|
 
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| REVIEW ARTICLE |
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| Year : 2013 | Volume
: 4
| Issue : 4 | Page : 125-130 |
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Advances in pregnancy management in carriers of hemophilia
Rezan Abdul-Kadir1, Joanna Davies2, Susan Halimeh3, Claudia Chi2
1 Departments of Obstetrics and Gynaecology; The Haemophilia Centre and Thrombosis Unit, Royal Free Hospital, Hampstead, London, UK
2 The Haemophilia Centre and Thrombosis Unit, Royal Free Hospital, Hampstead, London, UK
3 Medical Thrombosis and Haemophilia Treatment Centre, Duisburg, Germany
| Date of Web Publication | 26-Feb-2014 |
Correspondence Address:
Rezan Abdul-Kadir
The Haemophilia Centre and Thrombosis Unit, Royal Free Hospital, Pond Street, Hampstead, London, NW3 2QG, UK
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/1658-5127.127894
Recent advances in prenatal diagnosis and multidisciplinary management has improved the reproductive outlook for carriers of hemophilia and their offspring. Pre-pregnancy planning allows the woman and her partner to explore reproductive options and prepares the family for the potential delivery of an affected male infant. Non-invasive methods of prenatal diagnosis are advancing, with the aim of providing a definitive test for hemophilia. Carriers of hemophilia have an increased risk of primary and secondary postpartum hemorrhage. The affected male offspring is potentially at risk of cranial bleeding during delivery. A multidisciplinary approach provides advanced planning for the optimum mode of delivery and provision of appropriate haemostatic cover to reduce the risk of bleeding complications. This review summarises current recommendations for pregnancy management in carriers of hemophilia, from the initial pre-pregnancy counseling through to delivery and care of the neonate. Keywords: Delivery, hemophilia, labor, pregnancy, prenatal diagnosis
How to cite this article:
Abdul-Kadir R, Davies J, Halimeh S, Chi C. Advances in pregnancy management in carriers of hemophilia. J Appl Hematol 2013;4:125-30 |
| Introduction | |  |
Pregnancy and delivery are life-changing events for every expectant mother but pose specific challenges for carriers of hemophilia who might have a boy with severe hemophilia. Despite recent advances in hemophilia treatment, it remains an incurable lifelong condition. Children born today can experience a near normal life expectancy and excellent health-related quality of life due to the delivery of comprehensive care through specialized hemophilia centers worldwide. [1] This outlook however, is dependent on the provision of high-quality, multidisciplinary pregnancy care from the outset.
| Pre-Pregnancy Care | | |
Preconception counseling remains an important aspects of obstetric management. [2] Carrier status should be confirmed prior to conception ideally by constructing an accurate family tree and confirmatory genetic diagnosis. Obtaining a thorough bleeding history in the woman and her family, and laboratory assessment of baseline factor levels will provide an appreciation of the carrier's bleeding tendency.
The carrier mother and her partner should be provided with information about the probability of a bleeding disorder and the implications this will have on any affected offspring. A discussion of all the reproductive options should take place, including (i) natural conception with prenatal diagnosis (PND) and the option of termination if the fetus is affected; (ii) natural conception without PND, accepting the risk and consequence of hemophilia in the offspring; (iii) adoption; (iv) considering assisted conception techniques with donor egg; and (vi) if available, considering preimplantation genetic diagnosis (PIGD). The latter technique involves in vitro fertilization (IVF), with the identification and selection of non-affected embryos for transfer back to the uterus. [3] This is both costly and has limited success rates (22% chance for a live birth). Successful cases have been reported where the specific hemophilia mutation was identified and the resulting offsprings were unaffected by hemophilia. [4],[5] The selection of only unaffected embryos for transfer as well has ethical implications. PIGD is not considered in most cultures for non-medical indications. There is a widespread aversion to the process of eugenics and the ability to select offspring with desirable characteristics, even those unaffected by genetic conditions, is controversial. On the other hand, PIGD may be more acceptable to couples that are averse to selected termination of affected fetuses for religious reasons. Because of these limitations and the ethical concerns raised, PIGD is not an option for the majority of hemophilia families worldwide. [6]
| Prenatal Diagnosis | | |
Specific PND of hemophilia is only achieved by invasive testing. The uptake of PND and womens' attitudes toward it vary widely across different countries and cultures. In families with hemophilia, opting for PND with an outlook of performing early termination of pregnancy is not a common practice. In a study conducted in the Netherlands, most hemophilia carriers objected to termination of affected pregnancies because they did not consider hemophilia to be a sufficiently severe condition. [7] Religion is a strong determinant in an individual's consideration of terminating pregnancy. Other important factors include the severity of the condition within the family and the carriers' previous experience with the condition. [8] Therefore, in the majority of cases PND is opted for to determine the hemophilia status, to psychologically prepare the family and to guide appropriate obstetric management. A multidisciplinary approach involving clinical geneticists, counselors and fetal medicine specialists can provide expert support to enable the couple to reach a decision that is appropriate to their situation.
