Abstract

Objective:

To describe serum levels of calcium, copper, selenium, magnesium, iron and zinc and evaluate their relationship with maternal socio-demographic characteristics and dietary variables in women in the first trimester of pregnancy.

Method:

Cross-sectional study with 1279 participants from the INMA cohorts.

Results:

The concentrations of the elements analyzed were within the normal range. Associations with higher levels of these metals were found for calcium with white meat intake (p = 0.026), for copper with excess body weight (p < 0.01), low social class (p = 0.03) and being multipara (p < 0.01), for magnesium with being over 35 years old (p = 0.001), high social class (p = 0.044), primiparous status (p = 0.002) and low daily intake of bread (p = 0.009) and legumes (p = 0.020); for zinc with university education (p = 0.039) and residence in Gipuzkoa (p < 0.01), and for selenium with residence in Valencia (p< 0.01), university education (p = 0.001), vitamin B₆ supplementation (p = 0.006), fish intake (> 71 g/day) (p = 0.014) and having been born in Spain (p = 0.001). Further, lower iron levels were associated with being overweight (p = 0.021) or obese (p < 0.001) and vitamin B₁₂ supplementation (p = 0.006).

Conclusions:

Our results suggest that trace elements in the analyzed cohorts are adequate for this stage of pregnancy. The variability in these elements is mainly linked to socio-demographic and anthropometric variables.

Keywords:
Serum; Trace elements; Pregnancy

Resumen

Objetivo:

Describir las concentraciones de calcio, cobre, selenio, magnesio, hierro y zinc en muestras de suero de gestantes en el primer trimestre y evaluar la relación con las características sociodemográficas maternas y las variables de dieta.

Método:

Estudio transversal con 1279 participantes de las cohortes INMA.

Resultados:

Las concentraciones de los elementos analizados estuvieron dentro de los límites de referencia. El calcio se asoció con el consumo de carne blanca (p = 0,026). Los valores elevados de cobre se asociaron con tener exceso de peso (p < 0,01), clase social baja (p = 0.03) y ser multípara (p < 0,01). Los valores más elevados de magnesio se asociaron con tener más de 35 años (p = 0,001), clase social alta (p = 0,044), ser primípara (p = 0,002) y bajo consumo diario de pan (p = 0,009) y legumbres (p = 0,020). El zinc se asoció con tener estudios universitarios (p = 0,039) y con la cohorte de Gipuzkoa (p < 0,01). Los valores más altos de selenio se asociaron con la cohorte de Valencia (p < 0,01), tener estudios universitarios (p = 0,001), tomar suplementos de vitamina B₆ (p = 0,006), consumo de pescado >71 g/día (p = 0,014) y ser española (p = 0,001). Los valores más bajos de hierro se asociaron con tener exceso de peso (p = 0,021) u obesidad (p < 0,001) y con tomar suplementos de vitamina B₁₂ (p = 0,006).

Conclusiones:

Nuestros resultados sugieren que los oligoelementos en las cohortes analizadas son adecuados para esta etapa del embarazo. La variabilidad de estos elementos está asociada principalmente a las variables sociodemográficas y antropométricas.

