Chemical elements and preeclampsia - An overview of current problems, challenges and significance of recent research

Journal of Trace Elements in Medicine and Biology 59 (2020) 126468

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Chemical elements and preeclampsia - An overview of current problems, challenges and significance of recent research

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Katarzyna Gajewskaa,*, Anna Błażewicza, Marzena Laskowskab, Przemysław Nizińskia, Weronika Dymara - Konopkab, Łukasz Komstac a

Chair of Chemistry, Department of Analytical Chemistry, Medical University of Lublin, Poland Chair and Department of Obstetrics and Perinatology, Medical University of Lublin, Poland c Department of Medicinal Chemistry, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, Poland b

ARTICLE INFO

ABSTRACT

Keywords: Chemical elements Preeclampsia Pregnancy

Objectives: Data on the elemental status, redistribution of the elements, role of occupational exposure and dietary assessment in preeclampsia (PE) are scarce. There are many disparities in the findings of essential and non-essential elements’ role in PE. In this article we overview the changes in the content of selected elements in pregnancy complicated with the disorder of complex and not fully understood etiology. We have focused on important limitations and highlighted shortcomings in research from the last ten years period. Methods: The Scopus and PubMed electronic databases have been searched for English-language articles published within the time interval 2008–2018, with full text available and with the key words “preeclampsia” and “chemical element” (i.e. separately: Cd, Pb, As, Ni, Mo, Co, Cr, Mn, Se, I, Fe, Sr, Cu, Zn, Mg, K and Na) appearing in the title, abstract or keywords. Results: A total of 48 publications were eligible for this overview. Surprisingly only 4% of papers considered environmental exposure, 8%- diet and 2 %- comorbid diseases. In most published papers, occupational exposure was neglected. Meta-analysis was possible for seven elements in serum (Ca, Cu, Fe, Mg, Mn, Se, Zn), and two elements (Se, Zn) in plasma. It showed negative shift for most elements, however only several were statistically significant. Conlusions: The overview of the published data on PE and chemical elements yields varied results. Some of the reasons may be the difference in not duly validated method of determination, and huge discrepancies in study designs. The lack of detailed description of studied and control population and small number of samples constitute the most common limitations of such studies. Many of them describe the use of a single analytical procedure, therefore the quality of research may be insufficient to obtain reliable results. A history of elements’ status and intake before and during pregnancy is usually not examined. Dietary assessment should be done at different stages of pregnancy, and whenever possible in the periconceptional period as well. It still needs to be established whether the deficiency of certain elements or their excess may be an etiopathogenic factor and a developmental cause of PE, and if it may serve as a target of actions in the causal treatment or even prevention of the occurrence of this disease.

1. Introduction Preeclampsia (PE) is a disorder typical for human pregnancy and it constitutes one of the reasons for elevated perinatal mortality. It is estimated that it affects 2–8% of pregnancies worldwide [1]. It affects the mother, the unborn baby and the neonate [2]. PE is diagnosed in the presence of hypertension (blood pressure ≥140/90 mmHg) and proteinuria (> 300 mg/24 h) after the 20th week of pregnancy or, exceptionally, immediately after childbirth [3,4]. Its etiology remains

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uncertain and it is called a disease of theories. The main symptom is hypertension, although a woman with a pregnancy complicated by PE, besides hypertension, suffers from multiple organ dysfunctions [5,6]. At present, patients at increased risk of PE are identified on the basis of clinical symptoms. The most important are: infertility, the occurrence of PE during the previous pregnancy, elevated body mass index, pre-diabetes, and chronic hypertension. The diagnostic problems are complex and involve diagnosis based on non-specific symptoms (newly detected hypertension + proteinuria > 20 week of pregnancy), atypical

Corresponding author. E-mail address: [email protected] (K. Gajewska).

https://doi.org/10.1016/j.jtemb.2020.126468 Received 13 March 2019; Received in revised form 4 December 2019; Accepted 10 January 2020 0946-672X/ © 2020 Elsevier GmbH. All rights reserved.

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PE (without hypertension or proteinuria or occurring at any other time of pregnancy), 10–15 % of HELLP syndrome, which is a life-threatening complication (haemolysis, elevated liver enzymes and thrombocytopenia), and 35–40 % cessation without hypertension or proteinuria. Moreover, the diagnosis is difficult for patients with concomitant diseases such as hypertension or renal disease. Most cases of early PE or severe PE have no predictive symptoms or pregnancy risk factors, and the gestational age is not included in the severity classification of preeclampsia. Although the main symptom is hypertension, it is more than hypertension associated with pregnancy. PE is characterized by an increased vascular resistance, increased activation of the coagulation system, and reduction of intravascular volume, secondary to an increased endothelial cell permeability leading to a reduced perfusion of all maternal organs, including the uterus, kidney, brain and placenta [5,6]. Although the exact pathogenesis of PE is unknown, an abnormal development of the placenta and the uterine-placental vascular system may be the primary cause of PE [7]. The importance of immune system changes and the role of proinflammatory cytokines and an increased inflammatory response in the development of this disease are highlighted in the literature [8–11]. In general, many authors agree that oxidative stress, inflammation factors, lack of immunological balance and endothelial dysfunction are involved in developing symptoms of PE [11,12]. During gestation, the excess or deficiency of elements, namely the so-called trace elements (TE), may contribute to an endothelial tissue dysfunction [13]. Many authors link the importance of TE deficiencies with PE based on their essential roles in normal cell function as enzyme cofactors, redox sensors, and structural elements [14]. Recent studies emphasize the role of trace elements status in PE diagnosis [13,14], but routine analysis of clinical samples for the determination of the content of specific elements is not routinely performed until today. Studies on an appropriate supplementation in deficient groups are not common as well. Unfortunately, the proper elemental analysis in pregnancy complicated by PE is largely unexplored in practice, and some reports present conflicting findings which in some degree may result from poor quality of the research. Data on the elemental status of preeclamptic women are insufficient. Moreover, understanding the metabolic modes of action of some elements (e.g. selenium, iodine) in both health and in disease remains incomplete. Therefore, we consider the elements’ determination in body fluids and tissues in preeclampsia and disease development of being worthy of attention. In this review we are considering reported information about the significance of elemental analysis or its absence in PE studies from the analytical and methodological perspective. While reviewing the literature of the last decade (i.e. 2008–2018) on the research into the relationship between various elements and PE, we have highlighted the problems and challenges that researchers are faced with seeking to identify not only potential but real biomarkers of PE among chemical elements. The information presented here comes from different populations around the world and as far as we know there is no an international multicenter retrospective large cohort study examining the associations between preeclampsia and chemical elements’ alterations in the organism. A nationwide cohort study on the effects of certain chemical elements on markers of risk of PE is also rare [15].

separately, or many at the same time) in preeclampsia; 3) any age of study population; 4) any gestational age; 5) any severity of the disease; 6) any type of body fluid and tissue sample; and 7) “preeclampsia” and selected “chemical element” were appearing in the title, abstract or keywords. 2.2. Exclusion criteria Exclusion criteria were as follows: 1) papers that were not available in English; (2) papers containing insufficient data; (3) papers that did not allow access to full texts or relevant data; (4) papers which were not original publications (including reviews, mini-reviews, letters, and comments); and (5) papers considering only the increased blood pressure in pregnancy without referring to an accepted full definition of PE [4]. A total of 48 publications were eligible for this overview. Surprisingly only 4% of papers considered environmental exposure. In most published papers, occupational exposure was neglected. The relevance of the elements’ determination in body fluids and tissues for the diagnosis of preeclampsia and monitoring of disease development and recent investigations of essential and non-essential elements status in PE It is obvious that the achievement and maintenance of a desirable level of macro and micronutrients in the human diet, and consequently in the human body is an important public health objective. Thus, the assessment of element nutritional status and health risks, as well an exposure-risk assessment for potentially toxic elements (it is suggested to use the term „toxic concentration” rather than „toxic element”) are of fundamental importance. Research in the field of essential and nonessential elements in health and disease undergo continuous development. Whether an element is essential or not is often unclear or undecided. Terms „apparently nonessential” and “not known to be essential” are in use. It is claimed that of all elements known so far, 19 (some sources claim about 16, others claim over 20 elements) are absolutely required for human life. They are the so-called “essential elements”. Vanadium, chromium, nickel, silicon, fluorine are suggested to be essential (beneficial) [16], while there is no evidence that tin is an essential element for humans [17]. Essential trace elements (e.g. chromium, cobalt, copper, iron, manganese, molybdenum, selenium, zinc, and other elements) occur in very small amounts (usually less than 1–10 parts per million) as constituents of living organisms, and are necessary for their growth, development, and health. They are involved in enzymatic activities, immunological reactions, and physiological mechanisms. The proper functioning of the organism and the health of human beings depend on the chemical composition of body fluids and tissues, and the elemental composition of the human organism is a subject to changes depending on the physiological state and dietary habits. In the human body the elements are present in an ionic form, or are joined in different types of molecular compounds. The chemical composition of tissues and biological fluids is dependent on biological processes, in which hormones and enzymes take part. Elements are part of metalloenzymes, have building and regulating functions, are enzyme activators, components of certain vitamins, electrolytes, participate in oxidative reduction processes. Unfortunately, many biological properties of elements have not been fully explained, although experimental research has been ongoing for many decades [18]. There are certain ranges of elements levels in tissues and body fluids that are considered “normal” [https://www.mayomedicallaboratories. com]. An exceeding of the values that are considered “normal” disrupts the functioning of cells and tissues and can result in serious disorders. The self-regulatory mechanisms sometimes become seriously disturbed by several factors already known (such as diet, stress, diseases, or infections) and others that need to be identified. It is also important to refer the so-called “toxic” (imprecise term, as mentioned above, however commonly used) elements, which can compete with the essential

