Risks of adverse obstetric outcomes among female survivors of adolescent and young adult cancer in England (TYACSS): a population-based, retrospective cohort study.

BACKGROUND: There are limited data on the risks of obstetric complications among survivors of adolescent and young adult cancer with most previous studies only reporting risks for all types of cancers combined. The aim of this study was to quantify deficits in birth rates and risks of obstetric complications for female survivors of 17 specific types of adolescent and young adult cancer. METHODS: The Teenage and Young Adult Cancer Survivor Study (TYACSS)-a retrospective, population-based cohort of 200 945 5-year survivors of cancer diagnosed at age 15-39 years from England and Wales-was linked to the English Hospital Episode Statistics (HES) database from April 1, 1997, to March 31, 2022. The cohort included 17 different types of adolescent and young adult cancers. We ascertained 27 specific obstetric complications through HES among 96 947 women in the TYACSS cohort. Observed and expected numbers for births and obstetric complications were compared between the study cohort and the general population of England to identify survivors of adolescent and young adult cancer at a heighted risk of birth deficits and obstetric complications relative to the general population. FINDINGS: Between April 1, 1997, and March 31, 2022, 21 437 births were observed among 13 886 female survivors of adolescent and young adult cancer from England, which was lower than expected (observed-to-expected ratio: 0·68, 95% CI 0·67-0·69). Other survivors of genitourinary, cervical, and breast cancer had under 50% of expected births. Focusing on more common (observed ≥100) obstetric complications that were at least moderately in excess (observed-to-expected ratio ≥1·25), survivors of cervical cancer were at risk of malpresentation of fetus, obstructed labour, amniotic fluid and membranes disorders, premature rupture of membranes, preterm birth, placental disorders including placenta praevia, and antepartum haemorrhage. Survivors of leukaemia were at risk of preterm delivery, obstructed labour, postpartum haemorrhage, and retained placenta. Survivors of all other specific cancers had no more than two obstetric complications that exceeded an observed-to-expected ratio of 1·25 or greater. INTERPRETATION: Survivors of cervical cancer and leukaemia are at risk of several serious obstetric complications; therefore, any pregnancy should be considered high-risk and would benefit from obstetrician-led antenatal care. Despite observing deficits in birth rates across all 17 different types of adolescent and young adult cancer, we provide reassurance for almost all survivors of adolescent and young adult cancer concerning their risk of almost all obstetric complications. Our results provide evidence for the development of clinical guidelines relating to counselling and surveillance of obstetrical risk for female survivors of adolescent and young adult cancer. FUNDING: Children with Cancer UK, The Brain Tumour Charity, and Academy of Medical Sciences.

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.

Fertility preservation for girls and young women with cancer: population-based validation of criteria for ovarian tissue cryopreservation.

BACKGROUND: Ovarian tissue cryopreservation with later reimplantation has been shown to preserve fertility in adult women, but this approach remains unproven and experimental in children and adolescents. We aimed to assess the use of the Edinburgh selection criteria for ovarian tissue cryopreservation in girls and young women with cancer to determine whether we are offering this invasive procedure to the patients who are most at risk of premature ovarian insufficiency. METHODS: Cryopreservation of ovarian tissue has been selectively offered to girls and young women with cancer who met the Edinburgh selection criteria since 1996. Between Jan 1, 1996, and June 30, 2012, 410 female patients younger than 18 years at diagnosis were treated for cancer (including leukaemia and brain tumours) at the Edinburgh Children's Cancer Centre, which serves the whole South East of Scotland region. We determined the ovarian status of these patients from review of clinical records and classified them as having premature ovarian insufficiency or not, or as unable to be determined. Patients younger than 12 years at time of data cutoff (Jan 31, 2013) were excluded from the analysis. FINDINGS: 34 (8%) of the 410 patients met the Edinburgh selection criteria and were offered ovarian tissue cryopreservation before starting cancer treatment. 13 patients declined the procedure and 21 consented, and the procedure was completed successfully in 20 patients. Of the 20 patients who had ovarian tissue successfully cryopreserved, 14 were available for assessment of ovarian function. Of the 13 patients who had declined the procedure, six were available for assessment of ovarian function. Median age at the time of follow-up for the 20 assessable patients was 16·9 years (IQR 15·5-21·8). Of the 14 assessable patients who had successfully undergone ovarian cryopreservation, six had developed premature ovarian insufficiency at a median age of 13·4 years (IQR 12·5-14·6), one of whom also had a natural pregnancy. Of the six assessable patients who had declined the procedure, one had developed premature ovarian insufficiency. Assessment of ovarian function was possible for 141 of the 376 patients who were not offered cryopreservation; one of these patients had developed premature ovarian insufficiency. The cumulative probability of developing premature ovarian insufficiency after treatment was completed was significantly higher for patients who met the criteria for ovarian tissue cryopreservation than for those who did not (15-year probability 35% [95% CI 10-53] vs 1% [0-2]; p<0·0001; hazard ratio 56·8 [95% CI 6·2-521·6] at 10 years). INTERPRETATION: The results of this analysis show that the Edinburgh selection criteria accurately identify the few girls and young women who will develop premature ovarian insufficiency, and validate their use for selection of patients for ovarian tissue cryopreservation. Further follow-up of this cohort of patients is likely to allow refinement of the criteria for this experimental procedure in girls and young women with cancer. FUNDING: UK Medical Research Council.

