Miscarriage is common in the general population, with at least 12–13.5 % of recognized pregnancies resulting in spontaneous miscarriage [26, 27]. An increased risk of miscarriage and placental abruption resulting in recurrent foetal loss or premature delivery among women with afibrinogenemia [8, 28, 29] or FXIII deficiency [30, 31] has been reported. A study of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis (ISTH) reported a high incidence of spontaneous miscarriage (38 %) and also stillbirth in 15 women with 64 reported pregnancies fulfilling the criteria of familial dysfibrinogenemia and thrombosis not due to other causes [32]. It is generally believed that women with bleeding disorders are protected from miscarriage by the hypercoagulable state of pregnancy, but whether women with bleeding disorders other than familial dysfibrinogenaemia have an increased risk of miscarriage is unclear. Only two reports describe miscarriages: the first a case report of miscarriages in four out of eight pregnancies in a hypoprothrombinemic woman [33]; and the second, excessive bleeding after two early pregnancy losses in a series including ten pregnancies in four women affected with FVII deficiency [34]. Similarly, Kumar and Mehta reported four pregnancies in a woman with FX severe deficiency [35]: two pregnancies resulted in preterm labour and birth at 21 and 25 weeks’ gestation (both babies died in the neonatal period). The mother was treated early in two subsequent pregnancies with regular FX replacement, and she delivered healthy babies at 34 and 32 gestational weeks of gestation. Whilst, prophylactic factor replacement therapy seemed to improve pregnancy outcome in this patient, other case reports have described successful term pregnancies in women with severe FX deficiency without antenatal prophylaxis [36, 37]. 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 is not contraindicated in patients with RBDs but requires a multidisciplinary approach for specialist management of affected women. As previously discussed, pregnancy is accompanied by increased concentrations of fibrinogen, FVII, FVIII, FX, and vWF, while FII, FV, and FIX are relatively unchanged, making women with RBDs at risk of bleeding during pregnancy. However, bleeding during pregnancy is a symptom reported in women with afibrinogenemia and severe FX deficiency [29, 35, 37, 38]. Siboni et al. collected information on menarche, bleeding during pregnancy and the postpartum period in 35 women affected with RBDs and 114 controls. These data showed bleeding during pregnancy in 21 % of patients vs 6 % of controls, however, this difference was not statistically significant P = 0.11) [39]. Six successful pregnancies were achieved by afibrinogenemic women who received fibrinogen replacement therapy throughout pregnancy. Vaginal bleeding began at around 5 weeks’ gestation in cases where replacement therapy was not commenced [40].

There is limited data on the changes of FXIII level during pregnancy, however it was recently confirmed that FXIII significantly reduces during gestation with a significant decrease in the third trimester [41]. In a recent systematic review by Sharief and Kadir on a total of 192 pregnancies women affected with FXIII-A and B deficiency, antepartum haemorrhage (APH: bleeding after 24 weeks gestation) occurred in five out of 65 at term pregnancies (7 %), in one case the woman was on prophylactic therapy (since the 32 week of gestation) [42]. Interestingly, patients affected with FXIII-B deficiency showed a higher frequency of APH (3/11, 27 %) compared to patients affected with FXIII-A deficiency (2/54, 4 %) [42]. Bleeding during early pregnancy was reported in one woman only [43].

PPH can be an anticipated problem in women with bleeding disorders. At the end of a normal pregnancy, an estimated 10–15 % of a woman’s blood volume, or at least 750 mL/min, is lost through the uterus within the first few weeks after birth [44]. Normally after delivery of the baby and placenta, the uterine musculature or myometrium contracts around the uterine vasculature and the vasculature constricts in order to prevent exsanguination. Retained placental fragments and lacerations of the reproductive tract may also cause heavy bleeding, but the single most important cause of PPH is uterine atony [45].

Despite the critical role of uterine contractility in controlling postpartum blood loss, women with bleeding disorders are at an increased risk of PPH. There are multiple case reports and several case series documenting the incidence of PPH in women with bleeding disorders [24, 35, 46–48], but there are limited data that compare women with bleeding disorders to controls. PPH was found to be the most common obstetric complication occurring in 45 % (14/31 deliveries) among ten patients affected with hypofibrinogenemia [49], while a high incidence of postpartum thrombosis, predominantly venous, was noted among dysfibrinogenemic women (7/15, 47 %) [32]. PPH was also reported in 13 (76 %) of 17 deliveries among nine women with FV deficiency [50], which appears to be associated with an increased risk of developing this complication (especially in women with low FV activity levels). Although at a lower rate, PPH was also reported in patients with deficiencies of FVII [51], FX [52], or FXI [24]. Particularly interesting is the latter report of a large study of 164 pregnancies in 62 women with FXI deficiency (levels <17 IU/dL) showing that 69 % of the women never experienced PPH during 93 deliveries without any prophylactic cover with FXI replacement. The authors therefore argued that prophylactic treatment is not mandatory for these women, especially in the context of vaginal delivery (however, excessive bleeding at delivery did occur in around 20 % of deliveries not covered by replacement therapy).

