INVITED REVIEW Gynecological and obstetrical manifestations of inherited bleeding disorders in women F. PEYVANDI, I. GARAGIOLA and M. MENEGATTI U.O.S. Dipartimentale per la Diagnosi e la Terapia delle Coagulopatie, A. Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca ` Granda Ospedale Maggiore Policlinico, Universita ` degli Studi di Milano, Luigi Villa Foundation, Milan, Italy To cite this article: Peyvandi F, Garagiola I, Menegatti M. Gynecological and obstetrical manifestations of inherited bleeding disorders in women. J Thromb Haemost 2011; 9 (Suppl. 1): 236–245. Summary. Patients affected by bleeding disorders present a wide spectrum of clinical symptoms that vary from a mild or moderate bleeding t endency to s ignificant e pisodes. Women with inherited bleeding disorders are particularly disadvantaged since, in addition to suffering from general bleeding symptoms, they are also a t risk o f bleeding complications from regular haemostatic challenges during menstruation, pregnancy and childbirth. Moreover, such disorders pose important problems for affected women due to their reduced quality of life caused by limitations in activities and work, and alteration of t heir reproductive life. These latter problems include excessive menstrual bleeding or menorrhagia, miscarriage, bleeding complications during p regnancy and after delivery a nd their related complications such as acute or chronic anaemia. T he management of these women is difficult because of considerable inter-individual variation. Moreover, reliab le information on clinical management is scarce, only a few available long term prospective s tudies of large cohorts provide evidence-based guideline a bout diagnosis and treatment. Keywords: haemophilia, management, platelet disorders, rare bleeding disorders, von Willebrand d isease, w omen. Introduction Women are more likely to manifest a bleeding disorder as they have more opportuni ties to experience bl eeding cha llenges in their lifetime due to the natural cycle of menses and reproduction. Menstruation and o vulation may be a sso ciated with sig nifican t bleeding leading to the li mitation in conduct- ing daily activities, changes in social f u nctioning a nd adverse effect on quality o f life. At least 5–10% of women at reproductive ag e wi ll seek medical attention fo r men orrhagia [1]. The World Health Organisation (WHO) estimates that 18 million women worldwide are afflicted [ 2]. A variety of organic, endocrine, gynaecologic or other systemic causes may be respon sible for m enorrh agia; however, an underlying aetiology is identified in only 50% of cases [3]. Organic causes include infections of any g en itourin ary origin and bleeding disorders a s well as organic dysfunction as hepatic or renal failure. Chroni c liver d isease impairs production of clotting factors and reduces hormone metabolism (e.g. oestrogen). Any of these problems may lead to heavy uterine b leeding. The most common endocrinologic cause of heavy menstrual bleeding in adolescent girls is anovulatory d ysfunctional uterine bleeding owing to the immaturity of the hypotha- lamic–pituitary–ovarian axis. Anatomic aetiologies for men- orrhagia include uterin e fibroi ds, en dometrial po lyps and hyperplasia. Intra Uterine Device (IUD) placement, steroid hormones, chemotherapy agents, hypothalamic depressants, phenytoin and anticoagulants, which could al so cau se increased menstrual bleeding [4]. The considerable proportion ofwomenwithmenorrhagia(20%), who are comp rehen- sively tested for h aemostatic abnormalities, are f o und to have underlying bleeding dis orders such as von Willebran d disease (VWD), platelets function alteration or rare bleeding disorders (RBDs: deficiencies of c oagula tion factors s uch as fi b rinogen, factor (F)II, FV , FV + FVIII, F VII, F X, FXI and FXIII). Menorrhagia is only one of the gynaecological problems that women with bleeding disorders are more likely to experience, being at risk of o ther problems t hat may present with increased bleeding in conditions such as haemorrhagic ovarian cysts, endometriosis, hyperplasia, polyps, fibroids, pregnancy and childbirth. Pregnancy and childbirth, two important stages in the life of a woman, pose a special clinical ch allenge i n w omen with inherited bleeding disorders, since information about these issues are really scarce and limited to few c ase reports. A n accurate counselling for women affected with bleeding disor- ders is therefore recommended. Pathophysiology of abnormal uterine bleeding (menorrhagia) In the presence of ovulatory cycles, withdrawal of progester- one triggers a cascade of molecular and cellular events within the endometrium, initiating its breakdown and culminating in Correspondence: Flora Peyvandi, MD, PhD, Angelo Bianchi Bonomi Haemophilia and Thrombosis Centre, University of Milan, Via Pace, 9 -20122, Milan, Italy. Tel.: +39 02 55035414; fax: +39 02 54100125. E-mail: flora.peyvandi@unimi.it Journal of Thrombosis and Haemostasis, 9 (Suppl. 1): 236–245 DOI: 10.1111/j.1538-7836.2011.04372.x Ó 2011 International Society on Thrombosis and Haemostasis menstruation. During menstruation higher levels of prosta- glandin E2 a nd prostaglandin F2a in menstrual fluid are found in menorrhagic women when compared with those with normal menses [ 5,6]. Furthermore, the release of p rostaglandin E2, prostaglandin F2a and prostacyclin by the endometrium and myometrium during menstruation are increased in tissues obtained f rom m enorrhagic w omen [7,8]; and i ncreased concentrations of prostaglandin E receptors are also found in myometrium [9]. Recent studies on the function of prostaglandin receptors in endometrium have shown that prostanoids promote angiogenesis and may have a role in aberrant neovascularisation leading to dysfunctional uterine bleeding [10]. Moreover, local endometrial aberrations are considered to be the major contributing factor to essential menorrhagia. Kooy et al. [11] demonstrated that patients with menorrhagia have high endometrial endothelial cell prolifer- ation indices, supporting the hypothesis that disturbed angio- genesis may be a direct cause of excessive menstrual bleeding. In addition, fibrinolytic activity is significantly elevated in the endometrium of most women with ovulatory dysfunctional uterine bleeding [12]. The pathophysiology of abnormal uterine bleeding during menstruation in women affected by haemostasis defects could be b ased o n the aberran t for mation o f a platelet pl ug th at is a crucial fi rst s tep in t he r egulation of bl ood flow [13]. Thus, it is not surprising that platelet dysfunction and VWD have both been associated wi th menorrhagia, sometimes of a severe nature, and that me norrhagia is a common presenting symptom among f emale p atients with VWD. From a historical pe rspec- tive, it is i nteresting to note that the first patient identified with this disorder by Erik von Willebrand in 1926 eventually died of uncontrollable menstrual b leeding a t a ge 13 years. Menorrhagia History and definition The term ÔmenorrhagiaÕ appeared for the first time in the late 1700s and one of the earliest