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Expert Rev Clin Immunol. Author manuscript; available in PMC 2016 June 22.
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Published in final edited form as:

Expert Rev Clin Immunol. 2015 ; 11(9): 1055–1063. doi:10.1586/1744666X.2015.1056780.

Immunomodulatory Role of Vitamin D in the Pathogenesis of

Preeclampsia
Tyler A. Smith1,2, Daniel R. Kirkpatrick1,2, Oormila Kovilam, M.D.2, and Devendra K.
Agrawal1,*
1Centerfor Clinical & Translational Science, Creighton University School of Medicine, Omaha,
NE, USA
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2Department of Obstetrics and Gynecology, Creighton University School of Medicine, Omaha,

NE, USA

Summary
Worldwide, preeclampsia is a significant health risk to both pregnant women and their unborn
children. Despite scientific advances, the exact pathogenesis of preeclampsia is not yet fully
understood. Meanwhile, the incidence of preeclampsia is expected to increase. A series of
potential etiologies for preeclampsia have been identified, including endothelial dysfunction,
immunological dysregulation, and trophoblastic invasion. In this literature review, we have
critically reviewed existing literature regarding the research findings that link the role of vitamin D
to the pathogenesis and immunoregulation of preeclampsia. The relationship of vitamin D with the
suspected etiologies of preeclampsia underscores its clinical potential in the diagnosis and
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treatment of preeclampsia.

Keywords
Cathelicidin; Endothelial dysfunction; Immunomodulation; Preeclampsia; Vitamin D

Introduction
Hypertension-related disorders of pregnancy are leading causes of morbidity and mortality
for pregnant women and their infants worldwide (1). Preeclampsia is defined as new onset
hypertension with proteinuria that may be accompanied by end organ dysfunction (1–3). To
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*
Corresponding author: Devendra K. Agrawal, Ph.D. (Biochem), Ph.D. (Med. Sciences), MBA, FAAAAI, FAHA, FAPS, FIACS
Senior Associate Dean for Clinical & Translational Research, Director, Center for Clinical & Translational Science, The Peekie Nash
Carpenter Endowed Chair in Medicine, Professor of Biomedical Sciences, Internal Medicine, and Medical Microbiology &
Immunology, CRISS II Room 510, 2500 California Plaza, Omaha, NE, 68178, USA, Tel: (402) 280-2938; Fax: (402) 280-1421,
[email protected].
Financial and competing interest’s disclosure
The authors were supported by research grants R01 HL106042, R01 HL112597, and R01 HL120659 to DK Agrawal from the Office
of the Director of National Institutes of Health and the National Heart Lung and Blood Institute, NIH, USA. The content of this review
is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health,
USA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest
in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
 Smith et al. Page 2

be categorized as preeclampsia, these symptoms must occur in a previously healthy pregnant

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woman after 20 weeks of gestation (1–3).

Preeclampsia is associated with adverse maternal and fetal outcomes including placental
abruption, cerebral hemorrhage, hepatic failure, pulmonary edema, renal failure,
disseminated intravascular coagulation, low birth weights, blindness, progression to
eclampsia, and death (2, 4). In addition to these adverse outcomes, preeclampsia has been
associated with the development of maternal heart disease later in life (1). Despite the
severity of this disease, its exact etiology is incompletely understood (5), and is currently an
area of active research.

Recent investigations have underscored the importance of vitamin D levels as a potential risk
factor in the development of preeclampsia (2, 3). In this article, we reviewed and
summarized much of the existing literature on the role of vitamin D in preeclampsia. We
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conducted a literature search via MEDLINE COMPLETE using the terms related to vitamin
D, preeclampsia and pregnancy. Search terms included: preeclampsia, vitamin D, vitamin D
pregnancy, vitamin D immune regulation, vitamin D preeclampsia, pathogenesis
preeclampsia, trophoblastic invasion vitamin D, placenta vitamin D, and placenta vitamin D
preeclampsia. Articles published from 2001–2015 were included, with the majority being
published after 2010.

Epidemiology of Preeclampsia
Preeclampsia occurs in an estimated 7.5% of pregnancies worldwide (6), and in about 3.4%
of pregnancies in the United States (7). Some estimates place the preeclampsia incidence as
high as 8% of all pregnancies worldwide (7). There is evidence that increases in
preeclampsia risk factors, including obesity, will cause the incidence of preeclampsia to rise
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(6–8). For example, an article by Jeyabalan et al. (7) observed that, as obesity rates rise, the
rates of preeclampsia seem to increase concomitantly.

