Measured menstrual blood loss in women with a bleeding disorder or using oral anticoagulant therapy Marion A. van Eijkeren, MD, PhD: Godelieve C. M. L. Christiaens, MD, PhD: Ary A. Haspels, MD, PhD: and Jan J. Sixma, MD, PhDb
Utrecht, The Netherlands Bleeding disorders in women are associated with a high incidence of menorrhagia, but few objective data exist. Whether oral anticoagulant therapy in women is also associated with a higher incidence of menorrhagia is unknown. We measured menstrual blood loss in six women with various congenital or acquired bleeding disorders and in 11 women treated with oral anticoagulant therapy. Mean menstrual blood loss in women with a bleeding disorder was 219 ml (range, 60 to 568 ml); five women had menorrhagia. In women treated with oral anticoagulant therapy, mean menstrual blood loss was 98 ml (range, 9 to 239 ml), and five women had menorrhagia. Of the six women with normal menstrual blood losses, two had losses in the high normal range (60 to 80 ml). No correlation existed between anticoagulant state and menstrual blood loss. The data support the close association between bleeding disorders and menorrhagia and suggest that oral anticoagulants increase menstrual blood loss. (AM J OBSTET GVNECOL 1990;162:1261-3.)
Key words: Menorrhagia, bleeding disorder, oral anticoagulant therapy
Material and methods
Menorrhagia is generally believed to be a major symptom in women with a bleeding disorder. I. 2 Women treated with oral anticoagulant therapy also more often complain of menorrhagia. Menorrhagia is defined as a measured menstrual blood loss of more than 80 ml from a normal secretory endometrium after a normal ovulation, because the incidence of anemia increases significantly above this level.' Some investigators consider 60 ml as the upper normal limit of menstrual blood loss because this already causes iron deficiency, as reflected in low serum ferritin levels! The definition of menorrhagia requires a direct assay of menstrual blood loss because subjective menstrual blood loss assessments are unreliable." 5 In populations of healthy women in Western Europe, mean menstrual blood loss varies from 34 to 44 ml and menorrhagia occurs in 9% to 14%.3.6 Dramatic case reports exist of severe menorrhagia in women with a bleeding disorder,!· 2 but only of 10 women has measured menstrual blood loss been documented. 7 • 8 Nine of these 10 women had a menstrual blood loss of more than 80 ml, up to 1000 ml. No data are available on menstrual blood loss in women treated with oral anticoagulant therapy. This study was designed to contribute data on measured menstrual blood loss in both categories of women.
Women with a bleeding disorder attending the Department of Gynaecology and Obstetrics or the Department of Haematology at the University Hospital, Utrecht, and women treated with oral anticoagulation therapy with coumarin derivates attending the Thrombosis Center of the City of Utrecht, were asked to enter the trial. Inclusion criteria were as follows: younger than 45 years of age, regular menstrual cycle, normal uterus as assessed by bimanual palpation, no hormonal medication, no intrauterine contraceptive device, and except for women taking oral anticoagulant therapy, no medication that could interfere with hemostatis. Menstrual blood loss was measured once with the alkaline hematin method, as described previously.9 Recent hematologic laboratory findings of women with a bleeding disorder were collected. In women treated with oral anticoagulant therapy, a Thrombotest (modified prothrombin time test with bovine thromboplastin) was determined to evaluate the anticoagulant state around the time of menstruation. Thrombosis Centers in The Netherlands use the Thrombotest to control oral anticoagulant therapy.lo To determine a relation between menstrual blood loss and Thrombotest, the Spearman rank correlation coefficient was calculated.
From the Department of Gynaecology and Obstetrics" and the Department of Haematology,' University Hospital. Received for publication October 27, 1989; accepted February 5, 1990. Reprint requests: M. A. van Eijkeren, MD, PhD, Leidseweg65, 3531 BD Utrecht, The Netherlands.
Hematologic characteristics and menstrual blood loss data of six women with bleeding disorders are illustrated in Table I. Various types of bleeding disorders were included, such as congenital factor II deficiency, Glanzmann's thrombasthenia, acquired thrombocytopathia and thrombocytopenia, idiopatic thrombocyto-
611119899
Results
1261
1262 van Eijkeren et al.