2. Search strategy and study selection A comprehensive search was conducted from June 2008 to June 2018. The PubMed database and Scopus were used to obtain relevant articles based on inclusion criteria. 2.1. Inclusion criteria We used the following inclusion criteria: 1) any study design; 2) studies focusing on determinations of chemical elements, i.e. Cd, Pb, As, Ni, Mo, Co, Cr, Mn, Se, I, Fe, Sr, Cu, Zn, Mg, K and Na (each one 2

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elements even at low levels of exposure. The knowledge of these relationships is crucial to understand the effects of their presence on metabolism and is definitely helpful in predicting the susceptibility to certain dysfunctions associated with elemental dyshomeostasis. The studies on the inter-elemental correlations have shown that some essential elements (e.g. Co, Cr, Cu, K, Fe, Mg, Ca, Mn, Mo, Se and Zn) can have a protective role against the toxic ones [19]. The literature also indicates that nutritional deficiencies for certain groups of elements may increase the absorption of toxic metals, alter the metabolism of other elements, or increase the excretion of the essential elements [20], and it is emphasized that the deficiency of many trace elements is being more common than a single deficiency. It would not be possible to study the inter-elemental interactions without the earlier thorough investigation of the content of many elements in different biological matrices [21]. Typically, analyses are carried out in serum, whole blood or urine, and less often in hair or nail samples. Unfortunately for many elements, up to today, no mechanisms of action and their functions in the body have been fully identified. Additionally, the clarification of the relationship between environmental exposure and the biological activity of a given element is a challenging task [22]. Knowing and understanding the results of the elemental analysis is essential for the diagnosis, treatment and prevention of many disorders for both the mother and the baby developing in her womb. Mineral deficiencies in pregnant women are known to cause birth defects of the central nervous system, and growth disorders in the newborn [23].

Ghesquière et al. [30] suggested that supplementation of calcium (1 g/ day) may reduce the risk of PE especially to patients with low baseline calcium intake. While initial findings are promising, further research is necessary to estimate such risk for a larger population of preeclamptic women with optimal calcium intake. Calcium and magnesium have a significant relationship with blood pressure. Recently, Elmugabil et al. [31] have shown a significant relationship between PE and the content of Ca and Mg in the serum (Ca reduction and Mg elevation were observed). However, the work of other researchers did not confirm the association of Mg and Ca with PE (the studies concerned the second and third trimesters of pregnancy) [32]. Unfortunately, only serum samples have been tested in that study. As far as sodium and potassium are concerned, the findings of serum Na and K levels in preeclampsia compared with normal pregnancy are inconclusive. It was found that pregnant women with PE with high dietary salt and low potassium intake may have greater maternal and neonatal morbidity risk than pregnant women with PE under low dietary salt and high potassium intake [33]. Some studies reported an elevated serum potassium level in preeclampsia compared with healthy pregnant women [34]. Recently, a significantly reduced serum sodium levels in preeclamptic in comparison to normotensive pregnant women has been observed [35], while other studies reported no significant difference [36]. Zinc - present in metallothioneins, cofactor and constituent of approximately 200 enzymes, selenium - essential for certain enzymes, including several anti-oxidants: superoxide dismutase (SOD) glutathione peroxidase, and copper (Cu -containing enzyme SOD is a key enzyme in suppressing the amounts of superoxide anion radicals, Cutransporting protein in plasma, i.e. ceruloplasmin, also possesses an important redox capacity are usually considered as being involved in PE manifestation and development. Copper, like other transition elements, is involved in many biochemical processes (e.g. cellular respiration), although can also catalyze the formation of free radicals, thus research on the potential role of copper in PE is justified. As for an oxidative stress, it must be emphasized that during normal gestation, reactive oxygen species (ROS) generation are known to be increased and necessary for proper physiology [37–39]. Iodine contributes to redox balance during pregnancy and the antioxidant function of iodine and iodine deficiency as a risk factor of preeclampsia have been reported. Unfortunately, the mechanism of action of iodine in the placenta is not fully understood [40]. Despite the several intensive studies on TE and PE, the exact mechanisms of the redox-active transition metals and oxidative stress in preeclampsia are still enigmatic [41]. Thus, the question whether the level and ratio changes of trace elements in the body may be utilized in the identification of disease progression and grade in PE remains open. Zn, Cu or Se are extremely important during the rapid fetal growth. Zinc, among many important roles in the body, has antioxidant functions, copper is required for a multiplicity of functions including mitochondrial oxidative phosphorylation and protection against oxidative stress. Since Zn is a structural component of the cytoplasmatic antioxidant enzyme Cu,Zn-superoxide dismutase (SOD) the observed hypozincemia in PE may result in the generation of oxidative stress by weakening antioxidant defense mechanisms. It was suggested that the causes of decreased Zn in mother’s serum were associated with the possible transition of Zn from mother to fetus and with the increased lipid peroxidation leading to lower levels of transporter proteins and estrogen hormone in PE [42]. It was suggested that higher copper/zinc ratios in plasma were associated with increased risk of developing PE [1]. At present, pre-diabetes, infertility, the occurrence of PE during the previous pregnancy, elevated body mass index, and chronic hypertension are most common clinical features used for identification of patients at increased risk of PE. The already mentioned oxidative-induced imbalances and disturbances of elemental homeostasis are not only important in the etiopathogenesis of preeclampsia, but also in type 2 diabetes [43,44]. Diabetes and PE have several common mechanisms.

2.3. Studies of selected elements linked to PE The number of elements that may have a significant association with PE remains unknown. The right balance both of chemical elements in tissues and body fluids, as well as balanced oxido-reductive state of cells constitute a key and undeniable factor of proper pregnancy development. For example the epidemiologic studies have revealed an inverse relationship between calcium intake during pregnancy and the incidence of PE [24]. Other studies revealed that calcium supplementation did not reduce the risk of developing preeclampsia [25]. The World Health Organization has issued a strong recommendation that pregnant women should receive calcium supplements to prevent preeclampsia. WHO recommends 1500–2000 mg calcium for pregnant women with low dietary calcium intakes, particularly those at higher risk of gestational hypertension [26]. It was reported that changes in the concentration of calcium during gestation can be used as preeclampsia biomarker [13], however it is unlikely that a single marker (e.g. change in Ca content) will prove to be an accurate predictive tool for preeclampsia. Since PE can sometimes occur even without warning signs it is absolutely necessary to have adequate and early indicators of upcoming threats. However, to find an indicator of clinical disease requires intensive studies including method validation with an adequately powered trials linked to biomarker qualification. Calcium has been proposed as being relevant to the described condition. More than a decade ago Bringman et al. [27] found that women with severe preeclampsia had significantly lower serum levels of both total and ionized calcium, whereas total and ionized magnesium levels were similar between the group of healthy and preeclamptic women. The findings on the decreased level of Ca in serum have been confirmed recently by the study of Al-Jameil et al. [28] which associates serum hypocalcemia and intracellular hypercalcemia with blood pressure elevation in PE. The same study also described significantly lower magnesium in serum (which may increase vascular resistance and consequently lead to blood pressure elevation). The determination of the content of calcium in the urine of women with PE has shown that hypocalciuria may be a predictor of PE, but the studies were conducted on a relatively small group of women (60) in the 20–30 age group [29]. 3

