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. 2023 Oct 2;6(10):e2339934.
doi: 10.1001/jamanetworkopen.2023.39934.

Treatments During Pregnancy Targeting ERBB2 and Outcomes of Pregnant Individuals and Newborns

Paul Gougis  1   2   3 , Beatriz Grandal  1 , Floriane Jochum  1   4 , Kevin Bihan  3 , Florence Coussy  1   5 , Solenn Barraud  1 , Bernard Asselain  6 , Elise Dumas  1 , Clara Sebbag  1   5 , Judicael Hotton  7 , Emmanuel Spaggiari  8 , Jean-Yves Pierga  5 , Raphaëlle Savarino  5 , Enora Laas  1   9 , Jean-Philippe Spano  2   10 , Fabien Reyal  1   7   9 , Anne-Sophie Hamy  1   5
Affiliations

Treatments During Pregnancy Targeting ERBB2 and Outcomes of Pregnant Individuals and Newborns

Paul Gougis et al. JAMA Netw Open. .

Abstract

Importance: Targeted therapies directed against ERBB2 are the cornerstone of medical treatment for ERBB2-positive breast cancers but are contraindicated during pregnancy.

Objectives: To describe the association of exposure to anti-ERBB2 agents during pregnancy with pregnancy and fetal or newborn outcomes, and to compare the risk and types of adverse outcomes reported more frequently in this context than after exposure to other anticancer agents.

Design, setting, and participants: For this case-control study, All reports with a pregnancy-related condition and an antineoplastic agent (Anatomical Therapeutic Chemical classification group L01) registered in the World Health Organization international pharmacovigilance database VigiBase up to June 26, 2022, were extracted. All reports with a pregnancy, an antineoplastic treatment during pregnancy, and a cancer were retained. Reports with anticancer agents prescribed for nononcologic purposes were not included.

Exposure: The exposure group was defined as reports that mention anti-ERBB2 agents compared with exposure to other anticancer agents.

Main outcome and measures: The main outcome was the reporting odds ratio (ROR) for maternofetal complications in the group exposed to anti-ERBB2 agents compared with other anticancer agents, as determined using a disproportionality analysis.

Results: A total of 3558 reports (anti-ERBB2 agents, 328; other anticancer agents, 3230) were included in the analysis. In the group exposed to anti-ERBB2 agents, most reports were from the US (159 [48.5%]), the mean (SD) age of participants was 30.8 (10.4) years, and 209 patients (97.7%) were treated for breast cancers. The molecules most frequently involved in cases with anti-ERBB2 agents were trastuzumab (n = 302), pertuzumab (n = 55), trastuzumab-emtansine (n = 20), and lapatinib (n = 18). The outcomes overreported in these cases included oligohydramnios (ROR, 17.68 [95% CI, 12.26-25.52]; P < .001), congenital respiratory tract disorders (ROR, 9.98 [95% CI, 2.88-34.67]; P < .001), and neonatal kidney failure (ROR, 9.15 [95% CI, 4.62-18.12]; P < .001). Sensitivity and multivariable analyses found similar results. Toxic effects were also significantly overreported for trastuzumab-emtansine (cardiovascular malformation: ROR, 4.46 [95% CI, 1.02-19.52]) and lapatinib (intrauterine growth restriction: ROR, 7.68 [95% CI, 3.01-19.59]).

Conclusions and relevance: In this case-control study of 328 individuals exposed to anti-ERBB2 agents during pregnancy, exposure was associated with a severe specific adverse pregnancy and fetal or newborn outcomes compared with exposure to other anticancer treatments.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Spano reported receiving personal fees from MSD, Gilead, AstraZeneca, Lilly, Pfizer, Novartis, LeoPharma, Daiichi Sakyo, GSK, Exact Sciences, and PFOncology and grants from MSD Avenir outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Flowchart
All reports were extracted from VigiBase. Details of data extraction are provided in eTable 1 in Supplement 1. Terms associated secondarily with this request were not specific to pregnancy and were discarded. Reports also mentioned a suspect or interacting drug from the Anatomical Therapeutic Chemical (ATC) L01 class (antineoplastic drugs), which could have been prescribed for a cancer or noncancer indication. aMedDRA terms queried for “Reaction” were pregnancy, puerperium, and perinatal conditions (system organ classifications); fetal and neonatal investigations (high-level group term [HLGT]); neonatal and perinatal conditions (HLGT); neonatal respiratory disorders (HLGT); exposures associated with pregnancy, delivery, and lactation (high-level term [HLT]); fetal therapeutic procedures (HLT); induced abortions (HLT); and obstetric therapeutic procedures (HLT).
Figure 2.
Figure 2.. Description of Pregnancy and Fetal or Newborn Adverse Outcomes With Exposure to Anti-ERBB2 Drugs Compared With Exposure to Other Anticancer Drugs
Bars represent the percentage of each outcome divided by the total number of reports. Counts are also annotated. For congenital respiratory tract disorders, the anti-ERBB2 drug–exposed group included 2 reports of pulmonary hypoplasia, 2 reports of respiratory tract malformation, and 1 report of laryngomalacia. The exposure to other anticancer drugs group included 3 reports of diaphragmatic hernia and 2 reports of pulmonary hypoplasia. HT indicates hypertension; NOS, not otherwise specified.
Figure 3.
Figure 3.. Reporting Odds Ratios (RORs) of Pregnancy and Fetal or Newborn Adverse Outcomes With Exposure to Anti-ERBB2 Drugs Compared With Exposure to Other Anticancer Drugs
RORs are displayed as logarithmic data for the purpose of data visualization. HT indicates hypertension; NOS, not otherwise specified. aP ≤ .05. bP ≤ .001.
See this image and copyright information in PMC

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