Reproductive possibilities for the child with cancer

As the population of childhood cancer survivors steadily increases, currently estimated at 26,000 in the UK, investigators are focusing on improving our understanding of the late side effects associated with successful cancer therapy. Long-term survivors are at risk of developing a number of late sequelae including impaired fertility, adverse pregnancy outcomes and health problems in the offspring. Although not the highest priority at diagnosis, loss of fertility is one of the most devastating consequences of cytotoxic therapy for the long-term survivors. In this article we consider the late reproductive sequelae following treatment for childhood cancer and discuss the options for fertility preservation.     

Creating a continuum of care: integrating obstetricians and gynecologists in the care of young cancer patients

Cancer therapy can be lifesaving but significantly diminish female reproductive potential. This review provides an overview of the deleterious effects of cancer treatments on reproductive function, the fertility preservation options currently available for young women, and the outcomes of pregnancy after cancer treatment. In addition, special considerations for women who are diagnosed with cancer during pregnancy are discussed. To optimize the continuum of care for the patient, new corridors of communication between obstetricians, gynecologists, and oncology specialists must be developed to ensure the best outcomes for the patient, both in terms of cancer treatment and fertility preservation.     

Late reproductive effects of cancer treatment

Gynaecologists are seeing an ever-growing population of cancer survivors who are at risk from developing a broad range of adverse outcomes relating to cancer treatment. This review discusses the most commonly observed reproductive concerns in young people who are awaiting, or have undergone treatment for cancer. We also discuss the options for maintaining fertility in both men and women, and possible subsequent pregnancy outcomes. The fertility preservation options available to any particular cancer survivor will depend on age at the time of diagnosis and treatment, the cancer type and primary site, the stage and the type of treatment.     

Radiation damage to the uterus — Review of the effects of treatment of childhood cancer

At the present time approximately 1 in 1000 young people aged between 16 and 35 years will have been cured of cancer in childhood and some of the treatment regimens used will have predictable effects on their future fertility prospects. In young women who have been exposed to radiotherapy below the diaphragm, the reproductive problems include the risk of ovarian failure and significantly impaired development of the uterus. The magnitude of the risk is related to the radiation field, total dose and fractionation schedule. Premature labour and low birth weight infants have been reported after flank abdominal radiotherapy. Female long-term survivors treated with total body irradiation and marrow transplantation are also at risk of ovarian follicular depletion and impaired uterine growth and blood flow, and of early pregnancy loss and premature labour if pregnancy is achieved. Despite standard oestrogen replacement, the uterus of these young girls is often reduced to 40% of normal adult size. Uterine volume correlates with the age at which radiation was received. Regrettably, it is likely that radiation damage to the uterine musculature and vasculature adversely affects prospects for pregnancy in these women. It has been demonstrated that, in women treated with total body irradiation, sex steroid replacement in physiological doses significantly increases uterine volume and endometrial thickness, as well as re-establishing uterine blood flow. However, it is not known whether standard regimens of oestrogen replacement therapy are sufficient to facilitate uterine growth in adolescent women treated with total body irradiation in childhood. Even if the uterus is able to respond to exogenous sex steroid stimulation, and appropriate assisted reproductive technologies are available, a successful pregnancy outcome is by no means ensured. The uterine factor remains a concern and women who are survivors of childhood cancer and their carers must recognize that these pregnancies will be at high risk.     

Radiation damage to the uterus -- review of the effects of treatment of childhood cancer

