Elective freezing of embryos versus fresh embryo transfer in IVF: a multicentre randomized controlled trial in the UK (E-Freeze).

STUDY QUESTION: Does a policy of elective freezing of embryos, followed by frozen embryo transfer result in a higher healthy baby rate, after first embryo transfer, when compared with the current policy of transferring fresh embryos? SUMMARY ANSWER: This study, although limited by sample size, provides no evidence to support the adoption of a routine policy of elective freeze in preference to fresh embryo transfer in order to improve IVF effectiveness in obtaining a healthy baby. WHAT IS KNOWN ALREADY: The policy of freezing all embryos followed by frozen embryo transfer is associated with a higher live birth rate for high responders but a similar/lower live birth after first embryo transfer and cumulative live birth rate for normal responders. Frozen embryo transfer is associated with a lower risk of ovarian hyperstimulation syndrome (OHSS), preterm delivery and low birthweight babies but a higher risk of large babies and pre-eclampsia. There is also uncertainty about long-term outcomes, hence shifting to a policy of elective freezing for all remains controversial given the delay in treatment and extra costs involved in freezing all embryos. STUDY DESIGN, SIZE, DURATION: A pragmatic two-arm parallel randomized controlled trial (E-Freeze) was conducted across 18 clinics in the UK from 2016 to 2019. A total of 619 couples were randomized (309 to elective freeze/310 to fresh). The primary outcome was a healthy baby after first embryo transfer (term, singleton live birth with appropriate weight for gestation); secondary outcomes included OHSS, live birth, clinical pregnancy, pregnancy complications and cost-effectiveness. PARTICIPANTS/MATERIALS, SETTING, METHODS: Couples undergoing their first, second or third cycle of IVF/ICSI treatment, with at least three good quality embryos on Day 3 where the female partner was ≥18 and <42 years of age were eligible. Those using donor gametes, undergoing preimplantation genetic testing or planning to freeze all their embryos were excluded. IVF/ICSI treatment was carried out according to local protocols. Women were followed up for pregnancy outcome after first embryo transfer following randomization. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 619 couples randomized, 307 and 309 couples in the elective freeze and fresh transfer arms, respectively, were included in the primary analysis. There was no evidence of a statistically significant difference in outcomes in the elective freeze group compared to the fresh embryo transfer group: healthy baby rate {20.3% (62/307) versus 24.4% (75/309); risk ratio (RR), 95% CI: 0.84, 0.62 to 1.15}; OHSS (3.6% versus 8.1%; RR, 99% CI: 0.44, 0.15 to 1.30); live birth rate (28.3% versus 34.3%; RR, 99% CI 0.83, 0.65 to 1.06); and miscarriage (14.3% versus 12.9%; RR, 99% CI: 1.09, 0.72 to 1.66). Adherence to allocation was poor in the elective freeze group. The elective freeze approach was more costly and was unlikely to be cost-effective in a UK National Health Service context. LIMITATIONS, REASONS FOR CAUTION: We have only reported on first embryo transfer after randomization; data on the cumulative live birth rate requires further follow-up. Planned target sample size was not obtained and the non-adherence to allocation rate was high among couples in the elective freeze arm owing to patient preference for fresh embryo transfer, but an analysis which took non-adherence into account showed similar results. WIDER IMPLICATIONS OF THE FINDINGS: Results from the E-Freeze trial do not lend support to the policy of electively freezing all for everyone, taking both efficacy, safety and costs considerations into account. This method should only be adopted if there is a definite clinical indication. STUDY FUNDING/COMPETING INTEREST(S): NIHR Health Technology Assessment programme (13/115/82). This research was funded by the National Institute for Health Research (NIHR) (NIHR unique award identifier) using UK aid from the UK Government to support global health research. The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR or the UK Department of Health and Social Care. J.L.B., C.C., E.J., P.H., J.J.K., L.L. and G.S. report receipt of funding from NIHR, during the conduct of the study. J.L.B., E.J., P.H., K.S. and L.L. report receipt of funding from NIHR, during the conduct of the study and outside the submitted work. A.M. reports grants from NIHR personal fees from Merck Serono, personal fees for lectures from Merck Serono, Ferring and Cooks outside the submitted work; travel/meeting support from Ferring and Pharmasure and participation in a Ferring advisory board. S.B. reports receipt of royalties and licenses from Cambridge University Press, a board membership role for NHS Grampian and other financial or non-financial interests related to his roles as Editor-in-Chief of Human Reproduction Open and Editor and Contributing Author of Reproductive Medicine for the MRCOG, Cambridge University Press. D.B. reports grants from NIHR, during the conduct of the study; grants from European Commission, grants from Diabetes UK, grants from NIHR, grants from ESHRE, grants from MRC, outside the submitted work. Y.C. reports speaker fees from Merck Serono, and advisory board role for Merck Serono and shares in Complete Fertility. P.H. reports membership of the HTA Commissioning Committee. E.J. reports membership of the NHS England and NIHR Partnership Programme, membership of five Data Monitoring Committees (Chair of two), membership of six Trial Steering Committees (Chair of four), membership of the Northern Ireland Clinical Trials Unit Advisory Group and Chair of the board of Oxford Brain Health Clinical Trials Unit. R.M. reports consulting fees from Gedeon Richter, honorarium from Merck, support fees for attendance at educational events and conferences for Merck, Ferring, Bessins and Gedeon Richter, payments for participation on a Merck Safety or Advisory Board, Chair of the British Fertility Society and payments for an advisory role to the Human Fertilisation and Embryology Authority. G.S. reports travel and accommodation fees for attendance at a health economic advisory board from Merck KGaA, Darmstadt, Germany. N.R.-F. reports shares in Nurture Fertility. Other authors' competing interests: none declared. TRIAL REGISTRATION NUMBER: ISRCTN: 61225414. TRIAL REGISTRATION DATE: 29 December 2015. DATE OF FIRST PATIENT'S ENROLMENT: 16 February 2016.

