Nationwide status of progestogen treatment to prevent spontaneous preterm birth: A questionnaire survey for childbirth healthcare facilities in Japan

This study aimed to investigate the current status of progestogen treatment for pregnant women at a high risk for preterm birth (PTB) in childbirth healthcare facilities in Japan.


INTRODUCTION
Preterm birth (PTB) is defined as birth before 37 weeks of gestation.In the reports on the global data of perinatal diseases in 2014, the estimated incidence of PTB was approximately 10%.There is a wide variation in PTB rates across different regions and countries. 1The incidence of PTB in Japan has been approximately 6% in the past couple of decades, categorizing Japan as one of the countries with the lowest incidence. 2Despite advances in perinatal medicine, there has been no improvement in the PTB rate.][5] Thus, an effective approach for reducing the incidence of sPTB is necessary in this field.
Recently, progestogens, cerclage, and vaginal pessaries are attracted as major treatments for prevention sPTB in high-risk women and have been discussed their target cases and preventive effect.Commonly, short cervical length (CxL) and a history of prior sPTB are regarded as major factors increasing the risk of PTB. 6 Cervical cerclage is a classical option for pregnant women with those risk factors.However, this method is an invasive intervention, requiring anesthesia and surgery.][9][10] Prevention of sPTB in high-risk women by progestogen treatment is recommended by the clinical guidelines in several countries. 6Increasing evidence has proposed progestogen therapy can be another option. 6mong several modalities of progestogen treatment, intramuscular administration of 17α-hydroxyprogesterone caproate (17-OHPC) and vaginal administration of natural progesterone (VP) are the most intensively examined for their efficacy.A recent meta-analysis of randomized controlled trials showed the efficacy of both vaginal progesterone and 17-OHPC for prevention of PTB before 34 weeks' gestation in high-risk singleton pregnancies. 11According to another report using network meta-analysis techniques, 12 vaginal progesterone has clear evidence for preventing PTB before 34 weeks of gestation, whereas the evidence on 17-OHPC is relatively weak.Thus, there is some controversy regarding the efficacy of 17-OHPC in PTB prevention.In fact, a recent randomized controlled study demonstrated that 17-OHPC did not decrease recurrent PTB <35 weeks in women with a history of sPTB. 13nder the health insurance system in Japan, 17-OHPC is the only drug approved for pregnant women with a risk of miscarriage or PTB.As a serious problem, there is a gap in 17-OHPC usage between the approved dose (125 mg/week) under the Japanese insurance rule and the common dose for sPTB prevention (250 mg/ week).Moreover, the drug supply of 17-OHPC in Japan was stopped.Despite that, VP still has not been approved for the prevention of sPTB by the Japanese universal health insurance system.This situation presents a significant dilemma for obstetricians in Japan, and new solutions need to be found based on the opinions of Japanese obstetricians.
With this background, we conducted a nationwide survey of progestogen treatment for PTB prevention, aiming to confirm the necessity of future action to solve this contradiction of the drug regulation and insurance system related to progestogen use in Japan.

METHODS
This study was approved by Institutional Research Ethics Board of Nippon Medical School (B-2022-530) and was conducted in accordance with the provisions of the Declaration of Helsinki.Informed consent for each subject was not applicable in this study, because of the lack of sensitive personal information.
We sent an invitation through the mail to Japanese perinatal healthcare facilities listed by the Japanese Association of Obstetricians and Gynecologists (n = 2097) to participate in our online survey about progestogen use for preventing PTB.The responses were obtained from one representative obstetrician per facility.The analysis was conducted by classifying the facilities into perinatal medical centers, general hospitals, and private maternity clinics.
The questionnaire was composed of questions investigating the policies of progestogen usage in pregnant women at risk of PTB from 2019 to 2021.The type of progestogens used, patient selection criteria, and gestational period to start the prophylactic or therapeutic administration were asked in the survey.In addition, facilities that did not use progestogen for the prevention of PTB were questioned regarding their reason for not doing so.

Characteristics of participating institutions
Responses were received from 528 facilities (25.1%) among 2097 perinatal facilities managing childbirth in Japan.The distribution of the facility types among the participating facilities was as follows: perinatal medical centers (n = 155, 29.4%), general hospitals (n = 134, 25.4%), and private maternity clinics (n = 239, 45.3%).As a consequence, 92.3% of the total 168 perinatal medical centers in Japan were covered in this survey.

