Role of genetic analysis of products of conception and PGT in managing early pregnancy loss.

This article considers the addition of comprehensive 24-chromosomal microarray (CMA) analysis of products of conception (POC) to a standard evaluation for recurrent pregnancy loss (RPL) to help direct treatment towards expectant management versus IVF with preimplantation genetic testing for aneuploidies (PGT-A). The review included retrospective data from 65,333 miscarriages, a prospective evaluation of 378 couples with RPL who had CMA testing of POC and the standard workup, and data from an additional 1020 couples who were evaluated for RPL but did not undergo CMA testing of POC. Aneuploidy in POC explained the pregnancy loss in 57.7% (218/378) of cases. In contrast, the full RPL evaluation recommended by the American Society for Reproductive Medicine identified a potential cause in only 42.9% (600/1398). Combining the data from the RPL evaluation and the results of genetic testing of POC provides a probable explanation for the loss in over 90% (347/378) of women. Couples with an unexplained loss after the standard evaluation with POC aneuploidy accounted for 41% of cases; PGT-A may be considered after expectant management. Conversely, PGT-A would have a limited role in those with a euploid loss and a possible explanation after the standard workup. Categorizing a pregnancy loss as an explained versus unexplained loss after the standard evaluation combined with the results of CMA testing of POC may help identify patients who would benefit from expectant management versus PGT-A.

Expanding the role of chromosomal microarray analysis in the evaluation of recurrent pregnancy loss.

Multiple factors contribute to recurrent pregnancy loss (RPL). This review highlights the latest international guidelines for RPL workup, including immunological testing, by the American Society for Reproductive Medicine (ASRM), the European Society of Human Reproduction and Embryology (ESHRE), and the Royal College of Obstetricians and Gynaecologists (RCOG). These three societies recommend testing for antiphospholipid syndrome. ESHRE and RCOG also recommend thyroid peroxidase antibody testing, whereas ASRM does not. All guidelines advise against testing of natural killer cells, cytokines, antinuclear antibodies, human leukocyte antigen (HLA) compatibility, anti-HLA antibodies, and anti-sperm antibodies. However, when following ASRM, ESHRE or RCOG diagnostic guidelines, over 50% of cases have no identifiable cause. Genetic testing of products of conception (POC) can improve our understanding of unexplained RPL as aneuploidy is a common cause of RPL. Based on studies reporting results from chromosomal microarray analysis (CMA) of POC, we propose a novel algorithm for RPL evaluation. The algorithm involves following evidence-based societal guidelines (published by ASRM, ESHRE, or RCOG), excluding parental karyotyping, in combination with CMA testing of miscarriage tissue. When utilizing this new evaluation algorithm, the number of unexplained cases of RPL decreases from over 50% to less than 10%. As a result, most patients are provided an explanation for their loss and healthcare costs are potentially reduced. Patients with an otherwise negative workup with euploid POC, are classified as "truly unexplained RPL". These patients are excellent candidates for enrollment in randomized, controlled trials examining novel immunological testing and treatment protocols.

Update on preimplantation genetic testing for aneuploidy and outcomes of embryos with mosaic results.

Preimplantation genetic testing for aneuploidy (PGT-A) is used as a frequent add-on for in-vitro fertilization (IVF) to improve clinical outcomes. The purpose is to select a euploid embryo following chromosomal testing on embryo biopsies. The current practice includes comprehensive chromosome screening (CCS) technology applied on trophectoderm (TE) biopsies. Despite its widespread use, PGT-A remains a controversial topic mainly because all of the RCTs comprised only good prognosis patients with 2 or more blastocysts available; hence the results are not generalizable to all groups of patients. Furthermore, with the introduction of the highly-sensitive platforms into clinical practice (i.e. next-generation sequencing [NGS]), a result consistent with intermediate copy number surfaced and is termed "Mosaic," consistent with a mixture of euploid and aneuploid cells within the biopsy sample. The optimal disposition and management of embryos with mosaic results is still an open question, as many 'mosaics' generated healthy live births with no identifiable congenital anomalies. The present article provides a complete and comprehensive up-to-date review on PGT-A. It discusses in detail the findings of all the published RCTs on PGT-A with CCS, comments on the subject of "mosaicism" and its current management, and describes the latest technique of non-invasive PGT-A.

Perception of pain and the oocyte donor experience: a retrospective analysis of commercial US donors.

