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R. KADIR,* C. CHI* and P. BOLT ON-MAGGS *Haemophilia Centre and Thrombosis Unit, The Royal Free Hospital, London; and  Department of ClinicalHaematology, Manchester Royal Infirmary, Manchester, UK Summary. Rare bleeding disorders include deficiency in women with rare bleeding disorders seem to of fibrinogen, prothrombin, factor V, factor VII, persist throughout pregnancy especially if the defect factor X, factor XI and factor XIII together with is severe. Therefore women affected with these combined deficiency disorders, factor V+VIII defi- disorders are at risk of post-partum haemorrhage.
ciency, and deficiency of the vitamin K-dependent The fetus can also be affected and potentially at risk factors (factor II, VII, IX and X). They account for of bleeding complications. Specialised multidisciplin- 3–5% of all inherited coagulation disorders. Due to ary management is essential to minimise the potential their rarity, information about pregnancy complica- maternal and neonatal complications and ensure an tions and management is limited and mostly derived optimal outcome. This paper presents literature from case reports. Deficiency of fibrinogen and FXIII review for pregnancy complications in each of the are both found to be strongly associated with rare bleeding disorders. In addition general principles increased risk of recurrent miscarriage and placental for management of pregnancy, labour and delivery abruption. Factor replacement is used to reduce these risks. However, the risk of miscarriage and ante-partum complications is less clear in women with Keywords: labour and delivery, neonate, post-partum other bleeding disorders. Haemostatic abnormalities haemorrhage, pregnancy, rare bleeding disorders obstetrician, a haematologist and an anaesthetist to Pregnancy and childbirth pose a special clinical In this paper, we review the literature for preg- challenge in women with bleeding disorders. Infor- nancy complications in each of the rare bleeding mation about the management of pregnancy in the disorders. In addition, we discuss the general prin- rare disorders in particular is limited and mostly ciples for management of pregnancy, labour and derived from case reports. The rare disorders to be delivery for women affected with these disorders.
reviewed here include deficiencies of fibrinogen,prothrombin, factor V, factor VII, factor X, factor XI and factor XIII together with two combineddeficiency disorders, factor V+VIII deficiency, and Normal pregnancy is associated with a progressive deficiency of the vitamin K-dependent factors, II, VII, increase in the levels of several coagulation factors IX and X. Specialized multidisciplinary management including fibrinogen, FVII, FVIII, FX, FXII, von is essential to minimize the potential maternal and Willebrand factor (VWF) [1–9]. The rise in these neonatal complications. The team should include an coagulation factors is generally more marked in thethird trimester [1,3,4]. FII, FV, FIX, FXI and FXIIIlevels are slightly increased or unchanged during Correspondence: Rezan Kadir, Haemophilia Centre and Throm- normal pregnancy (Table 1) [3,4,10]. Similar changes bosis Unit, The Royal Free Hospital, Pond Street, London NW32QG, UK.
may also be seen in women with inherited bleeding Tel.: +44 20 7830 2068; fax: +44 20 7472 6759; disorders. This can lead to normalization of the e-mail: haemostatic defect in women with some bleeding disorders such as VWD or carriers of haemophilia Journal compilation Ó 2009 Blackwell Publishing Ltd Table 1. Haemostatic changes during normal pregnancy.
spontaneously but vaginal bleeding began at around5 weeks gestation in cases where replacement ther- apy was not commenced [21,30]. Aygoren-Pursunet al. [34] reported a woman with congenital afibri- nogenaemia receiving fibrinogen prophylaxis who developed a sub-chorionic haematoma in the first trimester. The sub-chorionic haematoma was identi- fied on ultrasound 1 day after a plasma fibrinogen nadir of 0.29 g L)1, which could either suggest the marked fibrinogen deficiency as the cause of the haemorrhage or reflect fibrinogen consumption by the developing haematoma. With subsequent regular F, factor; VWF, von Willebrand factor.
and intensified fibrinogen concentrate replacement, A. In rare bleeding disorders, the data are very the haematoma resolved over 6 weeks and the limited. In general, their haemostatic abnormalities woman delivered a healthy infant at term.
seem to persist throughout pregnancy, especially if Based on these observations, regular replacement the defect is severe. Although pregnancy is associated therapy throughout pregnancy is recommended in with an increase in FX level [8], it usually remains low women with afibrinogenaemia and should be com- in women with a severe deficiency [11,12]. Similarly, menced as soon as possible in pregnancy to prevent studies have found no significant rise in FVII levels early fetal loss [20]. Options for replacement therapy during pregnancy in women with homozygous include plasma-derived fibrinogen concentrate and (severe) FVII deficiency [13–16]. On the contrary, cryoprecipitate. Cryoprecipitate is not currently a significant rise in FVII level has been reported pathogen-inactivated while fibrinogen concentrate amongst women with heterozygous (mild/moderate) is heat-treated. Therefore, fibrinogen concentrate is FVII deficiency [17]. Inconsistent changes in FXI the preferred option especially when repeated treat- levels have been observed in pregnant women with ment doses are required. Kobayashi et al. suggested a FXI deficiency [18,19]. Overall, there does not appear fibrinogen level of >0.6 g L)1 and, if possible, to be a significant increase in FXI levels in these >1 g L)1 to prevent early fetal loss and bleeding women and most of them are likely to have subnor- complications [21]. Fibrinogen clearance increases as mal factor levels at term [18,19]. Similarly, haemo- the pregnancy progresses [35], and thus the amount static abnormalities in women with fibrinogen, of fibrinogen required to avoid placental abruption prothrombin, FV or FXIII deficiency are expected to increases with advancing gestation [21]. Similar continue throughout pregnancy [3,4,10,20–24].
