New expert advice on cancer in pregnancy.

Cancer in pregnancy is rare, and most physicians lack knowledge in handling pregnant cancer patients. This review summarises the present knowledge on this condition. In the Netherlands, an Advisory Board on Cancer in Pregnancy was established in 2012. The board supports Dutch physicians' decisions in the management of pregnant patients with cancer. In 2021 the International Advisory Board on Cancer in Pregnancy was established, and in continuation, the Danish Advisory Board on Cancer in Pregnancy (DABCIP) has now been founded. DABCIP consists of 22 members from 13 different medical disciplines.

Midkine characterization in human ovaries: potential new variants in follicles.

OBJECTIVE: To characterize the growth factor midkine (MDK) in the human ovary to determine whether MDK is produced locally within the ovary, examine whether different ovarian cell types are more likely to produce MDK, and determine whether there are any stage-specific variations during follicle growth. Previous studies have revealed that MDK potentially affects human follicle growth and oocyte maturation. Proteomic analyses in follicular fluid (FF) have identified MDK to functionally cluster together and follow a similar expression profile to that of well-known proteins involved in ovarian follicle development. Midkine has not yet been characterized in the human ovary. DESIGN: Descriptive study. SETTING: University Hospital. PATIENTS: The study included samples from 121 patients: 71 patients (aged 17-37 years) who underwent ovarian tissue cryopreservation provided granulosa cells (GC), cumulus cells, ovarian cortex, medulla tissue, and FF from small antral follicles (SAF); and 50 patients (aged 20-35 years) receiving in vitro fertilization treatment provided FF from preovulatory follicles before and after induction of final follicle maturation. INTERVENTIONS: None. MAIN OUTCOME MEASURES: MDK relative gene expression was quantified using a real-time quantitative polymerase chain reaction in cumulus cells, GC, and medulla tissue. Additionally, immunostaining and western blotting assays were used to detect MDK protein in the ovarian cortex, which contains preantral follicles, SAF, and medulla tissue. Furthermore, enzyme-linked immunosorbent assay analyses were performed to measure the concentration of MDK in FF aspirated from SAF and preovulatory follicles both before and 36 hours after inducing the final maturation of follicles. RESULTS: Immunostaining and reverse transcription-quantitative polymerase chain reaction revealed a more prominent expression of MDK in GC compared with other ovarian cell types. Intrafollicular MDK concentration was significantly higher in SAF compared with preovulatory follicles. In addition, different molecular weight species of MDK were detected using western blotting in various ovarian sample types: GC and FF samples presented primarily one band of approximately 15 kDa and an additional band of approximately 13 kDa, although other bands with higher molecular weight (between 30 and 38 kDa) were detected in medulla tissue. CONCLUSIONS: This is the first time that MDK has been immunolocalized in human ovarian cells at the protein level and that potentially different MDK variants have been detected in human FF, GC, and ovarian medulla tissue. Future studies are needed to sequence and identify the different potential MDK variants found to determine their functional importance for ovary and oocyte competence.

Incidence and outcomes of uterine rupture in women with unscarred, preterm or prelabour uteri: data from the international network of obstetric survey systems.

OBJECTIVE: Analysis of atypical cases of uterine rupture, namely, uterine rupture occurring in unscarred, preterm or prelabour uteri. DESIGN: Descriptive multi-country population-based study. SETTING: Ten high-income countries within the International Network of Obstetric Survey Systems. POPULATION: Women with unscarred, preterm or prelabour ruptured uteri. METHODS: We merged prospectively collected individual patient data in ten population-based studies of women with complete uterine rupture. In this analysis, we focused on women with uterine rupture of unscarred, preterm or prelabour ruptured uteri. MAIN OUTCOME MEASURES: Incidence, women's characteristics, presentation and maternal and perinatal outcome. RESULTS: We identified 357 atypical uterine ruptures in 3 064 923 women giving birth. Estimated incidence was 0.2 per 10 000 women (95% CI 0.2-0.3) in the unscarred uteri, 0.5 (95% CI 0.5-0.6) in the preterm uteri, 0.7 (95% CI 0.6-0.8) in the prelabour uteri, and 0.5 (95% CI 0.4-0.5) in the group with no previous caesarean. Atypical uterine rupture resulted in peripartum hysterectomy in 66 women (18.5%, 95% CI 14.3-23.5%), three maternal deaths (0.84%, 95% CI 0.17-2.5%) and perinatal death in 62 infants (19.7%, 95% CI 15.1-25.3%). CONCLUSIONS: Uterine rupture in preterm, prelabour or unscarred uteri are extremely uncommon but were associated with severe maternal and perinatal outcome. We found a mix of risk factors in unscarred uteri, most preterm uterine ruptures occurred in caesarean-scarred uteri and most prelabour uterine ruptures in 'otherwise' scarred uteri. This study may increase awareness among clinicians and raise suspicion of the possibility of uterine rupture under these less expected conditions.

