A systematic review of association between vitamin D levels and pre-eclampsia in pregnant womens - An old problem revisited

The bene(cid:976)icial effects of sunlight in preventing bone-related disorders have been well-known for centuries. Vitamin D is a modi(cid:976)ied steroid, synthesised under the in(cid:976)luence of sunlight in the skin. Low Vitamin D status has associated with a higher risk of pre-eclampsia in pregnant womens. The aim of this study was to undertake a systematic review of different studies investigat-ing the association between Vitamin D levels and pre-eclampsia in pregnant womens. A systematic review was undertaken. MEDLINE, PUBMED, EMBASE, Google Scholar were searched. The review protocol was designed to answer the question. Search terms (Preeclampsia and Vitamin D or 1,25 dihydroxy vitamin D). The search was con(cid:976)ined to peer-reviewed articles that were published in English and contained an abstract. Reference list of journal articles were also screened for additional citations (cid:976)itting our search criteria. Twenty-Seven studies were included in the systematic review that investigates the association between Vitamin D and pre-eclampsia. The present systematic review concludes that maternal vitamin D de(cid:976)iciency in pregnancy is signif-icantly associated with an elevated risk of preeclampsia. Pregnant womens should take vitamin D supplementation, expose themselves into the sunlight, and they should be physically active. Further taking Vitamin D supplementation in early pregnancy may be a simple way to reduce the risk of these adverse pregnancy outcomes. abstract. Reference list of journal articles were also screened for additional citations (cid:976)itting our search criteria.


A
The bene icial effects of sunlight in preventing bone-related disorders have been well-known for centuries. Vitamin D is a modi ied steroid, synthesised under the in luence of sunlight in the skin. Low Vitamin D status has associated with a higher risk of pre-eclampsia in pregnant womens. The aim of this study was to undertake a systematic review of different studies investigating the association between Vitamin D levels and pre-eclampsia in pregnant womens. A systematic review was undertaken. MEDLINE, PUBMED, EMBASE, Google Scholar were searched. The review protocol was designed to answer the question. Search terms (Preeclampsia and Vitamin D or 1,25 dihydroxy vitamin D). The search was con ined to peer-reviewed articles that were published in English and contained an abstract. Reference list of journal articles were also screened for additional citations itting our search criteria. Twenty-Seven studies were included in the systematic review that investigates the association between Vitamin D and pre-eclampsia. The present systematic review concludes that maternal vitamin D de iciency in pregnancy is significantly associated with an elevated risk of preeclampsia. Pregnant womens should take vitamin D supplementation, expose themselves into the sunlight, and they should be physically active. Further taking Vitamin D supplementation in early pregnancy may be a simple way to reduce the risk of these adverse pregnancy outcomes.

INTRODUCTION
Vitamin D is endogenously produced by the exposure of skin to sunlight, and it gets absorbed from the foods containing or supplemented with Vitamin D. Vitamin D is a group of steroid hormones originating from both diet and sunlight, and it also plays an important role in immunity and many aspects of cell functioning, and it is necessary for calcium and phosphorous metabolism. Vitamin D3, which is derived from skin synthesis by exposure to 7-dehydrocholesterol, concentrated in the basal and stratum spinosum stratums, to ultraviolet B (UV-B) radiation, is the main source of Vitamin D in humans (~90 percent). (Ra i, 2014;Dhok et al., 2020). Vitamin D is hydroxylated to form 25 hydroxyvitamin D [25(OH) vitamin D] in the liver. (Hollis, 2005) Maternal vitamin D de iciency is a popular public concept Decreased rates of low vitamin D status are found worldwide in pregnant mothers. (Halicioglu et al., 2012) The major causes of de iciency are poor nutrition, lack of exposure to sunlight, decreased vitamin D synthesis. (Gusain and Butola, 2020) Vitamin D has been correlated with numerous pregnancy developments, such as gene regulation and early placental pregnancy expression, fetomaternal immunological tolerance, and anti-in lammatory responses. (Shin et al., 2010) Vitamin D de iciency is recognized as a global health issue in the world.  In terms of its involvement in preeclampsia-associated pathophysiology, vitamin D de iciency has recently become more acute. (Hyppönen et al., 2013) Vitamin D has an immunosuppressive role in modulating pro-in lammatory reactions and reducing oxidative stress in PE, promoting angiogenesis through vascular endothelial growth factor ( VEGF) and gene regulation, and reducing blood pressure through the renin-angiotensin system. It has been documented that vitamin D de iciency in healthy women is correlated with increased secretion of proin lammatory cytokines. In vitro studies have shown that 1, 25(OH)2 D3 could modulate IL-6 and TNF-α expression by suppressing NF-κB. (Robinson et al., 2010;Holick, 2007) It has also been shown that vitamin D prevents activation and proliferation of T cells and stimulates IL-10 secretion and T-regulatory cell production, which are important for normal placental implantation in maternal immune tolerance. (Wei et al., 2012) Preeclampsia (PE) is a pregnancyspeci ic condition that affects several body systems, characterized by elevated blood pressure, proteinuria and elevated maternal and fetal mortality and morbidity after 20 weeks of pregnancy. (James et al., 2010;Roberts and Hubel, 2009;Laine et al., 2013) There are many factors in the development and progression of preeclampsia, such as maternal constitutional, angiogenetic, endothelial, syncytiotrophoblastic,(STMP) causes and in lammatory activation.

