Immune Checkpoint Inhibitors and Pregnancy: Analysis of the VigiBase® Spontaneous Reporting System

Noseda, Roberta; Müller, Laura; Bedussi, Francesca; Fusaroli, Michele; Raschi, Emanuel; Ceschi, Alessandro

doi:10.3390/cancers15010173

Cited by 12 publications

(12 citation statements)

References 49 publications

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“…None of the 45 explored maternofetal outcomes were overreported in the ICI-exposed group compared with the group exposed to other anticancer drugs. These findings align with a recent pharmacovigilance study using VigiBase that revealed no discernible patterns of maternal, fetal, or newborn toxic effects and no signals of disproportionate reporting within the ICI group compared with the other anticancer agents group . However, that study had several limitations.…”

Section: Discussionsupporting

confidence: 83%

“…In oncology, existing guidelines stipulate that medical professionals should closely observe and report any instances of pregnancy during both clinical trials and regular treatment. Recently, a study analyzed VigiBase reports involving ICI exposure during the peripregnancy period and potential associations with pregnancy-related outcomes . The analysis was restricted to spontaneous abortion, fetal growth restriction, and premature birth.…”

Section: Introductionmentioning

confidence: 99%

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Immune Checkpoint Inhibitor Use During Pregnancy and Outcomes in Pregnant Individuals and Newborns

Gougis,

Hamy,

Jochum

et al. 2024

JAMA Netw Open

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ImportanceWith the widespread use of immune checkpoint inhibitors (ICIs), concerns about their pregnancy outcomes through maternal exposure have emerged, and clinical comparative data are lacking.ObjectiveTo assess the risk of pregnancy-, fetal-, and/or newborn-related adverse outcomes associated with exposure to ICIs compared with exposure to other anticancer agents.Design, Setting, and ParticipantsIn this cohort study, all reports mentioning a pregnancy-related condition and an antineoplastic agent (Anatomical Therapeutic Chemical classification group L01) used for a cancer indication registered in the World Health Organization international pharmacovigilance database VigiBase up to June 26, 2022, were extracted.ExposureAnticancer agents, including ICIs, used during pregnancy for a cancer indication. Immune checkpoint inhibitors included blockers of programmed cell death 1 (PD1) or its ligand (PD-L1) or cytotoxic T-lymphocyte–associated protein 4 (CTLA4).Main Outcomes and MeasuresThe main outcome was the reporting odds ratio (ROR) for maternal, fetal, or newborn complications in patients treated with ICIs vs any other anticancer drug. Adverse events, categorized into 45 individual maternofetal adverse outcomes, were directly mapped to Medical Dictionary for Regulatory Activities preferred terms in VigiBase.ResultsA total of 3558 reports (ICI: 91 [2.6%]; other anticancer drugs: 3467 [97.4%]) were included in the analysis. In the ICI group, most reports were from the US (60 [65.9%]), and the mean (SD) patient age was 28.9 (10.2) years; in 24 of 55 reports with data on cancer type (43.6%), patients were treated for melanoma. The molecules involved in the ICI group were anti-PD1 (58 reports [63.7%]), anti-PD1 plus anti-CTLA4 (15 [16.5%]), anti-CTLA4 (13 [14.3%]), anti–PD-L1 (4 [4.4%]), and anti-PD1 plus anti–lymphocyte activation gene 3 (1 [1.1%]). An ICI was used in combination with a non-ICI anticancer agent in 10 participants (11.0%). Compared with other anticancer drugs, none of the 45 adverse outcomes identified were overreported in the group exposed to ICIs. However, preterm birth was significantly overreported for the anti-PD1 plus anti-CTLA4 combination compared with other anticancer drugs (12 of 15 [80.0%] vs 793 of 3452 [23.0%]; ROR, 13.87; 95% CI, 3.90-49.28; P &lt; .001) but not for anti–PD-L1 or anti-CTLA4 monotherapy. Three reports of possibly immune-related maternofetal events were identified: 1 case of maternal antiphospholipid syndrome leading to spontaneous abortion, 1 case of pneumonitis leading to neonatal respiratory distress syndrome and death, and 1 case of transient congenital hypothyroidism.Conclusions and RelevanceIn this cohort study of 91 individuals exposed to ICIs during pregnancy, ICI exposure was not associated with overreporting of specific adverse pregnancy, fetal, and/or newborn outcomes compared with other anticancer treatments. However, due to possible rare immune-related neonatal adverse events, ICI use in pregnant women should be avoided when possible, especially the anti-PD1 plus anti-CTLA4 combination.