Associations of IVF singleton birthweight and gestation with clinical treatment and laboratory factors: a multicentre cohort study.

STUDY QUESTION: Do IVF treatment and laboratory factors affect singleton birthweight (BW)? SUMMARY ANSWER: BWs of IVF-conceived singleton babies are increasing with time, but we cannot identify the specific treatment factors responsible. WHAT IS KNOWN ALREADY: IVF-conceived singleton babies from fresh transfers have slightly lower BW than those conceived naturally, whilst those from frozen embryo transfer (FET) cycles are heavier and comparable to naturally conceived offspring. Our recent studies have shown that BW varies significantly between different IVF centres, and in a single centre, is also increasing with time, without a corresponding change in BWs of naturally conceived infants. Although it is likely that factors in the IVF treatment cycle, such as hormonal stimulation or embryo laboratory culture conditions, are associated with BW differences, our previous study designs were not able to confirm this. STUDY DESIGN, SIZE, DURATION: Data relating to BW outcomes, IVF treatment and laboratory parameters were collated from pre-existing electronic records in five participating centres for all singleton babies conceived between August 2007 and December 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: Seven thousand, five hundred and eighty-eight births, 6207 from fresh and 1381 from FET. Infants with severe congenital abnormalities were excluded. The primary outcome of gestation-adjusted BW and secondary outcomes of unadjusted BW and gestation were analysed using multivariable regression models with robust standard errors to allow for the correlation between infants with the same mother. The models tested treatment factors allowing for confounding by centre, time and patient characteristics. A similar matched analysis of a subgroup of 379 sibling pairs was also performed. MAIN RESULTS AND THE ROLE OF CHANCE: No significant associations of birth outcomes with IVF embryo culture parameters were seen independent of clinic or time, including embryo culture medium, incubator type or oxygen level, although small differences cannot be ruled out. We did not detect any significant differences associated with hormonal stimulation in fresh cycles or hormonal synchronization in FET cycles. Gestation-adjusted BW increased by 13.4 (95% CI 0.6-26.1) g per year over the period of the study, and babies born following FET were 92 (95% CI 57-128) g heavier on average than those from the fresh transfer. LIMITATIONS, REASONS FOR CAUTION: Although no specific relationships have been identified independent of clinic and time, the confidence intervals remain large and do not exclude clinically relevant effect sizes. As this is an observational study, residual confounding may still be present. WIDER IMPLICATIONS OF THE FINDINGS: This study demonstrates the potential for large scale analysis of routine data to address critical questions concerning the long-term implications of IVF treatment, in accordance with the Developmental Origins of Health and Disease hypothesis. However, much larger studies, at a national scale with sufficiently detailed data, are required to identify the treatment parameters associated with differences in BW or other relevant outcomes. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the EU FP7 project grant, EpiHealthNet (FP7-PEOPLE-2012-ITN-317146). No competing interests were identified. TRIAL REGISTRATION NUMBER: N/A.

Morphokinetics of early equine embryo development in vitro using time-lapse imaging, and use in selecting blastocysts for transfer.