Prophylaxis and therapy using progestogens for pregnancies with a high risk of sPTB
In total, 528 institutions responded to the first question asking whether progestogens were used for pregnant women at high risk of sPTB (Table 1).In the responses, progestogens were used in 207 (39.2%) institutions, whereas they were not used in 297 (56.3%) institutions.Twenty-four institutions (4.5%) discontinued usage of progestogens within the last 3 years before this survey.Among the institution types, progestogens were utilized in 53.5% (n = 83) of perinatal medical centers, 33.6% (n = 45) of general hospitals, and 33.0%(n = 79) of private maternity clinics.
Table 2 showed the uses of different types of progestogen by facility type currently.Regarding the types of progestogens, 17-OHPC had been used in 170 institutions (82.1%).VP had been used in 20 institutions (9.7%) and oral progesterone (OP) in 17 institutions (8.2%).Sixteen institutions had used both 17-OHPC and VP, and five institutions used both 17-OHPC and OP.No clear trend related to facility classification was observed regarding the types of progestogens used.

Responses to the questions about 17-OHPC
Details of the facility-specific protocol for PTB prevention using 17-OHPC were investigated among the institutions using 17-OHPC (n = 170).Regarding prophylactic use, 17-OHPC use was indicated for women with a history of previous sPTB (74 institutions, 43.5%) or with an asymptomatic short cervix (48 institutions, 28.2%).17-OHPC was used in 64 institutions (37.6%) for therapeutic purposes in patients presenting with an increased risk of sPTB and some symptoms, including subjective uterine contractions, mild uterine bleeding, and cervical change.In 43 institutions (25.4%), the usage of progestogens was determined based on the individual judgment of the physicians.
The timing to initiate and end prophylactic use during pregnancy was analyzed from the responses of 170 institutions.The upper limit to start prophylactic progestogens was 16 weeks of gestation (WG) in 37.1% of institutions and 22 WG in 4.1% of institutions.In 48.2% of facilities, that upper limit was decided by physician discretion.The gestational weeks to stop progestogen usage was set at 24 WG in 7 institutions, at 28 WG in 5 institutions, at 34 WG in 36 institutions, and at 37 WG in 28 institutions.Individual physicians judged the timing for ending usage in 29 institutions.The criteria of CxL to start prophylaxis was assessed in the responses from 125 institutions.17-OHPC was used at CxL <15 mm in 3.5% of institutions, CxL <20 mm in 19.4% of institutions, CxL <25 mm in 35.5% of institutions, and CxL <30 mm in 8.8% of institutions.Uniform criteria among the physicians had not been set in 6.5% of institutions.The dosage of 17-OHPC was as follows: 125 mg/week in 107 of institutions (62.9%), 250 mg/week in 61 institutions (35.9%), and other doses in 2 institutions (1.2%).These results are presented in Figure 1.

Responses to the questions about VP
Details of the clinical management of pregnant women at high risk for sPTB using VP were investigated from the responses of 36 institutions.As for prophylactic use, VP was indicated for women with a history of previous sPTB in 15 institutions (41.7%), and with an asymptomatic short cervix in 15 institutions (41.7%).VP was used for therapeutic purposes in symptomatic women in 10 institutions (27.8%).In three institutions, the indication to use VP was based on the individual decision of the physicians.
The timing to initiate and end prophylactic use during pregnancy was analyzed from the responses of 33 institutions.The upper limit to start prophylactic progestogens was 16 WG in 10 institutions (27.8%) and 22 WG in 5 institutions (13.9%).There were no unified criteria shared among physicians in 18 institutions (50.0%).The criteria of CxL to start prophylaxis was assessed in the data from 31 institutions.VP was used at CxL <15 mm in 2 institutions (5.6%), CxL <20 mm in 11 institutions (30.6%),CxL <25 mm in 15 institutions (41.7%), and CxL <30 mm in 3 institutions (8.3%).The dosage of VP was as follows: 100 mg/day in 4 institutions (11.1%), 200 mg/week in 26 institutions (72.2%), 400 mg/day in 1 institution, and 200-600 mg/day in 1 institution.These results are presented in Figure 2.

Analysis of the institutions that had not introduced progestogens into sPTB management
As mentioned above, 297 institutions, (56.7% of the total responding facilities) had not yet introduced any  progestogen for prevention of sPTB.Twenty-four institutions had stopped progestogen treatment within the last 3 years before this survey.Among the 321 institutions not using progestogen currently, the prospect to start or restart progestogen treatment was asked.A total of 136 facilities (42.4%) responded that they did not intend to use progestogen in the future.Twenty-four facilities (7.5%) were considering using 17-OHPC after the trouble in domestic supply of 17-OHPC settles down.A total of 126 facilities (39.3%) were hoping to use VP if its usage for sPTB prevention would be approved by the insurance system or applying for off-label use to the ethics committee.Seven centers (2.2%) expressed a preference to use any progestogen, conditional on insurance coverage approval (Table 3).

