Valproate is an anticonvulsant that was approved in the 1960s and is widely prescribed for the treatment of epilepsy and bipolar disorder^［1］. It increases the risk of major congenital malformations, such as neural tube defects and intellectual disability of the offspring, when administered to pregnant women^［2,3］. Therefore, pharmacological treatments with valproate should be avoided where possible in childbearing-aged and pregnant women with epilepsy and bipolar disorder^［2,4］. Considering that at least 40% of pregnancies are unplanned or unintended, as indicated by several epidemiologic studies^［5-7］, physicians, neurologists, and psychiatrists consulting patients with epilepsy and bipolar disorder should avoid prescribing drugs with a high risk of teratogenicity, especially valproate, in girls and women of childbearing age.

Yoshimura and his colleagues’ report^［8］shows that the number of valproate prescription for female outpatients of childbearing ages (15–49 years) was only slightly lower than that for male outpatients of the same ages in Japan during the fiscal year 2014 (April 2014 to March 2015) by using the publicly available National Insurance Claims Database (NDB Open Data Japan, Available from https://www.mhlw.go.jp/stf/seisakunitsuite/bunya/0000177182.html). Given that valproate is contraindicated in pregnant women as a general rule^［9］, this finding demonstrates the possibility that valproate prescription to girls and women in preconception period with due consideration of increasing the teratogenic risks was insufficiently implicated in Japan in 2014–2015. Therefore, the recent guidelines^［10-13］indicate that valproate prescription should be avoided for childbearing-age women with potential pregnancy as much as possible. However, there were few studies regarding changes of valproate prescription in Japan after the fiscal year 2014.

The present study aimed to evaluate the changes over time in valproate prescription to girls and women of childbearing age using the NDB Open Data, which was released after the previous research (2015–2020). Drugs used in the analysis is described in Table 1.

In this study, we used prescription data from April 2015 to March 2021 from the NDB Open Data Japan. We examined the available prescription data of valproate in female and male outpatient data classified as total childbearing (age: 15–49 years), younger childbearing (age: 15–29 years), older childbearing (age: 30–49 years), and non-childbearing age (age: ≥ 50 years). The odds ratio (OR) was defined according to a following method. The proportion of the number of tablets prescribed to women of childbearing age (15–29 and 30–49 years) to the number prescribed to women aged ≥ 50 years was compared with the odds of the case group. The proportion of the number of tablets prescribed to men in the same age group as women of the childbearing age to the number of tablets prescribed for men ≥ 50 years was compared with the odds of the control group. The OR was finally calculated using the odds of the case and control groups. Specifically, a drug with an OR > 1.000 was prescribed at a higher rate to women of childbearing age than it was to men of the corresponding age. In contrast, an OR < 1.000 indicated that the drug was prescribed at a lower rate to women of childbearing age than to men of the corresponding age.

Table 2 describes the number and percentage of valproic acid prescriptions by number of prescribed tablets and by gender and age groups. The proportion of valproate prescription for younger women of childbearing age (15–29 years) showed a significant downward trend from 2014 to 2020. In 2014, the proportion of valproate prescriptions for women aged 15-29 years was 15.4% in 2014. Subsequently, the proportion of valproate prescriptions for women of childbearing age (15–29 years) gradually decreased each year thereafter and was 13.8% (in 2015), 13.1% (in 2016), 12.4% (in 2017), 11.9% (in 2018), 11.2% (in 2019), and 11.1% (in 2020).

The proportion of valproate prescriptions for men aged 15–29 years slightly decreased; the proportion of valproate prescriptions was 16.6% (in 2014), 16.6% (in 2015), 16.5% (in 2016), 16.2% (in 2017), 15.9% (in 2018), 15.8% (in 2019), and 15.6% (in 2020). In contrast, the proportion of valproate prescriptions for women aged ≥ 50 years had dramatically increased: 46.5% (in 2014), 48.1% (in 2015), 48.6% (in 2016), 49.6% (in 2017), 50.5% (in 2018), 51.5% (in 2019), and 52.0% (in 2020). The proportion of valproate prescriptions for people aged 30–49 years did not change significantly in both men and women.

Figure 1 shows the odds ratio by total childbearing ［15–49 years］, younger childbearing ［15–29 years］, and older childbearing age［30–49 years］, respectively.

