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Crit Rev Food Sci Nutr. Author manuscript; available in PMC 2019 March 24.
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Published in final edited form as:

Crit Rev Food Sci Nutr. 2018 March 24; 58(5): 755–769. doi:10.1080/10408398.2016.1220915.

Vitamin D and its impact on maternal-fetal outcomes in

pregnancy: A critical review
Shreya Agarwal1, Oormila Kovilam2, and Devendra K. Agrawal1,*
1Departmentof Clinical & Translational Science, Creighton University School of Medicine,
Omaha, NE 68178, USA
2Department of Obstetrics & Gynecology, Creighton University School of Medicine, Omaha, NE
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68178, USA

Abstract
The role of vitamin D beyond its classical function in calcium homeostasis has been of significant
interest in recent years. There has been expanding research on the pleiotropic role of vitamin D in
pregnancy and the implications of its deficiency on maternal-fetal outcomes. Several studies have
associated low maternal vitamin D status to adverse outcomes in pregnancy, including
preeclampsia, gestational diabetes, preterm births, low birth weight, and others. Several
randomized controlled clinical trials of Vitamin D supplementation during pregnancy have also
been conducted. Though some of the studies found improvement in pregnancy outcomes with
vitamin D supplementation, others have not shown any association. In this article, we have
critically reviewed the observational and interventional studies, published primarily within the past
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two years (January 2014 to February 2016) on the influence of vitamin D deficiency on pregnancy
and the impact of its supplementation. The potential underlying mechanisms of vitamin D in
regulating each of the outcomes have also been discussed.

Keywords
Pregnancy; Vitamin D; Maternal outcomes; Neonatal outcomes; Vitamin D supplementation

Introduction
Vitamin D is a secosteroid, which is also considered an important prohormone (Weinert et
al, 2015). Since vitamin D receptors (VDRs) are present in many cells and tissues
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throughout the body, many studies support the role of vitamin D in several physiological
functions beyond bone and muscle health (Joergensen et al, 2014). During pregnancy,

*
Corresponding author: Devendra K. Agrawal, Ph.D. (Biochem), Ph.D. (Med. Sciences), MBA, FAAAAI, FAHA, FAPS, FIACS,
Professor and Chairman, Department of Clinical & Translational Science, The Peekie Nash Carpenter Endowed Chair in Medicine,
Senior Associate Dean for Clinical & Translational Research, CRISS II Room 510, 2500 California Plaza, Omaha, NE, 68178, USA,
Tel: (402) 280-2938; Fax: (402) 280-1421, [email protected].
Financial and competing interests disclosure
The authors have no other relevant affiliations or financial involvement with any organization or entity with financial interest or
financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance
was utilized in the production of this manuscript.
 Agarwal et al. Page 2

vitamin D plays a vital role in embryogenesis, especially fetal skeletal development and
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calcium homeostasis (Hollis et al, 2011). Vitamin D deficiency is a growing health concern
worldwide in both adults and children (Weinert et al, 2015). Indeed, the findings from
several studies suggest the increasing prevalence of vitamin D deficiency in pregnancy and
the associated adverse maternal and fetal outcomes, such as gestational diabetes mellitus
(GDM), preeclampsia, small for gestational age (SGA), preterm births among others
(Palaniswamy et al, 2016) (Figure 1).

To further investigate the role of vitamin D in pregnancy and the improvement of outcomes
on its supplementation, many interventional and observational studies have been undertaken
but the results have not been consistent. Heterogeneity in the findings could be attributed,
but not limited, to the differences in ethnicity, geographical locations, amount of vitamin D
supplementation, and duration of supplementation. The methodology of the studies is not
consistent and cannot be compared since the studies were conducted at different stages of
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gestation. It is still not well defined as to how vitamin D supplementation modifies the risk
of the outcomes and whether vitamin D contributes to the etiopathogenesis of these diseases
or it is just a marker (Yin et al, 2014). Given the low cost of vitamin D supplementation, if
proven effective in pregnancy, it could bring about some major improvements in public
health worldwide (Christensen et al, 2012).

The impact of vitamin D deficiency during pregnancy has been discussed in a few recent
reviews and metaanalyses (Perez-Lopez et al, 2015; Harvey et al, 2014; Wei et al, 2015);
however, more randomized clinical trials (RCTs) and observational studies have been
conducted after the publication of the last review. Hence, this review article summarizes the
recent studies on the influence of vitamin D deficiency during pregnancy. The impact of
vitamin D supplementation on various maternal and fetal clinical endpoints has also been
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reviewed with critical discussion on the clinical and translational application of these
findings and identified gaps in our knowledge to conduct future prospective studies.

Methods
Literature search was performed using PubMed Database of the National Library of
Medicine, with date limits from January 2014 to February 2016, as the major emphasis of
our review was to critically review the recent findings on Vitamin D in pregnancy. We used
the keywords: Vitamin D, pregnancy, vitamin D supplementation, hypovitaminosis D,
preeclampsia, gestational diabetes, preterm birth, and other related terms. The studies of
interest included original papers and review articles on the influence of vitamin D deficiency
in pregnancy and the impact of vitamin D supplementation on the maternal and fetal
outcomes. References in these articles were searched for any other related articles. Duplicate
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articles were excluded. Articles were also excluded if they were not published in English
language; were unavailable in full text, or if the studies did not involve human subjects.
Sixty studies fit the criteria and hence, were critically evaluated in this review.

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Physiology of vitamin D and vitamin D deficiency

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Vitamin D is a fat-soluble vitamin with two major physiological forms: Ergocalciferol,

vitamin D2 and Cholecalciferol vitamin D3 (DeLuca, 2014). These two forms basically
differ in their side chain structure. While D2 is mainly obtained from plants and vegetable
sources, D3 is majorly synthesized in the skin on exposure to sunlight (UVB radiation) from
7 dehydrocholesterol (De-Regil et al, 2016). Both forms of vitamin D are also available as
dietary supplements. All the forms of vitamin D are activated only on enzyme-mediated
hydroxylation. The first hydroxylation reaction is mediated by 25α-hydroxylase, to produce
25 hydroxyvitamin D (25OHD) or calcidiol and takes place in the liver (Harvey et al, 2014).
This is followed by the next hydroxylation step in the kidney, mediated by 1α-hydroxylase,
to produce 1,25-dihydroxycholecalciferol (1,25-DHCC) or calcitriol (Wagner et al, 2012).
While 25OHD is the most abundant circulating form of vitamin D, 1,25-DHCC is the most
active form (Sahota, 2014). The hydroxylation reactions and the availability of active
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vitamin D are regulated by serum calcium and phosphorus and parathyroid hormone (PTH)
(Lips P, 2006).

Apart from its critical role in the regulation of calcium and phosphorus homeostasis for
skeletal development, vitamin D also mediates other functions, including anti-inflammation,
regulation of innate and acquired immunity, and prevention of cardiovascular diseases
(Christakos et al, 2016).

Based on the recommendations by the Institute of Medicine (IOM), the recommended daily
intake of vitamin D during pregnancy and lactation is 600 IU, taking into account the fetal
demands as well (Grant et al, 2014). The serum 25OHD is regarded as the best stable and
circulating biomarker for vitamin D status (Brannon et al, 2014). The cut-off value for
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vitamin D deficiency is set at 20 ng/ml while for vitamin D insufficiency it ranges from 20–
30 ng/ml (Ross CA et al IOM, 2011).

