Haemophilia in the first years of life
The authors stated that they had no interests which might be perceived as posing a conflict or bias.
Abstract
Summary. Surgery in infants and young children with haemophilia, when preceded by accurate diagnosis and accompanied by safe and effective factor prophylaxis, is not associated with a significant risk of haemorrhage. Haemophilic newborns undergoing circumcision or major surgery prior to diagnosis and in the absence of appropriate haemostatic prophylaxis remain as a concern. Inhibitor development has replaced haemorrhage as the major surgical complication in the developed world, largely because of the intensity of treatment used to secure haemostasis. For that reason only, essential surgery should be performed. Intracranial haemorrhage (ICH) during the neonatal period affects 3.5–4.0% of all haemophilia boys in countries with a good standard of health care, which is considerably (40–80 times) higher than expected in the normal population. Because of the high frequency of sporadic cases, ICH in the neonatal period can only be partially prevented by improved carrier diagnosis and counselling. Infections and thrombosis are the major serious complications of central venous lines. Large differences are seen in the frequency of these complications, the most plausible explanations are probably related to the protocol used for device care, the quality of education and the compliance of the users, an issue addressed in an on-going study.
Introduction
If haemophilia is known in the family, the disorder is usually diagnosed in the neonatal period. If it is a sporadic case, most children with the severe forms are diagnosed before the age of 1 year [1]. Haemophilia in the youngest children is a challenge to the parents and the team at the haemophilia treatment centre. The aim of this study was to cover a few aspects of haemophilia in early childhood, i.e. (I) aspects of surgical procedures, (II) intracerebral haemorrhages and (III) venous access using central venous lines.
I. Surgery in haemophilic infants and young children: a complicated beginning
The prevalence and outcomes of surgical procedures performed in infants and young children with haemophilia are not well documented in the literature. Excluding the birth process, the first year of life is generally uncomplicated by haemorrhage. The requirement for significant factor replacement therapy is limited and diagnosis can be delayed by the absence of both bleeding and/or a prior family history of haemophilia [2]. Under these circumstances, an unexpected major haemostatic challenge, such as surgery or major trauma, can pose a considerable threat to the haemophilic infant. The prime elements of this risk include: (i) complicating or life-threatening haemorrhage; (ii) transfusion-transmitted infection (TTI) from the transfusion of blood components; and, most importantly, (iii) inhibitor development associated with replacement therapy and the need for further surgery in the presence of a high titer antibody.
Surgery in haemophilic infants: haemorrhagic risk
The literature suggests that surgical bleeding risk in a haemophilic infant is initially related to the lack of a prior diagnosis and appropriate peri-operative replacement therapy. Fortunately, major surgery is uncommon during infancy and early childhood and, when it occurs, is usually indicated for the treatment of congenital anomalies. Older anecdotal publications suggest that the significant morbidity and mortality associated with high risk surgery may increase substantially for children who are co-afflicted with haemophilia, due to either the lack of diagnosis and/or inadequate factor replacement. Conversely, pre- and postlicensure studies of recombinant and plasma-derived factor VIII and IX concentrates, as well as the more recent anecdotal surgical literature, document that once the diagnosis is made and an appropriate prophylactic replacement strategy is implemented, complex surgery can be performed safely with a minimally increased risk of haemorrhage [3–9]. Minimum effective factor dosing also limits surgical haemorrhage in the developing world where resources are limited [10].