Cryopreservation of ovarian tissue as fertility preservation in young women with multiple sclerosis before stem cell transplantation.

BACKGROUND: Women of fertile age who receive autologous hematopoietic stem cell transplantation (AHSCT) due to multiple sclerosis (MS) are at risk of loss of ovarian function and infertility because of the conditioning regimen with alkylating agents. OBJECTIVE: To present our data on fertility preservation by ovarian tissue cryopreservation (OTC) in young women with MS before AHSCT. METHODS: Retrospective, observational cohort study RESULTS: Eight women had OTC. After AHSCT four had premature ovarian insufficiency (POI), and two of these had autotransplantation of their cryopreserved ovarian tissue. Both women regained ovarian function, and a spontaneous pregnancy was achieved resulting in the delivery of a healthy baby. CONCLUSION: OTC preserves fertility in young women with MS at risk of POI.

Reproductive and Endocrine Outcomes in a Cohort of Danish Women following Auto-Transplantation of Frozen/Thawed Ovarian Tissue from a Single Center.

Ovarian tissue cryopreservation (OTC) is a method of fertility preservation in girls and young women prior to gonadotoxic treatment. It is a safe and promising method to restore fertility. The initial recovery of endocrine function is high, but the longevity of the grafted tissue varies. In this single-center, combined retro- and prospective cohort study, we report the reproductive outcome and hormonal recovery following ovarian tissue transplantation (OTT) and evaluate possible predictors of the chance of pregnancy. The study includes 40 women from eastern Denmark undergoing 53 OTTs between 2003 and 2021. Permission to obtain retrospective data was given by the Danish Patient Safety Authorities and prospective data-collection by informed consent. Initial recovery of endocrine function was seen in 18/19 women with POI, and ongoing function of the grafted tissue in 7/14 two years from OTT. Live birth rate (LBR) was 41%, with 20 children to 39 women trying to conceive. Women who conceived had higher AFC at the time of OTC than women who did not (p ± 0.04). Repeated transplantations were not successful in terms of delivery. Half of all pregnancies were achieved by ART, but PRs were lower after ART than by spontaneous conception. LBRs after OTT are encouraging. Chance of pregnancy after OTT is correlated to ovarian reserve at OTC. Repeated transplantations were not successful in terms of unfulfilled pregnancy wish.

Fresh and cryopreserved ovarian tissue transplantation for preserving reproductive and endocrine function: a systematic review and individual patient data meta-analysis.

