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Original Investigation
January 8, 2020

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

Author Affiliations
  • 1Department of Clinical Pharmacology, Copenhagen University Hospital Bispebjerg and Frederiksberg, Copenhagen, Denmark
  • 2Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
JAMA Dermatol. 2020;156(3):303-311. doi:10.1001/jamadermatol.2019.4315
Key Points

Question  Is local podophyllotoxin use during pregnancy associated with increased risk of adverse fetal outcomes?

Findings  In this cohort study of more than 1.6 million pregnancies in Denmark from 1997 through 2016, compared with propensity score–matched unexposed pregnancies, no association was observed between podophyllotoxin exposure during pregnancy and adverse fetal outcomes, including major birth defects, spontaneous abortions, preterm births, small size for gestational age, and stillbirths.

Meaning  This study found that use of local podophyllotoxin during pregnancy did not appear to be associated with increased risk of major birth defects, spontaneous abortions, preterm births, small-for-gestational-age size, and stillbirths.


Importance  Podophyllotoxin 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 Participants  This 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.

Results  This 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 Relevance  Findings 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 authorities when prescribing podophyllotoxin.

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