Intratubular germ cell neoplasia of the human testis: heterogeneous protein expression and relation to invasive potential.

Testicular germ cell cancer develops from premalignant intratubular germ cell neoplasia, unclassified cells that are believed to arise from failure of normal maturation of fetal germ cells from gonocytes (OCT4(+)/MAGEA4(-)) into pre-spermatogonia (OCT4(-)/MAGEA4(+)). Intratubular germ cell neoplasia cell subpopulations based on stage of germ cell differentiation have been described, however the importance of these subpopulations in terms of invasive potential has not been reported. We hypothesized that cells expressing an immature (OCT4(+)/MAGEA4(-)) germ cell profile would exhibit an increased proliferation rate compared with those with a mature profile (OCT4(+)/MAGEA4(+)). Therefore, we performed triple immunofluorescence and stereology to quantify the different intratubular germ cell neoplasia cell subpopulations, based on expression of germ cell (OCT4, PLAP, AP2γ, MAGEA4, VASA) and proliferation (Ki67) markers, in testis sections from patients with preinvasive disease, seminoma, and non-seminoma. We compared these subpopulations with normal human fetal testis and with seminoma cells. Heterogeneity of protein expression was demonstrated in intratubular germ cell neoplasia cells with respect to gonocyte and spermatogonial markers. It included an embryonic/fetal germ cell subpopulation lacking expression of the definitive intratubular germ cell neoplasia marker OCT4, that did not correspond to a physiological (fetal) germ cell subpopulation. OCT4(+)/MAGEA4(-) cells showed a significantly increased rate of proliferation compared with the OCT4(+)/MAGEA4(+) population (12.8 versus 3.4%, P<0.0001) irrespective of histological tumor type, reflected in the predominance of OCT4(+)/MAGEA4(-) cells in the invasive tumor component. Surprisingly, OCT4(+)/MAGEA4(-) cells in patients with preinvasive disease showed significantly higher proliferation compared to those with seminoma or non-seminoma (18.1 versus 10.2 versus 7.2%, P<0.05, respectively). In conclusion, this study has demonstrated that OCT4(+)/MAGEA4(-) cells are the most frequent and most proliferative cell population in tubules containing intratubular germ cell neoplasia, which appears to be an important factor in determining invasive potential of intratubular germ cell neoplasia to seminomas.

Safety considerations for transplanting cryopreserved ovarian tissue to restore fertility in female patients who have recovered from Ewing's sarcoma.

Ewing's sarcoma (EWS) is a highly malignant cancer in children, adolescents and young adults. The chemotherapy required to treat female EWS patients may cause primary ovarian insufficiency and infertility as a side effect. Cryopreservation of ovarian tissue before the start of chemotherapy can potentially preserve fertility. When the patient has been cured and primary ovarian insufficiency has developed, transplantation of frozen/thawed ovarian tissue can restore ovarian function. The tissue is usually collected before chemotherapy is initiated, and malignant cells may contaminate the stored ovarian tissue, potentially causing recrudescence of the original cancer after transplantation. The risk of EWS metastasizing to the ovary is probably low but has not been studied in great detail. This review describes the available evidence on the risk of malignant cell contamination in the ovaries of EWS patients and presents a new case of malignant cells in an ovarian biopsy from a girl with EWS.