written uses were it was mentioned was a treatise in Latin (1775): ÔDisputatio medica, inauguralis, de menstruorum pro fluvio immodicoÕ [14]. T he term ÔmenorrhagiaÕ was r egularly u sed in publications throughout the 19th and 20th centuries, but the establish- ment of definitions for normal or abnormal menstrual loss has been difficult [15]. In 2006, the American College of Obstetricians and Gynecologists and the American Academy of Pediatrics issued a committee consensus report entitled ÔMenstruation in Girls and Adolescents: Using the Menstrual Cycle as a Vital SignÕ [16]. The consensus stated that normal menstruation begins at 11–14 years of age, the normal c ycle interval is 21–45 days, and the normal length of menstrual flow is 7 days or less with product use no more than 3–6 pads or tampons per day. Therefore, menorrhagia can be defined as heavy menstrual bleeding lasting for more than 7 days or resulting in the loss of more than 8 0 mL per menstrual cycle [17]. Differential diagnosis in women with menorrhagia It is important for t he clinician , when encountering women with menorrhagia, to understand whether bleeding symptoms represent a manifestation of a gynaecological problem or a disorder of haemostasis. Menorrhagia is often t he first clinical manifestation that women with bleeding disorders encounter, often at menarche; therefore, many affected patients initially attend their gynaecologist. Recently, a c onsensus o n diagnosis in women w ith menorrhagia was published by a n international experts p anel and recommendations were provided only if consensus could be reached [18]. Experts agreed that an underlying bleeding d isorder should be considered if any o f the following indicators are present: menorrhagia since m enarche; family history of a bleeding disorder; personal history of bleeding such as epistaxis, notab le bruising without injury, minor wound bleeding, bleeding of oral cavity or gastrointes- tinal tract without an obvious anatomic lesion, prolonged or excessive bleeding after dental extraction, unexpected postsur- gical bleeding, haemorrhage from ovarian cysts or corpus luteum, haemorrhage that required blood transfusion, failure of response t o c onventional management of menorrhagia [18]. However, only a relatively small proportion of these patients will have a t rue under lying disorder of haemostasis. Conse- quently, the discriminatory p ower of various bleeding symp- toms in predicting an underlying disorder of haemostasis has been incorporated into a scoring system (Ôbleeding score assessmentÕ) th rough the Intern ational Society of Haemostasis and Thrombosis network [19,20]. On the other hand, as measuring actual m enstrual blood loss is not feasible in clinical practice, Higham and colleagues devised the pictorial blood assessment chart (PBAC) as an alternative [21], to determine blood loss by visual self-assessment and scoring of sanitary pad and tampon saturation. Recently, a study was conducted t o develop a short, easy to administer screening tool for stratifying women with unexplained menorrhagia for haemostatic testing for underlying bleeding disorders. A combination of eight questions in four categories resulted in a sensitivity of 82% [95% confidence interval (CI): 75–90%] for bleeding disorders. Adding a PBAC score > 100 increased the sensitivity of the screening tool to 95% (95% CI: 91–99%) [22]. Eventually, women with a ÔpositiveÕ bleeding history n eed to be screened by coagulation tests including complete blood count (CBC), prothrombin time (PT), partial thromboplastin time (PTT), thrombin time (TT), VWD profile (VWF antigen, RiCof), FVIII levels, platelet function analyses (BT, PFA-100), FXIII l evels and other specific factors. If PT or PTT are prolonged, mixing test is necessary to distinguish deficiency of a coagulation factor from a natural inhibitor. If these tests turn out normal, studies of platelet function should be planned [23]. Menorrhagia in women with bleeding disorders In the last 20 years, it has been well-established that menor- rhagia is more prevalent in women with all bleeding disorders, however, using the PBAC, carriers of haemophilia and women Women with inherited bleeding disorders 237 Ó 2011 International Society on Thrombosis and Haemostasis affected with VWD and FXI deficiency were shown to h ave significantly higher menstrual scores [24]. The reported prev- alence of menorrhagia in carriers of haemophilia was estimated to be about 10–57% [25]. InwomenwithVWD,menorrhagiawasdeterminedtobea common and a major health problem: published data point out that in type 1 VWD, it occurs in 79–93% of women [26,27], whereas, in women with type 2 and type 3 VWD, the prevalence ranges from 32%–63% and 56–69%, respectively [28,29]. Menorrhagia in women with severe platelet dysfunction has been reported to be present in 51% of women with Bernard- Soulier syndrome [30]; data on i n women with GlanzmannÕs thrombasthenia are contrasting since two studies repo rt different frequencies of 13% and 98% [31,32]. In other bleeding disorders the reported prevalence was: 59% in women with FXI deficiency [33]; 35–64% in those with FXIII deficiency [34] a nd 35–70% in those with other rare factor deficiencies as reported in a number of case series [35]. From this reports it can also be inferred that menor- rhagia seems to be a major bleeding symptoms in women with rare bleeding disorders, regardless of factor level. Table 1 summarises populations, sample size and type of published studies described h erein. Nonetheless several stud- ies reported the prevalence of menorrhagia in women with bleeding disorders, only a few compare affected with healthy control women [26,36,37]. A recent study collecting informa- tion on prevalence of menorrhagia in 35 women affected with bleeding disorders comp ared to 114 c ontrols, reported that PBAC was significantly h igher in a ffected women than in controls (mean 258 vs. 171, P = 0.01) and menorrhagia had a prevalence of 71% of women with VWD, 53% in haemophilia carriers, 52% in women with RBDs and 46% in controls [38]. However, the prevalence reported in platelet disorders and in the majority of reports on rare coagulation disorders are not evid ence-based, because of t he small number of women who were analys ed. Complications and treatment of menorrhagia Women with menorrhagia often undergo unnecessary surgical interventions to relieve heavy menstrual bleeding, and at least Table 1 Populations, sample size and type of published studies herein reported Population (sample size) Type of study Reference Menorrhagia Haemophilia carriers (30) Prospective cohort 25 VWD type 1 (29) Case series 26 VWD type 1 (99) Survey 27 VWD type 2 (5) Case series 28 VWD registry on type 1, 2 and 3 Retrospective cohort 29 Bernard-Soulier syndrome (35) Case reports 30 GlanzmannÕs thrombasthenia (55) Case reports 31,32 FXI deficiency (20) Prospective cohort 33 FXIII deficiency (20) Case series 34 VWD (48 types 1, 2 and 3) Case – control 38 Haemophilia carriers (31) Coagulation deficiencies (35) Miscarriages Afibrinogenemia (6 in six reports) Case reports 35 Afibrinogenemia (18) Case serie Dysfibrinogenemia (1) Case report FXIII (16) Summary of case reports FXIII (10 in three reports) Case series Bleeding during pregnancy and delivery VWD (86) Case – control 36 Bernard-Soulier syndrome (9) Case reports 60 GlanzmannÕs thrombasthenia (16) Case reports 31 FXI deficiency (21) Case series 61 VWD (48 types 1, 2 and 3) Case – control 38 Haemophilia carriers (31) Coagulation deficiencies (35) Post partum hemorrhage Haemophilia carriers (32) Case series 69 VWD (2843) Database 70 Bernard-Soulier syndrome (7) Case reports 30 GlanzmannÕs thrombasthenia (7) Case reports 71 Hypofibrinogenemia (10) Case reports 72 FV (1), FVII (1) and FX deficiency (1) Case report 73–75 FXI deficiency (62) Case series 76 238 F. Peyvandi et al Ó 2011 International Society on Thrombosis and Haemostasis 60% of them undergo hysterectomy o r other surgical proce- dures, including endometrial ablation, dilatation and curettage. In 1973, Silwer published his experience with 18 women affected with VWD who underwent hysterectomy compared with 50 controls. Although there were no statistically significant differences, the women w ith VWD were more likely to require transfusion (50% vs. 30% of controls) and were less likely to be free of any bleeding complications (28% vs. 60% of controls) [39]. With a proper diagnosis of their condition, many women with bleeding disorders could avoid these complications and surgeries, decrease their severity of menstrual bleeding and improve their quality of life [40]. Recently, Skankar et al. evaluated the quality of life in 187 women with menorrhagia with or without inherited bleeding disorders (scoring general health, physical, social and mental functioning, pain, energy) concluding that women with bleed- ing disorders had a worse quality of life because they had all scales significantly affected (physical parameters were less affected in healthy women) [41]. The excessive blood loss can result in iron deficiency anaemia, which causes tiredness and fatigue affecting activities of daily living, socialising with friends or various recreational and sport activities [24]. Thus, menor- rhagia, which may be a source of inconvenience to women in general, is significantly more problematic for women affected with bleeding disorders. However, the average age of the women identified with an underlying haemostatic defect in these studies is approximately 35 years [25]. This means that diagnosis of the underlying haemostatic disorder is a relatively late one within the average duration of the reproductive lifespan. Earlier identification of women w ith menorrhagia and an underlying haemostatic defect should be beneficial in terms of allowing for the use o f specific haemostatic measures in t he management of the menorrhagia [36]. Management of menor- rhagia in women with bleeding disorders is based on medical (hormonal or haemostatic therapy) and surgical care with the primary aim of improving quality of life [42]. Drug therapy, based on levonorgestrel intrauterine system, combined hormonal contraceptive methods currently available (pill, transdermal contraceptive patches, vaginal rings), oral progestogens and gonadotropin-releasing hormone (GnRH) analogues, should be the first choice and the only option to preserve the reproductive function. In obligate haemophilia carriers, with a positive family history, clotting factor level should be established before the onset of menarche, t o anticipate t he possibility o f an a cute menorrhagia [43]. Haemostatic therapy includes antifibrin- olytic (tranexamic acid and aminocaproic acid) and DDAVP or desmopressin (1-desamino-8- D -arginine v aso- pressin), a synthetic vasopressin that stimulates the release of VWF from endothelial cell, in addition to replacement treatment with coagulation factors [43]. Surgical options should include conservative surgery (endometrial resection and ablation) with hysterectomy performed in cases of failed medical therapy and/or when fertility is no longer desired. In women with VWD, therapy should start on the first or second day of menses, with the specific therapeutic choice, dose, duration of therapy, and therapeutic monitoring [44]. In women with platelet dysfunction, intranasal desmopressin as well as tranexamic acid therapy have been demonstrated to reduce menstrual blood flow, but in severe disorders such as GlanzmannÕs thrombasthenia, platelets transfusions may be needed [45]; however repeated transfusions may result in the formation of alloimmune antiplatelet antibodies. Such anti- bodies are antigen-driven and are produced against different epitopes on the integrin they may block platelet aggregation, and lead to the rapid removal of transfused platelets by immune mechanisms. Recombinant FVIIa has been success- fully used as an alternative a pproach for e arly cessation of bleeding, often in association with anti-fibrinolytic agents [46]. There are few data on management of acute, severe menorrhagia, particularly in the adolescent or woman with a bleeding disorder; however, experts agreed that balloon tamponade, hormonal therapy (oestrogen) and antifibrinolytic treatment should be instituted while replacing clotting factor or platelets as indicated [18]. Tranexamic acid has been shown to be an effective medical management for menorrhagia in women with and without bleeding disorders [47]. Antifibrino- lytic agents are generally well-tolerated despite the unc ertain thrombotic risk reported in some studies [48–50]. Miscarriage Miscarriage i s relatively common in the general population, with 12–13.5% of recognised pregnancies resulting in sponta- neous a bortion, while there are case reports and case s eries documenting the increased risk of miscarriage in women with bleeding disorders [34]. In contrast, the limited number of reports on women with platelets disorders makes it impossible to draw any conclusions on the rate of m iscarriage in such defects [34]. Human GlanzmannÕs thrombasthenia can result from defects in the genes for either the aIIb or the b3 subunit. In a study by Hodivala-Dilke et al. [51], a knock-out b3 null-mice model revealing placentation defects that may also occur in human GlanzmannÕs thrombasthenia patients and may provide insight into preeclampsia of pregnancy was proposed. Haemorrhage in a layer of trophoblast, ReichertÕs membranes, was observed, which was probably due to a combination of leakage of maternal blood vessels and defective platelet function. Moreover, a second phenotype was observed in approximately 20% of b3–null maternally derived placenta the cell layers within the labyrinth appeared thickened and occluded sinus volume, thus decreasing efficient blood circu- lation and exchange of nutrients. This often led to necrosis within the labyrinth and compromised embryo survival [51]. It is generally believed that women with bleeding disorders are protected by the hypercoagulable state of pregnancy; however, an increased risk of miscarriage and placental abruption resulting in recurrent foetal loss or premature delivery among women with afibrinogenemia [52–54] or FXIII deficiency [55] has been reported. Both