OR > 1.000 indicates that the drug is prescribed at a significantly higher rate to women of childbearing age (15–29 or 30–49 years) than to male outpatients of the corresponding age. Also Figure 1 shows that the OR of women of childbearing age (15–29 years) dramatically decreased from 2014 to 2019. However, from 2019 to 2020, it remained flat.

The present longitudinal study indicated that the proportion of valproate prescriptions for younger women of childbearing age［15–29 years］ decreased every year between 2014 and 2019. Our finding was consistent with the recent survey for general practitioners in UK, reporting a trend toward a decrease in the prescription of valproate to women of childbearing age from 2004 to 2018^［10］.

Because this study is an observational study using NDB open data and the causal relationship is unclear, the decreased use of valproate in younger women of childbearing age ［15–29 years］ for every year between 2014 and 2019 may be influenced by several factors, including concerns about its safety during pregnancy, changes in treatment guidelines, increased use of alternative medications, and improved patient education. Multiple academic societies, including the European Academy of Neurology, issued a statement on the need to limit the use of valproate in girls and women of childbearing potential with epilepsy^［11］. Additionally, the Japanese Society of Perinatal Mental Health in 2017 recommended limiting the use of valproate in girls and women of childbearing age^［12］ (Available from http://pmhguideline.com). In addition, after the conference of Japanese Society of Perinatal Mental Health, guideline of Japanese Society of Psychiatry and Neurology had been updated to warn the use of valproate during perinatal period^［13］. Also, concerns about the safety of valproate use during pregnancy have led to warnings from regulatory agencies, such as the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), Japan’s Ministry of Health, Labor and Welfare (Available from https://www.mhlw.go.jp/content/11121000/000486507.pdf) and, the Japanese Society of Perinatal Mental Health (Available from http://pmhguideline.com) about the increased risk of birth defects and developmental disorders in the offspring^{［11,12,14］}. These warnings have likely increased awareness among healthcare providers and patients about the potential risks associated with valproate use during pregnancy. As a result, healthcare providers may have become more cautious about prescribing valproate to women of childbearing age, and patients may have become more informed about the potential risks and more likely to request alternative treatments.

Changes in treatment guidelines may have also contributed to the decreased use of valproate in young women. For example, the American Academy of Neurology and the Japanese Society of Neurology recommend avoiding valproate as a first-line treatment in women of childbearing age and using alternative medications, such as lamotrigine, levetiracetam, or oxcarbazepine, instead^［16,17］. These guidelines are based on evidence showing that these alternative medications have lower risks of birth defects and developmental disorders in offspring, and they reflect a growing awareness of the risks associated with valproate use during pregnancy.

Increased use of alternative medications may have also played a role in the decreased use of valproate in young women. Several alternative antiepileptic drugs, such as lamotrigine and levetiracetam, have been shown to be effective in treating epilepsy and are considered safer for use during pregnancy^［18］. Studies have shown that these medications have lower risks of major congenital malformations and developmental disorders than valproate^［19］. The availability and efficacy of these alternative medications may have made healthcare providers and patients more willing to consider alternatives to valproate.

Improved patient education may also have contributed to the decreased use of valproate in young women. Patients may have become more informed about the potential risks associated with valproate use during pregnancy through increased awareness campaigns and patient education materials. This may have led to more informed decision-making among patients and their healthcare providers, resulting in a decrease in the use of valproate in women of childbearing age.

In summary, the trend of decreased use of valproate in young women is likely the result of a combination of factors, including concerns about the safety of valproate during pregnancy, changes in treatment guidelines, increased use of alternative medications, and improved patient education.

Limitation

The main limitation of this study was that the data presented were based on the numbers of prescribed valproate tablets obtained from the publicly accessible NDB, not on data on individual patients prescribed the drug. Additionally, the NDB open data discloses only the top 100 products, making it difficult to ascertain the total number of products (30 products in 2014). In the NDB open data, only the total administered dose data is available, making it impossible to distinguish between new prescriptions and continued prescriptions. Therefore, it is anticipated that the prescription count for valproic acid may be decreasing for new prescription cases. However, this cannot be conclusively determined in the present study.

Contributors

RS conducted data collection and data entry, performed the statistical analysis, and wrote the manuscript.DS and KY TH provided constructive comments and revised the manuscript. All authors read and approved the final manuscript.

Financial support

None.

Conflict of interest

All authors declare that there is no conflict of interest related to this study.

Ethical approval

This study did not require ethics approval because publicly available materials were used.

Data availability

Not applicable.