Ovarian reserve, Reproductive function and Pregnancy outcomes among Female survivors of childhood Hodgkin lymphoma: results from the DCOG LATER-VEVO Later study

Abstract Study question What is the impact of treatment for Hodgkin lymphoma (HL) on clinical reproductive markers and pregnancy outcomes? Summary answer Impaired markers of ovarian reserve in childhood HL survivors substantiate risk of a reduced fertile life span. Pregnancy outcomes seem reassuring at a young age. What is known already Childhood Hodgkin Lymphoma (HL) is nowadays highly curable with survival rates over 90%. Chemotherapy and radiation are associated with late adverse effects including risk of reduced ovarian function and -reserve. Study design, size, duration This study was embedded within the DCOG LATER-VEVO study, a nationwide, multicenter, retrospective cohort study performed between 2004 and 2014, in which the reproductive ability of 1106 female childhood cancer survivors was studied and compared to 798 controls (siblings and females from the general population). Participants/materials, setting, methods The current analysis included all female childhood HL survivors, treated between 1963 and 2002, and controls who provided written informed consent to participate in the LATER-VEVO study. Data collection consisted of a questionnaire and timed clinical measurements (blood sample and transvaginal ultrasound). Serum anti-Mullerian hormone (AMH), FSH, inhibin B, the antral follicle count (AFC) and self-reported (first) pregnancy rates and -outcomes were evaluated in linear and logistic regression models . Main results and the role of chance 84 HL survivors and 798 controls were included, aged 29.6 (IQR 19.8-36.6) and 32.7 (IQR 19.7-49.6) years old at time of assessment. Median age at HL diagnosis was 13.4 years (IQR 6.4-16.4), with median time since diagnosis of 16.5 (IQR 8.4;36.6) years. Cyclophosphamide equivalent dose (CED-score) exceeded 6000mg/m2 in 56 women and 14 survivors received pelvic irradiation. All clinical markers were significantly deteriorated in survivors (odds-ratio for low AMH (<p10) 10.1 [95%CI 4.9;20.6]; low AFC (<p10) 4.6 [95%CI 2.1;9.9]; elevated FSH (>10IU/l) 15.3 [95%CI 5.7;41.1], low Inhibin B (<20ng/l) 3.6 [ 95%CI 1.7;7.7], all p < 0.001, 45 survivors and 413 controls). Pregnancy and live birth rates were comparable between survivors and controls (±80% live birth, ±20% miscarriage). However survivors were significantly younger of age at first pregnancy (27.0 years vs 29.0 yrs, P = 0.04, 42 survivors and 389 controls). Time to first pregnancy seemed to be increased in survivors (adjusted odds-ratio for time to pregnancy >12 months was 2.5 [95% CI 1.1;5.6] in survivors, p = 0.031). No significant differences in birth weight or gestational age were observed. Gonadotoxicity was specifically present after treatment with procarbazine and higher CED-score. No clear effect of age at diagnosis was observed. Limitations, reasons for caution The studied cohort comprised a relatively young population. Risk of premature ovarian insufficiency could not be assessed and a considerable number of women indicated they considered themselves too young to aim to achieve pregnancy. Heterogeneity in received treatment and sample size issues complicated the extent of the analyses. Wider implications of the findings HL survivors appear to have an impaired ovarian reserve, however chance to achieve pregnancy seems reassuring at a young age. Additional studies are needed to assess fertile life span and reproductive potential of HL survivors, in particular for current HL treatments that are hypothesized to be less gonadotoxic. Trial registration number NTR2922