May 1990
Am J Obstet Gynecol
Table I. Hematologic characteristics and
Table II. Indication for therapy, hematologic
menstrual blood loss data of six women with a bleeding disorder
characteristics, and menstrual blood loss data of 11 women using oral anticoagulant therapy
Bleeding disorder and recent laboratory data
Congenital factor II deficiency (hemoglobin 5.1 mmollL; factor II 9%; Simplate bleeding time >30 min)* Glanzmann's thrombasthenia (hemoglobin 8.7 mmollL; Simplate bleeding time >30 min) Acquired thrombocytopenia and thrombocytopathia (hemoglobin 5.1 mmollL; ferritin 2 flogfL; Simplate bleeding time >30 min; thrombocytes 99.10 9 fL) Idiopathic thrombocytopenia (hemoglobin 8.0 mmollL; thrombocytes 72.10 9 fL; Simplate bleeding time 9 min 30 sec) Idiopathic thrombocytopenia (hemoglobin 7.5 mmollL; thrombocytes 80.10 9 fL; Simplate bleeding time normal) Von Willebrand's disease (type IIa) (von Willebrand factor antigen 40% to 60%; hemoglobin 9.3 mmollL; Simplate bleeding time >30 min) Mean SD
Menstrual blood loss (ml)
568 140 320
142
86
60
219 193
*Normal values: hemoglobin >8 mmollL; thrombocytes > 150.109 fL; Simplate bleeding time 14 flogfL; factor II 65% to 130 %.
penia, and von Willebrand's disease. In five women menstrual blood loss exceeded the upper normal limit of 80 ml (range, 86 to 568 ml). The patient with von Willebrand's disease had a menstrual blood loss of 60 ml, which is in the high normal range. After menstrual blood loss assessment, the woman with congenital factor II deficiency was treated with antifibrinolytics, wellknown inhibitors of menstrual blood loss. II The woman with Glanzmann's thrombasthenia used iron medication and occasionally antifibrinolytics. A progesteronecontaining intrauterine contraceptive device was inserted into the uterus of the woman with an acquired bleeding disorder. These devices are known to diminish menstrual blood loss, in contrast to inert or coppercontaining intrauterine contraceptive devices. 12 The three other women were not treated. Table II shows indications for therapy, hematologic characteristics, and menstrual blood loss data of 11 women receiving oral anticoagulant therapy. Various indications for oral anticoagulant therapy existed: after cardiac or vessel surgery, after myocardial infarction, after puerperal deep venous thrombosis, or after osteotomy. Mean menstrual blood loss was 98 m!. Five women (45%) had menstrual blood losses of more than 80 ml (range 83 to 239 ml). Six women had menstrual
Patient No. I
2 3 4 5 6
7 8 9 10 II Mean SD
Indication for oral anticoagulant therapy
Thrombotest* (sec)
Menstrual blood loss (ml)
Artificial heart valve Artificial heart valve Artificial heart valve Artificial heart valve Aortic prosthesis:j: After myocardial infarction After myocardial infarction After myocardial infarction After puerperal deep venous thrombosis After puerperal deep venous thrombosis After osteotomy
131 141 62t 139 131 141 135 194 93t
29 209 22 71 154 239 9 75 51
122
83
II8 128 33
138 98 77
*Therapeutic ranges of Thrombotest: 120 to 200 seconds for patients with an artificial heart valve and an aortic prosthesis operation; 105 to 180 seconds for patients after deep venous thrombosis and after myocardial infarction, and 90 to 140 seconds for patients after osteotomy. tThrombotest times were too short. :j:Patient taking iron medication.
blood losses in the normal range, of which two were high normal (60 to 80 ml). Only one woman used iron medication (see Table II). Two Thrombotests were too short in duration (see Table II), all others were in the therapeutic range. The women whose Thrombotest times were too short had normal menstrual blood losses. No statistically significant correlation existed between menstrual blood loss and Thrombotest values.