BACKGROUND: Ovarian tissue cryopreservation involves freezing and storing of surgically retrieved ovarian tissue in liquid or vapour nitrogen below -190°C. The tissue can be thawed and transplanted back with the aim of restoring fertility or ovarian endocrine function. The techniques for human ovarian tissue freezing and transplantation have evolved over the last 20 years, particularly in the context of fertility preservation in pre-pubertal cancer patients. Fresh ovarian tissue transplantation, using an autograft or donor tissue, is a more recent development; it has the potential to preserve fertility and hormonal function in women who have their ovaries removed for benign gynaecological conditions. The techniques of ovarian tissue cryopreservation and transplantation have progressed rapidly since inception; however, the evidence on the success of this intervention is largely based on case reports and case series. OBJECTIVE AND RATIONALE: The aim of this study was to systematically review the current evidence by incorporating study-level and individual patient-level meta-analyses of women who received ovarian transplants, including frozen-thawed transplant, fresh or donor graft. SEARCH METHODS: The review protocol was registered with PROSPERO (CRD42018115233). A comprehensive literature search was performed using MEDLINE, EMBASE, CINAHL and Cochrane Central Register of Controlled Trials from database inception to October 2020. Authors were also contacted for individual patient data if relevant outcomes were not reported in the published manuscripts. Meta-analysis was performed using inverse-variance weighting to calculate summary estimates using a fixed-effects model. OUTCOMES: The review included 87 studies (735 women). Twenty studies reported on ≥5 cases of ovarian transplants and were included in the meta-analysis (568 women). Fertility outcomes included pregnancy, live birth and miscarriage rates, and endocrine outcomes included oestrogen, FSH and LH levels. The pooled rates were 37% (95% CI: 32-43%) for pregnancy, 28% (95% CI: 24-34%) for live birth and 37% (95% CI: 30-46%) for miscarriage following frozen ovarian tissue transplantation. Pooled mean for pre-transplant oestrogen was 101.6 pmol/l (95% CI: 47.9-155.3), which increased post-transplant to 522.4 pmol/l (95% CI: 315.4-729; mean difference: 228.24; 95% CI: 180.5-276). Pooled mean of pre-transplant FSH was 66.4 IU/l (95% CI: 52.8-84), which decreased post-transplant to 14.1 IU/l (95% CI: 10.9-17.3; mean difference 61.8; 95% CI: 57-66.6). The median time to return of FSH to a value <25 IU/l was 19 weeks (interquartile range: 15-26 weeks; range: 0.4-208 weeks). The median duration of graft function was 2.5 years (interquartile range: 1.4-3.4 years; range: 0.7-5 years). The analysis demonstrated that ovarian tissue cryopreservation and transplantation could restore reproductive and hormonal functions in women. Further studies with larger samples of well-characterized populations are required to define the optimal retrieval, cryopreservation and transplantation processes. WIDER IMPLICATIONS: Ovarian tissue cryopreservation and transplantation may not only be effective in restoring fertility but also the return of reproductive endocrine function. Although this technology was developed as a fertility preservation option, it may have the scope to be considered for endocrine function preservation.

[Fertility preservation].

Fertility preservation should be considered in girls and young women faced with a potentially gonadotoxic treatment such as chemotherapy. IVF can be performed with the aim to collect and freeze the oocytes, or ovarian tissue can be cryopreserved and transplanted back to the patient at a later stage. Whichever method is chosen depends upon the age of the patient, the gonadotoxicity of her treatment and the time frame. It is important to refer young cancer patients to fertility preservation counselling before treatment starts, as argued in this review.

Use of cryopreserved ovarian tissue in the Danish fertility preservation cohort.

OBJECTIVE: To evaluate the use of cryopreserved ovarian tissue in the Danish fertility preservation cohort. DESIGN: Retrospective cohort study. SETTING: University hospitals and fertility clinics. PATIENT(S): Ovarian tissue cryopreservation (OTC) was performed for 1,186 Danish girls and women from 1999-2020, of whom 117 subsequently underwent ovarian tissue transplantation (OTT). Subgroup 1 included 759 patients with a follow-up period of >5 years. Out of these, OTT rates were further analyzed for those patients who were alive and aged >24 years in July 2020 (subgroup 2; n = 554). INTERVENTION(S): OTC and OTT. MAIN OUTCOME MEASURE(S): OTT, death, donation of tissue. RESULT(S): In subgroup 1, 14% of the patients had undergone OTT, 18% had died, 9% had donated their tissue for research, and 59% still had their tissue stored. In subgroup 2, 19% had undergone OTT and for most diagnoses the OTT rates ranged from 15% to 22% with benign hematologic diseases having the highest OTT rate (35%). On the basis of the entire cohort, stratified age analysis indicated that women aged ≥30 years at OTC were more likely to return for OTT than women aged 18-29 years at OTC; mean storage times were 3.7 and 3.6 years, respectively. Only 4% of the girls aged <18 years at OTC had undergone OTT. CONCLUSION(S): The OTT rates depended on the diagnosis, age at OTC, and follow-up time. Specific criteria are needed for reporting and comparing OTT rates. Six out of 10 patients still had their cryopreserved tissue stored and longer follow-up is needed, especially for younger girls.

