Experiences and Outcomes of Fertility Testing in Male Adolescents with Sickle Cell Disease

Abstract

Adult males with sickle cell disease (SCD) may have abnormal semen parameters, raising the concern that SCD and/or treatments may impact fertility. Yet, studies that include adolescents are lacking. To determine if fertility testing is feasible in male adolescents with SCD, and to explore their experiences and outcomes of fertility testing, 33 adolescents who completed a web-based SCD reproductive health education program were offered a free semen analysis. Five (15%) obtained testing and each had abnormalities. Barriers to testing included lack of time and transportation and discomfort. Findings highlight the need for larger, longitudinal studies using innovative testing approaches.

There are numerous reproductive health care considerations specific to sickle cell disease (SCD),^1–3 and the potential impact of SCD and hydroxyurea on fertility is particularly salient.^4,5 The majority of individuals with SCD in high-resource settings are surviving into adulthood,^6–8 hydroxyurea use is expanding worldwide,⁹ most adolescents with SCD desire future biological parenthood,^5,10 and fertility testing and preservation methods are available but not currently integrated into standard clinical care.¹¹

Recent research in small cohorts show adult males with SCD who are treated and untreated with hydroxyurea have abnormal semen parameters, raising the concern that SCD and/or hydroxyurea may impact fertility.^3,12–14 Yet, few of these studies included adolescent males with SCD. To better understand the potential fertility impacts, larger and longitudinal studies that include adolescent males with SCD are needed, as this is the earliest timepoint that fertility testing (via semen analysis) and preservation (via proven methods [e.g., sperm banking]) is possible. However, individuals with SCD are known to face many barriers to receiving care (e.g., lack of transportation)¹⁵ that could also affect the feasibility of these studies, since semen samples are typically collected and analyzed at assisted reproductive diagnostic centers that have variable geographic distribution and accessibility.¹⁶ Thus, the aims of this study were to: 1) assess the feasibility of obtaining a semen sample at a reproductive diagnostic center from male adolescents with SCD, 2) describe their and their caregivers’ experiences with and barriers to testing, and 3) examine semen parameters of the adolescents who completed testing.

Methods and Results

English-proficient adolescent males (aged 14–22 years) with SCD (any genotype) who were receiving care at Nationwide Children’s Hospital (NCH) and who had not received a bone marrow transplant were recruited from November 2022-April 2023 to the IRB-approved study. English-proficient caregivers of enrolled adolescent males were also invited to participate. This study involved participants completing a novel web-based reproductive health program (i.e., Fertility edUcation To Understand Reproductive hEalth in Sickle cell disease (FUTURES)), which described potential fertility-related impacts of SCD, its treatments, and the purpose and process of fertility testing.

Adolescent participants ≥18 years of age and adolescents <18 years of age whose caregiver also participated were subsequently informed of the option for the adolescent to obtain a semen analysis at an off-site reproductive diagnostic center (with costs of testing and transportation to the center covered). Up to three attempts were made to contact eligible adolescents to gauge their interest in testing. If interested, the hematologist on the research team sent an order to the testing center, and the testing center coordinated the testing visit with the adolescent and/or caregiver. The research staff and testing center coordinator made multiple attempts to follow-up with adolescents who reported interest in testing but had not yet completed testing within the study time frame. The hematologist notified adolescents (and caregivers, if the adolescent was <18 years of age) who completed testing of their results.

All adolescents who were eligible for testing and caregivers of adolescents who were eligible for testing were invited to complete a qualitative interview to explore factors influencing the decision to complete testing. Three research staff trained and experienced in qualitative research methods developed semi-structured interview guides and conducted and transcribed verbatim the interviews. Adolescent and caregiver transcripts were coded separately using the constant comparison method¹⁷ and demonstrated strong interrater reliability (κ=.94). Fertility testing was considered feasible if ≥25% of the adolescents who received FUTURES completed testing. Demographic, medical, and treatment characteristics were abstracted from the medical record.

Thirty-three adolescents completed FUTURES. Of these, five (15%) submitted a sample for semen analysis (Table 1). A complete semen analysis is the current gold standard in diagnostic testing for the assessment of male reproductive potential. Each analysis provides information on multiple seminal parameters, including seminal volume, sperm concentration, sperm motility, seminal viscosity, and sperm morphology, among others. For each parameter, the World Health Organization (WHO) has published standardized procedures, reference ranges, and guidelines for the clinical evaluation and interpretation of factors affecting male fertility, which were used in this study.¹⁸ Sperm cells were observed in the ejaculates of all three adolescents who had never received hydroxyurea treatment. Two of these participants had sperm concentrations within the normal range, as defined by WHO criteria, while one exhibited low sperm concentration (oligospermia). Conversely, very few or no sperm cells were detectable in both participants currently receiving hydroxyurea treatment (cryptozoospermia and azoospermia, respectively).