replacement therapy may be required in women withhypofibrinogenaemia, depending on the fibrinogenlevel, bleeding tendency and previous obstetric his- tory [36]. Regular monitoring of fibrinogen levels Inherited abnormalities of fibrinogen consist of and ultrasound assessment for concealed placental quantitative (afibrinogenaemia and hypofibrinogena- bleeding and fetal growth are also recommended.
emia) and qualitative deficiencies (dysfibrinogena- Thrombotic events have also been reported in patients with inherited afibrinogenaemia [37–39]; hypodysfibrinogenaemia. Afibrinogenaemia refers to hence, the risks of bleeding and thrombosis should be a total absence of fibrinogen, while hypofibrinogena- considered and balanced during pregnancy. For emia is a milder form of the disorder with a decreased labour and delivery, in women with afibrinogena- level of fibrinogen. Both are associated with recurrent emia, replacement therapy to maintain a minimum miscarriages as well as placental abruption and fibrinogen level of 1.5 g L)1 and, if possible, postpartum haemorrhage (PPH) [21,25–27].
>2.0 g L)1 has been suggested for the prevention of In a total of 20 pregnancies among eight women placental abruption and PPH [21]. For women with with afibrinogenaemia, there were 12 miscarriages, hypofibrinogenaemia, intrapartum replacement is two perinatal deaths (a stillbirth at 24 weeks and a required if fibrinogen level is below 1.5 g L)1 and/ neonatal death following delivery at 27 weeks ges- or if the woman has a significant bleeding history.
tation) and six live births between 36 and 40 weeks The risk of neonatal bleeding should be assessed [21,25,28–33]. All successful pregnancies were when planning and managing labour and delivery.
The rare disorders are more common in the offspring throughout pregnancy. Pregnancies were established from consanguineous marriages, therefore it may be Ó 2009 The AuthorsJournal compilation Ó 2009 Blackwell Publishing Ltd appropriate to screen the husband of a woman with birth (9%) was noted amongst these women.
afibrinogenaemia for partial deficiency, particularly Placental abruption has also been reported in these if they are related. Afibrinogenaemia is an autosomal recessive disorder, if the father is unaffected (as The management of pregnancy in women with determined by a normal fibrinogen level), the infant dysfibrinogenaemia needs to be individualized, tak- at most is heterozygous and therefore, not at risk of a ing into account the fibrinogen level and personal significant haemorrhage during birth [21]. However, and family history of bleeding and thrombosis [20].
hypofibrinogenaemia can be inherited either as a No specific treatment is required in asymptomatic women. Women with a personal or family history of Afibrinogenaema and hypofibrinogenaemia are thrombosis should be offered antenatal prophylaxis also associated with a high risk of PPH. In a with low molecular weight heparin (LMWH) and literature review of congenital hypofibrinogenaemia, fibrinogen replacement therapy is given only if PPH was found to be the most common obstetric bleeding occurs. Conversely, replacement therapy complication occurring in 45% (14/31 deliveries) should be considered in women with a personal or among 10 patients [26]. Blood transfusion was family bleeding phenotype, especially if the bleeding required in all cases and hysterectomy in two. One tendency is significant or if the patient is undergoing patient presented with secondary PPH 1 week after invasive procedures. Concomitant thromboprophy- laxis with LMWH should also be considered as Paradoxically thrombotic events during puerpe- fibrinogen may precipitate venous thrombosis [20].
There is limited information on the management of women with dysfibrinogenaemia who have recurrent [35,37,38]. Roque et al. [35] described two preg- miscarriages. The options include the use of prophy- nancies in a woman with afibrinogenaemia who lactic LMWH and if this fails the use of fibrinogen received regular cryoprecipitate to maintain fibrino- replacement [20]. Yamanaka et al. [46] described a gen level >0.6 g L)1. She developed placental abrup- woman with dysfibrinogenaemia who had two first- tion at 36 weeks in her first pregnancy despite recent trimester miscarriages and two second-trimester fetal (within 24 h) cryoprecipitate infusion, and postpar- losses due to placental abruption. She was treated tum ovarian and renal vein thromboses in her second with fibrinogen replacement to maintain a fibrinogen pregnancy. It is unclear whether replacement therapy level of >1 g L)1 from 8 weeks’ gestation in her fifth has played a role in the development of thromboses pregnancy. Although complicated by vaginal bleed- or whether there is an unidentified thrombotic risk ing and preterm labour, a live male infant was factor that led to the placental abruption as well as the postpartum thrombotic event. Nevertheless, the risk of bleeding and thrombosis must be balanced in Women with dysfibrinogenaemia are also at risk of these patients. The postpartum management, includ- both postpartum thrombosis and haemorrhage [20].
