Comment on: Infertility and treatment-seeking practices among females and males with sickle cell disease in the Sickle Cell Disease Implementation Consortium registry

To the Editor:

Stevenson et al. recently reported the first study on the prevalence of infertility using the Sickle Cell Disease (SCD) Implementation Consortium (SCDIC) registry, showing 16.9% of males and 23% of females with SCD reported infertility,¹ in contrast to 12% of males and 11% of females in the general population.² We commend the authors for embarking on this important work, given the increasing need to address potential infertility in SCD.^3–5 However, the study’s methodological limitations suggest the prevalence of infertility in people with SCD remains uncertain.

First, population infertility rates are most accurately assessed among those who have attempted biological parenthood. Recent research examining US population-level infertility rates only included those who reported attempting pregnancy, resulting in substantive narrowing of the sample (from 10,251 to 2626 women⁶ and from 4928 to 157 men⁷), but the ability to more accurately assess infertility. In contrast, Stevenson et al. included the 2108 individuals (1224 females, 884 males) who completed infertility-specific questions in their prevalence calculation but did not report if these participants attempted pregnancy. They also did not integrate the published pregnancy data from females in the SCDIC registry into their fertile/infertile classification.^1,8

Second, sample characteristics (77% unmarried; 55% aged 18– 29 years) suggest some participants classified as “fertile” may not have attempted to conceive and may not have known if their fertility was impaired (which could underestimate infertility in the sample). For instance, 15%–33% of adolescents and young adults with SCD report they do not desire biological parenthood^9–11 and may not attempt it, at least not in early adulthood. Also, in the most recent National Inpatient Sample, the average age of pregnancy in women with SCD pregnancy was 27 years and did not differ from unaffected Black women.¹² While the average age of first paternity in SCD is not established, paternity appears to be low in a recent publication.¹³ Finally, Stevenson et al. cite a single, population-based infertility study (1982–2010) to provide relative context of the problem,⁹ whereas more contemporary data show that infertility rates among married/cohabiting women in the general population may be only 5%–8%.¹⁰

To conclude, we commend Stevenson et al. for this hypothesis generating work and agree “a fuller understanding of infertility and SCD in the United States may contribute to more patient-centered, robust fertility care for persons with SCD who seek genetic parenthood.”¹ With this goal, the infertility rates reported in this study should be interpreted cautiously, as the methodological limitations may misrepresent the problem. Rigorous population-based SCD studies are needed to: (i) determine infertility rates, (ii) inform guidelines for infertility risk and fertility preservation counseling, and (iii) characterize the infrastructure needed to deliver comprehensive, accessible reproductive health care. Finally, as people with SCD have diverse disease phenotypes and sex- and treatment-specific infertility risks, precision medicine approaches may be useful to inform individual infertility risk for this underserved and understudied population.