Characteristics of Maternal Venous Thromboembolism in Japan, 2018: A Retrospective Cohort Study with National Surveillance Questionnaire Conducted in Maternity Hospitals

Background: In Japan, deliveries by women of older maternal age and by women with overweight or obesity have recently increased. While, since 2008, the guidelines and practices to prevent the maternal VTE have been recommended. This study aims to clarify the incidence and characteristics of venous thromboembolism (VTE) in pregnant women in Japan to reduce the rate of mortality from VTE. Methods: Of 2299 institutions sent the surveillance questionnaire, 666 (29.0%) responded, and data from 295,961 women who gave birth in those institutions in 2018 were analyzed. We calculated the incidence and characteristics of VTE before and after the deliveries in the three types of institutions (perinatal medical centers, general hospital with obstetric facilities, and maternal clinic with beds). To clarify the incidence and characteristics of VTE, and to clarify the relationship between the incidence of the VTE and the types of institutions in 2018 in Japan. Results: At the responding institutions, 20 (0.0068%) died, and 243 women (0.082%) had VTE. Deep vein thrombosis was signicantly more common (0.0053%) than pulmonary thromboembolism (0.0019%; p < 0.0001). The incidence of antepartum VTE (0.0055%) was signicantly higher than that of postpartum VTE (0.0026%; p < 0.0001). Among the 165 women with antepartum VTE, perioperative pulmonary thromboembolism (30.0%) was more common than perioperative deep vein thrombosis (8.8%, p = 0.0150). The incidence of VTE after cesarean section (0.0074%) was signicantly higher than that after vaginal delivery (0.0012%; p < 0.0001). After cesarean section, the incidence of pulmonary thromboembolism (46.4%) was signicantly higher than that of deep vein thrombosis (10.8%; p < 0.0001). Of the women with VTE, four (1.6%) died. Conclusions: Obstetricians

In the retrospective study from 1991 to 2000 in Japan by the Japan Society of Obstetrical, Gynecological and Neonatal Hematology (JSOGNH) [6], the incidence of VTE before and after delivery was 0.046% (203 of 436,084 women).
In Japan, deliveries by women of older maternal age and by women with overweight or obesity have recently increased; thus, the risk of VTE may have increased. On the other hand, since 2008, the Japan Society of Obstetrics and Gynecology (JSOG) and JAOG have recommended guidelines and practices to prevent the maternal VTE [11,12], and so the incidence of VTE onset in Japan might have decreased since then.
As members of JSOGNH, we wish to reduce the rate of mortality from VTE among women in Japan.
The primary goal of this study was to clarify the incidence and characteristics of VTE, and to clarify the relationship between the incidence of the VTE and the types of institutions in 2018 in Japan. Furthermore, the secondary goal was to clarify the trend of VTE onset in Japan in comparison with those in previous studies [6,7].

Hypotheses
We built the following hypothesis, the frequency of VTE (DVT and PTE) onset and death induced by VTE in the pregnant women would be decrease in 2018 comparison with those of study from 1991 to 2000 in Japan.

