Authors: Gabriel Pezahso Kotam, Diana Baaba Morrison, Joel Nyarko Karikari, Akorli Obed Mawunyo, Jessica Kotam, George Nkrumah Osei, Patrick Adu
Categories: Review, Sickle cell disease, Reproductive health, Gonadal dysfunction, Vaso-occlusive crises, Fertility preservation
Source: Reproductive Health
Authors: Gabriel Pezahso Kotam, Diana Baaba Morrison, Joel Nyarko Karikari, Akorli Obed Mawunyo, Jessica Kotam, George Nkrumah Osei, Patrick Adu
Sickle cell disease (SCD) is a hereditary red blood cell disorder with multi-systemic manifestations, including chronic pain, anaemia, stroke, renal complications, and increased mortality. While these clinical features have been well documented, reproductive health complications among individuals with SCD remain comparatively underexplored.
The recurrent vaso-occlusive crises, resulting from microvascular obstruction, can lead to infarctions in the testes and ovaries, thereby impairing spermatogenesis and ovarian reserve. Other associated complications such as priapism and gonadal failure further compromise fertility. Furthermore, whereas chronic transfusion therapy is required in many patients, it predisposes to iron overload-induced gonadal dysfunction. Hydroxyurea has been implicated as a potential gonadotoxic and teratogenic agent. This narrative review presents current evidence on the impact of SCD on reproductive function in both males and females. Emerging strategies aimed at preserving reproductive potential and improving patient outcomes, including preconception counselling, oocyte and embryo cryopreservation, in vitro fertilisation (IVF), and preimplantation genetic testing are highlighted.
A deeper understanding of how SCD affects fertility, pregnancy, sexual health, and reproductive options is essential to patient-centered care and integrating systems thinking into a multi-disciplinary team approach to improve the overall reproductive health of SCD individuals.
The online version contains supplementary material available at 10.1186/s12978-025-02169-w.
Red blood cells (RBCs) transport oxygen to body tissues by traversing blood vessels, including capillaries (venules and arterioles). Due to the minute size of the capillaries, RBCs are adapted to morphological changes as they are exposed to shear forces while moving through these vessels [1]. However, the biconcave disc shape of RBCs [2] and their membrane structure [1], which confer elasticity and deformability on RBCs is lost in sickle cell disease. Sickle cell anaemia refers to a group of disorders caused by inheriting a pair of abnormal haemoglobin genes, including the sickle cell gene in an autosomal recessive pattern [3]. The sickle cell gene is acquired as a result of a single base change (GAG → GTG) in the sixth codon of exon 1 of the β-globin gene responsible for the synthesis of the β-globin polypeptide of the haemoglobin molecule (α2β2) [4]. When exposed to decreased oxygen levels, sickle haemoglobin tends to polymerize into long, fibrous, crescent structures [5], resulting in the blockage of microcirculation or larger vessels. This process often leads to infarcts in various organs, causing the painful episodes known as sickling crises [6]. Typically, these crises are more common in individuals with the homozygous form of sickling haemoglobin, where both inherited genes code for the abnormal haemoglobin (HbS).
Sickle cell disease is the most common life-threatening genetic disorder among people of African ancestry [7]. In Ghana, approximately 15,000 (2%) of new-borns are diagnosed with the SCD annually [8]. According to the 2018 Demographic Health Survey in Nigeria, the birth prevalence of severe sickle cell disease (HbSS or HbSC) was 1.5% of all births, while the prevalence of carriers was significantly higher − 19.7% for HbAS and 1.6% for HbAC [9]. Globally, more than 300,000 children are born with sickle cell disease each year, and alarmingly, the burden of this disease is disproportionately heavy in sub-Saharan Africa, where more than 75% of cases are recorded [10, 11]. Among these cases in Africa, an estimated 50–90% of affected children die before the age of 5 [7, 11]. The patients who survive beyond early childhood face a range of complications that have significant effects on their quality of life, as they have to cope with various complications and challenges that affect their physical, emotional, and social well-being [7]. These complications comprise severe anaemia, acute and chronic pains, bacterial infections, stroke [7], impotency, or infertility [12].
While pain, anaemia, and stroke among sickle cell patients are extensively studied [6, 13–17], the effects of sickle cell anaemia on the reproductive health of patients are less explored [18–20]. Many sickle cell anaemia (SCA)-related reproductive risks and concerns have been raised among girls and women of reproductive age, with particular concerns about menstruation, fertility, and pregnancy [19]. Also, men with SCA are at risk for impaired fertility due to the effects of the disease and treatments [21]. Men with sickle cell anaemia sometimes report experiencing sexual dysfunction as a result of pathological mechanisms linked to the condition. Impaired sperm production from testicular infarction, chronic anaemia, disruption of the hypothalamic-pituitary-gonadal axis, and recurrent priapism have been identified as potential contributors to compromised male sexual and reproductive health outcomes in affected individuals [21–23].