Vitamin D Physiology and Metabolism
Vitamin D is a classic steroid hormone involved in calcium homeostasis. The two major sources of Vitamin D are Vitamin D2 (Ergocalciferol) and Vitamin D3 (Cholecalciferol). (Gezmish and Black, 2013) D3 is the major source of human vitamin D (~90%) extracted from skin synthesis by exposure to ultraviolet B (UV-B) radiation of 7-dehydrocholesterol concentrated in the stratum basale and stratum spinosum. Latitude, season, aging, use of sunscreen, and pigmentation of the skin affect skin development of Vitamin D3. Naturally, ish liver oil, fatty ish, egg yolks, and liver contain large quantities of vitamin D. Vitamin D2 is derived from the diet and is contained in fungi from ultraviolet ergosterol irradiation. The two metabolites are transferred to the vitamin D binding protein (DBP) in the blood. (Barrett and McElduff, 2010) To become biologically active, these inactive Vitamin D metabolites must undergo a two-step hydroxylation process. Initially, vitamin D2 and D3 are hydroxylated in the maternal liver to form the inactive steroid precursor 25hydroxy-vitamin D (25[OH]D) via the action of vitamin D 25-hydroxylase, a cytochrome P450 enzyme (CYP27A1). The main circulating and stored source of vitamin D is 25[OH]D. Further hydroxylation occurs through the action of 25-hydroxyvitamin D -1-alpha-hydroxylase found in the maternal kidneys and placenta to form the active metabolite 1,25 hydroxy-vitamin D[1,25[OH]2D to enable biological activation. In a physiological regulatory loop, this mechanism in the kidneys is closely regulated by the parathyroid hormone, serum calcium and phosphorous levels. (Gezmish and Black, 2013) The serum 25(OH)D concentration is approximately 15 to 65ng / ml, and the circulating half-life of 25(OH)D is 2 to 3 weeks. The detection of 25-hydroxy-vitamin D (25[OH]D) is involved in calculating serum vitamin D levels. Due to the latter having a half-life of many minutes, we calculate 25[OH]D in comparison to the active 1,25[OH]D, compared to 3 weeks for the former. (Roberts and Hubel, 2009) The circulating 1,25(OH)2D concentration is strictly regulated primarily by PTH, phosphate, and calcium. Vitamin D,25(OH)D and 1,25(OH)2D are bound to vitamin D-binding protein (DBP) in circulation, a speci ic high-af inity transport protein also known as a serum or Gc-globulin group-speci ic portion. D concentrations of 1,25[OH]2 are far higher once pregnancy begins. (Hollis et al., 2011) However, there is a growing consensus that vitamin D intakes above the current recommendations may be associated with better health outcomes. (Ambad et al., 2020)
Cases-6.7236ng/ml, Controls-9.8862ng/ml P=0.004 (Bodnar et al., 2014) Maternal Vitamin D de iciency may be a risk factor for severe pre-eclampsia, but it is not associated with preeclampsia overall or its mild subtypes.  (Mohaghegh et al., 2015) Vitamin D levels was de icient in P.E Women's Case=15.2±13.6 ng/ml, Control=23.3±15.3 ng/ml p=0.001 (Rezaei et al., 2014) Vitamin D level of most pregnant womens was lower than normal. According to these indings, vitamin D de iciency can be considered as a risk factor for preeclampsia.
Cases=11.0±9.4ng/ml, Controls=16.3±10.0 P=0.003 (Karamali et al., 2015) Pregnant women who receive Vitamin D supplements had signi icantly increased serum Vitamin D levels compared to placebo, which reduces the risk of developing PE.
Case=5.5±3.32, Controls=8.05±4.81 p=0.001 Continued on next page Table 2 continued Author, year Key Findings of the studies Result (Scholl et al., 2013) Women who are vitamin D insuf icient develop secondary hyperparathyroidism, which is associated with an increased risk of pre-eclampsia.
18.4% of women whose 25(OH)D concentration were 20ng/ml. Risk of preeclampsia was increases 2.86-Fold (95% CI:1.28, 6.41 fold) early in gestation in these women. (Sadin et al., 2015) Pre-eclampsia can cause a decrease in the serum level of 25(OH)D.
Cases=6.88±9.46ng/ml, Controls= 13.41±8.05ng/ml p=0.688 search was con ined to peer-reviewed articles that were published in English and contained an abstract. Reference list of journal articles were also screened for additional citations itting our search criteria.