Influence of 17-OHPC outage
Discontinuation of 17-OHPC supply was scheduled in Japan for February 2022.Some institutions still had stock during this investigation; however, it was expected that 17-OHPC will be difficult to obtain before too long.A total of 170 institutions responded to the question asking the impact of the shortage, and 55.9% (n = 95) of the facilities responded that they were significantly affected by the suspension of the domestic supply of 17-OHPC, while 44.1% (n = 75) responded that they were not affected.A major reason (89.3%, n = 67 in 75) for denying the influence of 17-OHPC shortage was due to the limited number of pregnancies necessitating sPTB prevention.
Among the 95 facilities that reported being impacted by the shortage in their daily practice, 50.5% (n = 48) indicated that they hoped to use VP when VP usage becomes approved under the Japanese insurance system in the future.The institutions that were planning to start VP for sPTB prevention immediately, even without coverage by health insurance was limited to 12.6% (n = 12).Switching to oral progestin (OP) as a substitute for 17-OHPC was considered as a possible solution by 14.7% (n = 14).
Among the 75 facilities not affected by the 17-OHPC shortage, 4 facilities (5.3%) were planning to start using VP for high-risk sPTB, while 23 facilities (30.6%) expressed hopes to use VP in the future if its usage becomes approved under the Japanese insurance system.

