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Study Question: Is embryo culture in a closed time-lapse system associated with any differences in perinatal and maternal outcomes in comparison to conventional culture and spontaneous conception?, Summary Answer: There were no significant differences between time-lapse and conventional embryo culture in preterm birth (PTB, <37 weeks), low birth weight (LBW, >2500 g) and hypertensive disorders of pregnancy for singleton deliveries, the primary outcomes of this study., What Is Known Already: Evidence from prospective trials evaluating the safety of time-lapse incubation for clinical use show similar embryo development rates, implantation rates, and ongoing pregnancy and live birth rates when compared to conventional incubation. Few studies have investigated if uninterrupted culture can alter risks of adverse perinatal outcomes presently associated with IVF when compared to conventional culture and spontaneous conceptions., Study Design, Size, Duration: This study is a Swedish population-based retrospective registry study, including 7379 singleton deliveries after fresh embryo transfer between 2013 and 2018 from selected IVF clinics. Perinatal outcomes of singletons born from time-lapse-cultured embryos were compared to singletons from embryos cultured in conventional incubators and 71 300 singletons from spontaneous conceptions. Main perinatal outcomes included PTB and LBW. Main maternal outcomes included hypertensive disorders of pregnancy (pregnancy hypertension and preeclampsia)., Participants/materials, Setting, Methods: From nine IVF clinics, 2683 singletons born after fresh embryo transfer in a time-lapse system were compared to 4696 singletons born after culture in a conventional incubator and 71 300 singletons born after spontaneous conception matched for year of birth, parity, and maternal age. Patient and treatment characteristics from IVF deliveries were cross-linked with the Swedish Medical Birth Register, Register of Birth Defects, National Patient Register and Statistics Sweden. Children born after sperm and oocyte donation cycles and after Preimplantation Genetic testing cycles were excluded. Odds ratio (OR) and adjusted OR were calculated, adjusting for relevant confounders., Main Results and the Role of Chance: In the adjusted analyses, no significant differences were found for risk of PTB (adjusted OR 1.11, 95% CI 0.87-1.41) and LBW (adjusted OR 0.86, 95% CI 0.66-1.14) or hypertensive disorders of pregnancy; preeclampsia and hypertension (adjusted OR 0.99, 95% CI 0.67-1.45 and adjusted OR 0.98, 95% CI 0.62-1.53, respectively) between time-lapse and conventional incubation systems. A significantly increased risk of PTB (adjusted OR 1.31, 95% CI 1.08-1.60) and LBW (adjusted OR 1.36, 95% CI 1.08-1.72) was found for singletons born after time-lapse incubation compared to singletons born after spontaneous conceptions. In addition, a lower risk for pregnancy hypertension (adjusted OR 0.72 95% CI 0.53-0.99) but no significant difference for preeclampsia (adjusted OR 0.87, 95% CI 0.68-1.12) was found compared to spontaneous conceptions. Subgroup analyses showed that some risks were related to the day of embryo transfer, with more adverse outcomes after blastocyst transfer in comparison to cleavage stage transfer., Limitations, Reasons for Caution: This study is retrospective in design and different clinical strategies may have been used to select specific patient groups for time-lapse versus conventional incubation. The number of patients is limited and larger datasets are required to obtain more precise estimates and adjust for possible effect of additional embryo culture variables., Wider Implications of the Findings: Embryo culture in time-lapse systems is not associated with major differences in perinatal and maternal outcomes, compared to conventional embryo culture, suggesting that this technology is an acceptable alternative for embryo incubation., Study Funding/competing Interest(s): The study was financed by a research grant from Gedeon Richter. There are no conflicts of interest for all authors to declare., Trial Registration Number: N/A., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Study Question: Can use of a commercially available time-lapse algorithm for Day 5 blastocyst selection improve pregnancy rates compared with morphology alone?, Summary Answer: The use of a time-lapse selection model to choose blastocysts for fresh single embryo transfer on Day 5 did not improve ongoing pregnancy rate compared to morphology alone., What Is Known Already: Evidence from time-lapse monitoring suggests correlations between timing of key developmental events and embryo viability. No good quality evidence exists to support improved pregnancy rates following time-lapse selection., Study Design, Size, Duration: A prospective multicenter randomized controlled trial including 776 randomized patients was performed between 2018 and 2021. Patients with at least two good quality blastocysts on Day 5 were allocated by a computer randomization program in a proportion of 1:1 into either the control group, whereby single blastocysts were selected for transfer by morphology alone, or the intervention group whereby final selection was decided by a commercially available time-lapse model. The embryologists at the time of blastocyst morphological scoring were blinded to which study group the patients would be randomized, and the physician and patients were blind to which group they were allocated until after the primary outcome was known. The primary outcome was number of ongoing pregnancies in the two groups., Participants/materials, Setting, Methods: From 10 Nordic IVF clinics, 776 patients with a minimum of two good quality blastocysts on Day 5 (D5) were randomized into one of the two study groups. A commercial time-lapse model decided the final selection of blastocysts for 387 patients in the intervention (time-lapse) group, and blastocysts with the highest morphological score were transferred for 389 patients in the control group. Only single embryo transfers in fresh cycles were performed., Main Results and the Role of Chance: In the full analysis set, the ongoing pregnancy rate for the time-lapse group was 47.4% (175/369) and 48.1% (181/376) in the control group. No statistically significant difference was found between the two groups: mean difference -0.7% (95% CI -8.2, 6.7, P = 0.90). Pregnancy rate (60.2% versus 59.0%, mean difference 1.1%, 95% CI -6.2, 8.4, P = 0.81) and early pregnancy loss (21.2% versus 18.5%, mean difference 2.7%, 95% CI -5.2, 10.6, P = 0.55) were the same for the time-lapse and the control group. Subgroup analyses showed that patient and treatment characteristics did not significantly affect the commercial time-lapse model D5 performance. In the time-lapse group, the choice of best blastocyst changed on 42% of occasions (154/369, 95% CI 36.9, 47.2) after the algorithm was applied, and this rate was similar for most treatment clinics., Limitations, Reasons for Caution: During 2020, the patient recruitment rate slowed down at participating clinics owing to coronavirus disease-19 restrictions, so the target sample size was not achieved as planned and it was decided to stop the trial prematurely. The study only investigated embryo selection at the blastocyst stage on D5 in fresh IVF transfer cycles. In addition, only blastocysts of good morphological quality were considered for transfer, limiting the number of embryos for selection in both groups: also, it could be argued that this manual preselection of blastocysts limits the theoretical selection power of time-lapse, as well as restricting the results mainly to a good prognosis patient group. Most patients were aimed for blastocyst stage transfer when a minimum of five zygotes were available for extended culture. Finally, the primary clinical outcome evaluated was pregnancy to only 6-8 weeks., Wider Implications of the Findings: The study suggests that time-lapse selection with a commercially available time-lapse model does not increase chance of ongoing pregnancy after single blastocyst transfer on Day 5 compared to morphology alone., Study Funding/competing Interest(s): The study was financed by a grant from the Swedish state under the ALF-agreement between the Swedish government and the county councils (ALFGBG-723141). Vitrolife supported the study with embryo culture dishes and culture media. During the study period, T.H. changed his employment from Livio AB to Vitrolife AB. All other authors have no conflicts of interests to disclose., Trial Registration Number: ClinicalTrials.gov registration number NCT03445923., Trial Registration Date: 26 February 2018., Date of First Patient’s Enrolment: 11 June 2018., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Near infrared (NIR) spectroscopy is a technology proposed to facilitate non-invasive screening for the most optimal human embryo for uterine transfer. It has been proposed that the NIR spectral profile of an embryo's spent culture medium can be used to generate a viability score that correlates to implantation potential. As the initial proof of principle studies were all retrospective, our aim was to investigate whether NIR spectroscopy on spent embryo culture medium in an on-site, prospective setting could improve the ongoing single embryo transfer (SET) pregnancy rate after Day 2 and 5 transfers., Methods: We conducted a single-centre, double-blinded, randomized controlled trial in which the NIR group was compared with a control group. The primary outcome was the clinical pregnancy rate after 6-7 weeks of gestation per randomized patient. In the control group embryo selection was based only on traditional morphological evaluation while in the treatment group NIR spectroscopy was added to the morphological evaluation., Results: The study was terminated early as the analysis of the Data Safety Monitoring Board showed a very low conditional power of superiority for the primary outcome. Of the 752 patients calculated to be included in the study, 164 and 163 patients were randomized into the NIR and control groups, respectively. No significant difference in the ongoing pregnancy rate per randomized patient was found between the NIR and the control group, 34.8 versus 35.6%, (P= 0.97). The proportional difference between the study groups mean was -0.8% (95% confidence interval -11.4 to 10.2)., Conclusions: This study shows that adding NIR spectroscopy, in its present form, to embryo morphology does not improve the chance of a viable pregnancy when performing SET. The NIR technology appears to need further development before it can be used as an objective marker of embryo viability., Clinical Trials Identifier: ISRCTN23817363.