Invasive Methods of Prenatal Diagnosis
Currently the most established method for PND of hemophilia is chorionic villus sampling (CVS). CVS is carried out at 11-14 weeks gestation. A sample of placental DNA is obtained for genetic analysis via transabdominal needle biopsy under ultrasound guidance [Figure 1]. CVS prior to 10 weeks gestation is not recommended due to increased risk of limb defects. [9] CVS has a risk of miscarriage of around 1%. [10] Amniocentesis is offered in some centers after 15 weeks of gestation. The DNA is retrieved for genetic analysis via the collection of fetal cells in amniotic fluid. Similarly, this technique has an approximate 1% risk of procedure-related pregnancy loss. [11] Cordocentesis is carried out from 18 weeks gestation and involves the aspiration of fetal blood from the umbilical cord to measure coagulation factor levels. Cordocentesis is also carried out under ultrasound guidance. It carries an increased risk of miscarriage in comparison to CVS and amniocentesis. [12] The risk is potentially higher in fetuses affected with hemophilia due the risk of cord bleeding. [3] Thus, it is reserved for cases where genetic testing is either unavailable or inconclusive. However, it remains the only choice for PND in countries with no facilities for genetic diagnosis. [13] | Figure 1: Chorionic villus sampling (transabdominal) (with permission from RCOG patient information leaflet)
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In recent years, third trimester amniocentesis has been offered as an alternative method of PND for couples who wish to avoid the risk of miscarriage associated with invasive testing in early pregnancy. This enables appropriate obstetric management in particular decision making regarding the mode of delivery and whether the carrier mother needs to deliver at her local hospital or in a tertiary center. If the fetus is unaffected the mother can deliver in her local maternity unit without any obstetric restriction on the use of invasive monitoring or instrumental deliveries. [14] Unfortunately uptake is limited by the approximate 1% risk of complications associated with third trimester amniocentesis, mainly preterm delivery. [15] In addition, multiple attempts (>5%), bloodstained fluid (5-10%), failure to obtain a sample and culture failure (1%) are more common in third trimester compared to second trimester amniocentesis. [16],[17]
Non-invasive Methods for Prenatal Diagnosis
Currently non-invasive methods can only determine fetal gender. Traditionally this is carried out by ultrasonography with an accuracy of >99% in the second trimester. [18] It can be combined with the fetal anomaly scan so that no extra hospital visits are required. Determination of fetal gender by ultrasound is carried out at some specialized centers from as early as 11-week gestation. [19] However, sonographic identification of fetal gender at this gestation is not sufficiently reliable (85%) to base decisions regarding the need for further invasive testing. [20]
Determination of fetal gender is also possible through analysis of free fetal DNA (ffDNA) in the maternal circulation. The presence or absence of Y chromosome specific DNA sequences can be confirmed from as early as 8 weeks gestation with 97-100% accuracy [Table 1]. [21],[22],[23],[24] The ability to accurately determine fetal gender prior to 11 weeks using ffDNA has obvious value over ultrasound, allowing carriers of hemophilia with a female fetus to avoid invasive testing and the associated risk of miscarriage. | Table 1: Accuracy of first trimester foetal male gender determination by real-time polymerase chain reaction analysis of free foetal DNA (with permission from Avent and Chitty)
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PND of hemophilia using ffDNA has recently been reported using quantitative digital polymerase chain reaction technique in selected cases. [25] This rapidly developing technology has potential for offering a non-invasive method of PND but remains as a research tool.
