General recommendations

All patients with factor deficiencies should be registered with a hemophilia center. Women should be offered genetic counseling before conception in order to discuss the inheritance of their bleeding disorder, prenatal diagnosis, and, for some disorders, the option of preimplantation diagnosis may be available. Prenatal diagnosis is possible but is only recommended in couples who have had previous severely affected children or who are known to both be heterozygous carriers and at risk of having a severely affected child. In order to carry out prenatal diagnosis, the causative gene mutations or informative markers must first be identified in the parents, which can take time and should ideally be done before conception. Prenatal diagnosis can be carried out via chorionic villus sampling (CVS), amniocentesis, or fetal cord blood sampling (cordocentesis).

Pregnancy in women with these disorders should be managed in an obstetric unit within a hospital that has a hemophilia center. The patient should ideally be seen in a joint obstetric hematology clinic and be managed by a multidisciplinary team that includes an obstetrician who is a specialist in high-risk obstetrics and a hematologist with expertise in hemostasis and, where appropriate, a pediatric hematologist. Factor levels should be checked at booking, at 28 and 34 weeks’ gestation, and before any invasive procedures. More frequent checks may be required if prophylactic factor treatment is being given during pregnancy. When assessing the risk of bleeding in pregnant women with factor deficiencies, a detailed bleeding history, family history, and obstetric history should be obtained in association with factor levels. The management plan should be individualized for each patient and all women should have a written delivery plan made during the third trimester that is made available to all of those involved in the patient’s care (including the woman herself). Good communication between hematologists, obstetricians, anesthetists, midwives, and pediatricians is essential for the safe management of labor and delivery.

All women with factor deficiencies should deliver in a unit that has easy access to factor treatments and laboratory tests. Factor treatments are described separately for each bleeding disorder in this article. Having a severe bleeding disorder is not in itself an indication for a cesarean section delivery and, in most cases, normal vaginal delivery can be planned. In some cases, cesarean delivery may be deemed safer for obstetric indications. If the fetus is at risk of having a bleeding disorder, invasive monitoring, such as fetal blood sampling, fetal scalp electrodes, and the use of vacuum extraction and midcavity forceps, should be avoided. Prolonged second stage of labor also increases the risk of neonatal hemorrhage and therefore, in cases in which this is likely, an early recourse to cesarean section is recommended. Trauma to the maternal genital and perineal areas should be minimized during delivery.

The use of regional anesthesia/analgesia has often been denied to women with bleeding disorders because of the potential risk of spinal/epidural hematoma formation with subsequent spinal cord compression. Regional blocks can be used in women who have normalized their factor levels during pregnancy or who have normal factor levels as a result of treatment, but women should be adequately counseled about the risks and benefits of regional blocks and informed consent obtained. An experienced anesthetist should perform the procedure and the patient should be monitored for any signs of spinal/epidural hematoma, with prompt imaging of the spinal cord if any complications are suspected. Factor levels also need to be maintained in the normal range at the time of catheter removal. Regional blocks should not be used in situations in which hemostasis is not guaranteed, such as in patients with uncorrected severe deficiencies or in whom there is poor correlation between the bleeding risk and factor levels.

Pediatric hematologists and neonatologists need to be informed of the birth of any neonates with possible bleeding disorders. Cord blood samples should be collected if the neonate is at risk of being severely affected by a bleeding disorder, and intramuscular injections and surgery (eg, circumcision) should be delayed until the results are known. Several of the severe factor deficiencies are associated with neonatal cranial hemorrhage, which requires prompt diagnosis and treatment.

Women with factor deficiencies are at increased risk of primary and secondary postpartum hemorrhage (PPH). The third stage of labor should be managed actively in order to reduce the risk of PPH. Prophylactic factor replacement should be given to women who have suboptimal factor levels or a significant bleeding history. Treatment is recommended during delivery and for at least 3 days after vaginal delivery and 5 days after cesarean section.

Inherited abnormalities of fibrinogen

Inherited abnormalities of fibrinogen can be subdivided into quantitative defects in which there is a complete absence of fibrinogen (afibrinogenemia) or a reduced amount of fibrinogen (hypofibrinogenemia), and qualitative defects in which the fibrinogen produced does not function normally (dysfibrinogenemia). Patients can also have low levels of dysfunctional fibrinogen (hypodysfibrinogenemia). Afibrinogenemia is an autosomal recessive disorder with an estimated prevalence of 1 in 1 million. Hypofibrinogenemia can be inherited in an autosomal recessive or dominant fashion. Dysfibrinogenemia is an autosomal dominant disorder with an unknown incidence.

