Family size and duration of fertility in female cancer survivors: a population-based analysis.

OBJECTIVE: To assess family size and timescale for achieving pregnancy in women who remain fertile after cancer. DESIGN: Population-based analysis. SETTING: National databases. PATIENT(S): All women diagnosed with cancer before the age of 40 years in Scotland, 1981-2012 (n = 10,267) with no previous pregnancy; each was matched with 3 population controls. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The number and timing of pregnancy and live birth after cancer diagnosis, to 2018. RESULT(S): In 10,267 cancer survivors, the hazard ratio for a subsequent live birth was 0.56 (95% confidence interval, 0.53-0.58) overall. In women who achieved a subsequent pregnancy, age at live birth increased (mean ± SD, 31.2 ± 5.5 vs. 29.7 ± 6.1 in controls), and the family size was lower (2.0 ± 0.8 vs. 2.3 ± 1.1 live births). These findings were consistent across several diagnoses. The interval from diagnosis to last pregnancy was similar to that of controls (10.7 ± 6.4 vs. 10.9 ± 7.3 years) or significantly increased, for example, after breast cancer (6.2 ± 2.8 vs. 5.3 ± 3.3 years) and Hodgkin lymphoma (11.1 ± 5.1 vs. 10.1 ± 5.8 years). CONCLUSION(S): These data quantify the reduced chance of live birth after cancer. Women who subsequently conceived achieved a smaller family size than matched controls, but the period of time after cancer diagnosis across which pregnancies occurred was similar or, indeed, increased. Thus, we did not find evidence that women who were able to achieve a pregnancy after cancer had a shorter timescale over which they have pregnancies.

Fertility Preservation in Childhood Cancer: Endocrine Activity in Prepubertal Human Testis Xenografts Exposed to a Pubertal Hormone Environment.

Survivors of childhood cancer are at risk for long-term treatment-induced health sequelae, including gonadotoxicity and iatrogenic infertility. At present, for prepubertal boys there are no viable clinical options to preserve future reproductive potential. We investigated the effect of a pubertal induction regimen with gonadotrophins on prepubertal human testis xenograft development. Human testis tissue was obtained from patients with cancer and non-malignant haematological disorders (n = 6; aged 1-14 years) who underwent testis tissue cryopreservation for fertility preservation. Fresh and frozen-thawed testis fragments were transplanted subcutaneously or intratesticularly into immunocompromised mice. Graft-bearing mice received injections of vehicle or exogenous gonadotrophins, human chorionic gonadotrophin (hCG, 20 IU), and follicle-stimulating hormone (FSH, 12.5 IU) three times a week for 12 weeks. The gross morphology of vehicle and gonadotrophin-exposed grafts was similar for both transplantation sites. Exposure of prepubertal human testis tissue xenografts to exogenous gonadotrophins resulted in limited endocrine function of grafts, as demonstrated by the occasional expression of the steroidogenic cholesterol side-chain cleavage enzyme (CYP11A1). Plasma testosterone concentrations (0.13 vs. 0.25 ng/mL; p = 0.594) and seminal vesicle weights (10.02 vs. 13.93 mg; p = 0.431) in gonadotrophin-exposed recipient mice were comparable to vehicle-exposed controls. Regardless of the transplantation site and treatment, initiation and maintenance of androgen receptor (AR) expression were observed in Sertoli cells, indicating commitment towards a more differentiated status. However, neither exogenous gonadotrophins (in castrated host mice) nor endogenous testosterone (in intact host mice) were sufficient to repress the expression of markers associated with immature Sertoli cells, such as anti-Müllerian hormone (AMH) and Ki67, or to induce the redistribution of junctional proteins (connexin 43, CX43; claudin 11, CLDN11) to areas adjacent to the basement membrane. Spermatogonia did not progress developmentally but remained the most advanced germ cell type in testis xenografts. Overall, these findings demonstrate that exogenous gonadotrophins promote partial activation and maturation of the somatic environment in prepubertal testis xenografts. However, alternative hormone regimens or additional factors for pubertal induction are required to complete the functional maturation of the spermatogonial stem cell (SSC) niche.

