Thrombosis-related characteristics of pregnant women with antithrombin deficiency, protein C deficiency and protein S deficiency in Japan.

BACKGROUND:  We previously conducted a primary survey of pregnant women with hereditary thrombophilia based on national surveillance in Japan, but did not examine their thrombosis-related characteristics. Antithrombin (AT) deficiency, protein C (PC) deficiency and protein S (PS) deficiency are the major types of hereditary thrombophilia in Japan. METHODS: We examined their detailed information related to thrombosis, and evaluated peripartum outcomes in comparison with control data obtained from the Japan Society of Obstetrics and Gynecology. RESULTS: Definite or probable AT deficiency, PC deficiency and PS deficiency were observed in 80, 50, and 317 pregnancies, respectively, from 2014 to 2018 in Japan, with prevalence rates among total deliveries of 0.011%, 0.007%, 0.044%. The number of pregnancies with AT, PC and PS deficiency might have been as many as 27, 17 and 108 every year if complete answers had been provided. In the peripartum period of current pregnancies, 27.5% of women with AT deficiency, 28.0% with PC deficiency and 13.2% with PS deficiency developed thrombosis (p < 0.001 vs. control). Pregnant women with AT and PC deficiency were more susceptible to thrombosis than those with PS deficiency (P < 0.01). Of the thromboses, 92.3% occurred during pregnancy, 62.8% at less than 15 gestational weeks. The earliest onset of thrombosis was 5 gestational weeks. Prophylactic anticoagulation significantly prevented the onset of both antepartum and postpartum thrombosis (p < 0.0001). The rate of recurrent pregnancy loss in women with low PC or PS activities was significantly higher than in controls (p < 0.0001); however, it is unknown whether recurrent pregnancy loss is related to hereditary PS deficiency. There seem to have been few serious maternal or fetal/neonatal complications due to placental insufficiency related to a hypercoagulable state other than growth restriction. CONCLUSIONS: This survey revealed the thrombosis-related characteristics of pregnant women with hereditary thrombophilia in Japan. We suggest prophylactic anticoagulation to prevent maternal or fetal/neonatal complications.

Peripartum management of hereditary thrombophilia: results of primary surveillance in Japan.

This study investigated patients with thrombophilia and current peripartum management practices based on national surveillance in Japan. Between 2014 and 2018, antithrombin (AT), protein C (PC) and protein S (PS) deficiency were observed in 84, 67, and 443 pregnancies, respectively, with incidence rates among total deliveries at 0.012%, 0.009%, and 0.061%. The percentage of institutions that measured both antigens and AT, PC, and PS activity for the diagnosis of thrombophilia was 50.2%, and 46.9% of institutions did not perform gene analysis. Prophylactic anticoagulation therapy was used in the ante- and postpartum management of patients with AT deficiency at 67.1% and 66.3% of institutions, most commonly with 10,000 units of unfractionated heparin. Ante- and postpartum management of PC and PS deficiency was performed at 75.3% and 67.1% of institutions. Approximately half of the institutions performed peripartum prophylactic AT supplementation for AT deficiency. Low trough AT activity before supplementation was most commonly 50 ≤ < 70%, and the highest AT supplementation was 1500 ≤ < 3000 units. The number of pregnancies with AT, PC and PS deficiency might be as many as 29, 23 and 151 every year in Japan if complete answers were provided.

The epidemiological characteristics of thromboembolism related to oral contraceptives in Japan: Results of a national survey.

AIM: The aim of this study was to reveal the epidemiological characteristics of thromboembolism related to combined oral contraceptives (COCs) in Japan. METHODS: A survey of confirmed thromboembolism patients among Japanese COC users was conducted at randomly selected hospitals from across Japan. The survey examined six types of venous thromboembolism (VTE) and arterial thromboembolism (ATE) in all COC users: pulmonary embolism, deep vein thrombosis, other venous thrombosis, cerebral infarction, myocardial infarction, and other arterial thrombosis. The survey covered 5 years from 2009 to 2013. This study was approved in an ethical review by Hamamatsu University School of Medicine. RESULTS: Four hundred and twenty-five cases clearly related to COCs were analyzed. The annual estimated incidence rates per 10 000 person-years of VTE, ATE and all thromboembolisms in all COC users were 1.17, 0.33 and 1.50, respectively. The incidence of thromboembolism was 35.2% within 30 days from the start of COCs, 53.8% within 90 days, 66.9% within 180 days and 78.2% within 360 days regardless of progestin type. Age adjusted odds ratios in the obese and underweight groups were 2.33 and 0.98 for overall thromboembolism, 2.59 and 0.77 for VTE, and 1.11 and 1.28 for ATE compared with the standard group, respectively. Odds ratios for thromboembolism in non-O blood groups were 1.89 for overall thromboembolism, 2.16 for VTE, and 1.35 for ATE, when compared with the O blood group. CONCLUSION: The epidemiological characteristics of COC-related thromboembolisms were revealed in this national survey covering the years from 2009 to 2013.