Women who have quantitative defects of fibrinogen are at increased risk of miscarriage, placental abruption, and postpartum hemorrhage. The ability of fibrinogen to form a stable fibrin network is important in maintaining placental integrity. As pregnancy progresses, fibrinogen turnover increases, with most fibrinogen consumption occurring in the uteroplacental bed.

A literature review reveals 22 pregnancies in 10 women with afibrinogenemia, resulting in 12 miscarriages, 2 perinatal deaths, and 8 live births. Fibrinogen replacement was given throughout all of the successful pregnancies. A review of the literature on hypofibrinogenemia reported 44 pregnancies in 15 women, resulting in 13 miscarriages, 8 placental abruptions, and 14 postpartum transfusions. All women with afibrinogenemia should commence treatment with either fibrinogen concentrate or cryoprecipitate infusions as soon as pregnancy is confirmed. Fibrinogen concentrate is preferred because cryoprecipitate is not pathogen inactivated. In the first and second trimester, trough fibrinogen levels of greater than 0.5 g L ⁻¹ and, if possible, greater than 1.0 g L ⁻¹ should be attempted by giving 2 to 3 g week ⁻¹ . Fibrinogen levels should be checked weekly along with regular ultrasound assessment to monitor fetal growth and look for placental bleeding. The amount of fibrinogen required will increase throughout pregnancy as the fibrinogen clearance increases. In the later part of the third trimester, a trough level of greater than 1.0 g L ⁻¹ should be maintained. At the start of labor, a bolus of 4 g of fibrinogen concentrate should be administered followed by a continuous infusion of fibrinogen concentrate, intended to keep levels at more than 1.5 g L ⁻¹ during delivery and for 24 hours postpartum. Replacement treatment during pregnancy and delivery may also be required in women with hypofibrinogenemia, depending on their bleeding history, previous obstetric history, and fibrinogen levels. All women who have a fibrinogen level of less than 1.5 g L ⁻¹ or a significant bleeding history should receive replacement treatment intrapartum.

Less commonly, thrombotic events have been reported in association with pregnancy in women with hypofibrinogenemia and afibrinogenemia. Early mobilization, maintenance of adequate hydration, and compression stockings are recommended in the postpartum period. If there is a family or personal history of previous thrombotic events, thromboprophylaxis with low molecular weight heparin (LMWH) should be considered.

Dysfibrinogenemia is characterized by a wide variation in clinical phenotype, with both bleeding and thrombotic tendencies reported. A study of 64 pregnancies in 15 women with dysfibrinogenemia reported an increased rate of miscarriage (38%) and stillbirth (9%). Placental abruption, PPH, and thrombosis have also been reported. The management of pregnant women with dysfibrinogenemia should be individually tailored, taking into account any family or personal history of bleeding or thrombosis and any previous obstetric history along with fibrinogen levels. Approximately half of patients with this disorder are asymptomatic and do not need any treatment during pregnancy or delivery unless bleeding or thrombosis occurs. Standard postpartum thromboprophylaxis measures should be followed in asymptomatic patients.

In women with a personal or family history of thrombosis, antenatal and postpartum thromboprophylaxis should be given with LMWH and fibrinogen replacement should not be given unless the patient is bleeding. In women who have a history of bleeding or who require a cesarean section, fibrinogen replacement should be given to increase the fibrinogen levels to more than 1 g L ⁻¹ to cover delivery and should be continued, keeping levels at more than 0.5 g L ⁻¹ until wound healing has occurred. LMWH prophylaxis is also recommended after cesarean section along with compression stockings, good hydration, and early mobilization. Invasive monitoring during labor and instrumental deliveries should be avoided in case the neonate is affected. In patients who experience recurrent miscarriages, either prophylactic LMWH or fibrinogen concentrate treatment can be tried.

Inherited abnormalities of fibrinogen

Inherited abnormalities of fibrinogen can be subdivided into quantitative defects in which there is a complete absence of fibrinogen (afibrinogenemia) or a reduced amount of fibrinogen (hypofibrinogenemia), and qualitative defects in which the fibrinogen produced does not function normally (dysfibrinogenemia). Patients can also have low levels of dysfunctional fibrinogen (hypodysfibrinogenemia). Afibrinogenemia is an autosomal recessive disorder with an estimated prevalence of 1 in 1 million. Hypofibrinogenemia can be inherited in an autosomal recessive or dominant fashion. Dysfibrinogenemia is an autosomal dominant disorder with an unknown incidence.