Recent data from the Universal Data Collection (UDC) Surveillance Study confirmed that for 34% of 311 enrollees < 2 years old, the diagnosis of haemophilia is still made following a haemorrhagic event (CfDCaPUDCP) http://www.cdc.gov/ncbddd/hbd/documents/UDC8CDFc.pdf. Uncommonly, bleeding from unsuspected or undiagnosed haemophilia can itself lead to major surgery in the first few days or weeks of life, particularly following birth-related cranial or intra-abdominal trauma. However, although cranial haemorrhage may complicate 3.5% of all births, only a minority requires neurosurgical intervention [11,12]. Surgery for the control of intra-abdominal haemorrhage from splenic or subcapsular liver rupture has been reported but is also rare [13,14]. More often, as first noted in the Talmud, excessive bleeding from circumcision, a routine minor surgical procedure, is the diagnostic event for an infant with severe haemophilia [15]. In the UDC cohort previously described, postcircumcisional bleeding accounted for 31% of 144 primary haemorrhagic events (CfDCaPUDCP) http://www.cdc.gov/ncbddd/hbd/documents/UDC8CDFc.pdf.
Surgery in haemophilic infants: risk of transfusion-transmitted infection
Related to the haemorrhagic risk is the potential for TTI from the peri-operative transfusion of erythrocyte concentrate and/or fresh frozen plasma [16]. The risk of TTI from the most commonly transmitted hepatitis viruses has greatly diminished over time in the developed world [17]. However, although improved through the greater availability of safe and effective factor concentrates, the risk for hepatitis B and C transmission remains considerable for patients in the developing world, who also remain more likely to go undiagnosed or to receive non-specific peri-operative treatment with blood products despite a known diagnosis [18].
Surgery in haemophilic infants: inhibitor risk
With the advent of safe and effective replacement therapy, inhibitor development has replaced haemorrhage as the principal surgery-associated complication, particularly in young children with severe haemophilia A who require surgery within the 50 factor VIII (FVIII) exposure day (ED) window. The Canal and previously untreated patient (PUP) Cohort studies [16,19] reported that 25% and 19%, respectively, of each paediatric cohort underwent surgery between the ages of 6 and 52 months. In the largely European Canal study, 75% of these procedures were central venous catheter (CVAD) insertions. In this study, the adjusted relative risk (RR) of inhibitor development following intensive surgical prophylaxis with largely recombinant FVIII was 1.4 (CI 0.7–2.7), overall. However, when ≥5 days of surgical prophylaxis constituted the first FVIII exposure, the RR of developing an antibody further increased to 3.3 (CI 2.1–5.3)[16]. In the PUP retrospective analysis, the adjusted surgery-related RR was 2.4 (CI 1.2–4.8) for all inhibitors and 4.5 (2–10.1) for high titre antibodies [19]. Pre- and postlicensure PUP studies receiving recombinant or plasma-derived factor IX (FIX) have reported a low inhibitor risk with surgery [7,8].
Outside of Europe and South America, circumcision remains as the most common procedure performed in males, and bleeding is its most common complication (0.1–35%), even in otherwise healthy males [15]. In babies with known haemophilia, prophylactic haemostasis protocols vary widely and include 3–10 days of factor replacement, often by continuous infusion (CI), as well as local and systemic antifibrinolytics and fibrin glue [15,20]. The specific impact of treatment intensity for circumcision on inhibitor incidence is unknown.
A possible association between CI factor administration and inhibitor risk was postulated based on observations in adults and older children with moderate and mild haemophilia A [21]. This was not observed in severe haemophilia A adults [22,23]. In the absence of prospective randomized studies that control for other risk factors, the role of FVIII or FIX CI during surgery in inhibitor development in severe haemophilia remains unclear, particularly for young children. In one uncontrolled study, inhibitor development was observed in 2/43 children receiving CI FVIII, both of whom had fewer than 20 prior EDs [24]. For the moment, the haemostatic and cost-effective benefits of CI must be weighed against the unknown risk of inhibitor development with this modality.
Surgery in haemophilic infants with inhibitors
High titre inhibitor development complicates subsequent surgery in a young child with haemophilia. A review of the literature suggests that CVAD placement and removal represent the most common procedures in children with inhibitors [25–27]. Furthermore, although few bleeding complications are reported in the absence of an antibody, bleeding can occur with as many as 20% of CVAD placements in inhibitor patients [28].
