1 INTRODUCTION

The historical understanding of haemophilia was that men were affected while women were unaffected genetic transmitters only. Yet the different ways haemophilia affects women and girls are now clearly recognized: as individuals with haemophilia corresponding to their factor level, as symptomatic haemophilia carriers, or asymptomatic haemophilia carriers.¹ It is estimated that for every man with haemophilia there are 3−5 haemophilia carriers and approximately one-third of these women and girls will manifest below normal factor levels and have haemophilia.^2-4 These numbers are not reflected in national and international registries, highlighting issues of underdiagnosis and indicating a need to better identify all women and girls affected by haemophilia.⁵ This is especially important as research clearly demonstrates that carriers of haemophilia can experience abnormal bleeding symptoms, even those with normal factor levels.^{3, 6} These symptoms include heavy menstrual bleeding, post-partum haemorrhage, excessive post-surgical bleeding, epistaxis, easy bruising, oral cavity bleeding and musculoskeletal bleeding.^{3, 4, 7-10}

The first calls for systematic assessment of factor level in all haemophilia carriers to determine bleeding risk ‘for safety reasons alone’ date back to the 1990′s,^{11, 12} yet testing practices vary across Canadian Hemophilia Treatment Centre's (HTC) and many different timepoints may be suggested including: early childhood, if abnormal bleeding symptoms present, prior to surgical/dental procedures, around age of menarche, at age of consent, or prior to pregnancy.

Genetic testing for haemophilia has been available since the mid-1980′s for testing prior to pregnancy for family planning and identification of affected male children.^{11, 13} It is currently available to all potential carriers in Canada at the age of consent, and increasingly considered in adolescence when the child is able to give assent or even earlier in childhood if abnormal bleeding symptoms present. Although genetic testing of minors must be approached with caution, it is recommended when to the medical benefit of the child for assessment, monitoring or treatment purposes.¹⁴

In previous research, Canadian parents have reported frustration at the lack of consistency regarding testing practices nationwide and instances of testing refusal where parents were unable to obtain the testing they desired or felt that they compromised their relationship with their HTC by insisting on early testing for their daughters.¹⁵ Additionally, parents have been shown to have a preference for earlier testing as compared to healthcare providers (HCP), motivated by a desire to do what is best for their child.^15-18

It is almost universally recognized that when resources permit, a male-child at risk for mild haemophilia based on family history should have factor level testing in the first few years of life and often genetic testing as well. Yet despite the now established fact that one third of women and girls heterozygous for haemophilia will have mild haemophilia, it is not uncommon for a female child to have no testing (factor level or genetic testing) until much later in life. The absence of early recognition of a potential bleeding risk in young girls can have deleterious effects on the health and quality of life and delay access to appropriate care.¹⁹ Recently, some groups have released clear updated guidelines around haemophilia related testing for women and girls such as the ‘European principles of care for women and girls with bleeding disorders’ which calls for systematic factor level testing in early childhood, repeated prior to menarche, and genetic testing recommended when the individual is competent to understand results, or earlier if clinically indicated.²⁰

The extent to which testing recommendations have evolved in Canada is unknown, thus our study aim was to explore and describe the practice of haemophilia-related testing in young girls from the perspective of both HCP and parents in Canada. From HCP we aimed to describe the current testing recommendations being given out by Canadian HTC's and from parents we sought to describe their experiences as they made testing choices for their daughters.

2 MATERIALS AND METHODS

We conducted a descriptive mixed methods project with two study populations, HCP and parents of haemophilia carriers/potential haemophilia carriers. A convergent parallel design was used where quantitative and qualitative aspects were conducted simultaneously, analysed separately, but then merged for interpretation to fully answer the research question.

A convenience sampling method was used for both study groups. HCP were recruited via affiliation with the Canadian Association of Nurses in Hemophilia Care (CANHC) which includes nurses from all 26 HTC's across Canada. Parent participants were recruited via a one-page flyer distributed by provincial haemophilia societies.

The quantitative aspect of the study consisted of a five-question anonymous survey sent via email to all 45 active members of CANHC. One email reminder was sent 2 weeks after initial email contact. Consent was obtained at the beginning of the survey and slightly different questions were asked depending on the type of HTC the respondent was affiliated with, adult-only or paediatric/lifespan (Appendix A). Questions were related to the usual recommendations of their HTC for factor level testing of obligate and the potential carriers. HTC's that treat paediatric patients were also asked about usual recommendations around genetic testing of a minor when the request has been made by the family. No location-related data was collected in order to preserve anonymity as many Canadian provinces only have one HTC. Survey responses were exported to Microsoft Excel and organized as percentage of respondents who selected each answer category. Results were analysed collectively and then separately based on type of HTC (adult-only vs. paediatric/lifespan). As this is a descriptive study with the aim of summarizing the current landscape of recommendations being given by HTCs, no analysis of statistical significance was done.

The qualitative aspect of the study consisted of a structured interview carried out with parents of haemophilia carriers/potential carriers. Inclusion criteria were any English-speaking parent of an obligate or potential haemophilia carrier of any age residing in Canada. There were no exclusion criteria and parents of potential carriers who had received genetic testing of their daughters with negative results (i.e., not carriers) were still included as interview questions were related to experiences around testing decisions. The recruitment flyer instructed interested participants to contact study staff by phone or email, after which full study details were sent by email. Each participant underwent a structured interview via telephone or Microsoft Teams (conducted by M.C.) with consent obtained prior. Interview questions were related to the experience of haemophilia in the family, testing decisions, interactions with HCP including testing recommendations, and parental opinion on optimal timing of haemophilia-related testing in young girls (Appendix B). Parental responses to questions were transcribed in real-time with longer answers read back to participants to ensure accuracy of recorded written responses. Results were imported into Microsoft Excel and shown as the percentage of total participants in each response category. For longer responses regarding beliefs, testing experiences and decision-making factors, 10 key findings deemed highly relevant by the research team were selected. As interviews were not recorded and no transcripts were made, thematic analysis of these longer answers was not possible.