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Recently J. Lee [45] has observed an increase in the risk of developing diabetes in the group of women with previous pregnancies complicated by PE. In women with abnormal glucose tolerance or diabetes, the elevated risk of PE is noted. Schneider et al. [46] have also reported common risk factors for developing diabetes and PE in pregnant women such as advanced age, infertility, multiple pregnancy and elevated BMI. The mechanisms underlying the onset of these conditions are considered to be disorders of vascular endothelial function. The clinical manifestation of these conditions in pregnant women most often disappears with the completion of pregnancy, however, women in this group have a higher risk of developing hypertension or type 2 diabetes at a later age. Many researchers are particularly focused on the increased risk of developing hypertension and PE in women with diabetes, as evidenced by numerous studies. Diabetes itself is an independent factor in the development of PE. Interestingly, it was suggested that non pregnant patients who additionally suffered from hypertension had higher copper levels compared with diabetic patients [44]. Studies on larger women populations should confirm the purposefulness of a possible monitoring of copper levels in women with PE. Rice et al. have observed that in women with varying degrees of glucose intolerance, gestational hypertension and preterm delivery associated with these complications the risk of hypertension, hypertriglyceridemia, and metabolic syndrome in the next 5–10 years is increased [47]. An overview of research studies made by Wilson et al. [48] concerning zinc relationships with complications during pregnancy has shown that a half of published studies he reviewed proved that zinc may indeed influence hypertension. Unfortunately, most of the studies have not taken into account the level of zinc intake or zinc deficiency risk in the study groups. Therefore, the direct relationship of maternal zinc to successful completion of pregnancy was not possible to establish. Authors of a recent meta-analysis of zinc influence on PE risk highlighted the ambiguous results reported in scientific publications [49]. Their collective results (for 11 controls and 2 cross-sectional studies) suggested a lower level of Zn in PE. Regarding selenium, its compounds are toxic in large amounts, but trace amounts are necessary for cellular function in many organisms. Selenium is a component of the antioxidant enzymes glutathione peroxidase and thioredoxin reductase (which indirectly reduce certain oxidized molecules in animals and some plants). It is also found in three deiodinase enzymes, which convert one thyroid hormone to another (selenium in iodotyrosine deiodinase, as selenocysteine, plays a crucial role in determining the free circulating levels of triiodothyronine). Selenium is a key component of enzymes that prevent oxidative stress in the brain, secondly, it is required for many detoxification processes of heavy metals. Selenium inhibits lipid peroxidation (lipid peroxidation is prevented by phospholipid hydroperoxide glutathione peroxidase, a selenium-dependent peroxidase, which disables fatty acid peroxides). Xu et al. [50] conducted a meta-analysis to compare the blood selenium level in patients with preeclampsia and healthy pregnant women to determine the effectiveness of selenium supplementation in preventing preeclampsia. It was confirmed - based on data from both observational studies and from randomized controlled trials - that supplementation with selenium significantly reduces the incidence of preeclampsia (the relative risk for PE was 0.28 (0.09 to 0.84) for selenium supplementation (p = 0.02)). The cited authors emphasized the need for more frequent prospective clinical trials to find the association between selenium supplementation and preeclampsia, and to determine the dose, beginning time, and duration of selenium supplementation. Studies of Mistry et al. [51] highlighted a number of new and important insights in the discussed issue. The authors reported maternal plasma selenium, copper, zinc, and manganese concentrations in combination with associated antioxidant enzymes and markers of both antioxidant capacity and oxidative stress (ceruloplasmin activity, selenoprotein P, ferric-reducing ability of plasma activity (FRAP), GPxglutathione peroxidase activity, superoxide dismutase (SOD) activity,

catalase activity, and thiobarbituric acid-reactive substances (TBARS)). In contrast to some previous reports on selenium supplementation and risk of preeclampsia [50,52] the results do not support the suggestion that supplementation with Se and also with the other above-mentioned micronutrients could help prevent the development of preeclampsia in women after 15 weeks' gestation. It was suggested that the reduced selenium concentration and GPx activity and increased oxidative stress at delivery may be a consequence of the oxidative stress associated with preeclampsia, rather than a cause. This is another proof that even in the 200th anniversary of the discovery of Se, the nature and function of selenium in the living organisms is not fully known and must be further investigated. One of the expected consequences of imbalanced selenium levels in pregnancy complicated by PE may be an altered level of iodine in the body. Iodine is not only involved in thyroid function but together with selenium affects the development and proper functioning of the brain and other organs of both mother and fetus [53]. The role of iodine in pregnancy is crucial, therefore, taking into consideration that nonhormonal role of this element on metabolism is not fully explained, and disorders of its homeostasis have serious effects on an organism what was shown in our previous studies [20], it is reasonable to examine iodine content in the body of pregnant women with PE and other complicated diseases. The problem of iodine deficiency during pregnancy complicated by hypertension has been discussed in recent literature [54]. Another element that is rarely studied in terms of complications of pregnancy is cobalt. It was demonstrated that levels of cobalt were significantly lower in the PE group compared with the healthy pregnant women and healthy non-pregnant controls [55,56]. Clearly, further and preferentially multicenter investigations are necessary to confirm the findings. The importance of the mutual interactions between non-essential and essential elements in humans have been demonstrated in many research papers. It is known that Se and Zn can protect against the toxicity of Cd (one of the most harmful heavy metals present in the environment). Data from a study of Laine et al. [57] investigating placental levels of Cd, Se, and Zn suggested that Cd levels are associated with increased risk of PE and that essential elements may play an important role in reducing that risk. This pilot US study appears to suggest the key role that some metals play in reducing the risk/likelihood of Cddependent preeclampsia. However, a study on a larger group of pregnant women with PE-complicated pregnancies is necessary. In addition to the small number of patients, it is important to note that only one type of test specimen was taken into account (placenta) and there was no information on the interaction of cadmium with other important elements. A comparative study on a smaller population of women with and without PE conducted by Farzin & Sajadi [58] revealed that the levels of serum trace elements were altered in cases of preeclamptic pregnancy (e.g. serum Zn, Se, Mg and Ca levels were significantly lower in the preeclamptic women in comparison with the non- preeclamptic subjects). Gupta et al. [59] suggested that plasma zinc levels are significantly lowered in severe preeclampsia and eclampsia while the erythrocyte zinc levels do not show any significant change. No correlation between plasma or erythrocyte zinc levels and intrauterine growth restriction in PE was demonstrated. The question of whether a particular element is an etiologic factor of PE or complications requires a simultaneous evaluation of other biochemical parameters in the blood. An example is iron, which is essential for the proper functioning of respiration at the cellular level, is part of a number of enzymes including those relevant in the case of resistance to infection. It is also a cofactor of compounds involved in the synthesis and catabolism of certain hormones, and the production of substances essential for the functioning of lymphocytes. Due to its wide role in the functioning of different cells, the symptoms of the deficiency of this element are highly variable. It is suspected that the increased level of Fe 4

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in blood causes the generation of the oxidative stress in PE [60], and, with the well-known fact of hemoglobin increase in PE women [61], it is reasonable to investigate the mechanisms of elevation of Fe concentration in blood in reference to biochemical parameters in response for the oxidative stress. In addition, it should be emphasized that the assessment of ferritin level is more and more widely used in the assessment of inflammation and as an early marker of infection. This can be important for the course and treatment of many disorders, as well as for the evaluation of infectious complications in the mother and in the child. In addition, the assessment of iron stores in the body by measuring the concentration of ferritin and transferrin proteins as well as the measurement of total iron binding capacity (TIBC) may provide additional valuable information. Although anaemia is a late symptom of iron deficiency, the level of Fe is a good indicator of homeostasis in this regard. The histopathological studies of PE women's placenta show severe damage to vessels and cell damage and it is suggested that Fe species may be a factor in the generation of the oxidative stress of the condition, and capable of initiating lipid peroxidation [60]. Significantly higher serum Fe was found in women with PE compared with healthy pregnant and non-pregnant women from Turkey [55]. An accurate diagnosis of iron status during all trimesters of pregnancy presents challenges. Due to the large expansion in blood volume and red cell mass during the first half of pregnancy, iron stores are often decreased and it may lead to iron deficiency anaemia by the late-second or third trimester. Therefore, patients with PE should undergo frequent routine monitoring of the element level. It is obvious that redistribution of metals from storage sites into other tissues will affect the content of such elements in the blood. Therefore, it is more puzzling that only a few studies on PE include information both about the level and about the distribution ratio of elements in the blood. The distribution affected by many physiological factors (e.g. kidney function) between whole blood and serum can vary considerably for different elements. Research in this area should be considered a high priority for the preeclamptic patients and elemental distribution among cellular compartments of different cell types and tissues will certainly help to understand what is happening at the cell level during PE. An attention should be paid to the possible change in redistribution of elements to individual matrices (tissues, urine, or particular blood components) among women with PE comparing with healthy ones, remembering that the redistribution is not a synonym of the elements’ status in the organism. Such research is rare, however could bring us closer to answering the question about sources of the disturbances of elemental homeostasis in PE.

