Gynecological and obstetrical manifestations of inherited bleeding disorders in women

Authors

  • F. PEYVANDI,

    1. U.O.S. Dipartimentale per la Diagnosi e la Terapia delle Coagulopatie, A. Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Luigi Villa Foundation, Milan, Italy
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  • I. GARAGIOLA,

    1. U.O.S. Dipartimentale per la Diagnosi e la Terapia delle Coagulopatie, A. Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Luigi Villa Foundation, Milan, Italy
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  • M. MENEGATTI

    1. U.O.S. Dipartimentale per la Diagnosi e la Terapia delle Coagulopatie, A. Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Luigi Villa Foundation, Milan, Italy
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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

Abstract

Summary.  Patients affected by bleeding disorders present a wide spectrum of clinical symptoms that vary from a mild or moderate bleeding tendency to significant episodes. Women with inherited bleeding disorders are particularly disadvantaged since, in addition to suffering from general bleeding symptoms, they are also at risk of 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 their reproductive life. These latter problems include excessive menstrual bleeding or menorrhagia, miscarriage, bleeding complications during pregnancy and after delivery and their related complications such as acute or chronic anaemia. The management of these women is difficult because of considerable inter-individual variation. Moreover, reliable information on clinical management is scarce, only a few available long term prospective studies of large cohorts provide evidence-based guideline about diagnosis and treatment.

Introduction

Women are more likely to manifest a bleeding disorder as they have more opportunities to experience bleeding challenges in their lifetime due to the natural cycle of menses and reproduction. Menstruation and ovulation may be associated with significant bleeding leading to the limitation in conducting daily activities, changes in social functioning and adverse effect on quality of life. At least 5–10% of women at reproductive age will seek medical attention for menorrhagia [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 responsible for menorrhagia; however, an underlying aetiology is identified in only 50% of cases [3]. Organic causes include infections of any genitourinary origin and bleeding disorders as well as organic dysfunction as hepatic or renal failure. Chronic liver disease impairs production of clotting factors and reduces hormone metabolism (e.g. oestrogen). Any of these problems may lead to heavy uterine bleeding. The most common endocrinologic cause of heavy menstrual bleeding in adolescent girls is anovulatory dysfunctional uterine bleeding owing to the immaturity of the hypothalamic–pituitary–ovarian axis. Anatomic aetiologies for menorrhagia include uterine fibroids, endometrial polyps and hyperplasia. Intra Uterine Device (IUD) placement, steroid hormones, chemotherapy agents, hypothalamic depressants, phenytoin and anticoagulants, which could also cause increased menstrual bleeding [4]. The considerable proportion of women with menorrhagia (∼20%), who are comprehensively tested for haemostatic abnormalities, are found to have underlying bleeding disorders such as von Willebrand disease (VWD), platelets function alteration or rare bleeding disorders (RBDs: deficiencies of coagulation factors such as fibrinogen, factor (F)II, FV, FV + FVIII, FVII, FX, 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 other problems that 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 challenge in women with inherited bleeding disorders, since information about these issues are really scarce and limited to few case reports. An accurate counselling for women affected with bleeding disorders is therefore recommended.

Pathophysiology of abnormal uterine bleeding (menorrhagia)

In the presence of ovulatory cycles, withdrawal of progesterone triggers a cascade of molecular and cellular events within the endometrium, initiating its breakdown and culminating in menstruation. During menstruation higher levels of prostaglandin E2 and prostaglandin F2a in menstrual fluid are found in menorrhagic women when compared with those with normal menses [5,6]. Furthermore, the release of prostaglandin E2, prostaglandin F2a and prostacyclin by the endometrium and myometrium during menstruation are increased in tissues obtained from menorrhagic women [7,8]; and increased 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 proliferation indices, supporting the hypothesis that disturbed angiogenesis 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 based on the aberrant formation of a platelet plug that is a crucial first step in the regulation of blood flow [13]. Thus, it is not surprising that platelet dysfunction and VWD have both been associated with menorrhagia, sometimes of a severe nature, and that menorrhagia is a common presenting symptom among female patients with VWD. From a historical perspective, it is interesting to note that the first patient identified with this disorder by Erik von Willebrand in 1926 eventually died of uncontrollable menstrual bleeding at age 13 years.

Menorrhagia

History and definition

The term ‘menorrhagia’ 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): ‘Disputatio medica, inauguralis, de menstruorum profluvio immodico’ [14]. The term ‘menorrhagia’ was regularly used in publications throughout the 19th and 20th centuries, but the establishment 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 ‘Menstruation in Girls and Adolescents: Using the Menstrual Cycle as a Vital Sign’ [16]. The consensus stated that normal menstruation begins at 11–14 years of age, the normal cycle 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 80 mL per menstrual cycle [17].