As a disease, preeclampsia is devastating. For every 100,000 live births there is one maternal
death due to preeclampsia (9). For mothers that survive, long-term health risks have been
identified (1). Globally, ten-to-fifteen percent of all maternal deaths caused by obstetric-
related pathologies can be attributed to preeclampsia-related complications (4). Taken
together, these studies underscore the burden that preeclampsia represents to world health.

A graphic summary of major worldwide causes of obstetric morbidity and mortality,

including hypertensive-disorders, is provided in Figure 1.
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Diagnosis and Treatment of Preeclampsia

Clinical Diagnosis
The American College of Obstetricians and Gynecologists (ACOG) has established specific
guidelines for diagnosing preeclampsia, as summarized in Figure 2. The ACOG standards
are divided into three broad categories: hypertension, proteinuria, and proteinuria
alternatives. To be clinically diagnosed with preeclampsia, a woman must have been
pregnant for twenty weeks or more and must meet the following criteria: elevated blood

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pressure with proteinuria or elevated blood pressure with a “proteinuria alternative” (1). The
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specific diagnostic criteria are discussed in the following sections.

Hypertension—In the preeclampsia algorithm, systolic blood pressure greater than 140
mmHg or diastolic greater than 90 mmHg must be observed on at least two occasions with
more than four hours between blood pressure measurements (1). Alternatively, the systolic
pressure reading above 160 mmHg or diastolic pressure reading above 110 mmHg can meet
this requirement, if verified during the same office visit (1). Any woman past twenty weeks
gestation who meets these criteria is considered at elevated risk for preeclampsia.

Proteinuria—In the preeclampsia algorithm, proteinuria is diagnosed by the protein level

of greater than or equal to 300 mg in the 24-hour urine (1), a protein-to-creatinine ratio
greater than or equal to 0.3 (1), or a urine dipstick reading of 1+ (1). Although proteinuria is
often present in women with preeclampsia, it is not required to reach a clinical diagnosis.
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Proteinuria Alternatives—If a woman past twenty weeks gestation has new onset of
hypertension without proteinuria, she can still be diagnosed with preeclampsia if she
experiences new onset of any of the following: thrombocytopenia (platelet count less than
100,000 per μL), serum creatinine greater than 1.1 mg/dL, doubling of serum creatinine
concentration (with no history of renal disease), or liver transaminases at twice the reference
range (1).

Treatment
Currently the only curative treatment for preeclampsia is delivery (10). However, early
delivery can harm the fetus. Fortunately, both preventative and symptomatic treatment
modalities are available to preeclamptic women. The goal of these therapies is to manage the
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severity of maternal symptoms so that the fetus has more time to develop in utero. Research
endorsed by ACOG has concluded that small daily doses of aspirin (60–80 mg) have a slight
preventative effect (1). Accordingly, ACOG recommends low dose aspirin regimens to
women who are at high risk of developing preeclampsia after 12 weeks gestation (1).
Contrary to what has been done historically, bed rest and salt restriction have not been
shown to provide measurable benefit to women with preeclampsia (1).

The treatment of intrapartum preeclampsia depends on the severity of maternal symptoms.

The Task Force on Hypertension in Pregnancy has established a series of recommendations
regarding the management of women with preeclampsia. These guidelines are evidenced
based and each recommendation is supported by available scholarly evidence. The
treatments focus on monitoring proteinuria and hypertension, controlling hypertension,
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relaxing uterine smooth muscle, and, in extreme cases, relieving severe symptoms by
delivering the fetus (1). The following paragraphs summarize the specific suggestions of the
Task Force on Hypertension in Pregnancy.

Preecclamptic women at 34 weeks gestation or more—Women with unstable

symptoms that have reached 34 weeks gestation should receive medical stabilization and
labor induction (1). Women who have reached 34 weeks gestation that have controlled
preeclampsia should receive doses of corticosteroids to stimulate fetal lung development (1).

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Steroid doses are precautionary and antenatal steroid treatment prepares fetal lungs and
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increases the chance of survival in case emergency induction of labor becomes necessary.