Palabras clave:
Suero; Oligoelementos; Embarazo

Introduction

Trace elements are bioelements that play a significant role in keeping the body healthy.¹1. Bornhorst J, Kipp AP, Haase H, et al. The crux of inept biomarkers for risks and benefits of trace elements. Trends in Analytical Chemistry. 2018;104:183-90. The human body cannot produce them, and therefore, we need to obtain them at appropriate doses from our diet. Both deficiency and excess may have a negative impact on body functions and the body's needs vary depending on the stage of the growth. Nutrition is vital during pregnancy for both the expectant mother and the developing fetus. Notably, the nutritional requirements of pregnant women differ from those of non-pregnant women of the same age. They also vary according to the week of pregnancy, with few differences compared to non-pregnant women during the first trimester; demands increasing during the second trimester; and a sharp rise during the third trimester, due to the rapid development of the fetus. Daily dietary reference intakes (DRIs) for pregnant women in Spain, published by the Spanish Federation of Nutrition, Food and Dietetics Societies²2. Institute of Medicine (US) Subcommittee on Interpretation and Uses of Dietary Reference Intakes; Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. Dietary reference intakes (DRI) for Spanish Population. Act Diet. 2010;14:196-7. in 2010 were: 1000-1300 mg/d for calcium (Ca), 350-400 mg/d for magnesium (Mg), 1000 µg/d for copper (Cu), 27 mg/d for iron (Fe), 60 µg/d for selenium (Se) and 11-13 mg/d for zinc (Zn). Serum levels in the following ranges are considered normal: Ca 8.5-10.2 mg/dL, Fe 60-180 µg/dL, Mg 0.75-1.25 mmol/L, Cu 70-140 µg/dL, Se 70-150 ng/mL and Zn 0.66-1.10 µg/mL.³3. Rifai N, Horwath AR, Wittwer CT, editors. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 6th ed. Philadelphia: Elsevier; 2018.

Fe is necessary for proper development of the placenta, as well as bone and organ formation in the fetus. Iron-deficiency anemia is relatively common among pregnant women and may increase the risk of some complications, including preterm delivery and low infant birth weight. To prevent maternal anemia, it is recommended that pregnant women take a daily oral supplement of 30 to 60 mg of elemental Fe.⁴4. World Health Organization. The prevalence of anaemia in women: a tabulation of available information. 1992; 2nd ed.

Zn is important for protein synthesis, cell division, and nucleic acid metabolism. Deficiency in this element is manifested in different ways, depending on its severity, but in particular, may have a negative impact on the nervous and reproductive systems. Cu is essential for oxidative metabolism, cell growth, development of connective tissue and hemoglobin synthesis.⁵5. Bertinato J, L'Abbé MR. Maintaining copper homeostasis regulation of coppertrafficking proteins in response to copper deficiency or overload. J Nutr Biochem. 2004;15:316-22. Deficiency in this element can cause bone deformations, as well as cardiovascular problems. Se is part of the key enzyme glutathione peroxidase, seems to be involved in platelet function and helps to neutralize heavy metals such as mercury, lead, arsenic and cadmium. Further, deficiency in this element affects all components of the immune system. During pregnancy, there is active transport to the fetus through the placenta and Se deficiency is reported to be associated with a variety of adverse outcomes including miscarriage, preterm delivery, gestational diabetes and preeclampsia.⁶6. Mistry HD, Broughton Pipkin F, et al. Selenium in reproductive health. Am J Obstet Gynecol. 2012;206:21-30.

Mg is a key element for fetal growth and is one of the most abundant nutrients in the human body. It is involved in cellular respiration, protein synthesis, maintenance of cardiovascular health, regulation of cellular function and the action of collagen, among many other functions. Deficiency in Mg during pregnancy has been associated with preeclampsia and preterm delivery, as well as low infant birth weight.⁷7. Arun D, Aakriti B, Rosina M, et al. A comparative study of serum uric acid, glucose, calcium and magnesium in eclampsia and normal pregnancy. J Pathol Nepal. 2017;7:1155-61.

Lastly, Ca is another element necessary for normal fetal growth.⁸8. Diagbletey R, Darkwa EO, DeGratf-Johnson PK, et al. Serum calcium and magnesium levels in normal Ghanaian pregnant women: a comparative cross-sectional study. Open Access Maced J Med Sci. 2018;6:2006-11. Among its functions, in addition to providing structure and rigidity to the bones, it plays a key role in muscle contractility, the transmission of signals from the brain nerves to the rest of the body, the circulation of the blood and the production of hormones and enzymes for various body functions. Lower maternal serum Ca levels have been associated with pregnancy-induced hypertension and preeclampsia.