ing the use of postpartum prophylaxis, should take Among 15 women with familial dysfibrinogenaemia into account any personal and family history of and thrombosis not due to other causes, who all had bleeding and thrombosis. Standard measures such as at least one pregnancy, PPH was reported in two compression stockings, adequate hydration and early cases [43]. A high incidence of postpartum throm- bosis (7/15, 47%) was also noted amongst these Dysfibrinogenaemia is characterized by abnormal women. Therefore, intrapartum and postpartum fibrinogen function and transmitted as an autosomal management of these women should be individual- dominant trait. It has an unpredictable clinical ized based on their fibrinogen level as well as phenotype [20]. A database of over 250 patients personal and family history of bleeding and throm- showed that 53% were asymptomatic, 26% had a bosis. In asymptomatic women and those with a mild tendency to bleed and 21% had thrombosis, some of bleeding phenotype, no specific treatment other than whom also had haemorrhage [42]. A study of the close observation is required unless bleeding occurs Scientific and Standardization Committee of the [20]. Vaginal delivery can be managed conservatively International Society on Thrombosis and Haemosta- with treatment given to raise fibrinogen level to sis (ISTH) identified 26 cases that fulfilled the criteria >1 g L)1 above baseline if bleeding occurs. However, of familial dysfibrinogenaemia and thrombosis not if the bleeding tendency is significant or if the woman due to other causes [43]. The study included 15 is undergoing caesarean section, prophylactic treat- women with 64 reported pregnancies. A high inci- ment is recommended to raise fibrinogen level >1 dence of spontaneous miscarriages (38%) and still- g L)1 baseline and to maintain it >0.5–1 g L)1 until Journal compilation Ó 2009 Blackwell Publishing Ltd wound healing has occurred [20]. Standard measures during labour and delivery has been suggested to for venous thrombosis should be followed in all minimize bleeding complications [20]. As there are women with dysfibrinogenaemia. Postpartum pro- no specific prothrombin concentrates available, pro- phylaxis with LMWH is recommended for those thrombin complex concentrates are the treatment of with a personal or family history of thrombosis or choice [50]. However as these contain factors IX, X following caesarean section as such surgery is usually and some brands also contain FVII they may be performed under replacement cover [20].
thrombogenic and this should be borne in mind.
For those with a personal or family history of thrombosis, fibrinogen replacement therapy is only given if bleeding occurs. Tranexamic acid should alsobe avoided. Dysfibrinogenaemia is usually transmit- Information on pregnancy outcome and management ted as an autosomal dominant trait, therefore, it is in women with FV deficiency is also scarce. A series of important to regard the neonate as potentially 15 pregnancies in 11 heterozygote women (with FV affected and avoid invasive monitoring procedures activity levels about 50 IU dL)1) and three pregnan- and instrumental deliveries especially if the family cies in two homozygous women (with FV activity levels < 5 IU dL)1) has been reported [51]. Therewere no recurrent miscarriages, premature births and/or fetal losses in these women [51]. Pregnancy and delivery were not accompanied by any bleeding Prothrombin deficiency is the rarest inherited bleed- ing disorder with an estimated prevalence of 1:2 50 IU dL)1. In a series of 35 Iranian patients million in the general population [47]. It can be including 10 women, postoperative and postpartum classified as hypoprothrombinaemia, where there is a bleeding together affected 43% (15/35) of the patients parallel decrease in prothrombin antigen and activity [52]. In a literature review by Noia et al. [53], PPH level, or dysprothrombinaemia, where prothrombin occurred in 13 (76%) of the 17 deliveries among nine activity is reduced but the antigen level is normal or women. There were two forceps deliveries both slightly decreased [48]. The activity levels are usually complicated with vaginal haematoma [53,54].
<10 IU dL)1 amongst individuals with homozygous Women with FV deficiency especially those with low FV levels appear to be at increased risk of PPH.
60 IU dL)1 in heterozygotes. In dysprothrombina- Therefore, careful management of labour and the emia, the activity levels vary between 1 and immediate postpartum period is necessary. In women 50 IU dL)1 [48]. Bleeding manifestations may be with partial (heterozygous) deficiency and no history severe in homozygotes while absent in those with of bleeding, labour and delivery could be managed heterozygous hypoprothrombinaemia and they are expectantly [20]. However, in women with severe (homozygous) deficiency, substitution therapy with Catanzarite et al. [49] reported eight pregnancies FFP (as no FV concentrate is available) to raise FV in a woman with congenital hypoprothrominaemia level to above 15 [20]–25 [51] IU dL)1 is recom- (FII activity <1 IU dL)1). All the pregnancies were mended. These women should receive pathogen- complicated by first-trimester bleeding, four ended in inactivated plasma (either solvent-detergent sterilized miscarriage and four progressed to term without pooled plasma or individual units treated with replacement therapy. Spontaneous maternal sub- methylene blue). Close monitoring of FV levels is arachnoid haemorrhage occurred in one pregnancy also recommended to ensure that the required at 24 weeks’ gestation. Substitution therapy was haemostatic level has been achieved. Further doses given during labour and no excessive bleeding was may be necessary to maintain these levels during and noted at delivery. However, secondary PPH was after delivery. If caesarean section is performed, it is reported in one pregnancy. In a small Iranian series recommended that FV levels are maintained above including a total of 14 patients (gender split not this level until wound healing is established, i.e.