Preeclamptic women before 34 weeks gestation—Women with stable symptoms of

preeclampsia who have not yet reached 34 weeks gestation should be monitored closely in
an inpatient setting (1).. If these women present with a blood pressure over 160 mmHg
systolic or 110 mmHg diastolic, they should receive immediate antihypertensive therapy
(labetalol or hydralazine being common agents) to correct blood pressure abnormalities,(1).
Magnesium sulfate is recommended in women with preeclampsia as a means of preventing
progression to eclampsia (1). Magnesium is also indicated in women with eclampsia to slow
the progression of disease and to manage disease severity (1).

As per Task Force recommendations, if a woman continues to have severe symptoms of

preeclampsia after the administration of treatment, the fetus should be delivered (1). Severe
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symptoms of preeclampsia include: refractory hypertension, HELLP syndrome characterized

by hemolysis, elevated liver enzymes and low platelet count, eclampsia, placental abruption,
pulmonary edema, disseminated intravascular coagulation, evidence of fetal stress, or death
of the fetus (1).

Pathophysiology of preeclampsia
Although the exact cause of preeclampsia is unknown, recent research has identified a few
potential causes. These causes include endothelial cell dysfunction, immune dysregulation,
and dysfunctional trophoblastic invasion (2, 5, 11–14). Evidence in the literature links
vitamin D deficiency to each of these potential causes of preeclampsia (2, 5, 11, 12). This
review explores each of these putative causes of preeclampsia, followed by the discussion on
the role of vitamin D deficiency in their respective pathogenesis.
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Endothelial Dysfunction
Preeclampsia is a hypertensive disorder of pregnancy characterized by widespread
endothelial cell dysfunction (10). Recent studies have suggested that endothelial cell
dysfunction may be a major driving cause of preeclampsia (5). This hypothesis is supported
by the presence of increased levels of maternal anti-angiogenic cytokines, including soluble
fms-like tyrosine kinase 1 (sFlt-1), which is secreted by the placenta (5, 10, 11). For
example, Maynard et al. (10) found high concentrations of sFlt-1 weeks before the onset of
preeclampsia. The sFlt-1 competitively binds to placental growth factor and vascular
endothelial growth factor, inhibiting their ability to promote vascular invasion and
endothelial proliferation (5). The process by which sFlt-1 is thought to affect vascular cells
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is summarized in Figure 3. Research by Wei et al. (5) has shown that although sFlt-1 is
produced by the placenta in normal pregnancies, it is produced in significantly higher
quantities in preeclampsia. Wei hypothesized that increased levels of sFlt-1 may lead to
widespread vascular endothelial dysfunction (5). Manifestations of vascular endothelial
dysfunction include hypertension and proteinuria (two hallmarks of preeclampsia). These
studies support the claim that endothelial cell dysfunction contributes to the etiology of
preeclampsia (10).

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Vitamin D in Endothelial Dysfunction

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Although vitamin D has not been shown to directly change the sFlt-1-induced vascular
dysfunction pathway, recent in vitro studies have suggested that vitamin D may improve
angiogenesis (5). Evidence suggest that the opposite is also true. Wei et al, (5) for example,
found that gravid women with decreased vitamin D levels (below 50 nmol/L serum
25(OH)D level) had corresponding decreases in placental growth factor concentrations. This
study suggests that vitamin D insufficiency may underlie the endothelial dysfunction
associated with preeclampsia. Vitamin D appears to be important in maintaining vascular
endothelial stability and normal angiogenesis.

Immune Dysfunction
There have been several studies that suggest that immune dysfunction is involved in the
pathogenesis of preeclampsia. Supporting evidence for this hypothesis include the fact that
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women with autoimmune diseases have higher rates of preeclampsia (15), and women with
preeclampsia have higher levels of pro-inflammatory cytokines such as TNF-α and IL-6, as
well as lower levels of the anti-inflammatory cytokine IL-10 (14, 16). Several studies have
used animal models to demonstrate the potential role of these cytokines in the development
of preeclampsia. A study conducted by Sunderland et al. (17) found that pregnant baboons
given a 2-week infusion of low dose TNF-α developed increased blood pressure and
proteinuria. In a separate study, Orshal and Khalil (18) demonstrated that a two-fold increase
of IL-6 in pregnant rats lead to the development of hypertension. The authors hypothesized
that this finding is due to IL-6 inhibition of vascular relaxation and thus enhanced vascular
contraction (18). In a research study conducted by Lai et al. (19) it was found that an IL-10
knockout mouse exposed to a hypoxic environment developed preeclampsia. These studies
suggest that immune dysfunction, specifically with increased levels of IL-6 or the deficiency
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of IL-10, plays a significant role in the pathogenesis of preeclampsia.