| Management of Pregnancy | | |
Carriers of hemophilia have a wide range of factor levels (22-116 IU/dL) due to random inactivation of one of each pair of X chromosomes, [26] a process known as Lyonization More Details. [27] Carriers with levels in the region of 5-30 IU/dL are considered to have mild hemophilia and are termed "symptomatic". Pregnancy causes physiological correction of factor VIII (FVIII) levels in hemophilia A carriers, however, factor IX (FIX) levels remains largely unchanged in hemophilia B [Figure 2]. [28] Factor levels should be checked at booking of 28 and 34-week gestation to monitor the changes in pregnancy and identify those that require prophylactic treatment. [3] In addition, factor levels should be checked prior to undergoing invasive PND, termination or spontaneous miscarriage in early pregnancy. The FVIII levels are unlikely to have risen significantly in the first trimester and FIX levels will not increase. [29] The risk of bleeding from invasive procedures is increased if factor levels are <50 IU/dL and prophylaxis should be arranged. | Figure 2: Changes in factor VIII and IX levels during pregnancy (with permission from Chi et al., 2008
Click here to view |
| Management of Labor and Delivery | | |
Delivery is a critical period for hemophilia carriers and the affected fetus, with potential for bleeding complications. A delivery plan should be made in advance involving the multidisciplinary team including the obstetrician, hematologists, anesthetists and midwives. Delivery is not always necessary or feasible in a tertiary unit but is recommended if the carrier is at risk of bleeding, or carrying a potentially affected fetus. This insures that the necessary obstetric expertise is at hand, with a hemophilia center and laboratory that has readily available testing and coagulation factor treatments. [3]
The use of regional anesthesia in women with coagulation disorders has been controversial due to the risk of spinal hematoma causing acute spinal cord compression and irreversible paraplegia. [30] However, the risk is not increased when factor levels are above 50 IU/dL. Provision of regional block has been shown to be safe provided that the factor levels have normalized during pregnancy or are corrected with prophylactic treatment in women with inherited bleeding disorders. [31]
Women with factor levels <50 IU/dL at delivery are at risk of serious bleeding complications during the postpartum period. [3],[27] Studies have demonstrated an increased risk of primary and secondary postpartum hemorrhage (PPH) [29],[32],[33] correlating with low coagulation factor levels. Avoidance of traumatic deliveries and active management of the third stage are recommended to minimize the risk. Treatment or prophylaxis to prevent bleeding complications during delivery include tranexamic acid, and/or desmopressin [1-desamino-8-d-arginine vasopressin (DDAVP)], and factor replacement therapy.
Tranexamic acid is a synthetic inhibitor of plasminogen and plasmin-binding sites, thereby preventing the breakdown of fibrin substrate. It is widely used for prevention and treatment of bleeding in patients with inherited bleeding disorders. It has also been shown to be effective at reducing the bleeding during delivery of cesarean section, and postpartum hemorrhage in the general obstetric population. [34],[35],[36] DDAVP temporarily enhances plasma levels of von Willebrand factor (VWF), reducing FVIII clearance from the circulation and it is widely used for prevention and treatment of bleeding in carriers of hemophilia. DDAVP has an antidiuretic effect, therefore fluid restriction is advised and its prolonged use should be avoided. [37] DDAVP has been shown to be effective in reducing the bleeding complications associated with pregnancy and childbirth with a good safety record. [38]
Carriers of hemophilia A rarely require treatment with factor concentrates but FXI concentrate may be necessary in carriers of hemophilia B with levels <50 IU/dL. Recombinant factor products are the treatment of choice as these are not associated with viral transmission. [3]
Due to the rapid decline of pregnancy-induced rise in coagulation factors, carriers of hemophilia are at risk of secondary PPH (excessive vaginal bleeding from 24 hours to 6 weeks following delivery). In a study comparing puerperal loss, carriers of hemophilia had a significantly increased duration of lochia (39 days; range 21-58) compared to healthy controls (31 days; range 10-62; P = 0.03). [39] Tranexamic acid is recommended prophylactically to reduce the risk of secondary PPH in carriers of hemophilia, specifically those with low pre-pregnancy factor levels. [3] The recommended dose is 1g for 6-8 hours from the onset of labor and for 3-5 days following vaginal delivery or 7-10 days following cesarean section. [40]
| Management of the Fetus and Neonate | | |
Fetuses at risk of hemophilia should, in principle, be delivered in the least traumatic method. [41] Intracranial and/or extracranial hemorrhage can occur, and can be life threatening, or result in serious long-term neurological morbidity. In a systemic review of the literature, 102 neonates with hemophilia and cranial bleeds were identified in 33 studies, and a cumulative incidence of 3.6% of intracranial hemorrhage (ICH) was calculated to be in relation to delivery. [42] However, this is an average figure that includes all modes of delivery and is regardless of whether the hemophilia status of the fetus is known at the time of delivery.