Vitamin D deficiency is a global epidemic affecting people of all age groups with the
principal cause being the lack of exposure to sunlight (Holick et al, 2008). Others include
darker skin (high melanin content), aging, use of sunscreen and winters, all associated with
decreased dermal synthesis of vitamin D (Holick et al, 2008). Some pathological conditions
associated with low vitamin D include kidney failure, intestinal malabsorption, chronic
inflammation and liver failure and use of concurrent medications (Dusilova-Sulkova, 2009).
As a consequence, there is decreased bone density and greater susceptibility to fractures.
Children suffer from rickets, while adults develop osteopenia or osteoporosis. Additionally,
vitamin D deficiency is also associated with other co-morbid conditions like type 1 diabetes
mellitus, neoplasms, cardiovascular diseases and others (Dusilova-Sulkova, 2009).
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Vitamin D in pregnancy
During pregnancy, mobilization of maternal calcium increases to meet the demands of
adequate fetal bone mineralization (Olmos-Ortiz et al, 2015). As a consequence, a number
of physiological adaptations take place, including increased maternal serum calcitriol,
vitamin D binding protein (DBP), placental VDR and renal and placental CYP27B1 activity

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to maintain normal serum levels of 25OHD and calcium (Olmos-Ortiz et al, 2015). Maternal
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25OHD crosses the placenta and is the main form of vitamin D for the fetus (Marshall et al,
2016). Calcitriol rises during pregnancy, almost doubled by the end of third trimester and
then returns to normal levels after delivery (Marshall et al, 2016). During pregnancy, even
placenta and fetal kidney express 1α-hydroxylase stimulated by prolactin and placental
lactogen, though the major function is still performed by the maternal renal
hydroxylase(Olmos-Ortiz et al, 2015). Maternal serum calcium levels fall during pregnancy,
which can be attributed to a decrease in the serum albumin, but the ionized calcium levels
remain unchanged (Olausson et al, 2012). In fact, fetal serum calcium levels are higher than
maternal serum calcium levels, thereby requiring specific trans-placental carriers to transfer
calcium against the concentration gradient (Olmos-Ortiz et al, 2015). This is mediated by the
expression of calcium binding proteins in placenta, including calbindin D-9k and D-28k
(Halhali et al, 2010).
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The most important contribution of vitamin D during pregnancy is to escalate calcium

absorption and placental calcium transport (Olmos-Ortiz et al, 2015). Additionally, vitamin
D also regulates immune system and inhibits inflammation by restraining inflammatory
cytokines. including TNF-α, IFN-γ, IL-6, while promoting the release of antimicrobial
peptide cathelicidin hCTD in the placenta (Olmos-Ortiz et al, 2014). Calcitriol also plays an
important role in placental physiology. It stimulates endometrial decidualization, synthesis
of estradiol and progesterone and regulation of the expression of human chorionic
gonadotrophin (hCG) and human placental lactogen(hPL) in the placenta(Olmos-Ortiz et al,
2014).

All these effects indicate the vital importance of vitamin D during gestation and the potential
role of its deficiency on adverse maternal-fetal outcomes (Figure 2). Each maternal and fetal
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outcome investigated in the recent papers has been discussed in detail below with a tabular
representation of the recent observational studies in Table 1 and Table 2. The impact of
vitamin D supplementation has also been reviewed with a depiction of the recent
Randomized Controlled Trials shown in Table 3. Table 4 summarizes the level of evidence
of the impact of vitamin D on various maternal-fetal outcomes based on the GRADE
system.

Adverse Maternal Outcomes associated with vitamin D deficiency

Preeclampsia
Preeclampsia is defined as newly diagnosed hypertension (systolic blood pressure >140
mmHg, diastolic blood pressure >90 mmHg) after 20 weeks of gestation along with
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proteinuria (>300mg/day), and other organ dysfunction, including liver involvement,

hematological disturbance, neurological or renal complications (Roberts et al, 2016).
Pathogenesis is related to the release of angiogenic factors into maternal circulation, which
causes inadequate remodeling and trophoblastic invasion of spiral arteries, and consequently
shallow implantation and hypoxia, and even release of inflammatory mediators (Sircar et al,
2015; Singla et al, 2015). The protective role of vitamin D in preeclampsia can be explained
by multiple mechanisms. One of them is the immunomodulatory role of calcitriol in
regulating immune response. Defective control of effector T cells by regulatory T cells can

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lead to poor placental invasion, thereby leading to the release of placenta-derived

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vasoconstrictive factors, and consequently maternal hypertension and proteinuria (Hyppönen

et al, 2013). Vitamin D helps in maintaining the immune homeostasis and thus prevents
placental vasoconstriction and ultimately, preeclampsia (Hyppönen et al, 2013). Also,
vitamin D regulates the endothelial and vascular smooth muscle cell proliferation and
therefore, plays a role in regulating blood pressure through RAAS (Renin-Angiotensin-
Aldosterone system) (Hyppönen et al, 2013). Vitamin D has also been found to regulate
angiogenesis via its receptor elements in VEGF promoter and stimulating the expression of
VEGF in vascular smooth muscle cells. Calcitriol also helps to prevent cholesterol uptake by
the macrophages and vascular smooth muscle cells of the arterial walls, which is the
observed pathology in utero placental vessels of patients with preeclampsia (Hyppönen et al,
2013). Despite these findings, in other studies no causal relationship was found between
vitamin D supplementation and improvement/prevention of preeclampsia. These studies are
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discussed below.

Several observational studies were recently performed to investigate an association between

vitamin D deficiency and preeclampsia but the findings have been inconsistent. Eleven
observational studies have examined the association between preeclampsia and vitamin D;
Achkar et al (2015) carried out a nested case control study in Canada and concluded that
vitamin D deficiency (<30 ng/ml) was associated with increased risk of preeclampsia
(adjusted Odd’s Ratio (OR), 2.23; 95% Confidence Interval (CI) 1.29–3.83). Similar results
were also reported by other recent studies (Singla et al, 2015; Mohaghegh et al, 2015; Abedi
et al, 2014; Sadin et al, 2015). On the contrary, Bomba-Opon et al (2014) measured the
25OHD levels in 280 pregnant women in Poland and found no association between vitamin
D levels and markers of preeclampsia, including Pregnancy-associated plasma protein A
(PAPP-A), Placenta Growth Factor (PlGF), uterine artery pulsatility index and mean arterial
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pressure. Similarly, Schneuer et al(2014) reported no increased risk of preeclampsia in

vitamin D deficient pregnant women in a nested case control study conducted in 5109
pregnant women. Some other studies also described comparable outcomes (Gidlof et al,
2015; van Weert et al, 2016; Wetta et al, 2014; Burris et al, 2014).