environment and their association with the occurrence of PE among a population of women from Congo have shown elevated levels of elements (especially lead) in the urine of PE women compared to healthy women, although no cause of this phenomenon was found [66]. Recently conducted meta-analysis studies by Poropat et al. [67] led to the conclusions that levated blood lead concentrations in pregnant women are a major risk factor for preeclampsia. It was found that an increase of 1 μg/dL Pb in blood was associated with a 1.6% increase in the likelihood of PE, which appears to be the strongest risk factor for preeclampsia yet reported. Therefore, prophylactic calcium supplementation was recommended for pregnant women with blood lead concentrations above 5 μg/dL (Pb2+ disturbs intracellular Ca2+ homeostasis, and both ions compete at the plasma membrane for transport systems). A high blood lead level was observed in many different studies carried out on populations with PE from different regions of the world [68,69]. 2.5. Some frequent weak points and shortcomings in current research In the light of increasingly frequent and severe environmental threats, more elements need to be determined in relation to the described disease. Due to the limitations of current research, sometimes with controversial and contradictory results, we address the issue of above mentioned limitations. Since many factors can influence the net exposure to an environmental chemical (e.g. absorption, metabolism, excretion, location of exposure, etc.) the examinations of genetic susceptibility, health status, nutrition, demographic characteristics, lifestyle or behavioral factors (e.g., smoking habits or occupation), and route of exposure are undoubtedly necessary. Unfortunately, a comprehensive approach to this issue is not frequent in relation to PE research. It is important to know how the determined levels of specific elements in women with PE relate to normal (reference) levels obtained in reference populations (i.e. in healthy pregnant women). In this context, many problematic issues must be noted. In healthy pregnancy there are increased metabolic demands for micro and macronutrients. Usually, pregnant women are taking mineral supplements for deficiencies preventive purposes. Therefore, it is difficult to find a large group of women who do not take any supplements (either single or combined forms of various elements) throughout the pregnancy so that this group could serve as a reference (control group) to the PE group. Pregnant women experience physiological and metabolic changes over the course of pregnancy that may affect measured elemental levels, so levels among nonpregnant women may not be directly comparable [70]. Some differences were observed among mothers as a function of the number of previous pregnancies, education level, race and ethnicity, and country of birth. Age can also significantly affect the body burden of some elements [71]. Some of the mentioned differences could possibly be also explained by differences in lifestyle, BMI, diet and/or environmental exposures. The extent of deficiency or overexposure can be evaluated through the participation in well-designed representative studies, which have been performed on a national level. The China Nutrition and Health Survey 2010–2012 (CNHS 2010–2012) provided trace elements profiles in all population groups in China, including pregnant women [72]. The nationally representative cross-sectional study on 1400 pregnant Chinese women revealed the concentrations of 14 serum trace elements (iron, copper, zinc, rubidium, selenium, strontium, molybdenum, manganese, lead, arsenic, chromium, cobalt, vanadium, and cadmium), although it was unclear as to what the status of health of the pregnant women in this study was. The influence of subclinical infections and inflammation on serum trace elements levels was not evaluated. Despite these limitations the study provided clear evidence that all of the selected elements are visibly altered (serum Fe, Zn, and Se concentrations significantly decreased, whereas serum Cu, Sr, and Co concentrations elevated progressively compared with reference values) when classified

2.4. Studies of the exposure to toxic metals among preeclamptic women Recently Jacobo-Estrada et al. [62] presented an overview of the possible mechanisms involved in the multiple organ toxic effects in fetuses after the exposure to Cd during pregnancy. Zhang et al. [63] explored the effects of cadmium in the immune system of preeclamptic patients and rats. The results showed that the cadmium levels in the peripheral blood of preeclamptic patients were significantly higher than those observed in normal pregnancy. On the contrary, no significant differences in urinary Cd concentrations were found in preeclamptic women compared with non-preeclamptic women in the studies of Osorio-Yañez et al. [64]. The researches provided the evidence that significant decrease in third-trimester mean arterial pressure was associated with high dietary intake of micronutrients like calcium, magnesium, zinc, selenium and with increased urinary cadmium. Some animal studies demonstrated that an increased oxidative DNA damage in placenta could contribute to Cd-induced preeclamptic conditions [65]. Our overview of recent research indicates that regardless of whether the toxicity of a given element with clinical manifestations is rare or frequent, the changes in elemental homeostasis seem to be significant in PE. The studies concerning the exposure to toxic metals in the 5

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by age interval, residence, anthropometric status, and duration of pregnancy. It must be emphasized that only a small number of studies are based on women from populations where there is a high risk of specific element deficiency. This can be one of the reasons for existence several inconsistent results related to the levels of specific elements and a risk of PE. Studies of Gabbay et al. [73] which examined the association between calcium levels during the first trimester of pregnancy and preeclampsia in women with and without hypocalcemia (16% had hypocalcemia and 84% had a normal calcium level) suggested that hypocalcemia during the first trimester of pregnancy is not a risk factor for preeclampsia, while some other studies indicate that low dietary calcium intake may be a risk factor or risk marker for the development of hypertension, particularly for women with a history of gestational hypertension [74]. With regard to the elements investigated, apart from BMI, age, lifestyle, socioeconomic status, pharmacology applied, comorbid diseases, laboratory or clinical parameters, also the differences in analytical methodologies would justify some differences in metal concentrations between the two groups (control and with PE). Unfortunately, often nutritional habits or use of mineral and vitamin supplements that could account for differences in the observed concentrations are not investigated. Pregnant women, often without consulting the doctor, take various dietary supplements (highly advertised in the mass media) of not quite known composition and origin. It should be emphasized that it is unlikely that women are always aware of their own levels of the elements and know if they belong to the groups that exceed optimal doses. The problem of "fashionable" dietary supplements of universal availability not only in Poland but all over the world should also be looked at from the point of view of lacking data on the presence and content of toxic elements such as cadmium or lead in their composition. In current scientific literature, there are many shortcomings and limitations such as: single-element, and single-matrix studies, small populations of studied groups (limiting statistical power), lack of simultaneous studies in mothers and their offspring, and poorly described clinical characteristic of patients (Fig.1.). Since individual species of the elements differ greatly in their behavior in human organism, so the determination of these individual species, i.e. speciation studies which enable the analysis of different chemical-physical-physiological forms of the element and their relative distribution is of critical importance [75]. Unfortunately, to the best of our knowledge there is a lack of speciation studies between 2008–2018 in the aspect of preeclampsia. Fig.1. Amount (%) of studies regarding chemical elements in PE women published between 2008–2018 including selected variables. Most of the existing studies are not prospective including women planning pregnancy (both healthy and with various pathologies) and those tested during the 1 st, 2nd, 3rd trimester and after the labor.

Fig. 2. Amount (%) of research on PE and chemical elements published between 2008–2018 as a function selected methodological factors. * serum/blood ratio vs. other tissue or distribution between blood compartments.

Many of above-cited studies concern the examination of the population at a single point in time. A great insight into the importance of particular elements in the development of PE and pregnancy complications would be possible if the research applies both before planned pregnancy and during all trimesters. Unfortunately, there are not many studies having a prospective design in this research field. The reference ranges of respective elements vary quite significantly at times [75]. Furthermore, there is still a lack of multielement and multimatrix analysis combined with the daily intake of minerals in PE. Often there are unclear selection criteria to the tests, with no information on past and present addictions or applied pharmacotherapy. Extremely rare are studies of trace elements’ analysis of amniotic fluid, placenta, and umbilical cord blood. Determinations of several anions and cations (with substantial value for an organism under complex disorders with unclear etiology, like PE) are missing. Moreover, many studies describe the use of a single analytical procedure, therefore the quality of the analytical results is sometimes far from the accepted standards (Fig. 2). Fig. 2. Amount (%) of research on PE and chemical elements published between 2008–2018 as a function selected methodological factors Although the methodological basis for elemental status monitoring of the population has been developed a long time ago, some unstandardized methodological procedures of sample preparation are in use [76]. Equally important is the assurance of high quality of the preanalytical actions (like proper sample collection, sample storage and transport to the laboratory, and choice of optimal sample preparation procedures, i.e. procedures with optimized parameters which are easy to verify), so that a correct comparison between healthy and pathological pregnancies can be made. Unfortunately, most of the published articles do not include details about the entire analytical process. Many authors do not even mention how blood or other tissue were prepared for a specific measurement by the use of an analytical technique. Care must be taken when the type of sample is being selected. Free forms of the elements as well as complex forms (element association with a variety of ligands) result in differente bioavailability of the element [77]. There are elements, such as Se, for which the line between beneficial and toxic effects is narrow and depends both on the content of the element in the body as well as on its chemical forms. Therefore, a speciation analysis (i.e. the process of separating and quantifying different chemical forms of a compound or element, which can exhibit very different physiochemical properties, including varying toxicities) in clinical samples collected from a large population with PE is urgently needed. Speciation analysis is necessary to understand mechanisms of toxicity, biological activity, metabolism, and bioavailability of elements, thus more attention should be paid to include information about oxidation state, the nature of organic and inorganic

Fig. 1. Amount (%) of studies regarding chemical elements in PE women published between 2008–2018 including selected variables. 6

Journal of Trace Elements in Medicine and Biology 59 (2020) 126468

K. Gajewska, et al.

Table 1 Examples of determinations of selected elements in tissues and body fluids of women with PE. Element