The optimum mode of delivery for a fetus at risk of hemophilia remains the subject of debate and in this regard opinions and recommendations are variable. [43],[44],[45] Towner et al., published rates of intracerebral bleeding at birth in 583,000 live term singleton babies in the general population depending on mode of delivery. The highest rate of ICH (1 in 860) was seen in infants born by ventouse delivery, compared to the lowest rate (1 in 2750) following elective cesarean section. [46] A number of retrospective studies have reviewed the association between mode of delivery and risk of cranial bleeding in newborns with inherited bleeding disorders. [47],[48],[49],[50] Whilst it is clear from these studies that the risk of ICH is increased with instrumental delivery or following a difficult or prolonged labor; it is more difficult to define the relative risk of ICH in uncomplicated vaginal deliveries compared to planned elective cesarean sections.
The true incidence of cranial bleeding is not known as these studies have estimated incidence retrospectively. The signs and symptoms of ICH can be vague and a high index of suspicion is required to make the diagnosis. The onset of neurological signs in newborns with hemophilia often heralds a more extensive intracranial bleed. Such bleeds may result in long-term neurological impairment and morbidity rates of up to 25% have been reported. [51]
Current guidelines allow for vaginal delivery but recommend against instrumental delivery, with early recourse to cesarean delivery if labor becomes abnormal. [3] Unfortunately, it is not possible to predict if a woman undergoing planned vaginal delivery will require an emergency cesarean section. Planned elective cesarean may therefore be preferable especially in the fetus with severe hemophilia, as delivery can occur in a more controlled environment and is association with the lowest risk of ICH. [48] However, this has to be balanced with the increased risk to the carrier mother of bleeding and operative complications that are associated with repeat cesarean deliveries. [52] A clear discussion should take place between the multidisciplinary team and the pregnant carrier in advance of expected delivery date, and each case should be considered on an individual basis. A written plan for labor and delivery should be provided and made available to the team caring for the mother in labor. [14]
Currently, the United Kingdom Haemophilia Centre Doctors' Organization (UKHCDO) guideline for management of the neonate with hemophilia recommends ultrasound screening to exclude ICH prior to discharge in neonates with severe or moderate hemophilia. [41] However, cranial magnetic resonance imaging (MRI) and computed tomography (CT) scanning are superior in the detection of subdural bleeding and therefore should be performed in symptomatic infants when the ultrasound is normal. [41] Screening is also recommended if labor has been particularly prolonged or traumatic. The optimum mode of screening and the timing of such investigations are currently unclear. A prospective imaging study that clearly defines the incidence of cranial bleeding in the neonatal period is essential to improve management strategies.
Cord blood should be obtained after delivery from all male offspring of hemophilia carriers to assess coagulation factor activity. This allows identification and early management of neonates with hemophilia. [41] In the normal neonate FVIII levels are within normal range or mildly increased, due to the stress of labor. FIX levels are significantly reduced at birth and further reduced with prematurity. [53],[54] It is usually possible to diagnose moderate and severe forms of hemophilia from cord factor levels. However, it may not be possible to diagnose mild hemophilia and a repeat sample is recommended at 6 months of age. [41]
An awareness of the potential for iatrogenic bleeding in the neonate dictates management and therefore certain interventions, such as intramuscular injection, venepuncture and circumcision should be avoided until the coagulation status is known. A heel prick test can be carried out with caution but requires adequate pressure for at least 5 minutes after the procedure. [41] Vitamin K should be administered orally and vaccinations administered intradermally or subcutaneously. [3]
| Conclusion | | |
This review presents recommendations to reduce the bleeding risk associated with pregnancies in carriers of hemophilia A and B and their affected offspring. In addition, an update in the advances in preconception counseling and prenatal diagnosis are discussed. Most pregnancies in carriers will be uneventful, without bleeding complications, provided that consideration of the risk is carried out during various stages of pregnancy, in collaboration with the hematology team and laboratory monitoring.
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[Figure 1], [Figure 2]
[Table 1]
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