Can treatment for childhood leukemia increase the risk of infertility in pediatric patients?

Treatment for Childhood Leukemia Can Cause Infertility

Yes, treatment for childhood leukemia significantly increases the risk of infertility in both male and female patients, with the degree of risk depending on the specific chemotherapy agents used, radiation exposure, age at treatment, and cumulative doses received. 1

Primary Risk Factors for Infertility

Chemotherapy-Related Risks

Alkylating agents pose the greatest threat to fertility among chemotherapy drugs used in pediatric leukemia treatment. 1

• Cyclophosphamide at cumulative doses >7.5 g/m² carries high risk of permanent infertility in both sexes 2, 3
• The FDA label for cyclophosphamide explicitly warns that it "interferes with oogenesis and spermatogenesis" and "may cause sterility in both sexes," with sterility potentially being irreversible 3
• Etoposide, particularly at doses ≥5,000 mg/m², shows independent risk potential for infertility, especially in females 4
• Platinum-based agents (carboplatin and cisplatin) demonstrate independent risk for infertility in both sexes 4

Radiation Therapy Risks

Cranial radiotherapy used for CNS prophylaxis in acute lymphoblastic leukemia (ALL) can impair fertility through hypothalamic-pituitary dysfunction, even at the lower doses (18-24 Gy) used prophylactically. 2

• Girls treated with cranial radiotherapy around the time of menarche face particularly severe fertility deficits (relative fertility = 0.27) 5
• Boys treated before age 10 with high-dose (24 Gy) cranial radiotherapy without spinal radiation showed only 9% of control fertility rates 6
• Testicular radiation >2 Gy causes significant gonadal damage 1
• Total body irradiation (TBI) used in hematopoietic stem cell transplantation conditioning results in permanent infertility in most patients 1

Sex-Specific Mechanisms and Outcomes

Female Patients

Premature ovarian insufficiency and decreased ovarian reserve are the primary concerns, even when menstruation continues after treatment. 1

• Ovarian radiation doses as low as 5 Gy can affect ovarian function in postpubertal girls 2
• In prepubertal girls, doses ≥10 Gy are associated with impaired ovarian function, with doses ≥15 Gy conferring higher risk 2
• The sterilizing radiation dose decreases with age: 20.3 Gy in infants, 18.4 Gy at age 10, and 16.5 Gy at age 20 2
• Regular menstruation should not be assumed to equal normal fertility in female survivors 1

Male Patients

Germ cell dysfunction with resultant infertility is more common than testosterone insufficiency in males treated with alkylating agents and testicular radiation. 2

• Pelvic radiation and cumulative cyclophosphamide doses >9.5 g/m² are associated with high risk of permanent infertility 2
• Temporary azoospermia occurs in most men, with recovery of spermatogenesis in 50-80% of patients after 2-5 years following cisplatin-based therapy 2
• MOPP chemotherapy (>3 cycles) is considered a high-risk regimen for oligospermia and azoospermia 2

Critical Clinical Recommendations

Timing of Fertility Counseling

The NCCN and ASCO guidelines mandate that fertility counseling occur at diagnosis, before initiating any chemotherapy. 2, 1

• Despite guidelines, fertility risk is discussed only 26-83% of the time in practice 2
• Parents of prepubertal children require guidance on making fertility preservation decisions on behalf of minors 1
• Many survivors retrospectively report wishing they had received more information about fertility preservation options 1

Fertility Preservation Options

For post-pubertal males, sperm cryopreservation is standard practice and should be offered before treatment initiation. 1

• Collection can occur every 24 hours as needed 1
• Among 146 adolescent boys at risk, only 53.4% attempted sperm banking, with 43.8% successfully banking 2
• Parent or medical team recommendation significantly increases likelihood of completion 2

For females, established options include oocyte and embryo cryopreservation, while ovarian tissue cryopreservation should be considered for prepubertal girls at high risk. 1

• Oophoropexy (surgical displacement of ovaries out of radiation field) can minimize ovarian damage 2
• Embryo cryopreservation after IVF is highly successful in women <40 years but requires a male partner or sperm donor 2

Long-Term Surveillance Requirements

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 1, 7
• The COG Long-Term Follow-Up Guidelines recommend regular screening of at-risk patients to identify gonadotropin deficiency, delayed or arrested puberty, or premature ovarian failure 2
• In prepubertal survivors, onset and tempo of puberty, menstrual history, and Tanner stage should be evaluated annually until sexual maturity 2
• Baseline LH, FSH, and estradiol levels should be assessed at age 13 years 2

Common Clinical Pitfalls

Treatment during or post-puberty compared to treatment before puberty shows a trend toward increased infertility, particularly in male survivors. 4

• Age at treatment significantly influences fertility outcomes, with development of sterility depending on the state of gonadal function at time of treatment 3
• Fertility preservation discussions are often inadequately documented or omitted entirely 2
• Psychosocial providers should assist patients and families in decision-making about fertility preservation, particularly when distressed about potential infertility 2