Most published reports on the use of bypass therapy specifically for surgical prophylaxis in infants and young children with haemophilia and inhibitors confirm the safety and efficacy of activated recombinant FVII (rFVIIa) when infused at a dose of 90 μg kg−1 every 2–4 h [25–27,29]. The safety and efficacy of a limited number of doses of 90–100 μg kg−1 in neonates have been reported only within the context of off-label use of this product [30,31].
II. Intracerebral haemorrhages with focus on the neonatal period
The occurrence of intracranial haemorrhages (ICH) represents a serious event that may impair the life expectancy and impact the long-term prognosis of patients with haemophilia. Even if the mortality from ICH has decreased, it is still reported to be around 20% [32,33]. In regards to age, this complication occurs mainly at both extremities of life, i.e. in neonates and in the elderly [32]. ICH is a major cause of mortality, and morbidity is also considerable in surviving children, with possible neurological impairment and/or psycho-intellectual sequelae [34,35]. Even in countries where a dramatic improvement of life expectancy has been achieved for haemophilia patients, ICH remains as a major pediatric issue. Therefore, it may be of benefit to optimize the knowledge in this field, to educate parents and caregivers, aiming at the prevention, the detection and the early treatment of ICH in children with haemophilia.
Epidemiology of neonatal ICH
The outstanding haemostatic balance in the neonate is supposed to be efficient to balance the obstetrical trauma that might be particularly feared in newborns with haemophilia, leading to a common uneventful vaginal delivery. Nevertheless ICH sometimes occur and the significant incidence that has been observed in the first week of life in the case of laborious or instrumental delivery emphasizes the role of the traumatic obstetrical conditions [35]. In the latest series, in countries with a good standard of health care from North America and Europe, a rather uniform and steady incidence of 3.0–4.0% has been reported during the neonatal period [1,12,33–36]. This represents a significantly higher risk by comparison with non-haemophilic newborns for whom ICH incidence was reported from 0.03% in low-risk delivery (elective caesarean) to 0.1% in high-risk delivery with vacuum extraction, suggesting that the major risk factor for haemorrhage is complicated labour [37].
It might be hypothesized that some fatal cases of neonatal ICH, especially in a context of prematurity, may occur before the diagnosis of any bleeding disorder, leading to a somewhat underestimated incidence. This situation concerns above all sporadic or tricky cases that have already been associated with delayed diagnosis [38]. Conversely, we can assume that in the absence of clinical symptoms some ICH may remain undiagnosed in the neonatal period because routine imaging of the brain is usually not done in haemophilic newborns. In some cases, late imaging demonstrating the existence of lesions that originated from events in the neonatal period has corroborated this hypothesis [39].
Prevention and treatment of neonatal ICH
Even if some guidelines for haemophilia care include recommendations for the management of carrier women and the mode of delivery, successful prevention of ICH in newborns with haemophilia remains as a well-documented difficult task [40]. Actually, in identified carriers, prevention requires careful management and surveillance of the newborn, which means that the haemophilia specialist should transmit detailed information to obstetricians, anaesthesiologists and paediatricians in a multidisciplinary approach. However, we encounter some limits because the diagnosis of severe haemophilia often occurs without any knowledge of a previous case in the family [1,34,35,41]. The frequent unawareness of the mother’s status at the moment of the birth of her haemophilic son has been confirmed in a recent study where the sporadic forms of severe haemophilia A represent 55% of cases, greater than the classically established frequency of 30% of de novo cases. [42].
In some sporadic cases, we can assume that some misinformation does exist, with some carriers being not learned or not conscious of their status. These situations might be avoided with routine education of families via the patients’ associations and through accurate and updated genetic counselling at the comprehensive care centre, so that these women and their sons might benefit from prophylactic strategies during labour, delivery and the neonatal period. Conversely, a significant proportion of situations cannot be anticipated because of the high proportion of de novo mutations. Obviously, these children cannot benefit from the implementation of targeted recommendations appropriate for the delivery of identified carrier women. This recurrent situation highlights the requirement for the widespread educational targeting of caregivers in maternity hospitals, with respect to early identification of symptoms and presenting features of haemophilia.
