Nifedipine | Methylation Signal

Report from “International Workshop for Junior Fellows 2: Tocolytic treatment for prevention of preterm birth” at the 73rd Annual Congress of the Japan Society of Obstetrics and Gynecology

Tsuyoshi Murata1 , Yoko Aoyagi2, Hiroyuki Okimura3 and Akihiko Ueda4
1Department of Obstetrics and Gynecology, Fukushima Medical University School of Medicine, Fukushima, Japan
2Department of Obstetrics and Gynecology, Oita University, Oita, Japan
3Department of Obstetrics and Gynecology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
4Department of Gynecology and Obstetrics, Kyoto University, Kyoto, Japan

Abstract
At the 73rd Annual Congress of the Japan Society of Obstetrics and Gynecology, we discussed recent tocolytic treatments for the prevention of preterm birth with obstetricians from Korea and Taiwan. The rate of preterm birth in our countries has been increasing, and optimal tocolytic treatments are of great concern. Ritodrine hydrochloride was the ﬁrst available drug for tocolysis in our countries and is often administered for over 48 h, although it is not recommended for maintenance therapy in Western countries. Meanwhile, there are differences in the use of other
tocolytic drugs, based on approval of the drugs and the health insurance systems. Nifedipine and atosiban have not been considered ﬁrst-line agents in Japan. The long-term use of unnecessary tocolysis should be avoided, and the introduction of other tocolytic drugs, including nifedipine or atosiban, should be discussed.
Key words: Atosiban, Japan, Korea, magnesium sulfate, nifedipine, preterm birth, ritodrine hydrochloride, Taiwan, tocolytic treatment.

Introduction
The rate of preterm birth (PTB) is increasing world- wide, as well as in Japan.1,2 Prevention of PTB is a crucial issue for improving the prognosis of newborn babies. Tocolytic treatments in Japan are characterized by the frequent and long-term use of ritodrine hydro-
chloride and magnesium sulfate.3–5 However, these
drugs are associated with the risks of maternal and fetal side effects. Thus, appropriate use of tocolytic agents is required.
At the 73rd Annual Congress of the Japan Society of
Obstetrics and Gynecology, we discussed recent tocolytic

treatments for the prevention of PTB with Korean and Taiwanese doctors. Through these discussions, differ- ences in the use of tocolytic agents between the countries were revealed (Table 1). At the same time, we recog- nized several problems with tocolytic treatments in Japan. Here, we suggest a path for improving the man- agement of preterm labor (PTL).

Difference between Korea and Japan
The PTB rate in Korea has been increasing recently. In Korea, ritodrine hydrochloride and magnesium sulfate are prescribed to patients suffering from PTL, as in Japan. In addition, they can be administered atosiban,

Received: June 8 2021.
Accepted: July 20 2021.
Correspondence: Tsuyoshi Murata, Department of Obstetrics and Gynecology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan.
Email: [email protected]

Murata et al.

Table 1 Characteristics of tocolytic treatments in Korea, Taiwan, and Japan
Korea Taiwan Japan

Characteristics Long-term tocolysis is available but not recommended

Medications

Long-term tocolysis and hospitalization
are available

First choice Ritodrine hydrochloride Nifedipine
Second choice Atosiban

Ritodrine hydrochloride Ritodrine hydrochloride
Magnesium sulfate

Off-label use Magnesium sulfate
Nifedipine Atosiban

Nifedipine

which is not approved for use in Japan. Most Korean doctors believe that atosiban is an effective and safe drug. It has been reported that the frequency of mater- nal side effects and the rate of therapy discontinuation are lower for atosiban than for other drugs.6 However, this drug is expensive. Its use is also strictly limited in the National Health Insurance System in Korea. Thus, many Korean doctors prefer to use ritodrine hydro- chloride owing to its cost effectiveness and insurance coverage, as Japanese doctors do. Nifedipine is more frequently used in Korea than in Japan. In Japan, nifed- ipine is approved only for hypertension and ischemic heart disease under the National Health Insurance Sys- tem. The use of these two drugs, atosiban and nifedi- pine, for the prevention of PTB is more frequent in Korea than in Japan.