Exogenous Gonadotrophin Stimulation Induces Partial Maturation of Human Sertoli Cells in a Testicular Xenotransplantation Model for Fertility Preservation.

The future fertility of prepubertal boys with cancer may be irreversibly compromised by chemotherapy and/or radiotherapy. Successful spermatogenesis has not been achieved following the xenotransplantation of prepubertal human testis tissue, which is likely due to the failure of somatic cell maturation and function. We used a validated xenograft model to identify the factors required for Leydig and Sertoli cell development and function in immature human testis. Importantly, we compared the maturation status of Sertoli cells in xenografts with that of human testis tissues (n = 9, 1 year-adult). Human fetal testis (n = 6; 14-21 gestational weeks) tissue, which models many aspects of prepubertal testicular development, was transplanted subcutaneously into castrated immunocompromised mice for ~12 months. The mice received exogenous human chorionic gonadotropin (hCG; 20IU, 3×/week). In xenografts exposed continuously to hCG, we demonstrate the maintenance of Leydig cell steroidogenesis, the acquisition of features of Sertoli cell maturation (androgen receptor, lumen development), and the formation of the blood-testis barrier (connexin 43), none of which were present prior to the transplantation or in xenografts in which hCG was withdrawn after 7 months. These studies provide evidence that hCG plays a role in Sertoli cell maturation, which is relevant for future investigations, helping them generate functional gametes from immature testis tissue for clinical application.

Perinatal complications in female survivors of cancer: a systematic review and meta-analysis.

BACKGROUND: Observational studies have suggested that perinatal outcomes are worse in offspring of cancer survivors. We conducted a systematic review and meta-analysis to examine the risks of perinatal complications in female cancer survivors diagnosed before the age of 40 years. METHODS: All published articles on pregnancy, perinatal or congenital risks in female cancer survivors were screened for eligibility. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. RESULTS: Twenty-two studies met the inclusion criteria. Meta-analysis indicates that offspring of cancer survivors are at increased risk of prematurity (relative risk [RR]: 1.56; 95% confidence interval [CI] 1.37-1.77) and low birth weight (RR 1.47; 95% CI 1.24-1.73) but not of being small for gestational age (RR 0.99; 95% CI 0.81-1.22). Cancer survivors have higher rates of elective (RR: 1.38; 95% CI 1.13-1.70) and emergency caesarean section (RR: 1.22; 95% CI 1.15-1.30) as well as assisted vaginal delivery (RR: 1.10; 95% CI 1.02-1.18) and are at increased risk of postpartum haemorrhage (RR: 1.18; 95% CI 1.02-1.36). The risk of congenital abnormalities also appears increased (RR 1.10; 95% CI 1.02-1.20), but this is likely to be an artefact of analysis. Although meta-analysis of the effects of radiotherapy was not possible for all outcomes, there was an increased risk of prematurity (RR 2.27; 95% CI 1.34-3.82) and consistent findings of low birth weight (RR 1.38-2.31). Risk of being small for gestational age was increased only after high uterine radiotherapy dosage. CONCLUSION: The increased perinatal risks warrant a proactive approach from healthcare providers in both counselling and management of perinatal care for cancer survivors.

Perinatal risks in female cancer survivors: A population-based analysis.

BACKGROUND/OBJECTIVES: Advances in cancer management have resulted in improved survival rates, particularly in children and young adults. However, treatment may adversely affect reproductive outcomes among female cancer survivors. The objective of this study was to investigate their risk of adverse perinatal outcomes compared to the general population. DESIGN/METHODS: We performed a population-based analysis, including all female cancer survivors diagnosed before the age of 40 years between 1981 and 2012. Pregnancy and perinatal complications were identified through linkage of the Scottish Cancer Registry with hospital discharge records based on the Community Health Index (CHI) database. We compared 1,629 female cancer survivors with a first ever singleton pregnancy after diagnosis, with controls matched on age, deprivation quintile, and year of cancer diagnosis selected from the general population (n = 8,899). Relative risks and 95%-confidence intervals of perinatal risks were calculated using log-binomial regression. RESULTS: Survivors were more likely to give birth before 37 weeks of gestation (relative risk (RR]) 1.32, 95%-CI 1.10-1.59), but did not show an increased risk of low birth weight (<2.5kg: RR 1.15, 95%-CI 0.94-1.39), and were less likely to give birth to offspring small for gestational age (RR 0.81, 95%-CI 0.68-0.98). Operative delivery and postpartum haemorrhage were more common but approached rates in controls with more recent diagnosis. The risk of congenital abnormalities was not increased (RR 1.01, 95%-CI 0.85-1.20). CONCLUSION: Cancer survivors have an increased risk of premature delivery and postpartum haemorrhage, but their offspring are not at increased risk for low birth weight or congenital abnormalities. In recent decades there has been a normalisation of delivery method in cancer survivors, nevertheless careful management remains appropriate particularly for those diagnosed in childhood.

