Archives of Biochemistry and Biophysics 523 (2012) 3747

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Archives of Biochemistry and Biophysics

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Review

Vitamin D, the placenta and pregnancy

N.Q. Liu, M. Hewison
Department of Orthopaedic Surgery and Molecular Biology Institute, David Geffen School of Medicine at UCLA, 615 Charles E. Young Drive South, Los Angeles, CA 90095, USA

a r t i c l e

i n f o

Article history:
Available online 2 December 2011
Keywords:
Vitamin D
Preeclampsia
Preterm birth
Placenta
Decidua
VDR
CYP27B1
CYP24A1

a b s t r a c t
Impaired vitamin D status is common to many populations around the world. However, data suggest that
this is a particular problem for specic groups such as pregnant women. This has raised important questions concerning the physiological and clinical impact of low vitamin D levels during pregnancy, with
implications for classical skeletal functions of vitamin D, as well as its diverse non-classical actions.
The current review will discuss this with specic emphasis on the classical calciotropic effects of vitamin
D as well as the less well established immunological functions of vitamin D that may inuence pregnancy
outcome. The review also describes the pathways that are required for metabolism and function of vitamin D, and the various clinical complications that have been linked to impaired vitamin D status during
pregnancy.
2011 Elsevier Inc. All rights reserved.

Introduction
In the last 10 years there has been increased awareness of the
variability of vitamin D status in populations across the globe [1],
and a growing debate about the need for revised parameters for
vitamin D supplementation [2]. Recent reports by the Institute of
Medicine (IOM)1 have sought to clarify this by revising targets for
optimal vitamin D status, and recommended daily allowances for
safe intake of vitamin D [3]. However, it is important to recognize
that the IOM report focused specically on established calciotropic
and skeletal effects of vitamin D, and it remains unclear whether
similar guidelines will also apply to non-classical actions of vitamin D. Moreover, irrespective of the revised denitions for vitamin
D-sufciency and -insufciency, it is clear that sub-optimal
vitamin D remains a prevalent problem for 21st century society,
particularly for specic groups within the general population.
Prominent amongst these are pregnant women, where the functions of vitamin D appear to be diverse and complex. In the USA,
the 19881994 National Health and Nutrition Examination Survey
showed that 42% of African-American women of child-bearing age
were described as vitamin D-decient, with this being dened by
serum levels of the main circulating form of vitamin D (25-hydroxyvitamin D3, 25OHD3) less than 37.5 nM [4]. More recent studies of

vitamin D-deciency during pregnancy and lactation have underlined the magnitude of this problem [49]. For example, Bodnar
et al. showed that 83% of pregnant US black women and 47% of
pregnant white women were vitamin D-insufcient (<80 nM serum 25(OH)D3) at delivery, with similar values for neonates [5].
Studies of other populations in the USA [10,11], Canada [12,13],
the UK [14,15], Ireland [16], Europe [17], the Middle East and Asia
[1821], and Australia [15,22] have underlined the prevalence of
vitamin D-insufciency in pregnant women. In several of these reports it was observed that pregnant women with darker skin pigmentation were at even greater risk of low vitamin D status
when compared to pregnant women with lighter pigmented skin
[5,15,17,23]. The increasing evidence for vitamin D-insufciency
during pregnancy has prompted questions concerning the likely
physiological and clinical consequences of low serum levels of
25(OH)D3 for both the mother and fetus. A summary of the various
clinical problems that have been linked to maternal vitamin Dinsufciency during pregnancy is shown in Table 1. The aim of
the following review article will be to discuss our current understanding of the physiology of vitamin D during pregnancy, including both classical calciotropic actions and proposed non-classical
effects on inammation and immune function. The review will also
discuss the potential impact of low vitamin D status on pregnancy
outcomes, including adverse events such as preeclampsia and preterm birth.

Corresponding author. Fax: +1 310 825 5409.

E-mail address: mhewison@mednet.ucla.edu (M. Hewison).
Abbreviations used: IOM, Institute of Medicine; 25OHD3, 25-hydroxyvitamin D3;
1,25(OH)2D3, 1,25-dihydroxyvitamin D3; GcMAF, Gc protein-derived macrophageactivating factor; PTH, parathyroid hormone; FGF, broblast growth factor; PTHrP,
parathyroid hormone-related protein; uNK, uterine natural killer; GI, gastrointestinal;
TNFa, tumor necrosis factor a.
1

0003-9861/$ - see front matter 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.abb.2011.11.018

Vitamin D, reproduction and infertility

Vitamin D has been linked to fertility and reproduction at various stages of male and female reproductive function. Early studies

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N.Q. Liu, M. Hewison / Archives of Biochemistry and Biophysics 523 (2012) 3747

Table 1
Vitamin D and pregnancy: effects of vitamin D status and/or intake on maternal and
fetal health.
Clinical problem
Maternal
Preeclampsia
Bacterial vaginosis
Gestational diabetes
Preterm birth
Fetal/neonatal
Small for gestational age
Fetal skeleton/bone
Neonatal bone mass
Childhood bone mass
Asthma
Type 1 diabetes
Multiple sclerosis
Autism
Maternalfetal HIV transfer