How Do Young Women with Cancer Experience Oncofertility Counselling during Cancer Treatment? A Qualitative, Single Centre Study at a Danish Tertiary Hospital.

BACKGROUND: Adolescents and young adults (AYAs) with cancer are at risk of therapy-induced infertility. The importance of initial and specialized fertility counselling to this patient group is undisputed. Despite international guidelines, oncofertility counselling is still inadequate. The purpose of this study was to examine how female AYA cancer patients and survivors experienced initial and specialized oncofertility counselling, and to present their specific suggestions on how to improve the oncofertility counselling. METHODS: Twelve individual semi-structured interviews were performed with AYAs aged 20-35 with cancer or who were survivors. Participants were recruited via a youth support centre and social organization for AYAs with cancer. Data was analysed using thematic analysis. RESULTS: Three main themes were found: Support is needed for navigating the fertility information jungle; The doctor's approach determines the content of the patient consultation; Inadequate and worrying information causes mistrust and frustration. CONCLUSION: Results indicate a continuing problem regarding insufficient oncofertility counselling to AYAs with cancer. To ensure adequate and uniform information, especially in the initial oncofertility counselling, national guidelines for oncology specialists are suggested including multidisciplinary effort and collaboration between oncology and fertility specialists in mind. In addition, participants suggest focus on communication skills.

Management of major obstetric hemorrhage prior to peripartum hysterectomy and outcomes across nine European countries.

INTRODUCTION: Peripartum hysterectomy is applied as a surgical intervention of last resort for major obstetric hemorrhage. It is performed in an emergency setting except for women with a strong suspicion of placenta accreta spectrum (PAS), where it may be anticipated before cesarean section. The aim of this study was to compare management strategies in the case of obstetric hemorrhage leading to hysterectomy, between nine European countries participating in the International Network of Obstetric Survey Systems (INOSS), and to describe pooled maternal and neonatal outcomes following peripartum hysterectomy. MATERIAL AND METHODS: We merged data from nine nationwide or multi-regional obstetric surveillance studies performed in Belgium, Denmark, Finland, France, Italy, the Netherlands, Slovakia, Sweden and the UK collected between 2004 and 2016. Hysterectomies performed from 22 gestational weeks up to 48 h postpartum due to obstetric hemorrhage were included. Stratifying women with and without PAS, procedures performed in the management of obstetric hemorrhage prior to hysterectomy between countries were counted and compared. Prevalence of maternal mortality, complications after hysterectomy and neonatal adverse events (stillbirth or neonatal mortality) were calculated. RESULTS: A total of 1302 women with peripartum hysterectomy were included. In women without PAS who had major obstetric hemorrhage leading to hysterectomy, uterotonics administration was lowest in Slovakia (48/73, 66%) and highest in Denmark (25/27, 93%), intrauterine balloon use was lowest in Slovakia (1/72, 1%) and highest in Denmark (11/27, 41%), and interventional radiology varied between 0/27 in Denmark and Slovakia to 11/59 (79%) in Belgium. In women with PAS, uterotonics administration was lowest in Finland (5/16, 31%) and highest in the UK (84/103, 82%), intrauterine balloon use varied between 0/14 in Belgium and Slovakia to 29/103 (28%) in the UK. Interventional radiology was lowest in Denmark (0/16) and highest in Finland (9/15, 60%). Maternal mortality occurred in 14/1226 (1%), the most common complications were hematologic (95/1202, 8%) and respiratory (81/1101, 7%). Adverse neonatal events were observed in 79/1259 (6%) births. CONCLUSIONS: Management of obstetric hemorrhage in women who eventually underwent peripartum hysterectomy varied greatly between these nine European countries. This potentially life-saving procedure is associated with substantial adverse maternal and neonatal outcome.

