Association Between Fetal Safety Outcomes and Exposure to Local Podophyllotoxin During Pregnancy

Abstract

IMPORTANCEPodophyllotoxin is an antimitotic agent primarily used in the local treatment of anogenital warts. Data that enable the assessment of the fetal safety of podophyllotoxin use during pregnancy are lacking.OBJECTIVE To investigate the association between local podophyllotoxin exposure during pregnancy and risk of adverse fetal outcomes. DESIGN, SETTING, AND PARTICIPANTSThis cohort study obtained individual-level pregnancy data from various nationwide registries in Denmark from the study period of January 1, 1997, through December 31, 2016, resulting in a cohort of 1 650 649 pregnancies. Pregnancies with multiple records on overlapping dates and pregnancy records with implausible or missing information on gestational age were excluded. Local podophyllotoxin-exposed pregnancies were compared with unexposed pregnancies and matched in a 1:10 ratio according to propensity scores on a wide set of baseline characteristics. Five distinct study cohorts were constructed, one for each outcome analysis. Sensitivity analyses included a comparison of podophyllotoxin-exposed pregnancies with pregnancies with podophyllotoxin use only before pregnancy onset. Data analyses were performed from April 27, 2019, to June 26, 2019. EXPOSURES Filled prescription for local podophyllotoxin.MAIN OUTCOMES AND MEASURES Primary outcomes were major birth defects and spontaneous abortions. Secondary outcomes were preterm births, small-for-gestational-age (SGA) size, and stillbirths. Logistic regression was used to estimate the prevalence odds ratios (ORs) of major birth defects, preterm births, and SGA size, and Cox proportional hazards regression modeling was used to estimate hazard ratios (HRs) of spontaneous abortions and stillbirths. RESULTSThis study included 9229 pregnancies (mean [SD] maternal age at pregnancy onset, 27.7 [5.2] years) for the analyses of major birth defects and 18 590 pregnancies (mean [SD] maternal age at pregnancy onset, 26.4 [6.0] years) for the analyses of spontaneous abortions. Among the podophyllotoxin-exposed pregnancies, 29 infants (3.5%) were diagnosed with major birth defects, compared with 286 (3.4%) among the unexposed pregnancies. A total of 141 podophyllotoxin-exposed pregnancies (8.3%) ended in spontaneous abortion, compared with 1626 (9.6%) among the unexposed pregnancies. No statistically significant associations were found between podophyllotoxin exposure during pregnancy and major birth defects (prevalence odds ratio [OR], 1.02 95% CI, 0.69-1.50), spontaneous abortions (HR, 0.87; 95% CI, 0.73-1.04), preterm births (prevalence OR, 1.08; 95% CI, 0.86-1.35), SGA size (prevalence OR, 1.01; 95% CI, 0.85-1.22), or stillbirths (HR, 0.58; 95% CI, 0.18-1.86). Sensitivity analyses of the primary outcomes achieved similar results. CONCLUSIONS AND RELEVANCEFindings from this study suggest that podophyllotoxin use during pregnancy may be safe, as it did not appear to be associated with an increased risk of adverse fetal outcomes. These findings may help guide clinicians, patients, and drug regulatory authorit...

Clinical guideline for the diagnosis and treatment of cutaneous warts (2022)

“… 13 Podophyllotoxin and imiquimod were prohibited during pregnancy because their fetal teratogenic effect was grade C for pregnancy medication classified by FDA. 126 However, a cohort study 127 showed that there was no statistical relationship between podophyllotoxin exposure and nonexposure groups in birth defects, spontaneous abortion, preterm delivery, and stillbirth. The study concluded that the use of podophyllotoxin during pregnancy (the dose of podophyllotoxin was not specified in this cohort study, and exposure was based on the prescription of the drug) did not increase the risk of adverse fetal outcomes.…”

British association for sexual health and HIV national guideline for the management of anogenital warts in adults (2024)

“…At present, no self-applied topical agent is licensed for use during pregnancy or breastfeeding. Although recent safety data for imiquimod and podophyllotoxin are reassuring, 94,96 there is insufficient evidence to recommend either for routine use given the availability of safe and effective alternatives.…”

The role of intralesional immunotherapy in Condyloma Acuminata

“…The use of podophyllin is contraindicated in pregnancy. However, a recent analysis of 9229 pregnancies from January 1997 to December 2016 showed that podophyllotoxin didn't appear to be associated with an increased risk of adverse events to the fetus during pregnancy and is probably safe for use during pregnancy [38].…”