Reference
[194,197201,237,238]
[23,186,239]
[18,240242]
[184,243,244]
[245,246]
[247]
[216,248250]
[115,251]
[218,235,252255]
[230,231]
[232]
[256]
[190]

using rat models demonstrated specic binding of the active form

of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), in several
reproductive tissues including the uterus [24], and testis [24,25],
with expression of uterine receptor for 1,25(OH)2D3, the vitamin
D receptor (VDR), being stimulated by estrogens [26]. More recent
reports have conrmed expression of VDR in human female [27],
and male [28] reproductive tissues. Signicantly these latter studies also described expression of the vitamin D-activating enzyme
25-hydroxyvitamin D-1a-hydroxylase (CYP27B1) and the catabolic
enzyme vitamin D-24-hydroxylase (CYP24A1) in the male and female reproductive tracts [27,28], suggesting an autocrine or paracrine mode of action.
The precise role of locally synthesized 1,25(OH)2D3 in reproductive tissue has yet to be fully dened but may involve effects on
uterine and follicle development. Knockout of the mouse VDR
(Vdr) or CYP27B1 (Cyp27b1) genes has been shown to result in
uterine hypoplasia, decreased ovarian size, compromised folliculogenesis, absent corpora lutea, and markedly reduced female fertility [29,30]. Mature ovarian follicles with follicular antrum were
detected in the ovaries of 7 week-old wild-type mice, but not in
Vdr null mice [30]. In a similar fashion, no ovulation was observed
in Cyp27b1 knockout mice [29]. The extent to which the ovarian
phenotypes associated with Vdr or Cyp27b1 gene knockout can
be attributed to direct effects of 1,25(OH)2D3 is unclear. For example, fertility in Vdr knockout mice can be restored by feeding a high
calcium diet [31]. Likewise, estrogen treatment has been shown to
increase uterine weight in Vdr null mice, indicating that a lack of
estrogen production in the Vdr null ovaries may contribute to
the altered uterine development [30]. In other models of dysregulated vitamin D function such as vitamin D-decient female rats,
fertility is reduced by 75% and litter sizes are diminished by 30%
[32]. Meanwhile, other studies have reported that women with
higher levels of vitamin D level in serum and follicular uid are signicantly more likely to become pregnant following in vitro fertilization-embryo transfer [33].
Another facet of vitamin D that may also contribute to infertility
is the vitamin D binding protein (DBP) which has been linked to
endometriosis [34], a disease involving the ectopic implantation
of endometrial glands and stroma in the peritoneal cavity. Endometriosis affects about 10% of all women and 40% of women with
infertility [35]. It is widely accepted that the retrograde menstruation and the subsequent adhesion of endometrial tissues in the pelvis is the major cause in the pathogenesis of endometriosis.
Current studies have speculated that this is due to the scavenger
function of peritoneal macrophages, with this activity being linked
to DBP [36,37]. DBP acts not only as a carrier of vitamin D metabolites, but also a potent activator of macrophages in the form of Gc

protein-derived macrophage-activating factor (GcMAF) [38,39].

GcMAF can activate the scavenger function of macrophage
[39,40] without inducing the inammatory cytokines release from
macrophage [41]. Among the three major Gc genotypes/phenotypes of DBP, the Gc1F and Gc1S alleles are much more readily converted to GcMAF, whereas this activity is not observed with the
Gc2 allele [42]. A cross-sectional study reported that the Gc2 allele
is more prevalent in endometriosis patients and speculated that
the inability to promote GcMAF function in those carrying this allele may contribute to the implantation of endometriotic tissues
outside the uterus [34].
Vitamin D may also play a key role in fertility via effects on
maternal decidualization and trophoblast implantation, and these
effects are described later in the review.

Vitamin D metabolism in the placenta

In classical vitamin D endocrinology metabolism of pro-hormone
25(OH)D3 to active 1,25(OH)2D3, occurs primarily in the kidneys,
with proximal tubule cells expressing the enzyme that catalyzes this
conversion, CYP27B1. However, it is now clear that expression of
CYP27B1 is common to many other tissues outside the kidney
[43]. Prominent amongst these is the placenta which was identied
as a major extra-renal site for conversion of 25OHD3 to 1,25(OH)2D3
more than 30 years ago [44,45]. In these studies, primary tissue from
the both the maternal decidual and fetal placental (trophoblastic)
components of the placenta demonstrated 1a-hydroxylase activity,
and subsequent in vitro investigations showed that cultured human
syncytiotrophoblasts and decidual cells are also able to synthesize
1,25(OH)2D3 [4549]. The spatio-temporal organization of placental
CYP27B1 and the VDR across gestation has also been characterized,
conrming that the enzyme and receptor are localized to both the
maternal and fetal parts of the placenta. Signicantly, expression
of both CYP27B1 and VDR is more abundant in 1st and 2nd trimester
tissue relative to non-pregnant endometrial tissue and term placentas [50,51]. Co-expression of VDR, in both decidua [52] and trophoblast [53] supports the hypothesis that 1,25(OH)2D3 produced
by the placenta functions in a localized autocrine or paracrine fashion, rather than the endocrine synthesis observed in the kidney (see
Fig. 1) [50].
Renal synthesis of 1,25(OH)2D3 is tightly controlled by regulators such as parathyroid hormone (PTH) and broblast growth factor (FGF) 23 which inuence CYP27B1 transcription [54]. However,
renal activation of 25(OH)D3 is also strongly regulated by the vitamin D catabolic enzyme CYP24A1, which converts 25OHD3 and
1,25(OH)2D3 to less potent 24-hydroxylated metabolites [55]. By
contrast, in placenta, catabolic CYP24A1 activity appears to be
uncoupled from CYP27B1-mediated activation. Expression studies
have shown decreased levels of mRNA for CYP24A1 during early
stages of gestation [50]. More recent DNA analysis of placental tissue has shown that this may be due to gene silencing, as the
CYP24A1 gene promoter is methylated in this tissue [56]. The
resulting decrease in basal CYP24A1 promoter activity reduces
expression of the 24-hydroxylase enzyme, thereby preventing catabolic regulation of local 1,25(OH)2D3 production. This epigenetic
regulation of CYP24A1 is placenta-specic and not detected in
other somatic human tissues including umbilical cord tissue [56].
The conclusion from this seminal observation is that during pregnancy placental CYP27B1 activity occurs without any concomitant
CYP24A1-mediated catabolism. In this way, synthesis of active
1,25(OH)2D3 by the placenta will be maximized at the fetomaternal
interface (Fig. 1).
The physiological relevance of unfettered placental synthesis of
1,25(OH)2D3 is not entirely clear. During pregnancy circulating
levels of 1,25(OH)2D3 are elevated [57,58], and recent supplemen-

