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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - DrugsInPregnancy (Effects of Medication Use in Pregnancy on Infant Neurodevelopment)

Teaser

Summary

The background for the DrugsInPregnancy project is the current lack of knowledge about potential long-term effects of prenatal exposure to medications on the childâ€™s brain. Currently, thousands of pregnant women in the EU and worldwide are being prescribed medications for which we do not have sufficient information on fetal safety. The lack of knowledge stands in disturbing contrast to the frequent use of analgesics and psychotropic medications, and the public demand for information about the long-term safety on the childâ€™s developing brain. We believe that our current understanding of safety pharmacology is oversimplified and that medication prescribed during pregnancy may play an unrecognized role in the development of neurodevelopmental disorders.
The precise molecular mechanisms of most teratogenic processes are unknown but altered patterns of DNA methylation, which result in aberrant gene expression, are thought to play a vital role. With the recent juncture between availability/affordability of genome-wide mapping of DNA methylation, the DrugsInPregnancy project has just come within reach.

As pregnant women cannot be included in randomized controlled trials due to ethical considerations, we need to find alternative methods to establish fetal safety. As learned from the thalidomide catastrophe, results from animal studies cannot be directly extrapolated to humans and the structure or activity of the drug is generally not predictive of teratogenesis. Therefore, prospective, long-term pharmacoepidemiological studies among pregnant women offer the only real solution to fill the gap of knowledge concerning safety of pharmaceuticals in pregnancy.

The aim of the DrugsInPregnancy project is to determine how specific medication groups including antidepressants, benzodiazepines and several groups of analgesics may act on the childâ€™s developing brain from both dimensional and diagnosis perspectives. Moreover, the aim is to determine whether there are epigenetic mechanisms involved in human drug neurotoxicity.
In the DrugsInPregnancy project we have the unique opportunity to use several population-based registries and a population-based birth cohort including over 100,000 mother-child pairs and biological data (DNA samples from umbilical cord blood) to study how medications may act on the offspring. The size and richness of the available human data in this project - including epidemiological data of more than 100,000 pregnancies in combination with DNA samples (>90,000) and three nation-wide registries - makes this project extremely valuable.

Work performed

The main activities in the first period have laid the fundament for the success of the project. We have received and linked the necessary epidemiological data from the birth cohort and national registries. Cord blood samples for the first pharmacoepigenetic studies have been received, analysed and published. We have performed studies and published several publications in high ranking journal specifically assessing different aspects of data quality and availability of advanced methods for confounding control within reproductive pharmacoepidemiology. International presentations of our work has raised important debates on how child neurodevelopmental disorders and delays should be detected and how DNA-methylation analysis using cord blood should be correctly performed. We advocate that use of advanced methods for confounding control will enable causal inference about effects of prenatal exposure to medications on human neurodevelopment. We argue that psychometric instruments and diagnoses of developmental disorders have different strengths and weaknesses and will supplement each other. We advocate that without correction for cell type composition in studies on DNA-methylation erroneous conclusions will be made.

In the DrugsInPregnancy project, we found no substantial increased risk for externalizing, emotional, or social problems in preschool-aged children following prenatal SSRI-antidepressant exposure. We have found that prenatal exposure to low doses paracetamol is associated with reduced risk of ADHD, whereas high doses increases risk of ADHD in offspring. We have demonstrated that there is a link between use of high doses paracetamol among children with ADHD and altered DNA-methylation patterns.

Final results

Balancing on the cutting-edge between pharmacoepidemiology and epigenetics, the DrugsInPregnancy represents a true shift in paradigm by focusing on medication safety and the developing brain, and by following over 100 000 children from the womb into adolescence. Our findings are the first in the world to suggest that in children with ADHD, prenatal long-term exposure to paracetamol is associated with changes in the DNA methylation pattern in cord blood compared to non-exposed controls.
We expect that the DrugsInPregnancy project will provide us with a deeper understanding of effects of prenatal exposure to analgesics and psychotropics on DNA-methylation and neurodevelopmental disorders in offspring. We expect that the implications will not only be important for how we treat pregnant women, but for how we understand epigenetic mechanisms of human drug neurotoxicity.