Many randomized controlled trials (RCT) have been undertaken to determine the impact of
vitamin D supplementation in preeclampsia patients. In the past two years, three of the
investigations took place in Iran (Mojibian et al, 2015; Samimi et al, 2015; Asemi et al,
2015)and one each in India (Sablok et al, 2015) and Pakistan (Hossain et al, 2014). Positive
impact was found in some (Samimi et al, 2015; Asemi et al. 2015; Sablok et al, 2015)while
no significant impact was reported in others (Hossain et al, 2014). Similarly, Karamali et al
(2015) conducted a double blind placebo-controlled RCT in pregnant women at risk of
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preeclampsia determined by abnormal uterine artery waveform, and reported no significant

change in blood pressure with vitamin D supplementation. When combined supplementation
of vitamin D and calcium was given in an interventional study to at-risk preeclampsia
patients, significant improvement in the outcomes with reduced systolic and diastolic blood
pressure was observed in the vitamin D and calcium supplemented group compared to the
placebo group (Samimi et al, 2015). Similarly, Asemi et al (2015) also reported positive
outcomes on supplementation with vitamin D (400 IU) and multi-minerals (800 mg calcium,
200 mg magnesium, 8 mg zinc) over 9 weeks compared to placebo in at-risk preeclampsia

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patients. Recently, the published Cochrane review on vitamin D supplementation studies

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reported that women who receive vitamin D supplementation had lower risk of preeclampsia
but with only borderline significance (RR 0.52, CI 0.25–1.05), whereas combined vitamin D
and calcium supplementation significantly reduces the risk of preeclampsia (Risk Ratio
(RR): 0.51, CI 0.32–0.80) (De-Regil et al, 2016). Our analysis also supports the conclusion
of Cochrane review that vitamin D supplementation reduces the risk of preeclampsia.

Gestational Diabetes Mellitus (GDM)

Gestational diabetes mellitus is defined as hyperglycemia from glucose intolerance that
develops or is first diagnosed during pregnancy (Baz et al, 2016). Vitamin D plays a role in
glucose homeostasis by multiple mechanisms (Lithy et al, 2014). Firstly, it regulates the
calcium levels, which in turn regulates insulin production and secretion by the endocrine
pancreas (Al-Shoumer et al, 2015). It also improves the sensitivity of the target cells like
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adipose tissue, liver and skeletal muscles to insulin (Lithy et al, 2014). Through its role in
regulation of immune cells, it protects β cells from detrimental immune attacks and even
enhances their function (Al-Shoumer et al, 2015). Vitamin D deficiency or the dysfunction
of vitamin D receptors relates to the pathogenesis of type 1 and type 2 diabetes, but its role
in GDM remains inconclusive.

Eight observational studies have been recently conducted to study the association of vitamin
D with GDM. Arnold et al(2015) conducted a nested case control study in the United States
among pregnant women and reported an inverse relationship between vitamin D status in
early pregnancy and risk of gestational diabetes. A 5 ng/ml increase in vitamin D3 levels
was associated with reduction in GDM risk by 14%. Similar effects were reported by
Lacroix and colleagues (2014) in a prospective observational study in Canada and Lithy et
al(2014) in a cross sectional observational study in Arab women. On the contrary, multiple
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studies failed to establish a role of vitamin D in the prevention of GDM (Schneuer et al,
2014; Sunmin et al, 2014; Whitelaw et al, 2014; Loy et al, 2015; Flood-nichols et al, 2015).
The lack of consistent findings calls for large-scale prospective studies to evaluate the role of
vitamin D in GDM.

To test the effectiveness of vitamin D supplementation in the prevention or reduction of risk

of GDM, many randomized controlled clinical trials have been conducted. Six RCTs have
been conducted in this regard from January 2014 onwards (Mojibian et al, 2015; Sablok et
al, 2015; Hossain et al, 2014; Asemi et al, 2014; Asemi et al, 2013; Yap et al, 2014). Asemi
et al(2014) performed a randomized placebo controlled trial in Iranian pregnant women and
found positive impact of vitamin D and calcium supplementation on the metabolic profiles
of GDM patient with decrease in free plasma glucose, serum insulin, HOMA–IR, LDL
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cholesterol and total cholesterol. Few other studies, on the contrary, reported no beneficial
effects of vitamin D supplementation on GDM outcome (Sablok et al, 2015; Hossain et al,
2014). To compare and contrast the efficacy of different dosing patterns of vitamin D on
GDM, recently two clinical trials were undertaken; Yap et al (2014) conducted the study in
women with 25OHD levels less than 32 ng/ml before 20 weeks and randomized them to
receive oral vitamin D3 at 5,000 IU daily or 400 IU daily from 14 weeks until delivery, and
found no difference in the outcomes. Mojibain et al (2015) randomized pregnant women

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with 25OHD less than 30 ng/ml to receive 400 IU daily or 50,000 IU every 2 weeks until
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delivery, and found improved outcomes with high dose vitamin D supplementation. The
difference in the outcomes could be attributed to different dosages of vitamin D used for
intervention, as well as the varying dosing schedules in the two studies. Two recently
published meta-analyses of RCTs (De-Regil et al, 2016; Pérez-López et al, 2015), however,
showed same incidence of GDM with and without vitamin D supplementation. While
studies have shown varying results, the overall level of evidence is high for vitamin D
supplementation playing no role in the prevention of GDM.

Cesarean section (C-section)

Vitamin D receptors are present on smooth muscle cells, including uterine muscles, and
skeletal muscle cells. Vitamin D regulates the contractile proteins of uterine myometrial
cells (Loy et al, 2015). Vitamin D deficiency, therefore, may decrease the strength of the
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contractile muscles, causing prolonged labor or obstructed labor, indicating the need for C-
section (Sebastian et al, 2015). Vitamin D deficiency has also been postulated to cause
malformation of pelvis, which is yet another indication for C-section (Gernand et al, 2015).

Few studies have analyzed the association between vitamin D levels and cesarean sections.
Recently, five observational studies were conducted with mixed outcomes (Loy et al, 2015;
Sebastian et al, 2015; Gernand et al, 2015; Rodriguez et al, 2015). In a prospective cohort
study conducted in Spain in 2,382 mother child pairs, Rodriguez et al (2015) reported that
adequate vitamin D (25 OHD ≥ 30ng/ml) decreased the risk of C-section by obstructed labor
(RR=0.60, 95% CI 0.37, 0.97). In a multiethnic Asian cohort study conducted by GUSTO
study group (Loy et al, 2015), it was found that low vitamin D levels were associated with
increased risk of emergency C-sections in Chinese and Indian women, and not in Malay
women and overall there was no significant association. No association between vitamin D
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deficiency and risk of C-section was reported in other recent studies (Sebastian et al, 2015;
Gernand et al, 2015). The inconsistency in the findings might be due to the difference in
defining C-section in terms of indication, primary or secondary, emergency or elective
(Gernand et al, 2015).

There have not been any interventional studies undertaken to determine the association
between the two. Although analysis of the recent observational studies suggests that vitamin
D deficiency can increase the risk of C section, there is a need for investigators to conduct
RCTs to study the impact of vitamin D supplementation on C-section rates.

