Risk of major congenital malformations associated with first-trimester antihypertensives, including amlodipine and methyldopa: A large claims database study 2010-2019

Tomofumi Ishikawa; Hidekazu Nishigori; Manabu Akazawa; Keiko Miyakoda; Aoi Noda; Mami Ishikuro; Hirohito Metoki; Noriyuki Iwama; Masatoshi Saito; Junichi Sugawara; Hiroshi Kawame; Nobuo Yaegashi; Shinichi Kuriyama; Nariyasu Mano; Taku Obara

doi:10.1016/j.preghy.2023.01.001

Risk of major congenital malformations associated with first-trimester antihypertensives, including amlodipine and methyldopa: A large claims database study 2010-2019

Pregnancy Hypertens. 2023 Mar:31:73-83. doi: 10.1016/j.preghy.2023.01.001. Epub 2023 Jan 9.

Authors

Affiliations

¹ Laboratory of Biomolecule and Pathophysiological Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.
² Fukushima Medical Center for Children and Women, Fukushima Medical University, Hikarigaoka, Fukushima 960-1295, Japan.
³ Department of Public Health and Epidemiology, Meiji Pharmaceutical University, 2-522-1, Noshio, Kiyose, Tokyo 204-8588, Japan.
⁴ Clinical & Translational Research Center, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan.
⁵ Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8573, Japan; Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.
⁶ Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8573, Japan; Environment and Genome Research Center, Graduate School of Medicine, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8573, Japan.
⁷ Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8573, Japan; Division of Public Health and Hygiene, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, 1-15-1 Fukumuro, Miyagino-ku, Sendai, Miyagi 983-8536, Japan.
⁸ Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8573, Japan; Department of Gynecology and Obstetrics, Graduate School of Medicine, Tohoku University, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.
⁹ Department of Gynecology and Obstetrics, Graduate School of Medicine, Tohoku University, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.
¹⁰ Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8573, Japan; Environment and Genome Research Center, Graduate School of Medicine, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8573, Japan; Department of Gynecology and Obstetrics, Graduate School of Medicine, Tohoku University, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.
¹¹ Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8573, Japan; Department of Clinical Genetics, The Jikei University Hospital, 3-19-18 Nishi-Shimbashi, Minato-ku, Tokyo 105-8471, Japan.
¹² Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8573, Japan; Environment and Genome Research Center, Graduate School of Medicine, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8573, Japan; International Research Institute for Disaster Science, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8573, Japan.
¹³ Laboratory of Biomolecule and Pathophysiological Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan; Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.
¹⁴ Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8573, Japan; Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan; Environment and Genome Research Center, Graduate School of Medicine, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8573, Japan. Electronic address: obara-t@hosp.tohoku.ac.jp.

PMID: 36646019
DOI: 10.1016/j.preghy.2023.01.001

Abstract

Objectives: To evaluate the major congenital malformation (MCM) risk of first-trimester antihypertensive exposure, specifically of amlodipine and methyldopa.

Study design: A large administrative claims database was used.

Main outcome measures: The prevalence of antihypertensive prescriptions during pregnancy was described in 91,390 women giving birth between 2010 and 2019. The MCM risk of first-trimester antihypertensives was evaluated in 1,185 women diagnosed with hypertensive disorders in the first trimester. The MCM risk of first-trimester amlodipine and methyldopa was evaluated in 178 women who were prescribed antihypertensives in the first trimester.

Results: Antihypertensives were prescribed to 278 (0.30%) women during their first trimester. The prescription prevalence in the first trimester was highest for methyldopa (115, 0.13%), followed by amlodipine (55, 0.06%). Antihypertensives were prescribed to 2,955 (3.23%) women during pregnancy. Nifedipine (903, 0.99%) and nicardipine (758, 0.83%) were the most frequently prescribed oral and injectable antihypertensives during pregnancy, both with a significant increase in annual prevalence. Of the 1,185 women diagnosed with hypertensive disorders in the first trimester, antihypertensives were prescribed to 178 women. The adjusted odds ratio (aOR) of MCMs in the first-trimester prescription of any antihypertensive medication was 1.124 (95% confidence interval [CI], 0.618-2.045). Amlodipine and methyldopa were prescribed to 44 and 93 of the 178 women, respectively. The aORs of MCMs in the first-trimester prescription of amlodipine and methyldopa were 1.219 (95% CI, 0.400-3.721) and 0.921 (0.331-2.564), respectively.

Conclusions: The MCM risk of first-trimester exposure to antihypertensives, including amlodipine and methyldopa, was not suggested.

Keywords: Amlodipine; Antihypertensive; Birth defects; Methyldopa; Pregnancy; Teratogenicity.

MeSH terms

Amlodipine / therapeutic use
Antihypertensive Agents / therapeutic use
Female
Humans
Hypertension, Pregnancy-Induced* / drug therapy
Male
Methyldopa / therapeutic use
Pre-Eclampsia* / drug therapy
Pregnancy
Pregnancy Trimester, First

Substances

Antihypertensive Agents
Methyldopa
Amlodipine