This narrative review presents available findings on the impact of sickle cell disease on reproductive health in males and females. Although SCD is primarily an RBC disorder, its multi-organ manifestation leads to multiple derangements in the patient. Comprehensive understanding of some of these impacts such as how SCD affect sperm production, fertility, pregnancy, and sexual health can facilitate the need to adopt systems thinking approaches in the clinical management of the condition and improve patient outcomes. It can also guide counselling to set realistic expectations and appropriately plan pregnancies. Insights on how the disorder influences fertility and new-born health can inform population-level healthcare policies and assist resource allocation and design of culturally sensitive reproduction programs.
The methodological framework proposed by Arksey and O’Malley [24] was adopted for this evidence synthesis. Specifically, this evidence synthesis was characterised by research question identification, data search, screening and selection of eligible articles, data charting, and reporting. The research question “Why should sickle cell patients be concerned about reproductive health, what are the challenges they face, and what opportunities exist for improving the overall health of patients with sickle cell?”
We did a comprehensive search of relevant electronic databases including Scopus, PubMed, and Google Scholar. The following search terms and relevant keywords were used with Boolean operators (AND, OR) in the search sickle cell anaemia, reproduction, reproductive challenges, fertility, haemoglobin variants, hypogonadism, fertility risk, ovarian reserve, testicular infarction, and preconception care. A detailed search strategy is provided as a supplementary material.
The review considered peer-reviewed studies published in the English language from any region of the world that investigated the relationship between sickle cell anaemia and various reproductive deficiencies. However, unpublished and non-English articles were excluded. The exclusion of studies published in non-English languages was due to challenges in accurately interpreting and critically appraising them, as well as limited resources for translation. The data extracted were restricted to papers published between 2000 and 2024. Further screening of selected articles was undertaken using the Rayyan QCRI review manager. Subsequently, the titles, abstracts, and full texts of the selected articles were independently assessed by two reviewers who met thereafter to reconcile their respective article evaluations. Any discrepant article designation was re-evaluated by a third member of the research team to reconcile article evaluations. The evidence synthesis findings were then presented in a narrative format, profiling existing reproductive deficiencies and opportunities for advancing the overall health of individuals with sickle cell anaemia.
As illustrated in Fig. 1, twenty-seven (27) articles formed the primary evidence base for this research, published between 2000 and 2024, with the following cross-sectional studies (n = 11), case studies (n = 4), animal studies (n = 1), and review articles (n = 11). Quality assessment was conducted using validated tools appropriate for each study design.
Non-randomized studies (cross-sectional) were evaluated using the Mixed Methods Appraisal Tool (MMAT) version 2018, which assesses five specific criteria relevant to quantitative descriptive studies [25]. Among the 11 cross-sectional studies, 5 studies (50%) met 4 of the 5 MMAT criteria [23–29], while the remaining 6 studies (50%) met 3 of the 5 criteria [22, 30–34]. All review articles were appraised using the Scale for the Assessment of Narrative Review Articles (SANRA), a validated 6-item tool that evaluates narrative reviews across six domains [35]. Each domain is scored 0–2 points, yielding a maximum total score of 12 points. All review articles achieved scores ranging from 7 to 12 points (mean = 9.5). One study achieved a perfect score of 12 points [36], three studies scored 10 points [37–39], six studies scored 9 points [40–45], and one study scored 7 points [46].
Case studies [47–50] and animal studies [51] were not formally evaluated using standardized quality assessment tools due to the absence of widely recognized and validated assessment instruments specifically designed for these study types in the context of this research area.
Fig. 1A flowchart illustrating the screening for eligible studies
The key findings from the literature on the impact of SCA on reproductive health are summarised in a Venn diagram (Fig. 2) with the overlapping area representing shared health complications affecting both male and female SCA individuals. Studies that have provided evidence for these reproductive challenges are explored further in the subsequent sections.
