Changes in preterm and extremely preterm birth rates in Japan after the introduction of obstetrical practice guidelines in 2008

Obstetrical guidelines were established in Japan in 2008, and obstetrical diagnoses and treatments were subsequently standardized nationally. We examined changes in the preterm birth rate (PTBR) and extremely preterm birth rate (EPTBR) following the introduction of such guidelines.


INTRODUCTION
In Japan, evidence-based medicine has been recommended since the 2000s. In 2008, clinical practice guidelines in obstetrics were created. 1 Since then, the guidelines have been revised every 3 years to 2020. [2][3][4][5] In obstetrics, we anticipated that the implementation of such guidelines would lead to a reduction in the preterm birth rate (PTBR). In particular, the following four clinical items in the guidelines were thought to have the greatest impact on the PTBR: First, CQ301 (cervical insufficiency): In 2008, if cervical insufficiency was suspected in a previous pregnancy, careful follow-up or a prophylactic cervical cerclage was performed. For an existing pregnancy, careful follow-up or a therapeutic cervical cerclage was performed. In 2017, a change was made such that if follow-up was selected and cervical shortening observed, a therapeutic cervical cerclage was required. However, if signs of infection were found, in principle, treatment of the infection was given priority. 6 In addition, although a retrospective study, a paper described the effect of therapeutic cervical cerclage on the prolongation of pregnancy in cases of prolapsed fetal membranes. 7 Progesterone therapy has been described since 2014. However, the therapy is not covered by health insurance in Japan and, therefore, it was rarely implemented up to 2020. 8 Second, CQ302 (preterm labor): Attention has been drawn to chorioamnionitis. As for tocolytic agents, ritodrine hydrochloride has been used from April 1986, magnesium sulfate from 2006, and nifedipine from 2017. 4 Third, CQ303 (PROM): Pregnant women <34 gestational weeks (GWs) were managed with antibiotics between 2008 and 2020. Since 2011, if clinical chorioamnionitis is diagnosed at ≧26 GWs labor and delivery should be attempted within 24 h without waiting for a natural labor otherwise a cesarean section is then performed. 2 Finally, CQ601 (bacterial vaginosis: BV): It was consistently stated that no evidence existed that BV screening and the subsequent treatment of all pregnant women prevented preterm births from 2008 to 2020. [9][10][11] In 2008, the treatment of pregnant women with symptomatic BV using antibiotics was recommended. 1 In 2011, BV testing was promoted for all women with known high-risk factors for preterm delivery, such as a previous preterm delivery, and patients with BV were to be treated using antibiotics as soon as possible. 2 In addition, our papers are cited, in which it was reported that the prevalence of BV during pregnancy exceeded 20% in 2000, 2,12 as well as that the risk of therapeutic cervical cerclage was low in facilities providing screening and treatment for all pregnant women with BV. 2,13 In 2017, if BV screening and treatment were performed to prevent preterm births, it was required to be done before 20 GWs; those who were found to be positive were treated with antibiotics. 4,14 In other words, room has existed for the screening and treatment of all pregnant women with BV to prevent preterm birth at the physician's discretion since 2008.
In addition to the development of obstetrical guidelines, it has been pointed out that factors affecting the premature birth rate in Japan include an increase in births in older mothers, an increase in part-time workers (nonregular workers), and an increase in assisted reproductive technology (ART). [15][16][17] The premature birth rate for multiple pregnancies was high, [16][17][18] such that in April 2008, the Japan Society of Obstetrics and Gynecology (JSOG) decided that the number of embryos to be transferred in ART should be only one on principle to prevent multiple pregnancies. 19 To examine these effects, we investigated the aging of pregnant women, the employment rate of women of reproductive age, and the increase in ART.
With the development and enforcement of these obstetrical guidelines, and with regard to late childbearing, women's social advancement, and the development of ART, has the PTBR really decreased? We examined chronological changes in the PTBR and extremely preterm birth rate (EPTBR) in Japan from 1979 to 2021 and compared their frequencies with those in other countries. We also report on whether a difference in the PTBR and EPTBR from 2007 to 2020 exists in the eight regions of Japan.