FXIII and fibrinogen Women with inherited bleeding disorders 239 Ó 2011 International Society on Thrombosis and Haemostasis play an important role in placental implantation and mainte- nance of pregnancy. Homozygous FXIII-A deficient women are reported to experience recurrent pregnancy losses [55], but the cause of these losses is still unknown. Usually the implantation process initiates by the seventh day after ovula- tion. The blastocyst a dheres the surface e pithelium of endo- metrium and then giant trophoblasts begin to penetrate it. After penetration, the blastocyst intrudes into the underlying decidual stroma and giant trophoblasts expand into masses of both syncytiotrophoblasts and cytotrophoblasts [56]. When the cytotrophoblast invade endometrium a complex interaction involves FXIII-A which cross-links fibrinogen and fibronectin, both important for the attachment of the placenta to the uterus [57]. Thus, deficiency of FXIII-A at the site of implantation will adversely affect fibrin-fibronectin cross-linking, resulting in detachment of the placenta from the uterus and subsequent miscarriage [56,57]. Fibrinogen, a major blood glycoprotein, is a dimer of three polypeptide chains: Aa, Bb and c. The threeoverlapping hereditary abnormalities of fibrinogen, afibrinogenemia, dysfi- brinogenemia and hypofibrinogenemia, have been associated with recurrent pregnancy loss. Hypofibrinogenemic and exper- imental afibrinogenemic mice exhibited similar features of bleeding tendency and miscarriage [58]. Pregnant mice homo- zygous for a deletion of the Fg-cchain, which results in a total fibrinogen deficiency state, aborted the fo etus at the equivalent gestational stage seen in humans. The fibrinogen deficiency does not alter embryonic development, but formation of t he placenta and yolk sac is significantly compromised. The loss of embryo in afibrinogenemic mice is because of an abortive process that is initiated as an exacerbation of the haemorrhage that normally occurs around sixth day during the critical stage of maternal and foetal vascular development when the embryo is invading the maternal deciduas. This event g ives rise to a robust bleeding that causes extensive placental disruption resulting in the loss of embryo [58]. In conclusion, on the basis of the mouse model, the absence or a significant decrease in maternal fibrinogen is sufficient to cause rupture of the maternal vasculature affecting embryonic trophoblast infiltra- tion and leading to haemorrhagic miscarriage. Further studies are needed t o c onfirm whether inherited bleeding disorders, other than deficiency of fibrinogen or FXIII are associated with a higher rate of miscarriage. Pregnancy and delivery Pregnancy and delivery also pose a special clinical challenge in women with c oagulation disord ers, since i nformation about these issues are really scarce and limited to few case reports. Normally, pregnancy is accompanied by increased concentra- tions of fibrinogen, FVII, FVIII, FX and von Willebrand factor, particularly marked in the third trimester [59]. On the contrary, FII, FV, FIX and F XIII are r elatively unchanged [59]. A ll of these c hanges contribute to the hypercoagulable state of p regnancy, a nd, in women with b leeding disorders, contribute to improved haemostasis. The risk of bleeding in early pregnancy is unknown in carriers of haemophilia, but there is evidence that t he risk after 24 weeksÕ gestation is not increased [28]. A c ase-control study reports the experience of 86 w omen with VWD and 70 controls with bleeding problem during pregnancy. This report evidences that 1.3% of women w ith VWD have heavy bleeding that ended the pregnancy vs. 0.3% of controls (P = 0.0001) [35]. A review of Kriplani et al. [60] reported eight previous studies on pregnancy outcome in women with Bernard-Soulier syndrome. Only one patient had bleeding in the antenatal period, while most patients became symptomatic in the intrapartum a nd immediate p ostpartum period; pregnancy and delivery appeared uncomplicated in women w ith GlanzmannÕs thrombasthenia, as shown in a case report that analysed 21 pregnancies in 16 women with this platelet dysfunction [31]. A recent investigation by Siboni et al. collecting information on bleeding at the time of menarche, bleeding during pregnancy and the postpartum period in 35 women affected with different type of RBDs and 114 controls, recorded that bleeding during pregnancy was not more frequent in patients than in controls (21% vs. 6%, P = 0.11) [37]. Nonetheless, excessive bleeding at delivery was observed in 16% (4/25) of the pregnancies in a case series including 11 women with FXI deficiency with different coagulant activity [61]. Post partum haemorrhage Haemorrhage is the single leading cause of maternal mortality [62]. According to the World Health Organisation (WHO) pregnancy-related death s, in the last t wo decades were approximately 510.000 per year world-wide and 25% of them were due to severe bleeding occurring in the post-partum period [63,64]. The conventional definition of post partum haemorrhage (PPH) is a blood loss of > 500 mL in the first 24 h after delivery a nd > 1000 mL for caesarean sections within 24 h of delivery [ 65,66]. PPH is classified as p rimary when occurs within the first 24 h postpartum or secondary, occurring between24handupto6weeksofpostpartum.Themedian duration of bleeding after delivery is 21–27 days [67], but coagulation factors, elevated during pregnancy, return to baseline within 14–21 days [68]. Therefore, t here is a period of time when coagulation factors return to pre-pregnancy levels, but women could still be at risk of bleeding. Delayed or secondary PPH is rare in the general population; on the contrary, women with bleeding disorders are particularly vulnerable to this type of bleeding. The prevalence of primary and secondary PPH in haemo- philia carriers has been reported to be 22% and 9–11%, respectively [69]. However, two different series of women with VWD reported a lower prevalence of primary PPH (12.5– 18.5% of deliveries) and a higher prevalence of the secondary (20–25%) [34]. The most r ecent data documenting and comparing the incidence of PPH in women with VWD and controls come from US discharge database, reporting that 6% 240 F. Peyvandi et al Ó 2011 International Society on Thrombosis and Haemostasis of pregnancies in such women were complicated by PPH compared to 4% of controls (OR = 1.5; 95% CI: 1.1–2.0, P- value < 0.01) [70]. There are limited data of prevalence of PPH in women with severe platelet dysfunction [34]: among women affected with the Bernard-Soulier syndrome 3 of 7 (43%) experienced undefined PPH [30], while the prevalence of primary and secondary PPH in women with GlanzmannÕs thrombasthenia was estimated to be 57% and 43%, respectively [71]. In RBDs, PPH was found to be the most common obstetric complication occurring in 45% of the deliveries in 10 patients with hypofibrinogenemia [72], and in 76% (13/17) of deliveries in nine women with FV deficiency [73], who resu lted to be at higher risk of bleeding, especially if they are affected with the severe form of