Women who have quantitative defects of fibrinogen are at increased risk of miscarriage, placental abruption, and postpartum hemorrhage. The ability of fibrinogen to form a stable fibrin network is important in maintaining placental integrity. As pregnancy progresses, fibrinogen turnover increases, with most fibrinogen consumption occurring in the uteroplacental bed.

A literature review reveals 22 pregnancies in 10 women with afibrinogenemia, resulting in 12 miscarriages, 2 perinatal deaths, and 8 live births. Fibrinogen replacement was given throughout all of the successful pregnancies. A review of the literature on hypofibrinogenemia reported 44 pregnancies in 15 women, resulting in 13 miscarriages, 8 placental abruptions, and 14 postpartum transfusions. All women with afibrinogenemia should commence treatment with either fibrinogen concentrate or cryoprecipitate infusions as soon as pregnancy is confirmed. Fibrinogen concentrate is preferred because cryoprecipitate is not pathogen inactivated. In the first and second trimester, trough fibrinogen levels of greater than 0.5 g L ⁻¹ and, if possible, greater than 1.0 g L ⁻¹ should be attempted by giving 2 to 3 g week ⁻¹ . Fibrinogen levels should be checked weekly along with regular ultrasound assessment to monitor fetal growth and look for placental bleeding. The amount of fibrinogen required will increase throughout pregnancy as the fibrinogen clearance increases. In the later part of the third trimester, a trough level of greater than 1.0 g L ⁻¹ should be maintained. At the start of labor, a bolus of 4 g of fibrinogen concentrate should be administered followed by a continuous infusion of fibrinogen concentrate, intended to keep levels at more than 1.5 g L ⁻¹ during delivery and for 24 hours postpartum. Replacement treatment during pregnancy and delivery may also be required in women with hypofibrinogenemia, depending on their bleeding history, previous obstetric history, and fibrinogen levels. All women who have a fibrinogen level of less than 1.5 g L ⁻¹ or a significant bleeding history should receive replacement treatment intrapartum.

Less commonly, thrombotic events have been reported in association with pregnancy in women with hypofibrinogenemia and afibrinogenemia. Early mobilization, maintenance of adequate hydration, and compression stockings are recommended in the postpartum period. If there is a family or personal history of previous thrombotic events, thromboprophylaxis with low molecular weight heparin (LMWH) should be considered.

Dysfibrinogenemia is characterized by a wide variation in clinical phenotype, with both bleeding and thrombotic tendencies reported. A study of 64 pregnancies in 15 women with dysfibrinogenemia reported an increased rate of miscarriage (38%) and stillbirth (9%). Placental abruption, PPH, and thrombosis have also been reported. The management of pregnant women with dysfibrinogenemia should be individually tailored, taking into account any family or personal history of bleeding or thrombosis and any previous obstetric history along with fibrinogen levels. Approximately half of patients with this disorder are asymptomatic and do not need any treatment during pregnancy or delivery unless bleeding or thrombosis occurs. Standard postpartum thromboprophylaxis measures should be followed in asymptomatic patients.

In women with a personal or family history of thrombosis, antenatal and postpartum thromboprophylaxis should be given with LMWH and fibrinogen replacement should not be given unless the patient is bleeding. In women who have a history of bleeding or who require a cesarean section, fibrinogen replacement should be given to increase the fibrinogen levels to more than 1 g L ⁻¹ to cover delivery and should be continued, keeping levels at more than 0.5 g L ⁻¹ until wound healing has occurred. LMWH prophylaxis is also recommended after cesarean section along with compression stockings, good hydration, and early mobilization. Invasive monitoring during labor and instrumental deliveries should be avoided in case the neonate is affected. In patients who experience recurrent miscarriages, either prophylactic LMWH or fibrinogen concentrate treatment can be tried.