RESEARCH QUESTION: What is the relationship between oocyte donor characteristics and their pain perception, their expectation and experience of pain, and the interaction between pain and overall satisfaction with the donation process? DESIGN: Institutional Review Board approved, retrospective survey of commercial, US oocyte donors was emailed to recent donors recruited through Donor Egg Bank USA before 2020. RESULTS: Of the 503 opened emails, 246 individuals responded (48.9%). Most donors ranked their pain between minimal and moderate at all time points analysed. Altruistically motivated donors and parous donors were less likely to experience unexpected levels of pain. A high proportion (93.9%) of donors reported being informed of the risk of pain. Those who recalled being informed of the risk of pain were less likely to report higher levels of pain than expected. Although 94.2% of donors reported having an average to positive experience overall, 92.3% (12 out of 13 donors) in the group reporting a negative overall experience said they felt more pain than expected. CONCLUSIONS: Donors were well informed about the risk of pain. Altruistically motivated donors and parous donors were less likely to experience unexpected levels of pain. Report of unexpected levels of pain was highly related to low donor satisfaction.

Genetic Testing for Aneuploidy in Patients Who Have Had Multiple Miscarriages: A Review of Current Literature.

Recurrent pregnancy loss (RPL) is an obstetrical complication that affects about 3% of reproductive age couples. Genetic and non-genetic causes of RPL are multiple; however, aneuploidy is the most common obstetrical complication that can explain single and recurrent pregnancy loss (present in about 60% of recognized clinical pregnancies which result in a miscarriage). Parental karyotyping will only be of potential benefit for 2 to 5 percentage of RPL couples who are translocation carriers. Products of conception (POC) karyotype analysis has been used to direct management in RPL and has been shown to be cost-effective, but the technique has many limitations including high culture failure rate and maternal cell contamination. These limitations can be significantly reduced using POC chromosomal microarray (CMA) technology. We believe that POC genetic testing should be performed after the second and subsequent pregnancy loss using CMA. Although the results will not generally alter the course of treatment, the knowledge of the reason for the loss is of great emotional comfort to many patients. In addition, POC CMA performed in conjunction with a regular complete maternal RPL work-up will identify the group of truly unexplained RPL. Thus, only 10% of patients with RPL will complete an evaluation having a euploid loss and an otherwise normal work-up. This group of "truly unexplained RPL" would be ideal for new research trials and therapies. Pre-implantation genetic testing (PGT) technology has improved recently with day 5 trophectoderm biopsy as compared to biopsy on day 3 as well as with the addition of CMA and next-generation sequencing technologies. The most recent studies on PGT-SR (PGT-Structural rearrangement) show improved clinical and live birth rates per pregnancy, as well as decreased miscarriage rate for translocation carriers. PGT-A (PGT-aneuploidy) may have a limited role in RPL in cases with documented recurrent POC aneuploidy.

Genetic testing of products of conception in recurrent pregnancy loss evaluation.

Genetic testing of products of conception (POC) has been proposed as a tool to be used in the evaluation of patients with recurrent pregnancy loss (RPL). Following a complete RPL evaluation, POC results may reveal an aneuploidy and provide an explanation for the miscarriage in more than 55% of cases. When the cytogenetic result of the pregnancy loss reveals a euploid pregnancy, management should be directed towards the identification of treatable abnormalities. Furthermore, the results of POC testing might better define a subgroup of patients with unexplained RPL who may benefit from expectant management versus preimplantation genetics (aneuploid unexplained RPL) or investigational therapy (euploid unexplained RPL).

A View from the past into our collective future: the oncofertility consortium vision statement.

PURPOSE: Today, male and female adult and pediatric cancer patients, individuals transitioning between gender identities, and other individuals facing health extending but fertility limiting treatments can look forward to a fertile future. This is, in part, due to the work of members associated with the Oncofertility Consortium. METHODS: The Oncofertility Consortium is an international, interdisciplinary initiative originally designed to explore the urgent unmet need associated with the reproductive future of cancer survivors. As the strategies for fertility management were invented, developed or applied, the individuals for who the program offered hope, similarly expanded. As a community of practice, Consortium participants share information in an open and rapid manner to addresses the complex health care and quality-of-life issues of cancer, transgender and other patients. To ensure that the organization remains contemporary to the needs of the community, the field designed a fully inclusive mechanism for strategic planning and here present the findings of this process. RESULTS: This interprofessional network of medical specialists, scientists, and scholars in the law, medical ethics, religious studies and other disciplines associated with human interventions, explore the relationships between health, disease, survivorship, treatment, gender and reproductive longevity. CONCLUSION: The goals are to continually integrate the best science in the service of the needs of patients and build a community of care that is ready for the challenges of the field in the future.