Sample matrix

Analytical technique

Cd

blood blood serum placenta

Reference values: 0.0–4.9 μg/L Reference values: 0.0–5.0 μg/L F-AAS ↑ ICP-MS ↑

peripheral blood umbilical cord blood urine

ICP-MS

↑

ICP-MS

non significant difference ↑

hair serum maternal blood placenta

ICP-OES

Pb

umbilicalcord blood peripheral blood hair blood blood urine serum blood hair

ICP-MS

ICP-MS

Ni

Mo

Co

Cr

non significant difference ↑ ↑ non significant difference ↑

Reference values: 0.0–3.9 μg/g Reference values: 0.0−49 μg/L Reference values: 0.0−49 μg/L ICP-MS ↑ ICP-OES F-AAS ICP-OES

serum As

Significantly increased (↑) or decreased (↓) level in PE compared with normotensive controls

↑ ↑ non significant difference non significant difference

hair blood blood urine

Reference values: 0.0-0.9 μg/g Reference values: 0.0–12.0 μg/L Reference values: 0.0–12.0 μg/L ICP-MS ↑

hair serum serum serum urine

ICP-OES

non significant difference

Reference values: < 2.0 μg/L Reference values: ≤10.0 μg/L ICP-MS ↑

hair serum serum serum urine

non significant difference Reference values: 0.3–2.0 μg/L Reference values: no data ICP-MS ↑

serum

GF-AAS

serum serum serum serum urine

Reference values: 0.0-0.9 μg/L Reference values: ≤1.0 μg/L F-AAS ↓ F-AAS ↓ ICP-MS ↑

serum hair plasma

ICP-OES

↓

ICP-MS

serum serum urine

non significant difference

Reference values: < 0.3 μg/L Reference values: ≤ 5.0 μg/L ICP-MS ↑

serum

ICP-OES

hair

ICP-OES

non significant difference

non significant difference ↑

Mean content ± SD (number of PE patients)

Mean content ± SD (number of controls)

Certified Reference Materials

References

0.033 ± 0.020 μg/dL (47) 3.7 ng/g – median (86) 37.65 ± 1.84 μg/L (20)*

Mayo Clinic Laboratories Arup Laboratories 0.029 ± 0.027 μg/dL (48) 3.5 ng/g – median (86)

no no

[78] [79] [55] [57]

18.65 ± 1.22 μg/L (20)*

no

[63]

1.149 ± 0.126 μg/L (20)

1.266 ± 0.0845 μg/L (20)

1.78 μg/L – geometric mean (88) 3.96 ± 0.87 μg/g (43) 0.05 ± 0.04 mg/l (43)* 1.21 μg/L - median (51) 4.28 μg/kg wet weight - median (51) 0.28 μg/L- median (51) 38.33 ± 1.47 μg/l (40)*

0.53 μg/L – geometric mean (88) 3.75 ± 0.64 μg/g (23) 0.10 ± 0.3 mg/l (23)* 1.09 μg/L -median (51) 3.61 μg/kg wet weight median (51) 0.37 μg/L- median (51) 18.53 ± 0.98 μg/l (40)* Mayo Clinic Laboratories

no

[66]

yes

[76]

no

[80]

no

[81]

71.5 μg/L – geometric mean (88) 27.18 ± 2.13 μg/ dL (40)* 37.68 ± 9.17 μg/dL (115)* 72.27 ± 19.82 μg/g (43)*

Arup Laboratories 7.98 μg/L – geometric mean (88) 18.23 ± 2.34 μg/dL (40)* 14.5 ± 3.18 μg/ dL (25)* 58.77 ± 37.04 μg/g (23)*

0.20 ± 0.17 mg/L (43)*

0.16 ± 0.21 mg/L (23)*

[78] no

[79] [66]

no no yes

[68] [69] [76]

Mayo Clinic Laboratories 46.9 μg/L – geometric mean (88)* 7.63 ± 1.32 μg/g (43)* 0.06 ± 0.0 mg/L (43)* 13.8 μg/L – geometric mean (88) 6.86 ± 0.81 μg/g (43) 0.02 ± 0.0 mg/L (43)* 19.2 μg/L – geometric mean (88) 2.304 ± 0.173 μg/dl (60)*

0.127 ± 0.109 μg/dL (47)* 1.5 ± 0.6 μg/dL (59)* 2.07 μg/L- geometric mean (88) not detected 1.56 ± 0.74 μg/g (43) 1.9 ± 0.65 μg/L (37)*

Arup Laboratories 26.8 μg/L – geometric mean (88)* 5.47 ± 2.79 μg/g (23)* 0.49 ± 0.0 mg/L (23)* Mayo Clinic Laboratories Arup Laboratories 4.14 μg/L – geometric mean (88) 8.40 ± 1.31 μg/g (23) 0.14 ± 0.0 mg/L (23)* Mayo Clinic Laboratories Arup Laboratories 13.3 μg/L – geometric mean (88) 2.670 ± 0.172 μg/dl (60)* Mayo Clinic Laboratories Arup Laboratories 0.223 ± 0.112 μg/dL (48)* 2.5 ± 0.7 μg/dL (150)* 0.54 μg/L- geometric mean (88) 0.02 ± 0.0 mg/L (23)* 2.89 ± 4.99 μg/g (23) 2.1 ± 1.09 μg/L (51)*

0.24 ± 0.01 mg/L (43)*

Mayo Clinic Laboratories Arup Laboratories 0.88 μg/L- geometric mean (88) 0.05 ± 0.03 mg/L (23)*

13.31 ± 2.67 μg/g (43)

11.05 ± 7.62 μg/g (23)

4.57 μg/L- geometric mean (88)

[78] no

[79] [66]

yes

[76]

no

[78] [79] [66]

yes

[76]

no

[78] [79] [66]

no

[85]

no no no

[78] [79] [55] [56] [66]

yes

[76]

yes

[82]

no

[78] [79] [66]

yes

[76]

(continued on next page)

7

Journal of Trace Elements in Medicine and Biology 59 (2020) 126468

K. Gajewska, et al.

Table 1 (continued) Element

Sample matrix

Analytical technique

Mn

serum serum serum plasma

serum placenta

Reference values: < 2.4 μg/L Reference values: 0.0–2.0 μg/L ICP-OES ↓ ICP-MS non significant difference between type 1 diabetic women with and without PE F-AAS ↓ ICP-MS ↑ ICP-OES ↓ non significant difference ICP-MS non significant difference F-AAS ↓ F-AAS ↓ GF-AAS ↓ Reference values: 70−150 μg/L Reference values: 23−190 μg/L ICP-MS non significant difference between type 1 diabetic women with and without PE F-AAS ↓ ICP-MS ↑

serum

F-AAS

↓

urine

ICP-MS

↑

serum hair

ICP-OES

plasma

ICP-MS

serum serum

F-AAS GF-AAS

↓ non significant difference non significant difference ↓ ↓

serum

F-AAS

↓

umbilical cord blood maternalvenous cord-artery cord-vein plasma plasma serum

Spectrophotometry ICP-MS

serum urine serum hair plasma

Se

I

Fe

serum serum serum serum serum plasma

urine urine urine serum serum plasma

serum serum hair serum serum serum serum serum

Significantly increased (↑) or decreased (↓) level in PE compared with normotensive controls

Mean content ± SD (number of PE patients)

Mean content ± SD (number of controls)

0.072 ± 0.068 mg/L (40)* no data

Mayo Clinic Laboratories Arup Laboratories 0.125 ± 0.077 mg/L (40)* no data

0.58 ± 0.22 μg /dL (59)* 44.5 μg/L- geometric mean (88) 0.02 ± 0.0 mg/L (43)* 13.07 ± 0.95 μg/g (43)

Certified Reference Materials

References

no yes

[78] [79] [41] [43]

0.99 ± 0.23 μg /dL (150)* 9.2 μg/L- geometric mean (88) 0.03 ± 0.0 mg/L (23)* 13.57 ± 1.13 μg/g (23)

no no yes

[56] [66] [76]

2.8 ± 0.99 μg/L (37)*

2.8 ± 1.02 μg/L (61)*

yes

[82]

0.08 ± 0.02 mg/L (50)* 0.007 ± 0.001 μmol/L (49) 7.617 ± 0.293 μg/dL (60)*

0.14 ± 0.02 mg/L (58)* 0.017 ± 0.005 μmol/L (40) 10.847 ± 0.356 μg/dL (60)* Mayo Clinic Laboratories Arup Laboratories no data

no no no yes

[83] [84] [85] [78] [79] [43]

8.8 ± 3.0 μg/dL (59) 254.5 ng/g – median (86) 8.82 ± 2.10 μg/dL (60) 44.6 μg/L – geometric mean (88) 0.06 ± 0.01 mg/L (43) 24.42 ± 1.78 μg/g (43)

22.0 ± 7.0 μg/dL (150)* 237.5 ng/g – median (86)

no no

[56] [57]

10.47 ± 2.78 μg/dL (60) 27.2 μg/L – geometric mean (88) 0.14 ± 0.01 mg/L (23) 23.93 ± 2.62 μg/g (23)

yes

[58]

no

[66]

yes

[76]

45 ± 15 μg/L (37)

47 ± 15 μg/L (61)

yes

[82]