Preterm Delivery
One of the most common causes for preterm delivery is infection (Sangkomkamhang et al,
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2015). Vitamin D, through its role in anti-inflammatory pathways via nuclear factor-kB
inhibition, could play a role in decreasing the incidence of infections thereby, preterm births
(Thota et al, 2014). But the exact role of vitamin D in the pathogenesis of preterm birth has
not yet been clearly defined. Five observational and four interventional studies have
investigated their association with lack of consistency in the results. Bodnar et al (2015)
conducted a case control study with 1,126 cases and 2,327 controls in Pittsburgh, PA, USA.
Serum 25OHD was measured using liquid chromatography- tandem mass spectroscopy and

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a protective association of vitamin D sufficiency and preterm birth was found after adjusting
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confounding factors. Thota et al (2014) reported similar results. However, other studies did
not support the above findings (Schneuer et al, 2014; Wetta et al, 2014; Rodriguez et al,
2015).

Few recent interventional studies on vitamin D supplementation examined its role in the
prevention of preterm births. Hossain et al(2014) carried out a RCT of routine care (200 mg
ferrous sulfate and 600 mg calcium) vs vitamin D3 supplementation (4,000 IU daily) from
20 weeks of gestation till delivery in 207 pregnant women and reported comparable
outcomes in both the groups (p >0.05). Mojibian et al(2015) also reported similar findings.
On the contrary, Sablok et al (2015) found decreased incidence of preterm delivery in the
group with vitamin D supplementation (8.3%) compared to no intervention (21.1%) though
it was not statistically significant. Wagner et al(2015) carried out a post hoc analysis to
measure the strength of association between serum 25OHD levels at 3 times, one in each
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trimester and preterm birth. They found that maternal vitamin D status closest to the delivery
was most significantly associated with preterm birth, thereby proposing that later
intervention could be used as a rescue treatment to decrease the risk of preterm deliveries
(Wagner et al, 2015). Meta-analysis carried out by Pérez López et al (2015) showed no
significant impact of vitamin D supplementation on the prevention of preterm deliveries.
Though the level of evidence is moderate, our analysis shows no significant association
between vitamin D and preterm deliveries.

Recurrent pregnancy loss

One of the non-classical functions of vitamin D is the regulation of immune system. To
maintain maternal fetal interaction for a successful pregnancy, a dominant Th2 cell response
is required (Garrido-gimenez et al, 2015). Therefore, dysregulated immune function and
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autoimmunity could alter the immune response leading to pregnancy loss. Vitamin D
reportedly inhibits Th1 cells-mediated immune response and also the production of their
cytokines, including IFN-γ, IL-2 and TNF-α, while promoting the proliferation of Th2 cells
and their cytokines, including IL-4, IL-5, IL-6, IL-9, IL-13 (Wei et al, 2015). Such an effect
of vitamin D supports its role in the immunoregulation during implantation. This hypothesis
was examined by Ota et al, (2014) who conducted a retrospective study of 133 pregnant
women with a history of three or more pregnancy loss before 20 weeks of gestation. Serum
vitamin D levels and the markers of immunity were measured. The 47.4% of these women
had low vitamin D levels (<30 ng/ml). The levels of autoantibodies were significantly higher
in vitamin D-deficient group. These include anti-phospholipid antibody (APA) (p<0.005,
adjusted OR 2.22, CI 1.0–4.7), antinuclear antigen antibody, anti-ssDNA and
thyroperoxidase antibody. This was also followed by in vitro experiments and significantly
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decreased ratio of TNF-α/IL-10 expressing CD3+/CD4+ cells with 100 nM of vitamin D3

(31.3 ± 9.4 ng/ml, p<0.05) was found in cases compared to controls (40.4± 11.3 ng/ml).
Although no conclusion can be drawn based on the findings of a single study, but this calls
for more observational and interventional studies to establish the association between the
two.

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Postpartum depression
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Postpartum depression is the most common psychiatric condition occurring in the

postpartum period (Cherry et al, 2014). Vitamin D is believed to be a neurosteroid and has
been linked to the occurrence of depression (Anglin et al, 2013). There are various plausible
mechanisms relating postpartum depression with vitamin D deficiency. Firstly, VDRs are
located throughout the body including brain, so, in case of vitamin D-deficiency, the VDRs
in the brain may affect the hormones that are involved in the occurrence of mood disorders
(Fu et al, 2015). Vitamin D also plays a role in brain processes like neurotransmission,
neuro-immunomodulation and neuroprotection (Christesen et al, 2012). Thirdly, vitamin D
is involved in the synthesis of norepinephrine and dopamine, which gets imbalanced in
mood disorders (Eyles et al, 2013). Additionally, vitamin D maintains the antioxidant
glutathione in brain, thereby protecting brain from oxidative damage. Lastly, VDRs are
present in the areas of brain involved in planning, processing and formation of new
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memories (Eyles et al, 2013).

Many studies have been designed to investigate an association between postpartum

depression and vitamin D. Recently, four observational studies were performed in this
regard. Fu et al(2015) conducted a prospective cohort study in 248 pregnant women in China
to examine an association between serum vitamin D levels 24 hours after delivery and
postpartum depression. The investigators reported that serum 25OHD levels were
significantly higher in women with no postpartum depression (p<0.001). After adjusting for
confounders and using multivariate analysis, they found increased risk of postpartum
depression with 25OHD levels ≤ 10.2 ng/ml (OR 7.17, CI 3.81–12.94, p< 0.001). Gur et
al(2015) reported a significant association between mid-pregnancy vitamin D levels and
postpartum depression. They conducted this study in 678 Turkish pregnant women,
measured serum 25OHD level between 24–28 weeks of gestation and then assessed these
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women for postpartum depression using Edinburgh Postnatal Depression Scale (EPDS) at 1
week, 6 weeks and 6 months postpartum. The investigators also found significant negative
correlation between vitamin D levels and EDPS at all the three follow-up periods (r= −0.2,
−0.2, −0.3, respectively). Robinson et al (2014) also demonstrated a positive association
between vitamin D deficiency and postpartum depression. On the contrary, Gould et
al(2015) performed a similar study on a large cohort of 1,040 women in Australia. They
measured cord blood 25OHD and then evaluated these women for postpartum depression
symptoms using EPDS at six weeks and six months postpartum. They reported no
association between cord blood vitamin D levels and postpartum depression. Although the
results from various studies are conflicting, postpartum depression might be associated with
vitamin D deficiency but the studies have been inconsistent in their results and warrant more
extensive studies in this regard.
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Adverse fetal outcomes associated with vitamin D deficiency

Low birth weight (LBW) and Small for Gestational Age (SGA)
Vitamin D plays a role in fetal growth by regulating calcium homeostasis and parathyroid
hormone levels (Hollis et al, 2011). Maternal vitamin D adequacy improves the fetal
outcomes in the form of birth weight sufficiency that has been proven by many but not all