the deficiency. Although at a lower rate, PPH was reported also in a case of severe FVII deficiency [74], a case of moderate FX deficiency due to an abnormal FX rather than to a FX d eficiency [75] and in s evere FXI deficiency (levels < 17 IU dL) [76]. Salomon et al. performed a large study on 62 women affected with FXI deficiency (164 pregnancies) showing that 69% of women never experienced PPH during 93 deliveries without any prophylactic coverage. T hese authors therefore argued that prophylactic treatment is not mandatory for these women, especially with vaginal delivery (however, excessive bleeding at delivery still did occur on about 20% of deliveries not covered by FFP). On the contrary, it is well documented that the risk of delayed PPH is at least 25–30 fold higher in women with FXI deficiency [34]. Management of pregnancy and delivery For haemophilia carriers w ith subnormal facto r levels, despite the pregnancy-related rise of FVIII, in travenous access should be established and prophylactic treatment given, preferably using recombinant FVIII and FIX, to cover labour, delivery and immediate postpartum period, starting at onset of labour. The use of tranexamic acid has been also suggested to prevent secondary PPH [42]. Peripartum management of women with VWD at the beginning requires the laboratory evaluation for VWD that includes a basic coagulation panel, VWF:Ag assay, VWF:RCo assay and FVIII levels. The treatment should be instituted if the levels of VWF:RCo and FVIII are < 50 IU dL )1 before any invasive procedure and delivery. The mainstays of therapy are desmopressin (DDAVP) and plasma concentrates that contain VWF. DDAVP may be used in women w ith type 1 VWD; recent data indicate that some individuals have accelerated clearance of VWF; therefore, even patients with type 1 may benefit from a test dose of DDAVP and subsequent measure- ment of VWF:RCo to document treatment efficacy [77]. In women with type 2, the main problem is that, despite an increase in secretion of VWF after DDAVP, the VWF secreted will retain its intrinsic molecular dysfunction. Consequently, the preferred therapy for type 2 is the use of VWF concentrates [78]. However, a small s ubset of women with type 2 VWD respond to desmopressin. Identification of those i ndividuals requires a test dose of DDAVP and subsequent measurement ofVWF:RCo1and4hafterthedose.IftheVWF:RCo corrects after dose, DDAVP is acceptable treatment for those women. Minor-side effects of DDAVP include flushing, headache, gastrointestinal complaints, and transient hypo- or hypertension. Repeated dosing may lead to water retention and hyponatremia. Desmopressin is safe for the foetus because it does not cross the placenta in detectable amounts [78]. According to previous reports, women with VWD t ype 3 lack the physiological rise in VWF during pregnancy. Only few reports exist about the management of pregnancy and delivery in women with VWD type 3, hence few data about the clinical problems and their appropriate management are available. However, clinical experience suggests that bleeding at delivery and early postpartum is frequent without replacement therapy. There are limited data on management of pregnancy a nd delivery in women with inherited platelet disorders, but epidural anaesthesia should be avoided and platelet transfusion before and after delivery ( up to 6 days post partum) have been reported to reduce the risk of bleeding in women with GlanzmannÕs thrombasthenia [45]. The use of recombinant FVIIa has been proposed especially in individuals unresponsive to platelet transfusion because of isoimmunisation [46]. Reg- ular replacement therapy throughout pregnancy to maintain a minimum activity level is recommended in women with afibrinogenemia and should be commenced as soon as possible in pregnancy to reduce the probability o f early foetal loss [79,80]. Management of women with hypofibrinogenemia should follow similar recommendation depending on the fibrinogen level, individual bleeding tendency and family history, as well as previous obstetric history [81]. Thrombotic events during puerperium have also been reported among women with afibrinogenemia and hypofibrinogenemia [82], the potential for thrombosis associated with replacement therapy must be carefully evaluated a nd balanced against the risk of bleeding. The management of pregnancy in women with dysfibrinogenemia needs to be individualised, taking into account the fibrinogen level and personal a nd family history of bleeding and thrombosis [82]. No specific treatment is required in asymptomatic women. A s ignificant r ise in FVII level is observed during pregnancy in women with mild/moderate forms of FVII deficiency (hetero- zygotes) [36], but not in women with severe deficiency [83], who are more likely to be at risk of PPH, hence, prophylactic treatment is required for women with low FVII coagulant activity levels at term and/or significant bleeding history. Also women with severe F X deficiency and a history of adverse pregnancy outcome may benefit from replacement therapy during pregnancy [79], and to cover l abour and delivery to minimise the risk o f bleeding complications [84]. In FXIII deficiency a therapy should be c ommenced as early as possible in pregnancy to prevent foetal loss [85] and t he treatment s hould also be continued during labour and delivery [86]. On the contrary treatment is not mandatory for women with FXI deficiency, especially with vaginal delivery [76]; however, due to the unpredictable bleeding tendency in FXI deficiency, Women with inherited bleeding disorders 241 Ó 2011 International Society on Thrombosis and Haemostasis Table 2 Available recommendation for treatment in women with inherited bleeding disorders for menorrhagia (A) and d uring/after pregnancy (B) [46,76,87] (A) Menorrhagia VWD In women with VWD, therapy should start on the first or second day of menses, with the specific therapeutic choice, dose, duration of therapy, and therapeutic monitoring. Haemostatic therapy includes antifibrinolytic (tranexamic acid and aminocaproic acid) and/or DDAVP or desmopressin (1-desamino-8- D -arginine vasopressin), a synthetic vasopressin that stimulates the release of VWF from endothelial cell, in addition to replacement treatment with coagulation factors. Platelet disorders In women with platelet dysfunction, intranasal DDAVP as well as tranexamic acid therapy have been demonstrated to reduce menstrual blood flow, but in severe disorders such as GlanzmannÕs thrombasthenia, platelets transfusions may be needed. Rare coagulation disorders Therapeutic options for the control of menorrhagia in women with underlying coagulation disorders include: (1) Medical treatments: Anti-fibrinolytics Combined hormonal contraceptives Intranasal and subcutaneous DDAVP Oral contraceptives Levonorgestrel intrauterine device Clotting factor replacement (expecially in women with severe deficiency and acute bleeding. The role of clotting factors replacement as prophylaxis in severe bleeders need to be analysed) (2) Surgical treatments such as endometrial ablation and hysterectomy. (B) Pregnancy VWD type 