Long-Term Gonadal and Reproductive Toxicity of Maximum-Tolerated-Dose Hydroxyurea/Hydroxycarbamide in Children with Sickle Cell Disease: A Systematic Review

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@article{1722892,
      author = {Usman Ndabida Mohammed},
      title = {Long-Term Gonadal and Reproductive Toxicity of Maximum-Tolerated-Dose Hydroxyurea/Hydroxycarbamide in Children with Sickle Cell Disease: A Systematic Review},
      journal = {Iconic Research And Engineering Journals},
      year = {2026},
      volume = {10},
      number = {3},
      pages = {1004-1014},
      issn = {2456-8880},
      url = {https://www.irejournals.com/formatedpaper/1722892.pdf},
      abstract = {Background: Hydroxyurea (hydroxycarbamide) is the primary disease-modifying therapy for pediatric sickle cell disease (SCD), with guidelines recommending dose escalation to the maximum tolerated dose (MTD) from as early as 9 months of age. Its long-term effect on gonadal and reproductive function in childhood-treated individuals remains inadequately characterised. This review synthesises evidence on long-term gonadal and reproductive toxicity of MTD hydroxyurea initiated in childhood or adolescence for SCD. Methods: MEDLINE (PubMed) and Cochrane CENTRAL/CDSR were searched; ClinicalTrials.gov and WHO ICTRP-affiliated registries were searched for grey literature. Embase, Web of Science, and CINAHL could not be searched directly, which was mitigated through citation-chasing. Eligible studies reported gonadal, hormonal, or reproductive outcomes in individuals with SCD who initiated hydroxyurea before age 18. Risk of bias was assessed with ROBINS-I; findings were synthesised narratively by outcome domain. Results: Eighteen observational studies met eligibility criteria; no randomised controlled trial addressed this question. Male semen and spermatogonial-histology evidence was directly conflicting: some studies showed treatment-associated impairment with partial reversibility, while histology studies generally found no hydroxyurea-specific effect once disease-related baseline abnormality was accounted for. Female ovarian-reserve evidence was similarly divided between hormonal (AMH) studies suggesting diminished reserve and the only histological study, which found no difference in follicle density. Growth and pubertal development showed consistent evidence, with no hydroxyurea-specific signal across five studies (1997–2026). No study reported long-term pregnancy, paternity, or infancy-onset outcomes. Certainty of evidence was low or very low across all domains. Conclusions: Current evidence is insufficient to determine whether childhood-initiated MTD hydroxyurea causes clinically meaningful, irreversible gonadal or reproductive harm. Findings are more reassuring where methodology is most direct (tissue histology) and more concerning where it captures active-treatment status (semen analysis, AMH). Prospective, longitudinal studies with harmonised endpoints, particularly in infancy-treated children, are urgently needed; a relevant study (SAFE, NCT07116772) is underway.},
      keywords = {gonadal toxicity; hydroxyurea; hydroxycarbamide; fertility; sickle cell disease; systematic review.},
      month = {September},
      doi = {https://doi.org/10.64388/IREV10I3-1722892}
  }