Can leukemia in children increase the risk of infertility?

Leukemia Treatment—Not the Disease Itself—Poses the Primary Infertility Risk in Children

Leukemia itself rarely causes infertility in children, but the chemotherapy, radiation therapy, and hematopoietic stem cell transplantation (HCT) used to treat it place pediatric and adolescent patients at significantly increased risk for future infertility. 1

Understanding the Source of Infertility Risk

Treatment-Related Gonadotoxicity

• Cytotoxic chemotherapy, radiation therapy, and HCT are the primary culprits causing gonadal damage and subsequent infertility in pediatric leukemia patients 1
• The risk varies based on specific treatment regimens, cumulative doses, radiation fields, patient age at treatment, and sex 1, 2
• Alkylating agents (particularly cyclophosphamide) pose the greatest risk among chemotherapy drugs 1

Direct Disease Involvement (Rare)

• Testicular involvement occurs in only 1-2% of males with acute lymphoblastic leukemia (ALL), with slightly higher rates in T-ALL compared to B-ALL 1
• This direct gonadal involvement by leukemia is uncommon and not the primary fertility concern 1

Sex-Specific Risks and Mechanisms

Males

• Azoospermia (absence of sperm) is the primary concern, resulting from damage or depletion of germinal stem cells 1
• Moderate-to-high dose alkylating agents (cyclophosphamide >7.5 g/m², busulfan >600 mg/m², ifosfamide >60 mg/m²) carry high risk 1
• Testicular radiation >2 Gy causes significant gonadal damage 1
• Total body irradiation (TBI) used in HCT conditioning results in permanent infertility in most adolescent and young adult males 1

Females

• Premature ovarian insufficiency and decreased ovarian reserve are the main concerns, even when menstruation continues 1, 2
• Regular menstruation does not guarantee normal fertility, as ovarian reserve may be depleted 1
• Cranial radiotherapy (CRT) administered around the time of menarche shows particularly strong association with fertility deficits (relative fertility 0.27,95% CI 0.09-0.82) 3
• Pelvic radiotherapy dramatically increases infertility risk (adjusted OR 20.24,95% CI 4.69-87.29 in women) 4
• High-risk treatments (≥80% amenorrhea risk) include HCT with cyclophosphamide/TBI and external beam radiation to ovaries 1

Age-Dependent Vulnerability

• Treatment during or after puberty carries higher infertility risk compared to prepubertal treatment, particularly in males 4
• Girls treated with CRT around menarche face especially elevated risk 3
• Prepubertal patients have different pharmacokinetic profiles and organ immaturity affecting treatment toxicity 1

Critical Clinical Recommendations

Mandatory Fertility Counseling

• Fertility counseling is recommended for ALL pediatric and adolescent leukemia patients before starting treatment 1
• This discussion must occur at diagnosis, before initiating chemotherapy 1
• Parents of prepubertal children require guidance on making fertility preservation decisions on behalf of minors 1

Fertility Preservation Options

For Males:

• Sperm cryopreservation is standard practice for post-pubertal males and should be offered before treatment initiation 1, 5
• Collection can occur every 24 hours as needed 1
• For prepubertal boys, testicular tissue cryopreservation remains experimental with no established techniques in current practice 5

For Females:

• Established options include oocyte cryopreservation, embryo cryopreservation (requires 2-4 weeks) 1
• Ovarian tissue cryopreservation should be considered for prepubertal girls at high risk of premature menopause 1, 5
• Important caveat: Ovarian tissue cryopreservation in leukemia patients carries theoretical risk of reintroducing malignant cells upon transplantation, requiring careful consideration 2

Timing Considerations

• Time is critical—fertility preservation must be completed before starting chemotherapy or radiation 1
• Referral to fertility preservation/reproductive health programs should occur immediately upon diagnosis for eligible patients 1
• The urgent need to start leukemia treatment often conflicts with fertility preservation timelines, particularly for females requiring 2-4 weeks for established techniques 1, 2

Long-Term Surveillance

• Up to one-third of childhood cancer survivors who undergo fertility testing show evidence of suspected infertility 6
• Among leukemia survivors specifically, 26-31% who underwent fertility testing had suspected infertility 6
• Survivors require ongoing monitoring for premature ovarian failure, which may manifest years after treatment completion 1
• Female survivors with compromised fertility face additional health risks including osteoporosis and cardiovascular disease, requiring active management 3

Common Pitfalls to Avoid

• Do not assume regular menstruation equals normal fertility in female survivors—ovarian reserve may be significantly depleted despite cyclic menses 1
• Do not delay fertility counseling—many survivors report wishing they had received more information and options about fertility preservation 1
• Do not overlook prepubertal patients—while options are limited, families still require counseling about future fertility risks 1, 5
• Do not forget psychosocial support—fertility concerns significantly impact quality of life and require dedicated psychosocial assessment 1