Clinical outcomes of uninterrupted embryo culture with or without time-lapse-based embryo selection versus interrupted standard culture (SelecTIMO): a three-armed, multicentre, double-blind, randomised controlled trial.

BACKGROUND: Time-lapse monitoring is increasingly used in fertility laboratories to culture and select embryos for transfer. This method is offered to couples with the promise of improving pregnancy chances, even though there is currently insufficient evidence for superior clinical results. We aimed to evaluate whether a potential improvement by time-lapse monitoring is caused by the time-lapse-based embryo selection method itself or the uninterrupted culture environment that is part of the system. METHODS: In this three-armed, multicentre, double-blind, randomised controlled trial, couples undergoing in-vitro fertilisation or intracytoplasmic sperm injection were recruited from 15 fertility clinics in the Netherlands and randomly assigned using a web-based, computerised randomisation service to one of three groups. Couples and physicians were masked to treatment group, but embryologists and laboratory technicians could not be. The time-lapse early embryo viability assessment (EEVA; TLE) group received embryo selection based on the EEVA time-lapse selection method and uninterrupted culture. The time-lapse routine (TLR) group received routine embryo selection and uninterrupted culture. The control group received routine embryo selection and interrupted culture. The co-primary endpoints were the cumulative ongoing pregnancy rate within 12 months in all women and the ongoing pregnancy rate after fresh single embryo transfer in a good prognosis population. Analysis was by intention to treat. This trial is registered on the ICTRP Search Portal, NTR5423, and is closed to new participants. FINDINGS: 1731 couples were randomly assigned between June 15, 2017, and March 31, 2020 (577 to the TLE group, 579 to the TLR group, and 575 to the control group). The 12-month cumulative ongoing pregnancy rate did not differ significantly between the three groups: 50·8% (293 of 577) in the TLE group, 50·9% (295 of 579) in the TLR group, and 49·4% (284 of 575) in the control group (p=0·85). The ongoing pregnancy rates after fresh single embryo transfer in a good prognosis population were 38·2% (125 of 327) in the TLE group, 36·8% (119 of 323) in the TLR group, and 37·8% (123 of 325) in the control group (p=0·90). Ten serious adverse events were reported (five TLE, four TLR, and one in the control group), which were not related to study procedures. INTERPRETATION: Neither time-lapse-based embryo selection using the EEVA test nor uninterrupted culture conditions in a time-lapse incubator improved clinical outcomes compared with routine methods. Widespread application of time-lapse monitoring for fertility treatments with the promise of improved results should be questioned. FUNDING: Health Care Efficiency Research programme from Netherlands Organisation for Health Research and Development and Merck.

Cost-effectiveness analysis of lifestyle intervention in obese infertile women.