Data
Data for examining the PTBR and EPTBR over the 43 years from 1979 to 2021 in Japan were obtained from a database found on a website of the Japanese Ministry of Health, Labour and Welfare (JMHLW). 20 The PTBR and EPTBR in the eight regions of Japan for the 14 years from 2007 to 2020 were analyzed by order-made tabulation provided by the JMHLW. [21][22][23] We defined a PTBR as <37 GWs/live birth, and an EPTBR as <28 GWs/live birth. 24,25 The average ages at which mothers gave birth to their first, second, and third children, 26 the birth rates by fiveyear age group at reproductive age 27 and data on the employment rate and status of women 28,29 were obtained from the websites of the JMHLW and Japanese Ministry of Internal Affairs and Communications (JMIAC). Data on ART were obtained from the JSOG website. 30

Statistical analysis
A regression coefficient method was used to test chronological changes in the whole country between 1979 and 2021, and in each of the eight regions and the national average between 2007 and 2020. A general linear model by repeated measures analysis of variance (RM-ANOVA) was used to compare PTBRs and EPTBRs of the eight regions and the national average from 2007 to 2020. Comparisons between each region and the national average were adjusted by Tukey's multiple comparison method.
For statistical analyses, SPSS Statistics 25 (IBM Corporation) was used for a general linear model by RM-ANOVA, and EZR (Saitama Medical Center, Jichi Medical University) was used for an analysis of covariance to test slopes of the regression equation and Fisher's exact test. Microsoft Excel 2019 was used to draw graphs.

Approval by institutional review board
No ethics approval was necessary because studies were conducted for public health purposes using publicly available national surveillance data from JMHLW, JMIAC, and JSOG.

Chronological changes in the national PTBR and EPTBR between 1979 and 2021
Total live births from 1979 to 2021 were 50 706 432. The average PTBR was 4.96% and the average EPTBR was 0.206% (Table 1). The PTBR significantly increased by 2%, from 3.8% to 5.8%, from 1979 to 2007 ( p < 0.001). From 2008, the PTBR decreased significantly until 2020 ( p < 0.001) but increased in 2021 (Figure 1a). The EPTBR significantly increased by over twofold from 0.114% to 0.263% from 1979 to 2007 ( p < 0.001); however, this showed a significant decrease from 2008 until 2019 ( p = 0.02) but then increased in 2020 (Figure 1b). Thus, PTBRs and the EPTBR significantly decreased over the subsequent 13 years since the 2008 obstetrical guidelines were developed.
Chronological changes and differences in PTBR and EPTBR in the eight regions and the national average between 2007 and 2020 The total number of live births in Japan between 2007 and 2020 was 13 997 363. Excluding foreigners with unknown birthplaces and cases with unknown delivery weeks, target cases were 13 992 420 (Table S1) (Table S2).
The PTBRs and EPTBRs for each year in the eight regions are shown in Tables 2a and 2b, respectively  (Tables S3a and S3b). Figure 2a,b shows chronological changes in the PTBR and EPTBR for the average of the whole country and the eight regions of Japan. The national PTBR in Japan decreased significantly from 2007 to 2020 as determined using regression coefficients ( p < 0.001). With respect to the eight regions, Kanto, Chubu, Kinki, Shikoku, and Kyushu showed significant regression lines ( p = 0.007, p = 0.013, p = 0.002, p = 0.002, and p = 0.002, respectively); PTBRs were significantly decreased.
The national EPTBR in Japan showed a significant decrease ( p = 0.02) from 2007 to 2019 but increased in 2020. Therefore, the 14-year regression curve became nonsignificant ( p = 0.084) and the significant downward trend in EPTBR did not continue. Of the eight regions, only Kinki showed a significant decrease ( p = 0.003).
The average PTBR for the last 14 years in Japan was 5.68% (Table 2a). Table 3a shows the results of multiple comparisons using Tukey's method and a general linear model by RM-ANOVA for the PTBR over time in each region and nationally. Considering the overall data from 2007 to 2020, the PTBR in Hokkaido was significantly higher than those of the other seven regions and the T A B L E 1 PTBR and EPTBR in Japan between 1979 and 2021. national average (p < 0.001 for all). The PTBR in Kyushu was also significantly higher than the national average (p = 0.002), and the rates in Chugoku and Shikoku were significantly lower than the national average (p < 0.001 for each). The average EPTBR for the last 14 years in Japan was 0.255% (Table 2b). Table 3b shows the results of multiple comparisons of EPTBRs over time in each region and nationwide. The EPTBRs in Tohoku and Kyushu were significantly higher than the national average and those of the other six regions ( p < 0.001 for all).
Thus, both the PTBR and EPTBR decreased nationally between 2007, and 2020 or 2019, respectively. The PTBRs in Hokkaido and Kyushu and the EPTBRs in Tohoku and Kyushu were significantly higher than the national averages.