Dysfunctional Trophoblastic Invasion

Trophoblastic invasion and the formation of the placenta play a critical role in the
pathogenesis of preeclamspsia (14). Insufficient or reduced trophoblastic invasion can cause
placental hypoxia, which leads to increased production and release of pro-inflammatory
cytokines, anti-angiogenic factors, and a decrease in IL-10. This cascade of immune
dysfunction and changes in angiogenesis contribute to endothelial cell dysfunction, which
then leads to the clinical manifestations of preeclampsia (14). Studies have shown that
women with higher circulating IL-10 levels have lower blood pressure during pregnancy
(14). One study even demonstrated that the administration of an anti-IL-10 antibody to
pregnant baboons increased their blood pressure (14). One mechanism by which IL-10 is
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thought to lower maternal blood pressure is by inhibiting the pro-inflammatory Th1

cytokines, including TNF-α (14), which have been shown to raise maternal blood pressure, a
hallmark of preeclampsia.

Vitamin D as an Immune Regulator

Vitamin D receptors are found on nearly every tissue type in the human body (20). In
addition, vitamin D receptors are broadly present on nearly all immune cells, including T-

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lymphocytes (Th1, Th2, Tregs), B-lymphocytes, dendritic cells, Th17 cells, monocytes, and
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macrophages (21–23). The 1,25-dihydroxyvitamin D (1,25(OH)2D3), the hormonally active

form of vitamin D, modulates the expression of cytokines (21–23). When bound to its
receptor, 1,25(OH)2D3 has been shown to significantly affect transcriptional activity within
cells (23). Figure 4 illustrates some of the pathways by which vitamin D either inhibits or
up-regulates the expression of cytokines in dendritic cells, Th1 cells, Th2 cells, CD8+ cells,
T-regulatory cells, B-cells, monocytes, and macrophages (22, 23).

The 1,25(OH)2D3 decreases the activity of Th1 cells by decreasing the production of IFN-γ,
IL-2, IL-12 and TNF-α (21–23). This effect comes with a complementary increase in the
activity of Th2 cells, particularly because of an increase in IL-10, and a decrease in IL-2
secretion (21–23). 1,25(OH)2D3 has also been found to have an inhibitory effect on Th-17
cells (22). This effect is most likely tied to its inhibitory effect on IL-6 and IL-23 production
(22). Similarly, Akbar et al. (21) found 1,25(OH)2D3 to be inhibitory to the maturation of
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dendritic cells. This inhibitory action leads to a population of immature dendritic cells,
contributing to the inhibition of certain markers (including CD40, CD80, and CD86, and
MHC II) (21). The 1,25(OH)2D3 also causes a down-regulation in the dendritic cell
production of IL-12 and an increased production of IL-10 (21).

While largely inhibitory effects, 1,25(OH)2D3 has also been found to serve a stimulatory
function in certain pathways. For example, vitamin D contributes to the activation of T-
regulatory cells (2, 23). In the setting of pregnancy, increased T-regulatory cell activity is
essential for the development of a maternal environment in which there is no immune
response against the fetus (2). Vitamin D mediates its stimulatory effect on T-regulatory cells
by upregulating forkhead box protein 3 (FOXP3), a factor that supports the differentiation
and expansion of T-regulatory cells (22). This role is of significant clinical significance in
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the setting of organ transplants, inflammatory diseases, autoimmune diseases, and others.
1,25(OH)2D3 has also been found to increase the production of IL-1 (a pyrogen) and
cathelicidin (a bactericidal peptide) (22).