Factor II: prothrombin deficiency

Prothrombin deficiency is a rare autosomal recessive disorder with a prevalence of 1 per 2 million in the general population. It can be classified into 2 main phenotypes: hypoprothrombinemia (type 1 deficiency, characterized by a concomitant reduction of prothrombin antigen and activity levels), and dysprothrombinemia (type 2 deficiency, characterized by the production of a dysfunctional protein with reduced activity levels and normal antigen levels). Compound heterozygotes with combined defects have also been described. Complete deficiency of prothrombin has not been reported and is believed to be incompatible with life.

Patients with homozygous hypoprothrombinemia usually have prothrombin activity levels of less than 10 IU dL ⁻¹ and severe bleeding manifestations. In comparison, heterozygotes have levels between 40 and 60 IU dL ⁻¹ and are usually asymptomatic, but may have excessive bleeding after surgery. Individuals with dysprothrombinemia have both variable bleeding tendencies and prothrombin activity levels (between 1 and 50 IU dL ⁻¹ ).

There are insufficient published data to determine whether patients with prothrombin deficiency are at increased risk of miscarriage or to give definitive guidance on the management of pregnancy in patients with this disorder. Catanzarite and colleagues reported a woman with hypoprothrombinemia (factor [F]II activity <1 IU dL ⁻¹ ) who had had 8 pregnancies. All of the pregnancies were complicated by first trimester bleeding. Four of the pregnancies ended in miscarriage, with 2 having had ultrasound evidence of subchorionic hemorrhage before loss of pregnancy. The patient received prothrombin complex concentrate (PCC) before uterine curettage for all of the miscarriages and had no excessive bleeding. Four of the pregnancies reached term without any replacement treatment. The patient was given fresh frozen plasma (FFP) before delivery of her first child but had a delayed PPH requiring additional FFP, PCC, and blood transfusions. She was given PCC before the next 3 deliveries and had no PPH. An extra infusion of PCC was given after delivery of her fourth child because the placenta was found to have a large marginal clot. PPH has also been reported in a small Iranian series of 14 patients.

It is unknown whether prophylaxis during pregnancy can prevent miscarriages and improve overall outcomes. A prothrombin level of 20 to 30 IU dL ⁻¹ is believed to be required for normal hemostasis, and it is recommended that a prothrombin level of more than 25 IU dL ⁻¹ should be achieved during labor and delivery. There are no specific prothrombin concentrates, and therefore PCCs are the treatment of choice; these also contain FIX and FX and some also contain FVII in addition to FII, and therefore there is a potential risk that this treatment could be thrombogenic. There is approximately 1 unit of prothrombin per unit of FIX in vials of PCC, and doses of 20 to 30 IU kg ⁻¹ should be used. Major surgery or life threatening bleeds may require higher doses. Prothrombin has a long half-life (about 72 hours), allowing dosing every 2 to 3 days, and treatment should be guided by levels. If no PCC is available, virally inactivated FFP should be administered at a dose of 15 to 20 mL kg ⁻¹ , which will raise the FII level by approximately 25%. Treatment should also be given if there is serious bleeding during pregnancy, before invasive procedures, and if a cesarean section is required. It is uncertain whether treatment is beneficial in threatened miscarriages, but it would be reasonable to consider replacement in this situation.

FV deficiency

FV deficiency is an autosomal recessive disorder with a prevalence of approximately 1 per 1 million in the general population. Patients with type I deficiency have a quantitative defect (ie, low levels of antigen), and individuals with type II deficiency have a qualitative defect (ie, normal or mildly reduced antigen levels with reduced activity). Patients who are homozygotes or compound heterozygotes for mutations in the FV gene have severe deficiency that is characterized by FV levels of less than 10 to 15 IU dL ⁻¹ . Individuals with mild to moderate FV deficiency have FV levels of greater than 20% to 30% and are usually heterozygotes. There is limited correlation between the FV activity level and the clinical phenotype in this disorder. A wide variation in bleeding symptoms has been reported in patients with identical FV gene mutations or activity levels, including between related patients with identical genotypes. Taking an accurate bleeding history is therefore an important part of assessing the bleeding risk in patients with FV deficiency.

FV levels do not increase significantly during pregnancy. There is no reported increase in rates of miscarriage, premature births, or fetal deaths in patients with FV deficiency, and prophylaxis during pregnancy is not required unless the patient is undergoing an invasive procedure. Patients with severe deficiency are at risk of excessive bleeding at delivery and postpartum. A report of 2 pregnancies in patients with severe FV deficiency and literature review of a further 18 pregnancies showed that, of the 20 pregnancies, 11 (55%) were complicated by excessive bleeding that required transfusion of either FFP or whole blood. Another group reported PPH in 13 of 17 deliveries (76%) in 9 women with FV deficiency. A series of 15 pregnancies in 11 heterozygotic patients resulted in uneventful deliveries with no excessive bleeding without prophylaxis.