Maternal aging between 2007 and 2020
Maternal age at birth of first, second, or third child Figure 3a shows the average maternal age at the birth of the first, second, or third child (Table S4a). From 2007 to 2020, the age of the mother for her first child's birth increased from 29.4 to 30.7 years; the average ages for second and third children's births also increased.
Birth rate according to 5-year age groups for reproductive age Figure 3b shows changes in the birth rate in six categories of 5-year age groups for reproductive age (Table S4b). Employment rate and form according to reproductive age Figure 3c shows the employment rate according to reproductive age (Table S4c). From 2007 to 2020, the employment rate of 15-to 44-year-old women increased, meaning more women entered the workforce. From 2007 to 2020, the nonregular employment rate for women was 53.5%-54.4%, and that for men was 18.3%-22.1%. Women had a higher proportion of nonregular workers than men. 29 Number of births and multiple births due to ART from 2007 to 2020 Table 4a shows the total number of live births, number of multiple births, multiple birth rates, and the PTBR and EPTBR for multiple births. The PTBR and EPTBR for multiple births were 54.0% and 2.19%, respectively, in T A B L E 2 A The preterm birth rates in eight regions of Japan from 2007 to 2020.   1.87% in 2011 (p = 0.012) but then significantly increased up to 2020 ( p < 0.001). The total number of live and multiple births, total number of births and multiple births produced by in vitro fertilization, and ART birth rates and multiple birth rates are shown in Table 4b. The number of ART births increased linearly from 19 595 in 2007 to 60 598 in 2019 (Table 4b). The ART birth rate increased linearly from 1.80% in 2007 to 7.18% in 2020 (Table 4b). The ART multiple birth rate decreased significantly from 16.3% to 11.9% from 2007 to 2008 ( p < 0.01) and remained below the 2007 level of 16.3% until 2014. It exceeded that in 2015 and rose to 19.4% in 2020 ( Figure 4, Table 4b).
More notably, the increase in single births with ART

DISCUSSION
It was postulated that the implementation of obstetrical guidelines would lead to a reduction in the PTBR and EPTBR. In Japan, the PTBR and EPTBR increased significantly from 1979 to 2007. 31,32 This is despite the total number of yearly births decreasing by half, from 1.64 million to 810 000, over the 43-year period. 20 Notably, when obstetrical guidelines were introduced in 2008, both the national PTBR and EPTBR started to decrease, with the PTBR significantly decreasing until 2020 and the EPTBR significantly decreasing until 2019. It is therefore surmised that the creation and enforcement of obstetrical guidelines contributed to the reduction in the PTBR and EPTBR in Japan. In addition, it may be that the increase observed in the PTBR in 2021 and the increase in the EPTBR in 2020 may be due to the onset of the COVID-19 pandemic. However, several reports 33 concluded that COVID-19 increased the rate of preterm delivery, while others concluded that it had no effect. 34 In fact, according to a US report, the PTBR and EPTBR in 2019 and 2020 decreased from 10.23% and 0.66% to 10.09% and 0.64%, respectively. 35 It will be interesting to see the results of live births in 2021 and 2022, when COVID-19 infections increased in Japan.
A comparison of the PTBR in Japan as a whole and in the eight regions showed significantly higher PTBRs in Hokkaido and Kyushu (Figure 2a), meaning the potential existed for these to be reduced. In particular, the average PTBR was 6.23% in Hokkaido, which was significantly higher than that of the other seven Japanese regions and the overall average of 5.68% in Japan. We first obtained data from 2007 to 2014. The PTBR in Hokkaido was much higher than that in other regions and we theorized this might be due to the low population density of this region. The Hokkaido region occupies 22.1% of Japan's area; however, it has only 4.2% of the population. The population density is 64 people/m 2 in Hokkaido, the lowest compared to the Japanese average of 331 people/m 2 and is less than 1/20 of that of the Kanto region ( Figure S3). We postulate that the long distances required for traveling to maternity examinations and delivery, and the inconvenience of transportation due to snow during the winter, made medical treatment inconvenient and therefore caused the high PTBR in Hokkaido. However, in 2018, the PTBR dropped to 5.76%, which was not significantly different T A B L E 3 B P values of Tukey's pairwise multiple comparisons using RM-ANOVA in extremely preterm births.