specified) PPH was reported [47]. Based on this limited data, it is difficult to make recommendationfor the obstetric management of women with pro- thrombin deficiency. It is unknown whether prophy-lactic replacement therapy is required or not during FVII deficiency is the most common of the rare pregnancy. These women are considered potentially inherited bleeding disorders. It is associated with a at risk of PPH. A prothrombin level of >25 IU dL)1 wide spectrum of bleeding symptoms. Furthermore, Ó 2009 The AuthorsJournal compilation Ó 2009 Blackwell Publishing Ltd there is a relatively poor correlation between abso- derived FVII concentrates, plasma, prothrombin lute FVII level and the bleeding tendency; some complex concentrates and antifibrinolytics. How- individuals with very low FVII levels may have ever, rFVIIa (15–30 lg kg)1) is the treatment of minimal symptoms, whilst others with higher levels choice [50]. The use of tranexamic acid can be have a significant bleeding tendency [20]. In severe considered to prevent or control heavy postpartum (homozygous) FVII deficiency, the FVII levels are usually <10 IU dL)1, whereas levels of 40–60 IU dL)1are usual in heterozygotes [14,55]. Despite the poor correlation between FVII level and bleeding risk, aFVII level between 10 and 20 IU IU dL)1 is generally Although FX deficiency is associated with a variable adequate to achieve haemostasis for surgery or inva- bleeding tendency, patients with severe deficiency sive procedures and clinical manifestations do not (FX level <1 IU dL)1) tend to be the most seriously usually occur unless the FVII level is <10 IU dL)1 affected patients with rare coagulation defects [59].
Moderately affected patients (FX level 1–5 IU dL)1) A significant rise in FVII level is seen during may bleed only after haemostatic challenge, while pregnancy in non-deficient women. This has also mildly affected patients (FX level 6–10 IU dL)1) may been observed in women with mild/moderate forms be asymptomatic and may only be identified inci- of FVII deficiency (heterozygotes) [17], but not in dentally during routine screening or family studies women with severe deficiency [13–16]. In a series [50,59]. Factor X level of 10–20 IU dL)1 is generally including 10 pregnancies in four women, whose considered to be sufficient for haemostasis [50,60].
diagnosis of a mild/moderate FVII deficiency was In a recent review by Girolami et al. [61], 14 made after the pregnancy, no bleeding complications pregnancies in nine women with FX deficiency were related to delivery were reported, possibly reflecting identified in the literature. Pregnancy-related com- the protective effect of the pregnancy-induced rise in plications such as antepartum bleeding, retroplacen- factor level [17]. However, excessive bleeding was tal haematoma [11], preterm delivery [62,63] and reported after two early pregnancy losses. This may PPH [64] have been reported among these women.
be due to inadequate rise in the FVII level in early Kumar and Mehta [62] described four pregnancies in pregnancy. Consequently, prophylactic cover for a woman with FX severe deficiency. The two invasive procedures or incomplete miscarriage may pregnancies resulted in the birth of extremely be required particularly in women with FVII levels premature babies at 21 and 25 weeks’ gestation <15–20 IU dL)1. Although antepartum bleeding has following preterm labour and both died in the been reported in two woman with severe deficiency neonatal period. The mother was treated early in [16,55], the available data (albeit limited) do not pregnancy with regular FX replacement in her suggest an increased risk of miscarriage or antepar- subsequent pregnancies and she delivered healthy babies at 34 and 32 weeks’ gestation. Although the authors suggested that prophylactic factor replace- The management of affected patients is compli- ment had led to improved pregnancy outcome, cated by the variable bleeding tendency and the poor several other case reports have described successful correlation between FVII level and the bleeding risk term pregnancies in women with severe FX defi- [47,57]. In women with mild/moderate deficiency, ciency without antenatal prophylaxis [12,65,66].
FVII level may normalize at term, therefore replace- Nonetheless, these women should be followed-up ment therapy may not be required for labour and closely for any abnormal bleeding, retroplacental delivery [17]. However, this decision should be haematoma or premature labour. Replacement ther- individualized and should take into account the apy should be considered if bleeding occurs or if the mother’s bleeding tendency, FVII level in the third patient is undergoing invasive procedures. Women trimester and the mode of delivery. Women with with severe deficiency and a history of adverse severe deficiency or positive bleeding history are pregnancy outcome may benefit from replacement more likely to be risk of PPH. In a review of 12 therapy during pregnancy [20]. Replacement therapy published case reports, four pregnancies were is also required to cover labour and delivery in these complicated by PPH [13]. Therefore, prophylactic women to minimize the risk of bleeding complica- treatment is required for women with FVII level of tions [11,12]. Treatment options include prothrom- <10–20 IU dL)1 at term and/or significant bleeding bin complex concentrates or FFP. In women with FX history [13,16,55,58]. Current therapeutic options level of >10–20 IU dL)1 and no significant bleeding include recombinant factor VIIa (rFVIIa), plasma- history, a conservative approach could be adopted.
Journal compilation Ó 2009 Blackwell Publishing Ltd However, the decision should be individualized termination of pregnancy [18,19]. Severe placental taking into account obstetric factors such as outcome abruption requiring emergency caesarean section of previous pregnancies and mode of delivery.