The objective of this work was to describe serum levels of Ca, Fe, Mg, Se, Cu and Zn, and evaluate their relationship with maternal socio-demographic, anthropometric and dietary variables in women from cohorts from Valencia and Gipuzkoa (Spain) in their first trimester of pregnancy.

Method

Study population

Study participants were enrolled in the INMA Project (from the Spanish: Infancia y Medio Ambiente, meaning childhood and the environment: www.proyectoinma.org). A cross-sectional study was designed. We gathered information from women in the INMA Valencia and Gipuzkoa cohorts during their routine check-up in the first trimester of pregnancy (Valencia n = 855; Gipuzkoa n = 638). The final study population was composed of 1279 women (Valencia n = 656, Gipuzkoa n = 623). Samples were collected between February 2004 and June 2005 in Valencia and between May 2006 and February 2008 in Gipuzkoa, and Mg was only analyzed in the Valencia cohort (n = 656). Informed consent was obtained from all the participants before inclusion. The hospital ethics committees of each area approved the research protocols.

Socio-demographic and dietary characteristics

Data on socio-demographic characteristics were collected through questionnaires. Occupational status data were classified into two categories according to whether the women were in work. Social class was based on occupation and five categories were considered in accordance with the Spanish adaptation of the British Registrar General's Social class classification (I being the highest socioeconomic position and V the lowest). In order to increase the statistical power for the analysis, social class was further grouped into two categories: manual worker or lower class (IV and V) and non-manual worker or higher class (I-III). Educational level was classified according to the highest level attained into three categories: up to primary school, secondary school and university. Body mass index (BMI) before pregnancy was classified as underweight: < 18.5 km/m²; normal weight: 18.5-24.9 kg/m²; overweight: 25-29.9 kg/m²; or obese: ≥ 30 kg/m². Smoking status information was classified as: smoker during pregnancy, quit at the beginning of pregnancy, ex-smoker (quit earlier than at the beginning of pregnancy) or never-smoker. The daily consumption of alcohol was recorded as grams of alcohol consumed daily and was subsequently categorized into two categories: ≤ 5 g/day and > 5 g/day. Food and mineral or vitamin supplement intake was also evaluated using a food-frequency questionnaire (FFQ) during pregnancy. The FFQ used was a version of Willett's questionnaire adapted for use in a Spanish population⁹9. Vioque J, Gimenez-Monzo D, Navarrete-Muñoz EM, et al. Reproducibility and validity of a food frequency questionnaire designed to assess diet in children aged 4-5 years. PloS One. 2016;11:1-17.. Regarding vitamin and mineral supplementation, information was collected on the intake of vitamin B6,vitamin B12, vitamin D,Ca,Fe,Mg and Zn supplements. The food frequency variables were categorized at the median for the analysis.

Chemical analysis

Statistical analysis

Descriptive statistics were calculated for each metal. A bivariate analysis was carried out between each metal and the defined variables overall and by cohort. Student's t-test or analysis of variance was performed depending on the number of categories of the independent variable (see Appendix online). Multivariable linear regression models were built to estimate the association between serum levels of metals and the independent variables. The variables with a p ≤ 0.20 in the bivariate analysis were initially included in the models and those that were statistically significant (p < 0.05) were kept in the model, following a backward selection procedure. Statistical analyses were carried out using IBM SPSS for Windows, version 24.

We also performed permutational multivariate analysis of variance to test the null hypotheses of no association between multivariate variance in serum levels of Ca, Cu, Fe, Se and Zn, and socio-demographic and dietary variables. To this end, two multivariate linear models were built: the first only considered dietary explanatory variables; and the second, only socio-demographic explanatory variables. The method for variable selection that we applied was stepwise backward regression. Finally, we also built a joint (socio-demographic-dietary) model with the variables selected in the former step and then applied the method of Borcard et al.¹⁰10. Borcard D, Legendre P, Drapeau P. Partialling out the spatial component of ecological variation. Ecology. 1992;73:1045-55. to partition multivariate variance in serum levels of the metals into components explained by socio-demographic factors, by dietary factors, and by a shared fraction.

