Cumulative live birth rate of a blastocyst versus cleavage stage embryo transfer policy during in vitro fertilisation in women with a good prognosis: multicentre randomised controlled trial.

OBJECTIVES: To evaluate whether embryo transfers at blastocyst stage improve the cumulative live birth rate after oocyte retrieval, including both fresh and frozen-thawed transfers, and whether the risk of obstetric and perinatal complications is increased compared with cleavage stage embryo transfers during in vitro fertilisation (IVF) treatment. DESIGN: Multicentre randomised controlled trial. SETTING: 21 hospitals and clinics in the Netherlands, 18 August 2018 to 17 December 2021. PARTICIPANTS: 1202 women with at least four embryos available on day 2 after oocyte retrieval were randomly assigned to either blastocyst stage embryo transfer (n=603) or cleavage stage embryo transfer (n=599). INTERVENTIONS: In the blastocyst group and cleavage group, embryo transfers were performed on day 5 and day 3, respectively, after oocyte retrieval, followed by cryopreservation of surplus embryos. Analysis was on an intention-to-treat basis, with secondary analyses as per protocol. MAIN OUTCOME MEASURES: The primary outcome was the cumulative live birth rate per oocyte retrieval, including results of all frozen-thawed embryo transfers within a year after randomisation. Secondary outcomes included cumulative rates of pregnancy, pregnancy loss, and live birth after fresh embryo transfer, number of embryo transfers needed, number of frozen embryos, and obstetric and perinatal outcomes. RESULTS: The cumulative live birth rate did not differ between the blastocyst group and cleavage group (58.9% (355 of 603) v 58.4% (350 of 599; risk ratio 1.01, 95% confidence interval (CI) 0.84 to 1.22). The blastocyst group showed a higher live birth rate after fresh embryo transfer (1.26, 1.00 to 1.58), lower cumulative pregnancy loss rate (0.68, 0.51 to 0.89), and lower mean number of embryo transfers needed to result in a live birth (1.55 v 1.82; P<0.001). The incidence of moderate preterm birth (32 to <37 weeks) in singletons was higher in the blastocyst group (1.87, 1.05 to 3.34). CONCLUSION: Blastocyst stage embryo transfers resulted in a similar cumulative live birth rate to cleavage stage embryo transfers in women with at least four embryos available during IVF treatment. TRIAL REGISTRATION: International Clinical Trial Registry Platform NTR7034.

Home-based monitoring of ovulation to time frozen embryo transfers in the Netherlands (Antarctica-2): an open-label, nationwide, randomised, non-inferiority trial.

BACKGROUND: The growing field of assisted reproductive techniques, including frozen-thawed embryo transfer (FET), should lead the way to the best sustainable health care without compromising pregnancy chances. Correct timing of FET is crucial to allow implantation of the thawed embryo. Nowadays, timing based on hospital-controlled monitoring of ovulation in the natural cycle of a woman is the preferred strategy because of the assumption of favourable fertility prospects. However, home-based monitoring is a simple method to prevent patient travel and any associated environmental concerns. We compared ongoing pregnancy rates after home-based monitoring versus hospital-controlled monitoring with ovulation triggering. METHODS: This open-label, multicentre, randomised, non-inferiority trial was undertaken in 23 hospitals and clinics in the Netherlands. Women aged between 18 and 44 years with a regular ovulatory menstrual cycle were randomly assigned in a 1:1 ratio via a web-based randomisation program to home-based monitoring or hospital-controlled monitoring. Those who analysed the data were masked to the groups; those collecting the data were not. All endpoints were analysed by intention to treat and per protocol. Non-inferiority was established when the lower limit of the 90% CI exceeded -4%. This study was registered at the Dutch Trial Register (Trial NL6414). FINDINGS: 1464 women were randomly assigned between April 10, 2018, and April 13, 2022, with 732 allocated to home-based monitoring and 732 to hospital-controlled monitoring. Ongoing pregnancy occurred in 152 (20·8%) of 732 in the home-based monitoring group and in 153 (20·9%) of 732 in the hospital-controlled monitoring group (risk ratio [RR] 0·99 [90% CI 0·81 to 1·22]; risk difference [RD] -0·14 [90% CI -3·63 to 3·36]). The per-protocol analysis confirmed non-inferiority (152 [21·0%] of 725 vs 153 [21·0%] of 727; RR 1·00 (90% CI 0·81 to 1·23); RD -0·08 [90% CI -3·60 to 3·44]). INTERPRETATION: Home-based monitoring of ovulation is non-inferior to hospital-controlled monitoring of ovulation to time FET. FUNDING: The Dutch Organisation for Health Research and Development.

Comparing the cumulative live birth rate of cleavage-stage versus blastocyst-stage embryo transfers between IVF cycles: a study protocol for a multicentre randomised controlled superiority trial (the ToF trial).