The mode of delivery for pregnancy at risk of As FXI level does not rise during pregnancy, many homozygous FX deficiency is debatable. An elective caesarean section has been recommended due to the (<70 IU dL)1) factor level at term, thus be at risk risk of cranial and/or abdominal haemorrhage in the of excessive bleeding during delivery. In a case series newborn as a consequence of vaginal delivery [66].
including 11 women, excessive bleeding at delivery However, there have been case reports of successful was reported in 16% (4/25) of the pregnancies and neonatal outcomes following a normal vaginal none received prophylactic treatment [18]. On the delivery [11,12]. Furthermore, caesarean section other hand, there was no bleeding complication in may not completely eliminate the risk of serious five pregnancies where intra-partum replacement bleeding in these neonates and a case of a subdural therapy with FXI concentrates or FFP was given. In haemorrhage diagnosed antenatally in a fetus later another retrospective review of a total of 105 found to be homozygous for factor X deficiency has pregnancies in 33 women, excessive bleeding at been reported [67]. With limited data available in the delivery almost exclusively occurred in women with literature, elective caesarean section cannot be rec- a bleeding tendency [19]. A study of 164 pregnancies ommended for all women with FX deficiency and the in 62 women with severe FXI deficiency (FXI levels decision for the mode of delivery needs to be <17 IU dL)1) in Israel showed 69% (43) of the women never experienced PPH during 93 deliveries(85 vaginal delivery, eight caesarean sections) with-out any prophylactic cover [75]. The authors there- fore argued that prophylactic treatment is not FXI deficiency is an autosomally inherited condition.
mandatory for these women, especially with vaginal It is particularly common in Ashkenazi Jews with a delivery [75]. However, excessive bleeding at deliv- heterozygote frequency as high as 8% [68]. It has ery did occur in 24% (32/132) of vaginal deliveries been described in all racial groups, but the incidence and 17% (2/12) of caesarean section not covered by of severe deficiency in general is very low with an FFP, while all six caesarean section carried out under estimated at 1:1 million [69]. Factor XI levels are prophylactic cover were uncomplicated. In the same reduced (<15–20 IU dL)1) in homozygotes or com- study, excessive bleeding at delivery did not correlate to the genotype or FXI level. However, women with (20–70 IU dL)1) in heterozygotes [70–72] The con- a history of bleeding following earlier surgical dition is associated with a variable bleeding tendency challenges were more likely to have PPH [75].
and bleeding can occur in heterozygous as well as Due to the unpredictable bleeding tendency in FXI homozygous individuals. Spontaneous bleeding is deficiency, the decision for prophylaxis during labour very rare but haemorrhage can occur at sites prone to and delivery needs to be individualized and must take fibrinolysis after injury or surgery, and women with into consideration FXI level, personal/family bleed- partial as well as severe deficiency are at risk of ing history and the mode of delivery. Treatment menorrhagia and post-partum bleeding [18,73]. The options include tranexamic acid (for milder forms), bleeding tendency can be inconsistent within an FXI concentrates, FFP (if FXI concentrates unavail- individual and the family. It is also not clearly related able) and possibly rFVIIa. General recommendation to factor levels [71,73,74] or the genotype responsi- at present is that vaginal delivery can be managed ble for the condition [75]. This unpredictable nature expectantly with treatment on standby in women of factor XI deficiency makes management for with FXI levels between 15 and 70 IU dL)1 and no pregnancy and delivery difficult. Therefore, it is bleeding history despite haemostatic challenge [20].
important to identify whether the patient has a For those with FXI levels between 15 and 70 IU dL)1 clinical bleeding tendency and whether other coag- and a significant bleeding history or no previous ulation factors are involved, such as coexistence of haemostatic challenge, tranexamic acid can be used VWD and platelet function disorders [76].
to provide peripartum cover starting at the onset of Two retrospective case series in the UK including labour. However, for women with severe (FXI level 44 women with FXI deficiency showed that FXI <10–20 IU dL)1) deficiency, replacement therapy deficiency does not appear to be associated with an with FXI concentrate should be considered for all increased risk of miscarriage [18,19]. Both series modes of delivery. In women with partial deficiency reported excessive bleeding following miscarriage or (FXI level 20–70 IU dL)1), replacement therapy may Ó 2009 The AuthorsJournal compilation Ó 2009 Blackwell Publishing Ltd be required for caesarean section depending on the replacement therapy was not given during preg- bleeding history. In view of the thrombotic potential nancy. These data suggest that appropriate replace- of factor XI concentrate [50,77], low dose treatment ment therapy is crucial for pregnancy maintenance in of about 10 U kg)1 may be sufficient in women with these women. As pregnancies had been reported to establish spontaneously without replacement therapy 30 IU dL)1. In partial deficiency (where there has [84,85], it does not seem that subunit A is essential been a previous bleeding history) the peak level for either fertilization or early implantation. How- should be about 70 IU dL)1 and not exceed 100 ever, it is recommended that regular therapy (to IU dL)1. As for all blood products there are concerns maintain FXIII level at least >3 IU dL)1 [20] and, if about the risk of transfusion-transmitted infections.
possible, >10 IU dL)1 [24]) is commenced as early as Recombinant factor VIIa could be an alternative possible in pregnancy to prevent bleeding and preg- option that has been used to prevent surgical nancy loss. In all severely affected girls, monthly bleeding in these patients, particularly in the presence prophylactic infusions of FXIII concentrate are of a FXI inhibitor [78–80], although it is as yet recommended from the time of diagnosis and con- unlicensed in this setting. Its short half-life makes it less suitable for use to cover labour, but it could be The treatment should also be continued during used for management of an elective caesarean labour and delivery to minimize the risk of bleeding complications. However, higher FXIII levels may be Women with FXI deficiency are at increased risk of required for delivery [24]. Burrows et al. [22] both primary and secondary PPH. In the case series reported a successful outcome in a woman with including 11 women with FXI deficiency, the inci- FXIII deficiency whose FXIII levels were maintained dence of primary and secondary PPH was 16% and at approximately 3 IU dL)1 during pregnancy and 24%, respectively [18]. Consequently, prophylactic raised to 19 IU dL)1 at delivery. Kobayashi et al.
