Next Article in Journal
Exploration of the Topical Nanoemulgel Bearing with Ferulic Acid and Essential Oil for Diabetic Wound Healing
Previous Article in Journal
Comparative Study of Injected Alzheimer’s Disease Models in Rats: Insights from Experimental Research
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Pathophysiology
Volume 31
Issue 4
10.3390/pathophysiology31040048
pathophysiology-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Systematic Review

Interplay Between Vitamin D Levels and Heavy Metals Exposure in Pregnancy and Childbirth: A Systematic Review

by
Tania Flores-Bazán
1,
Jeannett Alejandra Izquierdo-Vega
2,
José Antonio Guerrero-Solano
3,
Araceli Castañeda-Ovando
4,
Diego Estrada-Luna
1 and
Angélica Saraí Jiménez-Osorio
1,*
1
Área Académica de Enfermería, Instituto de Ciencias de la Salud, Universidad Autónoma del Estado Hidalgo, Circuito Ex Hacienda La Concepción S/N, Carretera Pachuca-Actopan, San Agustín Tlaxiaca P.O. Box 42160, Hidalgo, Mexico
2
Área Académica de Medicina, Instituto de Ciencias de la Salud, Universidad Autónoma del Estado de Hidalgo, Circuito Ex-Hacienda de la Concepción S/N, Carretera Pachuca-Actopan, San Agustín Tlaxiaca P.O. Box 42160, Hidalgo, Mexico
3
Área Académica de Enfermería, Escuela Superior de Tlahuelilpan, Universidad Autónoma del Estado de Hidalgo, Av. Universidad s/n Centro, Tlahuelilpan P.O. Box 42780, Hidalgo, Mexico
4
Área Académica de Química, Instituto de Ciencias Básicas e Ingeniería, Universidad Autónoma del Estado de Hidalgo, Carretera Pachuca-Tulancingo Km 4.5 s/n, Mineral de la Reforma P.O. Box 42184, Hidalgo, Mexico
*
Author to whom correspondence should be addressed.
Pathophysiology 2024, 31(4), 660-679; https://doi.org/10.3390/pathophysiology31040048
Submission received: 25 September 2024 / Revised: 24 October 2024 / Accepted: 19 November 2024 / Published: 21 November 2024
Browse Figure
Versions Notes

Abstract

:
Background/Objectives: Vitamin D (VD) deficiency has been associated with increased risk of gestational disorders affecting the endocrine system, immune system, and neurodevelopment in offspring. Recent studies have focused on the interaction between toxic elements and micronutrients during pregnancy. This review analyzes the potential relationships between VD levels and heavy metals in pregnant women and their offspring. Methods: A systematic review was conducted according to PRISMA 2020 guidelines, using databases such as PubMed, ScienceDirect, Cochrane Library, and Google Scholar. Boolean operators ‘AND’ and ‘OR’ were applied with terms like ‘pregnancy’, ‘vitamin D’, ‘heavy metals’, and ‘newborns’. Results: From 4688 articles, 14 studies were selected based on relevance and quality. These studies measured the levels of metals like lead (Pb), cadmium (Cd), mercury (Hg), and arsenic (As), in biological samples including maternal blood, umbilical cord blood, placenta tissue, and meconium during different stages of pregnancy, showing an inverse relationship between VD deficiency and heavy metal concentrations, which could be related to the incidence of preterm birth. Conclusions: The review highlights the importance of maintaining adequate VD levels during pregnancy, suggesting that sufficient VD may mitigate the adverse effects of heavy metal exposure, potentially reducing pregnancy-related complications.

1. Introduction

Over the past two decades, there has been growing concern about the impact of both VD deficiency and heavy metal exposure during pregnancy on maternal and fetal health. VD deficiency is typically defined by circulating 25-hydroxyvitamin D (25OHD) levels of 30 nmol/L [1]. In recent years, meta-analyses of maternal VD concentrations have consistently confirmed an inverse relationship between maternal 25OHD levels and the risk of gestational complications, including gestational diabetes [2,3,4], preeclampsia [3,5,6,7], anemia [8], preterm birth [9,10], spontaneous pregnancy loss and miscarriage in the first trimester [11,12,13], COVID-19 severity [14] and delivering small-for-gestational-age infants [3,15]. These findings underscore the crucial role of VD in maternal and fetal health, extending beyond its well-established functions in calcium homeostasis and skeletal mineralization.
Multiple factors contribute to VD deficiency, including genetic variants, age, obesity, VD supplementation practices, and sunlight exposure, which is further influenced by factors like season, latitude, skin-covering clothing, skin pigmentation, sunscreen use, and outdoor activity levels [16,17,18,19]. Additionally, environmental pollutants, such as particulate matter (PM2.5 and PM10), have been linked to altered maternal VD status [20,21] and reduced VD levels in newborns [22]. Exposure to endocrine-disrupting chemicals like phthalates and bisphenol A has also been associated with an increased risk of VD deficiency during pregnancy [23] and interference with VD endocrine signaling (VDES) [24].
The rising pollution in industrialized countries has led to increased exposure to toxic metals and metalloids through contaminated water sources used for agriculture and human consumption. This exposure often involves a combination of multiple metals and metalloids, rather than a single element, which can lead to more severe effects due to their synergistic interactions [25]. Previous studies have established a link between such exposure and an elevated risk of spontaneous preterm birth [26]. Caserta et al. [27] emphasized the significant impact of early exposure to heavy metals on placental permeability and neonatal outcomes. Specifically, Pb, Cd, and Hg have been shown to cross the placental barrier, accumulate in amniotic fluid and fetal tissues, and are associated with various adverse infant health outcomes, including endocrine, immune, neurological, and developmental disorders. Additionally, Bauer et al. [28] report that perinatal exposure to metals such as arsenic (As), copper (Cu), manganese (Mn), and selenium (Se) may contribute to behavioral development abnormalities in offspring.
Recent studies have consistently reported a strong association between prenatal Pb exposure and VD deficiency [29]. However, the existing literature lacks a comprehensive understanding of how VD status interacts with this topic and remains limited, underscoring the need for further investigation into whether there is a positive or negative relationship between VD levels and the presence of heavy metals and metalloids in pregnant women. In this context, the aim of this systematic review is to examine the available clinical evidence on the interaction between VD and heavy metals/metalloids, with a particular focus on their potential impact on maternal and offspring health.

2. Materials and Methods

2.1. Study Protocol

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines [30]. The protocol for the review was registered in the Prospective International Registry of Systematic Reviews (PROSPERO) under registration number CRD42024575680 on 27 August 2024. Three authors participated in the database search and in establishing the inclusion and exclusion criteria. All authors equally contributed to assessing the selected articles and extracting data.

2.2. Eligibility Criteria

The eligibility criteria were established by the corresponding authors (T.F-B and A.S.J-O.). During the selection process, four team members (T.F-B., J.A.G-S., J.A.I-V., and A.S.J-O.) independently searched databases using keywords and reviewed the titles and abstracts of retrieved references to identify relevant studies. Inclusion criteria focused on original human studies evaluating the impact of heavy metals and VD levels in pregnant women and their offspring. Eligible studies included the analysis of biological samples, pregnancy pathology, vitamin D supplementation, and the presence of at least one heavy metal or metalloid, as well as studies involving neonates and offspring, with no restriction on publication years. Animal studies, chronic degenerative diseases, studies on pregnant minors, or studies unrelated to pregnancy were excluded. The selected studies were validated by all authors, and in case of disagreement, a working meeting was convened to reach a consensus.

2.3. Search Strategy

Our systematic review included case–control, cohort, observational, and controlled clinical trials that examined the effects of vitamin D and heavy metal/metalloid levels in pregnant women and their offspring. A systematic search was conducted through 3 August 2024, across multiple databases, including PubMed, ScienceDirect, Cochrane Library, and Google Scholar. The search strategy combined free-text terms and keywords “Vitamin D status” “Vitamin D” “25-hydroxyvitamin”, “Pregnancy”, “Heavy Metals”, “Metal concentrations” and “Metalloids”, utilizing Boolean operators (AND/OR) for optimal term combinations. For instance, search queries included (((“Vitamin D” [Mesh]) AND “pregnancy” [Mesh]) AND “Metals, Heavy” [Mesh]) OR “Metalloids” [Mesh]). During the search process, no date restriction and filters by item type were applied.

2.4. Study Quality Assessment

Study quality was assessed by two reviewers (T.F-B and A.S.J-O.) using the Joanna Briggs Institute (JBI) checklist [31], which is specifically designed for case–control, cohort, cross-sectional analytical, and randomized controlled trials. This checklist evaluates the risk of bias through 10 questions covering criteria such as sample selection, exposure assessment, risk of confounding, and the appropriateness of the statistical analysis. Each question was answered “yes”, “no”, “unclear”, or “not applicable”, and the percentage of “yes” responses was used to determine the overall quality of each study.
The quality of the articles was categorized into three levels:
  • Q1 (high quality, low risk of bias): ≥75% “yes” responses;
  • Q2 (moderate quality, unclear risk of bias): ≥50–74% “yes” responses;
  • Q3 (low quality, high risk of bias): ≥50–74% “no” responses.
Out of the 17 included studies, 10 were classified as high-quality (Q1), 4 as moderate-quality (Q2), and 3 as low-quality (Q3). Studies classified as low-quality were considered to have a high risk of bias and were therefore excluded from the final analysis. Only studies with adequate quality and a lower risk of bias were included in the review.

2.5. PECO Statement

A PECO (Population, Exposure, Comparator, and Outcome) framework was employed to formulate the research question, as detailed in Table 1, This approach provided a clear definition of the systematic review’s objectives, the search terms utilized, and the inclusion and exclusion criteria for studies related to the association of vitamin D and heavy metal levels during pregnancy and childbirth in the mother and offspring.

2.6. Data Extraction

Three reviewers (T.F-B., J.A.G-S., and A.S.J-O.) reached a consensus on the extracted data, which included title and year, study design, country, number of samples, biological sample and analysis, stage of pregnancy, VD supplementation or VD concentration, heavy metal/lloid evaluated, and significant findings. The research team conducted the comprehensive data analysis to perform a quantitative analysis of the effects. However, due to substantial heterogeneity among the elements evaluated during pregnancy, we opted to present this analysis as a systematic review.

