14 Hemophilia in women and girls and hemophilia carriers
1 Introduction
The hemophilia nomenclature distinguishes five clinically relevant categories of hemophilia in women/girls: women/girls with mild (FVIII/FIX >5% to <40%), moderate (FVIII/FIX 1-5%) or severe (FVIII/FIX <1%) hemophilia and symptomatic and asymptomatic hemophilia carriers (FVIII/FIX ≥40%) with and without a bleeding phenotype, respectively [1].
The term hemophilia carrier is used in discussions relating to genetic counselling, including obligatory and potential carriers, and hemophilia or symptomatic carrier when referring to bleeding phenotype.
Obligate carriers include any daughter of a father with hemophilia, any mother of a child with hemophilia who also have at least one family member with hemophilia or who is a known carrier of hemophilia and any mother of two or more children with hemophilia.
Potential carriers include any daughter, sister, mother, maternal grandmother, aunt, niece or female cousin of a carrier of hemophilia and any mother of a child with hemophilia and without family history of hemophilia.
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 [2].
1.1 RECOMMENDATION
- Hemophilia carriers should be registered at a hemophilia treatment centre.
1.2 RECOMMENDATION
- 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.
2 Bleeding symptoms and treatment
The most common manifestations among symptomatic carriers and women with hemophilia includes heavy menstrual bleeding (HMB), post-partum haemorrhage, and perimenopausal bleeding.
In addition, symptomatic carriers and women with hemophilia are at risk of being affected by bleeding following trauma or medical interventions (e.g., dental extractions or surgery) [2].
Symptomatic carriers and women with hemophilia should have a treatment plan prior to menarche [3].
Excessive menstrual bleedings may appear with the first or any following menstrual bleeding during the period of adolescence.
Hormonal therapy can be useful in managing HMB [5] and may be considered by a gynaecologist, with knowledge of bleeding disorders, working in collaboration with the HTC.
Treatment options include oral or transdermal formulations containing oestrogen/progesterone/progestin and levonorgestrel intrauterine device (IUD).
Haemostatic treatment options for the management of HMB include tranexamic acid, DDAVP and clotting factor replacements [6].
A screening for iron deficiency and anaemia should be performed at regular check-ups. If iron deficiency anaemia is diagnosed and substituted, a reassessment of current HMB treatment should be performed.
For treatment options during trauma and surgery please see chapter Surgery in hemophilia and chapter Treatment of bleeds.
3 Genetic counselling and testing
Genetic counselling is an essential component of comprehensive care for individuals and families with hemophilia.
Genetic counselling help both obligate and potential carriers of hemophilia to understand their bleeding risk and genetic risk [7].
Genetic testing should be offered to potential carriers when mature enough to understand the consequences of diagnoses and to give consent [8].
It’s important that the girl as well as her family understand that a normal FVIII/FIX level does not exclude carriership.
Before planning a family, the carrier and her partner should be offered contact with a genetic counsellor and an educational visit at the HTC.
Counselling should include education regarding hemophilia and assessment of hemophilia inheritance risks. Prenatal genetic testing options and relevant reproduction options should be reviewed.
5 Prenatal diagnosis
Evaluation of carrier status should be performed before pregnancy. Evaluation should include measurement of factor levels in the non-pregnant state as well as genetic testing, as normal factor levels do not preclude carrier status.
Preconception consultation at the hemophilia treatment centre or by a genetic counselor should be offered to all possible carriers and their partners. Counselling should include education regarding hemophilia, assessment of hemophilia inheritance risks and review of the prenatal testing options available and the associated risks of each method.
Methods include preimplantation genetic diagnosis (PGD), invasive prenatal diagnosis (chorionic villus sampling (CVS), amniocentesis, and cordocentesis), and non-invasive determination of free foetal DNA (ffDNA) in the maternal circulation and ultrasound detection of foetal sex [9,10].
PGD requires in-vitro fertilization and is an option for couples who would not consider giving birth to an affected infant or termination of an established pregnancy, and for those with concurrent infertility [11].
CVS is the most reliable method for prenatal diagnosis of hemophilia and is performed at 11-13 weeks of gestation. Later in pregnancy, an amniotic fluid sample can be used as DNA source for prenatal diagnosis. Both procedures are associated with a risk of miscarriage at approximately 1% [12].
All invasive procedures require a factor level ≥ 50% and factor substitution should be provided as needed.