N.Q. Liu, M. Hewison / Archives of Biochemistry and Biophysics 523 (2012) 3747

39

Fig. 1. Vitamin D metabolism and function during pregnancy. Schematic showing vitamin metabolism and key functional responses in maternal, placental and fetal systems.
Conversion of pro-hormone 25-hydroxyvitamin D3 (25(OH)D3) to 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in maternal kidneys catalyzed by the enzyme 25-hydroxyvitamin
D-1a-hydroxylase (CYP27B1) supports elevated serum levels of 1,25(OH)2D3 during pregnancy. However, this does not readily cross the placenta. Expression of CYP27B1 and
the vitamin D receptor (VDR) in maternal and fetal components of the placenta supports extra-renal synthesis of 1,25(OH)2D3 during pregnancy. In the fetal trophoblast, this
is enhanced by gene silencing of the catabolic enzyme vitamin D 24-hydroxylase (CYP24A1). The putative function of enhanced placental synthesis of 1,25(OH)2D3 appears to
be immunomodulatory.

tation trials have shown that this is strongly inuenced by the

availability of substrate for CYP27B1, namely serum 25(OH)D3
[59]. However, the source of this enhanced vitamin D activation
has yet to be fully dened, although animal studies indicate that
the rise in maternal serum 1,25(OH)2D3 is due to increased synthesis of this metabolite rather than decreased renal clearance [60,61].
Serum levels of 1,25(OH)2D3 during pregnancy may involve 1ahydroxylase activity in the maternal kidneys and/or placenta. The
increased expression of CYP27B1 and VDR in placental and decidual cells, as well as methylation-silencing of placental CYP24A1,
may has the potential to contribute to elevated maternal levels
of 1,25(OH)2D3 [62]. Indeed, studies using nephrectomized rats injected with 25(OH)D3 indicate that a small amount of the
1,25(OH)2D3 produced by the placenta is able to enter the maternal
circulation [63]. However, experiments using autosomal recessive
CYP27B1-decient models indicate that maternal kidneys are
likely to be the major source of increased maternal serum
1,25(OH)2D3 observed in pregnancy. Specically, Hannover pigs
that are homozygous for CYP27B1 deciency show no increase in
serum 1,25(OH)2D3 across gestation, even when pregnant with
heterozygous CYP27B1-expressing offspring [64]. Likewise, a case
report of a pregnant woman with impaired renal function showed
that during pregnancy her serum levels of 1,25(OH)2D increased
slightly but were much lower than those observed for normal pregnant women [65]. Similar observations have also been reported for
a pregnant woman with non-functioning kidneys receiving pharmacological doses of vitamin D2 [66]. Despite presenting with extremely high serum levels of 25(OH)D3 and normal capacity for

placental activation of vitamin D, the woman exhibited relatively

low serum levels of 1,25(OH)2D.
The underlying mechanism for increased renal production of
1,25(OH)2D3 in pregnant women is also unclear but, unlike adults,
appears to be independent of a rise in maternal PTH [6771].
Maternal CYP27B1 activity may be regulated by other activators
of the enzyme including parathyroid hormone-related protein
(PTHrP), estradiol, prolactin and placental lactogen [7274], all of
which are increased in pregnancy and which may help explain
the rise in maternal 1,25(OH)2D3 independent of PTH. Likewise,
calcitonin an important component of calcium homeostasis during
pregnancy [75], is known to promote transcription of CYP27B1
[76,77], and may therefore be a key determinant of placental vitamin D metabolism. Irrespective of the mechanism for increased
maternal 1,25(OH)2D3, it is important to recognize that this metabolite does not readily cross the placenta and fetal levels of
1,25(OH)2D3 are generally lower than in the mother [7882]. By
contrast, umbilical artery levels of 1,25(OH)2D3 are slightly higher
than umbilical venous levels, suggesting a role for fetal kidneys in
generating fetal serum 1,25(OH)2D3 [83]. In support of this, studies
using rats have shown that precursor 25(OH)D3 readily crosses the
hemochrial placenta [84] and similar transport is thought to occur
in humans. As a consequence, fetal levels of 25(OH)D3 are similar
to those found in the mother, so that fetal concentrations of
1,25(OH)2D3 are likely to be dependent of fetal-specic expression
and activity of CYP27B1. The fetal kidneys and fetal parts of the
placenta express CYP27B1 and can thus metabolize 25(OH)D3 to
1,25(OH)2D3 [85,86]. Fetal nephrectomy has been shown to lower

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N.Q. Liu, M. Hewison / Archives of Biochemistry and Biophysics 523 (2012) 3747