Pregnant women with FV deficiency should have a bleeding history review and an FV level checked during the third trimester so that a delivery plan can be made. Labor and delivery can be managed expectantly in women with partial FV deficiency and no significant bleeding history. In women with severe deficiency, FV levels should be increased to more than 15 to 25 IU dL ⁻¹ during delivery and, if a cesarean section is performed, this should be maintained until wound healing has occurred (ie, 5–7 days). No FV concentrate is currently available, therefore women should be treated with pathogen-inactivated FFP either in the form of solvent-detergent FFP (SD-FFP) or methylene blue–treated plasma. Because of the plasma processing, FV activity is reduced by 30% in SD-FFP compared with standard FFP and therefore a dose of 15 to 20 mL kg ⁻¹ of SD-FFP will have a lower posttransfusion increment of FV than standard FFP. It is therefore important to monitor FV levels. Plasma should be administered as soon as the patient is in established labor, and further doses given as dictated by the FV levels and clinical need. If a cesarean section is performed, FV levels should be maintained at more than 15 IU dL ⁻¹ until wound healing has occurred (ie, 5–7 days).

Prenatal diagnosis of FV deficiency is possible in families in which the parents have had a previous severely affected child and the gene mutation has been characterized. Cord blood can be taken at birth to measure FV levels in the baby. Severe and moderate deficiencies can be diagnosed at birth, but blood tests suggestive of a mild deficiency should be repeated when the child is older in order to confirm the diagnosis, because FV levels may not be reliable at birth. Bleeding is uncommon in the neonatal period but intracranial hemorrhage can occur and it is recommended that babies with an FV level of less than 15 IU dL ⁻¹ may have central nervous system imaging carried out in the first few days of life to exclude this. If bleeding does occur, neonates should be treated with 15 to 20 mL kg ⁻¹ of pathogen-inactivated plasma in order to increase FV levels to more than 15 IU dL ⁻¹ . Prophylactic plasma treatment is not required in asymptomatic FV-deficient neonates.

FVII deficiency

FVII deficiency is the most common of the rare bleeding disorders, with an estimated incidence of 1 in 300,000 to 500,000 in its severe form and 1 in 350 for heterozygotes. Clinical heterogeneity is described with little correlation between absolute FVII levels and bleeding risk. Some patients with very low FVII levels are asymptomatic, whereas others experience severe bleeding and some individuals with higher FVII levels may also bleed. Phenotypic heterogeneity has also been described in patients with identical FVII mutations, supporting the theory that other genetic or environmental factors may play an important role in modulating the bleeding risk in FVII deficiency. It is therefore important to take a thorough bleeding history when assessing patients with this disorder because a positive bleeding history predicts for bleeding.

Heterozygotes usually have FVII levels of 20 to 60 IU dL ⁻¹ and homozygotes with severe deficiency have levels of les than 10 IU dL ⁻¹ . Pregnancy induces a hypercoagulable state with increases of several coagulation factors in normal women and, in nondeficient women, FVII levels can increase up to fourfold during pregnancy, delivery, and the puerperium. A significant increase in levels has also been reported in pregnant heterozygotes with mild to moderate FVII deficiencies. A study of 10 pregnancies in 4 women who had undiagnosed mild/moderate FVII deficiency at the time of delivery reported that 2 of the pregnancies resulted in early loss requiring surgical evacuation with excessive intraoperative bleeding, suggesting that women with mild/moderate deficiencies may be at increased risk of bleeding early in pregnancy before their FVII levels increase. FVII replacement should therefore be considered for any invasive procedures or bleeding during early pregnancy. From the other 8 pregnancies, 5 resulted in vaginal deliveries and 3 babies were delivered via cesarean section with epidural anesthesia. The baseline FVII levels in these women ranged from 7 to 49 IU dL ⁻¹ . No anesthetic or major hemorrhagic complications were seen in these women who received no prophylactic treatment. Four pregnancies were reported in 3 women after the diagnosis of mild/moderate FVII deficiency. The FVII levels increased from a mean baseline of 33 IU dL ⁻¹ to a mean of 73 IU dL ⁻¹ in these women during pregnancy. Three of the women delivered by cesarean section and 1 by vaginal delivery, with all women receiving treatment with recombinant activated FVII (rFVIIa) before delivery. Three of the deliveries had no major bleeding, but 1 woman had excessive bleeding during a cesarean section.