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studies. Most of them are observational studies. In our search, we found 9 studies that
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reported this correlation; 3 were cross sectional studies, 3 were case control studies and 3
were prospective cohorts. Chen et al(2015) performed a population-based cohort, recruiting
3,658 mother-fetus pairs. Maternal serum 25OHD level was measured at anytime during
pregnancy. A positive correlation was found between maternal 25OHD levels and neonatal
birth weight (r = 0.477, p <0.001). Similar results were reported by other investigators
(Khalessi et al, 2015; Morgan C et al, 2016; Gernand et al, 2014; Mirzaei et al, 2015;
Aydogmus et al, 2016). Another study undertaken in China by Zhu et al(2015) measured the
cord blood 25OHD levels and its association with low birth weight and SGA in 1,491
neonates. They reported that per 10 nmol/L increase in the cord blood 25OHD level, birth
weight increased by 61.0 gm at concentration less than 40 nmol/L of 25OHD, and then
decreased by 68.5 gm at concentrations from 40–70 nmol/L. This is the first study to report
inverted U-shaped relationship between neonatal vitamin D status and fetal growth.
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However, other studies failed to establish any association between vitamin D levels and fetal
birth weight (Schneuer et al, 2014; Rodriguez et al, 2015). Conflicting results were found in
the interventional studies for vitamin D supplementation and its impact on offspring birth
weight. One of these studies conducted by Mojibian et al (2015) in Iranian pregnant women
found no difference on vitamin D supplementation on the fetal outcomes. Another RCT
carried out by Hossain et al(2014) found improved outcomes with vitamin D
supplementation, but the results did not reach statistical significance. Thus, most of the
findings suggest that vitamin D deficiency increases the risk of low birth weight infants.
However, large scale well-designed interventional studies are required to further establish
the role of vitamin D supplementation to improve fetal outcomes.

Respiratory infections
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Vitamin D receptors (VDRs) are present on almost every immune cells, and activation of
VDRs play a critical role in adaptive and innate immunity, along with the regulation of
inflammatory response (Esposito et al, 2015). There are multiple mechanisms by which
vitamin D could regulate inflammatory response: (i) vitamin D controls the activity of
macrophages and dendritic cells and various events in response to the activation of Toll-like
receptors in neutrophils (Greiller et al, 2015), (ii)vitamin D inhibits the function of dendritic
cells by restricting their maturation, antigen presentation and the production of cytokines,
like IL-12 and IL-23 (Esposito et al, 2015), (iii) vitamin D induces the expression of two
antimicrobial peptides, cathelicidin and β-defensin, which are critical in innate immunity
through chemotactic action and neutralization of toxins (Sá et al, 2015), and (iv) vitamin D
shifts the cytokine expression from type 1 to type 2 cells response, thus contributing to the
maintenance of self-tolerance (Wei et al, 2015). Thus, based on the potent
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immunomodulatory effect of vitamin D, several studies have linked vitamin D deficiency to

the increased risk of respiratory tract infections in children. It has been hypothesized that
maternal vitamin D deficiency increases the risk of respiratory tract infections in their
offspring. Few investigators recently studied this association. Five observational studies have
been conducted. Onwuneme et al(2015) performed a study in 94 preterm infants and found
that low serum 25OHD levels (<30 nmol/L) in pre-terms were associated with increased
oxygen requirements (p=0.008), increased duration of intermittent positive pressure
ventilation (p=0.032), and more requirement of assisted ventilation (p=0.013). Luczynska et

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 Agarwal et al. Page 11

al (2014) performed a prospective cohort study on 777 mother-child pairs in Germany and
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found a statistically significant association between 25OHD levels in cord blood and
susceptibility to lower respiratory tract infection (LRTI). The adjusted risk-ratio for vitamin
D deficient infants (<25 nmol/L) was 1.32 in comparison to the reference group (>50
nmol/L). In Turkey, Dinlen et al(2016) reported the same conclusions. They performed a
study in 60 infants, 30 with acute LRTI term infants and 30 controls matched for gestational
age, weight and gender and reported lower serum 25OHD levels in mothers of the study
group (p=0.0001). However, Jongh et al(2014) reported no association between the two
based on a cohort study performed on 2,025 mother child pairs in Southampton, UK with
mother’s serum 25OHD measured at 34 weeks’ gestation and infants followed up at 6,12
and 24 months for respiratory symptoms. In summary, maternal vitamin D deficiency can
increase the risk of respiratory infections in infants. This conclusion is yet to be confirmed
by interventional studies.
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Immunity and Allergies

As mentioned earlier, Vitamin D plays an important role in the immunomodulation through
its effect on the function of T and B lymphocytes. While in T cells, it promotes Th2 cell-
mediated anti-inflammatory response, in B cells vitamin D promotes the production of
immunoglobulins and inhibition of memory B cells and generation of plasma cells
(Szymczak et al, 2016).

To validate the association between maternal vitamin D status and development of allergies,
including eczema and asthma in their offspring, recently four observational studies and two
interventional studies have been carried out. In Taiwan, a study was conducted in 164
mother-child pairs cohort to study this association (Chiu et al, 2015) and reported protective
effect of vitamin D in protecting children from allergies, eczema and asthma after following
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up children for up to 4 years of age. Maslova et al(2014) conducted a prospective cohort

study in Denmark in 965 pregnant women and their offspring were followed until adulthood
for airway allergic diseases and lung function. In this study, higher levels of maternal
vitamin D ≥ 125 nmol/L was found to be associated with higher incidence of allergies in
children (Hazard Ratio, HR=1.81, 95% CI = 0.78–4.16). In UK, Miller et al(2015) studied
the association between maternal vitamin D and neonatal inflammatory and allergic
response by studying the response of neonatal nasal airway epithelial cells (AECs). They
reported that increased maternal vitamin D was associated with increased release of IL-10
by AECs after stimulation with TNF-α/IL-1β (p=0.024) or house dust mite (p=0.049). It
was concluded that there exists an association between maternal micronutrient intake and the
function of neonatal airway cells and hence may impact the development of asthma or
allergies later in life. Jones et al (2015) selected a cohort of mothers with history of atopy
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and investigated the association of vitamin D in them to the immune response in their
children and found that improving serum 25OHD level during pregnancy or early infancy
can lower the risk of allergies by inhibiting the inflammatory cytokines associated with
allergies.

This association has been of interest for carrying out interventional studies as well. Vitamin
D Antenatal Asthma Reduction Trial (VDAART) (Litonjua et al, 2016) was a randomized,

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 Agarwal et al. Page 12

double blind, placebo controlled trial conducted across three centers in the United States. A
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total of 881 pregnant women at 10–18 weeks’ gestation at high risk of having children with
asthma were included in the study. They reported that the risk of asthma and wheeze-related
disorders were lower in vitamin D supplemented women by 6.1% compared to the placebo
group, although it did not reach statistical significance. Another interventional study took
place in Japan (Norizoe et al, 2014) which studied the impact of maternal vitamin D
supplementation during lactation to improve the outcomes in infantile allergic disorders like
eczema. They concluded that although vitamin D supplementation did not decrease the
incidence of eczema, but it enhanced the risk of food allergies up to 2 years of age (RR 3.42,
95% CI: 1.02–11.77; p=0.030). In conclusion, there is still no definite evidence of whether
vitamin D supplementation increases or decreases the risk of allergies and therefore, requires
further exploration.

Anthropometry
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Vitamin D plays a primary role in bone remodeling, calcium homeostasis and muscle
functioning. Its deficiency in pregnancy is associated with impaired bone development, fetal
growth and other unfavorable effects on musculoskeletal system of the offspring (Kovacs et
al, 2014).