Recurrent pregnancy loss.

Recurrent pregnancy loss is a distressing pregnancy disorder experienced by ~2.5% of women trying to conceive. Recurrent pregnancy loss is defined as the failure of two or more clinically recognized pregnancies before 20-24 weeks of gestation and includes embryonic and fetal losses. The diagnosis of an early pregnancy loss is relatively straightforward, although progress in predicting and preventing recurrent pregnancy loss has been hampered by a lack of standardized definitions, the uncertainties surrounding the pathogenesis and the highly variable clinical presentation. The prognosis for couples with recurrent pregnancy loss is generally good, although the likelihood of a successful pregnancy depends on maternal age and the number of previous losses. Recurrent pregnancy loss can be caused by chromosomal errors, anatomical uterine defects, autoimmune disorders and endometrial dysfunction. Available treatments target the putative risk factors of pregnancy loss, although the effectiveness of many medical interventions is controversial. Regardless of the underlying aetiology, couples require accurate information on their chances of having a baby and appropriate support should be offered to reduce the psychological burden associated with multiple miscarriages. Future research must investigate the pathogenesis of recurrent pregnancy loss and evaluate novel diagnostic tests and treatments in adequately powered clinical trials.

A new algorithm for the evaluation of recurrent pregnancy loss redefining unexplained miscarriage: review of current guidelines.

PURPOSE OF REVIEW: Couples with recurrent pregnancy loss (RPL) are often referred to reproductive specialists to help determine the reason for their repeated losses. This review will help to develop a strategy that is effective in providing a diagnosis, efficient to administer, and cost-effective to the healthcare system. RECENT FINDINGS: International societies have published different recommendations for the evaluation of RPL, they consider it appropriate to initiate an evaluation after two (or three) clinical miscarriages. On the contrary, the clinician who follows these guidelines will only be able to offer a possible explanation to fewer than half of the couples being evaluated. Recently, genetic testing of miscarriage tissue using 24-chromosome microarray (CMA) analysis at the time of the second pregnancy loss coupled with testing based on society guidelines has been shown provide an explanation in more than 90% of cases. SUMMARY: New guidelines for the complete evaluation of RPL should consider adding 24-CMA testing on the miscarriage tissue. Providing couples with an explanation for recurrent loss assists them in dealing with the loss and discourages the clinician from instituting unproven therapies. Truly unexplained pregnancy loss can be reduced to less than 10% with this new algorithm. Incorporation of these strategies will result in significant cost savings to the healthcare system.

Fertility-related services in pediatric oncology across the cancer continuum: a clinic overview.

PURPOSE: Fertility-related services in pediatric oncology are increasing, but barriers to care remain and few structured programs are described in the literature. Therefore, the study objectives were (1) to characterize fertility-related services in a large pediatric oncology center and (2) to discuss recommendations for fertility-related services across the pediatric cancer continuum. METHODS: Medical records of all cases referred to our Fertility Preservation Clinic within a 3-year period were reviewed, which included 292 patients/survivors with malignant disease. Approximately half (n = 152/292, 52.1%) were cancer patients referred prior to treatment (n = 92/152) or while on active therapy (n = 60/152). The other half (n = 140/292; 47.9%) were survivors who had completed treatment. RESULTS: Referrals more than doubled over 3 years. Most patients referred before treatment were offered and opted for FP (72.8% attempted; 58.9% completed). More male than female patients opted for FP (77.6% vs. 22.4%), but completion rates were higher among females (93.3% vs. 76.9%). Rates of FP before treatment did not increase over time (p = .752). Many patients on-treatment were referred for infertility risk counseling, demonstrating information/support needs in this group. Referred survivors questioned their fertility post-treatment and completed fertility assessments, indicating intact fertility among few (~ 15%). CONCLUSIONS: This review demonstrated the acceptance and increasing need for fertility-related services in pediatric oncology across the cancer continuum, including FP before treatment, counseling during treatment, and fertility assessment in survivorship. Based on our experiences, current recommendations are discussed and include standardized procedures, streamlined referrals, adequate communication/education (of providers and families), and meeting specific needs of young cancer patients/survivors.

Single-nucleotide polymorphism microarray detects molar pregnancies in 3% of miscarriages.

