Neurobehavioral Development in Toddlers and Preschoolers in Relation to Prenatal Exposure of Mild Analgesics (NeuroToP - a COPANA Follow up)

Adhd, Analgesic Adverse Reaction, Autism Spectrum Disorder, Developmental Disability, Gonad Regulating Hormone Adverse Reaction, Language Development

Fundamental aspects of both neurological and reproductive function are established in fetal life, and there is a present increased awareness of the potential effects of fetal exposures on neurodevelopmental and reproductive health of offspring. Experimental and epidemiological research studies strongly suggest that paracetamol and NSAID are endocrine disruptive in the fetus, which could increase the risks of some neurodevelopmental, reproductive, and urogenital disorders. In recent years, there has been an increasing rate of neurodevelopmental disorders such as ADHD and autism. The original cohort, the Copenhagen Analgesic Study (COPANA), is the first prospective human study designed primarily to assess the effect of fetal exposure to mild analgesics on male and female reproductive function. If the same children are examined with relevant neurobehavioral testing during mid-childhood, the study design allows the investigators to assess the effect of mild analgesics as well as other EDCs on neurodevelopmental health.

Detailed Description In Denmark, mild analgesics such as acetaminophen (e.g. paracetamol) and non-steroidal anti-inflammatory drugs, NSAIDs (e.g. ibuprofen and acetylsalicylic acid), are sold over the counter, and up to 56% of pregnant women use mild analgesics during pregnancy. In vivo, in vitro, and ex vivo studies have shown that paracetamol directly perturbs hormone-dependent processes, which leads to disrupted reproductive development and neurodevelopment in both sexes. Fetal exposure in rodents has been shown experimentally to cause reproductive disorders of the male urogenital tract, including abnormalities in testicular function, sperm abnormalities, and sexual behavior. Experiments have shown disruption of female ovarian development resulting in reduced oocyte number and subsequent early ovarian insufficiency and reduced fertility. Fetal paracetamol exposure has been demonstrated to induce changes in neurotransmission in the brain manifesting in altered cognitive function, behavior, and locomotion. The studies have shown that the effect of paracetamol is dependent on the timing of exposure in relation to specific developmental processes, duration, and dose. Population-based cohort studies have reported associations of prenatal exposure to EDCs and language development, autism spectrum disorder scores, as well as externalizing and internalizing behavior scores. Phthalates are one example of an endocrine disrupter used in a variety of consumer products. Human studies suggest an association between phthalate exposure and cognitive development. However, adverse effects of the recently introduced phthalate substitutes have only been sparsely studied, which will be a focus point in this study. Animal studies suggest deleterious effects of fetal exposure to mild analgesics on both male and female gonadal development. In rodents, paracetamol administered in a single daily dose of 350 mg/kg at 13.5-21.5 days post coitum (dpc) was associated with reduced prostaglandin synthesis and delayed transition from germ cell mitosis to meiosis, causing fetal germ cell apoptosis in both female and male gonads. The long-term consequence seems to be most severe in the female, who becomes unable to form germ cells postnatally. In two studies, female offspring of mice treated with mild analgesics at 7 dpc to delivery and 13.5-21.5 dpc were born with reduced ovarian weight and with a 40-50% reduction in number of follicles. In adulthood, exposed animals gave birth to fewer pups per litter compared with controls. Use of acetylsalicylic acid (150-250 mg/kg/day) in early and mid-pregnancy (dpc 13-21) has shown to be antiandrogenic, causing shorter AGD and decreased testosterone production in rodents. Furthermore, studies of rodents suggest that in both males and females, adverse reproductive effects are passed on to the next generations, indicating altered and inherited programming of the genome, i.e., epigenetic. Effects on fetal germ cell development with therapeutically relevant concentrations of analgesics have been confirmed in various experimental animal models. Other medications, such as glucocorticoids and azoles, have previously been suggested to affect fetal germ cell development and will therefore also be incorporated in this study to adjust for possible effects when analyzing final data. Aniline is an organic compound found in many industrial products, pesticides, rubber, textiles, and tobacco smoke. The general population is inevitably exposed to aniline in daily life, and in vivo aniline is converted to paracetamol. In fact, studies have shown that paracetamol can be measured in urine samples of the general human population even with no prior intake of paracetamol, and similar to paracetamol, aniline has shown to exhibit similar anti-androgenic effects in male mice. To date, no prospective human studies have assessed the effect of analgesic exposure on neurobehavioral development. COPANA is the first prospective human study designed primarily to assess the effect of fetal exposure to mild analgesics on male and female reproductive function. By inviting the same families to participate in the present study, unique information about essential prenatal exposure patterns of analgesics as well as other potential EDCs (e.g., fungicides and phthalates) is already available. Furthermore, essential parameters for the gonadal function of the children have been established in the previous study. These parameters can be directly included in analyses of associations to neurobehavioral development. The primary objective of this study is to evaluate whether analgesic exposure during fetal life affects neurodevelopmental health in male and female toddlers and preschool children. Prenatal exposure to other potential endocrine-disrupting chemicals (e.g., fungicides and phthalates) on brain development will also be assessed. The families will be asked to complete inventories designed and validated to evaluate language development, ADHD and autism-like behavior, and gender-typical behavior-disorders that are more prevalent in gender-incongruent children and possibly linked with hormone-mediated brain development. To elucidate underlying mechanisms, the study includes an analysis of the children's epigenetic profile and genetic variation in specific genes/promoter regions affecting prostaglandin action in parents, boys, and girls.

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