Fig. 2Reproductive complications of sickle cell disease in males and females. The left section highlights female-specific conditions and feto-maternal complications, while the right section focuses on male reproductive issues. The overlapping area represents shared health complications affecting both sexes. (ROS: reactive oxygen species; HELLP: haemolysis, elevated liver enzymes, and low platelet count)
In males, hypogonadism is a condition characterised by impaired or deficient activity of the testes as demonstrated by impaired sperm production or defective and/or insufficient testosterone production [22]. While symptomatic hypogonadism affects 6–12% of healthy middle-aged and older men due to age-related testosterone decline, hypogonadism prevalence in men with sickle cell anaemia (SCA) is significantly higher, reaching up to 25% [23, 39]. Although some studies have addressed hypogonadism in the SCA population, the underlying aetiology still remains an open question that require well-controlled longitudinal studies for clarity [23]. By demonstrating lower testosterone and low or low-normal luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in male SCA individuals, some studies have suggested hypothalamic-pituitary dysfunction to be the cause of hypogonadism [52, 53]. However, the most accepted theory for hypogonadism is recurrent testicular infarction due to vaso-occlusion of the testes [22, 50]. In a case report, Alghamdi et al. provided a haematoxylin and eosin stained histological evidence of testicular blood vessel congestion with sickled red blood cells [47]. Although this was a single-centre case report, the histological evidence may be suggestive of a potential association between recurrent testicular infarction and gonadal dysfunction in affected individuals. In addition to ischemic injury, chronic inflammation, a hallmark of SCD, may exacerbate testicular damage through cytokine-mediated disruption. In contrast to the proposed hypogonadism in SCA patients, some studies have found decreased levels of the luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in people with sickle cell disease [23, 39]. This suggests a condition of secondary hypogonadism where the hypothalamus and pituitary do not signal appropriately to the testes. Additionally, other research has identified a state of compensated hypogonadism in SCA males, characterized by higher-than-normal levels of LH and FSH despite typical testosterone levels, indicating testicular dysfunction [22, 39]. Future meta-analyses of published data can help clarify hypogonadism-LH-FSH dynamics in SCD-related sperm production and/or hypogonadism.
In addition to testicular dysfunction, there may be abnormalities in the accessory sex organs, such as the seminal vesicles and the prostate glands of males with SCA. In a study comparing semen quality of SCA patients to control subjects, a significantly decreased ejaculate volume, sperm motility and abnormal spermatozoa morphology (spermatozoa with amorphous and tapered heads) was found among the SCA patients [54]. While these findings reflect impaired spermatogenesis, the notably reduced ejaculate volume also supports the possibility of abnormalities in the accessory sex glands, such as the seminal vesicles and prostate.
Priapism, a medical emergency characterized by painful penile erection lasting beyond 4 h in the absence of sexual arousal, is a dire complication of sickle cell anaemia. Recurrent episodes of priapism and its associated clinical management may precipitate erectile dysfunction or impotency in affected male SCA patients. Diggs and Ching were the first to report priapism in sickle cell patients in 1934 [55]. Since then, many studies have explored the association between sickle cell anaemia and priapism. It has been reported that about 30–45% of males with sickle cell anaemia suffer from priapism, and 30–47.5% of this cohort experience erectile dysfunction [51, 56, 57]. However, studies conducted in Togo, Nigeria, Senegal, and Jamaica reported that males with sickle cell anaemia are oblivious to the association between sickle cell anaemia and priapism [58]. Taken within the context of the higher SCA burden in those countries, this points to a public health neglect in which the potential reproductive issues experienced by male SCA individuals are not adequately addressed in these communities. Surprisingly, the pathophysiology of priapic attacks in SCA has been well-characterised in literature, meaning that data is available to inform public health discourse. Generally, priapism is grouped into non-ischemic and ischemic priapism. The non-ischemic priapism results from trauma or injury of the cavernosal artery leading to a painless tumescence [59]. On the other hand, the ischemic priapism result from the imbalance of vasodilation and vasoconstriction within the penis leading to the trapping of blood in the corpora cavernosa, and hence, a lasting painful tumescence [58]. Ischemic priapism is common among sickle cell patients, and it has been subdivided into stuttering priapism and major or fulminant priapism. Stuttering priapism exhibits a pattern of recurrent episodes of short-lasting penile erection while major priapism can last for more than 6 h [56].
Normally, penile erection occurs when nitric oxide (NO) is released within the corpora cavernosa by the enzymatic action of nitric oxide synthase produced by nitrergic neurons (nNOS) and the endothelium (eNOS). NO produced activates soluble guanylyl cyclase (sGC) which then converts guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). cGMP activates cGMP-dependent protein kinase (PKG). PKG subsequently causes the smooth muscles of the corpora cavernosa to relax, leading to infilling of the penis with blood (tumescence). After ejaculation, phosphodiesterase type-5 (PDE-5) is released in the cavernosal tissue, which in turn degrades the cGMP causing the penis to become flaccid.