INTRODUCTION: In vitro fertilisation (IVF) has evolved as an intervention of choice to help couples with infertility to conceive. In the last decade, a strategy change in the day of embryo transfer has been developed. Many IVF centres choose nowadays to transfer at later stages of embryo development, for example, transferring embryos at blastocyst stage instead of cleavage stage. However, it still is not known which embryo transfer policy in IVF is more efficient in terms of cumulative live birth rate (cLBR), following a fresh and the subsequent frozen-thawed transfers after one oocyte retrieval. Furthermore, studies reporting on obstetric and neonatal outcomes from both transfer policies are limited. METHODS AND ANALYSIS: We have set up a multicentre randomised superiority trial in the Netherlands, named the Three or Fivetrial. We plan to include 1200 women with an indication for IVF with at least four embryos available on day 2 after the oocyte retrieval. Women are randomly allocated to either (1) control group: embryo transfer on day 3 and cryopreservation of supernumerary good-quality embryos on day 3 or 4, or (2) intervention group: embryo transfer on day 5 and cryopreservation of supernumerary good-quality embryos on day 5 or 6. The primary outcome is the cLBR per oocyte retrieval. Secondary outcomes include LBR following fresh transfer, multiple pregnancy rate and time until pregnancy leading a live birth. We will also assess the obstetric and neonatal outcomes, costs and patients' treatment burden. ETHICS AND DISSEMINATION: The study protocol has been approved by the Central Committee on Research involving Human Subjects in the Netherlands in June 2018 (CCMO NL 64060.000.18). The results of this trial will be submitted for publication in international peer-reviewed and in open access journals. TRIAL REGISTRATION NUMBER: Netherlands Trial Register (NL 6857).

A Controlled Study on Vaginal Blood Flow During Sexual Arousal Among Early-Stage Cervical Cancer Survivors Treated With Conventional Radical or Nerve-Sparing Surgery With or Without Radiotherapy.

OBJECTIVE: Sexual problems among cervical cancer survivors may in part be caused by reduced vaginal blood flow due to damaged hypogastric nerves during radical hysterectomy with pelvic lymphadenectomy and/or by radiation-induced vaginal changes after pelvic radiotherapy. A nerve-sparing modification of radical hysterectomy (NSRH) may preserve vaginal blood flow. Vaginal blood flow during sexual arousal was compared between different treatment modalities. METHODS: We investigated premenopausal women treated for early-stage cervical cancer with radical hysterectomy (n = 29), NSRH (n = 28), NSRH with radiotherapy (n = 14), and controls (n = 31). Genital arousal and subjective sexual arousal in response to sexual stimuli were measured using vaginal photoplethysmography and a questionnaire. Results were compared by using a between-study (treatment groups) by within-study (stimulus) design. RESULTS: Participants were aged 29 to 51 years (mean, 42 years) and at 1 to 14 years (mean, 5 years) after treatment. Measured vaginal blood flow in women treated with NSRH was similar to controls. Women treated with radical hysterectomy had a significantly lower vaginal blood flow compared with controls overall and lower compared with the NSRH group during sexual stimulation. Women treated with radiotherapy had a vaginal blood flow intermediate between the other groups without significant differences. The erotic films were equally effective in enhancing subjective sexual arousal among treatment groups. CONCLUSIONS: Cervical cancer treatment with radical hysterectomy disrupts the vaginal blood flow response, and this may be prevented by conducting an NSRH. Treatment with radiotherapy did not significantly impact vaginal blood flow, but further investigation is needed with a larger sample.

Self-reported sexual, bowel and bladder function in cervical cancer patients following different treatment modalities: longitudinal prospective cohort study.

OBJECTIVE: Conventional radical hysterectomy with pelvic lymphadenectomy (RHL) for early-stage cervical cancer is associated with significant bladder, anorectal, and sexual dysfunction. Nerve-sparing modification of RHL (NS-RHL) has been developed with the aim to reduce surgical treatment-related morbidity. Postoperative radiation therapy (RT) is offered to patients with unfavorable prognostic features to improve local control. The aim of the study was to assess self-reported morbidity of various types of treatment in cervical cancer patients. METHODS: Self-reported symptoms were prospectively assessed before and 1 and 2 years after treatment by the Dutch Gynaecologic Leiden Questionnaire. RESULTS: Included were 229 women (123 NS-RHL and 106 conventional RHL). Ninety-four (41%) received RT. Up to 2 years (response rate, 81%), women reported significantly more bowel, bladder, and sexual symptoms compared with the pretreatment situation. No significant difference was found between the conventional RHL and NS-RHL with the exception of the unexpected finding that a smaller percentage in the NS-RHL group (34% vs 68%) complained about numbness of the labia and/ or thigh. Radiation therapy had a negative impact on diarrhea, urine incontinence, lymphedema, and sexual symptoms (especially a narrow/short vagina). CONCLUSIONS: In the current longitudinal cohort study, treatment for early-stage cervical cancer was associated with worse subjective bladder, anorectal, and sexual functioning, irrespective of the surgical procedure used. Postoperative RT resulted in a significant deterioration of these functions. The results have to be interpreted with caution in view of the study design and method used.