Comment The aim of this study was to collect objective data on menstrual blood loss of women with a bleeding disorder and of women receiving oral anticoagulant therapy. In the 10 women with a bleeding disorder whose menstrual blood loss has been documented, six more women are added in this study. The results are summarized in Table I. Five women had menorrhagia (blood loss up to 568 ml), and one woman had a high normal menstrual blood loss. We realize that this is a very select study group. Many women with bleeding disorders already had a hysterectomy or used antifibrinolytics or oral contraceptives to diminish their menstrual blood loss, and hence were not suitable for this study. Nevertheless, the data of this study, together with the above-mentioned studies,7' 8 substantiate that menorrhagia occurs in the majority of women with bleeding disorders, even in amounts of menstrual blood loss that are a threat to general health. This necessitates regular control of hemoglobin and ferritin levels, or both. Ef-
Volume 162 Number 5
fective treatments for menorrhagia in patients with bleeding disorders are combination oral contraceptives, oral or intramuscular progestogens, or progesteronecontaining intrauterine contraceptive devices. 12 If contraception is not desired, prostaglandin synthesis inhibitors and antifibrinolytics are the drugs of choice. 13 In this study the first data on menstrual blood loss of 11 women receiving oral anticoagulant therapy are presented (see Table II). Mean menstrual blood loss (98 ml) and incidence of menorrhagia (five of 11 women) were higher than described in populations of healthy women in Western Europe (34 to 44 ml and 9% to 14%, respectively)." 6 Although the study group is limited, these data suggest that oral anticoagulants may increase menstrual blood loss. Definite clarification of the relation between oral anticoagulants and menstrual blood loss should come from studies comparing menstrual blood loss in women first with, and later without, oral anticoagulant therapy. This could be realized in women after puerperal deep venous thrombosis or after on osteotomy. Both conditions require only a temporary treatment with oral anticoagulants. These studies also could answer the question whether or not preventive iron medication should be advised. This is of importance since common treatments for menorrhagia, such as combination oral contraceptives or antifibrinolytics, are relatively contraindicated in women receiving oral anticoagulant therapy. Until such studies are done, regular control of hemoglobin or ferritin levels should be considered in menstruating women receiving oral anticoagulant therapy. Since combination oral contraceptives are relatively contraindicated and inert or copper-containing intrauterine contraceptive devices increase menstrual blood loss, continuous administration of progestogens is the contraceptive of choice in women receiving oral anticoagulant therapy. The different administration forms of progestogens are described above. We thank H. Chin, H. K. Nieuwenhuis, and P. C. Scholten for their help in recruiting women for the study.
Menstrual blood loss with oral anticoagulants
1263
REFERENCES 1. Quick AJ. Menstruation in hereditary bleeding disorders. Obstet Gynecol 1966;28:37-48. 2. Vinazzer H. von. Uber storungen der Haemostase als Ursache von Menorrhagien. Geburtshilfe Frauenheilkd 1966;26:743-45. 3. Hallberg L, Hogdahl A, Nilsson L, Rybo G. Menstrual blood loss-a population study. Acta Obstet Gynecol Scand 1966;45:320-51. 4. Shaw ST, Aaronson DE, Moyer DL Quantitation of menstrual blood loss-further evaluation of the alkaline hematin method. Contraception 1972;5:497-513. 5. Chimhira TH, Anderson ABM, Naish C, Cope E, Turnbull AC, Relation between measured menstrual blood loss and patient's subjective assessment of loss, duration of bleeding, number of sanitary towels used, uterine weight and endometrial surface area. Br J Obstet Gynaecol 1980;87:603-9. 6. Cole SK, Billiwicz WZ, Thomson AM. Sources of variation in menstrual blood loss. Br J Obstet Gynaecol 1971; 78:933-9. 7. Fraser IS, McCarron G, Markham R, Resta T, Watts A. Measured menstrual blood loss in women with menorrhagia associated with pelvic disease or coagulation disorder. Obstet Gynecol 1986;68:630-3. 8. Makiirainen L, Ylikorkala O. Primary and myomaassociated menorrhagia: role of prostaglandins and effect of ibuprofen. Br.1 Obstet Gynaecol 1986;93:974-8. 9. Eijkeren MA van, Scholten PC, Christiaens GMCL, Alsbach GP.1, Haspels AA. The alkaline hematin method for measuring menstrual blood loss-a modification and its clinical use in menorrhagia. Eur J Obstet Gynecol Reprod Bioi 1986;22:345-5 I. 10. Dijk van-Wierda CA, Hermans .1, Loeliger EA, Roos J. Interlaboratory oral anticoagulant quality assessment by The Netherlands foundation of thrombosis services. Thromb Haemost 1977;37:509-22. ' 11. Nilsson L, Rybo G. Treatment of menorrhagia. AM.1 OBSTET GVNECOL 1971;110:713-20. 12. Bergqvist A, Rybo G. Treatment of menorrhagia with intrauterine release of progesterone. Br.1 Obstet Gynaecol 1983;90:255-8. 13. Eijkeren MA van, Christiaens GCML, Sixma .1.1, Haspels AA. Menorrhagia-a review. Obstet Gynecol Surv 1989; 44:421-29.