Ovarian function, fertility and reproductive lifespan in cancer patients.

INTRODUCTION: The increasing survival of girls and young women after cancer has led to a rapid growth in research into assessment of ovarian function after treatment. AREAS COVERED: This aim of this review is to discuss normal ovarian function over time, the impact of cancer treatment on ovarian function, the assessment of ovarian reserve after treatment, and pretreatment predictors of ovarian recovery. EXPERT COMMENTARY: Ovarian function damage after chemotherapy and radiotherapy will impact on fertility and reproductive lifespan, but with great variability. Age at menopause has implications for the duration of estrogen deficiency, with its own adverse health consequences. This has led to identification of the key treatment and patient factors at the time of treatment, notably age and ovarian reserve that impact on post-treatment ovarian function. However, most studies have used outcome measures such as ongoing menses, or biomarkers such as anti-mullerian hormone (AMH), with few reporting on fertility or age at menopause.

The impact of cancer on subsequent chance of pregnancy: a population-based analysis.

STUDY QUESTION: What is the impact of cancer in females aged ≤39 years on subsequent chance of pregnancy? SUMMARY ANSWER: Cancer survivors achieved fewer pregnancies across all cancer types, and the chance of achieving a first pregnancy was also lower. WHAT IS KNOWN ALREADY: The diagnosis and treatment of cancer in young females may be associated with reduced fertility but the true pregnancy deficit in a population is unknown. STUDY DESIGN, SIZE, DURATION: We performed a retrospective cohort study relating first incident cancer diagnosed between 1981 and 2012 to subsequent pregnancy in all female patients in Scotland aged 39 years or less at cancer diagnosis (n = 23 201). Pregnancies were included up to end of 2014. Females from the exposed group not pregnant before cancer diagnosis (n = 10 271) were compared with general population controls matched for age, deprivation quintile and year of diagnosis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Scottish Cancer Registry records were linked to hospital discharge records to calculate standardized incidence ratios (SIR) for pregnancy, standardized for age and year of diagnosis. Linkage to death records was also performed. We also selected women from the exposed group who had not been pregnant prior to their cancer diagnosis who were compared with a matched control group from the general population. Additional analyses were performed for breast cancer, Hodgkin lymphoma, leukaemia, cervical cancer and brain/CNS cancers. MAIN RESULTS AND THE ROLE OF CHANCE: Cancer survivors achieved fewer pregnancies: SIR 0.62 (95% CI: 0.60, 0.63). Reduced SIR was observed for all cancer types. The chance of achieving a first pregnancy was also lower, adjusted hazard ratio = 0.57 (95% CI: 0.53, 0.61) for women >5 years after diagnosis, with marked reductions in women with breast, cervical and brain/CNS tumours, and leukaemia. The effect was reduced with more recent treatment period overall and in cervical cancer, breast cancer and Hodgkin lymphoma, but was unchanged for leukaemia or brain/CNS cancers. The proportion of pregnancies that ended in termination was lower after a cancer diagnosis, and the proportion ending in live birth was higher (78.7 vs 75.6%, CI of difference: 1.1, 5.0). LIMITATIONS, REASONS FOR CAUTION: Details of treatments received were not available, so the impact of specific treatment regimens on fertility could not be assessed. Limited duration of follow-up was available for women diagnosed in the most recent time period. WIDER IMPLICATIONS OF THE FINDINGS: This analysis provides population-based quantification by cancer type of the effect of cancer and its treatment on subsequent pregnancy across the reproductive age range, and how this has changed in recent decades. The demonstration of a reduced chance of pregnancy across all cancer types and the changing impact in some but not other common cancers highlights the need for appropriate fertility counselling of all females of reproductive age at diagnosis. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by NHS Lothian Cancer and Leukaemia Endowments Fund. Part of this work was undertaken in the MRC Centre for Reproductive Health which is funded by the MRC Centre grant MR/N022556/1. RAA has participated in Advisory Boards and/or received speaker's fees from Beckman Coulter, IBSA, Merck and Roche Diagnostics. He has received research support from Roche Diagnostics, Ansh labs and Ferring. The other authors have no conflicts to declare.