Some studies have shown adverse effects of maternal vitamin D deficiency on the
anthropometric measures of the offspring. This includes one cohort study (Morales et al,
2015) and four RCTs (Hashemipour et al, 2013; Hossain et al, 2014; Nandal et al 2015;
Roth et al, 2015). Morales and colleagues(2015) conducted a study in a cohort of 2,358
pregnant women in Spain and measured serum 25OHD levels at any time during gestation.
Child’s femur length, bi-parietal diameter and abdominal circumference were noted through
ultrasound findings at 12, 20 and34 weeks of gestation. They found no association of
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maternal serum 25OHD level with femur length and a weak inverse association with bi-
parietal diameter at 34 weeks.

A single center randomized clinical trial in Pakistan reported no favorable outcomes on fetal
growth by vitamin D supplementation (Hossain et al, 2014). Nandal et al(2015) conducted a
case control study of 120 pregnant women in India and found that the women’s offspring
supplemented with vitamin D had higher birth weight and crown heel length compared to
the non-supplemented group (3.1 ± 0.485 kg vs 2.8 ± 0.705 kg and 49.35 ± 1.36 cm vs 48.67
± 2.12 cm, respectively). Similarly, Hashemipour et al (2013) conducted a randomized
controlled trial in 130 Iranian pregnant women and reported that mean length (p=0.01), head
circumference (p=0.001) and weight (p=0.01) were higher in the intervention group
compared to the control group. There is an ongoing trial in Dhaka, Bangladesh to estimate
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the effects of prenatal and postnatal supplementation of different doses of vitamin D vs

placebo on infant length at 1 year of age (Roth et al, 2015). In this study, healthy pregnant
women in second trimester have been randomized to receive either vitamin D 4,200 IU/wk,
16,800 IU/wk or 28,000 IU/wk and placebo in the postpartum period or 28,000 IU/wk in the
prenatal and postpartum period, and the infants will be followed up at regular intervals for
growth monitoring upto 1 year of age. A recently published meta-analysis of RCTs by
Pérez-López et al (2015) also concludes positive outcomes of vitamin D supplementation in

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 Agarwal et al. Page 13

pregnancy on offspring birth weight and length. Thus, our analysis of the published findings
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also supports that vitamin D supplementation in pregnancy has a positive impact on fetal
growth.

Vitamin D and autism

A recent meta-analysis by Wang et al (2015) investigated the possible mechanisms by which
vitamin D could potentially influence the occurrence of autism spectrum disorders in
children. Firstly, it influences the early brain development in children. It plays a role in
neuronal differentiation, neurotransmission and synaptic functions (Wang et al, 2015).
Secondly, as vitamin D is involved in the immune system homeostasis and autism is
considered an autoimmune disorder, so it is considered that vitamin D deficiency may alter
T cell activation profile and affect the adaptive immunity and cause preponderance to autism
(Currenti, 2010). Also, oxidative stress may increase the susceptibility to autism by their
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lethal interaction with genetically susceptible genes. Glutathione is an antioxidant that

protects the brain from the oxidative stress and vitamin D increases the level of glutathione
in the brain, thereby protecting it from preventable conditions like autism (Cannell, 2008).
Serotonin plays an essential role in controlling emotions. Vitamin D activates the serotonin-
synthesizing gene in the brain and inversely affects the serotonin production in peripheral
tissues (Patrick et al, 2014). It is seen that autistic individuals have lower concentration of
serotonin in brain and higher in their blood, indicating that vitamin D could be potentially
involved in the underlying pathogenesis. Lastly, vitamin D deficiency could increase the risk
of genetic mutations by inhibiting DNA repair of early mutations, and thus could contribute
to the appearance of autism (Wang et al, 2015).

An interventional study recently reviewed the benefits of vitamin D supplementation in

pregnant women to decrease the incidence of autism in the offspring. This was conducted by
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Stubbs et al(2016) whereby the investigators supplemented pregnant women with previous
autistic child, with 5,000 IU/day of vitamin D followed by supplementation of newborn with
1,000 IU/day vitamin D for first three years of life. These children were followed up at 18
and 36 months of age. The results were promising, with only 1 out of 19 children developing
autism (5%), compared to the general recurrence risk of 20%. This single recent study
suggests that vitamin D supplementation in pregnancy could reduce the risk of autism in
children, but more studies are warranted to confirm the conclusion.

CONCLUSION
Vitamin D deficiency is increasing worldwide, both in general population and in pregnant
women. In pregnancy, it has been found to be associated with increased incidence of adverse
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maternal and fetal outcomes, primarily preeclampsia, GDM, low birth weight and preterm
births. Other outcomes are still under study and no definite conclusions have been drawn
yet. The critical evaluation of the published findings on the maternal and fetal outcomes in a
large number of observational studies and critical trials in a large cohort provide high level
of evidence for an association between vitamin D and preeclampsia, GDM in maternal
outcomes and, small for gestational age and anthropometry in fetal outcomes (Table 4).
Other maternal-fetal outcomes have moderate level of evidence of association with vitamin

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 Agarwal et al. Page 14

D, as reported in other reports and meta analyses. In our review of the findings, we also
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found association between vitamin D and recurrent pregnancy loss and association between
vitamin D and autism, although the level of evidence remains low, thereby requiring
additional studies to confirm the association. However, the question still remains whether
there is any causal relationship between vitamin D deficiency and the maternal and fetal
outcomes or it is just one of the manifestations of these conditions. The etiology of the
various maternal and fetal outcomes is complex and multifactorial with many confounding
factors. To determine the benefits of vitamin D supplementation in pregnancy would require
further evaluation through large, multicenter double-blind randomized controlled clinical
trials, with a focus on specific adverse pregnancy outcomes. Additionally, dose-response
randomized trials would be helpful in identifying the optimal dosage for supplementation
and potential long-term side effects of vitamin D therapy.
Author Manuscript

Acknowledgments
This work was supported by research grants R01HL116042, R01HL112597, and R01HL120659 to DK Agrawal
from the Office of the Dietary Supplement, NIH Director’s Office and the National Heart, Lung and Blood Institute,
NIH, USA. The content of this review article is solely the responsibility of the authors and does not necessarily
represent the official views of the National Institutes of Health.

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 Agarwal et al. Page 20
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Figure 1.
The schematic diagram depicts the adverse maternal and fetal outcomes associated with
vitamin D deficiency.
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 Agarwal et al. Page 21
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Figure 2.
The sxhematic diagram depicts the activation of vitamin D by two hyroxylation steps, one
each in liver and kidney, followed by the normal physiological role of vitamin D in each
organ. The specific maternal and fetal repercussion of vitamin D deficiency are mentioned
below the dotted line.
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Table 1

Observational studies of vitamin D status in pregnancy and maternal outcomes

Study design Place of study Sample size Gestational age Vit D Assay Outcome analyzed Statistics (95% CI) Study authors Quality of
at Vit D assay method evidence
Agarwal et al.