3. Results

3.1. Study Selection and Characteristics

A comprehensive search of multiple databases, including PubMed, ScienceDirect, the Cochrane Library, and Google Scholar, was conducted, yielding a total of 4688 initial records: 347 from PubMed, 274 from ScienceDirect, 7 from Cochrane Library, and 4060 from Google Scholar. The search spanned from 3 August to 2 September 2024. After removing 628 duplicate records, 4060 unique studies were selected based on their titles and abstracts. From these, 152 studies were further evaluated in full-text form (Figure 1).
Applying predefined inclusion and exclusion criteria, 138 studies were excluded for the following reasons: 35 did not assess VD levels, 31 focused on non-pregnancy-related complications, 18 were considered irrelevant to the research question, and 54 measured heavy metals without corresponding VD measurements. Consequently, 14 full-text articles were assessed for eligibility.
Ultimately, the 14 studies met all inclusion criteria and were included in the final review. The study selection process, including the number of studies at each stage and the reasons for exclusion, is detailed in the PRISMA flow chart presented in Figure 1.
This review incorporated fourteen studies, encompassing diverse methodological designs: seven cohort, three cross-sectional, three observational, and one randomized clinical trial. The studies were geographically distributed across eight countries, with a preponderance in China, Canada, and Turkey. Participants included pregnant women, newborns, and, in some cases, mother–infant dyads. Exposure to heavy metals varied, encompassing both contaminated drinking water and unspecified environmental contaminants. Biological samples analyzed included blood, urine, meconium, and placenta. The primary analytical methods employed were Liquid Chromatography–Tandem Mass Spectrometry (LC-MS/MS), Inductively Coupled Plasma Mass Spectrometry (ICP-MS), and High-Performance Liquid Chromatography (HPLC). A total of 12,508 individuals contributed biological samples across the 14 included studies, summarized in Table 2.

3.2. Associations Between VD Levels and Heavy Metal Exposure During Pregnancy

The data on VD and metal measurements across studies are highly heterogeneous. Some studies measure serum VD concentrations using analytical methods such as immunoassays (used in six studies), mass spectrometry (used in four studies), and high-performance liquid chromatography (HPLC, used in three studies). Others estimate VD intake through food frequency questionnaires (used in five studies) or environmental exposure questionnaires (used in three studies). Additionally, maternal blood was analyzed in ten studies, umbilical cord blood (UCB) in five studies, and placentas in three studies. Only one study evaluated the effect of VD supplementation [38]. A recent study from 2024 was the only one that analyzed the relationship between VD levels and five As species in pregnant women during the late second and early third trimesters, using urine and blood samples. The results indicated that VD deficiency was associated with higher As concentrations. Although Pb and Cd are the most commonly evaluated metals in a single sample, recent studies have begun measuring multiple metals in a single sample, including venous blood, urine, UCB, placenta, and meconium across different gestational trimesters [32].
In the first trimester of gestation, Ti, Co, Cu, As, Se, Hg, and Tl were detected in 95% of maternal urine samples, while Ti, Cu, As, and Se were found in 98% of samples in a cohort from Nanjing Maternity and Child Health Care Hospital (Nanjing, China). Interestingly, it was determined that the relationship between Co levels and dental eruption timing is modified when the mother is not supplemented with VD during pregnancy (beta-value: 0.57, p = 0.016) [37].
In the middle of the gestational period, between the first and second trimesters, it has been observed that blood levels of Zn, Co, and VD decreased in pathologies such as hydatidiform mole (CHM), especially when Cd concentrations increased significantly [44]. In the LIFECODES cohort, higher VD levels in the first trimester were positively associated with lower urinary Pb and Se levels and were influenced by factors such as race. The mean VD level was 26 ng/mL, with 34% of women exhibiting low levels. Additionally, mean heavy metal concentrations were higher in women with VD levels below 20 ng/mL [35].
A study exploring the genetic basis of Pb toxicity in pregnant women identified an association between specific VD receptor (VDR) variants and lower Pb levels, suggesting that VD metabolism may play a protective role against Pb toxicity during pregnancy. The H8 haplotype, which combines alleles f, a, and b, was particularly associated with reduced Pb exposure in pregnant women. This finding could help identify individuals who are genetically less susceptible to Pb-related health risks [43]. Therefore, it is advisable to consider the presence of concomitant diseases in the design of future studies, as they may modify the direction of the results.
The most robust data comes from studies that evaluate both metal and VD levels throughout pregnancy. The MIREC study (Maternal-infant research on environmental chemicals), which involves ten cities across Canada, evaluated Pb, Cd, and Hg in maternal blood, UCB, and meconium. The findings revealed that these metals were detectable in maternal blood at both the beginning and end of gestation. VD concentrations were generally moderate to high, while heavy metal levels were elevated in the first trimester compared to the third. Exposure to Pb, As, and even minor increases in these metals were linked to an increased risk of preterm birth (PTB), and spontaneous preterm birth (SPTB). Participants with VD levels below 40 nmol/L exhibited a higher risk of PTB and SPTB, whereas levels above 50 nmol/L mitigate this risk, suggesting a protective role for VD against the adverse effects of blood Pb [33].
In another sub-analysis of the MIREC cohort, the directionality of the association between VD and toxic metals was evaluated using multivariate linear regression to determine if Cd and Pb are cross-sectionally and longitudinally associated with VD concentrations during pregnancy, adjusting for confounding variables such as smoking, a source of Cd. The analysis also included sociodemographic variables, parity, pre-pregnancy, and study site, as well as time-varying covariates across pregnancy, such as season, source of VD, and time spent outdoors. Cd concentrations in the first and third trimesters of pregnancy were inversely associated with VD, with the strongest association found at delivery, and this relationship was reduced by smoking status. Bidirectional analysis showed that VD in the first trimester predicts Cd changes in the third trimester. This suggests that blood metal levels at the end of pregnancy could be modified by initial VD concentrations [34]. In another MIREC cohort, Cd, Pb, Mn, and Hg concentrations were analyzed in the first trimester of pregnancy. Detectable levels of heavy metals were found in most maternal blood samples. Strong correlations were observed between metal concentrations in maternal blood and UCB except for Cd. Higher VD levels were linked to lower levels of Cd, Pb and Mn in maternal blood and Pb in UCB blood [42].
The findings from the South American cohort indicate that lithium (Li) exposure in water may negatively affect VD absorption during pregnancy. The study observed a correlation between blood and urinary Li levels, both of which increased with gestational age. Notably, the average VD concentration was found to be 41 nmol/mL, with a significant percentage of women (58%) having VD levels below 50 nmol/L and 19% below 30 nmol/L. Furthermore, the study concluded that seasonal variation did not significantly alter the relationship between VD and Li exposure (summer/fall versus spring/winter). An increase of 25 μg/L in blood Li levels was associated with 3.5 times higher likelihood of having VD concentrations below 50 nmol/L and 4.6 times higher likelihood of having VD levels below 30 nmol/L [41].
In another study analyzing serum, placental, and UCB samples from women who gave birth, it was found that placental samples from term newborns had higher concentration of VD and Mn, along with lower levels of Hg and Pb compared to preterm newborns. Despite these differences, both groups exhibited VD levels below the normal range, with placental VD concentrations notably higher in term newborns than in preterm ones. Additionally VDD was linked to adverse pregnancy outcomes, such as intrauterine growth restriction and preterm birth [40].
Moreover, a study in Bangladesh [38] investigated the effects of VD supplementation during pregnancy on metal distribution. The study administered VD3 doses of 4200, 16,800, or 28,000 IU starting in the second trimester. The results indicated that maternal and neonatal UCB concentrations of Pb and Cd were 6 to 7.4% higher in the VD supplementation groups compared to the placebo group, although the confidence intervals included the null value. Higher levels of VD supplementation (16,800 and 28,000 IU) were associated with an increased probability of detecting Pb and Cd in the UCB. The study emphasized the need for further data on calcium supplementation and the source of metals or time of exposure.