Differential diagnosis in women with menorrhagia

It is important for the 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 the first clinical manifestation that women with bleeding disorders encounter, often at menarche; therefore, many affected patients initially attend their gynaecologist. Recently, a consensus on diagnosis in women with menorrhagia was published by an international experts panel and recommendations were provided only if consensus could be reached [18]. Experts agreed that an underlying bleeding disorder should be considered if any of the following indicators are present: menorrhagia since menarche; family history of a bleeding disorder; personal history of bleeding such as epistaxis, notable bruising without injury, minor wound bleeding, bleeding of oral cavity or gastrointestinal tract without an obvious anatomic lesion, prolonged or excessive bleeding after dental extraction, unexpected postsurgical bleeding, haemorrhage from ovarian cysts or corpus luteum, haemorrhage that required blood transfusion, failure of response to conventional management of menorrhagia [18].

However, only a relatively small proportion of these patients will have a true underlying disorder of haemostasis. Consequently, the discriminatory power of various bleeding symptoms in predicting an underlying disorder of haemostasis has been incorporated into a scoring system (‘bleeding score assessment’) through the International Society of Haemostasis and Thrombosis network [19,20]. On the other hand, as measuring actual menstrual 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 to 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 ‘positive’ bleeding history need 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 levels 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 menorrhagia is more prevalent in women with all bleeding disorders, however, using the PBAC, carriers of haemophilia and women affected with VWD and FXI deficiency were shown to have significantly higher menstrual scores [24]. The reported prevalence of menorrhagia in carriers of haemophilia was estimated to be about 10–57% [25].

In women with VWD, menorrhagia was determined to be a 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 in women with Glanzmann’s thrombasthenia are contrasting since two studies report 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] and 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 menorrhagia 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 herein. Nonetheless several studies 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 information on prevalence of menorrhagia in 35 women affected with bleeding disorders compared to 114 controls, reported that PBAC was significantly higher in affected 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 evidence-based, because of the small number of women who were analysed.

Table 1.   Populations, sample size and type of published studies herein reported
Population (sample size)Type of studyReference
Menorrhagia
 Haemophilia carriers (30)Prospective cohort25
 VWD type 1 (29)Case series26
 VWD type 1 (99)Survey27
 VWD type 2 (5)Case series28
 VWD registry on type 1, 2 and 3Retrospective cohort29
 Bernard-Soulier syndrome (35)Case reports30
 Glanzmann’s thrombasthenia (55)Case reports31,32
 FXI deficiency (20)Prospective cohort33
 FXIII deficiency (20)Case series34
 VWD (48 types 1, 2 and 3)Case – control38
 Haemophilia carriers (31)
 Coagulation deficiencies (35)
Miscarriages
 Afibrinogenemia (6 in six reports)Case reports35
 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 – control36
 Bernard-Soulier syndrome (9)Case reports60
 Glanzmann’s thrombasthenia (16)Case reports31
 FXI deficiency (21)Case series61
 VWD (48 types 1, 2 and 3)Case – control38
 Haemophilia carriers (31)
 Coagulation deficiencies (35)
Post partum hemorrhage
 Haemophilia carriers (32)Case series69
 VWD (2843)Database70
 Bernard-Soulier syndrome (7)Case reports30
 Glanzmann’s thrombasthenia (7)Case reports71
 Hypofibrinogenemia (10)Case reports72
 FV (1), FVII (1) and FX deficiency (1)Case report73–75
 FXI deficiency (62)Case series76

Complications and treatment of menorrhagia

Women with menorrhagia often undergo unnecessary surgical interventions to relieve heavy menstrual bleeding, and at least 60% of them undergo hysterectomy or other surgical procedures, 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 with 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 bleeding 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, menorrhagia, 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 with menorrhagia and an underlying haemostatic defect should be beneficial in terms of allowing for the use of specific haemostatic measures in the management of the menorrhagia [36]. Management of menorrhagia 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, to anticipate the possibility of an acute menorrhagia [43]. Haemostatic therapy includes antifibrinolytic (tranexamic acid and aminocaproic acid) and 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 [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 Glanzmann’s thrombasthenia, platelets transfusions may be needed [45]; however repeated transfusions may result in the formation of alloimmune antiplatelet antibodies. Such antibodies 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 successfully used as an alternative approach for early 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]. Antifibrinolytic agents are generally well-tolerated despite the uncertain thrombotic risk reported in some studies [48–50].