1 DDAVP may be used; recent data indicate that some individuals have accelerated clearance of VWF; therefore, even patients with type 1 may benefit from a test dose of DDAVP and subsequent measurement of VWF:RCo to document treatment efficacy VWD type 2 In women with type 2, the main problem is that, despite an increase in secretion of VWF after DDAVP, the VWF secreted will retain its intrinsic molecular dysfunction. Consequently, the preferred therapy for type 2 is the use of VWF concentrates VWD type 3 Since women with VWD Type 3 lack the physiological rise in VWF during pregnancy, they should receive prophylaxis at the time of delivery to raise VWF factor levels at least to 50 IU dL )1 . Platelet disorders Platelet transfusion before and after delivery (up to 6 days post partum) have been reported to reduce the risk of bleeding in women with GlanzmannÕs thrombasthenia. The use of rFVIIa has been proposed in cases of isoimmunization. a- and hypo- fibrinogenemia Replacement therapy to maintain a minimum fibrinogen level of 1.5 mg dL )1 is suggested for the prevention of PPH in afibrinogenemia. For women with hypofibrinogenaemia, intrapartum replacement is required if fibrinogen level is below 1.5 mg dL )1 ) and/or the woman has a significant bleeding history. Thrombosis events were reported during puerpuerium, hence postpartum management, including the use of postpartum prophylaxis, should take into account any personal and family history of bleeding and thrombosis. Dysfibrinogenemia Women with dysfibrinogenaemia are also at risk of both postpartum thrombosis and PPH. Postpartum management of these women should be individualized based on their fibrinogen level as well as personal and family history of bleeding and thrombosis. FII Secondary PPH was reported in one pregnancy. Based on this limited data, it is difficult to make recommendation for the obstetric management. These women are considered potentially at risk of PPH. Prothrombin complex concentrate to maintain FII level > 20–30 IU Kg )1 . FV In women with partial deficiency and no history of bleeding, labour and delivery could be managed expectantly. Women with FV deficiency especially those with low FV levels appear to be at increased risk of PPH. Substitution therapy with FFP is recommended to raise FV level to above 15–25%. FV + VIII There are no enough data in relation to pregnancy in these women, the obstetric experience of women with FV deficiency and carriers of haemophilia could probably serve as a useful guide in these patients: FV > 15–25%; FVIII > 50% (combination of DDAVP or FVIII concentrate and virus inactivated FFP). FVII Women with low FVII levels or positive bleeding history are more likely to be risk of PPH, therefore, prophylactic treatment is required for women with FVII level of < 10–20%. rFVIIa (15–30 lgkg )1 ) should be the treatment of choice. FX Patients with severe FX deficiency (< 1%) tend to be the most seriously affected patients with RBDs, therefore they may benefit from replacement therapy during pregnancy and to cover labour and delivery to minimize the risk of bleeding complications. In women with FX level > 10–20% and no significant bleeding history, a conservative approach could be adopted. FXI Women with FXI deficiency are at increased risk of both primary and secondary PPH. Prophylactic treatment with tranexamic acid should be considered post delivery up to 2 weeks, particularly for those with a bleeding phenotype. The concomitant use of tranexamic acid and FXI concentrates should be avoided. FXIII The incidence of PPH in women FXIII deficiency is not known. Successful pregnancy in women with FXIII subunit A deficiency are generally only achieved with replacement therapy throughout pregnancy; a level > 10–20% during pregnancy should be considered. 242 F. Peyvandi et al Ó 2011 International Society on Thrombosis and Haemostasis especially during surgery, the decision for prophylaxis during labour and delivery needs to be individualised and must take into consideration FXI level, personal/family bleeding history and the mode of delivery. Based o n v ery limited available data, it is difficult to make recommendation for the obstetric man age- ment of women with prothrombin, FV and FV + FVIII deficiencies, therefore, careful management of labour and the immediate postpartum period is necessary. Table 2 reports available recommendation for the obstetric management of women with inherited bleeding disorders [46,76,87]. Counselling and prenatal diagnosis Preconceptual counselling should precede prenatal diagnosis in known women with inherited bleeding disorders. Genetic counselling should be carried out before conception to allow consideration of risk assessment of the potential carrier (in haemophilia) or state of heteroz ygosity in two partners of families a ffected with autosomal recessive bleeding disorders. The counselling should provide adequate information not only concerning risk of bleeding disorders, but also for suitable reproductive options and methods of prenatal testing that are available with the limitation and potential complication. The ideal management of women with inherited bleeding disorders is through multidisciplinary clinics with an ideal team including a laboratory haematologist, an obstetrician-gynaecologist, an anaesthesiologist, a family physician, a social worker, a pharmacist, and laboratory technician. Disclosure of Conflict of Interests Flora Peyvandi served as a consultant for CSL Behring on the issue of women with rare bleeding disorders. Isabella Garagiola and Marzia Menegatti do not have any conflicts of interest to disclose. References 1 K ouides PA. Blee ding symptom asse ssment and hemostasis evalu ation of menorrhagia. Curr Opin Hematol 2008; 15: 465–72. 2 Shaw JA, Shaw HA. Menorrhagia. Medscape, 2011 http://www. emedicine.com/MED/topic1449.htm.12 May 2011. 3 W arner P, Critchle y HO, Lumsden MA, Camp bell-Brown M, Douglas A, Murray G. Referral for menstrual problems: cross sectional survey of symptoms, reasons for referral, and management. Br Med J 2001; 323: 24–8. 4 W arner PE, Critchley HO, Lumsden MA, Campbell-Brown M, Douglas A, Murray GD. Menorrhagia I: measured blood loss, clinical features, and outcome in women with heavy periods: a survey with follow-up data. Am J Obstet Gynecol 2004; 190: 1216–23. 5 H agenfeldt K. The role of prostaglandins and allied substances in uterine haemostasis. Contraception 1987; 36: 23–35. 6 Rees M CP, A nderson ABM, D emers L M, Turnbull AC. Prosta- glandins in m enstrual fluid in menorrhagia and dysmenorrhoea. Br J Obstet Gynaecol 1984; 91: 673–80. 7 Rees MCP, Anderson ABM, Demers LM, Turnbull AC. Endometrial and myometrial prostaglandin release during menstrual cycle in relation to menstrual blood loss. J Clin Endocrinol Metab 1984; 58: 813–8. 8 Makarainen L, Ylikorkala O. Primary and myoma-associated men- orrhagia: role of prostaglandins and effects of ibuprofen. Br J Obstet Gynaecol 1986; 93: 974–8. 9 A delantado JM, Rees MCP, Lopez-Bernal A, Turnbull AC. Increased uterine prostaglandin E receptors in menorrhagic women. Br J Obstet Gynaecol 1988; 95: 162–5. 