4. Discussion

This review aimed to examine the available clinical evidence on the interaction between vitamin D and heavy metal/lloids, focusing on their potential impact on maternal and newborn health. By excluding animal models, we sought to reduce the risk of dose transfer bias between laboratory animals and humans.
During pregnancy, the fetus depends on the mother for VD supply through the UCB [46], and prenatal VD supplementation is associated with neonatal VD levels [47]. Therefore, maintaining adequate VD during pregnancy is not only essential for maternal health but also for fetal development. Natural sources of VD include ergocalciferol from plants and VD3 from sunlight exposure and animal products like eggs, fish, and meat. However, insufficient nutritional intakes among pregnant women are a recognized issue in many countries [48], making supplementation important to meet the recommended intake of VD and other micronutrients [49]. The recommended VD supplementation during pregnancy ranges from 600 to 2000 IU per day, depending on baseline levels and risk factors for deficiency [50].
Various external factors, such as latitude [51,52,53], race, ethnicity, skin color [54,55,56,57,58], and cultural practices that limit sun exposure, also contribute to VD deficiency and insufficiency, which remain significant public health concerns. Clinical studies often define VDD, insufficiency, and sufficiency by measuring circulating 25OHD levels [59,60]. According to the Institute of Medicine (IOM), 25OHD levels between 20 and 30 nmol/L are considered deficient, 31 to 50 nmol/L as insufficient, and levels above 50 nmol/L as sufficient. However, these definitions are not universally accepted. The Endocrine Society Practice Guideline [61], for instance, defines deficiency as concentrations below 50 nmol/L, insufficiency as 52.5 to 72.5 nmol/L, and sufficiency as 75 to 250 nmol/L. This discrepancy highlights the ongoing debate surrounding optimal VD levels, particularly during pregnancy. While there are no specific guidelines for VD levels in pregnancy, it is generally accepted that maintaining a 25OHD concentration of at least 50 nmol/L would meet the needs of 97.5% of the population. However, recent studies have emphasized the influence of environmental interactions between prenatal exposure to heavy metals and reduced maternal VD levels, both of which may exacerbate pregnancy complications and affect child health outcomes. In recent years, the impact of environmental conditions on VDD risk has gained recognition [52,62,63,64].
On the other hand, Pb is a well-known neurotoxicant. During pregnancy, the fetus requires calcium, and hormonal changes can cause Pb to be released from the mother’s bones [65]. Even in the absence of direct maternal exposure, women living in areas with higher Pb levels face a greater risk, and Pb can cross the placental and blood–brain barrier, affecting fetal blood and potentially altering DNA methylation, histone protein modifications, and microRNA expression. Pb exposure during pregnancy is associated with low birth weight, premature birth, behavioral and learning problems, and an increased risk of ADHD, autism, heart disease, cancer, and Alzheimer’s disease in offspring [66,67,68]. Certain dietary patterns, such as those high in leafy greens, have been linked to lower blood Pb concentrations in pregnant women [69].
Cd is recognized as a toxic metal that contributes to carcinogenesis and damages multiple organs and tissues. The United States Environmental Protection Agency classifies Cd as a probable human carcinogen (Group B1). Research indicates that Cd can be absorbed through various metal transporters including the calcium channel (TRPV6), zinc transporter 2 (ZnT2), iron-regulated transporter type proteins ZIP (ZIP-14), and proton-coupled divalent metal transporter (DMT-1) [70,71]. Exposure to Cd during pregnancy is linked to altered gene expression in the embryo, which can restrict fetal growth and development, leading to long-term organ dysfunction. Additionally, Cd affects placenta formation and function and is associated with epigenetic modifications, such as abnormal methylation [72,73,74]. It has been detected in UCB at lower concentrations than in maternal blood, and its presence is associated with low birth weight in offspring [75].
Hg in both elemental and organic forms can cross the placenta during pregnancy, posing risk to the developing fetus [76]. Methyl-Hg (MeHg) binds to sulfhydryl groups of cysteine, and due to its structural similarity to methionine, enters cells through amino acid transporters and binds to glutathione [77,78]. Placental transporters, including amino acid transporters LAT1 and rBAT, are involved in the uptake of MeHg in the placenta [79]. Hg concentrations in the placenta correlate with those in fetal organs and are linked to cognitive and language impairments, neural tube defects, and an increased risk of autism and ADHD [80,81].
As, a naturally occurring metalloid, is one of the primary contaminants found in drinking water worldwide, in its inorganic form arsenate (pentavalent As) and arsenite (As3+). As is a known carcinogen commonly present not only in drinking water, but also in various foods such as rice, vegetables, fruits, meats, and dairy products [82,83]. Once ingested, As is metabolized via glutathione S-transferase omega-1 (GSTO1), which utilizes glutathione (GSH) as a reducing agent, and As methyltransferase (AS3MT), which facilitates both oxidation and methylation using S-adenosylmethionine (SAM) as a methyl donor. This process leads to the sequential methylation of arsenic into mono-, di-, and trimethylated species, with continuous interconversion between oxidized and reduced forms following ingestion [84].
The U.S. Environmental Protection Agency (EPA) has set a maximum permissible limit of As in drinking water at parts per billion levels [85]. The potential impact of As exposure on pregnancy outcomes remains a topic of debate [86,87]. Some studies suggest a link between high As exposure during pregnancy and adverse effects such as PTB, low birth weight, gestational diabetes, infant mortality, and preeclampsia [88,89,90]. However, much of this research has been conducted in populations with high exposure levels, and there are concerns that As concentrations measured in urine during the first trimester may not accurately reflect exposure during critical physiological periods. Higher exposure levels may occur in the second and third trimesters, yet changes in glomerular filtration rate, plasma volume expansion, and increased methylation efficiency during pregnancy could introduce biases in exposure assessment. Moreover, there are limited data available on As exposure across the entire gestational period [91].
The prevalence of VDD in various populations and its association with diseases underscore the importance of understanding the underlying mechanisms. In particular, regarding maternal exposure to metals and its impact on UCB, VD remains a significant, yet poorly understood, area of research. Since the 1990s, it has been suggested that VD could increase the absorption of toxic metals, such as Pb and Cd, through calcium metabolism. Studies in chicks treated with cholecalciferol showed that calcium and phosphorus levels led to increased absorption of Pb and calcium, with VD-induced calcium-binding protein (CaBP) playing a role [92]. In children, blood Pb levels have been observed to rise during the summer, coinciding with increased VD synthesis [93].
Heavy metals have been shown to downregulate the transcription of cytochrome P450 mixed-function oxidases (CYPs), which are essential for various metabolic processes, including VD metabolism. Recent studies in mice that were fed organic calcium indicated lower mRNA levels of calcium transporters in the duodenum, correlating with reduced concentrations of Pb, Cd, As, parathyroid hormone expression, renal CYP27B1 activity, and 1,25(OH)2D3 levels. The CYP27B1 enzyme, expressed in the kidneys, placenta, and macrophages, plays a crucial role in the metabolism of VD [94]. In experiments involving rats exposed to Cesium 137, an increase in 1,25(OH)2D3 levels was observed without corresponding changes in plasma VD levels, and this was accompanied by decreased expression of cyp2r1 and cyp27b1 mRNA, despite the VD receptor mRNA levels remaining unchanged [95,96].
Polymorphisms in the CYP2R1 gene have been linked to variations in VD levels and conditions such as spontaneous abortion and gestational diabetes mellitus [97,98]. The CYP2R1 enzyme, which is expressed in the liver, is responsible for VD 25-hydroxylase activity [99]. Disruptions in the production of cholecalciferol can impair the absorption of VD, and genetic modifications in liver and kidney 25-hydroxylase can lead to decreased serum VD levels. Therefore, comprehensive analyses of the genome, transcriptome, and proteome are essential for understanding the genetic factors that influence the response to VD.
Another critical aspect to consider is the potential inverse relationship between heavy metal exposure and placental homeostasis. This disruption is thought to arise from oxidative stress, altered glutathione metabolism, and inhibition of Na+/K+-ATPase activity [100]. Since VD biosynthesis relies on hepatic metabolism, oxidative damage to mitochondria and the endoplasmic reticulum may explain the associations observed in longitudinal studies, leading to the suppression of VD3/D2 hydroxylation to 25OHD in the liver [59,101]. Given these complex interactions, animal studies are vital for investigating the effects of VD on the metabolism of metals and metalloids.

4.1. Limitations

The methodological differences between the studies included in this review present significant limitations for interpreting the results regarding the relationship between VD levels and heavy metal exposure during pregnancy. Variations in the biological material analyzed, such as maternal blood, UCB, placental tissue, and meconium, can influence the accuracy and comparability of the findings. Additionally, the considerable variability in sample size across studies may affect the generalization of the results. The geographical diversity of the studies, which spans different countries and environmental contexts, introduces further variability in heavy metal exposure and VD levels, complicating the interpretation of the observed associations. These methodological differences highlight the need for more homogeneous and standardized research to draw more robust conclusions about the relationship between VD levels and heavy metal exposure during pregnancy.

4.2. Future Directions

Based on current clinical evidence, animal studies are necessary to determine the causal relationships between VD and exposure to toxic materials. The limited number of available animal studies means that these relationships cannot be fully understood through clinical studies alone. Furthermore, the absence of preclinical research specifically addressing the impact of VD3 supplementation on the metabolism of toxic metals highlights a significant gap in our knowledge. This area of investigation holds the potential to answer fundamental questions posed by clinical researchers and physicians, particularly regarding whether VD influences the absorption of heavy metals during pregnancy.
The availability of various maternal and child cohorts worldwide, which provide continuous monitoring of pregnancy progression, suggests a promising future for clinical research in this area. Before implementing VD supplementation guidelines, it is crucial to thoroughly investigate the dynamics of heavy metals in maternal blood and UCB. Although some studies have explored the directionality of the relationship between VD and metal concentrations, there is a notable lack of studies that examine metal levels at different stages of pregnancy. However, the advancement of omics sciences, particularly metalloids, offers new possibilities. This technology enables the simultaneous evaluation of various metals and metalloids in a single run, which is especially advantageous when analyzing biological samples from newborns. For example, metabolomics is currently a powerful tool for monitoring metalloids in biological samples. It allows the identification and quantification of metabolites that can serve as biomarkers of heavy metal exposure, offering a comprehensive approach to assess metalloid toxicity and facilitating the early detection of adverse health effects [102]. Recent studies have shown that the application of metabolomics can help identify metabolite patterns associated with heavy metal exposure, which could be crucial for developing intervention and prevention strategies in public health [103].
Additionally, collecting comprehensive data on factors that modulate the VD response, including prior exposure to heavy metals, through detailed questionnaires is vital for multivariate analyses. This approach could help clarify the relationship between VD and heavy metal concentrations. Current evidence suggests a significant role of maternal VD levels early in pregnancy in reducing heavy metal concentrations at term, a finding that warrants further investigation in future studies.
Finally, we consider it relevant to propose some concrete measures to reduce the impact of heavy metals on the health of pregnant women and their children. Firstly, it is important to promote a nutrient-rich diet that includes foods that may help reduce the absorption of heavy metals, as well as supplements with VD. It is also suggested to educate and raise awareness among pregnant women through the implementation of educational programs and various types of informational materials to inform them about the risks associated with heavy metal exposure and common sources of contamination. Additionally, we believe it is essential for governments to ensure access to safe drinking water through monitoring and purification systems, as well as the development of policies that regulate the use of heavy metals in consumer products to minimize exposure. Finally, we hope that healthcare systems will incorporate screening programs to identify pregnant women with elevated levels of heavy metals within their routine medical control protocol for pregnant women, to promote the implementation of measures or treatments if necessary.