Epigenetic Effects of Vitamin D

A recent review article published by Hossein-Nazhad et al. (24) suggests that vitamin D has
effects on placental development, fetal development, and epigenetic expression of the
developing fetus (24). They conclude that vitamin D plays a role in placental implantation
by regulating implantation-associated genes, such as Homeobox A10. Hossein-Nazhad et al
(24) also found vitamin D to have potent immunosuppressive effects that play a role in
placental development. Neonatal rats, for example, who were exposed to low levels of
maternal vitamin D in utero had slowed cardiac development and decreased heart weight
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(24). In humans it has been found that 2-year-olds with dilated cardiomyopathy and
hypovitaminosis D experienced improvement in cardiac function after vitamin D
supplementation (24). This study also suggested that vitamin D deficiency during pregnancy
impairs both maternal skeletal health and fetal skeletal formation. Moreover, vitamin D
deficiency increases the risk that a fetus will develop chronic asthma, type 1 diabetes, food
allergy, type 2 diabetes, cardiovascular disease, osteoporosis, and cancer (24). This research

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underscores both immediate and long-term consequences of vitamin D deficiencies to both

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mother and fetus.

Role of Vitamin D in Preeclampsia

A number of investigators have recognized the potential role of vitamin D in preeclampsia
(11, 13, 23–32). For example, Xu et al. (11) conducted a retrospective study investigating
both maternal IL-6 levels and vitamin D levels in the third trimester. The study concluded
that women with maternal vitamin D deficiency are five-times more likely to develop
preeclampsia than their vitamin D competent counterparts (11). Xu and colleagues
hypothesized that since vitamin D influences the inflammatory response outside of
pregnancy, vitamin D deficiency may be associated with the increased inflammation seen in
preeclampsia (11). Xu et al. confirmed that there is an association between elevated IL-6
levels and the incidence of preeclampsia (11), and added that preeclamptic women have on
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an average 14% less vitamin D than healthy controls (11). Despite these associations, their
assertion that low maternal vitamin D levels lead to elevated IL-6 levels was not supported
(11). Xu et al. (11) concluded that, while the relationship between elevated IL-6,
hypovitaminosis D, and preeclampsia is not clear, there is in vitro evidence suggesting that
low vitamin D levels in non-pregnant patients are associated with increased inflammation
(11).

A study by Reslan et al. (13) similarly linked preeclampsia to low serum vitamin D levels,
and proposed an alternative explanation for the link between vitamin D deficiency and
preeclampsia. Rather than emphasizing the immune modulatory capabilities of vitamin D,
Reslan and colleagues hypothesized that preeclamptic changes are tied to decreased calcium
absorption in vitamin D deficient subjects (13). This study concluded that, as a major
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cofactor in calcium absorption, decreased plasma calcium is associated with increased blood
pressure and increased urine protein output (13). Reslan et al. used two animal models to
support this hypothesis. First, pregnant ewes have been shown to have decreased plasma
calcium that corresponds to preeclampsia-like effects (13). Similarly, in rats, decreased
plasma calcium increases the ability of angiotensin II to cause vascular smooth muscle
contraction (13). The authors concluded by proposing that decreased vitamin D led to
decreased calcium absorption, causing the systemic effects of preeclampsia.

A study by Diaz et al. (8) investigated the ability of placenta to synthesize 1,25(OH)2D3 and
the level of vitamin D receptor expression within placental cells. They proposed that
increased serum 1,25(OH)2D3 is one mechanism through which expectant mothers are able
to increase calcium absorption during pregnancy (8). They found that human placental tissue
synthesizes 1,25(OH)2D3 through cytochrome P450 1α-hydroxylase (8). They suggest that,
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since low levels of 1,25(OH)2D3 are associated with preeclampsia, there is a possibility that
preeclampsia and chronic hypertension during pregnancy may be due to deficient production
of 1,25(OH)2D3 by the placenta (8). Further, they found that syncytiotrophoblasts from
preeclamptic placentas had a reduced ability to synthesize 1,25(OH)2D3 when compared to
syncytiotrophoblasts from normotensive placentas (8). Preeclamptic placentas also
expressed less 1α-hydroxylase mRNA at all stages of pregnancy compared to normotensive
placental tissue (8). Diaz et al (8) proposed that deficiencies in circulating 1,25(OH)2D3

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levels in preeclampsia may be caused by deficient 1α-hydroxylase expression at the level of

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the placenta.

Robinson and co-investigators (3) suggested an association between low maternal 25-
hydroxyvitamin D (25(OH)D) and early onset severe preeclampsia (EOSPE). EOSPE is
associated with an increased risk of pre-term birth and an increased risk for vascular
pathologies later in life (3). Not only did Robinson et al. (3) find that women with EOSPE
had lower serum levels of 25(OH)D, they found that an increase of only 10 ng/ml in serum
25(OH)D level was enough to reduce the risk of developing preeclampsia (3). This research
suggests that vitamin D could potentially serve as both a marker for predicting preeclampsia
and a treatment to mitigate the risk of developing EOSPE (3).