1.3 ± 0.4 μmol/L (40) 4.306 ± 0.050 μg/dL (60) 32.10 + 1.50 μg/L (rural 70) 32.29 + 2.09 μg/L (urban 48) 22.17 ± 4.19 μg/L (18)*

no no

[84] [85]

no

[86]

↓

0.6 ± 0.1 μmol/L (49) 2.546 ± 0.068 μg/dL (60) 23.07 + 0.96 μg/L (rural 42) 24.67 + 0.75 μg/L (urban 32) 18.58 ± 5.21 μg/L (19)*

no

[87]

↓

98.6 ± 24.2 μg/L (43)

110.7 ± 19.4 μg/L (80)

no

[88]

111.6 ± 17.6 μg/L (80) 107.1 ± 25.7 μg/L (80) 58.51 ± 11.85 μg/L (40) 80.27 ± 17.12 μg/L (38) 0.09 ± 0.01 mg/L (30)

yes no no

[89] [90] [91]

no

[78] [79] [54]

yes

[78] [79] [43]

1.97 ± 1.32 μg/dL (48)* 179.94 ± 47.31 mg/L (23)* 449.39 ± 78.36 μg/g (23) 1.96 ± 0.32 mg/L (58)* 30.4 ± 16.1 μmol/L (30) 90.8 ± 39.6 μg/dL (30) 13.57 ± 7.16 μmol/L (37)

no yes

[55] [76]

no no no yes

[83] [91] [92] [93]

0.023 ± 0.002 mmol/L (27)

no

[97]

no data

↓ 82 ± 17.8 μg/L (43) ↓ 82.1 ± 17.4 μg/L (43) ET-AAS ↓ 51.75 ± 11.62 μg/L (40) GF-AAS ↓ 71.22 ± 16.95 μg/L (38) INAA non significant 0.09 ± 0.01 mg/L (29) difference Reference values: 75−851 μg/ 24 h Reference values: 26.0–705.0 μg/L; 93.0–1125.0 μg/ 24 h Spectrophotometry ↓ 4.25 ± 2.70 μg/dL (40) (Sandell–Kolthoff reaction) Reference values: 350−1450 μg/L Reference values: 300−1600 μg/L ICP-MS non significant no data difference between type 1 diabetic women with and without PE F-AAS ↑ 4.48 ± 3.35 μg/dL (47)* ICP-OES non significant 142.64 ± 129.00 mg/L (43)* difference 613.54 ± 107.29 μg/g (43) F-AAS ↓ 1.13 ± 0.22 mg/L (50) INAA ↓ 7.7 ± 8.1 μmol/L (29) autoanalyzer ↑ 103.9 ± 65.16 μg/dL (31) Spectrophotometry ↑ 18.87 ± 8.04 μmol/L (30) (TPTZ method) F-AAS non significant 0.019 ± 0.004 mmol/L (44) difference

Mayo Clinic Laboratories Arup Laboratories 20.89 ± 6.39 μg/dL (18) Mayo Clinic Laboratories Arup Laboratories no data

(continued on next page)

8

Journal of Trace Elements in Medicine and Biology 59 (2020) 126468

K. Gajewska, et al.

Table 1 (continued) Element

Sample matrix

Analytical technique

Sr

serum serum plasma serum

Reference values: no data Reference values: no data ICP-MS ICP-MS

serum serum serum serum

Reference values: 750−1450 μg/L Reference values: 800−1550 μg/L F-AAS ↑ F-AAS non significant difference ICP-OES ↓ ICP-MS non significant difference F-AAS ↑ F-AAS ↓ F-AAS non significant difference ICP-MS ↑

Cu

serum plasma serum serum serum urine

↑ ↑

Mean content ± SD (number of PE patients)

Mean content ± SD (number of controls)

Certified Reference Materials

References

199.5 μg/dL – median (38)* 111,6 μg/dL – median (50)

Mayo Clinic Laboratories Arup Laboratories 38 ± 1.4 μg/L (61) 27.4 ± 7.8 μg/L 2nd trimester(51) 33.5 ± 9.9 μg/L 3rd trimester (53) Mayo Clinic Laboratories Arup Laboratories 152.45 μg/dL – median (40) 103.6 μg/dL – median (50)

1.554 ± 0.53 mg/L (40)* no data

2.014 ± 0.43 mg/L (40)* no data

no yes

[41] [43]

2.65 ± 0.76 μg/dL (47)* 86.7 ± 16.5 μg/dL (59) 118.28 ± 16.92 μg/dL (60)

2.08 ± 0.46 μg/dL (48)* 162.4 ± 27.4 μg/dL (150)* 116.55 ± 15.23 μg/dL (60)

no no yes

[55] [56] [58]

226 μg /L – geometric mean (88)* 2.27 ± 0.25 mg/L (43)* 58.87 ± 17.32 μg /g (43) 1990 ± 380 μg/L (37)*

34.4 μg /L – geometric mean (88)* 5.19 ± 3.09 mg/L (23)* 78.78 ± 28.21 μg /g (23) 1920 ± 400 μg/L (61)*

no

[66]

yes

[76]

yes

[82]

1.98 ± 0.10 mg/L (50)* 7.9 ± 1.9 μmol/L (49) 34.93 ± 9.53 μg/dL (19)*

2.58 ± 0.06 mg/L (58)* 17.4 ± 3.3 μmol/L (40) 42.47 ± 8.23 μg/dL (18)*

no no no

[83] [85] [87]

47 ± 2 μg/L (37) 40.9 ± 13.9 μg/L- early-onset PE (39) 42.6 ± 10.8 μg/L- late-onset PE (67)

yes no

[78] [79] [82] [94]

no no

[78] [79] [1] [31]

serum hair plasma

ICP-OES

serum serum umbilical cord blood maternalvenous cord-artery cord-vein serum

F-AAS F-AAS ICP-MS

↓ ↓ non significant difference ↓ ↓ ↓

ICP-MS

↑

2264.6 ± 751.7 μg/L (43)*

1048 ± 851.1 μg/L (80)

no

[88]

↓ ↓ non significant difference ↓ ↓

581.6 ± 367.4 μg/L (43)* 608.3 ± 418.1 μg/L (43)* 33.91 ± 8.19 μmol/L (30)

949 ± 788.8 μg/L (80) 866.9 ± 812.6 μg/L (80) 32.04 ± 7.33 μmol/L (37)

yes

[93]

2.01 ± 0.83 mg/L (100)* no data (60)

2.76 ± 1.02 mg/L (100)* no data (30)

no no

[95] [96]

0.017 ± 0.002 mmol/L (44)

0.016 ± 0.002 mmol/L (27)

no

[97]

149.44 ± 27.11 μg/dL (95) 48.06 ± 20.89 μg/L (95)* 2.40 ± 0.64 mg/L (50)* 0.15 ± 0.07 mg/dL (40)

64.89 ± 30.52 μg/dL(92)* 12.03 ± 6.57 μg/L (92)* 1.30 ± 0.34 mg/L (50) 0.39 ± 0.02 mg/dL (40)* Mayo Clinic Laboratories Arup Laboratories 108.45 μg/dL – median (40) 1.306 ± 0.830 mg/L (40)* 102.0 μg/dL – median (50)

no

[98]

no no no no no

[99] [101] [78] [79] [1] [28] [31]

107.55 ± 22.74 mg/dL* (40)

no

[32]

1.30 ± 0.83 mg/L (40)* no data

no yes

[41] [43]

1.27 ± 0.41 μg/dL (48)* 68.2 ± 10.1 μg/dL (150) 8414.7 ng/g – median (86) 100.61 ± 20.12 μg/dL (60) 10.63 ± 1.82 μmol/L (75)

no no no yes no

[55] [56] [57] [58] [59]

plasma serum serum

Zn

Significantly increased (↑) or decreased (↓) level in PE compared with normotensive controls

serum urine serum serum serum serum serum serum serum serum

ICP-MS

F-AAS F-AAS Autoanalyzer + F-AAS F-AAS

non significant differnece F-AAS ↑ ↑ F-AAS ↑ F-AAS ↓ Reference values: 660−1100 μg/L Reference values: 600−1200 μg/L F-AAS ↓ ICP-OES ↓ F-AAS non significant differnece autoanalyzer non significant difference

serum plasma

ICP-OES ICP-MS

serum serum placenta serum plasma

F-AAS F-AAS ICP-MS F-AAS F-AAS

erythrocytes

cyanomethemoglobin metod on a centrifugal analyser

↓ non significant difference between PE and normotensive women ↓ ↓ ↑ ↓ non significant difference non significant difference

81.24 μg/dL – median (38) 0.671 ± 0.592 mg/L (40) 108.0 μg/dL – median (50) 108.00 ± 22.40 mg/dL- mild PE (20)* 107.50 ± 22.30 mg/dL- severe PE (20)* 0.67 ± 0.59 mg/L (40) no data