5. Conclusions

The presented review studies reveal diverse patterns in the relationship between VD levels and exposure to heavy metal/lloids during pregnancy, with variations depending on the trimester of gestation and the type of metal analyzed. Current evidence is highly heterogeneous, with differences in methods used to measure VD and metals. While some studies suggest that VDD is associated with higher concentrations of Pb, As, and other metals, the data are inconsistent and limited. Moreover, while VD supplementation during pregnancy shows effects on metal distribution, it has not been thoroughly investigated. The robust studies, such as the MIREC cohort, indicate that higher VD levels are associated with lower concentrations of certain metals like Pb, Cd and Mn in maternal blood and UCB, suggesting a potential protective role of VD. However, the variability in results underscores the need for further studies that consider factors such as genetics, prior metal exposure, and VD supplementation.
The relationship between VD and metal toxicity during pregnancy remains a critical area of research with significant implications for maternal and fetal health. Continued investigation is essential to clarify these mechanisms and develop appropriate interventions to protect the health of mothers and their offspring.

Author Contributions

A.S.J.-O.: Investigation/systematic search/extraction/Supervision/Review and Writing Original draft. T.F.-B.: Investigation/systematic search/extraction/editing. J.A.G.-S.: investigation/systematic search/extraction/editing. J.A.I.-V.: writing/investigation/editing. A.C.-O.: writing/investigation/editing. D.E.-L.: writing/investigation/editing. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by “Fondos Estatales Genéricos de la Universidad Autónoma del Estado de Hidalgo”, Number 2023-[Amp]-0080.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Holick, M.F.; Binkley, N.C.; Bischoff-Ferrari, H.A.; Gordon, C.M.; Hanley, D.A.; Heaney, R.P.; Murad, M.H.; Weaver, C.M. Evaluation, treatment, and prevention of vitamin D deficiency: An Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 2011, 96, 1911–1930. [Google Scholar] [CrossRef] [PubMed]
  2. Poel, Y.; Hummel, P.; Lips, P.; Stam, F.; Van Der Ploeg, T.; Simsek, S. Vitamin D and gestational diabetes: A systematic review and meta-analysis. Eur. J. Intern. Med. 2012, 23, 465–469. [Google Scholar] [CrossRef] [PubMed]
  3. Aghajafari, F.; Nagulesapillai, T.; Ronksley, P.E.; Tough, S.C.; O’Beirne, M.; Rabi, D.M. Association between maternal serum 25-hydroxyvitamin D level and pregnancy and neonatal outcomes: Systematic review and meta-analysis of observational studies. BMJ 2013, 346, f1169. [Google Scholar] [CrossRef]
  4. Zhang, M.-X.; Pan, G.-T.; Guo, J.-F.; Li, B.-Y.; Qin, L.-Q.; Zhang, Z.-L. Vitamin D deficiency increases the risk of gestational diabetes mellitus: A meta-analysis of observational studies. Nutrients 2015, 7, 8366–8375. [Google Scholar] [CrossRef] [PubMed]
  5. Tabesh, M.; Salehi-Abargouei, A.; Tabesh, M.; Esmaillzadeh, A. Maternal vitamin D status and risk of pre-eclampsia: A systematic review and meta-analysis. J. Clin. Endocrinol. Metab. 2013, 98, 3165–3173. [Google Scholar] [CrossRef]
  6. Akbari, S.; Khodadadi, B.; Ahmadi, S.A.Y.; Abbaszadeh, S.; Shahsavar, F. Association of vitamin D level and vitamin D deficiency with risk of preeclampsia: A systematic review and updated meta-analysis. Taiwan. J. Obstet. Gynecol. 2018, 57, 241–247. [Google Scholar] [CrossRef]
  7. Yuan, Y.; Tai, W.; Xu, P.; Fu, Z.; Wang, X.; Long, W.; Guo, X.; Ji, C.; Zhang, L.; Zhang, Y. Association of maternal serum 25-hydroxyvitamin D concentrations with risk of preeclampsia: A nested case-control study and meta-analysis. J. Matern. Fetal Neonatal Med. 2021, 34, 1576–1585. [Google Scholar] [CrossRef]
  8. Lima, M.S.; Pereira, M.; Castro, C.T.; Santos, D.B. Vitamin D deficiency and anemia in pregnant women: A systematic review and meta-analysis. Nutr. Rev. 2022, 80, 428–438. [Google Scholar] [CrossRef]
  9. Qin, L.-L.; Lu, F.-G.; Yang, S.-H.; Xu, H.-L.; Luo, B.-A. Does maternal vitamin D deficiency increase the risk of preterm birth: A meta-analysis of observational studies. Nutrients 2016, 8, 301. [Google Scholar] [CrossRef]
  10. Lian, R.-H.; Qi, P.-A.; Yuan, T.; Yan, P.-J.; Qiu, W.-W.; Wei, Y.; Hu, Y.-G.; Yang, K.-H.; Yi, B. Systematic review and meta-analysis of vitamin D deficiency in different pregnancy on preterm birth: Deficiency in middle pregnancy might be at risk. Medicine 2021, 100, e26303. [Google Scholar] [CrossRef]
  11. Zhang, H.; Huang, Z.; Xiao, L.; Jiang, X.; Chen, D.; Wei, Y. Meta-analysis of the effect of the maternal vitamin D level on the risk of spontaneous pregnancy loss. Int. J. Gynecol. Obstet. 2017, 138, 242–249. [Google Scholar] [CrossRef] [PubMed]
  12. Tamblyn, J.A.; Pilarski, N.S.; Markland, A.D.; Marson, E.J.; Devall, A.; Hewison, M.; Morris, R.K.; Coomarasamy, A. Vitamin D and miscarriage: A systematic review and meta-analysis. Fertil. Steril. 2022, 118, 111–122. [Google Scholar] [CrossRef] [PubMed]
  13. Chen, C.; Wang, S.; Zhang, C.; Wu, X.; Zhou, L.; Zou, X.; Guan, T.; Zhang, Z.; Hao, J. Association between serum vitamin D level during pregnancy and recurrent spontaneous abortion: A systematic review and meta-analysis. Am. J. Reprod. Immunol. 2022, 88, e13582. [Google Scholar] [CrossRef] [PubMed]
  14. Szarpak, L.; Feduniw, S.; Pruc, M.; Ciebiera, M.; Cander, B.; Rahnama-Hezavah, M.; Szarpak, Ł. The Vitamin D Serum Levels in Pregnant Women Affected by COVID-19: A Systematic Review and Meta-Analysis. Nutrients 2023, 15, 2588. [Google Scholar] [CrossRef]
  15. Chen, Y.; Zhu, B.; Wu, X.; Li, S.; Tao, F. Association between maternal vitamin D deficiency and small for gestational age: Evidence from a meta-analysis of prospective cohort studies. BMJ Open 2017, 7, e016404. [Google Scholar] [CrossRef]
  16. Thacher, T.D.; Clarke, B.L. Vitamin D insufficiency. Mayo Clin. Proc. 2011, 86, 50–60. [Google Scholar] [CrossRef]
  17. Tsiaras, W.G.; Weinstock, M.A. Factors influencing vitamin D status. Acta Derm. Venereol. 2011, 91, 115. [Google Scholar] [CrossRef]
  18. Vidailhet, M.; Mallet, E.; Bocquet, A.; Bresson, J.-L.; Briend, A.; Chouraqui, J.-P.; Darmaun, D.; Dupont, C.; Frelut, M.-L.; Ghisolfi, J. Vitamin D: Still a topical matter in children and adolescents. A position paper by the Committee on Nutrition of the French Society of Paediatrics. Arch. Pédiatr. 2012, 19, 316–328. [Google Scholar] [CrossRef]
  19. Chee, W.F.; Aji, A.S.; Lipoeto, N.I.; Siew, C.Y. Maternal vitamin D status and its associated environmental factors: A cross-sectional study. Ethiop. J. Health Sci. 2022, 32, 885–894. [Google Scholar] [CrossRef]
  20. Zhao, Y.; Wang, L.; Liu, H.; Cao, Z.; Su, X.; Cai, J.; Hua, J. Particulate air pollution exposure and plasma vitamin D levels in pregnant women: A longitudinal cohort study. J. Clin. Endocrinol. Metab. 2019, 104, 3320–3326. [Google Scholar] [CrossRef]
  21. Yang, D.; Chen, L.; Yang, Y.; Shi, J.; Huang, Z.; Li, M.; Yang, Y.; Ji, X. Effect of PM2. 5 exposure on Vitamin D status among pregnant women: A distributed lag analysis. Ecotoxicol. Environ. Saf. 2022, 239, 113642. [Google Scholar] [CrossRef] [PubMed]
  22. Baïz, N.; Dargent-Molina, P.; Wark, J.D.; Souberbielle, J.-C.; Slama, R.; Annesi-Maesano, I.; Group, E.M.-C.C.S. Gestational exposure to urban air pollution related to a decrease in cord blood vitamin D levels. J. Clin. Endocrinol. Metab. 2012, 97, 4087–4095. [Google Scholar] [CrossRef] [PubMed]
  23. Johns, L.E.; Ferguson, K.K.; Cantonwine, D.E.; McElrath, T.F.; Mukherjee, B.; Meeker, J.D. Erratum:“Urinary BPA and Phthalate Metabolite Concentrations and Plasma Vitamin D Levels in Pregnant Women: A Repeated Measures Analysis”. Environ. Health Perspect. 2019, 127, 019002. [Google Scholar] [CrossRef] [PubMed]
  24. Mousavi, S.E.; Amini, H.; Heydarpour, P.; Chermahini, F.A.; Godderis, L. Air pollution, environmental chemicals, and smoking may trigger vitamin D deficiency: Evidence and potential mechanisms. Environ. Int. 2019, 122, 67–90. [Google Scholar] [CrossRef]
  25. Long, J.; Huang, H.; Tang, P.; Liang, J.; Liao, Q.; Chen, J.; Pang, L.; Yang, K.; Wei, H.; Chen, M. Associations between maternal exposure to multiple metals and metalloids and blood pressure in preschool children: A mixture-based approach. J. Trace Elem. Med. Biol. 2024, 84, 127460. [Google Scholar] [CrossRef]
  26. Xu, R.; Meng, X.; Pang, Y.; An, H.; Wang, B.; Zhang, L.; Ye, R.; Ren, A.; Li, Z.; Gong, J. Associations of maternal exposure to 41 metals/metalloids during early pregnancy with the risk of spontaneous preterm birth: Does oxidative stress or DNA methylation play a crucial role? Environ. Int. 2022, 158, 106966. [Google Scholar] [CrossRef]
  27. Caserta, D.; Graziano, A.; Monte, G.; Bordi, G.; Moscarini, M. Heavy metals and placental fetal-maternal barrier: A mini-review on the major concerns. Eur. Rev. Med. Pharmacol. Sci. 2013, 17, 2198–2206. [Google Scholar]
  28. Bauer, J.A.; Romano, M.E.; Jackson, B.P.; Bellinger, D.; Korrick, S.; Karagas, M.R. Associations of Perinatal Metal and Metalloid Exposures with Early Child Behavioral Development Over Time in the New Hampshire Birth Cohort Study. Expo. Health 2024, 16, 135–148. [Google Scholar] [CrossRef]
  29. Mitra, P.; Sharma, S.; Purohit, P.; Sharma, P. Clinical and molecular aspects of lead toxicity: An update. Crit. Rev. Clin. Lab. Sci. 2017, 54, 506–528. [Google Scholar] [CrossRef]
  30. Page, M.J.; McKenzie, J.E.; Bossuyt, P.M.; Boutron, I.; Hoffmann, T.C.; Mulrow, C.D.; Shamseer, L.; Tetzlaff, J.M.; Akl, E.A.; Brennan, S.E. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ 2021, 372, n71. [Google Scholar] [CrossRef]
  31. Moola, S.; Munn, Z.; Tufanaru, C.; Aromataris, E.; Sears, K.; Sfetcu, R.; Currie, M.; Lisy, K.; Qureshi, R.; Mattis, P.; et al. Systematic Reviews of Etiology and Risk; Aromataris, E., Lockwood, C., Porritt, K., Pilla, B., Jordan, Z., Eds.; JBI Manual for Evidence Synthesis; JBI: Adelaide, SA, Australia, 2020. [Google Scholar]