Results

We analyzed data from serum samples of 1279 women (51.3% from the Valencia cohort). Sample size, percentages and missing values of all the variables are shown in Table 1. Overall, 92% had been born in Spain, 61.3% were 30 years old or older, with a mean age of 30.7 years (31.3 and 30.1 years for the Gipuzkoa and Valencia cohorts respectively), 50.1% lived in urban areas, 77.2% had secondary or university studies, 78.5% were active workers, 51% belonged to the lowest social class and 55% were primipara. In relation to other variables, 24.7% had excess body weight, 17.4% smoked during pregnancy, 14.9% had smoked but quit before pregnancy and 1.1% consumed more than 5 g of alcohol per day.

Sample size, missing data, mean, SD, minimum, maximum and percentiles (25^th, 50^th and 75^th) for each metal are presented in Table 2 by cohort. Mean and standard deviation of the levels were 94030.7 ± 4278.0 µg/L for Ca, 1614.8 ± 279.5 µg/L for Cu, 1113.9 ± 325.7 µg/L for Fe, 17032.5 ± 1006.4 µg/L for Mg, 79.56 ± 9.64 µg/L for Se and 642.1 ± 110.8 µg/L for Zn.

Table 3 summarizes the results of multiple linear regression models for each metal. Ca levels were related to daily white meat consumption (p = 0.026). Higher levels of Cu were related to excess body weight (p < 0.001), low social class (p = 0.003) and being multipara (p < 0.001). On the other hand,lower levels of Cu were related to bread intake of less than 42 g /day (p = 0.013) and residence in Gipuzkoa, after adjustment for the other variables. With reference to Se, higher levels were related to residence in Valencia (p < 0.001), having a university degree (p = 0.001),taking B6 vitamin supplements (p = 0.006) and a fish intake of more than 71 g/day (p = 0.008), after adjustment for the other variables. Women born outside Spain showed lower Se levels (p < 0.001). In regard to Fe, lower levels were related to having excess body weight (p = 0.021) or obesity (p < 0.01) and taking vitamin B12 supplements (p = 0.006). Higher levels of Mg were associated with being over 35 years old (p = 0.001), high social class (p = 0.044), primiparous status (p = 0.002) and low daily bread (p = 0.009) and legume (p = 0.020) intake, after adjustment for the other variables.

Finally, higher levels of Zn were related to having a university degree (p = 0.039) and being from the Gipuzkoa cohort (p < 0.001), and lower levels of Zn were related to being over 35 years old (p = 0.027), after adjustment for the other variables.

Table 4 shows that the multivariate variance in serum levels of Ca, Cu, Fe, Se and Zn was associated with body mass, parity, educational level and country of origin (socio-demographic model) and also with white bread and vitamin B6 intake (dietary model). BMI and country of origin emerge as the most important among the explanatory variables considered. Although the influence of both socio-demographic conditions and diet on serum levels appears to be rather modest, the partitioning of variance in the joint model (Fig. 1) suggests that, overall, socio-demographic conditions are more influential than diet itself. Table 5 summarizes the results of previous studies.

