Available online 9 January 2023

Author links open overlay panelAbstractObjectives

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.

Introduction

The number of pregnant women with chronic hypertension, hypertension occurring before pregnancy or by week 20 of pregnancy, is increasing as a result of advanced maternal age and medical comorbidities in pregnancy [1], [2], [3]. Chronic hypertension is associated with an increased risk of adverse pregnancy outcomes [4], [5], while antihypertensive treatment may also be associated with adverse pregnancy outcomes [4], [6]. Meanwhile, no firm conclusions on the teratogenic risk of antihypertensives have been drawn [7]; thus, further evidence, especially on the teratogenic risk of antihypertensives in early pregnancy, is necessary. Our previous study implied that methyldopa and amlodipine were relatively frequently prescribed in the first trimester in Japan [8]. Unlike methyldopa, amlodipine is contraindicated in the Japanese package insert (JPI) [9] and is not recommended for pregnant women with chronic hypertension based on the Japanese Society of Hypertension guidelines (JSH 2019) [1], while it is only considered for pregnant women with inadequate responses to other antihypertensives in the Japanese obstetrical practice guidelines [10]. Given that the evidence on the teratogenic risk of amlodipine and methyldopa in early pregnancy is limited, an epidemiological study evaluating the risks would provide important evidence to support decision-making regarding their use in patients with chronic hypertension. The primary objective of this study was to evaluate the risk of major congenital malformations (MCMs) associated with first–trimester exposure to antihypertensives, including amlodipine and methyldopa. The prevalence of antihypertensive prescriptions during pregnancy in the last 10 years, until 2019, in Japan was additionally evaluated to provide the latest evidence.

Section snippetsData source

A large administrative claims database from JMDC Inc. (Tokyo, Japan) [11], which contained all the inpatient, outpatient, and pharmacy claims received from insurers, was utilized. These claims include diagnoses, surgical and medical procedures, and prescribed medications. All the data can be recorded even if a subject transfers hospitals or uses multiple facilities. Standardized disease classifications and anonymous record linkages were used in the database [11]. Further details regarding the

Antihypertensives prescribed during pregnancy in 2010–2019

Population 1 comprised 91,390 women (Figure 1). Their delivery dates were estimated based on the earliest dates of selected diagnoses and surgical procedures for 46,262 women (50.6%), the earliest dates of any other delivery-related entries for 8,416 women (9.2%), and the 15th day of the neonatal birth month for 36,712 women (40.2%). A term of 294 days was uniformly assigned as the gestational period to 1,402 women (1.5%) whose gestational period exceeded this value. The mean maternal age at

Discussion

HDP is one of the most common complications during pregnancy, and treatment with antihypertensives is common [8], [30], [31]. According to the Japanese guidelines, methyldopa, labetalol, nifedipine (at a gestational age of ≥ 20 weeks), and hydralazine are recommended for the treatment of HDP as a first choice [1], [10]. Unlike JSH 2019, which mentions that methyldopa is the most commonly used treatment for HDP [1], this study indicates that nifedipine has been most frequently applied in the

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

We wish to thank the Research Group for Health Administrative Data and JMDC Inc.

Funding

This work was supported by grants from the Ministry of Health, Labour, and Welfare of Japan (H23-iyaku-ippan-006) and the Japan Society for the Promotion of Science (19K09746 and 20K16070). The funders had no role in the study design, collection, analysis, interpretation of data, writing of the report, or the decision to submit the article for publication.

Ethics statement

This study was approved by the Institutional Review Board of Tohoku University School of Medicine on July 19, 2016

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© 2023 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.