1.06 ± 0.44 μg/dL (47)* 45.8 ± 9.7 μg/dL (59)* 8892.0 ng/g - median (86) 76.49 ± 17.62 μg/dL (60) 10.46 ± 2.05 μmol/L mild PE (47) 9.28 ± 1.63 μmol/L severe PE (18) 239.04 ± 70.95 μmol/L mild PE (47) 245.72 ± 68.14 μmol/L severe PE (18)

238.18 ± 63.33 μmol/L (75)

(continued on next page) 9

Journal of Trace Elements in Medicine and Biology 59 (2020) 126468

K. Gajewska, et al.

Table 1 (continued) Element

Ca

Sample matrix

Analytical technique

Significantly increased (↑) or decreased (↓) level in PE compared with normotensive controls

Mean content ± SD (number of PE patients)

Mean content ± SD (number of controls)

Certified Reference Materials

References

urine

ICP-MS

↑

[66]

ICP-OES

yes

[76]

yes no no

[82] [83] [84]

umbilical cord blood maternalvenous cord-artery cord-vein serum serum

Spectrophotometry (colorimetry) ICP-MS

↑ ↑ ↑ ↓ non significant difference ↓

627 μg/L – geometric mean (88) 2.13 ± 3.01 mg/L (23)* 330.88 ± 29.70 μg/g (23) 487 ± 92 μg/L (61)* 0.98 ± 0.03 mg/L (58) 9.4 ± 0.8 μmol/L (40)

no

serum hair plasma serum serum

5863 μg/L – geometric mean (88)* 18.03 ± 30.28 mg/L (43)* 395.99 ± 48.60 μg/g (43) 514 ± 99 μg/L (37)* 0.77 ± 0.05 mg/L (50) 8.6 ± 1.4 μmol/L (49) 74.43 ± 14.99 μg/dL (19)

83.03 ± 8.85 μg/dL (18)

no

[87]

652.7 ± 668.6 μg/L (43)

575.5 ± 215.2 μg/L (80)*

no

[88]

947.3 ± 42.5 μg/L (43) 911.1 ± 220.2 μg/L (43) 0.7 ± 0.2 mg/L (29) 9.23 ± 1.43 μmol/L (30)

543.1 ± 226 μg/L (80)* 422.4 ± 145 μg/L (80)* 1.9 ± 0.5 mg/L (30)* 8.85 ± 1.43 μmol/L (37)

no yes

[91] [93]

plasma serum

0.69 ± 0.21 mg/L (100) no data (60)

0.87 ± 0.30 mg/L (100) no data (30)

no no

[95] [96]

serum

F-AAS Autoanalyzer + F-AAS F-AAS

non significant difference ↑ ↑ ↓ non significant difference ↓ ↓

0.016 ± 0.002 mmol/L (44)

0.015 ± 0.002 mmol/L (27)

no

[97]

serum

F-AAS

0.71 ± 0.26 mg/L (50)

0.73 ± 0.33 mg/L (50)

no

[99]

serum serum serum

F-AAS F-AAS F-AAS

non significant differnece non significant differnece ↓ ↓ ↓

0.88 ± 0.02 mg/L (40) 5.11 ± 0.21 mg/dL (40)* 15.64 ± 2.4 μmol /L (50)

no no no

[100] [101] [102]

serum serum hair serum serum serum serum

Reference values: 8.2–9.6 mg/dL Reference values: no data ICP-OES non significant difference autoanalyzer ↓ F-AAS ↓ o-cresolphtalein complex non significant one, without difference deproteinization method o-cresolphtalein complex non significant difference F-AAS ↓ ICP-OES ↓ non significant difference autoanalyzer ↓ INAA ↓ ICP-MS non significant difference (early-onset PE)

0.71 ± 0.04 mg/L (40) 2.94 ± 0.45 mg/dL (40)* 12.72 ± 1.7 μmol /L mild PE (25) 12.04 ± 1.4 μmol /L severe PE (25)

no

[78] [79] [25]

no no no

[28] [31] [32]

2.12 ± 0.3 mmol/L (20)*

yes

[36]

8.65 ± 2.14 mg/dL (60) 75.44 ± 2.06 mg/L (43)* 2394.75 ± 124.77 μg/g (43)

9.77 ± 3.02 mg/dL (60)* 107.61 ± 6.30 mg/L (23)* 2184.91 ± 160.69 μg/g (23)

yes yes

[58] [76]

2.15 ± 0.15 mmol/L (51)* 2.0 ± 0.4 mmol/L (29)* 2.18 ± 0.2 mmol/L early-onset PE (32)* 2.28 ± 0.1 mmol/L late-onset PE (53)* 2.36 ± 0.221 mmol/L (44)*

2.22 ± 0.13 mmol/L (51)* 2.2 ± 0.3 mmol/L (30)* 2.24 mmol/L –median 2nd trimester (43)* 2.29 ± 0.10 mmol/L- median 3rd trimester (53)* 2.32 ± 0.244 mmol/L (27)*

no no no

[80] [91] [94]

no

[97]

2.12 ± 0.15 mmol/L mild PE (25)* 1.94 ± 0.09 mmol/L severe PE (25)* 7.84 ± 0.87 mg/dL (60)*

2.45 ± 0.18 mmol/L (50)*

no

[102]

8.97 ± 0.69 mg/dL (60) Mayo Clinic Laboratories Arup Laboratories 106 ppm - median (96) 0.72 ± 0.07 mmol/L (90)* 19.330 ± 3.321 mg/L (40) 1.4 mg/dL - median (50)* 0.83 ± 0.08 mg/dL (40)*

no no

[104] [78] [79] [25]

no no no

[28] [31] [32]

0.85 ± 0.2 mmol/L (20)*

yes

[36]

1.87 ± 0.05 mg/dL (18) 1.78 ± 0.27 mg/dL (60)

no yes

[54] [58]

serum serum serum hair serum serum serum

Mg

ICP-MS F-AAS F-AAS

INAA F-AAS

serum

F-AAS

non significant difference ↓

serum

F-AAS

serum serum serum hair serum serum serum serum

colorimetry ↓ Reference values: 1.7–2.3 mg/dL Reference values: no data ICP-OES non significant difference ICP-OES ↓ F-AAS ↑ xylidyle blue non significant difference

serum

calmagite dye method

blood serum

autoanalyzer F-AAS

non significant difference ↓ ↓

1241 ppm - median (96) 2.23 ± 0.09 mmol/L (95)* 70.375 ± 4.661 mg/L (40)* 7.6 mg/dL - median (50)* 4.89 ± 0.34 mg/dL mild PE (20)* 5.05 ± 0.35 mg/dL severe PE (20)* 2.18 ± 0.2 mmol/L (20)*

117 ppm – median (96) 0.87 ± 0.21 mmol/L (94)* 13.585 ± 1.987 mg/L (40)* 1.9 mg/dL - median (50) 0.85 ± 0.11 mg/dL mild PE (20)* 0.84 ± 0.11 mg/dL severe PE (20)* 1.02 ± 0.4 mmol/L (20)* 1.63 ± 0.05 mg/dL (40)* 1.51 ± 0.34 mg/dL (60)*

Mayo Clinic Laboratories Arup Laboratories 1146 ppm - median (96) 2.26 ± 0.08 mmol/L (93)* 90.088 ± 6.389 mg/L (40) 8.1 mg/dL - median (50)* 4.96 ± 0.62 mg/dL (40)*

(continued on next page) 10

Journal of Trace Elements in Medicine and Biology 59 (2020) 126468

K. Gajewska, et al.

Table 1 (continued) Element

Sample matrix

Analytical technique

Significantly increased (↑) or decreased (↓) level in PE compared with normotensive controls

Mean content ± SD (number of PE patients)

Mean content ± SD (number of controls)

Certified Reference Materials

References

serum hair

ICP-OES

↓ non significant difference autoanalyzer

29.93 ± 0.41 mg/L (43)* 549.56 ± 29.34 μg/g (43)

38.73 ± 1.44 mg/L (23)* 451.71 ± 36.79 μg/g (23)

yes

[76]

non significant difference

0.76 ± 0.08 mmol/L (51)*

0.78 ± 0.06 mmol/L (51)*

no

↓ ↓

0.5 ± 0.2 mmol/L (49)* 0.942 ± 0.291 mmol/L (19)

1.0 ± 0.2 mmol/L (40)* 1.044 ± 0.244 mmol/L (18)

no no

[84] [87]

↑

3332.1 ± 1027 μg/dL (43)*

1499.1 ± 375 μg/dL (80)*

no

[88]

3326.9 ± 856 μg/dL (43)* 3300.3 ± 886 μg/dL (43)* 0.817 ± 0.489 mmol/L (44)*

1618.9 ± 290 μg/dL (80)* 1564.9 ± 291 μg/dL (80)* 0.815 ± 0.069 mmol/L (27)*

no

[97]

0.15 ± 0.09 mg/dL (40)* 0.67 ± 0.14 mmol/L mild PE (25)* 0.62 ± 0.11 mmol/L severe PE (25)* 2.81 mmol/ 24 h (15)