Ethics approval was granted by the Queen's University Health Sciences and Affiliated Teaching Hospitals Research Ethics Board prior to study commencement.

3 RESULTS

4 DISCUSSION

It is now increasingly recognized that all carriers of haemophilia should have early baseline factor level testing, with genetic testing generally performed later in adolescence/adulthood but considered earlier in certain circumstances.^{20, 21} Recommendations for early factor level testing for all carriers date back more than 30 years due to the increased risk of abnormally low levels, yet our results show this knowledge has not been translated into practice in Canada.^{11, 12} Collectively, our results demonstrate only 27% of HTCs recommend an early baseline factor level test (<10 years of age) for obligate carriers which decreases to 15% for potential carriers. Different recommendations for factor level testing are being given to obligate and potential carriers, despite there being no evidence of a difference in bleeding risk or likelihood of low factor levels with the two different types of carriership.²²

A possible explanation for these findings is the failure to separate assessment of bleeding risk from assessment of carriership.²² When genetic status is certain, as is the case with obligate carriers of haemophilia, parents and HCP may feel more comfortable proceeding with early factor level testing as part of bleeding risk assessment. Whereas when genetic status is uncertain as is the case with potential carriers, it has been suggested that parents and HCP may be more hesitant to proceed with early factor level testing for fear of establishing carrier status.^{22, 23} Additionally the historically pervasive and persistent belief that only men are affected by haemophilia, along with systemic sexism in the management of all women with bleeding disorders, likely contribute to why early assessment of bleeding risk with factor level testing is still not the universal standard of care for young girls in Canada.²⁴

Our results highlight the importance of adult Haematologists/HTC's in disseminating information about bleeding risk assessment and factor level testing in young girls. For many men affected by haemophilia, this will be their primary source of information regarding testing recommendations for their obligate carrier daughters. Yet our results show that for 67% of adult-only HTCs, testing recommendations centre on the presence of abnormal bleeding symptoms in the child which is a determination that parents reported is difficult to make, particularly when there is no connection to a paediatric HTC such as with fathers of obligate carrier daughters.

Our results indicate increasing acceptance of genetic testing in minors, particularly in the context of abnormal bleeding symptoms, as almost 75% of survey respondents said their HTC would agree to a family request for genetic testing under those circumstances. Increasing evidence of abnormal bleeding, particularly heavy menstrual bleeding, in girls who are carriers of haemophilia but have normal factor levels outlines the argument for genetic testing of potential carriers as a means of assessing bleeding risk, as opposed to for carrier identification alone.²⁵

Results of our parent interviews highlighted many previously documented findings in the literature such as: promoting health as the primary parental motivation for testing decisions,^{15, 16} difficulty differentiating normal and abnormal bleeding symptoms,^{15, 26} and the impact of delayed testing on diagnosis, symptom recognition, treatment and quality of life, particularly for heavy menstrual bleeding.^{3, 4, 19, 27, 28} Our finding that trauma associated with blood draws was reported at many different testing timepoints, both in early childhood and adolescence, is noteworthy as fear that the blood draw will be traumatic for a very young child can be a rationale for delayed testing. A previous study also reported the impact of family history, particularly delayed diagnosis and untreated bleeding in women, which led women to advocate for testing of their female family members.²⁶ The perceived parental benefit of knowing a child's haemophilia carriers status, both positive and negative results, has also been previously documented with positive effects on both the parent and child.¹⁶

Limitations of our study include a possible selection bias as families who have strong feelings about testing in young girls due to previous negative experiences may have been more likely to respond to the recruitment call. Additionally, as only English-speaking participants were involved in the study, results may not be representative of the French-speaking parts of Canada.

5 CONCLUSION

The current landscape of haemophilia-related testing recommendations for young girls in Canada varies widely with no clear consensus on the optimal timing of factor level or genetic testing. Our results show there are likely many girls in Canada, both potential and obligate carriers, who have been inadequately screened for bleeding risk and have not had a baseline factor level test completed. Results of our parent interviews show the negative consequences of delayed recommendations and inadequate screening. Updated, nationally affirmed testing recommendations are needed that align with research on bleeding in women and girls affected by haemophilia, such as the recently published ‘European principles of care for women and girls with inherited bleeding disorders’.²⁰ This consensus document calls for a systematic approach to testing of all females affected by haemophilia, with baseline factor level testing in early childhood, repeat factor level testing before menarche, and genetic testing for potentially affected individuals when they are competent to understand results with considerations for testing in childhood when clinically relevant.²⁰ Nationally recognized recommendations such as these will assist greatly in ensuring adequate screening, yet a concerted effort is also needed to identify the women and girls already missed. Next steps could include targeted proactive haemophilia carrier screening projects by pedigree analysis such as the one recently completed in Belgium.²⁹ Additionally, both healthcare professionals and non-medical organizations such as haemophilia societies are needed to increase awareness of updated testing recommendations and the necessity of bleeding risk assessment for all women and girls affected by haemophilia.

CONFLICT OF INTEREST STATEMENT

P.J. has funding from Bayer and consultancy with Star/Vega, Band/Guardian, Roche, Biomarin. M.C., J.G., E.W. and M.B. have no interests to declare.

ETHICS APPROVAL STATEMENT

Ethics approval was granted by the Queen's University Health Sciences and Affiliated Teaching Hospitals Research Ethics Board prior to study commencement. Informed consent was obtained from all participants prior to commencing study.