Annual incidence of severe ovarian hyperstimulation syndrome.

INTRODUCTION: Ovarian hyperstimulation syndrome (OHSS) is one of the major complications of assisted reproductive technology treatment. We assumed that it had declined in recent years owing to the options of new preventive strategies. The aim of the present study was to investigate the annual incidence of OHSS in Denmark in the course of a 17-year period. METHODS: This was a national register-based historical cohort study including all women with an OHSS diagnosis admitted to Danish hospitals between 2001 and 2017. Data included information on all OHSS diagnoses, duration of hospital stay, early pregnancy complications and other complications like thromboembolism and ovarian torsion. The annual number of initiated stimulated in vitro fertilisation (IVF)/intracytoplasmic sperm injection (ICSI) cycles was based on the annual reporting by the Danish Fertility Society. RESULTS: From 2001 to 2017, a total of 2,261 (1.2%) women with an OHSS admission were identified among 186,168 stimulated IVF/ICSI cycles. The annual incidence of OHSS varied from 0.9% to 1.2-1.4% with no overall change over time (p = 0.24. Early OHSS (defined as OHSS without a pregnancy in the cycle) was seen in 48.5% of the events, late OHSS (defined as OHSS with a pregnancy in the cycle) in 51.2% of cycles. Among all women with OHSS, 75% were hospitalised for more than 24 hours, with mean 4.3 and 6.2 days in hospital for early and late OHSS, respectively. CONCLUSIONS: The annual incidence of severe OHSS leading to a hospital admission remained stable for 17 years, which suggests that OHSS preventive actions like use of antagonist cycles, agonist triggering and freeze all should be better implemented in Denmark. FUNDING: none. TRIAL REGISTRATION: not relevant.

Epidemiological analysis of peripartum hysterectomy across nine European countries.

INTRODUCTION: Peripartum hysterectomy is a surgical procedure performed for severe obstetric complications such as major obstetric hemorrhage. The prevalence of peripartum hysterectomy in high-resource settings is relatively low. Hence, international comparisons and studying indications and associations with mode of birth rely on the use of national obstetric survey data. Objectives were to calculate the prevalence and indications of peripartum hysterectomy and its association with national cesarean section rates and mode of birth in nine European countries. MATERIAL AND METHODS: We performed a descriptive, multinational, population-based study among women who underwent peripartum hysterectomy. Data were collected from national or multiregional databases from nine countries participating in the International Network of Obstetric Survey Systems. We included hysterectomies performed from 22 gestational weeks up to 48 hours postpartum for obstetric hemorrhage, as this was the most restrictive, overlapping case definition between all countries. Main outcomes were prevalence and indications of peripartum hysterectomy. Additionally, we compared prevalence of peripartum hysterectomy between women giving birth vaginally and by cesarean section, and between women giving birth with and without previous cesarean section. Finally, we calculated correlation between prevalence of peripartum hysterectomy and national cesarean section rates, as well as national rates of women giving birth after a previous cesarean section. RESULTS: A total of 1302 peripartum hysterectomies were performed in 2 498 013 births, leading to a prevalence of 5.2 per 10 000 births ranging from 2.6 in Denmark to 10.7 in Italy. Main indications were uterine atony (35.3%) and abnormally invasive placenta (34.8%). Relative risk of hysterectomy after cesarean section compared with vaginal birth was 9.1 (95% CI 8.0-10.4). Relative risk for hysterectomy for birth after previous cesarean section compared with birth without previous cesarean section was 10.6 (95% CI 9.4-12.1). A strong correlation was observed between national cesarean section rate and prevalence of peripartum hysterectomy (ρ = 0.67, P < .05). CONCLUSIONS: Prevalence of peripartum hysterectomy may vary considerably between high-income countries. Uterine atony and abnormally invasive placenta are the commonest indications for hysterectomy. Birth by cesarean section and birth after previous cesarean section are associated with nine-fold increased risk of peripartum hysterectomy.