Utrecht, The Netherlands Bleeding disorders in women are associated with a high incidence of menorrhagia, but few objective data exist. Whether oral anticoagulant therapy in women is also associated with a higher incidence of menorrhagia is unknown. We measured menstrual blood loss in six women with various congenital or acquired bleeding disorders and in 11 women treated with oral anticoagulant therapy. Mean menstrual blood loss in women with a bleeding disorder was 219 ml (range, 60 to 568 ml); five women had menorrhagia. In women treated with oral anticoagulant therapy, mean menstrual blood loss was 98 ml (range, 9 to 239 ml), and five women had menorrhagia. Of the six women with normal menstrual blood losses, two had losses in the high normal range (60 to 80 ml). No correlation existed between anticoagulant state and menstrual blood loss. The data support the close association between bleeding disorders and menorrhagia and suggest that oral anticoagulants increase menstrual blood loss. (AM J OBSTET GVNECOL 1990;162:1261-3.)
Key words: Menorrhagia, bleeding disorder, oral anticoagulant therapy
Material and methods
Menorrhagia is generally believed to be a major symptom in women with a bleeding disorder. I. 2 Women treated with oral anticoagulant therapy also more often complain of menorrhagia. Menorrhagia is defined as a measured menstrual blood loss of more than 80 ml from a normal secretory endometrium after a normal ovulation, because the incidence of anemia increases significantly above this level.' Some investigators consider 60 ml as the upper normal limit of menstrual blood loss because this already causes iron deficiency, as reflected in low serum ferritin levels! The definition of menorrhagia requires a direct assay of menstrual blood loss because subjective menstrual blood loss assessments are unreliable." 5 In populations of healthy women in Western Europe, mean menstrual blood loss varies from 34 to 44 ml and menorrhagia occurs in 9% to 14%.3.6 Dramatic case reports exist of severe menorrhagia in women with a bleeding disorder,!· 2 but only of 10 women has measured menstrual blood loss been documented. 7 • 8 Nine of these 10 women had a menstrual blood loss of more than 80 ml, up to 1000 ml. No data are available on menstrual blood loss in women treated with oral anticoagulant therapy. This study was designed to contribute data on measured menstrual blood loss in both categories of women.
Women with a bleeding disorder attending the Department of Gynaecology and Obstetrics or the Department of Haematology at the University Hospital, Utrecht, and women treated with oral anticoagulation therapy with coumarin derivates attending the Thrombosis Center of the City of Utrecht, were asked to enter the trial. Inclusion criteria were as follows: younger than 45 years of age, regular menstrual cycle, normal uterus as assessed by bimanual palpation, no hormonal medication, no intrauterine contraceptive device, and except for women taking oral anticoagulant therapy, no medication that could interfere with hemostatis. Menstrual blood loss was measured once with the alkaline hematin method, as described previously.9 Recent hematologic laboratory findings of women with a bleeding disorder were collected. In women treated with oral anticoagulant therapy, a Thrombotest (modified prothrombin time test with bovine thromboplastin) was determined to evaluate the anticoagulant state around the time of menstruation. Thrombosis Centers in The Netherlands use the Thrombotest to control oral anticoagulant therapy.lo To determine a relation between menstrual blood loss and Thrombotest, the Spearman rank correlation coefficient was calculated.
From the Department of Gynaecology and Obstetrics" and the Department of Haematology,' University Hospital. Received for publication October 27, 1989; accepted February 5, 1990. Reprint requests: M. A. van Eijkeren, MD, PhD, Leidseweg65, 3531 BD Utrecht, The Netherlands.
Hematologic characteristics and menstrual blood loss data of six women with bleeding disorders are illustrated in Table I. Various types of bleeding disorders were included, such as congenital factor II deficiency, Glanzmann's thrombasthenia, acquired thrombocytopathia and thrombocytopenia, idiopatic thrombocyto-
611119899
Results
1261
1262 van Eijkeren et al.
