Menorrhagia is not the only gynaecological problem that women with bleeding disorders are more likely to experience. While women with bleeding disorders are at risk for the same obstetrical and gynaecological problems that affect all women, they appear to be disproportionately affected by conditions that are associated with bleeding [4] such as:
Haemorrhagic ovarian cysts
Haemorrhagic ovarian cysts may result from bleeding into the residual follicle (the corpus luteum) at the time of ovulation. This may result in bleeding into the follicle, intraperitoneal bleeding, bleeding into the broad ligament of the uterus or bleeding into the retroperitoneum. Haemorrhagic ovarian cysts are frequent particularly among VWD affected women (6%) [20], whereas in haemophilia carriers (10%) or women affected by other bleeding disorders (particularly in FXIII deficiency: 20-50%) the higher prevalence of ovarian cysts may also be associated with no bleeding. In women with bleeding disorders without documented haemorrhagic ovarian cysts, a high prevalence of mid-cycle pain or "Mittelschmerz", associated with bleeding at the time of ovulation, was reported (2/3 of the times) [21].
Endometriosis
Endometriosis is a painful inflammatory condition characterized by the presence of endometrial tissue at ectopic sites. The rate of endometriosis is increased in women with heavier menses presumably due to the increased rate of retrograde menstruation, a probable aetiology of endometriosis [22]. Thus women with bleeding disorders who have menorrhagia would similarly be at increased risk. Whether identification of bleeding disorders and appropriate intervention to reduce the menstrual loss would have an impact on the rate of endometriosis is currently unknown.
Endometrial hyperplasia and polyps
Endometrial hyperplasia is an abnormal proliferation of the glands and stroma of the endometrium caused by continuous exposure to oestrogen. The most common presenting symptom of this condition is abnormal uterine bleeding [23]. Polyps are masses resulting from a proliferation of the glandular tissue that lines the cervix or the uterus. Polyps also present with bleeding [24]. It is doubtful that women with bleeding disorders are more likely to develop endometrial hyperplasia or polyps, but it is very likely that these women will become symptomatic.
Fibroids
There is no evidence that women with bleeding disorders are more likely to develop fibroids (leiomyoma), even if a higher prevalence (32% vs 17% of controls) [25] was reported in women with VWD. Fibroids are known to contribute to the development of heavy menstrual bleeding. As women with bleeding disorders are more likely to develop heavy menstrual bleeding, they may be more likely to become symptomatic. In most of the studies of the prevalence of bleeding disorders among women with menorrhagia, the presence of fibroids was an exclusion [1,26], or their presence was not reported [27-31]. The presence of fibroids, or other uterine pathology, however, does not preclude a bleeding disorder. Fibroids may unmask a previously subclinical bleeding tendency and, in a woman with a diagnosed bleeding disorder, may cause problematic bleeding.
Miscarriages
Miscarriage is common in the general population, with 12-13.5% of recognized pregnancies resulting in spontaneous miscarriage [32,33]. When women were followed with serial serum human chorionic gonadotrophin measurements, a high miscarriage rate of 31% was found [34]. An increased risk of miscarriage and placental abruption resulting in fetal loss or premature delivery among women with deficiency of FXIII [35-38] or fibrinogen [4] has been reported. It is generally believed that women with bleeding disorders are protected by the hypercoagulable state of pregnancy but whether women with other bleeding disorders have an increased risk of miscarriage is unclear. In women with VWD and in haemophilia carriers the reported prevalence of miscarriage was respectively of 22-25% and 31% [24,39,40]. Further studies are needed to confirm whether inherited bleeding disorders, other than deficiency of FXIII or fibrinogen, are associated with a higher rate of miscarriage. Factor replacement is used to reduce the probability of miscarriage in women with deficiency of fibrinogen [4] or FXIII. Whether any treatment is available or necessary to reduce the risk of miscarriage in women with other bleeding disorders has not been reported.
Bleeding during pregnancy
Pregnancy is accompanied by increased concentrations of fibrinogen, FVII, FVIII, FX and von Willebrand factor (VWF). Factor VIII and VWF levels rise even in haemophilia carriers or women with VWD. Factor II, FV and FIX are relatively unchanged. Free protein S, the active, unbound form, is decreased during pregnancy secondary to increased levels of its binding protein, the complement component C4b. Plasminogen activator inhibitor type 1 (PAI-1) levels are increased. All of these changes contribute to the hypercoagulable state of pregnancy, and, in women with bleeding disorders, contribute to improved haemostasis. Despite improved haemostasis, however, women with factor deficiencies do not achieve the same factor levels as those of women without factor deficiencies [4]. Bleeding during pregnancy is a common symptom reported in women with bleeding disorders [41-44]. The optimal management of bleeding during pregnancy in women with bleeding disorders is uncertain.
Postpartum haemorrhage
Postpartum haemorrhage is an anticipated problem among women with bleeding disorders. At the end of a normal pregnancy, an estimated 10-15% of a woman's blood volume, or at least 750 mL/min, flows through the uterus [45]. Normally after delivery of the infant and placenta, the uterine musculature or myometrium contracts around the uterine vasculature and the vasculature constricts in order to prevent exsanguination. Retained placental fragments and lacerations of the reproductive tract may also cause heavy bleeding, but the single most important cause of postpartum haemorrhage is uterine atony [46]. Despite the critical role of uterine contractility in con trolling postpartum blood loss, women with bleeding disorders are at an increased risk of postpartum haemorrhage. There are multiple case reports and several case series documenting the incidence of postpartum haemorrhage in women with bleeding disorders [4] but there are limited data that compare women with bleeding disorders and controls. Delayed or secondary postpartum haemorrhage is rare in the general population (0.7% more than 24 h after delivery [47,48]). However, a higher prevalence of delayed postpartum haemorrhage was reported among women affected by VWD, FXI deficiency and haemophilia carriers [42,49,50], making delayed postpartum haemorrhage more than 10-25 times more common among women with bleeding disorders. Among all women, the median duration of bleeding after delivery is 21-27 days [51-53], but coagulation factors, elevated during pregnancy, return to baseline within 14-21 days [54]. Therefore, there is a period of time, 2-3 weeks after delivery, when coagulation factors have returned to pre-pregnancy levels, but women are still bleeding. Women with bleeding disorders are particularly vulnerable to delayed or secondary postpartum haemorrhage during this same period of time. The average time of presentation of postpartum haemorrhage in women with VWD was estimated to be 15.7 ± 5.2 days [55]. The implication is that women with bleeding disorders may require prophylaxis and/or close observation for several weeks.