(GRADE
system)

Case control India 74 cases and On enrollment ELISA Preeclampsia p= 0.0001 Singla et al, 2015 Moderate
100 controls

Case control Iran 59 cases and Before the onset ELISA, HPLC Preeclampsia OR 24.04 (2.10–274.8) Abedi et al, 2014 Low
59 controls of labor

Case control Iran 41 cases and Onset of labor ELISA Preeclampsia P=0.0001 Mohagegh et al, Moderate
50 controls 2015

Case control USA 717 cases and <26 weeks LC-MS Preeclampsia Adjusted RR 0.65 Bodnar et al, 2014 Moderate
2986 controls (0.43–0.98)

Case control Iran 40 cases and Anytime CLIA Preeclampsia P=0.002 Sadin et al, 2015 Moderate
40 controls

Case control USA 1126 cases <20 weeks LC-MS PTL P<0.01 Bodnar et al, 2015 Moderate
and 2327
controls

Case control USA 79 cases and At delivery CLIA, RIA PTL Thota et al, 2014 Moderate
113 controls
(Caucasian) P<0.01
(African American) P<0.04

Case control USA 839 cases and <26 weeks LC-MS PTL - Bodnar et al, 2015 Moderate
2629 controls

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Case control China 821 On admission ELISA PTL P<0.001 Zhu et al, 2015 High

Case control India 46 cases and At delivery ECLIA C-section OR 2.31 (0.77–6.92) Sebastian et al, Moderate
46 controls 2015

Nested case control Sweden 39 cases and 12 weeks ELISA Preeclampsia p=0.3 Gidlof et al, 2015 High
120 controls

Nested case control Canada 169 cases and <20 weeks ELISA Preeclampsia OR 2.23 (1.29–3.83) Achkar et al, 2015 Moderate
1975 controls
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Study design Place of study Sample size Gestational age Vit D Assay Outcome analyzed Statistics (95% CI) Study authors Quality of
at Vit D assay method evidence
(GRADE
system)

Nested case control USA 400 15–21 weeks LC-MS Preeclampsia OR 1.4 (0.7–3.0) Wetta et al, 2014 Moderate
Spontaneous preterm birth OR 1.3 (0.6–3.0)
Agarwal et al.

Nested case control Australia 5109 10–14 weeks CLIA Adverse pregnancy OR 1.20 (0.69–2.07) Schnueur et al, High
outcomes (SGA, preterm 2014
births, preeclampsia, GDM,
miscarriage and stillbirth)

Nested case control USA 135 cases and On enrollment LC-MS/MS GDM P<0.05 Arnold et al, 2015 Low
517 controls (Avg 16 weeks)

Cross sectional study Poland 280 11–13 weeks ECLIA Preeclampsia Not significant Bomba Opon et Low
al, 2014

Cross sectional study USA 1591 16.4–36.9 weeks CLIA/RIA Preeclampsia Adjusted OR 1.14 Burris et al, 2014 Moderate
(mean 27.9 (0.77–1.67)
weeks)
Gestational hypertension Adjusted OR 1.32
(1.01–1.72)

Cross sectional study Egypt 160 On enrollment RIA Glycemic control in GDM P<0.05 Lithy et al, 2014 Low

Cross sectional study UK 1467 26 weeks LC-MS GDM NS Whitelaw et al, Moderate
2014

Cross sectional study Turkey 687 24–28 weeks ELISA Postpartum depression at Gur et al, 2015 Moderate
1 week P=0.003
6 weeks P=0.004
6 months P<0.001

Crit Rev Food Sci Nutr. Author manuscript; available in PMC 2019 March 24.
Retrospective cross US 133 - LC-MS/MS Recurrent pregnancy loss - Ota et al, 2014 Low
sectional study

Prospective study Canada 655 6–13 weeks LC-MS/MS GDM OR 1.48, p=0.04 Lacroix et al, Moderate
2014

Prospective study Korea 523 12–14, 20–22, ECLIA GDM and pregnancy Adjusted OR 0.647. Park et al, 2014 Moderate
32–34 weeks outcomes (Apgar,
miscarriage, birth weight)

Prospective cohort study Netherlands 2074 12 weeks ELISA Pregnancy related OR 1.88 (0.79–4.48) Weert et al, 2016 Low
hypertensive disorders
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Study design Place of study Sample size Gestational age Vit D Assay Outcome analyzed Statistics (95% CI) Study authors Quality of
at Vit D assay method evidence
(GRADE
system)

Prospective cohort study Spain 2382 Avg 13.5 weeks HPLC GDM RR=0.92 (0.55,1.55) Rodriguez et al, High
2015
Agarwal et al.

PTL p>0.4
C-section RR=0.60 (0.37,0.97)
FGR, SGA, HC, B wt, p>0.4
length

Prospective cohort study Australia 796 18 weeks ELISA, LC-MS Postpartum depression OR 2.19 (1.26–3.78) Robinson et al, Moderate
2014

Cohort study Australia 1040 At delivery LC-MS/MS Postpartum depression at Gould et al, 2015 Moderate
6 weeks Adjusted RR 0.92,
p=0.11 (0.84–1.02)
6 months Adjusted RR=0.96,
p=0.41 (0.88–1.05)

Cohort study Singapore 940 26–28 weeks ID-LC-MS GDM (0.01–0.14) Loy et al, 2015 Moderate
C-section OR 1.39 (0.95–2.05)

Cohort study China 213 24–48 hrs after LC-MS/MS Postpartum depression P<0.0001, OR 7.17 Fu et al, 2015 Moderate
delivery (3.81–12.94)

Retrospective cohort study USA 235 5–12 weeks ELISA Pre- eclampsia, PTL, GDM, Adjusted OR 1.01 Flood-Nichols et Low
spontaneous abortion (0.961–1.057) al, 2015

Cohort study US 2798 <26 weeks LC-MS/MS C-section, prolonged labor Gernand et al, Moderate
and instrumental delivery 2015

Retrospective cohort study UK 995 11–13 weeks LC-MS/MS Mode of delivery P=0.53 Savvidou et al, Moderate

Crit Rev Food Sci Nutr. Author manuscript; available in PMC 2019 March 24.
2012

Abbreviations used: Vit D (vitamin D), ELISA (Enzyme Linked Immune sorbent Assay), CLIA (Chemiluminescent Immunoassay), LC-MS/MS (Liquid Chromatography tandem Mass Spectrometry),
HPLC (High performance liquid chromatography), RIA (Radio Immune sorbent Assay), GDM (gestational diabetes mellitus), PTL (Preterm labor), SGA (small for gestational age), B Wt (birth weight),
HC (head circumference), C-section (Cesarean section), FGR (Fetal growth rate)
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Table 2

Observational studies of vitamin D status in pregnancy and fetal outcomes

Study design Place of study Sample size GA at vit D assay Vit D assay Fetal Outcome Statistics (CI) Study authors Quality of
method evidence
Agarwal et al.