2.17 ± 0.21 mg/dL (40)* 0.79 ± 0.13 mmol/L (50)*

no no

[101] [102]

3.20 mmol/ 24 h (16)

no

[103]

0.80 mmol/L - median (18)* 2.37 mmol/L - median (18) 1.57 ± 0.72 mg/dL (60)*

0.70 mmol/L- median (18)* 2.02 mmol/L - median (18) no

[104]

serum [80] serum umbilical cord blood maternalvenous cord-artery cord-vein serum

serum K

Na

F-AAS Spectrophotometry (colorimetry) ICP-MS

F-AAS

serum serum

F-AAS F-AAS

urine

F-AAS

non significant difference ↓ ↓

urine serum serum urine

non significant difference ↑ ↑ non significant difference 1.43 ± 0.55 mg/dL (60)* Reference values: 17−77 mmol/24 h Reference values: 3.6–5.2 mmol/L Reference values: 3.3–5.0 mmol/L ISE Potentiometry ↓

serum serum

Flame photometry ISE Potentiometry

plasma erythrocytes colorimetry

amniotic fluid urine serum serum urine serum serum

↓ non significant difference ISE Potentiometry ↑ Reference values: 41−227 mmol/24 h Reference values: 135−145 mmol/L Reference values: 136−144 mmol/L ISE Potentiometry ↑ Flame photometry ↓ ISE Potentiometry non significant difference

Mayo Clinic Laboratories 52.2 ± 16.1 mEq/24 h (50) 3.45 ± 0.54 mmol/L (30) 4.3 ± 0.7 mmol/L (20) 4.25 mmol/L (1 - case report)

127 ± 42 mEq/ 24 h (50) 136.13 ± 4.17 mmol/L (30) 151 ± 1.5 mmol/L (20)*

[78]

Arup Laboratories 49.6 ± 22.7 mEq/24 h (50)

no

[79] [33]

3.98 ± 0.36 mmol/L (30) 4.2 ± 0.3 mmol/L (20)

no yes

[35] [36]

3.47 ± 0.28 mmol/L (52) Mayo Clinic Laboratories

no

[105] [78]

Arup Laboratories 123 ± 65 mEq/ 24 h (50) 142.17 ± 5.66 mmol/L (30) 140 ± 2.3 mmol/L (20)

no no yes

[79] [33] [35] [36]

Analytical techniques: ICP-MS: inductively coupled plasma mass spectrometry; ICP-OES: inductively coupled plasma optical emission spectrometry; INAA: instrumental neutron activation analysis; GF-AAS: graphite furnance atomic absorption spectrophotometry; ET-AAS: electrothermal atomic absorption spectrometry; FAAS: flame atomic absorption spectrophotometry; ISE: ion-selective electrode potentiometry; TPTZ: 2,4,6-Tripyndyl-s-triazine. *beyond the reference values given by Mayo Clinic Laboratories and Arup Laboratories.

ligands, and macromolecular complexes of the elements investigated. The appropriate compartment of the blood, the appropriate tissues which best reflect the content of the given element must be selected for the analysis. Often, the choice of the type of sample is guided by the available analytical conditions, like the sensitivity of the detection, and available procedures of sample preparations (e.g. digestion of the complex matrix, mineralization, or extraction allowing to separate analytes from other components/interferents in the sample). It is known that both the level of exposure (like in the case of toxic metals) and time of duration of the exposure, as well as time between sample collection and time of its analysis, impact the transport of some metals between blood compartments and tissues. In some cases, e.g. if a patient suffers from anemia, the correction for the hematocrit value should be taken into account when interpreting the data of the metal content in whole blood and in blood fractions. Table 1 presents examples of the most popular elements determined in various types of human samples in PE. The applied analytical techniques are included as well. These techniques are modern, sensitive, but they could guarantee higher quality results if they are verified by using

a different analytical method and are checked by another laboratory. We also check all of the papers whether or not they include information about using Certified Reference Materials (CRMs). Unfortunately the presentation of the use of CRMs is not a common practice for researchers of this subject (approx.15 % papers include such information, Table 1). Table 1. Examples of determinations of elements in tissues and body fluids in PE. As it can be seen from Table 1 the comparison of some of the data can yield opposite results. Some of the reasons may be caused by the difference in validation of the method and huge discrepancies in study designs. Moreover, the undetailed description of studied and control population in many studies makes such comparison more difficult to analyze. The findings of some presented studies may be conflicting due to the timing of sample collection and the small number of studied samples. It must be noticed that more detailed studies including a history of elements’ status and intake are required to enhance the understanding of the obtained data. Dietary assessment could be done at different stages of pregnancy, and whenever possible in the 11

Journal of Trace Elements in Medicine and Biology 59 (2020) 126468

K. Gajewska, et al.

Fig. 3. The meta-analysis of all found source studies for (A) Ca in serum, (B) Cu in serum, (C), Fe in serum, (D) Mg in serum, (E) Mn in serum, (F) Se in plasma, (G) Se in serum, (H) Zn in plasma, (I) Zn in serum. [32].1- mild PE; [32].2- severe PE; [59].1- mild PE; [59].2- severe PE; [86].1- rural patients; [86].2-urban patients; [94].1-early-onset PE; [94].2-late-onset PE; [102].1- mild PE; [102].2- severe PE.

all other ones describe negative significant shifts (Z = -2.010, p = 0.044; Fig.3G). Therefore it can be concluded, that Se level was decreased in PE patients. The same conclusion can be drawn for Zn. Only 4 studies are available for plasma, concluding some insignificant negative shift (Z = -1.254, p = 0.210; Fig.3H). Much more studies are available for serum, among which only two gave significant increase of the levels (Z = -3.159, p = 0.002; Fig.3I). Therefore, the overall conclusion for Zn is negative and significant shift in PE patients. In case of several studies the results were split to two groups and they were separately treated in the meta-analysis, indicated with numbered suffix in Fig. 3. For three of them ([32] [59], and [102]) patients were divided for two groups (mild PE and severe PE). In case of [94], two separate groups were analyzed for early-onset and late-onset PE, whereas in [86] the patients were divided to rural and urban groups. The appropriate annotations are included in caption of Fig. 3. In conclusion, it needs to be established whether the damage associated with the deficiency of some elements (e.g., selenium, zinc, copper, iodine) or the excess of not only the toxic ones may be an etiopathogenic factor and a developmental cause of PE, and if it may serve as a target of actions in the causal treatment or even prevention of the occurrence of this disease. The potential of modern instrumental analytical techniques should be more widely used taking into account the fact that over the past several decades, improved analytical techniques in clinical chemistry have yielded significant insights into the basis of numerous diseases.

periconceptional period as well. To assess critically the published studies, a RE (random effect) model meta-analysis was performed for seven elements in serum (Ca, Cu, Fe, Mg, Mn, Se, Zn), whereas for two of them (Se, Zn) it was also possible to perform this analysis for plasma. This gave 9 meta-analyses in total. The group sizes, means and standard deviations were extracted for all possible articles and combined together. The overall standardized mean deviate was calculated for each reference set with “metafor" package inside R computational environment. The results of this metaanalysis are presented in Fig. 3. Fig. 3. The meta-analysis of all found source studies for (A) Ca in serum, (B) Cu in serum, (C), Fe in serum, (D) Mg in serum, (E) Mn in serum, (F) Se in plasma, (G) Se in serum, (H) Zn in plasma, (I) Zn in serum. [32].1- mild PE; [32].2- severe PE; [59].1- mild PE; [59].2severe PE; [86].1- rural patients; [86].2-urban patients; [94].1-earlyonset PE; [94].2-late-onset PE; [102].1- mild PE; [102].2- severe PE. It can be concluded, that the majority of studies present lowered Ca levels with PE patients (Fig.3A). Although there are three studies presenting the opposite trend, the overall meta-analysis gives strong and significant shift towards the lower values (Z = -2.2, p = 0.022). The majority of Cu studies presents also negative shift, however the overall conclusion is not significant (Z = -1.375, p = 0.169; Fig.3B). The same observation can be done for Fe, where the results are divided almost in half, however negative studies present much larger shifts and the overall conclusion is computed towards the negative shift, but insignificant (Z = -1.131, p = 0.258; Fig.3C). The Mg levels are shifted towards negative direction and the shift is around the significance limit (Z = -1.923, p = 0.055), due to two studies presenting large differences in this direction. Nevertheless, five studies present positive insignificant shifts (Fig.3D). In the case of Mn, only five studies were available, but they are very consistent and all significant. Therefore, the overall conclusion can be that Mn levels are lowered in serum of PE patients (Z = -2.288, p = 0.022; Fig.3E). Only three studies present plasma selenium levels (Fig.3F). Two of them present significant negative shift, the third one shows also negative shift, but without statistical significance. Although we have only three studies, the overall conclusion tends to be significant and negative (Z = -2.703, p = 0.007). The analogous shifts were observed for Se serum levels. Here we have only one study presenting no shift, whereas

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