Discussion

We analyzed trace element levels in pregnant women in their first trimester of pregnancy. Our results reveal that the main variables related to these levels are BMI, social class and cohort. According to Abbassi-Ghanavati et al.¹¹11. Abbassi-Ghanavati M, Greer LG, Cunningham FG. Pregnancy and laboratory studies: a reference table for clinicians. Obstet Gynecol. 2009;114:1326-31., serum Ca between 88,000 µg/L and 106,000 µg/L can be considered normal and our results fall within this range (94,030.7 µg/L). Further, the Ca levels in our sample of pregnant women are in line with those observed in several previous studies⁷7. Arun D, Aakriti B, Rosina M, et al. A comparative study of serum uric acid, glucose, calcium and magnesium in eclampsia and normal pregnancy. J Pathol Nepal. 2017;7:1155-61.^,1212. Sukonpan K, Phupong V. Serum calcium and serum magnesium in normal and preeclamptic pregnancy. Arch Gynecol Obstet. 2005;273:12-6.^,1313. Ainy E, Ghazi AAM, Azizi F. Changes in calcium, 25(OH) vitamin D3 and other biochemical factors during pregnancy. J Endocrinol Invest. 2006;29:303-7. (with values of 95,900 µg/L, 97,000 µg/L and 92,000 µg/L respectively). On the other hand, they are a little higher than those obtained by Kanagal et al.¹⁴14. Kanagal D, Rajesh A, Rao K, et al. Levels of serum calcium and magnesium in pre-eclamptic and normal pregnancy. A study from Coastal India. J Clin Diagn Res. 2014;8. (89,700 µg/L), and Punthumapol and Kittichotpanich¹⁵15. Punthumapol C, Kittichotpanich B. Serum calcium, magnesium and uric acid in preeclampsia and normal pregnancy. J Med Assoc Thai. 2008;91:968-73. (89,900 µg/L), and much higher than those found in a study carried out in China by Tong¹⁶16. Tong M. Serum calcium. magnesium, of uric acid level and pregnancy induced hypertension syndrome relationship. Maternal Child Health Care China. 2010;25:23-5. (21,600 µg/L). Some studies have shown Ca levels to be related to body weight, levels being significantly lower in those with excess body weight,¹⁷17. Lewicka I, Kocylowski R, Grzesiak M, et al. Relationship between pre-pregnancy body mass index and mineral concentrations in serum and amniotic fluid in pregnant women during labor. J Trace Elem Med Biol. 2019;52:136-42.^,1818. Jafari-Giv Z, Avan A, Hamidi F, et al. Association of body mass index serum calcium and phosphate levels. Diabetes Metab Syndr. 2019;13:975-80. but we did not find any such relationship in our study. Regarding age, unlike other authors,¹⁸18. Jafari-Giv Z, Avan A, Hamidi F, et al. Association of body mass index serum calcium and phosphate levels. Diabetes Metab Syndr. 2019;13:975-80. we found an association close to statistical significance, levels decreasing with increasing age (p = 0.077).

Regarding Mg, our results (17,000 µg/L) are within the normal range for Mg of between 16,000 µg/L and 22,000 µg/L¹¹11. Abbassi-Ghanavati M, Greer LG, Cunningham FG. Pregnancy and laboratory studies: a reference table for clinicians. Obstet Gynecol. 2009;114:1326-31.. The levels we observed were similar to those reported by Kanagal et al.¹⁴14. Kanagal D, Rajesh A, Rao K, et al. Levels of serum calcium and magnesium in pre-eclamptic and normal pregnancy. A study from Coastal India. J Clin Diagn Res. 2014;8. (15,700 µg/L) and slightly lower than those observed by Punthumapol and Kittichotpanich¹⁵15. Punthumapol C, Kittichotpanich B. Serum calcium, magnesium and uric acid in preeclampsia and normal pregnancy. J Med Assoc Thai. 2008;91:968-73. (20,400 µg/L), Arun et al.⁷7. Arun D, Aakriti B, Rosina M, et al. A comparative study of serum uric acid, glucose, calcium and magnesium in eclampsia and normal pregnancy. J Pathol Nepal. 2017;7:1155-61. (20,300 µg/L) and Sukonpan and Phupong¹²12. Sukonpan K, Phupong V. Serum calcium and serum magnesium in normal and preeclamptic pregnancy. Arch Gynecol Obstet. 2005;273:12-6. (20,700 µg/L). In contrast, a study carried out in China by Li¹⁹19. Li Y. Relationship between pregnancy induced hypertension and serum calcium and magnesium. Lab Med Clin. 2010;7:546., showed levels of serum Mg well below those obtained in this study (9800 µg/L).