fetal levels of 1,25(OH)2D3 in sheep and rat models [87], further

emphasizing the importance of the fetal kidneys in maintaining
circulating levels of active vitamin D.
Function of vitamin D binding protein during pregnancy
Vitamin D and its metabolites are hydrophobic, the majority
being transported in the circulation through association with their
serum carrier DBP, with a small portion being associated with albumin and/or lipoproteins [88]. Serum levels of DBP increase between
46% and 103% during pregnancy [89], suggesting that DBP may play
a role in directing vitamin D metabolism and function during pregnancy. One possibility is that the rise in DBP is linked to the elevated
levels of circulating 1,25(OH)2D3 that are characteristic of pregnant
women [57,58]: serum levels of DBP in pregnant women have been
correlated with total serum levels of 1,25(OH)2D3 [90]. As a consequence of this rise in DBP concentration, the % of free (non-DBPbound) 1,25(OH)2D3 decreases during pregnancy, although the total
level of free 1,25(OH)2D3 is signicantly elevated [90]. Recent studies have shown that, unlike the maternal circulation, cord blood levels of 25(OH)D3 correlate with 1,25(OH)2D3 [91], indicating a
system for regulating vitamin D metabolism that is distinct from
the mother. In a similar fashion, concentrations of cord blood
1,25(OH)2D3 are not elevated during pregnancy in the same way
as the maternal blood, although there is a slight decrease in cord
blood levels of DBP, leading to a slight increase in cord blood free
1,25(OH)2D3 at gestational week 40 [57]. The signicance of this is
unclear but is suggestive of different physiological use of
1,25(OH)2D3 between the mother and fetus.
In contrast to 1,25(OH)2D3, maternal levels of total 25(OH)D3 remain fairly constant across pregnancy and thus the elevated DBP
levels result in a pronounced decrease in maternal free 25(OH)D3
early in pregnancy [57]. It is therefore possible that the increased
maternal production of 1,25(OH)2D3 early in gestation acts to compensate for the decreased maternal free 25OHD. DBP has higher
binding afnity for 25(OH)D3 than 1,25(OH)2D3, and in kidney epithelial cells DBP plays a pivotal role in vitamin D endocrinology by
facilitating the recovery of 25(OH)D3 from the glomerular ltrate.
In proximal tubule cells, 25(OH)D3 bound to DBP binds to the cell
surface megalin/cubilin receptor complex and is then internalized
via receptor-mediated endocytosis prior to activation by CYP27B1
in these cells [92]. Megalin/cubilin-mediated endocytosis of DBP
has also been reported for the import of 25(OH)D3 into other
CYP27B1-expressing target tissues, such as breast epithelial cells
[93]. However, for most other target cells the biological activity of
vitamin D metabolites appears to be in agreement with the free
hormone hypothesis, which states that unbound molecules achieve
their effects by simple diffusion across the plasma membrane [94].
As yet it is unclear whether vitamin D metabolites enter placental
cells by megalin-mediated endocytosis of DBP25(OH)D3, by diffusion of free hormone, or a combination of both mechanisms. Expression of megalin has been reported in the placenta [95], and appears
to be involved in placental recycling of albumin [96] but a functional
link with DBP has yet to be described. Nevertheless, it is possible to
speculate that the elevated production of DBP early pregnancy acts
to facilitate transfer of 25(OH)D3 (bound to DBP) via a magalinmediated mechanism similar to that characteristic of the kidney.
Vitamin D and the regulation of mineral homeostasis during
pregnancy
Adult humans depend on circulating concentrations of vitamin
D metabolites for maintaining bone health. Without sufcient serum 25(OH)D3 and renal synthesis of hormonal 1,25(OH)2D3, the
body cannot absorb calcium and phosphorus adequately, resulting

in hypocalcemia and secondary hyperparathyroidism associated

with skeletal calcium absorption. Calcium demands in pregnancy
are high and act to support both maternal calcium homeostasis
and fetal development and growth. Studies using rat models have
shown that the maternal rise in intestinal absorption of calcium
occurs by mid-pregnancy, prior to the onset of skeletal mineralization in the fetus [97]. This early increase in intestinal calcium uptake may allow the pregnant mother to accumulate calcium before
the peak fetal demand late in pregnancy [98]. Inadequate acquisition of calcium early in pregnancy may lead to a net loss of maternal skeletal calcium in later pregnancy. Maternal vitamin D
deciency has been found to cause skeletal demineralization
[99], and may also affect maternal bone turnover [100]. Markers
of bone formation and reabsorption in humans indicate that
maternal bone turnover is probably low in the rst half of pregnancy, with a potential increase in the third trimester. This corresponds to the time of peak calcium transfer to the fetus and may
result from mobilization of skeletal calcium stores to help supply
the fetus.
During fetal development, calcium and phosphorus are actively
transported across the placenta [101103], although the role of
1,25(OH)2D3 in this process is unclear [104]. Human fetuses typically accrete 2130 g of calcium by term, and 80% of this is accumulated in the third trimester [105]. In contrast to the situation
in adults, 1,25(OH)2D3 does not appear to be necessary for normal
fetal calcium homeostasis and bone mineralization [101]. Studies
using the Vdr knockout mice have shown that 1,25(OH)2D3 signaling is not essential for fetal skeletal mineralization [106], or maternal intestinal calcium uptake [107]. Other animal models have
shown that in the presence of maternal hypocalcemia due to
severe vitamin D deciency, fetuses maintain normal blood calcium and phosphate levels and have fully mineralized skeletons
at term [64,108111]. In humans recent reports have shown that
at term the cord blood calcium and skeletal mineralization are normal in fetuses of vitamin D-decient mothers [112,113]. However,
recent studies describing high-resolution 3D ultrasound analysis of
pregnant women showed that maternal vitamin D-insufciency
was associated with altered fetal skeletal function. Specically, fetuses from vitamin D-insufcient mothers had increased femur
metaphyseal cross-sectional area and femur splaying index,
whereas femur length showed no changes [114]. These data were
the rst to show in utero changes in skeletal morphology associated with vitamin D status, but also add to previous studies by
the authors showing that children born to mothers with vitamin
D insufciency during pregnancy exhibit decits in bone mineral
content at 9 years of age [115]. Whilst this is the rst study of its
kind to describe changes in fetal skeletal morphology relative to
maternal vitamin D status, the association cannot necessarily be
assumed to be causal. The precise mechanism by which changes
in maternal 25(OH)D3 affects the fetal skeleton remain unclear,
but it was interesting to note that differences in skeletal development occurred as early as week 19 of gestation, coincident with the
gestational rise in maternal levels of active 1,25(OH)2D3.