OBJECTIVE: To determine the frequency of molar pregnancy in miscarriage cases based on single-nucleotide polymorphism (SNP) microarray testing on products of conception (POC) tissue and to estimate the sensitivity of ultrasound and histopathologic evaluation for cases identified to be at risk for gestational trophoblastic disease. DESIGN: Retrospective cohort analysis. SETTING: Reference laboratory. PATIENT(S): POC specimens from 26,101 consecutive miscarriages. INTERVENTION(S): POC samples were sent to a single laboratory for analysis. Maternal age, gestational age, egg donor use, indication for testing, and additional clinical information were obtained from the requisition form and a survey sent to ordering providers. MAIN OUTCOME MEASURE(S): Rates of full paternal uniparental disomy (UPD), indicative of complete molar pregnancy, and triploidy of paternal origin, indicative of partial molar pregnancy, in POC samples. RESULT(S): Paternal triploidy was detected in 638 cases (2.8%) and full paternal UPD in 72 cases (0.3%). Of the cases with complete clinical information (224/710; 31.5%), histopathology and/or ultrasound did not detect 71% of partial molar pregnancies and 30% of complete molar pregnancies. CONCLUSION(S): Molar pregnancy, detected in 3.1% of all miscarriages in this study with the use of 24-chromosome SNP microarray testing, occurred significantly more frequently than previously estimated with the use of ultrasound and/or histopathology.

Parental Attitudes Toward Fertility Preservation in Female Adolescent Cancer Patients in Lebanon.

STUDY OBJECTIVE: To measure parental attitudes toward fertility preservation (FP) in female adolescent cancer patients in a Middle Eastern country to understand barriers to decision-making and decisional conflicts. DESIGN AND SETTING: A questionnaire was distributed to parents of all female adolescents at a tertiary care center from February 2018 to September 2018. PARTICIPANTS: A total of 70 families. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Parental attitudes toward FP. RESULTS: The educational level of parents was associated with the knowledge about the side effects of treatment (P < .001). FP options were not offered to parents in 60/70 (85.6%) of cases. Oocyte cryopreservation was an acceptable option for 23/70 (32.9%) of interviewed parents who agreed on collecting the oocytes using vaginal ultrasound. The fear of disrupting the hymen was the main reason for disapproval in 20/70 (28.6%) of cases. The religious preference of the family was a significant factor in the acceptance of vaginal ultrasound and vaginal oocyte retrieval. The educational level of parents, the monthly income, and the current employment status were not linearly associated with their acceptance to approve their daughters' undergoing oocyte cryopreservation through the vaginal route (χ2 = 100.651; P < .001). CONCLUSION: Parents are not aware of the effect of cancer treatment on future fertility of their daughters. Ethical, social, and religious barriers affect the decision-making for FP. However, a major interest exists among parents for FP, highlighting the importance of development of an oncofertility program, involving a multidisciplinary team to initiate proper counseling and guidance.

Comparison of celiac disease markers in women with early recurrent pregnancy loss and normal controls.

PROBLEM: Celiac disease (CD) is an autoimmune intestinal inflammatory disease triggered by gluten in the diet. Untreated CD has been associated with pregnancy loss and infertility. The purpose of this study was to screen unselected women with recurrent pregnancy loss (RPL) for markers of CD to determine whether a correlation exists between RPL and CD serum markers. METHOD OF STUDY: Frequencies of three serum markers of CD [tissue transglutaminase (TTG) IgA, endomysial (EMA) IgA, and deaminated gliadin peptide (DGP) IgA] were determined by enzyme-linked immunoassay (ELISA). Seven hundred and eight women who had two or more failed clinical pregnancies (cases) and one hundred women with at least one live birth and no miscarriages (controls) were included in this study. All cases had a full workup for RPL based on the American Society for Reproductive Medicine 2013 guidelines. Antiphospholipid antibodies (aPL) were correlated with CD markers based on their potential prothrombotic role. Results The results show no significant difference in the prevalence of CD autoantibodies when comparing the RPL patients with the controls. Over half of the patients who tested positive for serum markers for CD also had positive aPL. Conclusion Screening unselected women with RPL who are asymptomatic for CD is not supported based on these data. Women who test positive for CD may be candidates for aPL testing based on the association of adverse pregnancy outcomes.

Gonadal Functioning and Perceptions of Infertility Risk Among Adult Survivors of Childhood Cancer: A Report From the St Jude Lifetime Cohort Study.