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 girls and young women.

There is increasing interest and experience in the options available to preserve fertility in those about to undergo potentially gonadotoxic chemotherapy or radiation therapy, usually related to treatment for cancer. Recent years have seen the development of methods for prepubertal girls, female adolescents and adult women, although these remain less established than sperm cryopreservation for men. At present, the options for prepubertal boys remain experimental. Embryo cryopreservation following ovarian stimulation and IVF is a routine procedure technically and its success in the management of infertility is established. However, there are no data on uptake or success rates in the context of fertility preservation in women with cancer. Oocyte cryopreservation is technically challenging and requires ovarian stimulation, thus potentially resulting in a delay in cancer treatment. Oocyte vitrification offers increased success rates in comparison with slow freezing; however, this approach is also limited by the number of oocytes that can be obtained. The third possibility, ovarian tissue cryopreservation, can be performed without significant delay and is the only option for prepubertal girls. Worldwide, a small number of children have been born following reimplantation of frozen/thawed ovarian tissue. It is clear that fertility preservation is important for some girls and young women facing treatments that will compromise their fertility, but the availability of all approaches varies widely. Effective approaches for prepubertal boys are also required.

Physiological versus standard sex steroid replacement in young women with premature ovarian failure: effects on bone mass acquisition and turnover.

BACKGROUND: The aim of this exploratory study was to establish whether we could improve skeletal health with a physiological regimen of SSR in young women with premature ovarian failure (POF). PATIENTS AND METHODS: In an open-label randomized controlled crossover trial, 34 women with POF were randomized to 4-week cycles of pSSR (transdermal oestradiol, 100 µg daily for week 1, 150 µg for weeks 2-4; vaginal progesterone, 200 mg twice daily for weeks 3-4) or standard hormone replacement treatment (sHRT) (oral ethinyloestradiol 30 µg and 1·5 mg norethisterone daily for weeks 1-3, week 4 'pill-free') for 12 months. Bone mineral density (BMD) was measured by DEXA at study entry and after each 12-month treatment period. Blood samples for hormones and markers of bone formation (bone alkaline phosphatase, BALP and type I collagen N-terminal propeptide, PINP) and bone resorption (CrossLaps) were collected pre-/postwashout and after 3, 6 and 12 months of each treatment. RESULTS: Eighteen women, mean 27 (range 19-39) years, completed the study. Both regimens caused similar suppression of LH and FSH. Mean baseline lumbar spine BMD z-score was -0·89 (95% CI -1·27 to -0·51) and increased by +0·17 (CI +0·07 to +0·27) in response to pSSR (P = 0·003), compared with +0·07 (CI -0·03 to +0·18) during standard HRT (P = 0·2). During pSSR, the increment in lumbar spine BMD z-score was related positively to oestradiol (r = +0·49, P = 0·04) and inversely to FSH (r = -0·65, P = 0·004). Bone formation markers, BALP and P1NP increased in the pSSR arm (anova P < 0·001) but decreased in the sHRT arm (P < 0·01). Both treatments suppressed the bone resorption marker, CrossLaps (P < 0·001). CONCLUSION: We conclude that pSSR over 12 months has a beneficial affect on bone mass acquisition on the lumbar spine in women with POF, mediated by increased bone formation and decreased bone resorption.

Xenografting of human fetal testis tissue: a new approach to study fetal testis development and germ cell differentiation.

BACKGROUND: Abnormal fetal testis development can result in disorders of sex development (DSDs) and predispose to later testicular dysgenesis syndrome (TDS) disorders such as testicular germ cell tumours. Studies of human fetal testis development are hampered by the lack of appropriate model, and intervention systems. We hypothesized that human fetal testis xenografts can recapitulate normal development. METHODS: Human fetal testes (at 9 weeks, n = 4 and 14-18 weeks gestation, n = 6) were xenografted into male nude mice for 6 weeks, with or without hCG treatment of the host, and evaluated for normal cellular development and function using immunohistochemistry, triple immunofluorescence and testosterone assay. The differentiation and proliferation status of germ cells within xenografts was quantified and compared with age-matched controls. RESULTS: Xenografts showed >75% survival with normal morphology. In the first-trimester xenografts seminiferous cord formation was initiated and in first- and second-trimester grafts normal functional development of Sertoli, Leydig and peritubular myoid cells was demonstrated using cell-specific protein markers. Grafts produced testosterone when hosts were treated with hCG (P = 0.004 versus control). Proliferation of germ cells and differentiation from gonocytes (OCT4(+)) into pre-spermatogonia (VASA(+)) occurred in grafts and quantification showed this progressed comparably with age-matched ungrafted controls. CONCLUSIONS: Human fetal testis tissue xenografts demonstrate normal structure, function and development after xenografting, including normal germ cell differentiation. This provides an in vivo system to study normal human fetal testis development and its susceptibility to disruption by exogenous factors (e.g. environmental chemicals). This should provide mechanistic insight into the fetal origins of DSDs and TDS disorders.