Extra-skeletal effects of vitamin D during pregnancy

For many years it was assumed that the rise in maternal serum
1,25(OH)2D3 at the end of the rst trimester of pregnancy functions
primarily to modulate maternal or fetal calcium homeostasis.
However, studies of CYP27B1-decient animals [64,116] and an
anephric pregnant woman [65] suggest that the maternal renal
vitamin D system is still likely to be the major contributor to the
gestational rise in serum 1,25(OH)2D3 [104]. The question therefore arises as to function of the extensive capacity for activation
of vitamin D via placental expression of CYP27B1. The parallel

N.Q. Liu, M. Hewison / Archives of Biochemistry and Biophysics 523 (2012) 3747

induction of CYP27B1 and VDR in the placenta suggests that some

functions of vitamin D at the fetalmaternal interface are intracrine or paracrine [117]. One possible explanation is that
1,25(OH)2D3 acts as a locally synthesized regulator of placental
calcium transport, contrasting its classical endocrine effects on
calcium homeostasis [117]. However, in keeping with the many recent studies describing non-classical actions of extra-renal
1,25(OH)2D3 production [118], it is also possible that some key
functions of vitamin D during pregnancy are not directly associated
with calcium homeostasis and skeletal development.

Vitamin D, implantation and placental inammation

The process of implantation requires a functionally normal conceptus, a receptive endometrium, and a highly coordinated interaction between these two tissues [119]. Specically the embryonic
trophoblast establishes contact with, and invades the decidual
endometrium of the maternal uterus [120]. The uterine immune
system appears to be very important for control of normal blastocyst invasion and trophoblastic growth and differentiation [119],
with a successful pregnancy being dependent on maternal tolerance of paternal antigens present in the placenta and fetus itself.
Consequently, appropriate immunomodulation at the fetal
maternal interface is critical to the process of implantation [121].
Approximately 40% of all cells in the maternal decidual part of
the placenta are immune cells including of CD56+CD16-uterine
natural killer (uNK) cells, T lymphocytes (T cells), and macrophages, highlighting the important role of these cells in regulating
maternal mucosal function and the control of trophoblast invasion
[119]. With this in mind, and the known immunomodulatory properties of vitamin D, it has been hypothesized that local synthesis of
1,25(OH)2D3 in the placenta could act to promote successful
engraftment and growth of the fetalmaternal unit [122]. Although
a role for vitamin D in regulating implantation was rst postulated
more than 50 years ago [123], it was only much later that potential
mechanisms for this were proposed. These include animal studies
showing that administration of active 1,25(OH)2D3 promotes
endometrial decidualization [124]. However, more recent approaches have focused on two specic mechanisms for vitamin D
function at the fetalmaternal interface, with locally synthesized
1,25(OH)2D3 acting either as an immunomodulator, or as an
intracrine/paracrine regulator of implantation genes.
The proposed immunomodulatory function for vitamin D
during pregnancy [122] is based, in part, on the ability of
1,25(OH)2D3 to regulate immune function [125128]. Both the
receptor for 1,25(OH)2D3, VDR, [126,129,130] and CYP27B1,
[125,131,132] are expressed by cells from the immune system.
The presence of CYP27B1 in macrophages [133] and dendritic cells
[134] indicates that local synthesis of 1,25(OH)2D3 is central to the
immunomodulatory effects of vitamin D. These include effects on
adaptive immunity, with 1,25(OH)2D3 promoting more benign, humoral, type 2 helper T cell (Th2) responses whilst suppressing cellular Th1 responses [135,136]. In addition, 1,25(OH)2D3 enhances
tolerogenic immunity by inducing immunosuppressive regulatory
T cells (Treg) [137], whilst down-regulating inammation through
inhibition of interleukin-17 secreting Th17 cells [138]. However, in
spite of these observations there have been relatively few studies
of vitamin D-mediated immunomodulation during pregnancy. In
common with other cells from the immune system, uNK cells are
potently regulated by 25(OH)D3 or 1,25(OH)2D3 in vitro, with both
metabolites acting to suppress inammatory cytokine production
by the uNK cells [139]. Similar observations have also been reported for cultured trophoblastic cells [140], suggesting that vitamin D may act as a generalized anti-inammatory agent during
pregnancy.

41

Recent studies using mouse models of pregnancy have emphasized the contribution of the placental vitamin D system to antiinammatory responses in this tissue. Pregnant mice challenged
in vivo with the immunogen lipopolysaccharide (LPS), a toll-like
receptor (TLR) ligand, showed increased placental expression of
mouse Cyp27b1 and Vdr [141]. This was consistent with previous
studies showing LPS induction of CYP27B1 and VDR in human
monocytes [142144] and indicates a potential immunomodulatory function for the vitamin D system in the placenta. The importance of the latter is endorsed by further studies in which male and
female mice heterozygous for Cyp27b1 or Vdr were mated to generate fetuses with complete ablation of these genes. Placentas from
knockout fetuses showed no expression of Cyp27b1 or Vdr in fetal
(trophoblastic) cells, and demonstrated a complete dysregulation
of inammatory responses following immune challenge with LPS
[141]. Conversely, in the presence of 25(OH)D3 or 1,25(OH)2D3
wild type placentas showed suppressed inammatory responses
to LPS challenge [141]. These data strongly suggest that a key function of vitamin D during pregnancy is to support normal immune
responses and thereby minimize the detrimental effects of inammation at the fetalmaternal interface (Fig. 1).
The rst putative model for vitamin D and implantation proposed that induction of CYP27B1 at the fetalmaternal interface
by inammatory cytokines provides a mechanism for enhancing local concentrations of 1,25(OH)2D3 [119]. This, in turn, could act to
promote key factors associated with successful implantation,
including calbindin-D9K, a key vitamin D target gene which is
important in the process of implantation [145]. Other vitamin D target genes associated with implantation include HOXA10 [145],
which is expressed in both the embryonic and the adult reproductive tracts, predominantly in the uterus [146]. HOXA10 is necessary
for embryo implantation and fertility, as well as hematopoietic
development, and HOXA10 knockout mice show defective decidualization [147,148]. Direct up-regulation of HOXA10 mRNA and
protein expression by 1,25(OH)2D3 is mediated via a functional
vitamin D response element (VDRE) in the 50 regulatory region of
the HOXA10 gene promoter [147]. Studies in vitro have shown that
vitamin D can also stimulate synthesis of hormones involved in
pregnancy such as estradiol, progesterone, and hCG [149,150].
Given the importance of these hormones in maintaining the regulation of uteroplacental blood ow, placental neovascularization,
maternal immunotolerance to the fetal allograft [151], this is likely
to be another important function for vitamin D at the fetal
maternal interface early in pregnancy.
Vitamin D and bacterial killing during pregnancy
Vitamin D also promotes innate immune responses, most notably by stimulating antimicrobial activity [152,153]. In cells such as
monocytes, expression of VDR and CYP27B1 is potently induced following TLR activation [154]. The resulting increase in local synthesis of 1,25(OH)2D3 is then able to trigger vitamin D responses via
interaction with endogenous VDR, leading to transcriptional regulation of monocyte target genes. These include the antimicrobial
proteins, cathelicidin [155], and b-defensin 2 [156], which enhance
intracellular killing of bacteria. Furthermore, vitamin D has also
been shown to act as a promoter of autophagy, a cytosolic process
that promotes the autophagosomal environment for pathogen
killing [157]. All of these antibacterial responses appear to be
dependent on intracrine production of 1,25(OH)2D3, with this
mechanism, in turn, being dependent on the availability of substrate 25(OH)D3 for CYP27B1. As 25(OH)D3 is the major circulating
form of vitamin D, the innate antimicrobial effects of vitamin D will
therefore be highly inuenced by patient vitamin D status. This was
conrmed by studies using monocytes cultured in the presence of
serum from vitamin D-sufcient donors which showed much

