Expert consensus on neurodevelopmental outcomes in pregnancy pharmacovigilance studies

R L Bromley; M Bickle Graz; M Bluett-Duncan; C Chambers; P Damkier; K Dietrich; H Dolk; K Grant; S Mattson; K J Meador; H Nordeng; T F Oberlander; A Ornoy; A Revet; J Richardson; J Rovet; L Schuler-Faccini; E Smearman; V Simms; C Vorhees; K Wide; A Wood; L Yates; E Ystrom; T A Supraja; J Adams

doi:10.3389/fphar.2023.1094698

Expert consensus on neurodevelopmental outcomes in pregnancy pharmacovigilance studies

Front Pharmacol. 2023 Jun 1:14:1094698. doi: 10.3389/fphar.2023.1094698. eCollection 2023.

Authors

R L Bromley^{1

2}, M Bickle Graz³, M Bluett-Duncan¹, C Chambers⁴, P Damkier⁵, K Dietrich⁶, H Dolk⁷, K Grant⁸, S Mattson⁹, K J Meador¹⁰, H Nordeng^{11

12}, T F Oberlander¹³, A Ornoy¹⁴, A Revet^{15

16}, J Richardson¹⁷, J Rovet^{18

19}, L Schuler-Faccini²⁰, E Smearman²¹, V Simms²², C Vorhees²³, K Wide²⁴, A Wood²⁵, L Yates^{26

27}, E Ystrom^{28

29}, T A Supraja³⁰, J Adams³¹

Affiliations

¹ Division of Neuroscience, Faculty of Medicine, School of Biological Sciences, Biology and Health, University of Manchester, Manchester, United Kingdom.
² Royal Manchester Children's Hospital, Manchester Academic Sciences Park, Manchester, United Kingdom.
³ Neonatology, Department Woman-Mother-Child, Lausanne University Hospital, Lausanne, Switzerland.
⁴ Division of Environmental Science and Health, Department of Pediatrics, University of California San Diego School of Medicine, San Diego, CA, United States.
⁵ Department of Clinical Pharmacology, Odense University Hospital, Denmark and Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
⁶ Department of Environmental and Public Health Sciences, Division of Epidemiology, University of Cincinnati College of Medicine, Cincinnati, OH, United States.
⁷ Maternal, Fetal and Infant Research Unit, Faculty of Life and Health Sciences, Ulster University, Coleraine, United Kingdom.
⁸ Department of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, Seattle, WA, United States.
⁹ Center for Behavioral Teratology, San Diego State University, San Diego, CA, United States.
¹⁰ Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Palo Alto, CA, United States.
¹¹ Pharmacoepidemiology and Drug Safety Research Group, Department of Pharmacy, University of Oslo, Oslo, Norway.
¹² Department of Child Health and Development, Norwegian Institute of Public Health, Oslo, Norway.
¹³ Department Pediatrics and School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada.
¹⁴ Hebrew University Hadassah Medical School, Adelson School of Medicine, Ariel University, Jerusalem, Israel.
¹⁵ INSERM University of Toulouse 3, Toulouse, France.
¹⁶ Department of Child and Adolescent Psychiatry, Toulouse University Hospital, Toulouse, France.
¹⁷ UK Teratology Information Service, Newcastle, United Kingdom.
¹⁸ Department of Psychology, University of Toronto, Toronto, ON, Canada.
¹⁹ The Hospital for Sick Children, Toronto, ON, Canada.
²⁰ Genetics Department, Hospital de Clinicas de Porto Alegre, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil.
²¹ Department of Surgery, Emory University, Atlanta, GA, United States.
²² School of Psychology, Faculty of Life and Health Sciences, Ulster University, Coleraine, United Kingdom.
²³ Department of Pediatrics, Division of Neurology, University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.
²⁴ Department of Pediatrics, CLINTEC, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
²⁵ Clinical Sciences, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
²⁶ Northern Genetics Service, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle, United Kingdom.
²⁷ KRISP, University of KwaZulu-Natal, Durban, South Africa.
²⁸ Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway.
²⁹ PROMENTA Research Center, Department of Psychology, University of Oslo, Oslo, Norway.
³⁰ National Institute of Mental Health and Neurosciences NIMHANS, Bangalore, Karnataka, India.
³¹ Department of Psychology, University of Massachusetts Boston, Boston, MA, United States.

Abstract

Background: Exposure in utero to certain medications can disrupt processes of fetal development, including brain development, leading to a continuum of neurodevelopmental difficulties. Recognizing the deficiency of neurodevelopmental investigations within pregnancy pharmacovigilance, an international Neurodevelopmental Expert Working Group was convened to achieve consensus regarding the core neurodevelopmental outcomes, optimization of methodological approaches and barriers to conducting pregnancy pharmacovigilance studies with neurodevelopmental outcomes. Methods: A modified Delphi study was undertaken based on stakeholder and expert input. Stakeholders (patient, pharmaceutical, academic and regulatory) were invited to define topics, pertaining to neurodevelopmental investigations in medication-exposed pregnancies. Experts were identified for their experience regarding neurodevelopmental outcomes following medicinal, substances of misuse or environmental exposures in utero. Two questionnaire rounds and a virtual discussion meeting were used to explore expert opinion on the topics identified by the stakeholders. Results: Twenty-five experts, from 13 countries and professionally diverse backgrounds took part in the development of 11 recommendations. The recommendations focus on the importance of neurodevelopment as a core feature of pregnancy pharmacovigilance, the timing of study initiation and a core set of distinct but interrelated neurodevelopmental skills or diagnoses which require investigation. Studies should start in infancy with an extended period of investigation into adolescence, with more frequent sampling during rapid periods of development. Additionally, recommendations are made regarding optimal approach to neurodevelopmental outcome measurement, comparator groups, exposure factors, a core set of confounding and mediating variables, attrition, reporting of results and the required improvements in funding for potential later emerging effects. Different study designs will be required depending on the specific neurodevelopmental outcome type under investigation and whether the medicine in question is newly approved or already in widespread use. Conclusion: An improved focus on neurodevelopmental outcomes is required within pregnancy pharmacovigilance. These expert recommendations should be met across a complementary set of studies which converge to form a comprehensive set of evidence regarding neurodevelopmental outcomes in pregnancy pharmacovigilance.

Keywords: in utero exposure; medicines; neurobehavior; neurodevelopment; pharmacovigilance; pregnancy; teratogens.

Copyright © 2023 Bromley, Bickle Graz, Bluett-Duncan, Chambers, Damkier, Dietrich, Dolk, Grant, Mattson, Meador, Nordeng, Oberlander, Ornoy, Revet, Richardson, Rovet, Schuler-Faccini, Smearman, Simms, Vorhees, Wide, Wood, Yates, Ystrom, Supraja and Adams.

Grants and funding

This work has been completed as part of the ConcePTION study. The ConcePTION project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No. 821520. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation program and EFPIA.