Study design
We conducted a cohort study with a surveillance questionnaire. In May 2019, questionnaires were sent to all 2299 hospitals or maternity clinics listed as institutions with obstetric facilities by the JSOG on December 31, 2018. The chairman, chief or substitute of institutions responded by regular mail.
The surveillance questionnaire was designed by JSOGNH, and had four categories of questions: (1) the types and the specialties of institutions, (2) methods used to prevent maternal VTE onset, (3) incidence of maternal VTE (e.g., case numbers, types of VTE, period of VTE onset), and (4) outcomes (mortality induced by VTE) among pregnant women with VTE onset in 2018. The response from hospitals or maternal clinics that had no deliveries in 2018 was excluded.
The recommendations for thromboprophylaxis in Japan [11] are shown in Table 1. These were determined according to the modi ed guidelines of the Royal College of Obstetricians and Gynecologists [13] and of the American College of Chest Physicians [14,15]. Level C treatment consists of possible options that may favorably affect the outcome but for which it is unclear whether the possible bene ts outweigh the possible risks. Thus, care corresponding to level C recommendations is not necessarily provided.
The criteria of three types of institutions All institutions were categorized as one of three types. The rst type were perinatal medical centers (PMCs), which were de ned as hospitals with maternal-fetal intensive care units that had six beds or more and were always staffed by one or more speci ed obstetricians and one speci ed midwife or nursing staff for every three beds over a 24-h period, a neonatal intensive care unit that had nine or more beds and was always staffed by one or more speci ed pediatricians and one or more speci c nurses for every three beds over a 24-h period, a growing care unit that was always staffed by one speci c nurse for every six beds over a 24-h period, and a delivery room that was staffed by one or more speci c midwives and one or more anesthesiologists. The second type was a general hospital with obstetric facilities (GH), de ned as having one or more beds for deliveries by one or more obstetricians supported by one or more pediatricians and one or more anesthesiologists. The third type was a maternal clinic with beds (MC), de ned as a hospital with one or more beds for deliveries by one or more obstetricians with possible support by one or more pediatricians but no anesthesiologists.
All thromboembolisms were classi ed as one of four types: (1) DVT, (2) pulmonary thromboembolism (PTE), (3) other vein thrombosis (other VT), and (4) arterial thromboembolism (ATE). The combination of PTE with DVT was classi ed as PTE. Other VTs were de ned as thrombosis of more super cial veins, such as thromboembolisms of veins in the arm, ovary, colon, and brain.
Time of onset was classi ed as antepartum or postpartum (the latter of which included the period during labor). Operations during pregnancy were de ned as invasive procedures in the hospital, e.g., cervical cerclage, laparotomy, or laparoscopic ovarian cystectomy. Delivery mode was classi ed as vaginal delivery or cesarean section.

Statistical analyses
Data were calculated as frequencies. JMP Pro, version 14.0 (SAS Institute Inc., Cary, NC, USA), was used to perform the statistical analyses. We used Fisher's exact test to compare categorical variables. Pearson's product-moment correlation coe cient was used to measure linear correlations between two variables. In all analyses, a p value of less than 0.05 indicated statistical signi cance. In linear correlations, statistical signi cance also required a correlation coe cient (r) of -0.25 ≤ r ≤ 0.25.

Ethical approval
This study was approved by the Institutional Review Board of Hokkaido University Hospital (018-280), Hokkaido, Japan. It was performed in compliance with the Declaration of Helsinki. Consent was not obtained from patients, but the presented data are anonymous, and there is no risk of identi cation.

Patient and public involvement
No patients were involved in devising the research questions, the outcome measures, or the plans for recruitment, design, or implementation of the study. No patients were asked to advise on interpretation or writing up of results. There are no plans to disseminate the research study results to study participants or the relevant patient community.

Availability of data
The datasets generated and analyzed during the current study are not publicly available due to taking out to other facilities is restricted by the institutional review board but are available from the corresponding author on reasonable request. Routine thromboprophylaxis, both antepartum and postpartum, is described in Table 2. In accordance with the recommendation of thromboprophylaxis in Japan for pregnant women at high risk for VTE [11,12], unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) was routinely administered by 316 (47.4%) institutions before the women gave birth and by 382 (57.4%) institutions after; compression stockings were routinely applied by 326 (48.9%) institutions before the women gave birth and by 396 (59.5%) institutions after; and intermittent pneumatic compressions were applied by 162 (24.3%) institutions before the women gave birth and by 353 (53.0%) institutions after. The number of institutions in which UFH or LMWH was routinely administered and in which intermittent pneumatic compressions were applied to prevent postpartum VTE was signi cantly higher than those applying these measures to prevent antepartum VTE (p < 0.0001).

The characteristics of pregnant women with venous thromboembolism
The characteristics of pregnant women with VTE were shown in Table 2 and Table 3.   The relations between types of thromboembolism and onset The characteristics of the period of VTE onset are summarized in Table 4.   The characteristics of death from venous thromboembolism The characteristics of deaths from VTE are listed in Table 3 and Table 4.

