Background The presence of harmful environmental exposures, which disproportionately affects low-and-middle income countries (LMICs), contributes to >25% of deaths and diseases worldwide and detrimentally affects child neurodevelopment. Few resources succinctly summarize the existing literature on this topic. Our objective is to systematically review and characterize the evidence regarding the relationship between heavy metals and neurodevelopment of children in LMICs. Methods We conducted a medical librarian-curated search on multiple online databases to identify articles that included individuals <18 years living in a LMIC, quantitatively measured exposure to a heavy metal (either prenatal or postnatal), and used a standardized measurement of neurodevelopment (i.e. cognitive, language, motor, and behavior). Reviews, editorials, or case studies were excluded. Results were analyzed qualitatively, and quality was assessed. Results Of the 18,043 screened articles, 298 full-text articles were reviewed, and 100 articles met inclusion criteria. The included studies represented data from 19 LMICs, only one of which was classified as a low-income country. Ninety-four percent of postnatal lead and all postnatal manganese studies showed a negative association with metal exposure and neurodevelopment, which were the strongest relationships among the metals studied. Postnatal exposure of mercury was associated with poor neurodevelopment in only half of studies. Limited data on postnatal arsenic and cadmium suggests an association with worse neurodevelopment. Findings were mixed for prenatal arsenic and lead, although some evidence supports that the neurotoxicity of lead was amplified in the presence of manganese. Conclusions and potential impact We found that lead and manganese appear to consistently have a detrimental effect on the neurodevelopment of children, and more evidence is needed for mercury, arsenic, and cadmium. Better characterization of these effects can motivate and inform prioritization of much needed international policies and programs to reduce heavy metal exposures for young children within LMICs.

Background: The presence of harmful environmental exposures contributes to >25% of deaths and diseases worldwide. Child neurodevelopment is negatively impacted by environmental exposures, such as certain heavy metals. In low and middle-income countries, where numerous risk factors for poor neurodevelopment exist, it is unclear if this negative impact persists. Our objective with this systematic review is to evaluate the association between heavy metals and the neurodevelopment of children in low-and-middle income countries.     Methods: We conducted a search on PubMed MEDLINE, Embase, Cochrane Library, CINAHL, PsychInfo, Scopus, and Web of Science for articles that included individuals below the age of 18, quantitively measured exposure to a heavy metal and used a standardized measurement of neurodevelopment.      Results: Of the 15,250 screened articles, 292 full-text articles were reviewed, and 96 articles met inclusion criteria. These studies were conducted in 18 countries and included 46,080 participants ranging from birth – 18 years old. At least one domain of neurodevelopment was inversely correlated with 8/11 of arsenic studies, 3/3 of cadmium studies, 29/32 of lead studies, 11/11 of manganese studies, 9/18 of mercury studies, and 21/21 studies with multiple metals. There was no consistent evidence of arsenic affecting behavior; mercury negatively affected neurodevelopment in only half the studies, indicating that the benefits of consuming mercury-containing fish might outweigh the negative impact of mercury exposure; ethylmercury did not affect neurodevelopment; hair manganese was a much more consistent biomarker of manganese exposure than blood; and the neurotoxicity of lead was amplified in the presence of manganese.    Conclusions and potential impact: In low and middle-income countries, heavy metals have a significantly detrimental effect on the neurodevelopment of children, highlighting the need for more regulation.

A 26-month-old girl was referred to pediatric endocrinology with rapid growth, clitoromegaly, and abnormal laboratory findings. She was born at term with a birth weight of 3.568 kg and was discharged home at 2 days of life. Her newborn screen was normal and there was no history of consanguinity. At 6 months of age, she was referred to pediatric urology for "labial adhesions." However, her physical examination revealed complete posterior labial fusion, a prominent clitoris, and a urogenital sinus. Evaluation at that time revealed a 46, XX karyotype. The 17-hydroxyprogesterone (17OHP) level was 285 ng/dL and the testosterone level was 35 ng/dL. Normal values of 17OHP and testosterone in a child of her age are <147 ng/dL and <76 dL, respectively. The case was discussed independently with two pediatric endocrinologists, both of whom stated that her biochemical profile did not indicate congenital adrenal hyperplasia (CAH) and that an endocrine referral was not needed. Therefore, it was deduced that her physical findings were isolated congenital anomalies and that no further evaluation was needed.