At the present time approximately 1 in 1000 young people aged between 16 and 35 years will have been cured of cancer in childhood and some of the treatment regimens used will have predictable effects on their future fertility prospects. In young women who have been exposed to radiotherapy below the diaphragm, the reproductive problems include the risk of ovarian failure and significantly impaired development of the uterus. The magnitude of the risk is related to the radiation field, total dose and fractionation schedule. Premature labour and low birth weight infants have been reported after flank abdominal radiotherapy. Female long-term survivors treated with total body irradiation and marrow transplantation are also at risk of ovarian follicular depletion and impaired uterine growth and blood flow, and of early pregnancy loss and premature labour if pregnancy is achieved. Despite standard oestrogen replacement, the uterus of these young girls is often reduced to 40% of normal adult size. Uterine volume correlates with the age at which radiation was received. Regrettably, it is likely that radiation damage to the uterine musculature and vasculature adversely affects prospects for pregnancy in these women. It has been demonstrated that, in women treated with total body irradiation, sex steroid replacement in physiological doses significantly increases uterine volume and endometrial thickness, as well as re-establishing uterine blood flow. However, it is not known whether standard regimens of oestrogen replacement therapy are sufficient to facilitate uterine growth in adolescent women treated with total body irradiation in childhood. Even if the uterus is able to respond to exogenous sex steroid stimulation, and appropriate assisted reproductive technologies are available, a successful pregnancy outcome is by no means ensured. The uterine factor remains a concern and women who are survivors of childhood cancer and their carers must recognize that these pregnancies will be at high risk.     

宫腔镜对体外受精常见宫腔影响因素的评估和治疗结局

不孕症是指妇女原发不能受孕,也指妇女能受孕但不能妊娠至足月,该问题是困扰很多家庭的一大难题。因对其定义不同而导致不孕症发病率不同,不孕症的原因多种多样,而子宫腔内病变是常见的干扰不孕症患者胚胎植入的原因之一,因此对子宫腔内病变的评估是评价不孕症的核心部分。目前认为宫腔镜是最准确的诊断宫腔内病变的检查。为了优化生育治疗,越来越普遍地将宫腔镜检查作为体外受精（IVF）之前的常规检查,并且宫腔镜可同时对宫腔内病变进行治疗,使妊娠结局得以改善。阐述宫腔镜对接受IVF周期前几种最常见宫腔因素的评估及治疗前后对妊娠结局的影响。     

Pregnancy outcome of female survivors of childhood cancer: a report from the Childhood Cancer Survivor Study

OBJECTIVE: This study was undertaken to determine the effect, if any, of prior treatment with radiation therapy or chemotherapy for cancer diagnosed during childhood or adolescence on pregnancy loss, live births, and birth weight. STUDY DESIGN: We reviewed pregnancy outcome among female participants in the Childhood Cancer Survivor Study (CCSS) who returned a questionnaire. Eligibility for the CCSS included 5-year survivors who were <21 years old at diagnosis and who were diagnosed with an eligible cancer between January 1, 1970, and December 31, 1986, at the 25 participating CCSS institutions. The questionnaire included items regarding attempts to become pregnant, the occurrence of pregnancy, and the outcome of pregnancy (ie, live birth, stillbirth, miscarriage, abortion). Medical records of all members of the cohort were abstracted to obtain chemotherapeutic agents administered, the cumulative dose of drug administered for several drugs of interest, and the doses, anatomic regions, and dates of administration of all radiation therapy. RESULTS: One thousand nine hundred fifteen females reported 4029 pregnancies (63% live births, 1% stillbirths, 15% miscarriages, 17% abortions, 3% unknown or in gestation). There were no significant differences in pregnancy outcome by treatment. A higher, but not statistically significant, risk of miscarriage was present among women whose ovaries were in the radiation therapy field (relative risk [RR] 1.86, P =.14), were near the radiation therapy field (RR 1.64, P =.06), or were shielded (RR 0.90, P =.88). The rate of live birth was not lower for the patients treated with any particular chemotherapeutic agent. The offspring of the patients who received pelvic irradiation were more likely to weigh <2500 g at birth (RR 1.84, P =.03). CONCLUSIONS: This large study did not identify adverse pregnancy outcomes for female survivors treated with most chemotherapeutic agents. The offspring of women who received pelvic irradiation are at risk for low birth weight.     