Follicle Stimulating Hormone is an accurate predictor of azoospermia in childhood cancer survivors.

The accuracy of Follicle Stimulating Hormone as a predictor of azoospermia in adult survivors of childhood cancer is unclear, with conflicting results in the published literature. A systematic review and post hoc analysis of combined data (n = 367) were performed on all published studies containing extractable data on both serum Follicle Stimulating Hormone concentration and semen concentration in survivors of childhood cancer. PubMed and Medline databases were searched up to March 2017 by two blind investigators. Articles were included if they contained both serum FSH concentration and semen concentration, used World Health Organisation certified methods for semen analysis, and the study participants were all childhood cancer survivors. There was no evidence for either publication bias or heterogeneity for the five studies. For the combined data (n = 367) the optimal Follicle Stimulating Hormone threshold was 10.4 IU/L with specificity 81% (95% CI 76%-86%) and sensitivity 83% (95% CI 76%-89%). The AUC was 0.89 (95%CI 0.86-0.93). A range of threshold FSH values for the diagnosis of azoospermia with their associated sensitivities and specificities were calculated. This study provides strong supporting evidence for the use of serum Follicle Stimulating Hormone as a surrogate biomarker for azoospermia in adult males who have been treated for childhood cancer.

The impact of long-term follow-up care for childhood cancer survivors: A systematic review.

OBJECTIVES: Childhood cancer survivors are at risk of developing late treatment-related complications. In response, many hospitals worldwide have established follow-up clinics to monitor survivors as they age. However, there is limited evidence of the efficacy of these clinics in meeting the lifelong healthcare needs of survivors. In this review we collated evidence of the measurable impact of engagement in specialized survivorship care, on survivors' medical and psychosocial outcomes. DESIGN: We conducted a systematic review according to PRISMA guidelines, and assessed the quality of included studies using 'QualSyst'. DATA SOURCES: We screened 641 abstracts in Medline, Embase and CINAHL, yielding 9 eligible articles (N=5135 survivors). ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Articles were eligible if: participants were diagnosed with cancer prior to the age of 21; participants were classified as 'survivors' of childhood or adolescent cancer, usually defined as 5 years from diagnosis or 2 years from the end of treatment; studies evaluated the impact of engagement in long term follow-up (LTFU) care on medical, psychosocial or other outcomes in pediatric cancer survivors. RESULTS: One article evaluated primary care physician-led follow-up and the remainder evaluated specialized survivorship clinics. Survivors attending follow-up care tended to demonstrate higher knowledge about their treatment and diagnosis (n=2), and had more accurate late effects risk perception (n=3). Attendees also engaged in increased more regular surveillance, had fewer emergency department visits/hospitalizations (n=1), and more late effects detected (n=3), than non-attendees. CONCLUSIONS: There is a dearth of literature systematically evaluating the medical and psychosocial impact of follow-up care. Research suggests however, survivors engaged in follow-up care have better health and educational outcomes, highlighting the need for lifelong survivorship care and ongoing late effects education for survivors. Recalling survivors who become disengaged with follow-up care is also valuable, as their risk of treatment-related complications rises with age. Further systematic evaluation is urgently needed.

Pregnancy and Labor Complications in Female Survivors of Childhood Cancer: The British Childhood Cancer Survivor Study.

