Effects of Hydroxyurea on Fertility in Sickle Cell Disease; A Systemic Review and Meta-Analysis

Background: Hydroxyurea (HU) remains a widely available and clinically effective therapy for sickle cell disease (SCD). Whilst a substantial body of evidence documents the benefits of HU with acceptable short- and long-term toxicity profiles, concerns regarding its safety persist, particularly regarding fertility.

Methods: This systemic review and meta-analysis evaluated fertility parameters in males and females with SCD receiving HU therapy. Articles published from inception to July 2023 were searched in PubMed and EMBASE. Terms used in the research for primary endpoints were ““sickle cell disease” and “infertility” and “hydroxyurea”; “sickle cell disease” and “fertility” and “hydroxyurea”; “sickle cell anaemia” and “hydroxyurea” and “infertility”; “sickle cell disease” and “hydroxycarbamide” and “infertility”; and combination of the terms “sickle cell anaemia” and “hydroxycarbamide” and “infertility”. Our research focused on primary fertility outcomes stratified by male or female gender. Inclusion criteria were as follows: (i) Studies published in English from inception to the present day; (ii) Studies subjects (aged ≥ 6 years), prospective and retrospective cohort studies reporting frequency of outcomes of interests (semen parameters and female infertility events) stratified by HU therapy. Case reports, reviews, animal studies, duplications and studies on very young patients (aged < 6 years) were excluded. The Newcastle-Ottawa Scale was used to assess the quality and risk of bias of the included studies.

Results: A total of 160 articles were initially retrieved from PubMed and Embase. After applying the exclusion criteria, the full texts of 32 potentially relevant studies were reviewed. A total of 25 were excluded due to lack of relevant research (n=11), non-human research (n=4), not original research (n=6), case reports (n=3) and articles not in English (n=1). In total, 7 were finally included for meta-analysis (Figure). Four studies were included that evaluated the effects of HU on sperm parameters in males. Three studies were included that assessed anti-mullerian hormone (AMH) levels and ovarian reserves in females. Changes from baseline were used to identify compromised fertility. Amongst males, HU treatment negatively impacted the concentration of spermatozoa (MD= -15.48 million/mL; 95% CI: [-20.69, -10.26]; p< 0.001) which continued following treatment cessation (MD= -20.09 million/mL; 95% CI: [-38.78, -1.40]; P= 0.04). HU treatment also led to lower total sperm counts (MD= -105.87 million; 95% CI: [-140.61, -71.13]; P< 0.001) which persisted after treatment cessation (MD= -53.05 million; 95% CI: [-104.96, -1.14]; P= 0.05). Sperm volume, initial forward motility and morphology were unaffected by HU treatment. In females, HU treatment did not impact the mean AMH levels 2.01 (95% CI [1.58, 2.44] and a total of 67% patients treated with HU showed normal ovarian reserves (95% CI [53%, 82%]). The fertility of 33% of patients was however negatively impacted by HU therapy.

Conclusions: Our findings suggest that the use of HU for SCD impacts seminal fluid parameters in males and diminishes ovarian reserves in a significant number of females. Fertility preservation counselling should be considered in patients with SCD in both genders of reproductive age prior to HU therapy. Our study highlights the need for long-term multi-centric studies using consistent HU doses and outcome assessments to fully understand the impact of HU on fertility in SCD patients.