Miscarriage

Miscarriage is relatively common in the general population, with 12–13.5% of recognised pregnancies resulting in spontaneous abortion, while there are case reports and case series 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 miscarriage in such defects [34]. Human Glanzmann’s thrombasthenia can result from defects in the genes for either the αIIb or the β3 subunit. In a study by Hodivala-Dilke et al. [51], a knock-out β3 null-mice model revealing placentation defects that may also occur in human Glanzmann’s thrombasthenia patients and may provide insight into preeclampsia of pregnancy was proposed. Haemorrhage in a layer of trophoblast, Reichert’s 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 β3–null maternally derived placenta the cell layers within the labyrinth appeared thickened and occluded sinus volume, thus decreasing efficient blood circulation 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 play an important role in placental implantation and maintenance 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 ovulation. The blastocyst adheres the surface epithelium of endometrium 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: Aα, Ββ and γ. The threeoverlapping hereditary abnormalities of fibrinogen, afibrinogenemia, dysfibrinogenemia and hypofibrinogenemia, have been associated with recurrent pregnancy loss. Hypofibrinogenemic and experimental afibrinogenemic mice exhibited similar features of bleeding tendency and miscarriage [58]. Pregnant mice homozygous for a deletion of the Fg-γchain, which results in a total fibrinogen deficiency state, aborted the foetus at the equivalent gestational stage seen in humans. The fibrinogen deficiency does not alter embryonic development, but formation of the 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 gives 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 infiltration and leading to haemorrhagic miscarriage. Further studies are needed to confirm 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 coagulation disorders, since information about these issues are really scarce and limited to few case reports. Normally, pregnancy is accompanied by increased concentrations of fibrinogen, FVII, FVIII, FX and von Willebrand factor, particularly marked in the third trimester [59]. On the contrary, FII, FV, FIX and FXIII are relatively unchanged [59]. All of these changes contribute to the hypercoagulable state of pregnancy, and, in women with bleeding disorders, contribute to improved haemostasis.

The risk of bleeding in early pregnancy is unknown in carriers of haemophilia, but there is evidence that the risk after 24 weeks’ gestation is not increased [28].

A case-control study reports the experience of 86 women with VWD and 70 controls with bleeding problem during pregnancy. This report evidences that 1.3% of women with 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 and immediate postpartum period; pregnancy and delivery appeared uncomplicated in women with Glanzmann’s 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 deaths, in the last two 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 and > 1000 mL for caesarean sections within 24 h of delivery [65,66]. PPH is classified as primary when occurs within the first 24 h postpartum or secondary, occurring between 24 h and up to 6 weeks of postpartum. The median 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, there 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 haemophilia 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 recent data documenting and comparing the incidence of PPH in women with VWD and controls come from US discharge database, reporting that 6% 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 Glanzmann’s 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 resulted 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 deficiency [75] and in severe 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. These 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 with subnormal factor levels, despite the pregnancy-related rise of FVIII, intravenous 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 with 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 measurement 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 subset of women with type 2 VWD respond to desmopressin. Identification of those individuals requires a test dose of DDAVP and subsequent measurement of VWF:RCo 1 and 4 h after the dose. If the VWF: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 type 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 and 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 Glanzmann’s thrombasthenia [45]. The use of recombinant FVIIa has been proposed especially in individuals unresponsive to platelet transfusion because of isoimmunisation [46]. Regular 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 of 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 and 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 and family history of bleeding and thrombosis [82]. No specific treatment is required in asymptomatic women.

A significant rise in FVII level is observed during pregnancy in women with mild/moderate forms of FVII deficiency (heterozygotes) [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 FX deficiency and a history of adverse pregnancy outcome may benefit from replacement therapy during pregnancy [79], and to cover labour and delivery to minimise the risk of bleeding complications [84]. In FXIII deficiency a therapy should be commenced as early as possible in pregnancy to prevent foetal loss [85] and the treatment should 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, 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 on very limited available data, it is difficult to make recommendation for the obstetric management 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].

Table 2.   Available recommendation for treatment in women with inherited bleeding disorders for menorrhagia (A) and during/after pregnancy (B) [46,76,87]
(A) Menorrhagia
 VWDIn 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 disordersIn 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 Glanzmann’s thrombasthenia, platelets transfusions may be needed.
 Rare coagulation  disordersTherapeutic 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 1DDAVP 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 2In 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 3Since 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 disordersPlatelet transfusion before and after delivery (up to 6 days post partum) have been reported to reduce the risk of bleeding in women with Glanzmann’s thrombasthenia. The use of rFVIIa has been proposed in cases of isoimmunization.
 a- and hypo-fibrinogenemiaReplacement 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.
 DysfibrinogenemiaWomen 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.
 FIISecondary 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.
 FVIn 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 + VIIIThere 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).
 FVIIWomen 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 μg kg−1) should be the treatment of choice.
 FXPatients 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.
 FXIWomen 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.
 FXIIIThe 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.

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 heterozygosity in two partners of families affected 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.

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