Evidence for effects of weight on reproduction in women

Body weight, and its constituent components of fat mass and lean tissue, plays an important role modulating reproductive development and functioning. Body weight influences the timing of menarche and the capacity to achieve a pregnancy. The nature of this relationship appears to be some variant on a 'U' shape. Extremes in body weight are associated with infertility and a range of adverse outcomes for both mother and baby across the course of pregnancy and perinatal period. Whereas underweight is associated with poor fetal growth and elevated pregnancy loss, overweight is more strongly associated with diseases in pregnancy, pregnancy loss and stillbirth and high birth weight. An emerging area of interest is the role of obesity on fertility, and the intergenerational 'tracking' of high maternal body weight into the second and subsequent generations, resulting not only in an increased risk of metabolic disease, but also perturbed reproductive functioning in the offspring.     

Are children born after assisted reproductive technology at increased risk for adverse health outcomes?

As assisted reproductive technologies (ARTs) are increasingly used to overcome infertility, there is concern about the health of the children conceived. The empirical evidence for associations with outcomes related to child health is variable and should be evaluated with consideration of methodological shortcomings. Currently, there is convincing evidence that ART treatment may increase the risk of a few outcomes. Experimental laboratory studies document that various constituents in culture media affect various embryo characteristics both positively and negatively. Multiple-gestation pregnancy and birth are increased with ART, both because of multiple embryo transfer and embryo splitting. There is evidence of an increase in chromosomal abnormalities among pregnancies conceived using intracytoplasmic sperm injection and low birth weight and preterm delivery among singletons conceived with all types of ART; however, there remains uncertainty about whether these risks stem from the treatment or the parental infertility. For some outcomes, data of an increased risk with ART are suggestive at best largely because of lack of purposeful study of sufficient size and scope. These include specific perinatal morbidities, birth defects, developmental disabilities, and retinoblastoma. The evidence for an association between ART and spontaneous abortion is inconsistent and weak. There is inconclusive evidence that ART may be associated with genetic imprinting disorders. For childhood cancer, chronic conditions, learning and behavioral disorders, and reproductive effects there is insufficient empirical research to date, but given the data for more proximal outcomes, these outcomes merit further study. Future research needs to address the unique methodological challenges underlying study in this area.     

Fertility preservation in female cancer survivors.

The advancement of cancer therapies over the last few decades has significantly improved long-term survival of cancer patients, especially children and adolescents. As many of the therapeutic agents used are highly cytotoxic, cancer survivors have to pay the price of enduring various immediate and long-term side-effects. Unfortunately, gonadal failure and infertility are among the most common long-term side-effects, resulting in distress, lowered self-esteem and quality of life. Three modalities of fertility preservation can be offered to female patients prior to commencing their cancer treatment: embryo, oocyte and ovarian tissue cryopreservation. This paper reviews the outcomes for female patients who underwent fertility preservation in University College Hospital between 1995 and 2005, and post-therapeutic use of their frozen specimens. In addition, the effects of cytotoxic agents on fertility and ovarian function, and the range of fertility preservation available for female cancer sufferers are also discussed.     

Assisted reproduction and breast cancer

Breast cancer is the most frequent cancer in reproductive age women. Although well known causal link between estrogen and breast cancer, the impact of ovulation induction on the risk of breast cancer still remains to be clarified. One of the recently recognized long term adverse effects of adjuvant cytotoxic chemotherapy given for breast cancer is premature ovarian failure and infertility, both of which significantly compromise the quality of life of a cancer survivor. Thanks to significant developments in assisted reproductive technologies these patients may benefit from a wide range of fertility preservation options. The most established technique is embryo cryopreservation; oocyte cryopreservation can be considered in single women; both of which require at least 2 weeks of ovarian stimulation beginning with the onset of the patient's menstrual cycle. Novel ovarian stimulation protocols using tamoxifen and letrozole can be used to increase the margin of safety in estrogen sensitive breast tumors. When there is no time available for ovulation induction, ovarian tissue can be cryopreserved for future transplantation without delay in cancer therapy. The benefit of ovarian protection by gonadotropin-releasing hormone analogues is unproven and unlikely, and thus this treatment should not be recommended as the sole method of fertility preservation.     