FVII replacement may not be required before delivery in women with mild/moderate deficiency. A decision regarding treatment should be based on FVII levels in the third trimester, the expected mode of delivery, and, most importantly, the past bleeding history because of the poor correlation between FVII levels and bleeding risk.

No increase in FVII levels occurs in pregnant women with severe FVII deficiency, who usually have levels of less than 10 IU dL ⁻¹ . Antepartum hemorrhage has been described in 2 women with severe deficiency but there are not enough data to determine whether FVII deficiency increases the risk of miscarriage and antepartum hemorrhage. These women should also have FVII levels measured in the third trimester so that a delivery plan can be made. All women with an FVII level of less than 10 to 20 IU dL ⁻¹ at term, or with a significant bleeding history, should receive prophylaxis before delivery and in the postpartum period. Possible treatments include rFVIIa, or a plasma-derived FVII concentrate, or SD-FFP if concentrates are not available. The treatment of choice is rFVIIa, although the optimal dosing in pregnancy is not known. Several case reports have described the successful use of rFVIIa in pregnant women with severe FVII deficiency using a variety of regimes. Pehlivanov and colleagues reported a pregnant woman with an FVII level of 2% who received 60 μg kg ⁻¹ of rVIIa at complete dilatation of the cervix and then 30 μg kg ⁻¹ every 2 hours for 5 doses following vaginal delivery with no complications. Eskandari and colleagues described a pregnant woman with an FVII level of 1% who was given 50 μg kg ⁻¹ of rFVIIa at complete dilatation of the cervix and a second dose of 35 μg kg ⁻¹ 4 hours later with no excessive bleeding following vaginal delivery. Muleo and colleagues reported a pregnant woman with an FVII level of 6% who was given 20 μg kg ⁻¹ of rVIIa before cesarean section and then 10 μg kg ⁻¹ doses at 6 hourly intervals for 2 days with no excessive bleeding. Jiménez-Yuste and colleagues reported a woman with an FVII level of 3.7 IU dL ⁻¹ who, after pharmacokinetic studies, was given a bolus of 13.3 μg kg ⁻¹ of rVIIa before cesarean section, followed by a 3.33 μg kg ⁻¹ h ⁻¹ infusion for 48 hours, and then 1.66 μg kg ⁻¹ h ⁻¹ infusion for a further 48 hours without any hemorrhagic complications. An FVII level of 10 to 20 IU dL ⁻¹ is believed to be required to achieve hemostasis after invasive procedures or surgery. A dose of 15 to 30 μg kg ⁻¹ has been recommended to cover delivery.

Pregnancies in which there is a risk of a severely affected baby delivery should be planned to minimize the risk of bleeding. Diagnosis of FVII deficiency may be difficult in the neonatal period because FVII levels are physiologically low in the newborn, but cord blood should be taken at delivery for FVII levels if severe deficiency is suspected. There is a 15% risk of cerebral hemorrhage in severely affected neonates, and prophylaxis should be considered.

Carriers of hemophilia A and B

Hemophilia A and B are X-linked disorders that result in deficiencies in FVIII and FIX respectively. The incidence of hemophilia A is 1 in 5000 live male births and 1 in 30,000 live male births in hemophilia B. Female carriers of hemophilia are expected to have clotting factor levels around 50% of normal but, in 10% to 20% of carriers, extreme lyonization of the FVIII gene and FIX gene results in much lower factor levels (<40%). Carriers of hemophilia may therefore experience bleeding symptoms and may be at risk of bleeding, especially in those with levels of less than 10%.

Hemophilia carriers have a 25% chance of having an affected child, a risk of 1 in 2 for every male child. Prepregnancy counseling and mutation detection should be offered to all women who are possible carriers of hemophilia. This service enables carriership to be confidently diagnosed before pregnancy and allows the patient to be provided with information about reproductive choices and prenatal diagnosis. In a study of pregnant possible hemophilia carriers, those who were unaware of their carrier status at the time of delivery were more likely to have instrumental deliveries that are significant risk factors for intracranial and extracranial hemorrhage in newborn hemophiliacs.