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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Immune Checkpoint Inhibitor Use During Pregnancy and Outcomes in Pregnant Individuals and Newborns

Gougis,

Hamy,

Jochum

et al. 2024

JAMA Netw Open

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“…VigiBase is the World Health Organization's (WHO) global pharmacovigilance database of safety reports of suspected SARs that was developed and maintained by the WHO-Uppsala Monitoring Centre (WHO-UMC). It collects report forms of suspected SARs from more than 170 national pharmacovigilance centres participating in the WHO Programme for International Drug Monitoring (WHO PIDM) (Noseda et al, 2022).…”

Section: Study Design and Data Sourcesmentioning

confidence: 99%

Suspected adverse reactions to medications and food supplements containing Serenoa repens: A worldwide analysis of pharmacovigilance and phytovigilance spontaneous reports

Crescioli

Maggini

Raschi

et al. 2023

Phytotherapy Research

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The safety of Serenoa repens (SR)‐containing products was evaluated conducting a retrospective worldwide analysis of pharmaco‐ and phytovigilance report forms of suspected adverse reactions (SARs) collected up to 31 January 2022. Multivariate logistic regression was performed to estimate the odds ratios (ORs) of serious SAR. A total of 1810 report forms were analysed; 92% of subjects were males, with a median age of 69 years; 44% of cases were defined as serious. Subjects exposed to dietary supplements had a higher risk of developing serious SARs (OR: 1.60 [95% CI: 1.20–2.15]), as subjects exposed to 2–5 (OR: 1. 83 [95% CI: 1.30–2.58]) or more than 5 (OR: 3.45 [95% CI: 2.36–5.06]) suspect/interacting products. The probability of experiencing serious SAR was higher for subjects exposed to concomitant products (OR: 1.55 [95% CI: 1.15–2.08]), to more than four active compounds (OR: 4.38 [95% CI: 3.21–5.99]) and to SR for more than 14 days (OR: 1.89 [95% CI: 1.10–3, 22]), and lower for subjects exposed to higher doses of SR (OR: of 0.34 [95% CI: 0.20–0.58]). This evidence improves awareness on safety of SR containing products, suggesting the need of a further update of periodic reviews by national and international regulatory agencies.

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“…VigiBase was also previously investigated to address the fetal toxic effects of immune checkpoint inhibitors, for which no significant toxic effect was found. 10 The objective of this study was to perform a large-scale descriptive analysis of pregnancy and fetal or newborn outcomes after exposure to anti-ERBB2 agents and to determine the reporting odds ratio (ROR) of adverse pregnancy and fetal outcomes after exposure to anti-ERBB2 drugs relative to other non-anti-ERBB2 anticancer drugs in a case-control disproportionality analysis.…”

Section: Introductionmentioning

confidence: 99%

“…In oncology, current guidelines recommend that (1) any pregnancy occurring during a trial or routine oncologic care should be monitored and that both (2) maternofetal adverse drug reactions and (3) outcomes of maternofetal exposure to contraindicated drugs, such as anticancer drugs, should be reported to pharmacovigilance institutions, including normal pregnancies, and ultimately reported to VigiBase. VigiBase was also previously investigated to address the fetal toxic effects of immune checkpoint inhibitors, for which no significant toxic effect was found …”

Section: Introductionmentioning

confidence: 99%

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

Gougis,

Grandal,

Jochum

et al. 2023

JAMA Netw Open

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ImportanceTargeted therapies directed against ERBB2 are the cornerstone of medical treatment for ERBB2-positive breast cancers but are contraindicated during pregnancy.ObjectivesTo 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 ParticipantsFor 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.ExposureThe exposure group was defined as reports that mention anti-ERBB2 agents compared with exposure to other anticancer agents.Main Outcome and MeasuresThe 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.ResultsA 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 &lt; .001), congenital respiratory tract disorders (ROR, 9.98 [95% CI, 2.88-34.67]; P &lt; .001), and neonatal kidney failure (ROR, 9.15 [95% CI, 4.62-18.12]; P &lt; .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 RelevanceIn 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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Immune Checkpoint Inhibitors and Pregnancy: Analysis of the VigiBase® Spontaneous Reporting System

Cited by 12 publications

References 49 publications

Immune Checkpoint Inhibitor Use During Pregnancy and Outcomes in Pregnant Individuals and Newborns

Immune Checkpoint Inhibitor Use During Pregnancy and Outcomes in Pregnant Individuals and Newborns

Suspected adverse reactions to medications and food supplements containing Serenoa repens: A worldwide analysis of pharmacovigilance and phytovigilance spontaneous reports

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

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