STUDY QUESTION: What is the cost-effectiveness of lifestyle intervention preceding infertility treatment in obese infertile women? SUMMARY ANSWER: Lifestyle intervention preceding infertility treatment as compared to prompt infertility treatment in obese infertile women is not a cost-effective strategy in terms of healthy live birth rate within 24 months after randomization, but is more likely to be cost-effective using a longer follow-up period and live birth rate as endpoint. WHAT IS KNOWN ALREADY: In infertile couples, obesity decreases conception chances. We previously showed that lifestyle intervention prior to infertility treatment in obese infertile women did not increase the healthy singleton vaginal live birth rate at term, but increased natural conceptions, especially in anovulatory women. Cost-effectiveness analyses could provide relevant additional information to guide decisions regarding offering a lifestyle intervention to obese infertile women. STUDY DESIGN, SIZE, DURATION: The cost-effectiveness of lifestyle intervention preceding infertility treatment compared to prompt infertility treatment was evaluated based on data of a previous RCT, the LIFEstyle study. The primary outcome for effectiveness was the vaginal birth of a healthy singleton at term within 24 months after randomization (the healthy live birth rate). The economic evaluation was performed from a hospital perspective and included direct medical costs of the lifestyle intervention, infertility treatments, medication and pregnancy in the intervention and control group. In addition, we performed exploratory cost-effectiveness analyses of scenarios with additional effectiveness outcomes (overall live birth within 24 months and overall live birth conceived within 24 months) and of subgroups, i.e. of ovulatory and anovulatory women, women <36 years and ≥36 years of age and of completers of the lifestyle intervention. Bootstrap analyses were performed to assess the uncertainty surrounding cost-effectiveness. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Infertile women with a BMI of ≥29 kg/m2 (no upper limit) were allocated to a 6-month lifestyle intervention programme preceding infertility treatment (intervention group, n = 290) or to prompt infertility treatment (control group, n = 287). After excluding women who withdrew informed consent or who were lost to follow-up we included 280 women in the intervention group and 284 women in the control group in the analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Total mean costs per woman in the intervention group within 24 months after randomization were €4324 (SD €4276) versus €5603 (SD €4632) in the control group (cost difference of -€1278, P < 0.05). Healthy live birth rates were 27 and 35% in the intervention group and the control group, respectively (effect difference of -8.1%, P < 0.05), resulting in an incremental cost-effectiveness ratio of €15 845 per additional percentage increase of the healthy live birth rate. Mean costs per healthy live birth event were €15 932 in the intervention group and €15 912 in the control group. Exploratory scenario analyses showed that after changing the effectiveness outcome to all live births conceived within 24 months, irrespective of delivery within or after 24 months, cost-effectiveness of the lifestyle intervention improved. Using this effectiveness outcome, the probability that lifestyle intervention preceding infertility treatment was cost-effective in anovulatory women was 40%, in completers of the lifestyle intervention 39%, and in women ≥36 years 29%. LIMITATIONS, REASONS FOR CAUTION: In contrast to the study protocol, we were not able to perform the analysis from a societal perspective. Besides the primary outcome of the LIFEstyle study, we performed exploratory analyses using outcomes observed at longer follow-up times and we evaluated subgroups of women; the trial was not powered on these additional outcomes or subgroup analyses. WIDER IMPLICATIONS OF THE FINDINGS: Cost-effectiveness of a lifestyle intervention is more likely for longer follow-up times, and with live births conceived within 24 months as the effectiveness outcome. This effect was most profound in anovulatory women, in completers of the lifestyle intervention and in women ≥36 years old. This result indicates that the follow-up period of lifestyle interventions in obese infertile women is important. The scenario analyses performed in this study suggest that offering and reimbursing lifestyle intervention programmes in certain patient categories may be cost-effective and it provides directions for future research in this field. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by a grant from ZonMw, the Dutch Organization for Health Research and Development (50-50110-96-518). The department of obstetrics and gynaecology of the UMCG received an unrestricted educational grant from Ferring pharmaceuticals BV, The Netherlands. B.W.J.M. is a consultant for ObsEva, Geneva. TRIAL REGISTRATION NUMBER: The LIFEstyle RCT was registered at the Dutch trial registry (NTR 1530). http://www.trialregister.nl/trialreg/admin/rctview.asp?TC = 1530.

Premature ovarian insufficiency and perinatal parameters: A retrospective case-control study.

OBJECTIVE: The peak number of oocytes is reached during intrauterine development, after which numbers decline until reserves are depleted and a woman enters menopause. In premature ovarian insufficiency (POI), the process of follicle depletion occurs at a young age (generally taken as 40 years); the condition affects about 1% of women. In this study, we investigate whether women with POI had experienced a different perinatal milieu, as reflected in their birth weight or prematurity. STUDY DESIGN: In this retrospective case-control study, we evaluated whether women diagnosed with POI had a different birth weight or prematurity rate (<37 weeks) compared with women aged over 40 at natural menopause (the controls). Binary logistic regression models were used to analyze the data and correct for smoking. 59 women with POI and 92 controls were recruited. RESULTS: 13.6% of women diagnosed with POI were born prematurely, compared with 6.6% of controls (p=0.018). Corrected for gestational age, women with POI did not have a different birth weight compared with controls. As a consequence of the design of our study, mean age at time of interview differed significantly between groups, at 37.5 and 46 years respectively for women diagnosed with POI and controls. Years of oral contraception use, smoking, age at menarche, BMI and education levels were similar in the two groups. CONCLUSION: Our findings indicate that prematurity is a risk factor for POI. Prenatal factors contributing to prematurity, or postnatal factors that are the result of prematurity, may lead to early follicle depletion.

[Provisions for potentially raising the age limit for oocyte donation]. / Voorwaarden voor eventuele verhoging van de leeftijdsgrens bij eiceldonatiebehandeling.

The introduction ofoocyte donation has provided a new perspective on reproduction for women with premature ovarian failure. In contrast to other forms ofassisted reproductive technology, the success ofoocyte donation is not affected by the age of the future mother. This has prompted a discussion on raising the age limit to allow older women to become pregnant. The health risk for the future mother is increased in older women compared with younger women but does not appear to be a sufficient reason to disqualify older women from undergoing the procedure. Lack of information regarding the effect of very late parenthood on the medical, psychological and social well-being of the future child poses the greatest concern. Should the age limit be extended for oocyte donation, treatment should be restricted to a research setting with a protocol for single-embryo transfer and extensive follow-up regarding the well-being of the future child.