National survey of confirmed thromboembolism related to female hormones in Japan.

AIM: The aim of this study was to determine the number of thromboembolism patients among Japanese users of female hormones. METHODS: A survey of confirmed thromboembolism patients among Japanese users of female hormones was conducted at randomly selected hospitals from across Japan. The survey examined six types of venous thromboembolism (VTE) and arterial thromboembolism (ATE) in all users of female hormones, including women and men: pulmonary embolism (PE), deep vein thrombosis (DVT), other venous thrombosis (other VTE), cerebral infarction (stroke), myocardial infarction (MI) and other arterial thrombosis (other ATE). The survey covered 5 years from 2009 to 2013. This study was approved in an ethical review by the Hamamatsu University School of Medicine. RESULTS: The overall number of thromboembolism patients over the 5 years was estimated to be about 3211. They included 452 patients with PE, 795 with DVT, 157 with other VTE, 1228 with stroke, 478 with MI and 101 with other ATE. Among the abovementioned conditions, detailed information was available for 750 thromboembolism patients (645 women and 105 men), including 63 PE, 203 DVT, 159 PE + DVT, 65 other VTE, 189 stroke, 35 MI, 21 other ATE and 15 other cases. Thromboembolism increased year by year. The number of VTE was larger than that of ATE in younger people who used female hormones, while the number of ATE was larger than that of VTE in older people who used female hormones. CONCLUSION: The number and characteristics of thromboembolism patients among Japanese female hormone users were revealed in this national survey.

The incidence and prognosis of thromboembolism associated with oral contraceptives: Age-dependent difference in Japanese population.

AIM: We analyzed the incidence and prognosis of thromboembolism associated with combined oral contraceptives (COCs) by age groups in Japan. METHODS: A total of 581 events of venous thromboembolism (VTE) and arterial thromboembolism (ATE) associated with COCs were analyzed from the Pharmaceuticals and Medical Devices Agency database from 2004 to 2013. In a statistical analysis, a good-prognosis group included recovery cases and a poor-prognosis group involved unrecovered cases with some sequela and fatal cases. The significant difference between these two groups was calculated by Pearson's chi-square test, and the age-specific tendency and the trend of differences in prognosis according to different hormonal contraceptives were examined by Cochran-Armitage trend test. RESULTS: A total of 543 events were analyzed except 38 events due to unknown age, in which DVT only was the most frequent, followed by cerebral infarction, PE with DVT, PE only, cerebral vein thromboses. ATE ratio for overall thromboembolism tended to increase with advancing age (P = 0.0041). Good-prognosis group was common (291 cases in VTE and 83 cases in ATE), followed by poor-prognosis group (46 cases in VTE and 34 cases in ATE). All ATE cases had a significantly poorer prognosis in comparison with all VTE cases (P < 0.0001). Types of progestin and age difference, however, showed no trend in the differences between good-prognosis group and poor-prognosis group (P = 0.3548 and P = 0.6097). CONCLUSION: Thromboembolic events were the most frequent in the 40s. The ATE ratio for overall thromboembolism tended to increase with advancing age. All ATE cases had a significantly poorer prognosis in comparison with all VTE cases.

Risks of thromboembolism associated with hormone contraceptives in Japanese compared with Western women.