(GRADE
system)

Case control Iran 40 cases At delivery ELISA SGA P=0.003 Mirzaei et al, 2015 Moderate

Case control Turkey 30 cases and On admission LC-MS/MS LRTI in infants P=0.001 Dinlen et al, 2016 Moderate
30 controls

Case control India 60 cases and At delivery ELISA Birth weight P=0.004 Nandal et al, 2015 Moderate
60 controls

Nested case control Canada 607 cases and At delivery CLIA Neonatal outcomes (LBW, OR 0.47 (0.23–0.97) Morgan et al, 2016 Moderate
1027 controls SGA, preterm births)

Cohort study China 1491 At delivery RIA Birth weight and risk of P<0.001 Zhu et al, 2015 Moderate
SGA

Cohort study China 3658 Anytime during pregnancy RIA Birth weight r=0.477, p<0.001 Chen et al, 2015 Moderate

Cohort study Spain 2358 13–15 weeks HPLC Fetal growth and risk of Morales et al, 2015 High
overweight.
AC >= 90th percentile OR 1.50, P=0.041
(1.01–2.21)
EFW >= 90th percentile OR 1.47, P=0.046
(1.00–2.16)

Cohort study Taiwan 164 Before delivery LC-MS/MS Allergic disorders Chiu et al, 2015 Moderate
Eczema (at age 4) OR 0.12, p=0.012
(0.02–0.63)

Crit Rev Food Sci Nutr. Author manuscript; available in PMC 2019 March 24.
Asthma (at age 4) OR 0.22, p=0.038
(0.06–0.92)

Cohort study Denmark 32456 Mid pregnancy - Allergic diseases and P=0.21 Maslova et al, 2014 Low
asthma

Prospective cohort Germany 777 At delivery EIA Risk of LRTIs Adjusted RR 1.32 Luczynska et al, Moderate
(1.00, 1.73) 2014

Cross sectional Turkey 152 Anytime during pregnancy ELISA Perinatal outcomes Aydogmus et al, Low
2015
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Study design Place of study Sample size GA at vit D assay Vit D assay Fetal Outcome Statistics (CI) Study authors Quality of
method evidence
(GRADE
system)
C-section p=0.176
Perinatal complications OR 4.30 (1.85–9.99)
Agarwal et al.

SGA OR 4.7 (1.41–15.78)

Cross sectional Ireland 94 At delivery Vit D total Respiratory outcomes in Onwuneme et al, Low
automated preterm infants 2015
competitive
binding Oxygen requirement P=0.008
protein assay
Need for assisted P=0.13
ventilation
Duration of IPPV P=0.32

Cross sectional Iran 102 At delivery EIA LBW P=0.001 Khalessi et al, 2015 Moderate

Cross sectional Australia 225 At delivery LC-MS/MS Immunity and Allergies Jones et al, 2015 Moderate
Response to HDM by
IL-13 P=0.002
IL-5 P=0.001
IL-5 response to OVA P=0.009

Cohort study US 792 12–26 weeks LC-MS/MS SGA P=0.028 Gernand et al, 2014 Moderate

Abbreviations used: GA (Gestational age), Vit D (vitamin D), ELISA (Enzyme Linked Immune sorbent Assay), CLIA (Chemiluminescent Immunoassay), LC-MS/MS (Liquid Chromatography tandem
Mass Spectrometry), HPLC (High performance liquid chromatography), RIA (Radio Immune sorbent assay), EIA (Enzyme Immune assay), GDM (gestational diabetes mellitus), GHTN (Gestational
Hypertension), SGA (small for gestational age), LBW (low birth weight), HC (head circumference), CI (Confidence Interval), OR (Odd’s Ratio), RR (Risk Ratio), IPPV (Intermittent positive pressure
ventilation), AC (Abdominal circumference), ADHD (attention deficit hyperactivity disorder), EFW (estimated fetal weight), LRTI (Lower respiratory tract infections), C-section (Cesarean section), HDM
(House dust mites), OVA (ovalbumin).

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Table 3

Randomized Controlled Trials of vitamin D supplementation in pregnancy

Place of study No. of participants Intervention Vit D assay Duration of intervention Outcomes Study authors Quality of
method evidence
Agarwal et al.

(GRADE
system)

Iran 50 Placebo ELISA 6 weeks Metabolic profile of Asemi et al, 2013 High
Calcium 1000 mg/day + Vit D3 women with GDM
50,000 U on day 1 and 21

Australia 209 LD vit D3 400 U/day CLIA till delivery Primary: GDM Yap et al, 2014 High
HD vit D3 5,000 U/day Secondary: maternal and
neonatal outcomes

Iran 500 LD vit D 400 U/day - till delivery GDM, GHTN, pre- Mojibian et al, 2015 High
HD vit D 50,000 U/day eclampsia, preterm, LBW.

Pakistan 193 FeS04 200mg + Calcium 600mg/day CLIA 20 weeks to delivery Pregnancy outcomes Hossain et al, 2014 High
+ Vit D3 4,000 U/day (GDM, GHTN, preterm
labor, SGA, B wt, length,
HC, Apgar at 1 and 5 min)

India 180 No intervention ELISA Preterm, pre- eclampsia, Sablok et al, 2015 High
Vit D3 120,000 IU at 20, 24, 28 and GDM, LBW and Apgar
32 weeks scores at 1 and 5 minutes

Iran 60 Placebo ELISA 12 weeks Metabolic profiles in Samimi et al, 2015 High
Calcium 1000mg/day + vit D3 women at risk of pre-
50,000 IU every 2 weeks eclampsia

Iran 46 Placebo ELISA 9 weeks Outcomes in Pre- Asemi et al, 2015 High
MM 800mg Ca+ 200mg Mg+ 8mg eclampsia patients
Zn + Vit D3 400 IU

Iran 60 Placebo ELISA 12 weeks Metabolic profile and Karamali et al, 2015 High
Vit D3 50,000 IU every 2 wks outcomes in pre-eclampsia
patients

US 440 Placebo+ MV with Vit D 400 IU/day CLIA, LC-MS till delivery Asthma and recurrent Litonjua et al, 2016 High
Vit D +MV with Vit D 4400 IU/day wheezing in offspring

Crit Rev Food Sci Nutr. Author manuscript; available in PMC 2019 March 24.
Japan 164 Placebo 6 weeks Allergies like infantile Norizoe et al, 2014 High
Vit D3 800 IU/day eczema, atopic dermatitis,
food allergy and wheeze

Iran 130 MVI + Ca 400 IU/day ELISA 8 weeks Fetal growth (length, HC, Hashemipour et al, Moderate
MVI+ Ca 400 IU/day + Vit D3 weight) 2013
50,000 IU/ week

Abbreviations used: Vit D (vitamin D), MVI (Multivitamin Injection), ELISA (Enzyme Linked Immune sorbent Assay), CLIA (Chemiluminescent Immunoassay), LC-MS/MS (Liquid Chromatography
tandem Mass Spectrometry), GDM (gestational diabetes mellitus), GHTN (Gestational Hypertension), SGA (small for gestational age), LBW (low birth weight), HC (Head circumference),
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Table 4

Summary of the various maternal-fetal outcomes studies with the level of evidence of association with vitamin
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D.

Outcomes Total no. of studies Total no. of studies Quality of evidence

(observational) (interventional) (GRADE system)

Preeclampsia 11 3 High

Gestational Diabetes Mellitus 8 6 High

Cesarean section 5 0 Moderate

Preterm Delivery 5 4 Moderate

Recurrent pregnancy loss 1 0 Low

Postpartum Depression 4 0 Moderate

Low Birth weight and Small for gestational 9 2 High

age

Respiratory infections 5 0 Moderate

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Immunity and allergies 4 2 Moderate

Anthropometry 1 4 High

Autism 0 1 Moderate
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Crit Rev Food Sci Nutr. Author manuscript; available in PMC 2019 March 24.