Background: Female survivors of childhood cancer treated with abdominal radiotherapy who manage to conceive are at risk of delivering premature and low-birthweight offspring, but little is known about whether abdominal radiotherapy may also be associated with additional complications during pregnancy and labor. We investigated the risk of developing pregnancy and labor complications among female survivors of childhood cancer in the British Childhood Cancer Survivor Study (BCCSS). Methods: Pregnancy and labor complications were identified by linking the BCCSS cohort (n = 17 980) to the Hospital Episode Statistics (HES) for England. Relative risks (RRs) of pregnancy and labor complications were calculated by site of radiotherapy treatment (none/abdominal/cranial/other) and other cancer-related factors using log-binomial regression. All statistical tests were two-sided. Results: A total of 2783 singleton pregnancies among 1712 female survivors of childhood cancer were identified in HES. Wilms tumor survivors treated with abdominal radiotherapy were at threefold risk of hypertension complicating pregnancy (relative risk = 3.29, 95% confidence interval [CI] = 2.29 to 4.71), while all survivors treated with abdominal radiotherapy were at risk of gestational diabetes mellitus (RR = 3.35, 95% CI = 1.41 to 7.93) and anemia complicating pregnancy (RR = 2.10, 95% CI = 1.27 to 3.46) compared with survivors treated without radiotherapy. Survivors treated without radiotherapy had similar risks of pregnancy and labor complications as the general population, except survivors were more likely to opt for an elective cesarean section (RR = 1.39, 95% CI = 1.16 to 1.70). Conclusions: Treatment with abdominal radiotherapy increases the risk of developing hypertension complicating pregnancy in Wilms tumor survivors, and diabetes mellitus and anemia complicating pregnancy in all survivors. These patients may require extra vigilance during pregnancy.

Ovarian tissue cryopreservation for fertility preservation: clinical and research perspectives.

BACKGROUND: Small case series have reported successful live births after ovarian tissue cryopreservation and orthotopic transplantation, demonstrating that it can be of value in increasing the chance of successful pregnancy after treatment for cancer and other fertility-impacting diseases in adult women. OBJECTIVE AND RATIONALE: This review is intended to set out the current clinical issues in the field of ovarian tissue cryopreservation, and elucidate the status of laboratory studies to address these. SEARCH METHODS: We reviewed the English-language literature on ovarian tissue cryopreservation and in vitro maturation (IVM) of ovarian follicles. OUTCOMES: Ovarian tissue cryopreservation is increasingly used for fertility preservation and, whilst areas for development remain (optimal patient selection, minimizing risk of contamination by malignant cells and IVM protocols), there are emerging data as to its efficacy. We review the current status of ovarian tissue cryopreservation in girls and young women facing loss of fertility from treatment of cancer and other serious diseases. Increasingly large cohort studies are reporting on success rates from ovarian tissue cryopreservation giving an indication of likely success rates. Patient selection is necessary to ensure the safety and effectiveness of this approach, especially in the very experimental situation of its application to prepubertal girls. There are continuing developments in supporting follicle development in vitro. LIMITATIONS REASONS FOR CAUTION: The evidence base consists largely of case series and cohort studies, thus there is the possibility of bias in key outcomes. In vitro development of human ovarian follicles remains some way from clinical application. WIDER IMPLICATIONS OF THE FINDINGS: Ovarian tissue cryopreservation is becoming established as a valuable approach to the preservation of fertility in women. Its application in prepubertal girls may be of particular value, as it offers the only approach in this patient group. For both girls and young women, more accurate data are needed on the likelihood of successful childbirth after this procedure and the factors that underpin successful application of this approach, which will lead to its more effective use. STUDY FUNDING/COMPETING INTERESTS: The author's work in this field is supported by Medical Research Grant (MRC) grants G0901839 and MR/L00299X/1 and partially undertaken in the MRC Centre for Reproductive Health which is funded by MRC Centre grant MR/N022556/1. The authors declare that there is no conflict of interest that could prejudice the impartiality of the present research.

A Validated Normative Model for Human Uterine Volume from Birth to Age 40 Years.