The mean Cu level in our study population (1615 µg/L) was within the normal range of between 1120 µg/L and 1990 µg/L¹¹11. Abbassi-Ghanavati M, Greer LG, Cunningham FG. Pregnancy and laboratory studies: a reference table for clinicians. Obstet Gynecol. 2009;114:1326-31.. Similar levels have been observed in other studies²⁰20. Jariwala M, Suvarna S, Kiran Kumar G, et al. Study of the concentration of trace elements Fe, Zn, Cu. Se and their correlation in maternal serum, cord serum and colostrums. Ind J Clin Biochem. 2014;29:181-8.

21. Awadallah SM, Abu-Elteen KH, Elkarmi AZ, et al. Maternal and cord blood serum levels of zinc, copper, and iron in healthy pregnant Jordanian women. The Journal of Trace Elements in Experimental Medicine. 2004;17:1-8.^-2222. Choi R, Sun J, Yoo H, et al. A prospective study of serum trace elements in healthy Korean pregnant women. Nutrients. 2016;8:749. (1614 µg/L, and 1650 µg/L and 1750 µg/L, respectively). On the other hand, Cu levels considerably different from ours have been observed in China²³23. Zhang Z, Yuan E, Liu J, et al. Gestational age-specific reference intervals for blood copper, zinc, calcium, magnesium, iron lead and cadmium during normal pregnancy. Clin Biochem. 2013;46:777-80. and in Poland²⁴24. Polanska K, Hanke W, Krol A, et al. Micronutrients during pregnancy and child psychomotor development: opposite effects of zinc and selenium. Environ Res. 2017;158:183-9. (1026 µg/L and 1980 µg/L, respectively). Wilson et al.²⁵25. Wilson LR, Bianco-Miotto T, Leemaqz SY, et al. Early pregnancy maternal trace mineral status and the association with adverse pregnancy outcome in a cohort of Australian women. J Trace Elemen Med Biol. 2018;46:103-9. reported significantly higher levels in obese women than underweight, normal weight or overweight women, as in our study. We found a trend related to BMI (with the highest levels in obese women), while others have observed an opposite trend.¹⁷17. Lewicka I, Kocylowski R, Grzesiak M, et al. Relationship between pre-pregnancy body mass index and mineral concentrations in serum and amniotic fluid in pregnant women during labor. J Trace Elem Med Biol. 2019;52:136-42.

Again, in the case of Zn, the levels we observed (642 µg/L) lie within the normal range of between 570 µg/L and 880 µg/L.¹¹11. Abbassi-Ghanavati M, Greer LG, Cunningham FG. Pregnancy and laboratory studies: a reference table for clinicians. Obstet Gynecol. 2009;114:1326-31. These results were in agreement with those found in previous studies in Spain²⁶26. Izquierdo-Alvarez S, Castañón SG, Ruata MLC, et al. Updating of normal levels of copper, zinc and selenium in serum of pregnant women. J Trace Elem Med Biol. 2007;21 Suppl 1:49-52. and Iran²⁷27. Khoushabi F, Shadan MR, Miri A, et al. Determination of maternal serum zinc, iron, calcium and magnesium during pregnancy in pregnant women and umbilical cord blood and their association with outcome of pregnancy. Mater Sociomed. 2016;28:104-7. (654 µg/L and 749 µg/L, respectively). Studies carried out in China²³23. Zhang Z, Yuan E, Liu J, et al. Gestational age-specific reference intervals for blood copper, zinc, calcium, magnesium, iron lead and cadmium during normal pregnancy. Clin Biochem. 2013;46:777-80.^,2828. Shen PJ, Gong B, Xu FY, et al. Four trace elements in pregnant women and their relationships with adverse pregnancy outcomes. Eur Rev Med Pharmacol Sci. 2015;19:4690-7. and Poland²⁴24. Polanska K, Hanke W, Krol A, et al. Micronutrients during pregnancy and child psychomotor development: opposite effects of zinc and selenium. Environ Res. 2017;158:183-9. showed higher levels (920 µg/L, 900 µg/L and 910 µg/L, respectively), while studies carried out in Korea²²22. Choi R, Sun J, Yoo H, et al. A prospective study of serum trace elements in healthy Korean pregnant women. Nutrients. 2016;8:749. and India²⁰20. Jariwala M, Suvarna S, Kiran Kumar G, et al. Study of the concentration of trace elements Fe, Zn, Cu. Se and their correlation in maternal serum, cord serum and colostrums. Ind J Clin Biochem. 2014;29:181-8. showed lower levels (570 µg/L and 514 µg/L respectively). We found an association between Zn and educational level, which could be an indicator of social class. Nevertheless, other authors did not find this pattern²⁹29. Xiang H, Tao Y, Zhang B, et al. Protective effect of high zinc levels on preterm birth induced by mercury exposure during pregnancy: a birth cohort study in China. J Trace Elemen Med Biol. 2019;55:71-7..