  32. Zhang, J.; Bai, Y.; Chen, X.; Li, S.; Meng, X.; Jia, A.; Yang, X.; Huang, F.; Zhang, X.; Zhang, Q. Association between urinary arsenic species and vitamin D deficiency: A cross-sectional study in Chinese pregnant women. Front. Public Health 2024, 12, 1371920. [Google Scholar] [CrossRef] [PubMed]
  33. Fisher, M.; Marro, L.; Arbuckle, T.E.; Potter, B.K.; Little, J.; Weiler, H.; Morisset, A.S.; Lanphear, B.; Oulhote, Y.; Braun, J.M. Association between toxic metals, vitamin D and preterm birth in the Maternal–Infant research on environmental chemicals study. Paediatr. Perinat. Epidemiol. 2023, 37, 447–457. [Google Scholar] [CrossRef] [PubMed]
  34. Fisher, M.; Potter, B.; Little, J.; Oulhote, Y.; Weiler, H.A.; Fraser, W.; Morisset, A.-S.; Braun, J.; Ashley-Martin, J.; Borghese, M.M. Blood metals and vitamin D status in a pregnancy cohort: A bidirectional biomarker analysis. Environ. Res. 2022, 211, 113034. [Google Scholar] [CrossRef] [PubMed]
  35. Jukic, A.M.Z.; Kim, S.S.; Meeker, J.D.; Weiss, S.T.; Cantonwine, D.E.; McElrath, T.F.; Ferguson, K.K. A prospective study of maternal 25-hydroxyvitamin D (25OHD) in the first trimester of pregnancy and second trimester heavy metal levels. Environ. Res. 2021, 199, 111351. [Google Scholar] [CrossRef]
  36. Fang, X.; Qu, J.; Huan, S.; Sun, X.; Li, J.; Liu, Q.; Jin, S.; Xia, W.; Xu, S.; Wu, Y. Associations of urine metals and metal mixtures during pregnancy with cord serum vitamin D Levels: A prospective cohort study with repeated measurements of maternal urinary metal concentrations. Environ. Int. 2021, 155, 106660. [Google Scholar] [CrossRef]
  37. Wu, H.; Xu, B.; Guan, Y.; Chen, T.; Huang, R.; Zhang, T.; Sun, R.; Xie, K.; Chen, M. A metabolomic study on the association of exposure to heavy metals in the first trimester with primary tooth eruption. Sci. Total Environ. 2020, 723, 138107. [Google Scholar] [CrossRef]
  38. Jukic, A.M.Z.; Zuchniak, A.; Qamar, H.; Ahmed, T.; Mahmud, A.A.; Roth, D.E. Vitamin d treatment during pregnancy and maternal and neonatal cord blood metal concentrations at delivery: Results of a randomized controlled trial in Bangladesh. Environ. Health Perspect. 2020, 128, 117007. [Google Scholar] [CrossRef]
  39. Irwinda, R.; Wibowo, N.; Putri, A.S. The concentration of micronutrients and heavy metals in maternal serum, placenta, and cord blood: A cross-sectional study in preterm birth. J. Pregnancy 2019, 2019, 5062365. [Google Scholar] [CrossRef]
  40. Kucukaydin, Z.; Kurdoglu, M.; Kurdoglu, Z.; Demir, H.; Yoruk, I.H. Selected maternal, fetal and placental trace element and heavy metal and maternal vitamin levels in preterm deliveries with or without preterm premature rupture of membranes. J. Obstet. Gynaecol. Res. 2018, 44, 880–889. [Google Scholar] [CrossRef]
  41. Harari, F.; Åkesson, A.; Casimiro, E.; Lu, Y.; Vahter, M. Exposure to lithium through drinking water and calcium homeostasis during pregnancy: A longitudinal study. Environ. Res. 2016, 147, 1–7. [Google Scholar] [CrossRef]
  42. Arbuckle, T.E.; Liang, C.L.; Morisset, A.-S.; Fisher, M.; Weiler, H.; Cirtiu, C.M.; Legrand, M.; Davis, K.; Ettinger, A.S.; Fraser, W.D. Maternal and fetal exposure to cadmium, lead, manganese and mercury: The MIREC study. Chemosphere 2016, 163, 270–282. [Google Scholar] [CrossRef] [PubMed]
  43. Rezende, V.B.; Amaral, J.H.; Quintana, S.M.; Gerlach, R.F.; Barbosa, F., Jr.; Tanus-Santos, J.E. Vitamin D receptor haplotypes affect lead levels during pregnancy. Sci. Total Environ. 2010, 408, 4955–4960. [Google Scholar] [CrossRef] [PubMed]
  44. Kolusari, A.; Adali, E.; Kurdoglu, M.; Yildizhan, R.; Cebi, A.; Edirne, T.; Demir, H.; Yoruk, I.H. Catalase activity, serum trace element and heavy metal concentrations, vitamin A, vitamin D and vitamin E levels in hydatidiform mole. Clin. Exp. Obstet. Gynecol. 2009, 36, 102–104. [Google Scholar] [PubMed]
  45. Kolusari, A.; Kurdoglu, M.; Yildizhan, R.; Adali, E.; Edirne, T.; Cebi, A.; Demir, H.; Yoruk, I.H. Catalase activity, serum trace element and heavy metal concentrations, and vitamin A, D and E levels in pre-eclampsia. J. Int. Med. Res. 2008, 36, 1335–1341. [Google Scholar] [CrossRef] [PubMed]
  46. Salle, B.L.; Delvin, E.E.; Lapillonne, A.; Bishop, N.J.; Glorieux, F.H. Perinatal metabolism of vitamin D. Am. J. Clin. Nutr. 2000, 71, 1317s–1324s. [Google Scholar] [CrossRef]
  47. Liu, Y.; Ding, C.; Xu, R.; Wang, K.; Zhang, D.; Pang, W.; Tu, W.; Chen, Y. Effects of vitamin D supplementation during pregnancy on offspring health at birth: A meta-analysis of randomized controlled trails. Clin. Nutr. 2022, 41, 1532–1540. [Google Scholar] [CrossRef]
  48. Blumfield, M.L.; Hure, A.J.; Macdonald-Wicks, L.; Smith, R.; Collins, C.E. A systematic review and meta-analysis of micronutrient intakes during pregnancy in developed countries. Nutr. Rev. 2013, 71, 118–132. [Google Scholar] [CrossRef]
  49. Forsby, M.; Winkvist, A.; Bärebring, L.; Augustin, H. Supplement use in relation to dietary intake in pregnancy: An analysis of the Swedish GraviD cohort. Br. J. Nutr. 2024, 131, 256–264. [Google Scholar] [CrossRef]
  50. Holick, M.F. Vitamin D: Evolutionary, physiological and health perspectives. Curr. Drug Targets 2011, 12, 4–18. [Google Scholar] [CrossRef]
  51. Kinney, D.K.; Teixeira, P.; Hsu, D.; Napoleon, S.C.; Crowley, D.J.; Miller, A.; Hyman, W.; Huang, E. Relation of schizophrenia prevalence to latitude, climate, fish consumption, infant mortality, and skin color: A role for prenatal vitamin d deficiency and infections? Schizophr. Bull. 2009, 35, 582–595. [Google Scholar] [CrossRef]
  52. Alp, H.; Tekgündüz, K.; Akkar, M.K. Maternal and cord blood vitamin D status in high-altitude pregnancy. J. Matern. Fetal Neonatal Med. 2016, 29, 571–575. [Google Scholar] [CrossRef] [PubMed]
  53. Vergara-Maldonado, C.; Urdaneta-Machado, J.R. The Effects of Latitude and Temperate Weather on Vitamin D Deficiency and Women’s Reproductive Health: A Scoping Review. J. Midwifery Womens Health 2023, 68, 340–352. [Google Scholar] [CrossRef] [PubMed]
  54. Merewood, A.; Mehta, S.D.; Grossman, X.; Chen, T.C.; Mathieu, J.S.; Holick, M.F.; Bauchner, H. Widespread vitamin D deficiency in urban Massachusetts newborns and their mothers. Pediatrics 2010, 125, 640–647. [Google Scholar] [CrossRef]
  55. Li, W.; Green, T.J.; Innis, S.M.; Barr, S.I.; Whiting, S.J.; Shand, A.; von Dadelszen, P. Suboptimal vitamin D levels in pregnant women despite supplement use. Can. J. Public Health 2011, 102, 308–312. [Google Scholar] [CrossRef]
  56. Tian, Y.; Holzman, C.; Siega-Riz, A.M.; Williams, M.A.; Dole, N.; Enquobahrie, D.A.; Ferre, C.D. Maternal Serum 25-Hydroxyvitamin D Concentrations during Pregnancy and Infant Birthweight for Gestational Age: A Three-Cohort Study. Paediatr. Perinat. Epidemiol. 2016, 30, 124–133. [Google Scholar] [CrossRef]
  57. Wegienka, G.; Kaur, H.; Sangha, R.; Cassidy-Bushrow, A.E. Maternal-Cord Blood Vitamin D Correlations Vary by Maternal Levels. J. Pregnancy 2016, 2016, 7474192. [Google Scholar] [CrossRef]
  58. Alanazi, M.; Nabil Aboushady, R.M.; Kamel, A.D. Association between different levels of maternal vitamin-D status during pregnancy and maternal outcomes. Clin. Nutr. ESPEN 2022, 50, 307–313. [Google Scholar] [CrossRef]
  59. Bikle, D.D. Vitamin D metabolism, mechanism of action, and clinical applications. Chem. Biol. 2014, 21, 319–329. [Google Scholar] [CrossRef]
  60. Tsuprykov, O.; Buse, C.; Skoblo, R.; Hocher, B. Comparison of free and total 25-hydroxyvitamin D in normal human pregnancy. J. Steroid Biochem. Mol. Biol. 2019, 190, 29–36. [Google Scholar] [CrossRef]
  61. Ramasamy, I. Vitamin D Metabolism and Guidelines for Vitamin D Supplementation. Clin. Biochem. Rev. 2020, 41, 103–126. [Google Scholar] [CrossRef]
  62. Leffelaar, E.R.; Vrijkotte, T.G.; van Eijsden, M. Maternal early pregnancy vitamin D status in relation to fetal and neonatal growth: Results of the multi-ethnic Amsterdam Born Children and their Development cohort. Br. J. Nutr. 2010, 104, 108–117. [Google Scholar] [CrossRef] [PubMed]
  63. Judistiani, R.T.D.; Nirmala, S.A.; Rahmawati, M.; Ghrahani, R.; Natalia, Y.A.; Sugianli, A.K.; Indrati, A.R.; Suwarsa, O.; Setiabudiawan, B. Optimizing ultraviolet B radiation exposure to prevent vitamin D deficiency among pregnant women in the tropical zone: Report from cohort study on vitamin D status and its impact during pregnancy in Indonesia. BMC Pregnancy Childbirth 2019, 19, 209. [Google Scholar] [CrossRef] [PubMed]
  64. Yun, C.; Chen, J.; He, Y.; Mao, D.; Wang, R.; Zhang, Y.; Yang, C.; Piao, J.; Yang, X. Vitamin D deficiency prevalence and risk factors among pregnant Chinese women. Public Health Nutr. 2017, 20, 1746–1754. [Google Scholar] [CrossRef] [PubMed]
  65. Gulson, B.; Mizon, K.; Korsch, M.; Taylor, A. Revisiting mobilisation of skeletal lead during pregnancy based on monthly sampling and cord/maternal blood lead relationships confirm placental transfer of lead. Arch. Toxicol. 2016, 90, 805–816. [Google Scholar] [CrossRef]
  66. Tasin, F.R.; Ahmed, A.; Halder, D.; Mandal, C. On-going consequences of in utero exposure of Pb: An epigenetic perspective. J. Appl. Toxicol. 2022, 42, 1553–1569. [Google Scholar] [CrossRef]
  67. Tung, P.W.; Kennedy, E.M.; Burt, A.; Hermetz, K.; Karagas, M.; Marsit, C.J. Prenatal lead (Pb) exposure is associated with differential placental DNA methylation and hydroxymethylation in a human population. Epigenetics 2022, 17, 2404–2420. [Google Scholar] [CrossRef]
  68. RÍsovÁ, V. The pathway of lead through the mother’s body to the child. Interdiscip. Toxicol. 2019, 12, 1–6. [Google Scholar] [CrossRef]
  69. Taylor, C.M.; Doerner, R.; Northstone, K.; Kordas, K. Maternal Diet During Pregnancy and Blood Cadmium Concentrations in an Observational Cohort of British Women. Nutrients 2020, 12, 904. [Google Scholar] [CrossRef]
  70. Kovacs, G.; Danko, T.; Bergeron, M.J.; Balazs, B.; Suzuki, Y.; Zsembery, A.; Hediger, M.A. Heavy metal cations permeate the TRPV6 epithelial cation channel. Cell Calcium 2011, 49, 43–55. [Google Scholar] [CrossRef]