In SCD, this NO–PDE–5 axis is altered as a result of reduced NO bioavailability leading to a downstream decrease in PDE-5, and, hence a sustained erection [30, 51]. Mechanistically, as SCA is characterized by intravascular haemolysis, increased free haemoglobin and arginase are released into circulation. Haemoglobin reacts with nitric oxide to form methaemoglobin and nitrate, while arginase shunts the breakdown of arginine into ornithine instead of NO. Furthermore, the oxidative stress that accompanies SCA-induced crises generates superoxide that reacts with NO to produce peroxynitrite, a potent oxidizing agent. These SCA-induced events cumulatively reduce NO bioavailability leading to priapism in SCD patients [57, 60]. Moreover, during priapic attacks, occlusion induced by distorted RBCs in the corpora cavernosa leads to a sustained inflammatory reaction which in turn leads to erectile dysfunction or impotency [27].
In past years, although scientists suspected decreased fertility in women with sickle cell anaemia, there was very little evidence to back their hypothesis. Researchers therefore, used the number of pregnancies reported during the reproductive years of patients as a surrogate for fertility [61]. The incidence of pregnancy among SCA patients was compared to healthy controls, and the lower number of pregnancies in SCA women was used to infer that fertility was reduced in women with SCA [61]. In light of new evidence, it has been proposed that recurrent intravascular sickling, vessel occlusion, tissue infarction, and hypoxia associated with chronic anaemia could account for ovarian dysgenesis and premature ovarian failure in women with SCA [62]. The vaso-occlusive nature of sickle cell anaemia causes the obstruction of ovarian vessels by sickle red cells thereby leading to ischemia and reduced oxygen delivery to the ovarian tissue. This contributes to tissue damage and compromises ovarian function. The chronic hypoxic environment mediated by these occlusions can trigger inflammatory responses and oxidative stress, which further exacerbate cellular damage within the ovary [63–65]. Additionally, the increased turnover of red blood cells in SCA due to haemolytic episodes leads to elevated levels of free haemoglobin and haeme, which can heighten oxidative stress and inflammation. These can have a significant impact on ovarian follicles and granulosa cells, the essential components for follicular development and hormone production. The oxidative damage inflicted by the accumulation of free radicals impairs the quality and quantity of oocytes, contributing to the decline in ovarian reserve observed in women with SCA [63].
The gonadal hormone Anti-Mullerian hormone (AMH) is a member of the transforming growth factor-beta (TGF-b) superfamily of growth and differentiation factors produced by the granulosa cells during the early stages of follicle development [64, 66]. It is popular for its role in gender differentiation during foetal development. Production is increased until early adulthood, after which concentrations slowly decrease with increasing age and gradually fades 5 years before menopause when the stock of primordial follicles is exhausted [66]. Due to these, AMH has emerged as a useful marker for assessment of ovarian function and has been utilized in many studies to access ovarian reserve and predict fertility [31, 62, 64]. In a study assessing the ovarian reserve in women with sickle cell disease, Kopeika et al. found that the mean AMH in the SCA case group was 7.6 pmol/l, significantly lower than the 13.4 pmol/l in the control group. This signifies a higher incidence of diminished ovarian reserve in SCA patients [31]. Interestingly, the findings of Kopeika et al. aligned with a similar study conducted in Nigeria by Garba et al. who reported the mean serum AMH level in women with Hb SS (the most severe form of SCA) to be markedly lower (3.64 ng/mL) compared to women with Hb AA (7.35 ng/mL) [64].
Among the main therapeutic options for individuals with SCA are hydroxyurea treatment, hematopoietic stem cell transplantation, erythrocyte transfusion and gene therapy [67–69]. Hydroxyurea and chronic transfusion, both disease-modifying therapies, can decrease the occurrence of sickling complications, while haematopoietic stem cell transplantation and gene therapy are curative treatment options [68]. Erythrocyte transfusion raises haemoglobin, enhances oxygen delivery, and reduces the proportion of HbS-containing RBCs that can polymerize in deoxygenated states [70]. Chronic transfusion therapy can lessen and avoid stroke and vaso-occlusive crises; nevertheless, a notable possible side effect of chronic transfusion is iron overload.
Serum ferritin levels, transferrin saturation levels, soluble transferrin receptors, a complete blood count with RBC indices, and a peripheral blood smear (morphology examination) are mostly used to assess iron status in healthy persons [71]. In patients with SCA, interpreting serum ferritin as a marker for iron status is complicated. This is because ferritin is an acute phase reactant (levels rise during inflammatory states) and patients with SCA experience recurrent systemic inflammation, triggered by recurring vaso-occlusive crises [33, 44]. Each unit of packed RBCs contains approximately 0.5 mg of elemental iron per mL of transfused blood. Repeated transfusions are thus detrimental to patient health as each transfused unit introduces a substantial amount of iron into the patient’s body [72], unless these transfusions are coupled with iron chelation therapy to mob up excess free iron. The repeated transfusions coupled with the increased iron absorption from the gastrointestinal tract in response to the chronic anaemia in SCA individuals, sets up conditions favourable for iron overload.