We extracted 581 thromboembolic events associated with combined oral contraceptives (COC) that occurred between 2004 and 2013 in Japan, from the Pharmaceuticals and Medical Devices Agency database. The most common thromboembolic events associated with COC were deep vein thrombosis, pulmonary embolism and their combination. The reported thromboembolic events increased year by year, in association with an increase in the quantity of prescribed low-dose estrogen progestin after approval for health insurance coverage for dysmenorrhea in 2008 in Japan. The incidence of venous thromboembolism (VTE) in Japanese COC users is estimated to be lower compared with their Western counterparts. In contrast, the frequency of all thromboembolic events peaked at 90 days from the start of COC, as in Western studies. The risk of VTE in the overweight group (body mass index ≥ 25 kg/m2 ) was more than twofold higher than in the standard group, and age-specific incidence rate rose sharply after the age of 40. There were different VTE risks according to progestin type in Japan as in Western countries, but a definite conclusion about risk according to progestin type was not able to be reached at present. As for the risk of arterial embolism and thrombosis, the difference by progestin type was small, but it became higher at ≥50 years of age. Last, mortality rate caused by thromboembolism is extremely low among COC users.

Risks of thromboembolism associated with hormonal contraceptives related to body mass index and aging in Japanese women.

OBJECTIVE: The aim of this study is to estimate the risk of thromboembolism related to body mass index (BMI) and aging among users of hormonal contraceptives in Japan. METHODS: A case-control study of the risk of obesity and a descriptive study of the risk of age were conducted. We used the Pharmaceuticals and Medical Devices Agency database, and extracted thromboembolic events of combined oral contraceptive (COC) products. Control data were from the National Health and Nutrition Survey in Japan. Denominator of descriptive study was from IMS Health, JPM. RESULTS: A total of 306 thromboembolic events and 6423 controls were analyzed. The odds ratios (95% confidence interval) of the obesity groups (BMI ≥ 25) were 2.32 (1.71-3.15) for venous thromboembolism (VTE), 1.16 (0.62-2.18) for arterial embolism and thrombosis (ATE), and 1.83 (1.38-2.43) for overall thromboembolic events compared with the standard group (BMI of 18.5-24.9) as a reference. The estimated incidence rates of VTE, ATE and overall thromboembolic events per 10,000 person-years in users of therapeutic remedies for dysmenorrhea (35 µg ethinylestradiol combined with norethisterone, 20 µg ethinylestradiol combined with drospirenone and dienogest) among women aged 10-59 years from 2009 to 2013 were 2.38 (2.08-2.74), 0.63 (0.48-0.82), and 3.17 (2.81-3.57), respectively. This tendency was not seen for dienogest. CONCLUSIONS: The risk of VTE in the obesity group among COC users was more than 2 times higher than in the standard group. The incidence rates of VTE in Japanese users of all remedies for dysmenorrhea except dienogest were as high as in people in Western countries.

Thromboembolism as the adverse event of combined oral contraceptives in Japan.

BACKGROUND: The risk of thromboembolism associated with combined oral contraceptives (COCs) in Japanese women is not clear yet. The aim of this study is to estimate the current risk of thromboembolism among COC users in Japan. METHODS: We used the Pharmaceuticals and Medical Devices Agency (PMDA) database disclosed by PMDA from April 2004 to December 2013, and extracted thromboembolic events among adverse events from the adverse event information of COC products. RESULTS: Of the 581 thromboembolic events, venous thromboembolism (VTE) accounted for 394 events, arterial embolism and thrombosis (ATE) were 154, and thrombosis of unspecified sites was 33. In VTE, deep vein thrombosis and pulmonary embolism were the most frequent (78.4%), followed by cerebral vein thrombosis (11.4%). In ATE, cerebral infarction was the most frequent (76.0%) and approximately 6.9-fold higher than coronary heart diseases. The annual estimated incidence per 10,000 person-years of VTE, ATE and all thromboembolisms in current users of all COCs were 1.11 (95% confidence interval: 1.00-1.24), 0.37 (0.30-0.44), and 1.56 (1.42-1.71), respectively. The frequency of all thromboembolic events that developed within 90 days from the start of COCs was 45.5%, and that within 360 days was 81.2%. Sixteen deceased cases were suspected to be associated with thromboembolism, and the estimated mortality rate between 2009 and 2013 was 0.50 (0.30-0.84) per 100,000 person-years. CONCLUSIONS: Incidence rates of thromboembolism, particularly VTE, in Japanese current COC users became clear for the first time, being slightly lower than people in Western countries.