  71. Nakamura, Y.; Ohba, K.; Ohta, H. Participation of metal transporters in cadmium transport from mother rat to fetus. J. Toxicol. Sci. 2012, 37, 1035–1044. [Google Scholar] [CrossRef]
  72. Geng, H.X.; Wang, L. Cadmium: Toxic effects on placental and embryonic development. Environ. Toxicol. Pharmacol. 2019, 67, 102–107. [Google Scholar] [CrossRef] [PubMed]
  73. Castillo, P.; Ibáñez, F.; Guajardo, A.; Llanos, M.N.; Ronco, A.M. Impact of cadmium exposure during pregnancy on hepatic glucocorticoid receptor methylation and expression in rat fetus. PLoS ONE 2012, 7, e44139. [Google Scholar] [CrossRef] [PubMed]
  74. Jacobo-Estrada, T.; Santoyo-Sánchez, M.; Thévenod, F.; Barbier, O. Cadmium Handling, Toxicity and Molecular Targets Involved during Pregnancy: Lessons from Experimental Models. Int. J. Mol. Sci. 2017, 18, 1590. [Google Scholar] [CrossRef] [PubMed]
  75. Kippler, M.; Tofail, F.; Gardner, R.; Rahman, A.; Hamadani, J.D.; Bottai, M.; Vahter, M. Maternal cadmium exposure during pregnancy and size at birth: A prospective cohort study. Environ. Health Perspect. 2012, 120, 284–289. [Google Scholar] [CrossRef] [PubMed]
  76. Bose-O’Reilly, S.; McCarty, K.M.; Steckling, N.; Lettmeier, B. Mercury exposure and children’s health. Curr. Probl. Pediatr. Adolesc. Health Care 2010, 40, 186–215. [Google Scholar] [CrossRef]
  77. Hoffmeyer, R.E.; Singh, S.P.; Doonan, C.J.; Ross, A.R.; Hughes, R.J.; Pickering, I.J.; George, G.N. Molecular mimicry in mercury toxicology. Chem. Res. Toxicol. 2006, 19, 753–759. [Google Scholar] [CrossRef]
  78. Simmons-Willis, T.A.; Koh, A.S.; Clarkson, T.W.; Ballatori, N. Transport of a neurotoxicant by molecular mimicry: The methylmercury-L-cysteine complex is a substrate for human L-type large neutral amino acid transporter (LAT) 1 and LAT2. Biochem. J. 2002, 367, 239–246. [Google Scholar] [CrossRef]
  79. Straka, E.; Ellinger, I.; Balthasar, C.; Scheinast, M.; Schatz, J.; Szattler, T.; Bleichert, S.; Saleh, L.; Knöfler, M.; Zeisler, H.; et al. Mercury toxicokinetics of the healthy human term placenta involve amino acid transporters and ABC transporters. Toxicology 2016, 340, 34–42. [Google Scholar] [CrossRef]
  80. Tong, M.; Yu, J.; Liu, M.; Li, Z.; Wang, L.; Yin, C.; Ren, A.; Chen, L.; Jin, L. Total mercury concentration in placental tissue, a good biomarker of prenatal mercury exposure, is associated with risk for neural tube defects in offspring. Environ. Int. 2021, 150, 106425. [Google Scholar] [CrossRef]
  81. Ealo Tapia, D.; Torres Abad, J.; Madera, M.; Márquez Lázaro, J. Mercury and neurodevelopmental disorders in children: A systematic review. Arch. Argent. Pediatr. 2023, 121, e202202838. [Google Scholar] [CrossRef]
  82. Cubadda, F.; D’Amato, M.; Mancini, F.R.; Aureli, F.; Raggi, A.; Busani, L.; Mantovani, A. Assessing human exposure to inorganic arsenic in high-arsenic areas of Latium: A biomonitoring study integrated with indicators of dietary intake. Ann. Ig. 2015, 27, 39–51. [Google Scholar] [PubMed]
  83. Rehman, K.; Naranmandura, H. Arsenic metabolism and thioarsenicals. Metallomics 2012, 4, 881–892. [Google Scholar] [CrossRef] [PubMed]
  84. El-Ghiaty, M.A.; El-Kadi, A.O.S. The Duality of Arsenic Metabolism: Impact on Human Health. Annu. Rev. Pharmacol. Toxicol. 2023, 63, 341–358. [Google Scholar] [CrossRef] [PubMed]
  85. Agency for Toxic Substances and Disease Registry. Table 8-1 Regulations and Guidelines Applicable to Arsenic and Arsenic Compounds. Toxicological Profile for Arsenic. 2007. Available online: https://www.ncbi.nlm.nih.gov/books/NBK591644/table/ch8.tab1/ (accessed on 10 September 2024).
  86. Lewis, J.V.; Knapp, E.A.; Bakre, S.; Dickerson, A.S.; Bastain, T.M.; Bendixsen, C.; Bennett, D.H.; Camargo, C.A.; Cassidy-Bushrow, A.E.; Colicino, E.; et al. Associations between area-level arsenic exposure and adverse birth outcomes: An Echo-wide cohort analysis. Environ. Res. 2023, 236, 116772. [Google Scholar] [CrossRef]
  87. Shi, X.; Ayotte, J.D.; Onda, A.; Miller, S.; Rees, J.; Gilbert-Diamond, D.; Onega, T.; Gui, J.; Karagas, M.; Moeschler, J. Geospatial association between adverse birth outcomes and arsenic in groundwater in New Hampshire, USA. Environ. Geochem. Health 2015, 37, 333–351. [Google Scholar] [CrossRef]
  88. Quansah, R.; Armah, F.A.; Essumang, D.K.; Luginaah, I.; Clarke, E.; Marfoh, K.; Cobbina, S.J.; Nketiah-Amponsah, E.; Namujju, P.B.; Obiri, S.; et al. Association of arsenic with adverse pregnancy outcomes/infant mortality: A systematic review and meta-analysis. Environ. Health Perspect. 2015, 123, 412–421. [Google Scholar] [CrossRef]
  89. Salmeri, N.; Villanacci, R.; Ottolina, J.; Bartiromo, L.; Cavoretto, P.; Dolci, C.; Lembo, R.; Schimberni, M.; Valsecchi, L.; Viganò, P.; et al. Maternal Arsenic Exposure and Gestational Diabetes: A Systematic Review and Meta-Analysis. Nutrients 2020, 12, 3094. [Google Scholar] [CrossRef]
  90. Stone, J.; Sutrave, P.; Gascoigne, E.; Givens, M.B.; Fry, R.C.; Manuck, T.A. Exposure to toxic metals and per- and polyfluoroalkyl substances and the risk of preeclampsia and preterm birth in the United States: A review. Am. J. Obstet. Gynecol. MFM 2021, 3, 100308. [Google Scholar] [CrossRef]
  91. Ashley-Martin, J.; Fisher, M.; Belanger, P.; Cirtiu, C.M.; Arbuckle, T.E. Biomonitoring of inorganic arsenic species in pregnancy. J. Expo. Sci. Environ. Epidemiol. 2023, 33, 921–932. [Google Scholar] [CrossRef]
  92. Edelstein, S.; Fullmer, C.S.; Wasserman, R.H. Gastrointestinal absorption of lead in chicks: Involvement of the cholecalciferol endocrine system. J. Nutr. 1984, 114, 692–700. [Google Scholar] [CrossRef]
  93. Ngueta, G.; Gonthier, C.; Levallois, P. Colder-to-warmer changes in children’s blood lead concentrations are related to previous blood lead status: Results from a systematic review of prospective studies. J. Trace Elem. Med. Biol. 2015, 29, 39–46. [Google Scholar] [CrossRef] [PubMed]
  94. Tuckey, R.C.; Cheng, C.Y.S.; Slominski, A.T. The serum vitamin D metabolome: What we know and what is still to discover. J. Steroid Biochem. Mol. Biol. 2019, 186, 4–21. [Google Scholar] [CrossRef] [PubMed]
  95. Tissandie, E.; Guéguen, Y.; Lobaccaro, J.M.; Grandcolas, L.; Grison, S.; Aigueperse, J.; Souidi, M. Vitamin D metabolism impairment in the rat’s offspring following maternal exposure to 137cesium. Arch. Toxicol. 2009, 83, 357–362. [Google Scholar] [CrossRef] [PubMed]
  96. Li, H.-B.; Xue, R.-Y.; Chen, X.-Q.; Lin, X.-Y.; Shi, X.-X.; Du, H.-Y.; Yin, N.-Y.; Cui, Y.-S.; Li, L.-N.; Scheckel, K.G.; et al. Ca Minerals and Oral Bioavailability of Pb, Cd, and As from Indoor Dust in Mice: Mechanisms and Health Implications. Environ. Health Perspect. 2022, 130, 127004. [Google Scholar] [CrossRef]
  97. Liu, D.Y.; Li, R.Y.; Fu, L.J.; Adu-Gyamfi, E.A.; Yang, Y.; Xu, Y.; Zhao, L.T.; Zhang, T.F.; Bao, H.Q.; Xu, X.O.; et al. SNP rs12794714 of CYP2R1 is associated with serum vitamin D levels and recurrent spontaneous abortion (RSA): A case-control study. Arch. Gynecol. Obstet. 2021, 304, 179–190. [Google Scholar] [CrossRef]
  98. Wang, Y.; Wang, O.; Li, W.; Ma, L.; Ping, F.; Chen, L.; Nie, M. Variants in Vitamin D Binding Protein Gene Are Associated With Gestational Diabetes Mellitus. Medicine 2015, 94, e1693. [Google Scholar] [CrossRef]
  99. Strushkevich, N.; Usanov, S.A.; Plotnikov, A.N.; Jones, G.; Park, H.W. Structural analysis of CYP2R1 in complex with vitamin D3. J. Mol. Biol. 2008, 380, 95–106. [Google Scholar] [CrossRef]
  100. El-Boshy, M.; Refaat, B.; Almaimani, R.A.; Abdelghany, A.H.; Ahmad, J.; Idris, S.; Almasmoum, H.; Mahbub, A.A.; Ghaith, M.M.; BaSalamah, M.A. Vitamin D3 and calcium cosupplementation alleviates cadmium hepatotoxicity in the rat: Enhanced antioxidative and anti-inflammatory actions by remodeling cellular calcium pathways. J. Biochem. Mol. Toxicol. 2020, 34, e22440. [Google Scholar] [CrossRef]
  101. Permenter, M.G.; Dennis, W.E.; Sutto, T.E.; Jackson, D.A.; Lewis, J.A.; Stallings, J.D. Exposure to cobalt causes transcriptomic and proteomic changes in two rat liver derived cell lines. PLoS ONE 2013, 8, e83751. [Google Scholar] [CrossRef]
  102. Moore, L.E.; Karami, S.; Steinmaus, C.; Cantor, K.P. Use of OMIC technologies to study arsenic exposure in human populations. Environ. Mol. Mutagen. 2013, 54, 589–595. [Google Scholar] [CrossRef]
  103. Raza, A.; Tabassum, J.; Zahid, Z.; Charagh, S.; Bashir, S.; Barmukh, R.; Khan, R.S.A.; Barbosa, F., Jr.; Zhang, C.; Chen, H.; et al. Advances in “Omics” Approaches for Improving Toxic Metals/Metalloids Tolerance in Plants. Front. Plant Sci. 2022, 12, 794373. [Google Scholar] [CrossRef]
Pathophysiology 31 00048 g001
Figure 1. PRISMA flow diagram of the systematic review.
Figure 1. PRISMA flow diagram of the systematic review.
Pathophysiology 31 00048 g001
Table 1. PECO statement in this systematic review.
Table 1. PECO statement in this systematic review.
PECOEvidence
PopulationPregnant women and infants
ExposureExposure to naturally occurring heavy metal/lloids, or toxic environmental contaminants.
ComparatorComparison of metal and metalloid concentrations in biological samples with vitamin D levels in pregnant women and infants.
OutcomeRelationship or association between vitamin D levels and heavy metal concentrations in mothers and infants, as well as complications.
Table 2. Clinical studies examining the relationships between VD and heavy metal exposure during pregnancy in mother–infant pairs.
Table 2. Clinical studies examining the relationships between VD and heavy metal exposure during pregnancy in mother–infant pairs.
Ref.Title
and
Year		Study
Design		CountrySampleBiological Sample/AnalysisStage of Pregnancy/DeliveryVD Concentration/SupplementationHeavy Metal/Lloid EvaluatedSignificant FindingsRisk of Bias (Low, Medium, High)
[32]Association between urinary arsenic species and vitamin D deficiency: a cross-sectional study in Chinese pregnant women (2024)Cross-sectionalChinaPregnancy (n = 391)Urine/heavy metals (HPLC and ICP-MS)