Transabdominal pelvic ultrasound and/or pelvic Magnetic Resonance Imaging are safe, accurate and non-invasive means of determining the size and configuration of the internal female genitalia. The assessment of uterine size and volume is helpful in the assessment of many conditions including disorders of sex development, precocious or delayed puberty, infertility and menstrual disorders. Using our own data from the assessment of MRI scans in healthy young females and data extracted from four studies that assessed uterine volume using transabdominal ultrasound in healthy females we have derived and validated a normative model of uterine volume from birth to age 40 years. This shows that uterine volume increases across childhood, with a faster increase in adolescence reflecting the influence of puberty, followed by a slow but progressive rise during adult life. The model suggests that around 84% of the variation in uterine volumes in the healthy population up to age 40 is due to age alone. The derivation of a validated normative model for uterine volume from birth to age 40 years has important clinical applications by providing age-related reference values for uterine volume.

A Normative Model of Serum Inhibin B in Young Males.

Inhibin B has been identified as a potential marker of Sertoli cell function in males. The aim of this study is to produce a normative model of serum inhibin B in males from birth to seventeen years. We used a well-defined search strategy to identify studies containing data that can contribute to a larger approximation of the healthy population. We combined data from four published studies (n = 709) and derived an internally validated model with high goodness-of-fit and normally distributed residuals. Our results show that inhibin B increases following birth to a post-natal peak of 270 pg/mL (IQR 210-335 pg/mL) and then decreases during childhood followed by a rise at around 8 years, peaking at a mean 305 pg/mL (IQR 240-445 pg/mL) at around age 17. Following this peak there is a slow decline to the standard mature adult normal range of 170 pg/mL (IQR 125-215 pg/mL). This normative model suggests that 35% of the variation in Inhibin B levels in young males is due to age alone, provides an age-specific reference range for inhibin B in the young healthy male population, and will be a powerful tool in evaluating the potential of inhibin B as a marker of Sertoli cell function in pre-pubertal boys.

Fertility preservation in pre-pubertal girls with cancer: the role of ovarian tissue cryopreservation.

With the increasing numbers of survivors of cancer in young people, future fertility and ovarian function are important considerations that should be discussed before treatment commences. Some young people, by nature of the treatment they will receive, are at high risk of premature ovarian insufficiency and infertility. For them, ovarian tissue cryopreservation (OTC) is one approach to fertility preservation that remains both invasive and for young patients experimental. There are important ethical and consent issues that need to be explored and accepted before OTC can be considered established in children with cancer. In this review we have discussed a framework for patient selection which has been shown to be effective in identifying those patients at high risk of premature ovarian insufficiency and who can be offered OTC safely.

Screening and management of adverse endocrine outcomes in adult survivors of childhood and adolescent cancer.

5 year survival for childhood and adolescent cancer in developed countries is now in excess of 80% and the number of survivors of cancer continues to increase worldwide. After completion of therapy, many of these survivors will face a lifelong risk of endocrine late effects. We summarise the available evidence related to the prevalence and risk factors for endocrine late effects among adult survivors of childhood and adolescent cancer. Present screening, surveillance, and treatment recommendations differ by country and region, so we also highlight the continued effort to harmonise the international guidelines for this population.

Cancer treatment and gonadal function: experimental and established strategies for fertility preservation in children and young adults.

Preservation of gonadal function is an important priority for the long-term health of cancer survivors of both sexes and all ages at treatment. Loss of opportunity for fertility is a prime concern in both male and female cancer survivors, but endocrine effects of gonadal damage are likewise central to long-term health and wellbeing. Some fertility preservation techniques, such as semen and embryo cryopreservation, are established and successful in adults, and development of oocyte vitrification has greatly improved the potential to cryopreserve unfertilised oocytes. Despite being recommended for all pubertal male patients, sperm banking is not universally practised in paediatric oncology centres, and very few adolescent-friendly facilities exist. All approaches to fertility preservation have specific challenges in children and teenagers, including ethical, practical, and scientific issues. For young women, cryopreservation of ovarian cortical tissue with later replacement has resulted in at least 40 livebirths, but is still regarded as experimental in most countries. For prepubertal boys, testicular biopsy cryopreservation is offered in some centres, but how that tissue might be used in the future is unclear, and so far no evidence suggests that fertility can be restored. For both sexes, these approaches involve an invasive procedure and have an uncertain risk of tissue contamination in haematological and other malignancies. Decision making for all these approaches needs assessment of the individual's risk of fertility loss, and is made at a time of emotional distress. Development of this specialty needs better provision of information for patients and their medical teams, and improvements in service provision, to match technical and scientific advances.