treatment with tranexamic acid should be considered [84] described another uncomplicated vaginal deliv- post delivery up to 2 weeks, particularly for those ery in an affected woman whose FXIII levels were with a bleeding phenotype. The concomitant use of raised to 36 IU dL)1 at delivery. A FXIII level of tranexamic acid and FXI concentrates should be >20 IU dL)1, and if possible, >30 IU dL)1 during avoided due to the potential thrombogenicity of FXI labour/delivery has been suggested to minimize the concentrates [77,81] and attention should be given to risk of bleeding complications [24].
simple thromboprophylactic measures including FXIII concentrate is the treatment of choice, either adequate hydration and early mobilization.
plasma-derived or recombinant when available. Theyare superior to FFP or cryoprecipitate because theyprovide reliable and high concentrations of FXIII in minimum volume, and the plasma-derived product FXIII circulates in plasma as a tetramer composed of has fewer contaminating substances and is virally two A-subunits and two B-subunits. The subunit A of inactivated [86]. However, further studies are needed FXIII is the enzymatically active part, while the to establish the optimal dose and interval of admin- subunit B of FVIII is a plasma carrier protein [24].
There are three subtypes of FXIII deficiency: type 1 is The incidence of PPH in women FXIII deficiency is a combined deficiency of both subunits A and B, type not known. Successful pregnancy in women with II is a deficiency of subunit A and type III is a FXIII subunit A deficiency are generally only achieved with replacement therapy throughout pregnancy and In a review of case reports and series in the English at delivery [24]. Administered FXIII concentrate has a literature between 1966 and 1998, 61 women with long circulating half-life of 7–13 days [87]; hence FXIII deficiency (4 type 1, 55 type II and 2 type III) most of these cases were not complicated with PPH.
were identified [22]. Women with types I and III In a term pregnancy achieved with replacement conceived and delivered normally. However, the therapy in a woman with FXIII deficiency and a majority of women with type II had a history of history of eight recurrent miscarriages, persistent recurrent miscarriages. There were seven reported oozing from the uterine cavity occurred postpartum successful pregnancies among women with type II which was controlled after infusing one unit of deficiency and five had received FXIII replacement.
cryoprecipitate [88]. In a review of case reports and In a more recent literature review by Asahina et al.
series, women with types I and III FXIII deficiency [24], all women with deficiency of the FXIII subunit were found to conceive and deliver normally without A were found to miscarry, with one exception [83], if replacement therapy, but almost uniformly experi- Journal compilation Ó 2009 Blackwell Publishing Ltd enced PPH [22]. Therefore, postpartum prophylaxis on genetic analysis is feasible if the causative muta- should be considered in these cases.
tion is known or if there are informative geneticmarkers. There have been a small number of reportson the prenatal diagnosis of rare bleeding disorders, including FVII [90–93], FX [94,95] and FXIII defi- Patients with this rare bleeding disorder have con- ciencies [96,97] based on direct mutation detection, comitantly low but detectable levels of coagulant linkage analysis or a combination of these methods.
activity and antigen of both FV and FVIII, usually In the absence of genetic information, cordocentesis between 5 and 20 IU dL)1 [56]. As there are no to assess fetal coagulation factor level can be published data in relation to pregnancy in these considered for prenatal diagnosis [98,99]. Discussion women, the obstetric experience of women with FV on methods used for prenatal diagnosis is beyond the deficiency and carriers of haemophilia could proba- bly serve as a useful guide. FV levels in pregnancy do A close and continuing collaboration between not change, whereas FVIII levels rise throughout the obstetricians and haematologists is essential for the pregnancy. Therefore, any possible bleeding, espe- management of pregnancy in women with bleeding cially during labour and delivery, is likely to be disorders, ideally in a joint clinic especially for those dependent on the FV level. However, both levels with severe and rare disorders. Relevant coagulation should be monitored with FV levels kept above factor levels should be checked at booking, and at 28 15–20 IU dL)1 and FVIII levels above 50 IU dL)1 and 34 weeks of gestation, and prior to any invasive during delivery or for any invasive procedures [20].
procedure such as prenatal diagnostic tests andcervical cerclage. Analysis of factor levels at plannedintervals allows treatment to be managed in acute Inherited deficiency of the Vitamin K-dependent situations when urgent assays may be difficult to obtain. Advance planning for management of labour This disorder has been described in case reports in and delivery is most important part of antenatal care fewer than 20 kindreds worldwide [20]. Plasma provided for these women. A detailed written plan of defects include low levels of FII, FVII, FIX and FX management should be formulated during the third ranging from less than 1 to 30 IU dL)1 [56]. There is trimester of pregnancy and made available to the one report of a pregnancy in a woman with severe Vitamin K-dependent clotting factors (VKCFD) [89].
Her baseline FII, FVII, FIX and FX activities were <3 IU dL)1. She was maintained on vitamin K(15 mg day)1 orally). The course of her pregnancy A woman with an inherited bleeding disorder and was uneventful, but excessive bleeding occurred from her affected child may be exposed to various the episiotomy site requiring treatment with FFP.
haemostatic challenges during labour and delivery, There is no other data on management of pregnancy therefore potentially at risk of bleeding complica- and delivery in these women. Therefore, their man- tions. The general principles of the management of agement may be guided by the obstetric experience of labour and delivery in women with rare bleeding women with single deficiency of the factors involved.
disorders are similar to pregnancies at risk of There is a need to watch for potential bleeding haemophilia. Due to limited information available complications. Vitamin K should be continued in the literature, recommendations are generally throughout the pregnancy. Replacement therapy made based on evidence derived from case studies should be considered to cover delivery or for any or opinions and experiences of respected authorities [20]. It is recommended that women with severedeficiency or carrying an affected/potentially affectedfetus should deliver at a unit where the necessary Obstetric management – general principles expertise in the management of bleeding disordersand resources for laboratory testing and clotting factor treatments are readily available [100].