PURPOSE: To describe perceptions of infertility risk among adult survivors of childhood cancer, to test the concordance of survivors' risk perceptions and their adult fertility status, and to identify explanatory factors (sociodemographic factors, gonadotoxic treatments, reproductive history, sexual dysfunction) associated with these outcomes. PATIENTS AND METHODS: Adult childhood cancer survivors (N = 1,067; without children or a history of pregnancies) completed questionnaires that asked about infertility risk perceptions and participated in physical evaluations, including biomarkers of gonadal functioning (eg, semen analysis, blood hormone levels, menses). Multivariable regression models tested associations between explanatory factors and risk perceptions as well as concordance of perceptions and fertility status. RESULTS: Most childhood cancer survivors (61.9%) perceived themselves at increased risk for infertility, which was significantly associated with sociodemographic factors (older age, white ethnicity, being married/partnered, higher education), gonadotoxic treatments, fertility concerns, previous unsuccessful attempts to conceive, and sexual dysfunction (all P < .05). Laboratory-evaluated impaired gonadal function was found in 24.3% of female and 55.6% of male survivors, but concordance with survivors' risk perceptions was low (Cohen's κ < .19). Most survivors with discordant perceptions overestimated risk (ie, perceived being at risk, though fertility status seemed normal; 19.7% of male and 43.6% of female survivors), whereas a minority underestimated risk (ie, perceived no risk but were impaired/infertile; 16.3% of male and 5.3% of female survivors). Factors related to discordance included sociodemographics, gonadotoxic treatments, fertility concerns, and sexual dysfunction (all P < .05). CONCLUSION: Although childfree survivors may correctly consider themselves at risk for infertility on the basis of their previous treatments, such risk perceptions were discordant from laboratory-evaluated fertility status among many survivors in adulthood. Thus, repeated fertility-related communication throughout survivorship is essential, because treatment-indicated risk does not equal fertility status after treatment. Offering fertility testing to those who were at risk and/or those with fertility-related concerns is recommended.

Review of current guidelines for recurrent pregnancy loss: new strategies for optimal evaluation of women who may be superfertile.

The current evidence-based guidelines for the evaluation of recurrent pregnancy loss recommended by the American Society for Reproductive Medicine and by the European Society of Human Reproduction and Embryology are compared and contrasted in this review. The clinical use of either of these guidelines will result in a probable diagnosis for only half of the affected patients. New strategies for a full evaluation of recurrent pregnancy loss incorporating 24- chromosome microarary on the products of conception offer more explanations for patients and caregivers. This new algorithm should decrease the use of empiric, unproven treatments. Combining the results of genetic testing on the miscarriage tissue with the conventional diagnostic tests has made it possible to explain the etiology of pregnancy loss in more than 90% of the cases. This cost-saving strategy can decrease the emotional distress and frustration for both couples and physicians when it comes to management of recurrent pregnancy loss.

The National Physicians Cooperative: transforming fertility management in the cancer setting and beyond.

Once unimaginable, fertility management is now a nationally established part of cancer care in institutions, from academic centers to community hospitals to private practices. Over the last two decades, advances in medicine and reproductive science have made it possible for men, women and children to be connected with an oncofertility specialist or offered fertility preservation soon after a cancer diagnosis. The Oncofertility Consortium's National Physicians Cooperative is a large-scale effort to engage physicians across disciplines - oncology, urology, obstetrics and gynecology, reproductive endocrinology, and behavioral health - in clinical and research activities to enable significant progress in providing fertility preservation options to children and adults. Here, we review the structure and function of the National Physicians Cooperative and identify next steps.

Prevalence and Predictors of Sperm Banking in Adolescents Newly Diagnosed With Cancer: Examination of Adolescent, Parent, and Provider Factors Influencing Fertility Preservation Outcomes.