10 Jabbour HN, Sales KJ. Prostaglandin receptor signalling and function in human endometrial pathology. Trends Endocrinol Metab 2004; 15: 398–404. 11 K ooy J, Tay lor NH, Healy DL, R ogers PA. En dothelial cell pro- liferationintheendometiumofwomenwithmenorrhagiaandin women following endometrial ablation. Hum Reprod 1996; 11: 1067– 72. 12 G leeson N, Devitt M, Sheppard BL, B onnar J. Endometrial fibrino- lytic enzymes in women with normal men struation and dysfunctional uterine bleeding. Br J Obstet Gynaecol 1993; 100: 768–71. 13 Ch ristiaens G C, Sixma J J, Haspels A A. Morp hology of h aemo stasis in menstrual endometrium. Br J Obstet Gynaecol 1980; 87: 425–39. 14 Pe rrone au R. Disputatio medica, inauguralis, de menstruorum profluvio immodico. Edinburgh: Balfour & Smiellie, 1775. 15 M cKa y WJS. The History of Ancient Gynaecology. London: Bailliere, Tindall & Cox, 1901:302. 16 Diaz A, Laufer MR, Breech LL; American Academy of Pediatrics Committee on Adolescence, American College of Obstetricians and Gynecologists Committee o n Adole scent Health Care. Menstruation in girls and adolescents: using the menstrual cycle as a vital sign. Pediatrics 2006; 118: 2245–50. 17 ACOG Committee on Practice Bulletins: Gynecology, American College of Obstetricians and Gynecologists. ACOG practice bulletin: management of anovulatory bleeding. Int J Gynaecol Obstet 2001; 72: 263–71. 18 J ames AH, Kouides PA, Abdul-Kadir R, Edlund M, Federici AB, Halimeh S, Kamphuisen PW, Konkle BA, Martı ´ nez-Perez O, McLintock C, Peyvandi F, Winikoff R. Von Willebrand disease and other bleeding disorders in women: consensus on diagnosis and man- agement from an international expert panel. Am J Obstet Gynecol 2009; 201: 12.e1–8. 19 T os etto A, Ca stam an G, R ode ghie ro F. Assessing bleeding in von Willebrand disease with bleeding score. Blood Rev 2007; 21: 89–97. 20 Rodeghiero F, Tosetto A, Abshire T, Arnold DM, Coller B, James P, Neunert C, Lillicrap D; ISTH/SSC joint VWF and Perinatal/Pediatric Hemostasis Subcommittees Working Group. ISTH/SSC bleeding assessment tool: a standardized questionn aire an d a p roposal f or a n ew bleeding score for inherited bleeding disorders. J Thromb Haemost 2010; 8: 2063–5. 21 H i gham JM, OÕBrien PM, Shaw RW. Assessment of menstrual blood loss using a pictorial chart. Br J Obstet Gynaecol 1990; 97: 734–9. 22 Philipp CS, Faiz A, Dowling NF, Beckman M, Owens S, Ayers C, Bachmann G. Development of a screening tool for identifying women with menorrhagia for hemostatic evaluation. Am J Obstet Gynecol 2008; 198:163.e1–8. 23 Philipp CS, Dilley A, Miller CH, Evatt B, Baranwal A, Schwartz R, Bachmann G, Saidi P. Platelet f unctional d efects in women with unexplained menorrhagia. JThrombHaemost2003; 1: 477–84. 24 K adir RA, Edlund M, von Mackensen S. The impact of menstrual disorders on quality of life in women with inherited bleeding disorders. Haemophilia 2010; 16: 832–9. 25 Kadir RA, Economides DL, Sabin CA, Pollard D, Lee CA. Assess- ment of menstrual blood loss and gynaecological problems in patients with inherited bleeding disorders. Haemophilia 1999; 5: 40–8. 26 Ragni MV, Bontempo FA, Hasset AC. von Willebrand disease and bleeding in women. Hemophilia 1995; 5: 313–7. 27 K ouides PA, Phatak PD, Burkart P, Braggins C, Cox C, Bernstein Z, Belling L, Holmberg P, MacLaughlin W, Howard F. Gynaecological and obstetrical morbidity in women with type I v on Willebrand dis- ease: results of a p atient survey. Haemophilia 2000; 6: 643–8. Women with inherited bleeding disorders 243 Ó 2011 International Society on Thrombosis and Haemostasis 28 G reer IA, Lowe GD, Walker JJ, Forbes CD. Haemorrhag ic problems in obstetrics and gynaecology in patients with co ngenit al c oagulop a- thies. Br J Obstet Gynaecol 1991; 98: 909–18. 29 Federici AB. Clinical diagnosis of von WillebrandÕsdisease.Haemo- philia 2004; 10(Suppl. 4): 169–76. 30 L opez JA, Andrews RK, fshar-Kharghan V, Berndt MC. Bernard- Soulier syndrome. Blood 1998; 91: 4397–418. 31 George JN, Caen JP, Nurden AT. GlanzmannÕs thrombasthenia: the spectrum of clinical disease. Blood 1990; 75 : 1383–95. 32 T ooge h G, S harifia n R, Lak M, Safaee R, A rtoni A, Peyvandi F. Presentation and pattern of sym pto ms in 382 patients with Glanzmann thrombasthenia in Iran. Am J Hematol 2004; 77: 198–9. 33 K adir RA, Economides DL, Lee CA. Factor XI deficiency in women. Am J Hematol 1999; 60: 48–54. 34 Lak M, Peyvandi F, Ali Sharifian A, Karimi K, Mannucci PM. Pat- tern of symptoms in 93 Iranian patients with severe factor XIII defi- ciency. JThrombHaemost2003; 1: 1852–3. 35 J ames AH. More than meno rrhagia: a review of the obstetric and gynaecological manifestations of bleeding disorders. Haemophilia 2005; 11: 295–307. 36 Kirtava A, Drews C, Lally C, Dilley A, Evatt B. Medical, reproductive and psychosocial experiences of women diagnosed with von Wille- brandÕs disease receiving care in haemophilia treatment centres: a case- control study. Haemophilia 2003; 9: 292–7. 37 Kulkarni AA, Lee CA, Kadir RA. Pregnancy in women with con- genital factor VII. Haemophilia 2006; 12: 413–6. 38 S iboni SM, Spreafico M, Calo ` L, Maino A, Santagostino E, Federici AB, Pe yvandi F. Gynaecological and obstetrical problems in women with different bleeding disorders. Haemophilia 2009; 15: 1291–9. 39 Silwer J. von WillebrandÕs disease in Sweden. Acta Paediatr Scand 1973; 238: 1–159. 40 Kouides PA. Females with von Willebrand disease: 72 years as the silent majority. Haemophilia 1998; 4: 665–76. 41 Skankar M, Chi C, Kadir RA. Review of quality of life: menorrhagia in women with or w ithout in herited bleeding disorders. Haemophilia 2008; 14: 15–20. 42 Kadir RA, James AH. Reproductive health in women with bleeding disorders. World Federation of Hemophilia ( WFH), 2009; http:// www.wfh.org/2/docs/Publications/VWD_WomenBleedingDisorders/ TOH-48_Women-Reproductive-Health.pdf. 43 Lee CA. Hemophilia A and hemophilia B, in Inherited bleeding disorders in women (eds.LeeCA,KadirRA,KoudiesPA)Oxford: Wiley-Blackwell, 2009. 44 James AH. Women and bleeding disorders. Haemophilia 2010; 16(Suppl. 5): 160–7. 45 Philipp C. Platelet Disorders in Inherited Bleeding Disorders in Women (eds.LeeCA,KadirRA,KoudiesPA,eds).Oxford,UK:Wiley- Blackwell, 2009. 46 N urden AT. Glanzmann throm basthenia. Orphanet J Rare Dis 2006; 1:10. 47 L ethab y A, Farquhar C, Cooke I. Antifibrinolytics for heavy men- strual bleeding. Cochrane Database Syst Rev 2000; 4: CD000249. 48 Berntorp E, Follrud C, Lethagen S. No increased r isk of v enou s thrombosis in women taking tranexamic acid. Thromb Haemost 2001; 86: 714–5. 49 Sundstro ¨ mA,SeamanH,KielerH,AlfredssonL.Theriskofvenous thromboembolism associated with the use of tra nexamic acid and other drugs u sed to treat m enorrhag ia: a case-control study using the General Practice Research Database. BJOG 2009; 116: 91–7. 50 Ip PPC, Lam KW, Cheung CL, Yeung MC, Pun TC, Chan QK, Cheung AN. Trane xamic a cid-associat ed nec rosis an d intrale sional thrombosis of uterine leiomyomas: a clinicopathologic study of 147 cases emphasizing the importance of drug-induced necrosis and early infarcts in leiomyomas. Am J Surg Pathol 2007; 31: 1215–24. 