As for Se, our results were consistent with studies carried out in Spain³⁰30. Ferrer E, Alegría A, Barberá R, et al. Whole blood selenium content in pregnant women. Sci Total Environ. 1999;227:139-43. and Finland³¹31. Kantola M, Purkunen R, Kröger P, et al. Selenium in pregnancy: is selenium and active defective ion against environmental chemical stress? Environ Res. 2004;96:51-61. with reported values of 81 µg/L, while a study from India²⁰20. Jariwala M, Suvarna S, Kiran Kumar G, et al. Study of the concentration of trace elements Fe, Zn, Cu. Se and their correlation in maternal serum, cord serum and colostrums. Ind J Clin Biochem. 2014;29:181-8. found lower values of 70 µg/L. On the other hand, higher values were found in Korea,²²22. Choi R, Sun J, Yoo H, et al. A prospective study of serum trace elements in healthy Korean pregnant women. Nutrients. 2016;8:749. Spain²⁶26. Izquierdo-Alvarez S, Castañón SG, Ruata MLC, et al. Updating of normal levels of copper, zinc and selenium in serum of pregnant women. J Trace Elem Med Biol. 2007;21 Suppl 1:49-52. and Africa³²32. Ejezie FE, Okaka AC, Nwagha UI. Reduced maternal selenium levels in pregnant and lactating Nigerian women: should routine selenium supplementation be advocated? Niger J Med. 2012;21:98-102. (94 µg/L, 99.59 µg/L and 112.3 µg/L, respectively). In our study, Se levels appear to be related to fish consumption, which is consistent with other research findings.³³33. Barwick M, Maher W. Biotranference and bioamplification of selenium, copper, cadmium, zinc, arsenic and lead in a temperate seagrass ecosystem from Lake Macquarie, NSW, Australia. Mar Environ Res. 2003;56:471-502.