TABLE 1.

Semen analysis results

Testing Completed (n=5)
SCD Genotype	HbSC	HbSC	HbSS	HbSS	HbSS
Age (years)	21	18	22	20	15
Hydroxyurea Treatment	Never used	Never Used	On 22.1mg/kg/d; has been on it for >10 years	Never used	On 21.5 mg/kg/d; has been on it for >5 years
Volume (>1.5 ml)	1.0 mL	0.2 mL	3.4 mL	1.0 mL	1.4 mL
Viscosity (Normal: discrete droplets)	Normal	Moderate	Normal	Normal	Normal
Non-Liquefaction (0% at 30 minutes)	0%	0%	0%	0%	0%
Sperm Concentration (>15×106/ml)	52 × 106/mL	7 × 10 6 /mL	0	43 × 106/mL	0
Forward Progression (>32%)	66%	3%	0%	79%	0%
Activity (≥2+)	2+ to 2++	1++	0	2+	0
Round Cells (<5×106/ml)	3 × 106/mL	0 × 106/mL	0 × 106/mL	0 × 106/mL	0 × 106/mL
Agglutination (0%)	0%	0%	0%	0%	0%
Morphology (≥4%)	2%	6%	Unable to complete	8.5%	Unable to complete
Notes	Complete sample not collected	__	No sperm cells observed	__	1 motile and 1 non-motile sperm after centrifuging

Notes: reference ranges are provided under each variable name in the left most column, based on W.H.O. Laboratory Manual for the Examination and Processing of Human Semen (5^th Edition, 2010) guidelines. Abnormal values are bolded.

Twenty-eight adolescents (85%) did not complete testing (Median_age=16, [IQR=13, 19]; 15 with Hemoglobin (Hb)SS, 1 with HbSβ⁰, 8 with HbSC, 4 with HbSβ⁺; 19 who had ever received hydroxyurea; 13 who were currently receiving hydroxyurea). All adolescents who completed testing and one caregiver completed the qualitative interview. Ten adolescents who did not complete testing and seven caregivers of adolescents who did complete testing completed a barriers interview (Figure 1).

FIGURE 1.

Exemplar quotes from the qualitative interviews

Discussion

Despite providing reproductive health education, compensation to cover the costs of transportation and testing, and coordination with a local testing center, we found that only 15% of adolescent males with SCD pursued testing, suggesting this is not a feasible strategy. Our qualitative findings suggest that developmentally and culturally appropriate fertility education and increased advocacy for affordable reproductive healthcare for this population may facilitate adolescents with SCD to pursue fertility testing, whereas innovative methods to collect semen samples that limit patient discomfort and time constraints (e.g., mail-in testing where semen samples are collected at-home) are needed to reduce barriers.

Similar to studies in adults with SCD,^3,12–14 adolescents who completed testing in this study, including two with HbSC, had at least one abnormal semen parameter. Spermatogenesis can be detrimentally affected by a range of factors, including genetics, environmental exposures, and medical conditions and treatments. While azoospermia and cryptozoospermia were noted in those with HbSS on prolonged hydroxyurea treatment, oligospermia was also found in an individual with HbSC and no hydroxyurea exposure. More research is needed to elucidate these effects (e.g., what effect SCD and/or hydroxyurea has, whether or not these effects may be reversible) and examine actual fertility outcomes.

While these findings add to the potential concerns of male fertility impairment from the disease process itself or hydroxyurea, definitive conclusions about fertility and the barriers and facilitators to testing cannot be drawn given our small sample size and cross-sectional design. However, these findings support that a shared decision-making approach to hydroxyurea is indicated, based on evidence of numerous and indisputable health benefits of hydroxyurea,^19–22 emerging research on potential fertility impacts,^3,12–14 and no known rigorous studies confirming actual fertility impairment (a self-reported outcome that can only be assessed among those attempting biologic parenthood for >12 months) from SCD or hydroxyurea. Thus, these discussions should include what is known about the benefits of treatment and what is known and unknown about the potential impact of SCD and its treatments on fertility. Counseling should also take into consideration patients’ and families’ future genetic parenthood goals, and that fertility preservation, as a back-up for those who are on or considering hydroxyurea, remains largely inaccessible and not covered by insurance for those with SCD.²³ In conclusion, these findings further underscore the need for innovative strategies to examine semen parameters and fertility in male youth with SCD to ensure that they are able to achieve their health and reproductive goals.

Abbreviations:

SCD

Sickle cell disease

NCH

Nationwide Children’s Hospital

FUTURES

Fertility education to understand reproductive health in sickle cell disease

WHO

World Health Organization

Hb

Hemoglobin