. 2025 Dec;48(12):1387-1397.

doi: 10.1007/s40264-025-01581-2. Epub 2025 Aug 5.

Teratogenic Risk Impact Mitigation (TRIM): Development of Explicit Criteria to Facilitate Decisions Regarding Teratogenic Risk Mitigation Strategies

Celeste L Y Ewig¹, Yanning Wang^{1

2}, Nicole E Smolinski^{1

2}, Gita A Toyserkani³, Cynthia LaCivita⁴, Leila Lackey³, Sara Eggers³, Leyla Sahin³, Reem S Abu-Rustum⁵, Brian T Bateman⁶, Anick Berard⁷, Christina D Chambers⁸, Beth Choby⁹, Elizabeth A Conover¹⁰, Michael F Greene¹¹, Sonia Hernández-Díaz¹², Denise J Jamieson¹³, Sarah G Običan¹⁴, Janine E Polifka¹⁵, Kay Roussos-Ross¹⁶, Jeanne S Sheffield¹⁷, Sharon Voyer Lavigne¹⁸, Ellen M Zimmermann¹⁹, Susan B Laffan²⁰, Anthony M DeLise²¹, Alicia W Gilsenan²², Tarek A Hammad²³, Christian Hampp²⁴, Janet R Hardy²⁵, Caitlin A Knox²⁴, Kristine Shields²⁶, Meredith Y Smith^{27

28}, Rachel E Sobel²⁴, Melissa S Tassinari²⁹, Judith C Maro³⁰, Sonja A Rasmussen³¹, Almut G Winterstein^{32

33

34}

Affiliations

¹ Department of Pharmaceutical Outcomes and Policy, University of Florida, College of Pharmacy, Malachowsky Hall, 1889 Museum Road, Suite 6300, Gainesville, FL, 32611, USA.
² Center for Drug Evaluation and Safety, University of Florida, Gainesville, FL, USA.
³ Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
⁴ Independent, Potomac, MD, USA.
⁵ Department of Obstetrics and Gynecology, University of Florida College of Medicine, Gainesville, FL, USA.
⁶ Stanford University School of Medicine, Palo Alto, CA, USA.
⁷ Faculty of Pharmacy, University of Montreal; and CHU Sainte-Justine, Montreal, Canada.
⁸ University of California, San Diego, CA, USA.
⁹ Independent, Memphis, TN, USA.
¹⁰ University of Nebraska Medical Center, Omaha, NE, USA.
¹¹ Department of Obstetrics and Gynecology, Harvard Medical School, Boston, MA, USA.
¹² Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹³ University of Iowa Health Care, Iowa City, IA, USA.
¹⁴ Department of Obstetrics and Gynecology, University of South Florida, Tampa, FL, USA.
¹⁵ University of Washington, Seattle, WA, USA.
¹⁶ Departments of OBGYN, Psychiatry, University of Florida, Gainesville, FL, USA.
¹⁷ Johns Hopkins Medicine, Baltimore, MD, USA.
¹⁸ UConn Health, Farmington, CT, USA.
¹⁹ Division of Gastroenterology, Hepatology and Nutrition, University of Florida, Gainesville, FL, USA.
²⁰ Amgen R&D, Translational Safety and Bioanalytical Sciences, Thousand Oaks, CA, USA.
²¹ Novartis Pharmaceutical Company, East Hanover, NJ, USA.
²² RTI Health Solutions, Research Triangle Park, NC, USA.
²³ Takeda Development Center Americas, Inc., Cambridge, MA, USA.
²⁴ Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA.
²⁵ Independent, Greater Montreal, Quebec, Canada.
²⁶ Independent, Philadelphia, PA, USA.
²⁷ Evidera, Inc., New London, NH, USA.
²⁸ University of Southern California Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, Los Angeles, CA, USA.
²⁹ Independent, Harwich Port, MA, USA.
³⁰ Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA.
³¹ Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³² Department of Pharmaceutical Outcomes and Policy, University of Florida, College of Pharmacy, Malachowsky Hall, 1889 Museum Road, Suite 6300, Gainesville, FL, 32611, USA. almut@ufl.edu.
³³ Center for Drug Evaluation and Safety, University of Florida, Gainesville, FL, USA. almut@ufl.edu.
³⁴ Department of Epidemiology, University of Florida, Gainesville, FL, USA. almut@ufl.edu.

PMID: 40762949
PMCID: PMC12605566
DOI: 10.1007/s40264-025-01581-2

Teratogenic Risk Impact Mitigation (TRIM): Development of Explicit Criteria to Facilitate Decisions Regarding Teratogenic Risk Mitigation Strategies

Celeste L Y Ewig et al. Drug Saf. 2025 Dec.

. 2025 Dec;48(12):1387-1397.

doi: 10.1007/s40264-025-01581-2. Epub 2025 Aug 5.