Under physiological conditions, transferrin is typically 30% saturated with iron, ensuring a balance that prevents iron toxicity. With chronic transfusion, the body receives a significant amount of additional elemental iron. Transferrin becomes 100% saturated and free iron, also termed non-transferrin-bound iron (NTBI), thus circulates in the blood [72, 73]. NTBI can be deposited in parenchymal tissues such as the testes [32, 74], ovaries [29, 75], and the pituitary [29, 32, 75]. Furthermore, iron is known to play a part in the production of free radicals and reactive oxygen species (ROS), which are implicated in the pathogenesis of several human diseases [76, 77]. In males SCD individuals, NTBI deposition in the testes leads to impaired testicular function and can result in oligospermia, azoospermia, abnormal sperm morphology, and decreased sperm motility [32, 74]. In female SCD individuals, iron overload in the ovarian follicular fluid impairs oocyte maturational development [29]. Furthermore, in both males and females, accumulation of NTBI in the pituitary also has detrimental effects on the anterior pituitary leading to hypogonadotrophic hypogonadism [75]. Collectively, the transfusion-induced iron overload in SCA individuals may lead to long-term sexual dysfunction.
Hydroxyurea is the only drug approved for mitigating the severity of SCA in both children and adults by modifying the progression of the disease [42, 78]. Hydroxyurea induces foetal haemoglobin (Hb F), decreasing the proportion of Hb S in circulation, and thus reduces the extent of intracellular haemoglobin polymerization which consequently reduces the severity of SCA [42, 78–82]. Although the exact mechanism remains elusive, hydroxyurea induces HbF production which improves erythrocyte deformability, lowers the risk of haemolysis, reduces neutrophilia, and reduces organ-related damages [42, 82].
Hydroxyurea inhibits ribonucleotide reductase, the rate-limiting enzyme in the formation of deoxyribonucleotide triphosphates (the building blocks in DNA synthesis) thereby compromising the integrity of DNA [41, 42]. The long-term use of hydroxyurea is associated with potential risks of reproductive impairment [78]. Based on hydroxyurea’s ability to disrupt nucleotide pools which results in stalling of the replication fork, collapse, and formation of double-stranded DNA breaks, it is classified as genotoxic [42]. In vitro animal studies have produced convincing evidence suggesting that continuous hydroxyurea exposure has teratogenic effects. Many studies have also reported its rapid cell-killing abilities (especially in dividing cells) [41, 46]. Scott WJ et al. demonstrated the embryotoxic effects and DNA synthesis inhibition of hydroxyurea after supra-pharmacological doses (250–1000 mg/kg) of hydroxyurea were injected intraperitoneally in female pregnant rats [83]. In males, it can cause reduced sperm count and motility, leading to infertility. In females, it may disrupt the menstrual cycle and affect fertility [34, 46, 78, 84]. This evidence suggests that hydroxyurea may have adverse effects on the reproductive health of both males and females because sperm and ovaries are rapidly dividing.
Sahoo et al. (2016) investigated the effects of hydroxyurea on seminal fluid parameters in 100 patients with sickle cell disease (SCD) in India, aged 18 to 45 years. The patients received low-dose hydroxyurea therapy at 10 mg/kg/day from September 2011 to October 2013. Before initiating therapy, the mean sperm concentration was 54.28 ± 16.2 million/mL, and normal morphology averaged 85.3 ± 10.27%. During therapy, the mean sperm concentration declined to 39.26 ± 29.32 million/ml, and normal morphology decreased to 73.3 ± 30.96%. Oligospermia was observed in 10 patients (20%) and azoospermia in 5 patients (10%). The study found a statistically significant reduction in sperm concentration (p < 0.0001), along with decreases in morphology and motility. Following the discontinuation of hydroxyurea for three months, 11 out of 15 patients (73%) with oligospermia or azoospermia recovered, while 4 patients (27%) showed no improvement [85].
In a retrospective study, Berthaut et al. (2008) found that hydroxyurea treatment lasting between 2 and 10 years was associated with reductions in ejaculate volume (from 2.93 to 2.32 mL), sperm concentration (42.13 to 25.37 million/mL), total sperm count (124.77 to 83.86 million), and the proportion of normal sperm morphology (22.3% to 18.91%). While these findings suggest a potential negative effect of hydroxyurea on semen quality, the retrospective design limits causal inference [34].