DISCUSSION
In the present study, we surveyed the current situation and the problems in obstetric practice regarding the use of progestogen for prevention of sPTB in Japan.Progestogen was used in 39.2% of the responded institutions surveyed, and 17-OHPC was used in 87.4% of them.VP was used only in 15.4% of the institutions surveyed, although there were many facilities that recognized the benefits of VP and were hoping to use it.More than half of the facilities (59%) indicated concern that the upcoming discontinued supply of 17-OHPC in Japan would cause serious problems with the clinical management of pregnant women at a high risk of sPTB.
The efficacy of progestogen for sPTB prevention has been investigated by numerous randomised control trials (RCTs) in the past few decades, vaginal progesterone and intramuscular administration of 17-OHPC are representative progestogens for which the evidence have been accumulated extensively. 11,12The International Federation of Gynecology and Obstetrics recommends the use of those progestogens for pregnant women at high risk for PTB with a prior history of PTB and a short cervix. 14espite the global trend, this study showed that only 39.2% of perinatal facilities in Japan currently use progestogen for PTB prevention.In Japan, about half of deliveries are managed in private maternity clinics and the other half in tertiary medical facilities, such as perinatal medical centers and general hospitals.This study indicated that the use of progestogen for PTB prevention is less frequent in private clinics than in tertiary medical facilities (Table 1).More importantly, 42.4% of the facilities that did not use progestogens responded that they did not plan to start using them in the near future.It is possible that the current evidence on the efficacy of progestogen is not well understood among medical workers in primary perinatal facilities.Considering prophylactic administration should be done regardless of the type of medical facility, it is necessary to take actions to update the knowledge about the prevention approach for PTB among all types of perinatal facilities.In Japan, usage of intramuscular 17-OHPC for women at risk for PTB is approved under the public health insurance system, whereas VP has not yet been approved for PTB prevention.In light of this, the present survey showed that 17-OHPC, but not VP, was used in the majority of the institutions utilizing progestogen for sPTB prevention.There is some controversy regarding the efficacy of 17-OHPC for sPTB prevention, since its effectiveness is inconsistent among the outcomes of previous RCTs.An initial report on PTB prevention using 17-OHPC by Meis et al. demonstrated a substantial reduction in the rate of recurrent preterm delivery among women at high risk for sPTB. 15On the contrary, 17-OHPC did not decrease the rate of recurrent PTB before 35 WG in women with a history of previous sPTB in a recent multicenter RCT (the PROLONG study). 13herefore, it is generally thought that the efficacy of 17-OHPC is limited compared with VP. 12 Therefore, the European Medicines Agency has not approved 17-OHPC for PTB prevention.Additionally, FDA approval for 17-OHPC (Makena ® ), a drug used to reduce risk of sPTB, was formally withdrawn in April 2023.16 In this context, the situation in Japan where insurance coverage is restricted to 17-OHPC without approval of VP for PTB prevention is inconsistent with global trends.
Another problem with regard to 17-OHPC in Japan is the usable dosage under the regulation of the public health insurance system.A dosage of 250 mg/week is common in past studies showing the efficacy of 17-OHPC. 17However, under the regulation of Japanese public health insurance, the upper limit of the 17-OHPC dosage is 125 mg/week.With this regulation, the dosage of 17-OHPC used was 125 mg/week in more than half of the facilities (55.3%) in the present study.There is a concern that the dosage restrictions imposed by the insurance system hinder sufficient efficacy of 17-OHPC.
Accumulating evidence suggests that prophylactic use of VP is one of the efficient approaches for PTB prevention, although there are discrepancies in recommendations for the similar risk population among the other clinical guidelines.The National Institute of Clinical Excellence in the United Kingdom 18 recommends to offer VP or cervical cerclage to women who have both of a history of sPTB and a short cervix at 16 + 0 to 24 + 0 WG.The American College of Obstetricians and Gynecologists 19 recommends VP for asymptomatic short CxL without a history of PTB.Compared with VP, lower levels of recommendation are given to 17-OHPC in those clinical guidelines.At all events, recent systematic reviews 12,20 have demonstrated that the evidence on the efficacy for PTB prevention by 17-OHPC is less credible than that for VP.In Japan, a multicenter, double-blind, randomized trial reported that prophylactic vaginal progesterone for women with mild cervical shortening reduced PTB. 21However, the use of VP is limited to luteal support in the procedure of assisted reproductive technologies under the pharmaceutical affairs law in Japan.Since the use of VP for PTB prevention has not yet been approved under Japanese law, 17-OHPC is the only drug choice available for prophylaxis of PTB.This survey revealed that there is a strong desire to use VP for prevention of PTB among Japanese obstetricians since hope to use of VP is presented in 51.1% (n = 87 in 170) of the facilities currently using 17-OHPC and 39.3% (n = 126 in 321) of the facilities that had not conducted PTB prevention by progestogen.The discrepancy between medical evidence and the legal regulation on drug approval poses a dilemma for Japanese obstetricians.
In addition, cervical cerclage is recognized by the public health insurance system in Japan for prevention of sPTB with patients presenting with a short cervix or cervical incompetency.A small number of studies 22,23 had directly compared the administration of VP versus cervical cerclage to prevent sPTB.However, Conde-Agudelo et al. 24 conducted a study by new indirect meta-analysis that demonstrated no statistically significant differences between VP and cerclage in preventing PTB <35 and <32 WG and composite perinatal morbidity/mortality in women with a singleton gestation, previous sPTB, or second-trimester short cervix by ultrasonography.Although cervical cerclage is recognized by the public health insurance system for women with high-risk sPTB, this method is an invasive intervention, requiring anesthesia and surgery.Physicians and high-risk women can make a choice for either VP or cerclage for the prevention of sPTB based on individual medical conditions, if VP will be approved as a medical treatment for sPTB in the future in Japan.
In this study, the survey was conducted by sending a post-mail asking to complete the online questionnaire to an invitation to perinatal healthcare facilities listed by the Japanese Association of Obstetricians and Gynecologists.In the requested information, we asked one obstetrician to answer questions on behalf of the facility.If we requested each member of The Japanese Association of Obstetrics and Gynecology to complete a questionnaire, several physicians in one institution may have answered.We selected postal mail as the means of obtaining only one answer from each institution.Consequently, 25.2% (528/2097) of the facilities managing the request responded to the questionnaire representing each facility.The response rate in this study had dropped low level.We could not send reminders for the completion of this questionnaire because of the cost of postal mail.That may be one of the reasons for the low response rate.This low response rate among all types of obstetric facilities could be a limitation of this study.However, it should be noted that the response rate among perinatal medical centers was high (92.3%:155/165).Considering that perinatal medical centers mainly manage pregnancies at high risk for PTB, the data obtained from this survey met the purpose of understanding the current situation about

T A B L E 1
Usage of progestogen for prevention or treatment of sPTB in the past 3 years.

F I G U R E 1
The current state of 17-OHPG usage.(a) Indications for the use 17-OHPC (selecting all that apply).(b) Gestational weeks of treatment initiation for prevention sPTB.(c) Cervical lengths at treatment initiation for cervical shortening.(d) Dosage of 17 OHPC.17-OHPC; 17α-hydroxyprogesterone caproate; sPTB; spontaneous preterm birth.F I G U R E 2 The current state of natural vaginal progesterone.(a) Indications for the use VP (selecting all that apply).(b) Gestational weeks of treatment initiation for prevention sPTB.(c) Cervical lengths at treatment initiation for cervical shortening.(d) Dosage of VP. sPTB; spontaneous preterm birth; VP; natural vaginal progesterone.

T A B L E 3
Prospective progestogen use for high-risk sPTB women at currently non-prescribing facilities.
The use of the progestogen types currently categorized by facility (selecting all that apply).
Abbreviation: sPTB, spontaneous preterm birth.T A B L E 2 Hoping to use VP with approval of health insurance (or applying for off-label use to the ethics committee)