Regions
Hokkaido  Comparing the EPTBR of Japan with those of other countries, it is notably lower than that of the United States (Table S5 and Figure S1) 35,36 as well as the F I G U R E 3 (a) Trends in mean age of mother by live birth order in Japan. (b) Birth rate by female age (5-year groups) 2007-2020 (per 1000 Japanese female population). (c) Employment rate by female age (5-year groups) and the whole of Japan (percentage). accurately estimated EPTBRs of other regions of the world ( Figure S2b). 37 Even if low, the EPTBR in Hokkaido rose to 0.291% and the PTBR was highest at 6.65% in 2013, the year we conducted a questionnaire survey on uterine cervical cancer (UCC), Chlamydia trachomatis (CT) and BV screening rates of pregnant women in this region in February. This was also when we collected detailed information on the time of BV screening and diagnostic methods used. In 2012, UCC and CT screening rates reached 100%, as per guidelines. Bacterial vaginosis was universally screened for in 75.4% of 28 956 eligible cases; however, 7944 patients (27.4%) adopted a Nugent score in the screening before 20 weeks of gestation. 40 The therapeutic effect was not expected. Screening before 12 weeks of gestation and adoption of a Nugent score were then encouraged. These actions were taken as countermeasures against the high PTBRs in 2013. The results of this questionnaire survey were reported at the 11th HPC on August 17, 2013, and published in a paper in 2016. 40 Comparing EPTBRs in Japan as a whole and in the eight regions, the average EPTBRs of 0.312% in Tohoku T A B L E 4 A Multiple birth rate, PTBR, and EPTBR in multiple births in Japan.  41 Looking at birth rates in reproductive age groups, the relative birth rate shifted to an older age group of 30 years and above. Thus, these findings suggest that the aging of pregnant women means they are more likely to give birth prematurely due to the many complications of pregnancy. 16,42 A rise in the employment rate from 2007 to 2020 was observed for the reproductive age range from 15 to 44 years. The nonregular employment rate for women was about 2.5 times higher than men, 29 and they were more likely to give birth prematurely. 17 In April 2008, we investigated the effects of reducing the number of fertilized eggs returned to the uterus to one during in vitro fertilization. 19 Importantly, PTBRs were similar for multiple births (Relative risk, 1.07; 95% CI, 1.02-1.13) when comparing ART pregnancies to natural conception; however, these doubled for singleton births. 43 The proportion of multiple births produced by in vitro fertilization as a percentage of all multiple births significantly decreased from 2007 to 2008, increased from 2015 more than that in 2007, and then rose gradually until 2020. This is because ART pregnancies increased sharply from 2007 to 2019.

Total live births
Looking at single pregnancies in ART, an increase of 32 134 births from 2007 to 2015 was noted. The PTBR of singleton pregnancies in ART was twice that of natural conception. 44,45 Preterm births increased by 1796 (1796 = 32 134 Â 0.0559) in 2015. Converting this to the PTBR, this was a 0.18% (1796/100 5271 Â 100% = 0.18%) increase. Reducing the number of fertilized eggs returned to the uterus to just one was effective in reducing preterm births from 2007 to 2008; however, the preterm birth pressure due to ART increased every year thereafter. The PTBR in 2015 decreased by 0.20% (0.20% = 5.79%À5.59%) compared to 2007. These are some of the reasons why the PTBR has decreased by 0.38%.
From 2007 to 2019, the aging of pregnant women, increase in the employment rate at reproductive age, and increase in pregnant women using ART have brought about pressures on the number of premature births. However, the PTBR and EPTBR showed a significant decline up to 2019 after peaking in 2007 suggesting obstetrical guidelines influenced these rates.
However, despite the enforcement of obstetrical guidelines, a significant difference in the PTBR and EPTBR was noted between the eight regions of Japan. In areas where the PTBR and EPTBR were found to be high, investigating the cause and taking countermeasures may be the key to further reducing the premature birth rate in Japan.
This paper has limitations. The factors affecting preterm births are many, including medical causes. 46,47 In addition, economic and social factors, 48,49 as well as other factors such as anxiety, 50 have been implicated in preterm births. We have not considered these elements and believe that further examinations are necessary in the future.
In summary, although the PTBR and EPTBR in Japan showed a significant increase from 1979 to 2007, the introduction of obstetrical guidelines in 2008 was followed by a reduction in these rates. We therefore suspect that such guidelines contributed to reductions observed in the PTBR and EPTBR, despite pressures on premature births such as the aging of women of childbearing age, an increase in the employment rate of women of F I G U R E 4 Chronological change in ART birth rate and ART multiple birth rate in Japan between 2007 and 2020. ART, assisted reproductive technology; TLB, total live birth; TMB, total multiple live birth.
reproductive age, and an increase in pregnant women due to ART.

AUTHOR CONTRIBUTIONS
Tsuyoshi Saito was a supervisor of the study; Takashi Yamada, Kazutoshi Cho, Kazuo Sengoku, and Tasuku Mariya were responsible for the acquisition of data and statistical analysis. Satoshi Shimano designed this study and was also the chief investigator. All authors contributed to the writing of the final manuscript and have approved the final article.