethnicity in future intervention studies

Health of the newborn is often of interest in trials of vitamin D supplementation in

In all obstetric outcomes, it must be acknowledged that 25(OH)D status is primarily

caesarean section and preterm delivery111,112. Similarly, African-American women are

Several intervention studies assessing the effect of vitamin D supplementation on umbilical

Br Med Bull. Author manuscript; available in PMC 2018 June 15.

41,44,48,115,117–119. Nonetheless, vitamin D supplementation consistently reduced the

Vitamin D and Fetal Development

Br Med Bull. Author manuscript; available in PMC 2018 June 15.

Br Med Bull. Author manuscript; available in PMC 2018 June 15.

Similarly, Zhu et al found a positive relationship between maternal 25(OH)D status at 18

25(OH)D < 50 nmol/l compared to those above this level 148.

supplementation on offspring bone mineralisation was published. Sixty-four women of

Three more recently published studies of gestational vitamin D supplementation report on

Br Med Bull. Author manuscript; available in PMC 2018 June 15.

osteoporosis in later life 157.

Maternal pregnancy vitamin D status, epigenetics and developmental

Br Med Bull. Author manuscript; available in PMC 2018 June 15.

receptor and is essential in the nuclear action of 1,25(OH)2-vitamin D. Methylation at one

In this section, we have mainly focussed on epigenetic mechanisms associating vitamin D

Conclusions and knowledge gaps

Br Med Bull. Author manuscript; available in PMC 2018 June 15.

on whether a higher level supplementation is necessary for particular individuals. Further

Br Med Bull. Author manuscript; available in PMC 2018 June 15.

endocrinology and metabolism. 2017; 102(8):2941–9. [PubMed: 28575224]

Br Med Bull. Author manuscript; available in PMC 2018 June 15.

journal of clinical nutrition. 1995; 61(3):514–23. [PubMed: 7872214]

Br Med Bull. Author manuscript; available in PMC 2018 June 15.

women. J ClinEndocrinolMetab. 2003; 88(1):157–61.

Br Med Bull. Author manuscript; available in PMC 2018 June 15.

preeclampsia. Am J Obstet Gynecol. 2014; 210(2):149.e1–7. [PubMed: 24080305]

Br Med Bull. Author manuscript; available in PMC 2018 June 15.

Br Med Bull. Author manuscript; available in PMC 2018 June 15.

2009; 94(3):940–5. [PubMed: 19106272]

Br Med Bull. Author manuscript; available in PMC 2018 June 15.

Br Med Bull. Author manuscript; available in PMC 2018 June 15.

infants. Acta Paediatr. 2009; 98(8):1360–2. [PubMed: 19594476]

1749–57. [PubMed: 20139235]

Br Med Bull. Author manuscript; available in PMC 2018 June 15.

gene expression in the offspring. JNutr. 2005; 135(6):1382–6. [PubMed: 15930441]

Br Med Bull. Author manuscript; available in PMC 2018 June 15.

62). 2008. http://www.guidance.nice.org.uk/cg62

Br Med Bull. Author manuscript; available in PMC 2018 June 15.