Inclusion Criteria
1. Clinical data on Vitamin D concentration in association with pre-eclampsia in any global setting.
2. Subjects that included pregnant participants aged 18years and above without medical comorbidities.

RESULTS
The structured literature search resulted in 181 articles. 12 Duplicate articles were removed, 17 articles were excluded based on titles and abstracts, 8 articles were identi ied through relevant reference, 29 articles were excluded based on inclusion criteria, 22 animal studies were excluded, and 26 relevant articles were selected according to the inclusion and exclusion criteria. The reviewed studies included 21 case-control studies, 4 cohort studies, 1 doubleblinded placebo study and 1 cross-sectional study.
Only the articles in English were considered in the study. A detailed summary of the search strategy and the result is presented in Figure 1 and Tables 1  and 2.

DISCUSSION
During pregnancy, vitamin D de iciency has been associated with a range of severe and long-term offspring health problems, including impaired growth, skeletal problems, type 1 diabetes, asthma and schizophrenia. Vitamin D has been involved in providing essential signals among placental trophoblast models in gene regulation and expression in early placental development. There is concern regarding vitamin D de iciency that the absence of these signals may play a critical role in placental development at Stage I, contributing to the eventual identi ication of Stage II and preeclampsia diagnosis. Pre-eclampsia pathogenesis includes a variety of biological processes that may be directly or indirectly impaired by vitamin D, including immune dysfunction, placental implantation, abnormal angiogenesis, excessive in lammation and hypertension.
In a major prospective study on vitamin D and preeclampsia performed by (Scholl et al., 2013), a two-fold increase in the incidence of preeclampsia was found to be less than 20 ng/ml in circulating vitamin D concentrations. Several studies have shown an increased risk of preeclampsia with maternal vitamin D de iciency or insuf iciency, as well as low total vitamin D intake. (Scholl et al., 2013) A case-control study performed by (Sadin et al., 2015) included 40 preeclampatic women aged 18 to 45 years in the study. In their report, 60% of preeclampatic women were vitamin D de icient with a level of vitamin D below 10ng / ml, and 40% were vitamin D de icient. Maternal vitamin D de iciency, including its effects on placental function and in lammatory response, is a common public health issue during pregnancy. (Shin et al., 2010) In early 2007, (Bodnar et al., 2007) observed the association between pre-eclampsia and vitamin D, claiming that a 50nmol / l decrease in vitamin D concentration doubles the risk of PE in pregnant women. (Bodnar et al., 2007) A study conducted by (Sadin et al., 2015) reported that the maternal 25(OH)D concentration was less than 10ng / ml, correlated with a 15-fold increase in the odds ratio of pre-eclampsia (adjusted OR, 14.98; 95 percent CI, 4.01-55.95). (Sadin et al., 2015) In a broad cohort sample, 1873 pregnant women participated and were divided into 4 groups, and serum levels of vitamin D were calculated using other parameters. In pregnant women, half of the pregnant women surveyed had Vitamin D de iciency and preeclampsia (OR 1.75, CI 1.16-2.58; P=0.010). (Bener et al., 2013) Since the research included a prospective longitudinal study of 221 participants, out of which 28 participants developed preeclampsia (42.6nmol / l, IQR 32.7-72.4,p=0.21), their study indicates that vitamin D de iciency and insuf iciency were prevalent in groups of women at high risk of preeclampsia. (Shand et al., 2010) A nested case-control study showed preeclampsia lowers Vitamin D concentration at a mean gestational age of 14 weeks. Women with 25(OH)D < 30nmol/L had a greater risk of developing PE(Adjusted odds ratio, 2.23;95%con i-dence interval,1.29-3.83). (Achkar et al., 2015) Vitamins supplementation therapy in pregnancy could help in reducing the incidence of gestational hypertension/preeclampsia. (Ambad et al., 2020)

CONCLUSION
The present systematic review revealed that maternal vitamin D de iciency in pregnancy is signi icantly associated with an elevated risk of preeclampsia. Pregnant womens should take vitamin D supplementation, expose themselves into the sunlight, and they should be physically active. Further taking Vitamin D supplementation in early pregnancy may be a simple way to reduce the risk of these adverse pregnancy outcomes.

Con lict of Interest
The authors declare that they have no con lict of interest for this study.