子宫腺肌病合并不孕患者的生殖预后及助孕策略

在子宫结构异常疾病中，子宫腺肌病在育龄妇女中有较高的发病率。随着影像技术和治疗水平的提高，越来越多的研究表明子宫腺肌病可能影响育龄妇女的生育能力。子宫腺肌病合并不孕的机制尚不明确，子宫内膜容受性异常、子宫结合带的结构异常、免疫功能异常等可能是子宫腺肌病患者生育能力低下的原因。希望保留生育能力的主要治疗方案有药物治疗、辅助生殖技术（ART）和手术切除子宫腺肌病灶。目前，ART可以改善子宫腺肌病合并不孕症患者的妊娠结局，促性腺激素释放激素类似物对生殖有积极的影响，在子宫腺肌病合并不孕症应用中有很重要的价值。综述子宫腺肌病合并不孕症影响生育的可能机制、生殖结局及治疗策略以探讨子宫腺肌病与不孕的关系。     

Fertility preservation and pregnancy outcome after malignancy

PURPOSE OF REVIEW: The overall survival and cure rates of patients with childhood and adult malignancies have improved dramatically, but cancer treatment can be associated with diminished reproductive potential. However, research on the preservation of fertility in these patients has given patients new options. This article discusses the mechanisms of reproductive failure after cancer therapy and the currently available fertility preservation strategies. RECENT FINDINGS: Ovarian transposition is still a viable option if radiotherapy is to be used alone. Modifications in assisted reproductive technology that decrease peak estradiol levels are ideal for breast cancer survivors. Embryo freezing technology offers excellent pregnancy rates. Oocyte freezing is available for women without a partner, but there is more limited experience with this technique. Understanding the concepts of graft function after the autotransplantation of frozen-thawed ovarian tissue has resulted in great strides in the technical requirements for success. SUMMARY: Gonadotropin-releasing hormone analogues are the only available medical protection means for gonadotoxic chemotherapy. Assisted reproductive technology offers excellent results, but the protocols require a delay in implementing chemotherapy. Despite recent reports of embryo development after the transplantation of cryopreserved-thawed ovarian tissue, clinical experience is limited and the technique remains experimental.     

高龄女性不孕诊治指南

随着越来越多的育龄夫妇推迟其生育计划,以及我国“二孩政策”全面放开,高龄希望生育父母的比例逐渐增加。然而,随着女性年龄增加,卵巢功能逐渐下降,且子宫肌瘤、瘢痕子宫、盆腔炎症等发生率显著增加,不孕症的发生率逐渐增加。高龄女性即使通过辅助生殖技术(ART)获得成功妊娠,妊娠并发症风险和内、外科合并症的发生风险亦会随年龄增大而增加,如流产、胎死宫内、低出生体质量、早产以及妊娠期糖尿病和高血压疾病等。对于高龄不孕患者的诊治策略目前尚缺乏一致性,患者的诊治疗效更是参差不齐。基于以上情况,中国医师协会生殖医学专业委员会组织生殖内分泌及ART专家编写了本“高龄女性不孕诊治指南”,希望本指南可以规范我国高龄不孕女性患者的诊治流程。本指南从高龄女性的生育状况、需要进行的相关生育力评估及指标解读以及高龄女性孕前身体和营养准备、咨询、相关妊娠风险评估等入手进行深入探讨,分析了目前临床、实验室的热点问题:高龄女性子代遗传学特征及评估、咨询以及相应的实验室筛查、诊断方法和操作规范。另外,对于高龄女性妇产科及内外科合并症发生率高的状况,针对不同合并症状况探讨了相应的诊疗规范。最后,综合各方面情况制定了高龄女性不孕症的助孕策略,为高龄不孕女性的诊治提供依据和指导。     

The cost of preterm birth and cesarean section as a result of infertility and its treatment: A review