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higher levels of cathelicidin expression compared to monocytes

cultured with vitamin D-insufcient serum [154]. Similar observations have also been made using serum from vitamin D-insufcient
subjects supplemented with vitamin D to restore optimal vitamin D
status [158]. In this case, the effect of vitamin D supplementation
was dependent on increased serum 25(OH)D3, with no observable
changes in circulating levels of 1,25(OH)2D3 [158].
Although studies of vitamin D-induced antibacterial activity
have focused primarily on monocytes and macrophages, it is
important to recognize that a wide range of cell types express TLRs
and have the necessary machinery to respond to infection. These
include granulocytic cells such as neutrophils which provide a rapid response to infection and inammation, and which also show
1,25(OH)2D3-induced antibacterial activity [159]. Other studies
have demonstrated the induction of CYP27B1 in keratinocytes as
part of a mechanism to promote epidermal antimicrobial responses following wounding of the skin [160]. In a similar fashion,
CYP27B1 expression has been reported in the gastrointestinal (GI)
tract [43], and this may play a role in mediating immune responses
and protection against inammation within the GI tract [161,162].
With these observations in mind, it seems likely that CYP27B1 will
fulll a similar barrier function during pregnancy.
The link between vitamin D and immune function during gestation is endorsed, in part, by the heterogeneous cells that make up
the placenta [163]. For example, within maternal decidua, expression of CYP27B1 is not restricted to decidualized stromal cells but
is also detectable in decidual macrophages [51,164]. Maternal and
fetal cells are able to mediate both innate [165167] and adaptive
[163,168] immunity, so that vitamin D may inuence both of these
arms of the immune system during pregnancy, including implantation, as well as responses to infection and inammation. In vitro
studies using primary human placental tissue and cells have
shown that treatment with 25(OH)D3 and its intracrine conversion
to 1,25(OH)2D3 induces expression of antimicrobial cathelicidin in
both maternal decidua [139] and fetal trophoblast [169]. In the latter, 25(OH)D3-mediated induction of cathelicidin also stimulated
killing of Escherichia coli, emphasizing the importance of this
mechanism as part of the placental response to infection. Other
studies have shown a similar link between vitamin D and cathelicidin in monocytes from cord blood, suggesting a broader benet of
vitamin D-induced innate immunity in protecting the fetus and
new born babies [91].
Vitamin D deciency and adverse outcomes of pregnancy
The increasing evidence for global vitamin D-insufciency during pregnancy raises the question of the possible physiological and
clinical consequences of impaired maternal vitamin D status during pregnancy. As outlined in Section 5, it is likely that some effects
of maternal vitamin D-insufciency will be manifested through its
classical effects on fetal skeletal development in utero [114].
However, there is now increasing evidence that vitamin D has a
much wider range of activities during pregnancy, with broader
clinical consequences for vitamin D-insufciency. A summary of
the various clinical problems that have been linked to maternal
vitamin D-insufciency during pregnancy is shown in Table 1.
These include effects on both maternal and fetal physiology, and
incorporate classical and non-classical responses to vitamin D. In
the remainder of the current section the effects of vitamin D status
on maternal infection, preterm birth, preeclampsia, and fetal
development and programming are discussed in greater detail.
Vitamin D, infection, inammation and preterm birth
A strong body of evidence has implicated infection in the pathogenesis of preterm (<37 weeks of pregnancy) and early preterm