Background: It has been claimed that the risks to the child resulting from vitrification as compared with the slow-freezing technique, may be higher owing to the high concentrations of potentially toxic cryoprotectants. We therefore retrospectively compared the obstetric and neonatal outcomes in a cohort of children born after transfer of vitrified blastocysts, fresh blastocysts and slow-frozen early cleavage stage embryos., Methods: All children born after transfer of vitrified blastocysts (n = 106), fresh blastocysts (n = 207) and slow-frozen early cleavage stage embryos (n = 206) during the period January 2006 to May 2008 at Fertility Center Scandinavia were included. Data on obstetric and neonatal outcomes were obtained from medical records from the antenatal and delivery clinics., Results: For singletons, there were no significant differences between the groups in gestational age, mortality or birth defects. After adjustment for parity and BMI, birthweight was significantly higher in singletons born after transfer of vitrified blastocysts as compared with after transfer of fresh blastocysts (median 3560 versus 3510 g, P = 0.0311). More singletons born after transfer of fresh blastocysts were small for gestational age compared with singletons born after transfer of vitrified blastocysts (12.1 versus 3.0%, P = 0.0085). A higher rate of major post-partum haemorrhage was observed in the vitrified blastocyst group as compared with the other two groups (25.0 versus 6.0 and 7.5%)., Conclusions: No adverse neonatal outcomes were observed in children born after transfer of vitrified, as compared with fresh blastocysts or after transfer of slow-frozen early cleavage stage embryos.