May 1990
Am J Obstet Gynecol
Table I. Hematologic characteristics and
Table II. Indication for therapy, hematologic
menstrual blood loss data of six women with a bleeding disorder
characteristics, and menstrual blood loss data of 11 women using oral anticoagulant therapy
Bleeding disorder and recent laboratory data
Congenital factor II deficiency (hemoglobin 5.1 mmollL; factor II 9%; Simplate bleeding time >30 min)* Glanzmann's thrombasthenia (hemoglobin 8.7 mmollL; Simplate bleeding time >30 min) Acquired thrombocytopenia and thrombocytopathia (hemoglobin 5.1 mmollL; ferritin 2 flogfL; Simplate bleeding time >30 min; thrombocytes 99.10 9 fL) Idiopathic thrombocytopenia (hemoglobin 8.0 mmollL; thrombocytes 72.10 9 fL; Simplate bleeding time 9 min 30 sec) Idiopathic thrombocytopenia (hemoglobin 7.5 mmollL; thrombocytes 80.10 9 fL; Simplate bleeding time normal) Von Willebrand's disease (type IIa) (von Willebrand factor antigen 40% to 60%; hemoglobin 9.3 mmollL; Simplate bleeding time >30 min) Mean SD
Menstrual blood loss (ml)
568 140 320
142
86
60
219 193
*Normal values: hemoglobin >8 mmollL; thrombocytes > 150.109 fL; Simplate bleeding time 14 flogfL; factor II 65% to 130 %.
penia, and von Willebrand's disease. In five women menstrual blood loss exceeded the upper normal limit of 80 ml (range, 86 to 568 ml). The patient with von Willebrand's disease had a menstrual blood loss of 60 ml, which is in the high normal range. After menstrual blood loss assessment, the woman with congenital factor II deficiency was treated with antifibrinolytics, wellknown inhibitors of menstrual blood loss. II The woman with Glanzmann's thrombasthenia used iron medication and occasionally antifibrinolytics. A progesteronecontaining intrauterine contraceptive device was inserted into the uterus of the woman with an acquired bleeding disorder. These devices are known to diminish menstrual blood loss, in contrast to inert or coppercontaining intrauterine contraceptive devices. 12 The three other women were not treated. Table II shows indications for therapy, hematologic characteristics, and menstrual blood loss data of 11 women receiving oral anticoagulant therapy. Various indications for oral anticoagulant therapy existed: after cardiac or vessel surgery, after myocardial infarction, after puerperal deep venous thrombosis, or after osteotomy. Mean menstrual blood loss was 98 m!. Five women (45%) had menstrual blood losses of more than 80 ml (range 83 to 239 ml). Six women had menstrual
Patient No. I
2 3 4 5 6
7 8 9 10 II Mean SD
Indication for oral anticoagulant therapy
Thrombotest* (sec)
Menstrual blood loss (ml)
Artificial heart valve Artificial heart valve Artificial heart valve Artificial heart valve Aortic prosthesis:j: After myocardial infarction After myocardial infarction After myocardial infarction After puerperal deep venous thrombosis After puerperal deep venous thrombosis After osteotomy
131 141 62t 139 131 141 135 194 93t
29 209 22 71 154 239 9 75 51
122
83
II8 128 33
138 98 77
*Therapeutic ranges of Thrombotest: 120 to 200 seconds for patients with an artificial heart valve and an aortic prosthesis operation; 105 to 180 seconds for patients after deep venous thrombosis and after myocardial infarction, and 90 to 140 seconds for patients after osteotomy. tThrombotest times were too short. :j:Patient taking iron medication.
blood losses in the normal range, of which two were high normal (60 to 80 ml). Only one woman used iron medication (see Table II). Two Thrombotests were too short in duration (see Table II), all others were in the therapeutic range. The women whose Thrombotest times were too short had normal menstrual blood losses. No statistically significant correlation existed between menstrual blood loss and Thrombotest values.