Effect of sphingosine-1-phosphate on activation of dormant follicles in murine and human ovarian tissue.

In vitro activation of resting ovarian follicles, with the use of mechanical stress and/or pharmacological compounds, is an emerging and novel approach for infertility treatment. The aim of this study was to assess the sphingolipid, sphingosine-1-phosphate (S1P), as a potential in vitro activation agent in murine and human ovarian tissues and isolated follicles. Juvenile murine ovaries and donated human ovarian tissues, from 10 women undergoing ovarian tissue cryopreservation for fertility preservation, were incubated with or without 12 µM S1P for 3 h for quantitative PCR analysis, and 12 h for xenotransplantation or culture studies. Gene expression analyses were performed for genes downstream of the Hippo signaling pathway. Murine ovaries and isolated murine and human preantral follicles showed significantly increased mRNA expression levels of Ccn2/CCN2 following S1P treatment compared to controls. This increase was shown to be specific for the Hippo signaling pathway and for the S1P2 receptor, as co-treatment with Hippo-inhibitor, verteporfin and S1PR2 antagonist, JTE-013, reduced the S1P-induced Ccn2 gene expression in murine ovaries. Histological evaluation of human cortical tissues (5 × 5 × 1 mm; n = 30; three pieces per patient) xenografted for 6 weeks and juvenile murine ovaries cultured for 4 days (n = 9) or allografted for 2 weeks (n = 48) showed no differences in the distribution of resting or growing follicles in S1P-treated ovarian tissues compared to controls. Collectively, S1P increased Ccn2/CCN2 gene expression in isolated preantral follicles and ovarian tissue from mice and human, but it did not promote follicle activation or growth in vivo. Thus, S1P does not appear to be a potent in vitro activation agent under these experimental conditions.

Improving the maturation rate of human oocytes collected ex vivo during the cryopreservation of ovarian tissue.

PURPOSE: The aim of the present study was to improve the in vitro maturation (IVM) procedure using oocytes from surplus ovarian tissue after fertility preservation. METHODS: Twenty-five patients aged 17-37 years were included in the study. Maturation was compared between oocytes collected in HEPES-buffered medium or saline, and we determined whether transport on ice prior to oocyte collection affected maturation. Two different IVM media were used that were supplemented with and without recombinant human midkine. Mature oocytes were assessed for aneuploidy using next-generation sequencing (NGS). RESULTS: On average, 36 immature oocytes were collected from each patient (range 7-90, N = 895). Oocytes recovered from HEPES-buffered medium matured at a higher rate than oocytes recovered from saline (36% vs 26%, p < 0.01). Ovarian transportation on ice prior to the procedure negatively affected maturation compared with non-transported samples (42% vs 27%, p < 0.01). The addition of midkine improved maturation rate (34% vs 27%, p < 0.05). On average, 11 MII oocytes were obtained per patient (range 1-30). NGS of 53 MII oocytes and their first polar bodies indicated that 64% were euploid. CONCLUSIONS: The study demonstrated unexpectedly high number of immature oocytes collected from surplus ovarian tissue without any stimulation. The overall MII rate was one in three, resulting in a total number of MII oocytes that was similar to the number obtained after ovarian stimulation. If these MII oocytes prove suitable for IVF, they will provide a substantial improvement in fertility preservation for patients and advance IVM as an interesting platform for further improvements in assisted reproduction.

The precise ovarian volume is significantly associated with serum concentrations of antimüllerian hormone, the luteinizing hormone/follicle-stimulating hormone ratio, and total testosterone.