Background: A pre-ovarian block (POB) technique can be used for pain relief during oocyte retrieval in IVF. The local anaesthetic is deposited in the vaginal wall and between the vaginal wall and the peritoneal surface near the ovary using ultrasound guidance. The aim of this study was to test whether analgesia with POB resulted in improved pain relief compared to paracervical block (PCB)., Methods: A prospective, randomized, multicentre study of POB versus PCB (10 ml of 1% lidocaine each) with 183 patients randomized to POB (n = 96) or PCB (n = 87) was performed. Randomization (via a computer-generated list) was balanced for age, previously completed IVF cycles, degree of anxiety, estimated number of follicles, BMI, premedication and centre. Pain was measured using a visual analogue scale (VAS, 0-100 mm) and given as median values. The primary end-point of this study was overall VAS pain score for both sides during the oocyte retrieval procedure., Results: Overall pain during the entire oocyte retrieval was 22 (POB) and 16 (PCB) (P = 0.42). No differences were found in degree of anxiety, premedication, dose of alfentanil, fertilization rate, number of good-quality embryos or clinical pregnancy rate., Conclusions: No differences were found in overall pain experienced during the entire oocyte retrieval procedure with POB compared to PCB.

We report two cases of infertility treatment in couples where males suffered from Kartagener's syndrome (KS) and a total absence of motile sperm in the ejaculate. A total of three ICSI cycles was carried out. In all cycles, viable ejaculated or testicular spermatozoa were selected using the hypo-osmotic swelling (HOS) test. Case 1: In the first ICSI cycle total fertilization failure occurred after using ejaculated spermatozoa. In the following cycle testicular spermatozoa were used for ICSI, resulting in 75% fertilized oocytes and a pregnancy. Case 2: In the same ICSI cycle 50% of the oocytes were injected with ejaculated and 50% with testicular spermatozoa. The fertilization rates were 44 and 56% respectively and high quality embryos were achieved in both groups. One single embryo derived from testicular sperm was transferred with a resulting singleton pregnancy. In conclusion, testicular sperm for ICSI seem to have reliable fertilization capacity in men with KS, while ejaculated sperm, even if tested viable, seem more unpredictable. HOS test for selection of viable sperm for ICSI is recommended when ejaculated as well as testicular sperm are used for ICSI.

Background: In many fertility centres, intracytoplasmic sperm injection (ICSI) with epididymal or testicular spermatozoa is a routine treatment for men with azoospermia. In this prospective study, the physiological consequences after testicular sperm aspiration (TESA), using suction and a 19 gauge needle, were evaluated., Methods and Results: Thirty-five consecutive men with azoospermia underwent TESA. Testicular ultrasonography with Doppler flow imaging was performed and testicular volumes were evaluated pre-operatively and 3 months after aspiration. If focal testicular lesions were found, further examinations were performed 6 and 9 months after TESA. Serum FSH, testosterone and antisperm antibodies (ASA) were analysed. Focal testicular lesions were seen in four out of 61 testes (6.6%) at the 3 month investigation point. Three lesions were resolved after 6 months and all after 9 months. Testicular echogenicity remained unchanged in 50 cases (82%) 3 months after TESA. Four men (11.4%) reported severe subjective discomfort post-operatively, but only one had a medical consultation where an intratesticular haematoma was diagnosed. There were no significant changes in FSH and testosterone after surgery and testicular volumes were similar after 3 months. There were three borderline cases of ASA in serum, but none was classified as ASA-positive., Conclusions: The puncture method of testicular sperm aspiration seems to be a safe method for sperm retrieval, with minimal physiological consequences.