In a different study, Robinson et al. (27) investigated vitamin D levels in women who had
both EOSPE and gave birth to an infant that was small for gestational age (SGA). The study
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found mothers of SGA infants to have low serum levels of 25(OH)D relative to the mothers
of children with normal gestational sizes (27). Robinson suggested that vitamin D affects the
placenta and fetal growth by changing gene expression (27). Robinson et al. further observed
that 1,25(OH)2D3 also acts on endothelial cells, increasing the transcription of vascular
endothelial growth factor (VEGF), leading to vasculogenesis (27).

Bodnar et al. (28) found that serum 25(OH)D concentrations in early pregnancy were 15%
lower in women who ultimately developed preeclampsia than healthy controls. They also
observed, similar to Xu et al. (11), that vitamin D deficiencies in early pregnancy increase
the odds of developing preeclampsia by five times (compared to healthy controls) (11, 28).
Bodnar et al. (28) concluded that there was a strong inverse relationship between serum
vitamin D levels before 22 weeks gestation and the risk of developing preeclampsia.
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As stated above, Royle et al. (14) suggest that defective trophoblastic invasion leads to the
development of preeclampsia is through an increase in TNF-α, and a decrease in IL-10.
Similarly, vitamin D acts as an immune modulator by increasing the expression of IL-10 and
decreasing the expression of Th1 mediated pro-inflammatory cytokines such as IFN-γ, IL-2,
and TNF-α (Figure 4). A deficiency in vitamin D causes a cascade of changes in cytokine
expression that closely mirrors the cytokine changes caused by incorrect trophoblastic
invasion. This observation gives one possible explanation as to how a vitamin D deficiency
leads to the development of preeclampsia.

Collectively, these findings suggest that the immunomodulatory capabilities of vitamin D

underlie its role in the pathogenesis of preeclampsia.
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Inconclusive or No Association
Shand et al. (26) conducted a prospective cohort study of 221 women by measuring serum
25-hydroxyvitamin D at 10 and 20 weeks gestation. According to their article, they found
78% of women were vitamin D insufficient (serum 25-hydroxyvitamin D <75 nmol/l) and
53% were vitamin D deficient (serum 25-hydroxyvitamin D <50 nmol/l). Despite the
findings of widespread deficiency and insufficiency of serum 25-hydroxyvitamin D, they
found no difference in the rates of pre-eclampsia, gestational hypertension, or adverse

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pregnancy outcomes. Despite this finding, they do acknowledge that low maternal vitamin D
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is associated with poor fetal bone mineralization, and a greater chance of the fetus
developing asthma and type 1 diabetes later in life (26). They further acknowledge that more
research is needed at different gestational ages to further investigate the association of
vitamin D in preeclampsia (26).

Expert commentary & five-year view

While the exact etiology of preeclampsia remains unknown, several potential causative
factors have been proposed. Specifically, the research emphasizes endothelial damage as a
result of oxidative processes, immune dysfunction, and trophoblastic invasion (2, 5, 11–14).
Given the indispensable role of vitamin D in the regulation of cytokines and immune
processes, vitamin D insufficiency is a likely contributor to the processes that damage
endothelial cells in preeclamptic women (5, 14, 16).
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Despite many research findings showing an association between low maternal vitamin D and
preeclampsia (23 -,44), one prospective study we found disputed these findings and found no
association between the development of the disease and maternal vitamin D levels at 10 and
20 week gestation in women at high risk for developing preeclampsia (26). Research by
Christensen and co-investigators (33) evaluated these studies and noted that many studies
that find no relationship between vitamin D and preeclampsia have small sample sizes. More
research needs to be done to determine both the pathogenesis of preeclampsia, and what role
vitamin D plays in the development, progression, and outcomes of this disease.

References
Reference annotations
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* Of interest

** Of considerable interest

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Key Issues
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• Further Randomized controlled trials using vitamin D supplementation pregnant

women is needed to establish a link between preeclampsia and vitamin D.

• Preeclampsia continues to be a major cause of maternal and fetal morbidity and

mortality worldwide.