Authors

Affiliations

¹ Department of Pharmaceutical Outcomes and Policy, University of Florida, College of Pharmacy, Malachowsky Hall, 1889 Museum Road, Suite 6300, Gainesville, FL, 32611, USA.
² Center for Drug Evaluation and Safety, University of Florida, Gainesville, FL, USA.
³ Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
⁴ Independent, Potomac, MD, USA.
⁵ Department of Obstetrics and Gynecology, University of Florida College of Medicine, Gainesville, FL, USA.
⁶ Stanford University School of Medicine, Palo Alto, CA, USA.
⁷ Faculty of Pharmacy, University of Montreal; and CHU Sainte-Justine, Montreal, Canada.
⁸ University of California, San Diego, CA, USA.
⁹ Independent, Memphis, TN, USA.
¹⁰ University of Nebraska Medical Center, Omaha, NE, USA.
¹¹ Department of Obstetrics and Gynecology, Harvard Medical School, Boston, MA, USA.
¹² Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹³ University of Iowa Health Care, Iowa City, IA, USA.
¹⁴ Department of Obstetrics and Gynecology, University of South Florida, Tampa, FL, USA.
¹⁵ University of Washington, Seattle, WA, USA.
¹⁶ Departments of OBGYN, Psychiatry, University of Florida, Gainesville, FL, USA.
¹⁷ Johns Hopkins Medicine, Baltimore, MD, USA.
¹⁸ UConn Health, Farmington, CT, USA.
¹⁹ Division of Gastroenterology, Hepatology and Nutrition, University of Florida, Gainesville, FL, USA.
²⁰ Amgen R&D, Translational Safety and Bioanalytical Sciences, Thousand Oaks, CA, USA.
²¹ Novartis Pharmaceutical Company, East Hanover, NJ, USA.
²² RTI Health Solutions, Research Triangle Park, NC, USA.
²³ Takeda Development Center Americas, Inc., Cambridge, MA, USA.
²⁴ Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA.
²⁵ Independent, Greater Montreal, Quebec, Canada.
²⁶ Independent, Philadelphia, PA, USA.
²⁷ Evidera, Inc., New London, NH, USA.
²⁸ University of Southern California Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, Los Angeles, CA, USA.
²⁹ Independent, Harwich Port, MA, USA.
³⁰ Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA.
³¹ Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³² Department of Pharmaceutical Outcomes and Policy, University of Florida, College of Pharmacy, Malachowsky Hall, 1889 Museum Road, Suite 6300, Gainesville, FL, 32611, USA. almut@ufl.edu.
³³ Center for Drug Evaluation and Safety, University of Florida, Gainesville, FL, USA. almut@ufl.edu.
³⁴ Department of Epidemiology, University of Florida, Gainesville, FL, USA. almut@ufl.edu.

PMID: 40762949
PMCID: PMC12605566
DOI: 10.1007/s40264-025-01581-2

Abstract

Background: Preventing fetal exposure to teratogenic medications is an important target for risk mitigation efforts. Decisions about risk mitigation efforts specific to teratogenic medications are complex.

Objectives: The Teratogenic Risk Impact and Mitigation (TRIM) tool was developed as an innovative decision support tool to facilitate prioritization of teratogenic medications for risk mitigation strategies.

Methods: We employed a modified Delphi study design involving experts across teratology, obstetrics/gynecology, and medication safety. Panelists proposed decision criteria in three focus groups, followed by e-Delphi rounds to reach a consensus on criteria regarding three dimensions: (1) completeness; (2) relevance; and (3) distinctiveness. Aggregated feedback from each round was used to inform revision of the criteria in subsequent rounds.

Results: A total of 33 candidate criteria proposed by 32 focus group participants were organized into ten distinct criteria for the Delphi process. Consensus (defined as > 85% agreement on all three dimensions) was reached after three e-Delphi rounds, resulting in six criteria: (1) background use among persons of reproductive potential; (2) overall medication benefit considering severity of the indication and availability of alternatives; (3) seriousness of the teratogenic outcome; (4) risk of the teratogenic outcome; (5) certainty regarding teratogenicity; and (6) the risk of exposure during pregnancy.

Conclusions: We established measurable criteria to inform decisions when prioritizing teratogenic medications for risk mitigation programs. Criteria are consensus based and consistent with relevant regulatory guidance. Future work will operationalize these criteria and determine specific weights to facilitate medication-specific TRIM scores. Through its explicit framework, the TRIM tool may support consistent, transparent, and rational decision making and help optimize the contribution of risk mitigation programs to public health.