Fe levels between 720 µg/L and 1430 µg/L can be considered normal,¹¹11. Abbassi-Ghanavati M, Greer LG, Cunningham FG. Pregnancy and laboratory studies: a reference table for clinicians. Obstet Gynecol. 2009;114:1326-31. and our results are in that range (1114 µg/L). Similar results have been reported in China²³23. Zhang Z, Yuan E, Liu J, et al. Gestational age-specific reference intervals for blood copper, zinc, calcium, magnesium, iron lead and cadmium during normal pregnancy. Clin Biochem. 2013;46:777-80. and India²⁰20. Jariwala M, Suvarna S, Kiran Kumar G, et al. Study of the concentration of trace elements Fe, Zn, Cu. Se and their correlation in maternal serum, cord serum and colostrums. Ind J Clin Biochem. 2014;29:181-8. (900 µg/L and 1132 µg/L respectively), while some studies have shown slightly lower values²¹21. Awadallah SM, Abu-Elteen KH, Elkarmi AZ, et al. Maternal and cord blood serum levels of zinc, copper, and iron in healthy pregnant Jordanian women. The Journal of Trace Elements in Experimental Medicine. 2004;17:1-8.^,2727. Khoushabi F, Shadan MR, Miri A, et al. Determination of maternal serum zinc, iron, calcium and magnesium during pregnancy in pregnant women and umbilical cord blood and their association with outcome of pregnancy. Mater Sociomed. 2016;28:104-7.^,2828. Shen PJ, Gong B, Xu FY, et al. Four trace elements in pregnant women and their relationships with adverse pregnancy outcomes. Eur Rev Med Pharmacol Sci. 2015;19:4690-7. (690 µg/L, 800 µg/L and 744 µg/L respectively), and another study in China,³⁴34. Liu X, Zhang Y, Piao J, et al. Reference values of 14 serum trace elements for pregnant Chinese women: a cross-sectional study in the China Nutrition and health Survey 2010-2012. Nutrients. 2017;9:309. found values slightly higher than ours (1500 µg/L). We observed that being overweight or obese was associated with significantly lower serum Fe levels, a pattern that has been observed previously¹⁵15. Punthumapol C, Kittichotpanich B. Serum calcium, magnesium and uric acid in preeclampsia and normal pregnancy. J Med Assoc Thai. 2008;91:968-73.^,2525. Wilson LR, Bianco-Miotto T, Leemaqz SY, et al. Early pregnancy maternal trace mineral status and the association with adverse pregnancy outcome in a cohort of Australian women. J Trace Elemen Med Biol. 2018;46:103-9..

Social inequalities in dietary habits have been widely described and indicate that the lowest social classes tend to have less balanced and less healthy diets. Pregnant women with lower social status have fewer healthy habits, including a less healthy diet, more harmful behaviors, and poorer monitoring during pregnancy. Indeed, the role of education as a social determinant of diet has been confirmed by several authors as the most robust independent predictor of healthy dietary habits.³⁵35. Freisling H, Elmadfa I, Gall I. The effect of socioeconomic status on dietary intake, physical activity and body mass index in Austrian pregnant women. J Hum Nutr Diet. 2006;19:437-45.

The strengths of the study are the sample size (n = 1279) and the fact that we gathered data on and adjusted models for a large number of factors in the first trimester, especially socio-demographic characteristics. Regarding its limitations, the descriptive and crosssectional character of the design means that we cannot ascertain causality in the associations observed, measurements were taken at only one point during pregnancy, and the spectroscopy measurements of the metals were element-specific not species-specific. Another limitation is that the information regarding some of the behavioral variables (smoking and alcohol consumption) was selfreported, an approach which may underestimate the prevalence of socially disapproved behaviors.

Conclusions

Our results indicate that the Ca, Cu, Se, Fe, Mg and Zn levels in both cohorts were adequate and within the ranges considered normal for pregnant women. More than half of the sample did not take supplements, except in the case of vitamin B₁₂ (72%). Among the variables considered, those with the best explanatory value of the levels of these trace elements were anthropometric and socio-demographic variables and within these, BMI, social class, educational level and cohort. This study will serve as a basis for future research, in particular, to identify trends in these elements through pregnancy and their possible relationship with the later development of the child.

Transparency declaration

The corresponding author on behalf of the other authors guarantee the accuracy, transparency and honesty of the data and information contained in the study, that no relevant information has been omitted and that all discrepancies between authors have been adequately resolved and described.

Acknowledgements

We want to acknowledge all the INMA families for their altruistic participation in the study, without which it would have not been possible to carry out this work. We also wanted to thank Nerea Urbieta for her contribution to the work.

References

Appendix.   Supplementary data

Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.gaceta.2021.07.006.

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