Comment The aim of this study was to collect objective data on menstrual blood loss of women with a bleeding disorder and of women receiving oral anticoagulant therapy. In the 10 women with a bleeding disorder whose menstrual blood loss has been documented, six more women are added in this study. The results are summarized in Table I. Five women had menorrhagia (blood loss up to 568 ml), and one woman had a high normal menstrual blood loss. We realize that this is a very select study group. Many women with bleeding disorders already had a hysterectomy or used antifibrinolytics or oral contraceptives to diminish their menstrual blood loss, and hence were not suitable for this study. Nevertheless, the data of this study, together with the above-mentioned studies,7' 8 substantiate that menorrhagia occurs in the majority of women with bleeding disorders, even in amounts of menstrual blood loss that are a threat to general health. This necessitates regular control of hemoglobin and ferritin levels, or both. Ef-
Volume 162 Number 5
fective treatments for menorrhagia in patients with bleeding disorders are combination oral contraceptives, oral or intramuscular progestogens, or progesteronecontaining intrauterine contraceptive devices. 12 If contraception is not desired, prostaglandin synthesis inhibitors and antifibrinolytics are the drugs of choice. 13 In this study the first data on menstrual blood loss of 11 women receiving oral anticoagulant therapy are presented (see Table II). Mean menstrual blood loss (98 ml) and incidence of menorrhagia (five of 11 women) were higher than described in populations of healthy women in Western Europe (34 to 44 ml and 9% to 14%, respectively)." 6 Although the study group is limited, these data suggest that oral anticoagulants may increase menstrual blood loss. Definite clarification of the relation between oral anticoagulants and menstrual blood loss should come from studies comparing menstrual blood loss in women first with, and later without, oral anticoagulant therapy. This could be realized in women after puerperal deep venous thrombosis or after on osteotomy. Both conditions require only a temporary treatment with oral anticoagulants. These studies also could answer the question whether or not preventive iron medication should be advised. This is of importance since common treatments for menorrhagia, such as combination oral contraceptives or antifibrinolytics, are relatively contraindicated in women receiving oral anticoagulant therapy. Until such studies are done, regular control of hemoglobin or ferritin levels should be considered in menstruating women receiving oral anticoagulant therapy. Since combination oral contraceptives are relatively contraindicated and inert or copper-containing intrauterine contraceptive devices increase menstrual blood loss, continuous administration of progestogens is the contraceptive of choice in women receiving oral anticoagulant therapy. The different administration forms of progestogens are described above. We thank H. Chin, H. K. Nieuwenhuis, and P. C. Scholten for their help in recruiting women for the study.
Menstrual blood loss with oral anticoagulants
1263
REFERENCES 1. Quick AJ. Menstruation in hereditary bleeding disorders. Obstet Gynecol 1966;28:37-48. 2. Vinazzer H. von. Uber storungen der Haemostase als Ursache von Menorrhagien. Geburtshilfe Frauenheilkd 1966;26:743-45. 3. Hallberg L, Hogdahl A, Nilsson L, Rybo G. Menstrual blood loss-a population study. Acta Obstet Gynecol Scand 1966;45:320-51. 4. Shaw ST, Aaronson DE, Moyer DL Quantitation of menstrual blood loss-further evaluation of the alkaline hematin method. Contraception 1972;5:497-513. 5. Chimhira TH, Anderson ABM, Naish C, Cope E, Turnbull AC, Relation between measured menstrual blood loss and patient's subjective assessment of loss, duration of bleeding, number of sanitary towels used, uterine weight and endometrial surface area. Br J Obstet Gynaecol 1980;87:603-9. 6. Cole SK, Billiwicz WZ, Thomson AM. Sources of variation in menstrual blood loss. Br J Obstet Gynaecol 1971; 78:933-9. 7. Fraser IS, McCarron G, Markham R, Resta T, Watts A. Measured menstrual blood loss in women with menorrhagia associated with pelvic disease or coagulation disorder. Obstet Gynecol 1986;68:630-3. 8. Makiirainen L, Ylikorkala O. Primary and myomaassociated menorrhagia: role of prostaglandins and effect of ibuprofen. Br.1 Obstet Gynaecol 1986;93:974-8. 9. Eijkeren MA van, Scholten PC, Christiaens GMCL, Alsbach GP.1, Haspels AA. The alkaline hematin method for measuring menstrual blood loss-a modification and its clinical use in menorrhagia. Eur J Obstet Gynecol Reprod Bioi 1986;22:345-5 I. 10. Dijk van-Wierda CA, Hermans .1, Loeliger EA, Roos J. Interlaboratory oral anticoagulant quality assessment by The Netherlands foundation of thrombosis services. Thromb Haemost 1977;37:509-22. ' 11. Nilsson L, Rybo G. Treatment of menorrhagia. AM.1 OBSTET GVNECOL 1971;110:713-20. 12. Bergqvist A, Rybo G. Treatment of menorrhagia with intrauterine release of progesterone. Br.1 Obstet Gynaecol 1983;90:255-8. 13. Eijkeren MA van, Christiaens GCML, Sixma .1.1, Haspels AA. Menorrhagia-a review. Obstet Gynecol Surv 1989; 44:421-29.