However, there is still limited evidence from well-controlled prospective studies to back these reproductive side effects of hydroxyurea. Others argue that these reproductive effects are due to the SCA condition itself and not the hydroxyurea intervention [86]. Speakers at the 25th European Hematology Association argued that there is a well-demonstrated reduction in sperm count even without hydroxyurea as 40% of males with SCA have abnormally low sperm counts [46]. Also, despite the genotoxic effects of hydroxyurea in many animal studies, the doses administered and plasma concentrations were mostly 5 − 10 times higher compared to therapeutic doses in human patients [38]. Thus, well-controlled longitudinal studies in humans, designed to account for potential confounders and using physiologically/therapeutically relevant doses are required to provide a direct causal evidence on the potential impact of hydroxyurea therapy on reproductive functions in SCA individuals.
Pregnancy is fraught with diverse physiological changes such as haemostasis hypercoagulability, and heightened metabolism. These and many other physiological changes aggravate SCA, predisposing SCA mothers and foetuses to adverse pregnancy outcomes including maternal and neonatal/foetal death [87]. Maternal mortality associated with SCA ranges from 1 to 9.2% [40]. This is somehow accompanied by a 2-fold risk of neonatal/foetal death compared with those without SCA.
SCA mothers are at risk of developing complications such as preeclampsia, HELLP (haemolysis, elevated liver enzymes and low platelet count syndrome), vaso-occlusive crisis, acute chest syndrome, etc [88]. Also, SCA mothers are vulnerable to infections (such as pneumonia and pyelonephritis) due to auto-splenectomy amidst their immunocompromised state during pregnancy. SCA mothers are likely to experience thromboembolic events such as deep vein thrombosis or stroke, especially when their pregnancy is compounded with a hypercoagulable state. Furthermore, SCA mothers have a high risk of stillbirth and miscarriage due to microvascular damage and decreased utero-placental circulation resulting from SCA-associated vaso-occlusive crisis and hypertension [88]. Preterm birth (>5Ibs, 8-ounce foetal birth weight) is raised in SCA pregnancy [36]. It is believed the increase in prostaglandin levels might be the cause of preterm deliveries [88]. To the foetus, SCA pregnancy results in complications such as foetal growth restriction, low birth weight, and foetal distress during labour [40]. Taken together, the risk of foeto-maternal morbidity and mortality is elevated in SCA individuals compared to non-SCA individuals.
It should be noted that there are geographic dimensions to these statistics since SCA patients from developed countries have a lower risk of developing foeto-maternal adverse outcomes than those from low-income countries [87]. This equally raises the question about the potential contributions of epigenetic modifiers and social determinants of health in these adverse pregnancy-related outcomes in SCA individuals. Notably, there are significant regional differences in the burden of feto-maternal complications among SCA pregnant women. In high income countries, the odds of maternal mortality in women with SCD compared with those without SCD are 3.54. However, this same comparison in low and middle income countries (LMICs) shows a relatively higher odds of maternal mortality in pregnant women with SCD compared with those without SCD (OR = 22.8, p < 0.001) [35]. This striking difference in maternal mortality is attributed to a plethora of reasons. While pregnant women with SCA in high-income countries benefit from early screening, multidisciplinary obstetric-hematologic care, and ready access to emergency services and blood transfusions, those in LMICs, particularly sub-Saharan Africa, experience disproportionately high feto-maternal morbidity and mortality.
In a study conducted at Korle Bu teaching hospital, Ghana, the researchers compared the outcomes before and after implementing a multidisciplinary care team for pregnant women with SCD [89]. The team included obstetricians, midwives, haematologists, pulmonologists, paediatricians and intensivists working collaboratively in managing SCD pregnant women. They found that during the post-intervention period, the maternal mortality rate reduced by 89%, that is, from 10,791 to 1,176 per 100,000 live births within 13 months of implementing the intervention. Perinatal mortality rate, on the other hand reduced by 62.2% - that is, from 60.8 to 23.0 per 1000 births [89]. This dramatic reduction highlights how improved access to specialized care can transform outcomes.
Also, prophylactic regular blood transfusion is indicated in managing SCD pregnancy, especially in SCD patients who have experienced previous obstetrical complications (3). However, patients in low- and middle-income countries (LMICs), where SCD is highly prevalent, may not benefit from this because of resource constraints [89, 90]. This approach is capital-intensive, involving the need for specialised equipment and experienced apheresis teams.
These systemic deficiencies warrant the need for strategic investment in maternal health infrastructure, enhancement of transfusion services, workforce development, and integration of SCA-specific pregnancy management into national maternal health guidelines.
Available practices for sickle cell patients to maintain their fertility and minimise intra-pregnancy risks include preconception care, cryopreservation, in-vitro fertilization, and pre-implantation genetic testing.