Difference between Taiwan and Japan
The PTB rate in Taiwan is also increasing.7,8 Tocolysis for abdominal tightness and short cervix and mainte- nance tocolysis are widely accepted. Ritodrine hydro- chloride is the most common treatment for PTL in Taiwan, similar to that in Japan. As per the recom- mendations, the clinical need for ritodrine hydrochlo- ride after 48 h needs to be reassessed, a practice also followed in Japan. Nifedipine is more frequently used in Taiwan than in Japan. However, nifedipine is not covered by insurance for PTL in both Taiwan and
Japan. In Taiwan, atosiban is sometimes used to treat PTL, and the therapeutic efﬁcacy of atosiban for PTL has been reported.9 However, atosiban is expensive and not covered by insurance. In both Japan and Tai- wan, the appropriate tocolytic agent for PTL is
selected based on gestation weeks, symptoms, and cost.

Problems of PTB prevention in Japan
Based on discussions with doctors from Korea and Tai- wan, we identiﬁed several problems regarding the cur- rent status of tocolytic treatments. First, it was found that not only in Japan but also in Korea and Taiwan,
obstetricians choose ritodrine hydrochloride as the ﬁrst drug for tocolysis and often use it for maintenance tocolysis for over 48 h,5 although it is not rec-
ommended for maintenance tocolysis globally because of its adverse maternal side effects.10–12 Because rit- odrine hydrochloride has been approved for tocolysis in our countries, it is quite natural for obstetricians to choose it as the ﬁrst-line treatment agent. Second,
nifedipine and atosiban, which are considered safe
tocolytic agents in Western countries,6,12,13 have not been considered ﬁrst-line agents in Japan because of the lack of approval. Although many Japanese obstetri- cians believe that nifedipine use in pregnant women with PTL is safe, off-label use of nifedipine would be a
major concern if used for tocolysis. Moreover, in addi- tion to the lack of approval issue, the high cost of atosiban would make it the last choice for tocolysis, as the cost is one of the most signiﬁcant factors in choos- ing a tocolytic agent. Overall, not only the evaluation
of the biological effects of tocolytic agents but also an assessment of a tocolytic agent in terms of its socioeco- nomic factors is needed. In addition, the evaluation of the effects of tocolytic agents on fetal and neonatal con- ditions may elucidate the utility of tocolysis.14,15

Suggestions from junior fellows
The PTB rate increased annually from 4.1% in 1980 to 5.3% in 2000 but has remained unchanged since then (5.6% in 2019) in Japan. Although Japan has failed to reduce the PTB rate further, the early neonatal mortal- ity rate remained low at 0.9% in 2019, which is among the lowest in the world.8 Long-term use of ritodrine

Report from IWJF 2

hydrochloride and magnesium sulfate is frequently used during long-term hospitalization, which is avail- able under the universal coverage health insurance sys- tem. Based on the discussions and problems listed above, we propose the following suggestions. First, the long-term use of unnecessary tocolytic agents should be avoided. Although ritodrine hydrochloride is tradi- tionally used and the cheapest among anti-PTB medi- cations in Japan, Korea, and Taiwan, considering the maternal adverse effects, the JSOG should continue to encourage short-term use of ritodrine. Second, the introduction of new anti-PTB medications, including nifedipine or atosiban, should be discussed. Approval of anti-PTB medications is a major encouraging factor in the use of these agents as treatment options. Further
research is needed on the safety, efﬁcacy, and cost-
effectiveness of anti-PTB medications in Japan, as well as on stratiﬁcation of high-risk patients to modulate the intensity of treatment levels.

Acknowledgments
We gratefully acknowledge Dr. Akihiko Sekizawa, Dr. Yoichi Kobayashi, Dr. Satoru Nagase, Dr. Yasuhisa Terao, Dr. Keiko Koide, Dr. Yoshimitsu Kuwabara, Dr. Masayuki Sekine, Dr. Hideaki Yahata, and Dr. Nozomu Yanaihara for the opportunity to discuss this novel issue of obstetrics and for their advice in the review of this manuscript. We also gratefully acknowl- edge Dr. Oh Jina from KSOG and Dr. Lee Howard Hao from TAOG for discussing recent trends of tocolytic treatments in our countries.

Conﬂict of interest
None declared.

Author Contributions
Tsuyoshi Murata, Yoko Aoyagi, Hiroyuki Okimura, and Akihiko Ueda contributed equally to this work.

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