Discussion
Our ndings emphasized four points: (1) The incidence of VTE in PMCs was higher than GHs or MCs; (2) the incidence of postpartum PTE onset was signi cantly higher and the incidence of postpartum DVT onset was signi cantly lower than those during pregnancy; (3) the incidence of PTE in association with cesarean section was signi cantly higher than that of DVT; and (4) of 243 women with VTE, 4 (1.6%) died, and all 4 had PTE.
To the best of our knowledge, this is the rst study to demonstrate that the incidence of VTE onset in perinatal medical centers was higher in spite of their higher incidence of thromboprophylaxis. Many pregnant women who delivered in PMCs were apparently at higher risk of VTE.  [3]. In our study, as mentioned, of the four women who died of PTE, three (75.0%) died in PMCs. These data indicate that 12.4 women would have died of PTE in 2018. The maternal deaths from PTE in Japan might be more numerous than those in the previous reports [3,6,7].
Of 203 women with VTE in the 1991-2000 study in Japan by JSOGNH [6], 127 (62.6%) had DVT and 76 (37.4%) had PTE. In that study and ours, the incidences of PTE in Japan were similar (17.4 to 18.9 per 100,000, p = 0.6405); however, the incidence of DVT increased 82% between that study and ours (29.1 to 53.0 per 100,000; p < 0.0001).
Comparison with the risks of VTE onset during the rst trimester, second trimester, third trimester antepartum, the risk of VTE onset during the rst 6 weeks' postpartum are signi cantly higher [16,17], and the peak of VTE onset occurred in the rst 3 week [17]. While, in the previous report, the frequencies of VTE onset at antepartum and at postpartum were similar (48.9% and 51.1%) among all women with VTE [16]. In our study, among the 243 women with VTE, the frequency of PTE onset at antepartum was low in comparison with at postpartum (35.7% vs. 64.3%), while, the frequency of DVT onset at antepartum was high in comparison with at postpartum (79.6% vs. 20.4%). The women with DVT onset was more than those with VTE. Thus, the ratio of VTE onset at antepartum were high in comparison with at postpartum (67.9% vs. 32.1%; Table 4).
In the 30 years between 1966 and 1995 in the United States [18], the incidence of VTE was more than ve times higher after delivery (511.2 per 100,000) than before delivery (95.8 per 100,000), and the incidence of VTE (151.8 per 100,000) was more than three times higher than that of PTE (47.9 per 100,000). In general, antepartum PTE is less common than postpartum PTE. In the period 1966-1995 in the United States, the incidences of PTE rose from 10.6 to 159.7 per 100,000 [18]. In the 1991-2000 study in Japan [CI], 2.02-5.95; p < 0.0001). In 2018 (our study), those were 1.80 (95% CI, 1.04-3.11) and 3.91 (95% CI, 2.65-5.76), respectively. Thus, obstetricians should be strongly encouraged to administer antepartum thromboprophylaxis to decrease incidence of antepartum DVT in Japan.
Between 1966 and 1995 in the United States [18], the incidence of postpartum PTE decreased by more than 50%. In a 2004-2014 study in the United States [10], the incidence of postpartum DVT decreased by 10% (from 32 to 29 per 100,000), and the incidence of postpartum PTE increased 14% (from 14 to 16 per 100,000). In the 1991-2000 study in Japan [6,7], 63 women had postpartum DVT and 59 had postpartum PTE. Between the time of that study and ours, the incidence of postpartum DVT in Japan decreased 25% (from 14.4 to 10.8 per 100,000), and that of postpartum PTE decreased 9.6% (13.5 to 12.2 per 100,000; Fig. 1B). However, these trends were not signi cantly different (p = 0.1803 and p = 0.6147).
The 2004-2014 study in the United States [10] had no data about the incidence of antepartum VTE (DVT or PTE). In the 1991-2000 study in Japan and our study, the incidences of antepartum PTE were similar (3.9 to 6.8 per 100,000; p = 0.0962); however, the incidence of antepartum DVT increased 187% (14.7 to 42.2 per 100,000, p < 0.0001) (Fig. 1A).
It is possible that the nding of an increase in antepartum DVT might be attributable to the bias of the surveillance questionnaire. In the 1991-2000 study in Japan, the data were obtained from 102 institutions, which included 68 university hospitals and 34 general hospitals [6,7]. In our study, the 666 institutions included 63 university hospitals (9.5%). However, we suggest that the incidence of antepartum DVT might have increased for four reasons. First, most obstetricians began to pay more attention to antepartum VTE onset and became more skillful at diagnosing DVT after the 2008 publication of guidelines with the recommendation of thromboprophylaxis in Japan. Thus, the number of diagnoses of antepartum DVT would have increased. Second, of the institutions