Infertility, irrespective of receipt of fertility treatment, is associated with an increased risk of adverse pregnancy outcomes, including cesarean section (CS) and preterm birth (PTB). These complications are associated with significant physical, mental, emotional, social, and financial costs to individuals, healthcare systems, and society at large. Although multiple pregnancy is one of the most significant contributors to the elevated CS and PTB rates in women receiving fertility treatment, singleton pregnancy is also at an increased risk of these outcomes. Single embryo transfer policies through publicly funded in vitro fertilization programs have demonstrated beneficial health outcomes and cost savings. Low-dose aspirin prophylaxis may be considered for PTB reduction in patients with infertility. Finally, upstream prevention strategies such as lifestyle modification and social policies to address the underlying needs for fertility treatment may also beneficially impact both CS and PTB rates.     

子宫内膜不典型增生和早期子宫内膜癌保守治疗方案分析

随着癌症发病的年轻化,患有子宫内膜癌的育龄期女性越来越多。为了保留生育能力,大部分患者倾向于保守治疗。故而众多研究者提出了子宫内膜不典型增生和早期子宫内膜癌的保守治疗方案,并在临床上进行了小样本研究。传统治疗以口服大剂量孕激素为主,然而多数口服孕激素治疗的患者复发率高、并发症多。左炔诺孕酮宫内缓释节育系统通过局部作用于子宫内膜,可减少大量孕激素对机体造成的不良反应。宫腔镜能够精准切除病灶,保护正常子宫内膜,相对降低了发生不孕、流产风险。二甲双胍的抗肿瘤作用能增加孕激素的有效率。通过综述子宫内膜不典型增生和早期子宫内膜癌各种保守治疗后的缓解率、复发率和妊娠结局,为临床上在治疗前对每位患者的自身因素及疾病特点进行评估,以采取对患者最有益的治疗方案及管理模式提供依据。     

Pregnancy complications in women with polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. There is an increasing body of evidence indicating that PCOS may have significant implications for pregnancy outcomes and long-term health of a woman and her offspring. Whether or not PCOS itself or the symptoms that coincide with PCOS, like obesity and fertility treatment, are responsible for these increased risks is a continuing matter of debate. Miscarriage rates among women with PCOS are believed to be increased compared with normal fertile women, although supporting evidence is limited. Pregnant women with PCOS experience a higher incidence of perinatal morbidity from gestational diabetes, pregnancy-induced hypertension, and preeclampsia. Their babies are at an increased risk of neonatal complications, such as preterm birth and admission at a neonatal intensive care unit. Pre-pregnancy, antenatal, and intrapartum care should be aimed at reducing these risks. The use of insulin sensitizing drugs to decrease hyperinsulinemic insulin resistance has been proposed during pregnancy to reduce the risk of developing preeclampsia or gestational diabetes. Although metformin appears to be safe, there are too few data from prospective, randomized controlled trials to support treatment during pregnancy.     

A review of fertility preservation in patients with breast cancer

Breast cancer remains the most common cancer diagnosed in women and causes more lost disability-adjusted life years (DALYs) than any other cancer worldwide; however, improvements in therapies have led to increased survival and therefore a new focus on quality of life following treatment. Fertility is an important concern among cancer survivors of reproductive age. The purpose of this article is to contextualize the importance of oncofertility services for women with breast cancer and review options for fertility preservation, including oocyte/embryo cryopreservation, GnRH agonist therapy, and ovarian tissue cryopreservation. We also discuss special considerations for preimplantation genetic testing for women with germline pathogenic mutations associated with breast cancer, as well as issues related to endocrine therapy. Finally, we review barriers to accessing fertility preservation services, including cost of treatment and lack of referral to reproductive care providers or fertility preservation programs.     

有生育要求子宫内膜异位症患者的手术处理

子宫内膜异位症是引起育龄期女性慢性盆腔痛、痛经及不孕的主要因素之一,对有生育要求的患者,手术是最佳治疗方法的观点已得到公认。手术方式的选择至关重要,积极去除子宫内膜异位症病灶,可有效改善妊娠率,缓解疼痛。文章针对有生育要求子宫内膜异位症患者的手术方式及效果进行了探讨。