Toxicity of chemotherapy and radiation on female reproduction.

One of the most devastating consequences of cancer treatment in the young female population is ovarian damage, resulting in diminished fertility potential. The extent of damage is related to age, chemotherapeutic regimen, and dose of pelvic radiation received. It is crucial that physicians know the impact each of these factors has on future fertility to advice patients on fertility preservation options. Anticancer drugs injure the female reproductive system through ovarian follicular and stromal damage. Although the exact mechanisms of damage remain unclear, it is essential to better understand these mechanisms to develop methods to diminish ovarian injury.

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.

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.

Normal ovarian function and assessment of ovarian reserve in the survivor of childhood cancer.

Increasingly young people survive cancer in childhood and as a result complications of its treatment are becoming more common and important. Premature ovarian failure is recognized as a complication of radiotherapy to a field that includes the pelvis and alkylating-agent-based chemotherapy. Young pre-pubertal girls are not protected from the effects of gonadal toxic therapy. A young woman, successfully treated for cancer during childhood, may experience regular periods in the presence of a significantly reduced ovarian reserve. There is, however, no reliable measure of ovarian reserve available for the individual woman. Assessment of ovarian function relies on the use of surrogate markers such as follicle stimulating hormone, inhibin-B, and anti-mullerian hormone as well as ultrasound assessment of ovarian volume and antral follicle count. We discuss the physiology of normal ovarian function, the effects of cancer treatments on ovarian function and the techniques for evaluation of ovarian reserve in survivors of childhood cancer.

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.

Do doctors discuss fertility issues before they treat young patients with cancer?

BACKGROUND: Many children treated for cancer are at risk of infertility, but for girls and prepubertal boys, all fertility preservation techniques remain experimental. We have assessed UK practice relating to information provision about the effects of cancer treatment on fertility and options for fertility preservation. METHODS: Paediatric oncologists prospectively completed a data form for each new patient registered over a 12 month period. RESULTS: Data were available on 1030 patients (68% of total registered). The effect of cancer treatment on fertility was discussed with 63% of patients. Of these, 61% were judged to be at high or medium risk of fertility problems. Discussions took place more commonly with boys than girls; the commonest reason for discussion not occurring was young age. The majority (83%) of post-pubertal boys assessed as high/medium risk of infertility were referred for semen cryopreservation. This rate fell to 39% of those in early puberty. Only 1% (n=4) of girls were referred to an assisted conception unit. CONCLUSIONS: These data indicate a high awareness of the potential adverse effects of therapy on fertility among UK paediatric oncologists. High referral rates for older boys indicate that current guidelines are followed, but there is a need for fertility preservation techniques for girls and younger boys.

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.

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.

Pregnancy in women who had cancer in childhood.

The majority of female cancer survivors will have normal reproductive function and would be expected to have a successful pregnancy. For the minority of young women who have received significant cytotoxic insult to the reproductive organs and yet still manage to conceive, pregnancy must be considered a high risk condition and these patients should be managed by a multidisciplinary specialist team. Female survivors of childhood cancer who are able to become pregnant carry an excess risk of preterm delivery and low birth weight baby. This restricted foetal growth and inability of the uterus to carry the foetus to term is associated with radiation-induced damage to the uterus. Chemotherapy does not appear to be associated with adverse pregnancy outcomes. However, prospective follow-up of cohorts of patients treated with contemporary therapies, frequently involving more intensive therapies are required to determine the risk. A number of large multi-centre studies, are underway and will provide new insights into pregnancy outcomes in survivors of childhood cancer.