The antenatal course and management of specific In view of the unpredictable nature of labour and the possibility of requiring an emergency caesarean Prenatal diagnosis is only considered when the section, it may be reasonable to maintain haemo- fetus is at risk of severe deficiency and both parents static levels during labour and delivery equivalent to are known heterozygotes. Prenatal diagnosis based that recommended for major surgery. Factor levels Ó 2009 The AuthorsJournal compilation Ó 2009 Blackwell Publishing Ltd *For general guidance only, personal and family bleeding history must be taken intoconsiderations when deciding the need for prophylaxis. Please refer to text.
 Normal ranges used at the Royal Free Haemophilia Centre and Thrombosis Unitlaboratory, normal ranges from individual laboratory should be used.
àg L)1.
§Dependent on bleeding history. Please refer to text.
may not be accessible in the acute setting, thus literature in relation to fetuses with rare bleeding planning for delivery can be done on the basis of the disorders and knowledge is extrapolated from expe- third-trimester levels. In general, for women with rience of newborns with severe or moderate haemo- subnormal factor levels, intravenous access should be philia [102,103]. Ljung et al. [102] reviewed 117 established and prophylactic treatment given to children with moderate to severe haemophilia born cover labour and delivery. The haemostatic levels in Sweden between 1970 and 1990 and found 23 required for labour and delivery in women with neonatal bleedings associated with delivery. The risk inherited bleeding disorders are shown in Table 2.
of head bleeding was 3% (3/87) with vaginal However, they can vary depending on the mode of delivery, 64% (11/17) with vacuum extraction and delivery and the individual’s bleeding tendency.
15% (2/13) with caesarean section. Head bleeding If there is a particular concern over the factor has also been reported after an elective caesarean levels in the mother and delivery at a unit affiliated section in neonates with severe bleeding disorders with an onsite haemophilia centre is deemed neces- [104,105]. These data indicate that the risk of serious sary, planned delivery may be considered to ensure bleeding during normal vaginal delivery is small and timely arrival of the mother during labour [101].
delivery by a caesarean section is not expected to However, induced labour is likely to be prolonged eliminate this risk [102]. Therefore, normal vaginal and associated with the need for instrumental deliv- delivery is generally not contraindicated, but the use ery or emergency caesarean section, particularly in of vacuum extraction or forceps, or prolonged labour primigravida women with unfavourable cervix at the especially prolonged second stage of labour, should start of induction. In these cases, a multidisciplinary be avoided [102,106]. Delivery should be achieved team of obstetrician, haematologist, anaesthetist and by the least traumatic method and early recourse to neonatologist together with the mother should per- caesarean section should be considered to minimize form a careful risk assessment. In some circum- the risk of neonatal bleeding complications. Low stances, an elective caesarean section could be forceps delivery may be considered less traumatic considered less traumatic to both the mother and than a caesarean section when the head is deeply engaged in the pelvis and an easy outlet delivery is Invasive intrapartum monitoring techniques such anticipated. Care should also be taken in minimizing as fetal scalp electrodes and fetal blood sampling maternal genital and perineal trauma in order to should be avoided in pregnancies where the fetus is at reduce the risk of excessive bleeding at delivery risk of a bleeding disorder because of the additional risk of scalp haemorrhage. Affected fetuses are at riskof serious head bleeding, including cephalohaema- toma and intracranial haemorrhage, from the processof birth. The safest method of delivery for fetuses at Regional analgesia provides the most effective labour risk is controversial. There are no data in the pain relief currently available [107] and it allows the Journal compilation Ó 2009 Blackwell Publishing Ltd women to remain alert during labour. It avoids the cannot be guaranteed. The use of regional block is need for a general anaesthesia and its associated risks contraindicated in these circumstances. Table 3 when a caesarean section is required. It is associated presents the prerequisites for the use of regional with quicker mobilization, earlier establishment of block in women with inherited bleeding disorders.
breastfeeding and gastrointestinal function and bet- The decision on its use should be individualized and ter Apgar scores when compared with general made in advance antenatally. The mother should be counselled on the risks and benefits of regional block The use of regional block techniques has been and its alternatives. Careful assessment of the coag- controversial in women with bleeding disorders due ulation status and advance planning for the need and to the potential risk of epidural/spinal haematoma.
availability of prophylaxis is also essential.