5.1 RECOMMENDATION
- Possible carriers of hemophilia should be offered preconception counselling that includes reproductive implications and choices.
5.2 RECOMMENDATION
- Testing should include assessment of factor level and genetic testing.
6 Pregnancy management and delivery
Pregnancy and delivery should be managed by a multidisciplinary team of specialists, including a haematologist, an obstetrician/gynecologist and an anaesthesiologist.
Female carriers of hemophilia A or B do not have increased risk of miscarriage [4,5,13].
Female carriers may have low factor levels that increases their risk of bleeding during pregnancy and in the postpartum period. Factor VIII levels rise during pregnancy but may not reach sufficient levels to prevent bleeding complications. FIX levels do not increase during pregnancy [14].
Factor levels should be assessed in the third trimester around gestational week 32-34 to evaluate the need for factor replacement therapy during delivery and in the post-partum period.
A clear plan for delivery should be made by the multidisciplinary team, shared with the patient, and documented in the medical record.
Factor replacement therapy should be provided to carriers with subnormal factor levels in the third trimester. If required, factor replacement therapy should be administered to target levels of 100% for labour and delivery and maintained ≥ 50% for at least 3-4 days after vaginal delivery and at least 5-7 days after caesarean delivery [14–16].
Factor levels ≥ 50% is required for insertion and removal of an epidural catheter and for spinal anesthesia [17].
Tranexamic acid may be used as supplement to factor replacement therapy or as stand-alone treatment for carriers with factor levels within the normal range.
Decisions regarding anaesthesia and method of delivery should be made by the multidisciplinary team and shared decision making with the patient.
Vaginal delivery of an infant with severe hemophilia is not recommended against as the risk of intracranial hemorrhage is not significantly increased as compared to caesarean delivery [18]. However, the obstetrician should carefully discuss with the carrier patient the maternal and foetal risks of vaginal delivery versus a planned caesarean delivery.
Delivery of infants known or suspected to have hemophilia must be atraumatic regardless of route of delivery to decrease the risk of bleeding complications [14].
Forceps and vacuum extraction vaginal delivery as well as invasive procedures to the foetus such as foetal blood sampling and internal foetal scalp electrodes should be avoided [19].
Caesarean section should be considered early when vaginal labour does not proceed as expected. These instructions should be documented as part of the delivery plan in the patient’s medical record.
6.1 RECOMMENDATION
- Pregnant carriers of hemophilia should have their factor VIII/IX levels measured in the third trimester (GA 32-34) in order to plan for factor replacement therapy during delivery and post-partum.
6.2 RECOMMENDATION
- Factor levels should be maintained ≥ 50% during delivery and post-partum.
6.3 RECOMMENDATION
- A delivery plan should be made by the multidisciplinary team (haematologist, obstetrician, anaesthesiologist) and shared decision making with the patient.
6.4 RECOMMENDATION
- Delivery should be atraumatic, and use of forceps, vacuum extraction as well as invasive procedures to the foetus avoided.
6.5 Post-partum care
Factor VIII levels in carriers return to baseline levels 7-10 days after birth [20,21], but sometimes earlier and increases the risk of secondary post-partum bleeding.
Bleeding may occur up to 35 days post-partum and should be monitored and treated accordingly with factor replacement therapy and tranexamic acid [22]. DDAVP can occasionally be used in carriers of hemophilia A to improve haemostasis post-partum but should be used with caution in breast-feeding women.
Haemoglobin, factor levels and bleeding should be monitored as needed 1-2 months post-partum.
6.6 RECOMMENDATION
- Secondary post-partum bleeding may occur when factor VIII levels return to baseline.
6.7 RECOMMENDATION
- Bleeding, haemoglobin and factor VIII should be monitored and treated as needed in the entire post-partum period.
6.8 New-born testing
Cord blood should be collected from all male infants of carriers of hemophilia to assess clotting factor levels for early identification and management of hemophilia.
Of note, while it usually is possible to diagnose severe and moderate hemophilia A at birth and often possible to diagnose severe and moderate hemophilia B at birth, detection of mild hemophilia A and B may require repeated screening at 6 months of age.
Vitamin K should be administered orally to neonates with low factor levels [23].
6.9 RECOMMENDATION
- Cord blood sampling and diagnostic testing is recommended for all male new-borns of hemophilia carriers.
6.10 RECOMMENDATION
- Vitamin K should be administered orally.