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Aluminium (Al) is a non-essential neurotoxicant and there is limited information regarding exposure to Al in utero. This study sought to evaluate the in utero exposure to Al in urban South African women, its effects on birth outcomes and possible synergistic effects between Al, essential and neurotoxic elements such as lead (Pb), mercury (Hg) and arsenic (As), as well as a a potential sex-dependent response to these elements in neonates. This study has found elevated levels of Al in urban women at delivery. The Spearman’s rank correlation coefficients (p-value) of the association between maternal serum Al and birth outcomes (gestational age and parity), and between maternal serum Al and Cu, Zn and Se, were statistically significant. However, in the general and the stratified models, no association was found between any of the birth outcomes and maternal serum Al. The association between maternal serum Al and neurotoxic elements at delivery showed a significant positive correlation for Pb only (rho = 0.361; p < 0.001) which was found to be sex-dependent in neonates (males, rho = 0.285; p < 0.004 and females, rho = 0.444, p < 0.001). Our preliminary findings indicate that in utero exposure to Al is an emerging concern requiring further research and directives from public health authorities.
This cross-sectional study was performed in the urban centre of Cape Town, situated along the Atlantic coast of South Africa. Study participants were women who were admitted for delivery at the largest maternity public hospital in Cape Town. The procedure for inclusion in the study was as follows: at admission women were informed about the study by medical personnel on duty and a research assistant who distributed an information sheet/pamphlet about the study. Those who agreed to participate signed an informed consent form and agreed to donate blood before delivery, answer a socio-demographic questionnaire by interview and allow access to, and use of, data related to birth outcomes and birth complications, if any. The participation rate was high with more than 90% of women approached agreeing to participate in the study. Participation was voluntary and confidentiality was assured. Women were also informed that they could withdraw from the study at any time. A total of 200 women participated in the study. From each woman 10 mL of venous blood was collected into a non-additive tube to obtain serum for analyses of Al and other trace metals. An additional 10 mL of maternal blood was collected into Ethylene diamine tetracetic acid (EDTA) tubes for the analyses of other metals (both trace and neurotoxic) using the Venoject sterile system and Becton, Dickinson & Company (BD, Franklin Lakes, NJ, USA) collection tubes. Blood for serum analyses was centrifuged and the serum was transferred into acid-washed polypropylene tubes with acid-washed plastic pipettes and frozen at −20 °C until analysed. The Analyses of samples for the selected elements manganese (Mn), Hg, Pb and As in maternal whole blood have been described previously [17,38,39,40]. For the measurement of Al, Cu, Zn and Se in serum, samples were diluted 20-fold with a diluent (ammonia 2.5 mL; butanol 6 mL, 0.1% triton-X 50 µL and EDTA 50 µg in 500 mL deionized water). The following internal standards were also added to the diluent: indium (In, 25 µL), germanium (Ge, 25 µL), scandium (Sc, 25 µL), rhodium (Rh, 250 µL) and iridium (Ir, 250 µL). The instrument (Agilent inductively coupled plasma mass spectrometer (ICP-MS) 7900) was calibrated with calibration standards prepared in the diluent using a multi-element custom standard (SPECTRASCAN–SS028226). The concentrations of the standards for Al ranged from 0.1 to 50 µg/L, and for Cu, Zn and Se, from 0.1 to 100 µg/L. The internal standards used were Sc for Al and Ir for Se. Ge was used as an internal standard for both Cu and Zn. All the samples were prepared in 15 mL NuncTM Trace Metal free tubes (Thermo Scientic, Johannesburg, South Africa). Blank samples were run in the beginning and after every 10 samples to check for carryover. The ICP-MS instrument (Agilent Technologies, Santa Clara, CA, USA) was run in general purpose mode, using helium gas. The mass/charge ratio of 27 was used for Al detection, and 63 and 66 was used for Cu and Zn, respectively. The integration time of 0.5 s was used for all three analytes. Each analyte was measure in triplicate, and reported as an average,. The average result was accepted if the RSD% was less than 10%. The calibration curves were accepted