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Conflict of interest statement

Declarations. Funding: This study was funded by contract HHS75F40121C00188 with the US FDA. Expert panelist volunteered their time and were not compensated for the participation. The views in this article are those of the authors and not necessarily those of the FDA. Conflicts of interest/competing interests: Cynthia LaCivita was formerly with the Center for Drug Evaluation and Research, US FDA, Silver Spring, MD, USA. She is currently a consultant to Glaxo Smith Kline, United BioSource, and Stallergenes. Anick Berard is the holder of a Canada Research Chair, and a Louis Boivin Family Research Chair on Medications and Pregnancy. The Centers for Disease Control and Prevention receives research funding from the following industry sponsors and a foundation: Amgen, AstraZeneca, GlaxoSmithKline, Janssen Pharmaceuticals, Pfizer, Inc., Regeneron, Hoffman La-Roche-Genentech, Genzyme Sanofi-Aventis, Takeda Pharmaceutical Company Limited, Sanofi, UCB Pharma, USA, Leo Pharma, Sun Pharma Global FZE, Gilead, Novartis, and the Gerber Foundation. Sonia Hernández-Díaz consulted for Roche and Moderna; participated as an investigator in projects funded by Takeda and UCB; and was an advisor for the Antiepileptic and the Antipsychotics Pregnancy Registries, which are funded by multiple companies. Sarah G. Običan has served in the last 2 years as an expert witness working in acetaminophen litigation and polychlorinated biphenyls. Christian Hampp is an employee and shareholder of Regeneron. Caitlin A. Knox is an employee and shareholder of Regeneron and a shareholder of Vertex Pharmaceuticals. Meredith Y. Smith is a shareholder in Thermo Fisher Scientific, Amgen, AbbVie, Abbott, and Eli Lilly. Rachel E. Sobel is an employee and shareholder of Regeneron and a shareholder of Pfizer Inc. Sonja A. Rasmussen serves on scientific advisory committees for several pregnancy registries, including registries for Harmony, Axsome, and Biohaven, recently acquired by Pfizer, Novo Nordisk, and Myovant Sciences. Almut G. Winterstein has received research funding from Merck and has served as a consultant for Merck, Bayer KG, Ipsen, Lykos, Syneos, and Novo Nordisk. Almut G. Winterstein is an Editorial Board member of Drug Safety. Almut G. Winterstein was not involved in the selection of peer reviewers for the manuscript nor in any of the subsequent editorial decisions. Nicole E. Smolinski owns stock through inheritance in Baxter, Cardinal Health, CVS Health, Edwards LifeSciences, and Takeda unrelated to this work. All other authors have no conflicts of interest that are directly relevant to the content of this article. Ethics approval: This study was approved by the University of Florida Institutional Review Board (IRB202102721). Participants were informed that their participation in the study implied consent. Consent to participate: All expert panel members provided consent for their participation in this study. Consent for publication: Not applicable. Availability of data and material: Not applicable. Code availability: Not applicable. Authors’ contributions: All authors (1) made substantial contributions to the conception or design of the work, or the acquisition, analysis, or interpretation of data for the work; (2) drafted of the work or reviewed it critically for important intellectual content; (3) gave final approval of the version to be published; and (4) agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Figures

**Fig. 1**
Study flow. *TRIM* Teratogenic Risk Impact Mitigation

**Fig. 2**
Responses for attributes “criterion omission” and “consolidation” in Delphi Round 1

**Fig. 3**
Responses for attributes “criterion omission” and “consolidation” in Dephi Round 2

See this image and copyright information in PMC

References

1. US Food and Drug Administration (FDA). Risk evaluation and mitigation strategies (REMS) 2023. https://www.fda.gov/drugs/our-perspective/risk-evaluation-and-mitigation.... Accessed 25 June 2025.
1. Sarpatwari A, Brown BL, McGraw SA, Dejene SZ, Abdurrob A, Santiago Ortiz AJ, et al. Patient and caregiver experiences with and perceptions of risk evaluation and mitigation strategy programs with elements to assure safe use. JAMA Netw Open. 2022;5(1): e2144386. - DOI - PMC - PubMed
1. Sarpatwari A, Brown BL, McGraw SA, Dejene SZ, Abdurrob A, Kesselheim AS. Physician experiences with and perceptions of risk evaluation and mitigation strategy programs with elements to assure safe use. PLoS ONE. 2023;18(7): e0288008. - DOI - PMC - PubMed
1. Sarpatwari A, Lu Z, Russo M, Zakoul H, Lee SB, Toyserkani GA, et al. How do risk evaluation and mitigation strategies impact clinical practice? A national survey of physicians. Clin Pharmacol Ther. 2024;115(6):1293–303. - DOI - PubMed
1. US Food and Drug Administration (FDA). Risk evaluation and mitigation strategy (REMS) public dashboard 2024. https://www.fda.gov/drugs/risk-evaluation-and-mitigation-strategies-rems.... Accessed 25 June 2025.

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Teratogenic Risk Impact Mitigation (TRIM): Development of Explicit Criteria to Facilitate Decisions Regarding Teratogenic Risk Mitigation Strategies

Affiliations

Teratogenic Risk Impact Mitigation (TRIM): Development of Explicit Criteria to Facilitate Decisions Regarding Teratogenic Risk Mitigation Strategies

Authors

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Abstract

Conflict of interest statement

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