Tadalafil treatment for preeclampsia (medication in preeclampsia; MIE): a multicenter phase II clinical trial

Abstract

Purpose

To evaluate the effectiveness and safety of tadalafil treatment for hypertensive disorder of pregnancy (HDP).

Materials and methods

In an open-label, randomized clinical trial, singleton pregnancies with HDP between 20 and 33 weeks of gestation were randomized to take 20 mg oral tadalafil every day (tadalafil treatment group) or no drug (conventional treatment group). The primary outcome was prolongation of pregnancy from randomization to delivery. However, this article primarily focuses on the safety assessments performed in the tadalafil treatment for HDP population, because the safety of using PDE5 inhibitors as therapeutic agents for fetal growth restriction (FGR) has been a problem worldwide.

Results

From October 2016 to March 2018, 28 patients were randomized to each group and two cases were excluded (tadalafil treatment group: 12 cases; conventional treatment group: 14 cases). The significant adverse events related to tadalafil did not occur in the tadalafil treatment group. Among maternal adverse events, specifically with regard to headaches, there were significant differences between the two groups (0% in tadalafil group versus 43% in conventional treatment group; p = .02). There was no difference in the prolongation period of pregnancy that served as primary outcomes in both the groups (17.5 d in tadalafil group versus 16.5 d in conventional group, p = .96). The significant adverse events occurred at the same frequency as between the conventional treatment group and the tadalafil treatment group. And, maternal headache decreased significantly in the tadalafil treatment group.

Conclusions

Tadalafil treatment is safe for pregnant women with HDP. Moreover, tadalafil did not prolong the gestational period in pregnant women with HDP.

Keywords:

• Hypertension
• neonatal adverse events
• phosphodiesterase (PDE)-5 inhibitor
• preeclampsia
• tadalafil

Acknowledgements

We would like to thank the TADAFER participants, site investigators, research staff at the participating sites, and staff at the Mie University Clinical Research Support Center. We appreciate the assistance of Takashi Umekawa who made a great contribution to this study, but sadly passed away at a young age prior to completion of this study.

Disclosure statement

No potential conflict of interest was reported by the authors.

Author contributions

Conception and design of the study: Tomoaki Ikeda, Tadashi Kimura, Akihiko Sekizawa.

Analysis and interpretation of data: Yuki Nishimura and Toru Ogura.

Collection and assembly of data: Fumi furuhashi, Hiroaki Tanaka, Shintaro Maki, Shoichi Magawa, Masafumi Nii, Kayo Tanaka, Masayuki Endoh, Tadashi Kimura Tomomi Kotani, Akihiko Sekizawa and Tomoaki Ikeda.

Drafting of the article: Fumi Furuhashi and Hiroaki Tanaka.

Critical revision of the article for important intellectual content: Fumi Furuhashi and Hiroaki Tanaka.

Final approval of the article: Hiroaki Tanaka.

Additional information

Funding

This work was supported by the Japan AMED as the Project for Baby and Infant in Research of Health and Development to Adolescent and Young adult, Japan Society for the Promotion of Science KAKENHI [grant Number 17K16846], and in part by the Takeda Science Foundation. The authors declare no competing financial interests.