The main finding of the present study was that Cu was the only trace element in umbilical cord blood found to be inversely and independently related to birth weight, the highest Cu concentrations were found in the SGA group. In addition, anthropometric parameters were inversely related with Mn, and no association with birth weight was observed for the other trace elements. In maternal blood, a significant trend in Ba and Mg levels, decreasing from SGA to LGA, was observed. The study is important due to the assessment of a large number of trace element levels in healthy pregnant women and their newborns, providing relevant information about their effects on birth weight and the potential adverse health outcomes later in life.
Interestingly, Cu is a trace element that is involved in the function of several cuproenzymes that are essential for life, and their requirement increases during pregnancy . Although information about the effect of trace elements, simultaneously assessed, on fetal growth is scarce [15, 24–26], a negative association between Cu concentrations in umbilical cord and maternal blood and birth weight has been previously observed [15, 25]. In these previous studies, the status of other essential trace elements, Fe, Zn, Se and molybdenum (Mo), in maternal and umbilical cord blood did not influence birth weight.
The concentrations of Cu for adequate fetal development and a possible “safe level” are still unknown in humans. Copper toxicity during pregnancy and its effects on developmental outcome have been examined in considerable detail in animal models. Excess Cu has been reported to result in growth retardation in rat fetuses . A strong inverse relationship was seen between increasing Cu concentrations and larval growth of a fathead minnow model . Several genes associated with growth regulation were down-regulated following exposure to high Cu concentrations . Although the harmful effects of high concentrations of Cu on the birth weight of newborns have been demonstrated, it is unclear if these concentrations are the cause or consequence of intrauterine growth restriction.
Even though the observed Cu in umbilical cord blood was the only independent factor related to birth weight, a positive relationship between Cu levels in umbilical cord and maternal blood was observed. The placenta is the essential interface between maternal and fetal circulation that normally maintains the proper balance of the metabolic needs of the fetus. However, it can be irreversibly damaged by oxidative stress, losing adequate functioning . The role of the placenta in the transfer of some toxic elements from mother to fetus during gestation has been demonstrated . The presence of a disrupted placental barrier may contribute to excessive Cu transport from the maternal blood to fetal circulation.
More recently there has been a focus on the possible effects of Mn on fetal development and pregnancy outcome. Manganese is an essential mineral nutrient in humans and other animals and is required for normal amino acid, lipid, protein, and carbohydrate metabolism. However, Mn exposure also has the potential to produce toxicity [18, 21, 31, 32]. The primary source of Mn is through diet, but exposure may also occur environmentally because of its abundance in the earth’s crust and it commonly being found in the air, water, and soil . The effect of prenatal Mn levels on neonatal growth remains unclear [21, 34].
Studies have provided information concerning the relationship between Mn and birth weight [13, 14, 16, 20, 34]. Vigeh et al.  observed significantly lower levels of Mn in mothers who delivered infants with intrauterine growth retardation compared to mothers who delivered AGA babies. Conversely, Mn concentrations in cord blood were significantly higher in infants with intrauterine growth retardation. Zota et al.  performed nonlinear spline and quadratic regression models to test the hypothesis of an inverted U-shaped relationship between Mn levels and birth weight. These investigators found no association between umbilical cord blood Mn and infant birth weight in adjusted multivariate linear regression models. However, they did find a non-linear relationship between maternal blood Mn and infant birth weight . These findings are similar to those recently found by Chen et al.  and Eum et al. , suggesting that both lower and higher Mn exposure is associated with lower birth weight. In a multicenter study by Yu et al., cord serum Mn was not associated with birth weight after adjusting for potential confounders . However, there was a linear relationship between cord serum Mn and birth length. In the present study a clear association between Mn in umbilical cord blood and birth weight, length and head circumference was present in the univariate analyses, even though it was not found to be an independent factor.
The results of the study demonstrate that Ba and Mg in maternal blood are inversely and significantly related to all the anthropometric parameters of the newborns. Higher concentrations of Mg in cord blood of infants with intrauterine growth retardation, as compared with normal weight-newborns were observed by Barbosa et al. . However, maternal samples were not available . To the best of our knowledge, no study focused on Ba effects has been published.
In contrast, the association was practically non-existent between anthropometric parameters and the remaining trace elements, As, Co, Cr, Fe, Se, and Zn in both umbilical cord and maternal blood. In previous studies, the association varies widely between birth weight and trace elements such as Se, Zn, Fe, Cr and Mg, [15, 17, 19, 34–38]. Reasons to explain the discrepancies between studies are not clear, but may be related to the diversity of unknown factors that could contribute to fetal development, heterogeneity in populations, and non-uniformity in the study designs and techniques used.
In the present research additional information is provided such as the effect of other factors on fetal growth, i.e. maternal smoking and female sex, and shorter gestational age, which were significantly associated with decreased birth weight. Conversely the presence of anemia was associated with increased weight in newborns.
The findings of this study need to be interpreted within their strengths and limitations. Combining several trace elements in newborns and mothers, along with other variables of interest, the study analyses the association with anthropometric characteristics of the newborn, demonstrating the importance of Cu levels in umbilical cord. In spite of the fact that the exact toxicity limits of trace elements in the newborn are not exactly known, this study provides data on concentrations of Cu and its association with lower birth weight. This knowledge is important considering the known association between fetal growth and the development of chronic disease in adulthood [1, 3–6]. The study has limitations related to the small sample size, limiting the statistical power. Factors such as pre-pregnancy BMI, weight gain during pregnancy, socio-economic level and environmental risk were not included. Even though the sample is not representative of the general population, the inclusion of healthy pregnant women and their newborns along with a large number of trace elements led to a complete sample for analysis. Additionally, important indicators and predictors of maternal nutritional status were included such as maternal anemia and smoking habit. Moreover, given the cross-sectional design of the study, it is not possible to establish inference of causality with the factors analysed.