13 Hemophilia in women and girls and hemophilia carriers

Revision by: Anna Olsson (Gothenburg)

13.1 Background

The hemophilia nomenclature distinguishes five clinically relevant categories of hemophilia carriers: women/girls with mild, moderate or severe hemophilia, symptomatic and asymptomatic hemophilia carriers (FVIII/FIX \(\ge\) 40%) with and without a bleeding phenotype, respectively [185]. It is suggested that the term hemophilia carrier is used in discussions relating to genetic counselling and hemophilia or symptomatic carrier when referring to bleeding phenotype. Hemophilia carriers should be registered at a hemophilia treatment center. The factor levels in carriers are expected to be about 50% of the levels of non-carriers, but due to X-chromosome inactivation the factor levels may vary from very low to the upper limit of normal values [186]. Obligate and potential hemophilia carriers should have their FVIII/FIX levels measured to establish their baseline levels prior to invasive procedures and childbirth or if abnormal bleeding symptoms. Genetic testing should be offered to potential carriers when mature enough to understand the consequences of diagnoses and to give consent [187]. It’s also important that the girl as well as her family understand that a normal FVIII/FIX level does not exclude carriership.

13.2 Bleeding symptoms

The most common bleeding manifestations among symptomatic carriers and women and girls with hemophilia include menorrhagia, post-partum hemorrhage and perimenopausal bleeding as well as bleeding following trauma or medical interventions. Girls with hemophilia and symptomatic carriers should have a treatment plan prior to menarche. Excessive bleedings may appear with the first or any following menstrual period during the adolescence. Hemostatic therapeutic options for the management of menorrhagia include tranexamic acid, DDAVP and clotting factor replacements. Hormonal therapy should be considered and, if appropriate, introduced by a gynecologist with knowledge of bleeding disorders in collaboration with HTC [188].

13.3 Prenatal diagnosis

Before planning a family the carrier and her partner should be offered contact with a genetic counselor and an educational visit at the HTC. Counselling should include education regarding hemophilia, assessment of hemophilia inheritance risks and review of the prenatal testing options available. Non-invasive methods to determine fetal sex include analysis of free fetal DNA (ffDNA) in the maternal circulation and ultrasound based on visualization of external genitalia from late second trimester [189,190]. Chorionic villus sampling (CVS) is the principal method used for prenatal diagnosis of hemophilia. The procedure is performed during the 11 to 13th week of gestation. If later in pregnancy, an amniotic fluid sample may be used as DNA source for prenatal diagnosis. Both procedures are associated with a risk of miscarriage at approximately 1% [191]. Pre-implantation genetic diagnosis (PGD) may be an option for couples who would not consider termination of a pregnancy and for those with concurrent infertility [38]. Hemostatic cover should be arranged prior to any invasive procedure if the factor level is <50%.

13.4 Management of pregnancy and delivery

Knowledge of fetal gender allows appropriate management of labor and delivery. During pregnancy the FVIII levels in carriers of hemophilia A may increase sufficiently to permit safe hemostasis during delivery. In carriers of hemophilia B the FIX level cannot be expected to increase to the same extent [192]. Pregnant carriers of hemophilia should have their factor levels checked at gestation week 32-34 to allow appropriate management of delivery and to assess the need for prophylactic treatment. A clear delivery plan should be shared with the carrier and written in her medical file. Generally, prophylactic treatment to prevent from bleeding during delivery and postpartum is given to carriers with subnormal factor levels. If treatment is required, factor levels of 100% should be aimed for to cover labor, delivery, and the immediate postpartum period. The treatment should be continued to maintain factor levels above 50% for at least three to four days after vaginal delivery and five to seven days after cesarean section [192]. Tranexamic acid may be used in combination with replacement therapy and as a sole therapy for carriers with factor levels within normal range when clinically required. The risk for secondary postpartum hemorrhage is increased when clotting factors return to pre-pregnancy levels after delivery and tranexamic acid should be continued postpartum as needed [193]. Delayed bleeding up to 35 days postpartum is possible and should be monitored accordingly. DDAVP may be used in carriers of hemophilia A to improve hemostasis after the child is born. Factor levels above 50%, or raised to above 50% by prophylactic treatment, are required for insertion and removal of an epidural catheter and for spinal anesthesia [194]. Delivery of infants suspected to have hemophilia must be atraumatic regardless of route of delivery. Assisted vaginal delivery, vacuum extraction and use of forceps, as well as fetal blood sampling and fetal scalp electrode should be avoided for male babies at risk of hemophilia [195]. Cesarean section should be considered early when needed to avoid emergency cesarean. Cord blood sampling and diagnostic testing is recommended for all male babies. Vitamin K should be administered by an oral regimen to neonates with low factor levels [196].