This can lead to spinal cord compression and cause Regional block in women with bleeding disorders permanent neurological damage. The risk of spinal should be performed by an experienced anaesthetist.
and epidural haematomas after neuraxial block is Regular assessment of neurological function allows rare both in the general population (1 in 150 000– early recognition of potential complications. It is 200 000) and in the obstetric population (0.2–3.7 in advisable to use the lowest concentration of local 100 000) [111–113]. However, this risk is signifi- anaesthetic agent to achieve adequate analgesia while cantly increased in the presence of coagulation preserving motor function. Any suspicions of a spinal abnormalities [113]. In obstetric practice, three of epidural haematoma should prompt assessment with the ten case reports of spinal/epidural haematoma magnetic resonance imaging for early diagnosis.
were associated with coagulation defects [114]. For Surgical decompression, if indicated, should be this reason, coagulopathy is regarded as a contrain- performed as soon as possible because adverse dication to regional block and consequently women neurological outcome is directly related to the time with inherited bleeding disorders are often denied interval from haematoma formation to surgical this option. In a recent retrospective review, the safe decompression. It is also important to consider the use of regional block was described in 36 pregnancies risk of bleeding during removal of the epidural among women with various inherited bleeding dis- catheter as spinal haematoma can also occur at the orders, including FXI and FVII deficiencies [115].
time of removal [113]. Therefore, assessment of the Regional block can be offered safely to women coagulation status and continuation of prophylaxis, with inherited bleeding disorders provided their if indicated, are equally important for the removal of coagulation defect has normalized during pregnancy or corrected by prophylactic treatment. However, itis important not to underestimate the potential risks of regional block techniques especially in those withsevere or unpredictable disorders where haemostasis The inheritance of the rare bleeding disorders isusually autosomal recessive, with the exception of Table 3. Conditions for the use of regional block in women with some of the fibrinogen disorders. In families where inherited bleeding disorders during labour and delivery.
both parents are either affected or carriers of a rare Multidisciplinary management involving haematologists, inherited bleeding disorder, the fetus could poten- anaesthetists, obstetricians and the mother tially be severely affected. In these cases, a cord Detailed counselling on the benefits and risks of regional block blood sample should be collected from neonates to assess coagulation status and clotting factor levels.
This enables early identification and management of Careful assessment of coagulation status including assessment of clotting factor during the third trimester and personal and newborns at risk of haemorrhagic complications.
Intramuscular injections should be avoided in neo- Availability of therapeutic products and adequate response nates until the coagulation status is known. Vitamin K should be given orally and routine immunizations Plan of management made antenatally, clearly documented given intradermally or subcutaneously. Any surgical and readily available to professionals attending the women in procedures (e.g. circumcision) should be delayed until the coagulation status of the neonate is known.
Normalization of coagulation defect either because of pregnancy itself or by prophylactic treatment When assessing the neonatal clotting factor levels, Meticulous technical skills in the administration of regional appropriate normal ranges must be used. Many factors correlate with gestational age only reaching Awareness and surveillance for symptoms and signs of near adult levels at 6 months of age. It may not be possible to diagnose mild forms of inherited bleeding Ó 2009 The AuthorsJournal compilation Ó 2009 Blackwell Publishing Ltd disorders at birth, and levels should be repeated at a to maintain the haemostatic level for at least later date. There is usually no clinical indication for 3–5 days after vaginal delivery or 5–7 days following urgent diagnosis of the heterozygous state. FV and caesarean section to prevent primary and secondary FVIII are at the normal adult levels at birth.
PPH. The use of oral tranexamic acid for 3–4 dayspost vaginal delivery or 7–10 days following caesar-ean section can also be considered in some cases.
However, the potential for thrombosis associated Postpartum haemorrhage is classified as primary or with replacement therapy must be carefully evalu- secondary PPH. Primary PPH is traditionally defined ated and balanced against the risk of bleeding.
as a blood loss of more than 500 mL (or 1000 mL Uterine atony is the commonest cause for PPH.
for severe PPH) in the first 24 h after delivery, while Active management of third stage of labour has been secondary PPH refers to excessive bleeding occurring shown to be associated with a significant reduction in between 24 h and 6 weeks post delivery. Women blood loss and the need for blood transfusion [116].
with inherited bleeding disorders are at an increased This entails the administration of a prophylactic risk of both primary and secondary PPH. The three uterotonic agent (e.g. oxytocin) after delivery of the main principles for reducing the risk of PPH are: baby, early cord clamping and controlled cord prophylactic treatment to normalize their haemo- traction of the umbilical cord. Misoprostol, a new static status, measures to avoid uterine atony and and inexpensive prostaglandin E1 analogue that can be given orally, sublingually and rectally, appears to required, prophylactic replacement therapy is given be a promising uterotonic for the prevention of PPH[117]. Its administration can be associated withunpleasant side-effects including vomiting, diar- Table 4. Risk factors and causes of postpartum haemorrhage rhoea, fever and shivering. A recent pharmacokinet- ics study has found lower peak levels but a reduction in adverse effects with rectal compared with the oral route [118,119]. In our unit, we use rectal misopr- ostol (600 mcg) in adjunct to active management of third stage in women with inherited bleeding In the event of an operative delivery, meticulous attention to haemostasis is required during surgery to minimize blood loss. Care must also be taken to minimize maternal genital and perineal trauma as women with inherited bleeding disorder are at particular risk of developing perineal haematoma [18,120]. It is important not to overlook the obstetric risk factors and causes (Table 4 ) of PPH in women with inherited bleeding disorders. In case of haem- *Not exclusive; data from Stones et al. [125] and Sheiner et al.
orrhage, after initial assessment and restoration of circulatory volume, local causes should be excluded Table 5. Therapeutic options for women with inherited bleeding disorders in pregnancy.
FXIII concentrates (rFXIII in clinical trial) F, factor; r, recombinant; SD plasma, fresh frozen plasma virally inactivated using a solvent detergent technique; PCC, prothrombincomplex concentrates; VKCFD, hereditary combined deficiency of the vitamin K-dependent clotting factors.
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