Potential safety signal of pregnancy loss with vascular endothelial growth factor inhibitor intraocular injection: A disproportionality analysis using the Food and Drug Administration Adverse Event Reporting System.

Objectives: Intraocular administration of vascular endothelial growth factor (VEGF) inhibitors may be associated with pregnancy loss. However, little is known about intraocular anti-VEGF therapy during pregnancy. Here, we conducted a pharmacovigilance study using a spontaneous reporting database to evaluate the relationship between intraocular VEGF inhibitors and pregnancy loss. Methods: We used the JAPIC AERS database which is composed of the Food and Drug Administration Adverse Event Reporting System (FAERS) dataset preprocessed by the Japan Pharmaceutical Information Center (JAPIC) to investigate the VEGF inhibitors ranibizumab, aflibercept, and bevacizumab. Disproportionality analyses were conducted for VEGF inhibitors and pregnancy loss. The lower limit of the 95% confidence interval (CI) of the reporting odds ratio (ROR) > 1 and a minimum of three reported cases of pregnancy loss were the detection criteria used in the current study. Results: In the FAERS, 19 pregnancy loss cases were reported for ranibizumab with an ROR of 4.44 (95% CI: 2.42-8.16), 6 for intraocular bevacizumab with an ROR of 32.25 (95% CI: 3.88-267.9), and 4 for intraocular aflibercept with an ROR of 5.37 (95% CI: 1.34-21.49). All these drugs met the detection criteria. Conclusion: Potential safety signals of pregnancy loss were obtained from intraocular administration of VEGF inhibitors during pregnancy. These signals should be validated using a causal design study.

Pregnancy Loss Signal from Prostaglandin Eye Drop Use in Pregnancy: A Disproportionality Analysis Using Japanese and US Spontaneous Reporting Databases.

BACKGROUND: There is limited research regarding the use of glaucoma medicines during pregnancy. Prostaglandins contract uterine smooth muscle; however, it is not clear whether prostaglandin eye drops are associated with pregnancy loss in pregnant women. OBJECTIVES: We conducted a pharmacovigilance study using spontaneous report databases from Japan and the USA to evaluate the association between pregnancy loss and the use of prostaglandin eye drops during pregnancy. METHODS: The Japanese Adverse Drug Event Report database and the Food and Drug Administration Adverse Event Reporting System were used for analysis. Disproportionality analyses and a review of individual case safety reports were conducted. RESULTS: As for prostaglandin eye drops in pregnancy-related reports, there were eight reports involving latanoprost in the Japanese Adverse Drug Event Report database and no reports of pregnant women using other prostaglandin eye drops. In the Food and Drug Administration Adverse Event Reporting System, there were 25 reports involving latanoprost, 23 involving bimatoprost, 13 involving travoprost, and three involving tafluprost. The drug safety signal was detected during latanoprost usage and pregnancy loss. In the Japanese Adverse Drug Event Report database, there were five reports of pregnancy loss related to latanoprost, with a reporting odds ratio of 12.84 (95% confidence interval 3.06-53.86), and in the Food and Drug Administration Adverse Event Reporting System, pregnancy loss was reported in 12 cases of latanoprost usage with a reporting odds ratio of 4.35 (95% confidence interval 1.98-9.54). Uterine contractions were observed as concomitant adverse events in one case. CONCLUSIONS: Although a disproportionality analysis cannot determine causality, we need to keep an eye on the signal detected in this study. This signal should be validated using a causal design study.

Signal of Miscarriage with Aripiprazole: A Disproportionality Analysis of the Japanese Adverse Drug Event Report Database.

INTRODUCTION: With recent advances in medicines, many patients with schizophrenia have become able to conceive. One common second-generation antipsychotic given to patients with schizophrenia is aripiprazole. The label information of aripiprazole in Japan states that according to one case report "there is a report of miscarriage in clinical trial". OBJECTIVE: The aim of this study was to evaluate the relationship between aripiprazole and miscarriage by conducting a disproportionality analysis of an adverse drug event report database. METHODS: We conducted a disproportionality analysis of second-generation antipsychotic exposure during pregnancy using the Japanese Adverse Drug Event Report database, which is a spontaneous reporting database in Japan. We investigated aripiprazole and other approved second-generation antipsychotics in Japan. In accordance with the previous report, we created a data set for analysis consisting of pregnancy-related reports. RESULTS: A potential signal for miscarriage was detected for aripiprazole [proportional reporting ratio: 2.39, χ 2: 13.77, reporting odds ratio (95% confidence interval): 2.76 (1.62-4.69); n = 18]. In contrast, no potential signal for miscarriage was detected for other second-generation antipsychotics. CONCLUSION: Through our analysis of the Japanese Adverse Drug Event Report database, we found a potential signal for miscarriage for aripiprazole. Safety information on the use of aripiprazole during pregnancy is very limited. Therefore, we suggest that the potential signal detected in our analysis be explored further.

[Methodology for Estimating the Risk of Adverse Drug Reactions in Pregnant Women: Analysis of the Japanese Adverse Drug Event Report Database].

Safety information regarding drug use during pregnancy is insufficient. The present study aimed to establish an optimal signal detection method to identify adverse drug reactions in pregnant women and to evaluate information in the Japanese Adverse Drug Event Report (JADER) database between April 2004 and November 2014. We identified reports on pregnant women using the Standardised MedDRA Queries. We calculated the proportional reporting ratio (PRR) and reporting odds ratio (ROR) of the risk factors for the two known risks of antithyroid drugs and methimazole (MMI) embryopathy, and ritodrine and fetal/infant cardiovascular events. The PRR and ROR values differed between all reports in the JADER database and those on pregnant women, affecting whether signal detection criteria were met. Therefore we considered that reports on pregnant women should be used when risks associated with pregnancy were determined using signal detection. Analyses of MMI embryopathy revealed MMI signals [PRR, 159.7; ROR, 669.9; 95% confidence interval (CI), 282.4-1588.7] but no propylthiouracil signals (PRR, 1.98; ROR, 2.0; 95%CI, 0.3-15.4). These findings were consistent with those of reported risks. Analyses of fetal/infant cardiovascular events revealed ritodrine signals (PRR, 2.1; ROR, 2.1; 95%CI, 1.4-3.3). These findings were also consistent with reported risks. Mining the JADER database was helpful for analyzing adverse drug reactions in pregnant women.