if the r-squared value was greater than 0.999. A calibration verification standard (prepared from a different standard–LGC Custom multi standard-VHG-ZLGC1574-100) was run with every batch at 5 µg/L and 50 µg/L, with an acceptance criteria of 5%. Two certified reference controls, SeronormTM Trace Elements Serum Level 1 (Lot no 11309438, Sero Ltd., Billingstad, Norway) and Level 2 (Lot no 1309416), were analysed with every analytical run in intervals of 10 samples for quality assurance of all element measurements. The limits of quantitation (LoQ) for Al, Cu, Zn and Se were 0.15, 0.06, 0.31 and 0.17 µg/L, respectively. Al was detected in all serum samples. The % recovery of the certified controls was between 90 and 113 for both levels. The laboratory participates in the Royal College of Pathologists of Australasia (RCPA) quality-assurance programme for whole blood, serum and urine. The results obtained are consistently accepted with no indication of bias. All precautions to eliminate and prevent contamination at collection and during preparation of samples were applied throughout. Covariate information was obtained during the questionnaire-based interview and from medical records. Maternal weight, height, blood pressure and haemoglobin levels were recorded at the hospital on admission. From the medical records, the following neonate characteristics were retrieved: birth weight (g), birth length (cm), head circumference (cm) and gestational age (weeks), Apgar score at 1 and 5 min, and placenta weight (g). Pre-term labour was defined as mothers giving birth at less than 37 weeks of gestational age. Education was categorised as no education to completed primary school, completed secondary school and any level of tertiary education attained. Maternal tobacco smoking during pregnancy was defined as yes or no. Exposure to environmental tobacco smoke (ETS) was defined as exposure to tobacco smoke from smoking by others in the household. A binary classification was used for exposure to indoor smoke from the burning of fossil fuel (wood and coal) for the purpose of heating or cooking, separating study participants into those exposed to fossil fuel and those not exposed (for example, those using electricity). Dietary questions relating to the intake of proteins, carbohydrates, dairy products, tea, coffee, bottled water, vitamin supplementation, fruits, as well as vine, root and leafy vegetables, were assessed and classified as daily, at least once a week and seldom (both for pre-pregnancy and during pregnancy). The statistical analyses were performed using STATA (StataCorp, 2013. Stata Statistical Software: Release 13. College Station, TX, USA: StataCorp LP). Bivariate analyses between maternal serum Al exposure and covariates were evaluated by Spearman’s correlation coefficient. List-wise deletion was used so that the analysis was only run on cases which had a complete set of data. Most of the assumptions for linear regression were not met in this study’s data, therefore, non-parametric method quantile regression was used. Quantile regression analysis helps to understand the association between variables outside of the mean of the data unlike the ordinary least squares regression. It is carried out to understand outcomes that are non-normally distributed and that have non-linear relationships with independent variables [41]. Although, quantile regression can be used to test the group differences across the distribution (25th, 50th, 75th quantiles) of an outcome variable, this study focussed only on the 50th quantile i.e., the median of the outcome variable maternal serum Al [41]. All statistical tests were two-tailed and statistical significance was set at p < 0.05. The work was carried out in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki). Ethics approval for the study was obtained from the Human Research Ethics Committee of the University of Witwatersrand in Johannesburg (Protocol no. {"type":"entrez-nucleotide","attrs":{"text":"M10742","term_id":"147973","term_text":"M10742"}}M10742), and from the relevant provincial Department of Health. In addition, the chief executive officer (CEO) of the hospital had to confirm that he/she allowed the research work to proceed. Identical procedures were followed in terms of obtaining consent from participants. Confidentiality was maintained by assigning identification numbers to all study participants. During the informed consent process, it was emphasised that participation was voluntary and could be withdrawn at any time.
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