Assessment of ovarian reserve. Ovarian biopsy is not a valid method for the prediction of ovarian reserve.

The evaluation of ovarian reserve, often critical for the elderly infertile woman, is notoriously difficult and inaccurate. The place of ovarian biopsy in this evaluation has been hotly disputed for three decades, but not resolved. To examine the feasibility of ovarian biopsy for this purpose, a project was designed to estimate the total number of oocytes in a human ovary and investigate whether any biopsy regimen is representative of the follicular reserve in an individual. Ovaries removed from patients of reproductive age during operations not involving ovarian pathology were utilized to count the number and type of follicles found in multiple biopsies of 2 and 5 mm and in the whole ovary. Representative results taking into account the total number of follicles found in the whole ovary showed that predicted values based on the biopsies were extremely varied. We concluded that due to the huge variation in the distribution of follicles across the surface of the ovary, there is no place for this procedure in clinical evaluation of reproductive ageing in the individual patient.

Treatment concepts for premature ovarian failure.

Treatment concepts for premature ovarian failure concern restoration, preservation, and substitution of ovarian function. To date, there is no effective treatment to restore ovarian function. Preservation of ovarian function using cryopreservation and auto- or xenotransplantation will be possible in the near future. Regulation of the dynamics of the oocyte pool through GDF9 or AMH is not envisaged in the near future. Developments in estrogen receptor research may change treatment concepts in hormone replacement therapy.

[Premature ovarian failure]. / Prematuur ovarieel falen.

Premature ovarian failure is characterized by secondary oligomenorrhoea or amenorrhoea and serum follicle stimulating hormone (FSH) levels above 40 IU/l before or at the age of 40. The incidence is 1:1000 below age 30 and 1:100 below age 40. In the majority of cases a cause can not be identified. The chance to conceive spontaneously after premature ovarian failure is estimated at 5-10%. There is no treatment available to restore ovarian function and increase the pregnancy rate. In vitro fertilisation using oocyte donation is the only successful fertility treatment option. Climacteric symptoms can be treated with hormone replacement therapy. In the absence of symptoms and when bone mineral density is normal there is no need for hormone replacement therapy. In the near future cryopreservation of ovarian tissue will offer some hope to women at risk to develop premature ovarian failure, e.g. women from families with familial premature ovarian failure and women scheduled to undergo chemotherapy or radiotherapy at a young age.

Incipient ovarian failure and premature ovarian failure show the same immunological profile.

PROBLEM: Incipient ovarian failure (IOF) is characterized by regular menstrual cycles, infertility and a raised early-follicular FSH in women under 40. IOF might be a precursor or a mitigated form of premature ovarian failure (POF). Disturbances in the immune system may play a role in ovarian failure. METHOD OF STUDY: Autoantibodies and lymphocyte subsets were determined in 63 POF patients, 50 IOF patients, and 27 controls. RESULTS: The prevalence of autoantibodies did not differ between the groups. There was a statistically significant difference in lymphocyte subsets between the control group and the POF group, with the IOF group taking an intermediate position. We found a decrease in percentage of T-suppressor cells with a rise in T-helper/T-suppressor cell ratio, a decrease in natural killer cells, and an increase in B lymphocytes and HLA-DR positive T cells. CONCLUSIONS: These data support the concept that IOF is a mitigated form of POF. The question remains whether these changes are the cause or the consequence of the ovarian failure.

Premature ovarian failure: a systematic review on therapeutic interventions to restore ovarian function and achieve pregnancy.

Infertility is an important issue for patients with premature ovarian failure (POF). Although oocyte donation offers an alternative method to achieve a pregnancy, many patients seek to reproduce with their own gametes. We performed a literature search to evaluate the possibility of pregnancy following diagnosis, and the additional value of treatment strategies. We found 52 case reports, eight observational studies, nine uncontrolled studies and seven controlled trials. Due to a strong variability in study design, patient selection and mode of intervention, it was not possible to combine the data of the seven studies to perform a meta-analysis. None of the studies showed a statistically significant difference between both (or more) study groups. Due to a lack of incorporation of a placebo group, preference of any treatment over no treatment could not be established. Importantly, the collected data of observational, uncontrolled and controlled studies indicate that POF patients still have a 5-10% chance to conceive following diagnosis. Approximately 80% of the reported pregnancies resulted in the birth of a healthy child. There is no evidence that any treatment can enhance this pregnancy rate.