Preconception care is a set of pre-pregnancy proactive interventions that aim to identify and modify biomedical, behavioural, and social risks to an individual’s health before conception (in the case of men, before impregnating a spouse), to improve foeto-maternal pregnancy outcome [91]. In the context of SCA women, preconception care aims to address any potential risk and optimize nutritional well-being before pregnancy ensues. In males, this may include measures to ensure sperm health including motility, appropriate sperm count and semen volume and reduce the incidence of priapism. Despite SCA being the most prevalent genetic disease in Africa, preconception care for the SCA patients is largely neglected [92]. It is essential to help young women with SCA gain knowledge of genetic inheritance, specify their reproductive health intentions (their parenting plan), and engage in reproductive health behaviours that align with their parenting plan before conception [93]. Ideally, in regions like sub-Saharan Africa where SCA is prevalent, preconception care should be broadened to include screening of prospective partners during the prenuptial period to encourage informed evidence –based decision making in spousal selection as a proactive approach to minimize SCD burden.
Preconception care should entail holistic genetic counselling, medical evaluation, lifestyle modification, and medication review [94]. Ideally, the preconception care plan should be tailored to each patient’s specific needs; the assessment should start with preconception counselling to discuss potential SCA complications and risks to the pregnancy and review of medications [95]. During the process of preconception care, there is the need to review medications that pose a risk to the foetus. Studies have recommended that hydroxyurea treatment be discontinued at least three months before conception in both men and women [88, 95, 96]. Adequate folic acid intake is advised to reduce the risk of neural tube defect in the baby and improve haemoglobin formation [97]. Iron chelation therapy is advised to be discontinued at least 3 months before conception [88]; however, if chelation is necessary for iron overload, the pregnancy should ideally be postponed [95].
Cryopreservation refers to freezing cells and tissues at sub-zero temperatures (−1 °C to −10 °C and lower) to halt all biological activity and maintain their viability and physiological capabilities for future use [98]. Fertility cryopreservation in humans refers to the technique of freezing and storing reproductive cells, such as eggs (oocytes) and embryos, for future use. A growing number of people are choosing to retain their reproductive possibilities and have more control over their family planning through fertility cryopreservation. The risks and success of available fertility preservation techniques, including embryo and oocyte cryopreservation, should be discussed with patients facing fertility-threatening therapies [91]. Given the elevated risk of infertility that engulfs patients with SCA, there is the need to employ measures that aim at preserving fertility in these individuals while administering standard care.
Oocyte and embryo cryopreservation is a feasible option that should be made available to female SCA individuals, especially those who undergo Haematopoietic Stem Cell Transplant, (HSCT), as a medium of preserving fertility. Exposure to myeloablative and gonadotoxic conditioning regimens before HSCT are the clearest indications of fertility preservation considerations [99]. These conditioning regimens (also applicable in those undergoing gene therapy) rely on radiation and/or chemotherapy agents which often result in Primary Ovarian Insufficiency (POI) [49]. During the process of oocyte preservation, there is ovarian stimulation to produce multiple eggs which are then retrieved and stored for future use. The eggs are fertilized and cryopreserved in embryo cryopreservation. However, the potential adverse risks of cryopreservation should be discussed with SCA individuals to facilitate informed decision-making process. Nickel et al. (2022) revealed that Oocyte cryopreservation is a risk for ovarian hyperstimulation syndrome (OHSS) and is characterized by hypercoagulability, electrolyte abnormalities, ascites, pulmonary oedema, etc [99]. The stimulation process is associated with increased levels of serum estradiol which is thrombogenic due to its effects on procoagulant factors (factor VII, X, and antithrombin III) as well as its stimulatory effect on platelet aggregation [49]. Patients with SCA are already at high risk of thrombosis, and these ovarian stimulation medications not only make them hypercoagulable but also increase vaso-occlusive crises. It is essential to safeguard the general well-being of the patient while trying to preserve fertility. Thus, neutralizing the negative effects of these medications used during ovarian stimulation is a major step in achieving this. Gonadotropin-releasing hormone (GnRH) antagonists have gained popularity for their effectiveness in reducing the incidence of OHSS [100]. Enoxaparin, a low-molecular-weight heparin, has also been employed as a thromboprophylaxis agent in sickle cell anaemia (SCA) patients undergoing gonadotropin stimulation to mitigate the heightened risk of thrombotic events [91]. Therefore, co-administering GnRH to reduce the risk of OHSS and enoxaparin to alleviate the risk of thrombosis will help safeguard the well-being of these patients and also preserve their fertility.