It is not known whether hemophilia carriers have an increased risk of miscarriage or early pregnancy bleeding. Chi and colleagues performed a retrospective review of 41 hemophilia A carriers and 12 hemophilia B carriers who had received obstetric care in a 10-year period. They reported 13 miscarriages in 90 pregnancies (14%) and 2 cases of early pregnancy bleeding that had both occurred in low-factor-level carriers of hemophilia B. Hemorrhage occurred after a termination of pregnancy in a patient with an FVIII level of 42 IU dL ⁻¹ and after an evacuation of retained products in a carrier with a normal FVIII level. A retrospective survey on pregnancies in 46 hemophilia carriers reported 25 miscarriages in 120 pregnancies (21%). Three of the women (7%) experienced 2 or more miscarriages. Coagulation factor replacement should be considered in patients with low factor levels who have bleeding, miscarriages, terminations of pregnancy, or invasive procedures during pregnancy. There is no evidence of an increased risk of antepartum hemorrhage after 24 weeks’ gestation.

FVIII levels increase significantly during pregnancy in most hemophilia A carriers; however, a small percentage still have low levels at term. FIX levels do not increase in carriers of hemophilia B during pregnancy. Factor levels should be checked in pregnant hemophilia carriers at booking and at 28 and 34 weeks’ gestation in order to plan the optimal management of labor and delivery. A delivery plan should be formulated in the third trimester. In patients who have opted not to have prenatal diagnosis, it is helpful if the gender of the fetus is determined before delivery either by ultrasound or by assessing free fetal DNA in a maternal blood sample for the presence of Y chromosome–specific DNA. If the fetus is known to be male or the gender is unknown, vacuum extraction, high-cavity and midcavity forceps deliveries, prolonged labor, and invasive monitoring techniques such as the use of fetal scalp electrodes or fetal blood sampling should be avoided. There is a 50% chance that a male fetus will be affected by hemophilia and be at risk of hemorrhagic complications.

FVIII or FIX concentrate (preferably recombinant) should be given during labor if factor levels in the third trimester are less than 50 IU dL ⁻¹ . Desmopressin (1-desamino-8- d -arginine vasopressin [DDAVP]) can be used to raise FVIII levels in some carriers of hemophilia A but has no effect in hemophilia B. Fluid intake should be restricted for 24 hours following each dose in patients who are given desmopressin because fluid retention can occur. It is safe for women to breast feed following desmopressin administration.

Babies with hemophilia are at risk of severe intracranial bleeding from the birth process and there is debate about the safest mode of delivery. In a review of 117 children born with severe or moderate hemophilia, 23 neonatal bleeds were reported. The risk of cranial bleeding was 64% with vacuum extraction, 15% with cesarean section, and 3% with normal vaginal deliveries. Normal vaginal deliveries were recommended, but there is an increased risk of bleeding in babies if there has been a prolonged second stage of labor. An early decision to carry out a cesarean section is recommended in patients who are likely to have prolonged labor or difficult vaginal deliveries. If factor levels are greater than 50 IU dL ⁻¹ , regional blocks can be used but should be performed by an experienced anesthetist. Intramuscular injections and nonsteroidal anti-inflammatory drugs should not be administered in low-level carriers of hemophilia.

After delivery the pregnancy-induced increase of FVIII rapidly decreases. Hemophilia carriers have increased rates of primary and secondary PPH. In normal women, the rates of primary PPH are 5% to 8%, and 0.8% for secondary PPH. In comparison, the incidence of primary PPH and secondary PPH in hemophilia carriers are 22% and 11% respectively. Patients are also at risk of perineal hematomas. Active management of the third stage of labor should be practiced and factor levels should be maintained at more than 50 IU dL ⁻¹ for 3 days in vaginal deliveries and 5 days after cesarean section. Antifibrinolytic agents should also be considered.

Cord blood samples for factor assays should be taken from all male babies born to hemophilia carriers to allow early identification of hemophiliac neonates. Intracranial hemorrhage occurs in 1% to 4% of neonates affected by hemophilia. Cranial imaging should be arranged for hemophiliac neonates if the labor has been prolonged, the delivery has been traumatic, or if a cerebral bleed is suspected. Factor concentrate should be given to neonates suspected of having a cranial bleed in order to raise the factor level to 100 IU dL ⁻¹ .