OBJECTIVE: To evaluate potential associations between concentrations of antimüllerian hormone (AMH) and T as well as the LH/FSH ratio and the unbiased precise ovarian volume obtained after unilateral ovariectomy. DESIGN: Cohort study. SETTING: University hospital. PATIENT(S): A total of 765 patients having one ovary surgically removed for fertility preservation. Inclusion criteria were age >15 years and ovarian volume <25 mL; 386 women had one or more hormone parameter (AMH, LH, FSH, or total T) determined before oophorectomy. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): A precise weight of the ovary was equated with ovarian volume. Associations between ovarian volume and AMH, the LH/FSH ratio, T concentrations, and body mass index (BMI) were evaluated. Patient characteristics in relation to ovarian volume cutoff values between 8 and 12 mL were also examined. RESULT(S): Ovarian volume was significantly positively associated with concentrations of AMH, the LH/FSH ratio, and T. Ovarian volume, concentrations of AMH and LH, and the LH/FSH ratio were significantly augmented in women having ovarian volumes above a threshold of 8, 9, and 10 mL compared with those below. Average age, FSH, and T concentrations did not differ between below and above the 10 mL threshold. There was a significant association between BMI and ovarian volume and BMI and T, while other hormone parameters were nonsignificant. CONCLUSION(S): The precise ovarian volume reflected ovarian activity measured as circulating concentrations of AMH and T as well as the LH/FSH ratio. These significant associations showed continuous progression, and a 10 mL threshold offered no clear difference compared with other volume threshold values.

[Fertility counselling of younger women after cancer treatment].

Girls and younger women of fertile age are at risk of infertility and premature ovarian insufficiency, if they have received chemotherapy or radiotherapy. While many are offered fertility preservation before treatment, many are left with a need for follow-up after treatment, which is pointed out in this review. At the fertility clinic at Rigshospitalet, Denmark, a follow-up clinic has been introduced for previous cancer patients with focus on reproductive health, including assessment of ovarian function, planning of future pregnancies and initiation of hormone replacement therapy if needed.

Ovarian stimulation and assisted reproductive technology outcomes in women transplanted with cryopreserved ovarian tissue: a systematic review.

OBJECTIVE: To systematically review reproductive outcomes of assisted reproductive technology (ART) treatment in women transplanted with frozen-thawed ovarian tissue. DESIGN: Systematic review in accordance with guidelines from Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). SETTING: Not applicable. PATIENT(S): Women undergoing ovarian tissue transplantation (OTT) and subsequent ART. INTERVENTION(S): Literature search in PubMed and Scopus databases. MAIN OUTCOME MEASURE(S): Time from OTT to initiation of ART, stimulation protocol, and conventional ART outcome measures. RESULT(S): Twenty studies (including 15 case reports), specifying ART treatments and outcomes of 40 women undergoing OTT were identified. Multiple stimulation protocols were applied, with the modified natural cycle as the most frequently used. In total, 195 ART cycles were performed (4.0 cycles per patient) resulting in 1.5 follicles and 1.0 mature oocyte retrieved per cycle. Empty follicle rates ranged from 23% to 35% in the three largest cohort studies. Twenty-five women (62.5%) had one or more pregnancies, of which 28.6% were lost, resulting in a total of 20 live births (22 children). Overall the pregnancy rates varied from 3.9% to 19.3% and live-birth rates from 3.9% to 14.0% per cycle in the three cohort studies. Fertility treatment was initiated shortly after OTT in some centers, while others awaited natural conception before embarking on ART treatment. CONCLUSION(S): The reported pregnancy and live-birth rates for women undergoing OTT and ART were considerably lower than those of the general in vitro fertilization (IVF) population, corresponding to patients with poor ovarian reserve. In general, ART outcomes are underreported, and there is a lack of consensus regarding the timing of ART in relation to OTT and the type of ovarian stimulation protocol.

Chromosome errors in human eggs shape natural fertility over reproductive life span.

Chromosome errors, or aneuploidy, affect an exceptionally high number of human conceptions, causing pregnancy loss and congenital disorders. Here, we have followed chromosome segregation in human oocytes from females aged 9 to 43 years and report that aneuploidy follows a U-curve. Specific segregation error types show different age dependencies, providing a quantitative explanation for the U-curve. Whole-chromosome nondisjunction events are preferentially associated with increased aneuploidy in young girls, whereas centromeric and more extensive cohesion loss limit fertility as women age. Our findings suggest that chromosomal errors originating in oocytes determine the curve of natural fertility in humans.