Familial idiopathic premature ovarian failure: an overrated and underestimated genetic disease?

The incidence of familial cases of premature ovarian failure varies from 4 to 31%. Recall bias may explain part of the variance. Thorough evaluation of alleged affected relatives showed a lower incidence than the original family history suggested. In the present study the incidence of familial cases was 12.7%. Pedigree studies on affected families showed a mode of inheritance suggestive of autosomal dominant sex-limited transmission or X-linked inheritance with incomplete penetrance. An adequate family history can distinguish between familial or sporadic premature ovarian failure. The risk of female relatives developing premature ovarian failure may be as high as 100% in familial premature ovarian failure, or as low as 1% in sporadic cases.

Corticosteroids do not influence ovarian responsiveness to gonadotropins in patients with premature ovarian failure: a randomized, placebo-controlled trial.

OBJECTIVE: To determine the effect of corticosteroids on ovarian responsiveness to exogenous gonadotropins in patients with idiopathic premature ovarian failure (POF). DESIGN: Placebo-controlled, randomized, double-blind, multicenter study. SETTING: Two tertiary care academic centers for reproductive endocrinology and fertility and two general teaching hospitals. PATIENT(S): One hundred patients with idiopathic POF intended to enter the study. The study was discontinued after 36 patients failed to ovulate. INTERVENTION(S): Endocrine and immune parameters were tested on days 1 and 15. On day 1, subjects were randomized to receive either 9 mg of dexamethasone daily or placebo. From day 5 onward, 300 IU of hMG daily was added for 10 days in both groups. The dosage of dexamethasone was decreased stepwise in the second week and discontinued after day 15. Patients were monitored by transvaginal ultrasonography and by determining serum E2 levels. MAIN OUTCOME MEASURE(S): Ovulation rate. Fifty patients would have to be included in each study group to detect a statistically significant difference of 20% in the ovulation rate between the two groups with alpha = 0.05 and beta = 0.1 (one-tailed test). RESULT(S): No ovulation was recorded in the first 36 patients. Interim analysis showed that the 95% confidence intervals of an ovulation rate of 0 were 0-17% for the dexamethasone arm (n = 19) and 0-19% for the placebo arm (n = 17). Because the preset objective (a difference of 20%) would never be reached, the study was discontinued. CONCLUSION(S): Corticosteroids do not influence ovarian responsiveness to gonadotropins in patients with idiopathic POF.

Ovulation induction in premature ovarian failure: a placebo-controlled randomized trial combining pituitary suppression with gonadotropin stimulation.

OBJECTIVES: To determine the effect of pituitary suppression with a GnRH agonist (GnRH-a) on the success of ovulation induction with exogenous gonadotropins in patients with premature ovarian failure (POF). DESIGN: Placebo-controlled, randomized, double-blind study. The data were analyzed with a Fisher exact test. SETTING: A tertiary care academic center for Reproductive Endocrinology and Fertility. PATIENTS: Thirty patients with POF, 15 in each group. INTERVENTIONS: The study consisted of four phases: phase 1, no interventions; phase 2, a 4-week period in which the patients received either 1,000 micrograms intranasal buserelin acetate daily or placebo; phase 3, a 3-week period during which the patients additionally received hMG in weekly augmented doses, two, four, and six ampules daily in the first, second, and third weeks, respectively. Ovulation was induced whenever the follicular diameter reached 18 mm and/or total 24-hour estrogen excretion > 140 micrograms (500 nmol). Luteal support was 5,000 IU hCG every 72 hours; phase 4, no interventions. RESULTS: Follicular growth was seen in five patients of the agonist group and in four patients of the placebo group. Three of 15 patients in the agonist group ovulated versus none in the placebo group. The difference was not statistically significant. CONCLUSIONS: The fact that 3 of 15 cycles cotreated with a GnRH-a were ovulatory versus none in the placebo-treated group appeared not to be enough evidence to demonstrate that pituitary suppression with a GnRH-a improves the success of ovulation induction with exogenous gonadotropins in patients with POF.

Analysis of peripheral blood lymphocyte subsets, NK cells, and delayed type hypersensitivity skin test in patients with premature ovarian failure.