(<34 weeks of pregnancy) delivery. This includes animal studies

where administration of microorganisms or microbial antigens induces preterm delivery [170]. In addition, there are extensive clinical data showing increased risk of prematurity in pregnant women
with systemic infection such as kidney infection with E. coli,
malaria and typhoid fever as well as intrauterine infection
including chorioamnionitis [171173]. More recently, periodontal
infection has been postulated to be a risk factor for preterm delivery [174]. Preterm delivery caused by infection is believed to result
from the actions of pro-inammatory cytokines secreted as part of
the maternal and/or fetal host response to microbial invasion
[175178]. Enhanced expression of pro-inammatory cytokines
such as interleukin (IL)-1, IL-6 and tumor necrosis factor a (TNFa)
is associated with preterm delivery [179], and these factors have
been detected in elevated concentrations in the amniotic uid,
serum and gestational tissues of women with preterm babies
[180]. The pro-inammatory cytokines can be induced by a number of stimuli, including bacterial endotoxins, and they have been
shown to promote spontaneous labor and premature rupture of
membranes (PROM) via their actions on the gestational tissues
[181183].
Maintenance of normal pregnancy requires efcient coordination of antimicrobial and anti-inammatory responses within the
fetalplacental unit [176,177]. It is therefore possible to speculate
that vitamin D plays a signicant role in modulating both of these
processes, thereby helping to maintain a normal, healthy pregnancy. However, there have been relatively few studies to address
this. One report has described a high prevalence of vitamin
D-insufciency in preterm infants [184], while another nested control trial showed no link between maternal vitamin D status and
preterm birth [185]. Other epidemiology studies have shown that
maternal vitamin D-insufciency is associated with increased rates
of bacterial vaginosis in the 1st trimester of pregnancy [186].
Bacterial vaginosis is an over-growth of the natural vaginal microora by mixed anaerobic bacteria that can lead to infection of other
tissue such as the placenta (chorioamnionitis) and potentially detrimental inammatory responses [187]. This type of infection is
one of the most important risk factors for adverse events in pregnancy and has been linked to preterm birth, PROM and perinatal
infection [176]. In view of the potent antibacterial properties of
vitamin D, it seems likely that local conversion of 25(OH)D3 to
1,25(OH)2D3 will help to prevent or minimize infection in both
vaginal tissue and the placenta.
The precise mechanisms associated with vitamin D-mediated
antibacterial and/or antiviral activity in the placenta have yet to
be fully dened. In humans vitamin D-induced expression of
trophoblastic cathelicidin has been shown to promote intracellular
killing of E. coli in trophoblasts [169]. However, it is unclear
whether this mechanism is universal. The induction of antibacterial
proteins such as cathelicidin by vitamin D requires the presence of
specic VDRE in target gene promoters, and these have been shown
to restricted to higher primates, with other mammals such as mice
showing no equivalent induction of antibacterial proteins [188].
This suggests that vitamin D regulation of this antibacterial innate
immunity is a relatively recent evolutionary development,
although it is important to recognize that non-primates may use
vitamin D to induce alternative antibacterial mechanisms, including induction of the reactive oxygen species such as nitric oxide
[189].
Vitamin D-insufciency has also been linked to increased risk of
maternal to child transmission (MCTC) of human immunodeciency virus (HIV) [190]. In the latter study the authors proposed
that the lower levels of MCTC in vitamin D-sufcient women
may be due to improved innate immune response to infection.
Given the fundamental role of the placenta in vertical transmission
of HIV from mother to the fetus [191], it is possible to speculate

N.Q. Liu, M. Hewison / Archives of Biochemistry and Biophysics 523 (2012) 3747

that vitamin D-induced innate immune responses within the placenta may play a role in combating MCTC of viral infections in general. Another link between vitamin D and spontaneous preterm
birth comes from proteomic studies showing increased levels of
DBP in human cervicalvaginal uid from women who experienced preterm labor [192]. The functional signicance of this is unclear but elevated levels of DBP during pregnancy may inuence
the function of vitamin D metabolites, notably 25(OH)D3.
Vitamin D deciency and preeclampsia
Preeclampsia is a common and serious complication of pregnancy affecting 310% of pregnancies worldwide [193]. It is a leading cause of maternal death and a major contributor to maternal
and perinatal morbidity. Preeclampsia is characterized by maternal
hypertension and proteinuria, which is associated with shallow
trophoblast invasion, impaired spiral artery remodeling, reduced
placental perfusion, oxidative stress, and increased inammatory
responses [194196]. Epidemiology suggests that there is a strong
link between vitamin D-insufciency and preeclampsia [197201].
Likewise, a cohort study of nulliparous pregnant women in Norway
showed a 27% reduction in risk of preeclampsia in women taking
vitamin D supplements relative to those who did not take supplements [194]. However, not all studies have demonstrated association between vitamin D status, gestational blood pressure and
subsequent preeclampsia [202]. Moreover, as yet, there have been
no blinded prospective trials to assess the possible protective effects of enhanced maternal vitamin D status with respect to
preeclampsia.
The precise mechanism by which vitamin D may inuence the
pathophysiology of pre-eclampsia is at present unclear, although
dysregulation of the vitamin D-activating enzyme CYP27B1 has
been described in trophoblastic cells from the placentas of preeclampsia mothers [203]. Maternal vitamin D status may inuence
preeclampsia through a variety of mechanisms including immunomodulatory, inammatory and angiogenic responses [204,205].
However, although the immunomodulatory properties of 25(OH)
D3 and 1,25(OH)2D3 have been proposed as a potential functional
link between vitamin D and preeclampsia [206], there have been
few if any functional studies to investigate this. Vitamin D may also
inuence preeclampsia through regulation of the renin-angiotensin
system (RAS) [196,207]. RAS is a regulatory cascade that plays a key
role in regulating blood pressure, electrolyte balance, and homeostasis, and inappropriate stimulation of the RAS has been associated
with hypertension, heart attack, and stroke. Therefore, tight regulation of renin synthesis and secretion is essential for effective regulation of blood pressure [208]. Renin cleaves angiotensinogen to
angiotensin-I (ANG I), which is then further cleaved by the enzyme
angiotensin-converting enzyme (ACE) to biologically active angiotensin-II (ANG II) [196]. Several recent studies have shown that serum levels of 1,25(OH)2D3 are inversely associated with blood
pressure or plasma renin activity [208213], with vitamin D acting
as a negative endocrine regulator of the RAS by direct transcriptional
suppression of renin gene expression [208]. Studies of the Vdr gene
knockout mouse have shown that VDR ablation activates the RAS
and leads to accumulation of ANG II and subsequent more severe renal damage in the renal brosis model [214].
There are two major types of angiotensin receptors: AT1 and
AT2. Activation of AT1 induces vasoconstriction, sympathetic activity, aldosterone release, and in doing so increases blood pressure,
whereas AT2 is involved in fetal tissue development [196].
Trophoblasts are rich in AT1 receptors and responsive to the ANG
II in the circulation. Multiple genes are regulated by AT1 receptor
signaling and include those encoding secreted proteins associated
with trophoblast invasion and angiogenesis [196]. RAS is believed
to play a critical role in regulation of placental blood ow and