The aim of this study was to report the outcome of all clinical pregnancies obtained after intracytoplasmic sperm injection (ICSI) performed during a 5 year period at two fertility clinics, with special reference to delivery outcome associated with different sperm origin and quality and the transfer of fresh or frozen-thawed pre-embryos. A total of 1293 clinical pregnancies was analysed. Deliveries occurred in 75.9% (n = 982) and early spontaneous abortion, late spontaneous abortion and ectopic pregnancy in 21.4, 1.0 and 1.2% respectively. Multiple birth occurred in 21.3% (208 sets of twins and one set of triplets) of the deliveries, with the highest incidence in the epididymal sperm group (30.2%) and lowest in the cryopreserved group (13.7%). A total of 1192 infants was born. Preterm birth occurred in 15.7% of all deliveries. Preterm birth was not related to sperm origin or quality but was related to multiple birth. The prematurity rate was 8.4%, 42.3% and 100% for singletons, twins and triplets respectively. Singleton infants born after cryopreservation as embryos had a significantly higher birthweight than the ejaculated sperm group with fresh embryo transfer. The perinatal mortality rate was 11.7 per 1000 born infants. Eighty-seven of the 1192 infants (7.3%) had a malformation, 40 of which were minor. The perinatal mortality rate and the malformation rate were similar in the different subgroups. Prenatal karyotyping was performed on 149 fetuses (12.5%) and abnormal results were found in four cases (2.7%). In conclusion, obstetric outcome of ICSI pregnancies was similar to that of conventional IVF and was not influenced by sperm origin or quality. The high incidence of multiple births is still the major concern.

Various procedures for sperm recovery in azoospermic men have been described, from open testicular biopsy to simple needle aspiration from the epididymis and the testis. Fifty-one obstructive and 86 non-obstructive azoospermic men were treated to compare the recovery of spermatozoa obtained by percutaneous aspiration from the epididymis (PESA) and aspiration/extraction from the testis (TESA, TESE) with histopathology. If TESA failed, the work up proceeded with TESE. All patients were karyotyped. Spermatozoa were recovered by PESA or TESA in all obstructive men (51/51 patients). In 22 out of 86 patients with non-obstructive azoospermia, testicular spermatozoa could be successfully recovered by TESA. In five additional patients TESE was successful in recovering spermatozoa where TESA had failed. In 43 patients, neither TESA nor TESE was successful. Sixteen patients chose not to proceed with TESE. Seven out of 86 patients had an abnormal karyotype in the non-obstructive group (8%), none in the obstructive group. In the non-obstructive patient group testicular histopathology showed hypospermatogenesis, incomplete maturation arrest and germ cell aplasia with focal spermatogenesis in cases where spermatozoa were recovered and complete germ cell aplasia, complete maturation arrest and fibrosis in cases where no spermatozoa were found. Spermatozoa were recovered by PESA or TESA from all patients with obstructive azoospermia and from approximately 40% of patients with non-obstructive azoospermia by TESA or TESE. Retrieval of viable spermatozoa in the infertility work-up was highly predictable for sperm recovery in subsequent ICSI cycles. TESA performed under local anaesthesia seems almost as effective as more invasive procedures in recovering testicular spermatozoa, both in obstructive and non-obstructive azoospermic men.

Percutaneous epididymal sperm aspiration (PESA) for retrieval of spermatozoa for intracytoplasmic sperm injection (ICSI) is a new simplified technique in the treatment of men with obstructive azoospermia. There has been a fear that the PESA procedure, being blind, could cause damage to the epididymal duct system and make it impossible to retrieve spermatozoa if a repeated procedure is required. We report here on repeated PESA procedures from the same unilateral epididymis. Twenty-seven men with obstructive azoospermia were investigated retrospectively regarding sufficiency of the number of motile spermatozoa for ICSI, fertilization rate (FR) and possibility of collecting spermatozoa for cryopreservation in repeated PESA procedures. Sufficient motile spermatozoa for ICSI were found in a similar proportion of men at the first two attempts: 91 and 89% respectively. Fertilization rate and the possibility of collecting spermatozoa for cryopreservation were also similar at the first two PESA procedures: 62 versus 67% and 33 versus 33% respectively. At the third procedure, motile spermatozoa for ICSI were retrieved in 86% (6/7), FR was 47% and spermatozoa were cryopreserved in one case. Two men underwent a fourth PESA. In both cases, a sufficient number of motile spermatozoa for ICSI was found and FR was 62%. This study shows that in men with obstructive azoospermia, PESA can be repeated on the same unilateral epididymis up to three times, with good opportunity of retrieving sufficient motile spermatozoa for ICSI.