The incidence of PPH in women with FXIII deficiency is not known, however primary PPH was reported in 16/65 (25 %) pregnancies in 12 women with FXIII-A and B deficiency; interestingly a higher frequency of PPH was observed in patients with FXIII-B deficiency compared to those affected with FXIII-A deficiency (82 % vs 13 %) [42]. Successful pregnancy in women with FXIII subunit A deficiency is generally achieved only with replacement therapy throughout pregnancy and at delivery [53]. No data are published on the rate of PPH in women affected with FII deficiency. Among all women, the median duration of bleeding after delivery is 21–27 days [54, 55], but coagulation factors, elevated during pregnancy, return to baseline within 14–21 days [56]. Therefore, there is a period of time, 2–3 weeks after delivery, when coagulation factors have returned to pre-pregnancy levels but women are still bleeding. Women with bleeding disorders are particularly vulnerable to delayed or ‘secondary’ PPH during this same period of time. The implication is that women with bleeding disorders may require prophylaxis and/or close observation for several weeks after delivery.

The combined performance of the screening coagulation tests, the prothrombin time (PT) and activated partial thromboplastin time (APTT), is usually applied to identify RBDs of clinically significant severity. A prolonged APTT with a normal PT is suggestive of FXI deficiency (after exclusion of FVIII, FIX, and FXII deficiencies). The reverse pattern (normal APTT and prolonged PT) is typical of FVII deficiency, whereas the prolongation of both tests directs further analysis towards identification of possible deficiencies of FX, FV, or prothrombin. The sensitivity of the PT and APTT to the presence of coagulation factor deficiencies is dependent on the test system employed [57, 58]. All coagulation tests that depend on the formation of fibrin as the end point are necessary to evaluate fibrinogen deficiency, hence, in addition to the PT and APTT, the thrombin time (TT) also has to be performed. These three tests show infinitely prolonged clotting times in the case of afibrinogenemia and results are variable in the case of hypodys- or dys-fibrinogenemia. Specific assays of factor coagulant activity are necessary when the degree of prolongation of the global tests suggests the presence of clinically significant deficiencies. Factor antigen assays are not strictly necessary for diagnosis and treatment but are necessary to distinguish type I from type II deficiencies. However, these data are important in the characterisation of deficiency of fibrinogen or FII, where a normal antigen level associated with reduced activity (dysfibrinogenemia and dysprothrombinemia) is associated with higher risk of thrombosis.

The standard laboratory tests of haemostasis (PT, APTT, fibrinogen level, platelet count, bleeding time) are normal in FXIII deficiency. The diagnosis of FXIII deficiency is established by the demonstration of increased clot solubility in 5 M urea, dilute monochloroacetic acid, or acetic acid. However, this method is not quantitative and not standardized. The sensitivity of these assays mainly depends on the fibrinogen level, on the reagents used to trigger the coagulation of the plasma (thrombin and/or Ca²⁺), on specific features of the solubilizing agent, and on the concentration of FXIII. In a UK National External Quality Assessment Scheme (NEQAS) study, 15 combinations of these variables were used among participant laboratories [59], and the clot solubility test detected only very severe FXIII deficiency (where the FXIII activity in the patient’s plasma was significantly <5 %). If clot solubility in these reagents is found, a mixing study (FXIII activity determination on a mixture of patient and normal plasma) is needed to exclude the presence of a FXIII inhibitor. FXIII activity should also be determined quantitatively by a chromogenic assay that measures the incorporation of fluorescent or radioactive amines into proteins [60]. Specific ELISA tests have been developed to establish FXIII-A and FXIII-B antigen levels [61]. Diagnostic tests for RBDs may be ordered by a gynaecologist or the family physician, or alternatively, the woman may be referred directly to a specialist haemostasis centre. However, interpretation of abnormal or borderline results usually requires referral to a specialist haematology (or an internal medicine) consultant. These assays are routinely available in many coagulation laboratories in Europe and North America but are seldom carried out, so that proficiency and standardization may be limited.

RBDs are usually due to DNA defects in genes encoding the corresponding coagulation factors [2]. Exceptions are the combined deficiencies of coagulation FV and FVIII and of vitamin-K-dependent proteins (FII, FVII, FIX, and FX) caused, respectively, by mutations in genes encoding proteins involved in the FV and FVIII intracellular transport mechanism (LMAN1 and MCFD2) and in genes that encode enzymes involved in posttranslational modifications and in vitamin K metabolism (GGCX and VKORC1) [62–65]. The pattern of inheritance is usually autosomal recessive for all RBDs, except for FXI, where in some cases, missense mutations have been shown to exert a dominant negative effect through heterodimer formation between the mutant and wild-type polypeptides, resulting in a pattern of dominant transmission [66]. The identification of gene defects in patients with RBDs could represent the basis on which to carry out prenatal diagnosis in families that already have one affected child with a severe bleeding history. Molecular characterization and subsequent prenatal diagnosis gain importance particularly in developing countries, where patients with these deficiencies rarely survive beyond childhood and where management is still largely inadequate; therefore, prenatal diagnosis is an important option for the prevention of the birth of children affected with RBDs and severe bleeding manifestations, particularly in regions with low economic resources and a high rate of consanguineous marriages.