routinely performing thromboprophylaxis, MCs had the lowest frequencies, especially for antepartum thromboprophylaxis (Table 2). To decrease incidence of antepartum VTE, an extensive and systematic campaign to encourage antepartum thromboprophylaxis according to the recommendations in Japan [11,12] may be necessary. Third, the numbers of pregnant women at high risk for antepartum DVT (e.g., women older than 35 and those who became pregnant after assisted reproductive technology) in Japan have increased. Hyperemesis, antepartum bed rest, and ovarian hyperstimulation syndrome are risk factors for VTE. Fourth, antepartum laboratory tests of coagulation and brinolysis are not performed to screen for thrombophilia in Japan. Thus, thrombophilia in pregnant women is sometimes not diagnosed before the occurrence of antepartum or postpartum VTE.
In many cases of antenatal VTE, onset is during the during the third trimester [16,17] or during the rst trimester [19][20][21]. Thus, antepartum VTE is a signi cant concern, and thromboprophylaxis has been recommended [21,22]. The Royal College of Obstetricians and Gynecologists recommends that women who undergo invasive surgery during pregnancy should be given prophylactic anticoagulation therapy [13]. The 1991-2000 study in Japan had no data about the incidence of perioperative VTE (DVT or PTE) during pregnancy [6,7]. In our study, among the 165 women with antepartum VTE, the incidence of perioperative PTE during pregnancy was signi cantly higher than that of perioperative DVT. According to the guidelines about thromboprophylaxis in Japan (Table 1), pregnant women who undergo surgery during pregnancy are at moderate risk for VTE; however, they may have to be considered at high risk to decrease the incidence of perioperative VTE (especially PTE) during pregnancy.
In a 2004-2014 study in the United States [10], the incidence of DVT by cesarean section decreased 40% (from 94 to 56 per 100,000 deliveries); however, the incidence of PTE by cesarean section was not observed to decrease (20, 30, and 23 per 100,000 deliveries in 2012, 2013, and 2014, respectively). In Japan, the incidences of DVT and PTE after cesarean section in the 1991-2000 study were similar to those in our study; however, the incidence of both DVT and PTE after cesarean section decreased 32.7% (from 97.3 to 65.5 per 100,000; p = 0.0214; Fig. 1C). Thus, performing thromboprophylaxis after cesarean section in Japan would be safe and effective.
In the 2004-2014 study in the United States [10], the incidence of neither DVT nor PTE after vaginal deliveries decreased. In Japan, the incidences of DVT and PTE after vaginal delivery in the 1991-2000 study were similar to those in our study (Fig. 1D). Thromboprophylaxis after vaginal delivery by women at high risk for VTE should be promoted more extensively among obstetricians to decrease the incidence of VTE after delivery.
To our knowledge, this is the rst study to demonstrate that the incidences of other VT and ATE onset among pregnant women. In the present study, the frequencies were very low (8.8 and 1.4 per 100000, respectively). Furthermore, no woman was died from other VT or ATE. Thus, there might be few obstetricians who considered the incidences of other VT and ATE onset among pregnant women. Further studies are required to determine the risk factors of other VT or ATE onset among pregnant women.
Our study had some strength. First, the selection bias of the institutions was low because the surveillance questionnaire was sent to all 2299 hospitals or maternal clinics reported to treat deliveries in Japan. Second, we had access to the data about incidence of perioperative VTE during pregnancy, which was reported by few previous studies. Finally, we were able to describe the relations between VTE onset and the type of institutions.
This study, however, also had some limitations. First, the surveillance questionnaire did create the potential for bias. Second, we had no detailed information about the patients' backgrounds, e.g., age, times of previous deliveries, history of thrombophilia or previous VTE, number of gestational weeks at delivery, number of gestational weeks at onset of antepartum VTE, number of postpartum days at VTE onset, and whether thromboprophylaxis was performed. Finally, the data for only 1 year (in 2018) were available. Thus, our results alone could not describe the trend of incidence and mortality of VTE. However, we compared them with the incidence of VTE found in a previous study in Japan.

Conclusion
Thromboprophylaxis should be promoted more extensively among obstetricians to decrease the incidence of VTE, inasmuch as the incidences of antepartum and postpartum VTE have increased in Japan.