Instrumental delivery and above all vacuum extraction have been identified as major risk factors to be avoided for a newborn at risk for haemophilia [43]. If normal vaginal delivery is the recommended routine mode of delivery for a pregnant haemophilia carrier, the screening for some potential hazards such as cephalo-pelvic disproportion may also be critical [12]. Moreover, it has been reported that extracranial haemorrhages frequently accompany ICH and a significant bleed in such a location should raise the suspicion of a concomitant ICH and underlying coagulopathy [43,44]. Even if somewhat non-specific (anaemia, pallor and apnea) and sometimes more unambiguous (seizures, lethargy and paresis), these recurrent symptoms must be recognized by caregivers in maternity hospitals as possibly because of ICH [12,33,39].
In the absence of high level evidence-based guidelines, questions such as the role of ultrasound scan (screening or targeted imaging) and the treatment approach (prophylactic or early curative), have been discussed and remain under debate [11,16,33,40]. The role of imaging should be considered along with the optimal timing of discharge from hospital, because it has been observed that ICH occur rather early (mean 4–5 days) [12]. There is greater consensus on the need for replacement therapy for a cephalic or sub-galealic haematoma as well as intensive and prolonged treatment for ICH. The recent findings demonstrating that early intensive treatment is a major risk factor for inhibitor development while prophylaxis might have protective effects suggest that regular prophylaxis might be considered if early and/or intensive treatment is required [16].
ICH in older children
Few data provide specific estimations of ICH during and after the neonatal period. The largest series reported 88 patients with ICH in a 5-year survey of 3269 haemophiliacs (2.7%; 0.0054 case per year) in the US [45]. In this series, the role of trauma does not appear pre-eminent (22%), the mortality rate is high (18.2%), severe haemophilia and the presence of inhibitors are independent risk factors, confirming previous publications. It was recently reported in a retrospective study that computed tomography of the head after trauma may be useful in boys with haemophilia, demonstrating some bleeds occur even in asymptomatic patients with a normal neurological exam [46].
The potential protective role of regular prophylaxis is difficult to assess. We can presume that when delivered as full regimen schedule (20–40 U kg−1 at least thrice per week in haemophilia A and twice in haemophilia B, it may be efficient in preventing ICH and other life-threatening bleeds in severe haemophilia. Extensive experience with long-term prophylaxis supports this assumption. However, its low frequency makes it impossible to address this issue in a randomized prospective study. In any case, as ICH does also occur in mild and moderate cases, particularly after trauma, prophylaxis cannot provide the ultimate solution [12,33,44].
III. Central venous lines – why such diverse experiences?
For most haemophilia centres and families, the first choice of venous access is a peripheral vein and this is usually sufficient for the planned therapy [47,48]. However, in many cases, the use of a central venous line (CVL) is necessary and will facilitate treatment of the youngest children with the most problematic peripheral venous access. Implantation of a central venous catheter device introduces a risk that has to be balanced against the potential benefits in the individual patient. Sometimes, it is a combined medical and social indication for the use of a CVL because it may enable treatment at home by the parents.
Infections are the most frequent complications associated with the use of central venous lines in children with haemophilia [49]. Several retrospective studies that include data from a substantial number of patients have reported approximately 0.2–0.3 infections per 1000 catheter-days (mainly Port-A-Caths) [50–53]. However, some studies have shown a much higher frequency of infections, 1–2/1000 catheter-days [54,55]. In a meta-analysis of 48 studies with 2704 patients and 2973 central venous access devices (of which only 77% were implanted), the average frequency of infection was 0.66 per 1000 catheter-days [56]. It is well known that implantable devices, such as the Port-A-Cath, have a lower infection rate compared with that of external catheters. Patients with inhibitors have more infections probably because of minimal bleeding around the port after use. Table 1 shows other potential factors that may influence the rate of infection [49,57]. The most important are probably related to aseptic measures, quality of education and the compliance of the users, whether these are parents or health-care professionals.