Blood/VD (LC-MS/MS)		Second and third trimesterNo supplementation
Concentrations: <12 ng/mL (n = 60)		Species to As (As3+, As5+, MMA, DMA and AsB)Subjects with higher levels of As3+ were more likely to develop VDD.
Also, those with VDD showed significantly higher concentrations of As3+ and DMA compared to subjects without deficiency		Low
[33]Association between toxic metals, vitamin D and preterm birth in the maternal-infant research on environmental chemicals study (2023)CohortCanadaPregnancy (n = 1851)Blood/heavy metals and VD (SG)First and third trimesterNo supplementation
Concentration: The mean 25OHD level was first trimester (69.7 nmol/L) and third trimester (78.4 nmol/L)		Cd, As, Pb and HgIn pregnant women, blood Pb levels were generally low; a positive correlation was found between elevated blood Pb and an increased risk of PTB.
VD levels may influence this relationship, as the risk of SPTB was significantly higher when elevated concentrations of Pb and As were observed, along with a decrease in VD levels below 50 nmol/L.		Low
[34]Blood metals and vitamin D status in a pregnancy cohort: a bidirectional biomarker analysis (2022)Cross-sectionalCanadaPregnancy (N = 3554)Blood/heavy metals and VD (ELISA and LIAISON, LC-MS/MS)First trimester (n = 1905)
Third trimester (n = 1649)
Delivery (n = 1542)		No supplementation
Concentration: ≥50 nmol/L
First trimester (85% participants)
Third trimester (87% participants)
Delivery (84% participants)
<30 nmol/L (4% participants)		Pb and CdVD concentrations were associated with lower metal concentration in blood during the third trimester, with a 9% reduction in Cd and a 3% reduction in Pb. These findings suggest that VD may play modulatory role in regulating Cd and Pb concentrations during pregnancyLow
[35]A prospective study of maternal 25-hydroxyvitamin D in the first trimester of pregnancy and second trimester heavy metal levels (2021)CohortBostonPregnancy (n = 322)Blood/VD (LIAISON)
Urine/heavy metals (SG)		First and second trimesterNo supplementation
The mean 25OHD was 26 ng/mL (34% presented low levels in first trimester)		As, Ba, Be, Cd, Hg, Pb, Sn, Tl, U, W, Cu, Cr, Mn, Mo, Ni, Se and Zn (second trimester)Pregnant women with low VD levels exhibited significantly higher concentrations of Pb, Sn and W. In particular, Pb concentrations were 54% higher, and the detection rate of W was 1.58 times greater in women with insufficient VD levels compared to those with adequate VD levels.Low
[36]Association of urine metals and mixtures during pregnancy with cord serum vitamin D levels: A cohort study with repeated measurements of maternal urinary metal concentrations (2021)CohortChinaMother–newborn pairs (n = 598)Mothers: urine/VD (ICP-MS)
UCB/heavy metals (LC-MS/MS)		All trimesters of pregnancy and deliveryNo supplementation
The mean 25OHD was 16.76 ng/mL		Al, V, Cr, Mn, Co, Ni, Cu, Zn, As, Se, Rb, Sr, Ag, Cd, Cs, Ba, Tl, Pb, Th and UMaternal exposure to Co, Tl and V during pregnancy is associated with decreased total VD levels in UCB, heightening the risk of neonatal VDD. Moreover, combined exposure to these metals shows a synergistic effect on VD status, suggesting a higher risk of deficiency in newborns exposed to multiple contaminants.Low
[37]A metabolomic study on the association of exposure to heavy metals in the first trimester with primary tooth eruption (2020)CohortChinaPregnancy (n = 244)
Infants (n = 183)		Urine/heavy metals (ICP-MS)
Oral examination		First trimesterSupplementation: Pregnancy (n = 88)
Infants (n = 171)
Concentration: not reported		Ti, V, Fe, Co, Cu, As, Se, Cd, Sn, Hg, Tl and U (Pregnancy)No significant associations were identified between heavy metal exposure during the first trimester and the eruption of primary teeth, except for Co, Cd and As. Higher Co concentrations were positively linked to delayed eruption of the first tooth and negatively associated with the number of teeth at one year of age, as well as with VD supplementation.Medium
[38]Vitamin D treatment during pregnancy and maternal and neonatal cord blood metal concentrations at delivery: results of a randomized controlled trial in Bangladesh (2020)Randomized controlled trialBangladeshPregnancy (n = 619)
Newborns (n = 516)		Maternal and UCB/VD and heavy metals (ICP-MS and LC-MS/MS)DeliverySupplementation: groups (4200, 16,800 and 28,000 UI VD3 for week/second and third trimesters)
The median 25OHD level was 25 nmol/L		Cd, Pb, Hg and MnMean Pb y Cd concentrations in UCB were higher in the supplemented groups compared to the placebo group, particularly those receiving higher VD treatments (16,800 and 28,000 IU).Low
[39]The concentration of micronutrients and heavy metals in maternal serum, placenta, and cord blood: A cross-sectional study in preterm birth (2019)Cross-sectionalIndonesiaMother–infant pairs (n = 51)Maternal serum, placenta and UCB/VD and heavy metals (ICP-MS and LC-MS/MS)DeliveryNo supplementation
Concentration: not specified		Pb and HgLower concentrations of Cu samples were observed in term infants than in PTB, also associated with lower levels of VD and higher concentrations of heavy metals.Low
[40]Selected maternal, fetal and placental trace element and heavy metal and maternal vitamin levels in preterm deliveries with or without preterm premature rupture of membranes (2018)CohortArgentinaPTB with PPROM: (n = 33)
PTB without PPROM: (n = 35)		Maternal serum/VD and heavy metals (FAES, HPLC)
Placental and UCB/heavy metals (FAES)		Third trimester
Delivery		No supplementation
Concentration: with PPROM: 0.0116 ± 0.0058
Without PPROM: 0.0163 ± 0.0088		Mg, Pb, Zn, CdCompared to PTB with PPROM, it is associated with lower maternal serum Mg concentrations, increased placental Mg concentrations, and reduced Zn concentrations in both maternal and UCB. Additionally, patients with PPROM show elevated levels of VD. Cd and Pb concentrations did not differ between the two groups for maternal or UCB.Low
[41]Exposure to lithium through drinking water and calcium homeostasis during pregnancy: A longitudinal study (2016)CohortArgentinaPregnancy (n = 178)Urine/heavy metals (ICP-MS and LC-HG)
Blood/VD and heavy metals (ICP-MS)		All trimesters of pregnancyNo supplementation
The median 25OHD level was 41 nmol/L (58% or the women)
19% had <30 nmol/L		Li, As and CsIncreased Li concentrations were associated with a fivefold higher risk of having VD concentrations < 30 nmol/L. Low VD levels are detrimental to both maternal and fetal health.Low
[42]Maternal and fetal exposure to cadmium, lead, manganese and mercury: The MIREC study (2016)CohortCanadaPregnancy (n = 1938)Blood/VD and heavy metals (ICP-MS)
UCB/heavy metals (ICP-MS)
Meconium/heavy metals (ICP-MS)		First and third trimester
Delivery		Supplementation: yes, but not clear
Concentrations: not clear		Pb, Cd, Mn and HgVD intake was significantly associated with lower levels of Cd, Pb and Mn in maternal blood, as well as reduced Pb levels in UCB.Low
[43]Vitamin D receptor haplotypes affect lead levels during pregnancy (2010)ObservationalBrazilPregnancy (n = 256)Blood/VD and heavy metals (PCR)
UCB/VD and heavy metals (PCR)		Third trimester
Delivery		Supplementation: not reported
Concentrations: not reported		PbVDR H8 haplotype was associated with lower Pb levels in maternal serum. The H8 and H4 haplotypes were associated with lower %Pb-S/Pb-B ratios than the H1 haplotype.Low
[44]Catalase activity, serum trace and heavy metal concentrations, vitamin A, vitamin D and vitamin E levels in hydatidiform mole (2009)ObservationalTurkeyHPW (n = 24)
HNPW (n = 24)
CHM (n = 24)		Blood/VD and heavy metals (HPLC and AAS)First trimesterSupplementation: not reported
Concentrations: not clear		Cd, Cu, Zn and CoIn CHM patients, low VD concentrations and significantly elevated Cd and Fe levels were observed when compared to the HPW and HNPW groups.Medium
[45]Catalase activity, serum trace and heavy metal concentrations, vitamin A, D and E levels in preeclampsia (2008)ObservationalTurkeyHPW (n = 48)
HNPW (n = 50)
PE
(n = 47)		Blood/VD and heavy metals (HPLC and AAS)Third trimesterSupplementation: not reported
Concentrations: not clear		Cd, Cu, Zn and CoSerum levels of VD, A and E were significantly lower in the PE group compared to the HPW and HNPW groups. Likewise, the concentrations of Cd, Cu, and Fe were significantly higher in the PE group than in the HPW and HNPW groups.Medium
AAS: Atomic Absorption Spectroscopy; Ag: silver; Al: aluminum; As: arsenic; As3+: arsenite; As5+: arsenate; AsB: arsenobetaine; Ba: barium; Be: beryllium; Cd: cadmium; Co: cobalt; Cr: chromium; Cs: cesium; Cu: copper; CHM: complete hydatidiform mole; Cr: chromium; Cu: copper; DMA: dimethylarsinic acid; ELISA: Enzyme-Linked Immunosorbent Assay; FAES: Flame Atomic Emission Spectrophotometer; Fe: iron; Hg: mercury; HNPW: healthy non-pregnant women; HPW: healthy pregnant women; HPLC: High-Performance Liquid Chromatography; ICP-MS: Inductively Coupled Plasma Mass Spectrometry; LC-HG: Liquid Chromatography Coupled with Hydride Generation; LC-MS/MS; Liquid Chromatography–Tandem Mass Spectrometry Method; Li: lithium; LIAISON: chemiluminescence immunoassay; MMA: monomethylarsonic acid; Mn: manganese; Mg: magnesium; Mo: molybdenum; Ni: nickel; Pb: lead; PE: preeclamptic women; PPTB: Premature Rupture of Membranes; PPROM: preterm premature rupture of membranes; PCR: Polymerase Chain Reaction; PTB: Preterm Birth; Rb: rubidium; Se: selenium; SG: specific gravity; Sn: tin; Sr: strontium; Th: thorium; Ti: titanium; Tl: thallium; U: uranium; UCB: umbilical cord blood; V: vanadium; VD3: cholecalciferol; VDD: vitamin D deficiency; VDR: polymorphisms of the vitamin D receptor gene; W: tungsten; Zn: zinc.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Flores-Bazán, T.; Izquierdo-Vega, J.A.; Guerrero-Solano, J.A.; Castañeda-Ovando, A.; Estrada-Luna, D.; Jiménez-Osorio, A.S. Interplay Between Vitamin D Levels and Heavy Metals Exposure in Pregnancy and Childbirth: A Systematic Review. Pathophysiology 2024, 31, 660-679. https://doi.org/10.3390/pathophysiology31040048

