Reproductive Function and Outcomes in Female Survivors of Childhood, Adolescent, and Young Adult Cancer: A Review

Abstract

Some survivors of childhood, adolescent, and young adult cancer are at increased risk of gonadal dysfunction and adverse pregnancy outcomes. We reviewed currently available literature that evaluated reproductive function and pregnancy outcomes of female cancer survivors diagnosed before the age of 25 years. High-dose alkylating agent chemotherapy and abdominal/pelvic radiotherapy adversely affect gonadal function in a dose-related fashion, with older age at exposure conferring greater risk as a result of the age-related decline in ovarian reserve. Gonadal injury clinically manifests as ovarian hormone insufficiency (delayed or arrested puberty, premature ovarian insufficiency, or premature menopause) and infertility. The effect of molecular-targeted agents on ovarian function has not been established. For female cancer survivors who maintain fertility, overall pregnancy (relative risk, 0.67 to 0.81) and live birth rates (hazard ratio, 0.79 to 0.82) are lower than those in the general public. Pregnancy in cancer survivors also may be associated with risks to both the mother and the fetus related to miscarriage; preterm birth; and, rarely, cardiomyopathy. Women at risk for these complications require preconception assessment and counseling from both obstetricians and oncology providers. The risk for inherited genetic disease in offspring conceived after cancer treatment exposure is not increased. The optimization of reproductive outcomes and minimization of risks of pregnancy complications in survivors requires informed, risk-based assessment and monitoring.

Fig 1.

Harmonized recommendations for premature ovarian insufficiency (POI) surveillance in survivors of childhood, adolescent, and young adult cancer. POI is a clinical condition that develops in any adult female before age 40 years that is characterized by the absence of menses for > 4 months and two elevated serum follicle-stimulating hormone (FSH) levels in the menopausal range (on the basis of the maximum threshold of the laboratory assay used). (*) Treatments with evidence of causing POI include alkylating agents in general (level A evidence), cyclophosphamide, procarbazine (level C evidence), and radiotherapy to a field that includes the ovaries (level A evidence). (†) At least annually, with increasing frequency as clinically indicated on the basis of growth and pubertal progression. (‡) At least for girls of ≥ 11 years of age and for girls with primary amenorrhea (age 16 years). (§) If amenorrhea, measured FSH and estradiol randomly; if oligomenorrhea, measured during early follicular phase (days 2 to 5). (ǁ) This assessment should be performed after ending oral contraceptive pill/sex steroid replacement therapy use, ideally after 2 months without oral contraceptive pills. (¶) The absence of initiation of puberty (Tanner stage 2 breast development) in girls ≥ 13 years of age or failure to progress in pubertal stage for ≥ 12 months. AMH, anti-Müllerian hormone; level A, high level of evidence; level B, moderate/low level of evidence; level C, very low level of evidence. Reprinted with permission.

Fig 2.

Assessment of the postpubertal survivor. AFC, antral follicle count; AMH, anti-Müllerian hormone; POI, premature ovarian insufficiency.