Purpose To estimate the prevalence of sperm banking among adolescent males newly diagnosed with cancer and to identify factors associated with banking outcomes. Patients and Methods A prospective, single-group, observational study design was used to test the contribution of sociodemographic, medical, psychological/health belief, communication, and developmental factors to fertility preservation outcomes. At-risk adolescent males (N = 146; age 13.00 to 21.99 years; Tanner stage ≥ 3), their parents, and medical providers from eight leading pediatric oncology centers across the United States and Canada completed self-report questionnaires within 1 week of treatment initiation. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% CIs for specified banking outcomes (collection attempt v no attempt and successful completion of banking v no banking). Results Among adolescents (mean age, 16.49 years; standard deviation, 2.02 years), 53.4% (78 of 146) made a collection attempt, with 43.8% (64 of 146) successfully banking sperm (82.1% of attempters). The overall attempt model revealed adolescent consultation with a fertility specialist (OR, 29.96; 95% CI, 2.48 to 361.41; P = .007), parent recommendation to bank (OR, 12.30; 95% CI, 2.01 to 75.94; P = .007), and higher Tanner stage (OR, 5.42; 95% CI, 1.75 to 16.78; P = .003) were associated with an increased likelihood of a collection attempt. Adolescent history of masturbation (OR, 5.99; 95% CI, 1.25 to 28.50; P = .025), banking self-efficacy (OR, 1.23; 95% CI, 1.05 to 1.45; P = .012), and parent (OR, 4.62; 95% CI, 1.46 to 14.73; P = .010) or medical team (OR, 4.26; 95% CI, 1.45 to 12.43; P = .008) recommendation to bank were associated with increased likelihood of sperm banking completion. Conclusion Although findings suggest that banking is underutilized, modifiable adolescent, parent, and provider factors associated with banking outcomes were identified and should be targeted in future intervention efforts.

Effect of cranial irradiation on sperm concentration of adult survivors of childhood acute lymphoblastic leukemia: a report from the St. Jude Lifetime Cohort Study†.

STUDY QUESTION: Does lower dose (<26 Gy) cranial radiation therapy (CRT) used for central nervous system prophylaxis in acute lymphoblastic leukemia (ALL) adversely affect sperm concentration or morphology? SUMMARY ANSWER: CRT doses <26 Gy had no demonstrable adverse effect on sperm concentration or morphology. WHAT IS KNOWN ALREADY: Treatment with alkylating agents produces oligospermia and azoospermia in some patients. No prior study has been large enough to evaluate the independent effects of alkylating agents and lower dose (<26 Gy) CRT on sperm concentration or morphology. STUDY DESIGN, SIZE, DURATION: This cross-sectional study included male adult survivors of pediatric ALL who had received alkylating agent chemotherapy with or without CRT and who enrolled in the St. Jude Lifetime Cohort Study (SJLIFE) from September 2007 to October 2013. PARTICIPANTS/MATERIALS, SETTING, METHODS: The inclusion criteria were males, ≥18 years of age, ≥10 years after diagnosis, treated at St. Jude Children's Research Hospital for ALL, and received alkylating agent chemotherapy. Semen analyses were performed on 173 of the 241 (78.1%) adult survivors of pediatric ALL who had received alkylating agent chemotherapy with or without CRT. Cumulative alkylating agent treatment was quantified using the cyclophosphamide equivalent dose (CED). Log-binomial multivariable models were used to calculate relative risks (RRs) and 95% CI. MAIN RESULTS AND THE ROLE OF CHANCE: Compared to those without CRT, risk of oligospermia or azoospermia was not increased for CRT <20 Gy (P = 0.95) or 20-26 Gy (P = 0.58). Participants 5-9 years of age at diagnosis compared to those 0-4 years of age (RR = 1.30, 95% CI, 1.05-.61) or those treated with 8-12 g/m2 CED (RR = 2.06, 95% CI, 1.08-3.94) or ≥12 g/m2 CED (RR = 2.12, 95% CI, 1.09-4.12) compared to those treated with >0 to <4 g/m2 CED had an increased risk for oligospermia or azoospermia. LIMITATIONS, REASONS FOR CAUTION: Our study relied on the results of one semen analysis. ALL survivors who did not participate in SJLIFE or who declined to submit a semen analysis may also have biased our results regarding the proportion with azoospermia or oligospermia, since those who provided a semen specimen were less likely to have previously fathered children compared to those who did not. The lower rate of previous parenthood among participants may have resulted in a higher observed frequency of azoospermia and oligospermia. WIDER IMPLICATIONS OF THE FINDINGS: Treatment with <26 Gy CRT did not increase the risk of oligospermia or azoospermia, although a CED exceeding 8 g/m2 and an age at diagnosis of 5-9 years did increase risk of oligospermia and azoospermia. These findings can be used to counsel adult survivors of pediatric ALL. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Institutes of Health (grant numbers CA 21765, CA 195547, CA00874) and the American Lebanese Syrian Associated Charities (ALSAC). The authors have no competing interests to declare.