In-vitro fertilization (IVF) in conjunction with pre-implantation and genetic testing can provide reproductive options for individuals with SCA who want to have children while minimizing the risk of passing on the genetic condition to their offspring [101]. The objective of pre-genetic testing is to avoid transmission of genetic disorders from parents to their children [48]. IVF involves the retrieval of ovaries, fertilizing them with sperm in a laboratory and transferring the resulting embryo into the woman’s uterus. For patients with SCA, IVF provides the opportunity to screen for the presence of the disease before implantation.
It is worth noting that fertility preservation through cryopreservation may face some challenges such as immature oocytes expressing reduced maturation and increased chromosomal abnormalities which ultimately affects survival. The preservation also promotes uncontrolled follicular activation reducing long-term fertility potential [102]. Preimplantation genetic testing could be affected by technical challenges such as mosaicism, which is a condition where embryos contain multiple cell lineages. This can potentially lead to embryos with chromosomal aberrations or inappropriate discarding of viable embryos [103, 104].
The cost of a single IVF cycle in the United States can go as high as $25,000, and multiple cycles are usually required for successful pregnancy [105, 106]. This cost is mostly paid out of pocket as this cost is mostly not covered by insurance. Thus, the cost is mostly prohibitive for many families of low and middle social economic class. In developing countries where sickle cell anaemia is most prevalent, the economic barriers are more pronounced. In Sub-Saharan Africa where sickle cell affects millions, there are very few infrastructures for assistive reproductive technologies [107]. There are also only a few trained personnel and specialized laboratories, making some of these procedures seem out of reach for most individuals. The high costs therefore create disparities in access based on socioeconomic status, limiting these technologies to affluent populations [108]. Again, religious and cultural perspectives influence the willingness of individuals to accept these technologies. Successful implementation therefore requires coordinated efforts across clinical, policy, and research domains to develop more accessible, affordable, and ethically sound approaches to reproductive care for this vulnerable population.
Inarguably, SCD is associated with a huge economic impact to the individual patient, the community and national budgets. Although this narrative review did not quantify the economic cost of SCA, it is undeniable that attempts by SCA individuals to have a routine family life is challenging. Taken together with the psychological and mental health challenges associated with the disease, regions like SSA with a high SCA burden should be at the forefront in measures aimed at reducing the disease burden. Unfortunately, these at-risk nations lag in regenerative medicine disciplines like gene therapeutics, induced pluripotent stem cell research, and CRISPR-Cas targeted gene editing technologies.
There should be conscious national and sub-regional policies aimed at actively selecting against SCD since it follows a Mendelian monogenic inheritance pattern. Such proactive public health pursuit can only materialise through the establishment of population-based genetic screening at all levels of the healthcare system particularly at the primary level where technical expertise and resources are limited. Every effort ought to be made to institutionalize a functional multi-disciplinary pre-conception care team comprising geneticist, nutritionist, haematologist, mental health experts, fertility specialists and other relevant stakeholders. The crucial role of the mental health expert cannot be over emphasised given the mental and psychological strain imposed on the patient by the SCA itself as well as the anxiety associated with reproduction options. Unfortunately, expertise in these relevant specialties may not be readily available in resource-limited settings where SCA may also be prevalent. Instructively, the limited human resource expertise in remote communities should inspire the health authorities to involve opinion leaders in the communities, churches, mosques and other social/religious organisations into a community of practice that will train these stakeholders to frontier community education about SCD inheritance and prevention strategies. Although efforts have been made through assistance from donor agencies in the implementation of newborn screening programmes (NSP) for SCD, these are usually centralised in a few regional and teaching hospitals, given the unfavourable operational cost and the technical expertise required to operationalise these NSP. Thus, the need for accessible, sensitive, specific, user-friendly, and affordable point-of-care diagnostic devices that can complement the existing NSPs could go a long way in facilitating population-level screening. Recognising the essential role of POCT devices to facilitate decentralised diagnostic access, the World Health Assembly passed a resolution urging member states to take steps to strengthen diagnostic access [109]. We anticipate that in the spirit of this resolution, intra-country health ministries and sub-regional bodies will take a central role in SCD research and development and facilitate indigenous POCT devices in this prevalent but neglected disease to begin to turn the tide through informed spousal selection at the premarital stage.
Sickle cell disease (SCD) presents significant reproductive health challenges for both males and females, including impaired sperm production, priapism, ovarian damage, and pregnancy complications. Factors such as hypogonadism, iron overload, and the effects of treatments like hydroxyurea further complicate fertility in individuals with SCD. As the survival rates of SCD improves, there is a need to operationalize a multi-disciplinary team of professionals with cross-cutting expertise to raise awareness and implement effective healthcare strategies to improve reproductive health and overall quality of life for those affected.
Supplementary Material 1.