AMA Style

Flores-Bazán T, Izquierdo-Vega JA, Guerrero-Solano JA, Castañeda-Ovando A, Estrada-Luna D, Jiménez-Osorio AS. Interplay Between Vitamin D Levels and Heavy Metals Exposure in Pregnancy and Childbirth: A Systematic Review. Pathophysiology. 2024; 31(4):660-679. https://doi.org/10.3390/pathophysiology31040048

Chicago/Turabian Style

Flores-Bazán, Tania, Jeannett Alejandra Izquierdo-Vega, José Antonio Guerrero-Solano, Araceli Castañeda-Ovando, Diego Estrada-Luna, and Angélica Saraí Jiménez-Osorio. 2024. "Interplay Between Vitamin D Levels and Heavy Metals Exposure in Pregnancy and Childbirth: A Systematic Review" Pathophysiology 31, no. 4: 660-679. https://doi.org/10.3390/pathophysiology31040048

APA Style

Flores-Bazán, T., Izquierdo-Vega, J. A., Guerrero-Solano, J. A., Castañeda-Ovando, A., Estrada-Luna, D., & Jiménez-Osorio, A. S. (2024). Interplay Between Vitamin D Levels and Heavy Metals Exposure in Pregnancy and Childbirth: A Systematic Review. Pathophysiology, 31(4), 660-679. https://doi.org/10.3390/pathophysiology31040048

Article Metrics

Back to TopTop