| • Implanted or external catheter |
| • If the patient has an inhibitor |
| • Age < 6 years |
| • Strict adherence to aseptic techniques (in particular hand wash!) |
| • Education and re-education of parents |
| • Prophylactic antibiotics in association with invasive procedures (for example dental work) |
| • Topical anaesthetic cream (EMLA) should by removed by detergent and antiseptic solution |
| • The port should not be used in case of haematoma or infection in the skin above the port |
| • How frequently the port is used |
| • The type of concentrate or substance infused in the catheter, i.e. risk of fibrin film on catheter surface |
Catheter-related thrombosis is the second most important complication with CVL in haemophilia children. Most catheters, at least occasionally, develop a fibrin sheath at the tip or outer surface of the catheter that prevents aspiration or causes some resistance to infusion in the catheter [58]. This is in most instances harmless but may theoretically progress to a micro-thrombosis without clinical significance or a radiologically evident thrombosis with or without clinical symptoms. During the first 10 years of Port-A-Cath usage in haemophilia, there were few reports of thromboses and many publications did not report any thromboses despite long follow-up periods [50,55,59,60]. Most of these studies were retrospective and venography was usually not routinely performed. This has been done in a few studies which showed an unexpectedly high frequency of thrombosis [61,62]. The series by Price et al. revealed radiological signs of thrombosis in 13/16 (81%) children although the clinical relevance of these findings was not clear in all cases [61]. The duration of catheter placement seems to be important: the longer the catheter has been in place, the higher the risk.
Is it reasonable to assume that clinical signs have been overlooked in the studies reporting almost no thrombotic events or is the discrepancy caused by other factors? The studies with a high frequency of thromboses include many patients with inhibitors undergoing immune tolerance induction. As several studies have clearly shown that infections are more frequent in inhibitor patients compared with those without an inhibitor, one may speculate, that one reason for the observed frequency of thromboses may be concomitant or previous infections and that the thrombotic process is promoted by a pro-inflammatory state. Table 2 shows that other factors one may speculate can be of importance for the development of thrombosis.
| • The frequency of infection |
| • Genetic prothrombotic factors [62] |
| • Choice of vein (catheter preferably in the right jugular vein) |
| • The type and size of catheter |
| • The position of the tip of catheter |
| • The routines for flush, heparin-lock, ‘fibrinolytic flush’, etc. of the catheter |
| • The type of concentrate or substance infused in the catheter, i.e. risk of fibrin film on catheter surface |
| • The time the catheter has been implanted |
It is challenging and unsatisfactory that we, after so many years of use at different centres, still have such diverse experiences of the risk of complications with CVLs. With the aim of shedding some light on these questions, a pilot study is ongoing among both centres that have experienced few problems (infections and thrombosis) as well as those that have reported a high frequency of problems. In this survey, jointly conducted between the paediatric haemophilia centres in Toronto, Canada and Malmö, Sweden, we will closely compare the institutional CVL standard of care protocols at the centres. Variables under investigation include selection of patients, frequency of inhibitor patients, surgical implantation methods, education of care-givers/parents, choice of catheter material, aseptic techniques, concentrates infused, usage for blood sampling, surveillance routines, routine monitoring for complications and, of course, the actual frequency of complications/patient year related to these factors. Further studies are required to identify several crucial risk factors for the complications associated with implantable venous access system use in small children.
Acknowledgements
The Swedish results presented in this review were supported by grants from the Swedish Research Council (no. 13493) and the University of Lund (ALF). In this paper, the principal authors of the different sections were: (I) Donna DiMichele; (II) Hervé Chambost; (III) Rolf Ljung & Ann-Marie Stain.
