Adverse Events During Pregnancy Associated With Entecavir and Adefovir: New Insights From a Real-World Analysis of Cases Reported to FDA Adverse Event Reporting System

Abstract

Background: Due to the embryotoxicity found in animal studies and scarce clinical data in pregnant women, it is still controversial whether entecavir (ETV) and adefovir dipivoxil (ADV) are safe during human pregnancy. This is of paramount importance when counseling pregnant women with hepatitis B virus (HBV) on risks and benefits to their offspring.Objective: To quantify the association between administration of ETV and ADV in pregnant women and occurrence of adverse events (AEs) during pregnancy (AEDP).Methods: Pregnancy reports from the FDA Adverse Event Reporting System (FAERS) were used to perform a retrospective analysis of AEDP associated with ETV or ADV. Disproportionality analysis estimating the reporting odds ratio (ROR) was conducted to identify the risk signals. A signal was defined as ROR value >2, and lower limit of 95% confidence interval (CI)> 1.Results: A total of 1,286,367 reports involving AEDP were submitted to FAERS by healthcare professionals. Of these, there were 547 cases reporting ETV and 242 cases reporting ADV as primary suspected drugs. We found a moderate or strong signal for increased risk of spontaneous abortion when comparing ETV with tenofovir disoproxil fumarate (TDF) and telbivudine (LdT), with RORs equal to 1.58 (95% CI, 1.09–2.30) and 2.13 (95% CI, 1.04–4.36), respectively. However, when the included reports were limited to indication containing HBV infection, no signals for increased AEDP were detected. Futhermore, a strong signal for increased risk of spontaneous abortion was identified in patients with HBV infection when comparing ETV or ADV with lamivudine (LAM), with RORs of 3.55 (95% CI, 1.54–8.18) and 2.85 (95% CI, 1.15–7.08), respectively.Conclusion: We found a strong signal for increased risk of spontaneous abortion in patients with HBV infection taking ETV or ADV, in comparison with those prescribed with LAM. Moreover, no obvious signal association of human teratogenicity with exposure to ETV or ADV was identified in fetuses during pregnancy. Nevertheless, owing to the limitations of a spontaneous reporting database, which inevitably contains potential biases, there is a pressing need for well-designed comparative safety studies to validate these results in clinical practice.

New Adverse Drug Reaction Signals from 2017 to 2021—Genuine Alerts or False Alarms?

“…After applying the inclusion and exclusion criteria, we found 56 new suspected ADRs arising from 24 drugs (involving a wide range of antibiotics, biologics and CNS drugs) [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35]. We then narrowed down the search to focus on more recent articles published within the years 2017-2021.…”

“…Table 2 gives full details of the drugs, new ADR signals as well as details of subsequent citing literature and any further detailed assessment of the ADR signal. After applying the inclusion and exclusion criteria, we found 56 new suspected ADRs arising from 24 drugs (involving a wide range of antibiotics, biologics and CNS drugs) [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35].…”

Safety of entecavir antiviral therapyduring an accidental pregnancy in patients with chronic hepatitis B

“…That is, accidental pregnancies for mothers with CHB treated with ETV in the first and second trimesters do not need to be terminated. No obvious association of human teratogenicity with exposure to ETV was reported in fetuses during pregnancy ( 21 ). However, previous studies have reported inconsistent results to the present study.…”

Hepatitis B and C in Pregnancy and Children: A Canadian Perspective

“…Indeed, in an Australian study, they found that brief exposure to lamivudine in pregnancy was associated with a high risk (19%) of developing lamivudine resistance [ 53 ]. Entecavir is not recommended in pregnancy due to possible teratogenicity in animals [ 54 ]. Most recently, the new formulation of TDF, tenofovir alafenamide (TAF) has also been studied in pregnancy.…”