51 H odiva la-Dilke KM, McHugh KP, Tsakiris DA, Rayburn H, Crow- ley D, Ullman-Cullere ´ M, Ross FP, Coller BS, Teitelbaum S, Hynes RO. b3-integrin-deficient mice are a model for Glanzmann throm- bastenia showing placental defects and reduced survaival. J Clin Invest 1999; 103: 229–38. 52 LakM,KeihaniM,ElahiF,PeyvandiF,MannucciPM.Bleedingand thrombosis in 55 patients with inherited afib rinogenaemia. Br J Hae- matol 1999; 107: 204–6. 53 E vron S, Anteby SO, Brzezinsky A, Samueloff A, Eldor A. Congenital afibrinogenemia and recurrent early abortion: a case report. Eur J Obstet Gynecol Reprod Biol 1985; 19: 307–11. 54 Kobayashi T, Kanayama N, Tokunaga N, Asahina T, Terao T. Pre- natal and peripartum management of congenital afibrinogenaemia. Br JHaematol2000; 109: 364–6. 55 Burrows RF, Ray JG, Burrows EA. Bleeding risk and reproductive capacity among patients with factor XIII deficiency: a case p resenta- tion and review of the literature. Obstet Gynecol Surv 2000; 55: 103–8. 56 AsahinaT,KobayashiT,OkadaY,ItohM,YamashitaM,Inamato Y, Terao T. Studies on the role of adhesive proteins in maintaining pregnancy. Horm Res 1998; 50(Suppl 2): 37–45. 57 Wartiovaara J, L eivo I, Virtanen I, Vaheri A, Graham CF. Cell surface and extracellular matrix glycoprotein fibronectin. Expression in embryogene sis and in teratocarcinoma differentiation. Ann NY Acad Sci 1978; 312: 132–41. 58 Iwaki T, Sandoval-Cooper MJ, Paiva M, Kobayashi T, Ploplis VA, Castellino FJ. Fibrinogen stabilizes placental-maternal attachment during embryonic development in the mouse. Am J Pathol 2002; 160: 1021–34. 59 Stirling Y, Woolf L, North WR, Seghatchian MJ, Meade TW. Hae- mostasis in normal pregnancy. Thromb Haemost 1984; 52: 1 76–82. 60 Kriplan i A, Singh BM, So wbe rnika R, Choudhry VP. Successful pregnancy outcom e in Bernard-Soulier syndrome. J Obstet Gynaecol Res 2005; 31 : 52–6. 61 Kadir R A, Lee CA, Sabin C A, Pollard D, E conomide s DL. Pregnancy in women with von Willebrand Õs disease or factor XI deficiency. Br J Obstet Gynaecol 1998; 105: 304–21. 62 Khan KS, Wojdyla D, Say L, Gu ¨ lmezoglu AM, van Look PFA. WHO analysis of causes of maternal death: a systematic review. Lancet 2006; 367: 1066–74. 63 WHO, UNICEF, UNFPA, The World Bank. Maternal mortality in 2005: estimates developed by WHO, UNICEF, UNFPA, and the World Bank. W orld Health Organization, edito r. Geneva: WHO Press, World Health Organization, 2005: 16–7, 23–27, 29–38. 64 Hill K, AbouZhar C, Wardlaw T. Estimates of maternal mortality for 1995. Bull World Health Organ 2001; 79: 182–93. 65 World Health Organization. Managing Complications in Pregnancy and Childbirth: A guide for midwives and doctors. Geneva: Departmen t of Reproductive Health and Research, World Health Organization, 2003. 66 Cunningham FG, Gant NF, Leveno KJ, Gilstrap LC III, Hauth JC, Wenstrom KD (editors). Obstetrical hemorrhage. Williams Obstetrics, 21st edn. New York: McGraw-Hill Professional, 2001: 619–70. 67 M archant S, Alexander J, Garcia J, Ashurst H, Alderdice F, Keene J. AsurveyofwomenÕs experiences of vaginal loss from 24 hours to three months after childbirth (the BLiPP Study). Midwifery 1999; 15: 72–81. 68 Dahlman T, Hellgren M, Blomba ¨ ck M. Changes in blood coagulation and fibrinolysis in the normal puerperium. Gynecol Obstet Invest 1985; 20: 37–44. 69 Ka dir RA, Economides DL, Braithwaite J, Goldman E, Lee CA. The obstetric experience of carriers of haemophilia. Br J Obstet Gynaecol 1997; 104: 803–10. 70 James AH, Jamison MG. Bleeding events and other complications during pregnancy and childbirth in women with von Willebrand dis- ease. J Thromb Haemost 2007; 5: 1165–9. 71 S herer DM, Lerner R. GlanzmannÕs thrombasthenia in pregnancy: a case and review of the literature. Am J Perinatol 1999; 16: 297–301. 72 Goo dwin TM. Congenital hypofibrinogenemia in pregnancy. Obstet Gynecol Surv 1989; 44: 157–61. 244 F. Peyvandi et al Ó 2011 International Society on Thrombosis and Haemostasis 73 Noia G, De Carolis S, De Stefano V, Ferrazzani S, De Santis L, Carducci B, De Santis M, Caruso A. Factor V deficiency in pregnancy complicated by Rh im munization and placenta previa. A case report and review of the literature. Acta Obstet Gyne col S cand 1997; 76: 890–2. 74 R izk DE, Castella A, Shaheen H, Deb P. Factor VII deficiency de- tected in pregnancy: a case report. Am J P erinatol 1999; 16: 223–6. 75 Girolami A, Lazzarin M, Scarpa R, Brunetti A. Further studies on the abnormal factor X (factor X F riuli) coagulation disorder: a report of another family. Blood 1971; 37: 534–41. 76 Salomon O , Steinberg DM, Tamarin I, Zivelin A, Seligsohn U. Plasma replacement therapy d uring labor is no t mandatory for wom en with severe factor XI deficiency. Blood Coagul Fibrinolysis 2005; 16: 37–41. 77 Pacheco LD, Costantine MM, Saa de GR, Mucowski S, Hankins GDV, Sciscione AC. von Willebrand disease and pregnancy: a prac- tical a pproach for the d iagnosis and treatment. Am J Obstet Gynecol 2010; 15: 194–200. 78 Mann ucci PM. Treatment of von WillebrandÕsDisease.N Engl J Med 2004; 351: 683–94. 79 Bolton-Maggs PH, Perry DJ, Chalmers EA, Parapia LA, Wilde JT, Williams MD, Collins PW, Kitchen S, Dolan G, Mumford AD. The rare coagulation disorders – review with guidelines for management from the United Kingdom Haemophilia Centre DoctorsÕ Organisa- tion. Haemophilia 2004; 10 : 593–628. 80 T rehan AK, Fer gusson IL. Conge nital afibrinogenaemia a nd suc- cessful pregnancy outcome. B r J Obstet Gynaecol 1991; 98: 722–4. 81 FrenkelE,DuksinC,HermanA,ShermanDJ.Congenitalhypofi- brinogenemia in pregnancy: report of two cases and review of the literature. Obstet Gynecol Surv 2004; 59: 775–9. 82DupuyE,SoriaC,MolhoP,ZiniJM,RosenstinglS,LaurianC, Bruneval P, Tobelem G. Embolized ischemic lesions of toes in an afibrinogen emic patient: possible relevance to in vivo. Thromb Res 2001; 102: 211–9. 83 Robertson LE, Wasserstrum N, Banez E, Vasquez M, S ears DA. Hereditary fact or VII deficien cy in pregna ncy: perip artum trea tment with factor VII concentrate. Am J Hematol 1992; 40: 38–41. 84 B ofill JA, Young RA, Perry KG Jr. Successful pregnancy in a woman with severe factor X deficiency. Obstet Gynecol 1996; 88: 723. 85 Rodeghiero F, Castaman GC, Di Bona E, Ruggeri M, Dini E. Suc- cessful pregnancy in a woman with congenital factor XIII deficiency treated with substitutive therapy. Report of a second case. Blut 1987; 55: 45–8. 86 Asahina T, K obayashi T, Takeuchi K, Kanayama N. Congenital blood coagulation factor XIII deficiency and successful deliveries: a review of the literature. Obstet Gynecol Surv 2007; 62: 255–60. 87 Kadir R, Chi C, Bolton-Maggs P. Pregnancy and rare bleeding disord ers . Haemophilia 2009; 15: 990–1005. Women with inherited bleeding disorders 245 Ó 2011 International Society on Thrombosis and Haemostasis . prevalent in women with all bleeding disorders, however, using the PBAC, carriers of haemophilia and women Women with inherited bleeding disorders 237 Ó 2011 International. INVITED REVIEW Gynecological and obstetrical manifestations of inherited bleeding disorders in women F. PEYVANDI, I. GARAGIOLA and M. MENEGATTI U.O.S.