PROBLEM: Premature ovarian failure (POF) probably belongs to the group of autoimmune endocrinopathies. Cell-mediated immune parameters were investigated. Sex steroids have a profound effect on the immune system. POF patients and postmenopausal control women (PM) were tested with or without estrogen substitution. METHOD: A novel FACS analysis system (using double labeling techniques) was used in 30 patients with POF to enumerate the subjects of peripheral blood lymphocytes and NK cells. Eighteen PM women and 30 healthy men and women served as controls. We also tested the delayed type hypersensitivity skin test (DTH) toward Candida in the POF patient group to be informed on their cell-mediated immune function. RESULTS: The numbers of blood lymphocytes, CD3+, CD4+ and CD8+T cells, were not abnormal in POF patients. However, HLA-DR+T cells were increased in POF patients and in PM women (P < 0.05). These elevated numbers were partially reversible by estrogen substitution. The number of CD19+ cells (B cells) was elevated, whereas CD3-/CD16+/CD56+ cells (NK cells) were decreased in POF patients (P < 0.05), irrespective of estrogen substitution. DTH skin tests toward 0.1% Candidin (0.1 ml intradermal injection) were negative in 11 out of 20 tested POF patients, compared to only 2 out of 10 tested controls (P < 0.05). CONCLUSION: POF patients show numerous immune cell abnormalities. These abnormalities were only partially due to estrogen deficiency. We hypothesize that these abnormalities either lead to ovarian autoimmunity or may have direct effects on the ovarian function.

Dysfunction of monocytes and dendritic cells in patients with premature ovarian failure.

PROBLEM: Due to the presence of ovarian antibodies it has been suggested that premature ovarian failure (POF) belongs to the autoimmune endocrinopathies. Monocytes and the monocyte-derived dendritic cells play a prominent role in the initial stages of endocrine autoimmune reactions: the accumulation of monocytes/dendritic cells and the clustering of dendritic cells in endocrine organs is one of the first phenomena of an autoimmune endocrinopathy. METHOD: This report describes a study on (1) the chemotactic responsiveness of blood monocytes, and (2) the cluster capability of blood dendritic cells in POF patients. The monocyte chemotaxis was determined using the cell's capability to polarize (changes in shape determined by light microscopy) under the influence of the chemoattractant, N-formyl-methionyl-leucyl-phenylalanine (fMLP). The cluster capability of dendritic cells was tested by allowing the dendritic cells to form aggregates with allogenic lymphocytes in vitro. RESULTS: The blood monocytes of 46% of a total of 28 POF patients showed a decreased fMLP induced monocyte polarization in comparison to healthy control values. None of the young female controls (N = 28) and postmenopausal women (N = 17), showed such a defective monocyte polarization. The blood dendritic cells of 36% of the POF patients showed a decreased cluster capability. Defects in monocyte polarization and dendritic cell clustering were not affected by therapies aimed at changes in the estrogen levels or gonadotropin levels of the patients [using estrogen substitution therapy, gonadotropin-releasing hormone (GnRH) analog, follicle-stimulating hormone (FSH)]. CONCLUSIONS: A redistribution of active monocytes and of active dendritic cells from the peripheral blood to the ovaries may be the cause of the described abnormalities. Since similar abnormalities in monocyte function and dendritic cell function have been described in Graves' disease and type I diabetes, the data strengthen the view that POF is one of the endocrine autoimmune diseases.

Efficacy of a synthetic mesh sling in keeping the small bowel in the upper abdomen to prevent radiation enteropathy in gynecologic malignancies.

Radiation therapy in gynecological malignancies is limited by the frequent occurrence of radiation enteropathy at effective dose levels of 45 Gy and higher. Elevation of the small bowel out of the true pelvis should enable doses of up to 60-70 Gy to be given without damaging the small bowel. We report a feasibility study concerning elevation of the small bowel out of the true pelvis, by creating an intra-abdominal sling with a synthetic mesh. Twelve patients with pelvic gynecological malignancies were included since 1986. In all patients peroperative application of the mesh was possible. In ten patients adequate elevation of the small bowel was achieved. Two patients showed a right-sided herniation of a small bowel loop on a control barium opacification, performed 1 week postoperatively. In one of these a fistula occurred after resecuring the mesh. The most important problem in this study, as has also been reported elsewhere, was a herniation of a small bowel loop. The incidence is probably inversely correlated with the skill of the surgeon and will therefore be reduced with increasing experience. Future long-term studies should address the issue whether or not radiation enteropathy can be prevented by this method.

Hypertrophic cardiomyopathy and pregnancy: a report of three cases.

In this paper three pregnancies in association with hypertrophic cardiomyopathy are reported. Management of pregnancy and delivery are discussed based upon recommendations in literature.