• Although the precise pathophysiology of preeclampsia has not been established,

is thought to occur due to a combination of endothelial cell dysfunction,
immune dysfunction, and insufficient or reduced trophoblastic invasion.

• Vitamin D has been shown to improve angiogenesis and some research suggests
that low serum vitamin D may contribute to endothelial cell dysfunction.

• Vitamin D has been shown to act as an immune modulator, and there are vitamin
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D receptors found on almost all immune cells.

• Vitamin D increases IL-10 production and decreases IL-6 production. Increased

levels of IL-6 have been associated with preeclampsia, and decreased levels of
IL-10 have also been associated with the disease.

• A deficiency in vitamin D causes a decrease in the expression of IL-10 and an

increased expression of Th1-mediated pro-inflammatory cytokines such as IFN-
γ, IL-2, and TNF-α. This closely resembles the cytokine changes that take place
due to insufficient or reduced trophoblastic invasion. This observation gives one
possible explanation as to how a vitamin D deficiency leads to the development
of preeclampsia.

• Vitamin D’s role in changing calcium absorption may also play a role in the
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pathogenesis of preeclampsia.
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Figure 1.
A summary of preeclampsia epidemiology. Worldwide up to 8% of all pregnancies are
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complicated by preeclampsia. In the United States 3.5% of pregnancies are complicated by

preeclampsia. In 2014 the World Health Organization (WHO) published a paper entitled:
Global causes of maternal death: a WHO systematic analysis, and some of their findings are
summarized here. This figure summarizes the most common causes of maternal death.
Preeclampsia is included in the “hypertension” category.
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Figure 2.
A proposed algorithm for diagnosing preeclampsia based on the 2013 American College of
Obstetricians and Gynecologists Task Force on Hypertension Pregnancy.
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Figure 3.
Soluble Fms-like Tyrosine Kinase 1 (sFlt-1)-mediated Vascular Endothelial Dysfunction:
Preeclampsia is a hypertensive disorder of pregnancy characterized by widespread
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endothelial cell dysfunction. Preeclamptic mothers have an increased level of circulating

anti-angiogenic cytokines such as sFlt-1. sFlt-1 acts by competitively binding to placental
growth factor and vascular endothelial growth factor, inhibiting their ability to promote
vascular invasion and endothelial proliferation. This dysfunction results in hypertension and
proteinuria, both of which are hallmarks of preeclampsia.
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Figure 4.
Cellular effects of the active form of vitamin D (1,25(OH)2D3) acts as an immune
modulator. The 1,25(OH)2D3 modulates immune cells including: dendritic cells, CD4+ T-
cells, CD8+ T-cells, T-regulatory cells (T-Regs), TH-17 cells, monocytes and macrophages.
In dendritic cells 1,25(OH)2D3 inhibits differentiation, maturation, and immunostimulatory
effects. The 1,25(OH)2D3 also decreases dendritic cell expression of MHC class II, CD40,
CD80, CD86. The activation of vitamin D receptors (VDR) also causes dendritic cells to
decrease synthesis of IL-12 and increases IL-10 production, which acts to stimulate TH2
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expression and inhibit TH1 expression. In both CD4+ and CD8+ T-lymphocytes,
1,25(OH)2D3 binding to the VDR causes a five-fold increase in VDR expression. In vitro,
1,25(OH)2D3 inhibits the expression of IL-2, IFN-γ, and TNF-α. A decrease in the
expression of these cytokines decreases TH1 cell proliferation and skews immunity to a Th2
mediated response. The 1,25(OH)2D3 also increases IL-4 production by TH2 cell, further
inducing TH2 cell proliferation. In addition, 1,25(OH)2D3 has a stimulatory effect on
FOXP3+ T-regulatory cells (T-Regs), causing differentiation and expansion. The
1,25(OH)2D3 has also been shown to inhibit Th17-cells by inhibiting IL-6 and IL-23
cytokine production. The 1,25(OH)2D3 decreases the activity of both antigen presenting
cells (APC) and T-cells, leading to decreased B-cell proliferation, plasma-cell
differentiation, and immunoglobulin secretion. Although most of the effects of 1,25(OH)2D3
on the immune system are inhibitory, it stimulates the activity of the innate immune system.
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The 1,25(OH)2D3 has been shown to stimulate monocyte proliferation in vitro, and it caused
an increase in the production of IL-1 and cathelicidin (a bactericidal peptide) by monocytes
and macrophages.

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