43

fetoplacental circulation and appears to be a key factor in the initiation of preeclampsia [196]. Studies of transgenic rats expressing
the human angiotensinogen and renin genes demonstrated hypertension, proteinuria, and AT1-AA production during pregnancy
[207], underlining the critical role of renin in the development of
preeclampsia. In this way it is possible that increased renin activity
in pregnant women with low serum vitamin D may provide a
mechanism linking vitamin D and preeclampsia.
Vitamin D, fetal development, and programming
Vitamin D is involved in the regulation of cellular differentiation and apoptosis and can exert effects on fetal skeletal growth,
development of the immune system, and the brain. As fetal vitamin
D status is dependent on maternal levels of serum 25(OH)D3 [215],
it is clear that maternal vitamin D deciency during pregnancy
may affect growth and development in utero. This is illustrated
by recent studies of the link between maternal vitamin D status
and fetal skeletal growth detailed in Section 5 [114]. However,
maternal levels of vitamin D during pregnancy may also inuence
health of offspring during infancy, and in later life [62]. Children
born to mothers with vitamin D insufciency during pregnancy exhibit decits in bone mineral content at 9 years of age [115]. A prospective cohort study has also shown that maternal vitamin D
status affects bone growth in early childhood [216]. In this case
postnatal vitamin D supplementation to improve the vitamin D
status of children only partly ameliorated the differences in bone
growth induced by maternal vitamin D status during the fetal period. As a consequence the authors concluded that intrauterine deciency of vitamin D may have permanent consequences despite
improved postnatal nutrition. Adverse effects of maternal vitamin
D insufciency do not appear to be restricted to the classical skeletal effects of vitamin D. For example, several reports have linked
maternal vitamin D with altered fetal lung and/or immune development, and childhood asthma and respiratory tract infection
[201,217221].
In addition to effects on fetal development and childhood diseases outlined above, it has also been suggested that vitamin Dinsufciency in utero may have an impact on diseases in later life
in other words fetal programming of adult disease [222].
Gestational vitamin D insufciency has been linked to a range of
adult-onset disorders, such as, osteoporotic bone disease [223], altered brain development and adult mental health [224229], autoimmune disease [230232], asthma [218,233,234], and food
allergies [217,218,233,235]. Fetal programming requires a critical
window during fetal development in which the fetus is particularly
sensitive to changes that persist throughout the adulthood [222].
Therefore, low vitamin status during this critical window may have
a persisting impact on adult health outcomes [222]. At present the
hypothesized role of vitamin D in fetal programming is based primarily on epidemiology. However, in the coming years it is highly
likely that this will be claried by more functional studies that further explore the molecular cellular mechanisms of actions of vitamin D at the fetalmaternal interface during pregnancy. The
controlled, prospective studies with vitamin D supplementation
are also required in understanding the effects of vitamin D on fetal
development, and in shedding light on the role of vitamin D in prevention and treatment of these adverse consequences.
Vitamin D supplementation and pregnancy
An important recent development has been the expansion of
trials to assess the clinical benets of vitamin D supplementation
during pregnancy. However, given the nature of the clinical setting
in which supplementation takes place, this remains a controversial

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N.Q. Liu, M. Hewison / Archives of Biochemistry and Biophysics 523 (2012) 3747

issue with many safety considerations [236]. Clinical trials involving pregnant women in Turkey found that vitamin D supplementation during pregnancy could both decrease maternal bone
resorption and enhance bone mass in offspring during later life
[100]. Despite this, the supplementation regimen (400 IU/d of vitamin D3 and 1000 mg/d of calcium) was not sufcient to normalize
25(OH)D3 levels in the pregnant women, suggesting that higher
doses of 25(OH)D3 should be given to pregnant women [100]. This
important issue was addressed in a recent, double-blind, randomized clinical trial carried out to assess the safety and effectiveness
of vitamin D supplementation during pregnancy [59]. In this trial,
women with a singleton pregnancy received 400, 2000, or 4000 IU
of vitamin D3 per day from 12 to 16 weeks of gestation until delivery. The maternal and neonatal circulating concentrations of
25(OH)D3 were assessed along with possible side-effects. The primary aim of this study was to determine maternal and neonatal
serum 25(OH)D3 at delivery, and to also asses the relative efcacy
of the different supplementation regimens in achieving an optimal
serum 25(OH)D3 level of 80 nM. Women receiving 4000 IU/day
dose and their offspring were more likely to reach this optimal level at delivery, and this was achieved without any evidence of vitamin D toxicity, hypercalcemia and hypercalciuria, or an increase in
adverse events during pregnancy, regardless of race or ethnicity
[59]. This important study provides a platform for future trials to
safely investigate the wide-ranging health benets of vitamin D
supplementation during pregnancy.
Conclusions
There is now increasing evidence that vitamin D exerts diverse
effects during pregnancy. In its classical endocrine setting vitamin
D remains an important component of maternal calcium homeostasis. However, it is now clear that the actions of vitamin D are likely
to extend far beyond this, most notably effects on infection and
immunity during pregnancy. The current review highlights the potential array of maternal and fetal responses that may be inuenced
by vitamin D and, importantly, that may be dysregulated by vitamin D insufciency. Further studies are required to fully dene
the molecular and cellular mechanisms that underpin the proposed
functions of vitamin D during pregnancy. It will also be important
to develop new animal models to explore the metabolism and function of vitamin D in reproductive tissues. Finally another important
future development will be the expansion of clinical trials to assess
the clinical benets of vitamin D supplementation for both mother
and child.
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