The use of time-lapse imaging (TLI) in the evaluation of morphokinetics associated with invitro developmental competence is well described for human, cattle and pig embryos. It is generally accepted that embryos that complete early cleavage sooner are more likely to form blastocysts and that timing of later events, such as blastocyst formation and expansion, are predictive of implantation potential and euploid status. In the horse, morphokinetics as a predictor of developmental competence has received little attention. In this study we evaluated the morphokinetics of early equine embryo development invitro for 144 oocytes after intracytoplasmic sperm injection and report the timings of blastocyst development associated with ongoing pregnancy for the first time. There was a tendency for time of cytoplasmic extrusion and first cleavage to occur earlier in the embryos that went on to form blastocysts (n=19) compared with those that arrested, and for first cleavage to occur earlier in blastocysts that established pregnancies that were ongoing (n=4) compared with pregnancies that were lost (n=2). TLI was clinically useful in identifying blastocysts when evaluation of morphology on static imaging was equivocal.

Study protocol: E-freeze - freezing of embryos in assisted conception: a randomised controlled trial evaluating the clinical and cost effectiveness of a policy of freezing embryos followed by thawed frozen embryo transfer compared with a policy of fresh embryo transfer, in women undergoing in vitro fertilisation.

BACKGROUND: Infertility affects one in seven couples; many of these need in vitro fertilisation (IVF). IVF involves external hormones to stimulate a woman's ovaries to produce eggs which are harvested surgically. Embryos, created in the laboratory by mixing eggs with sperm, are grown in culture for a few days before being replaced within the uterus (fresh embryo transfer). Spare embryos are usually frozen with a view to transfer at a later point in time - especially if the initial fresh transfer does not result in a pregnancy. Despite improvements in technology, IVF success rates remain low with an overall live birth rate of 25-30% per treatment. Additionally, there are concerns about health outcomes for mothers and babies conceived through IVF, particularly after fresh embryo transfer, including maternal ovarian hyperstimulation syndrome (OHSS) and preterm delivery. It is believed that high levels of hormones during ovarian stimulation could create a relatively hostile environment for embryo implantation whilst increasing the risk of OHSS. It has been suggested that freezing all embryos with the intention of thawing and replacing them within the uterus at a later stage (thawed frozen embryo transfer) instead of fresh embryo transfer, may lead to improved pregnancy rates and fewer complications. We aim to compare the clinical and cost effectiveness of fresh and thawed frozen embryo transfer, with the primary aim of identifying any difference in the chance of having a healthy baby. METHODS: E-Freeze is a pragmatic, multicentre two-arm parallel group randomised controlled trial where women aged ≥18 and < 42 years, with at least three good quality embryos are randomly allocated to receive either a fresh or thawed frozen embryo transfer. The primary outcome is a healthy baby, defined as a term, singleton, live birth with appropriate weight for gestation. Cost effectiveness will be calculated from a healthcare and societal perspective. DISCUSSION: E-Freeze will determine the relative benefits of fresh and thawed frozen embryo transfer in terms of improving the chance of having a healthy baby. The results of this pragmatic study have the potential to be directly transferred to clinical practice. TRIAL REGISTRATION: ISRCTN registry: ISRCTN61225414 . Date assigned 29/12/2015.

Preliminary investigation of the prevalence and implantation potential of abnormal embryonic phenotypes assessed using time-lapse imaging.

This retrospective, single site observational study aimed to delineate five abnormal embryonic developmental phenotypes, assessing their prevalence, development potential and suitability for inclusion in embryo selection models for IVF. In total, 15,819 embryos from 4559 treatment cycles cultured in EmbryoScope® incubators between January 2014 and January 2016 were included. Time-lapse images were assessed retrospectively for five abnormal embryo phenotypes: direct cleavage, reverse cleavage, absent cleavage, chaotic cleavage and cell lysis. The prevalence of each abnormal phenotype was assessed. Final embryo disposition, embryo quality and implantation rate were determined and compared with a control embryo cohort. The collective prevalence for the five abnormal phenotypes was 11.4%; chaotic cleavage and direct cleavage together constituted 9.7%. Implantation rates were 17.4%, 0%, 25%, 2.1% and 0% for direct, reverse, absent, chaotic cleavage and cell lysis, respectively. The overall implantation rate for all abnormal embryos with known implantation status was significantly lower compared with the control population (6.9% versus 38.7%, P < 0.0001). The proportion of good quality embryos in each category of abnormal cleavage remained below 25%. Embryos exhibiting an abnormal phenotype may have reduced developmental capability, manifested in both embryo quality and implantation potential, when compared with embryos of normal phenotype.

Transfer of thawed frozen embryo versus fresh embryo to improve the healthy baby rate in women undergoing IVF: the E-Freeze RCT.

BACKGROUND: Freezing all embryos, followed by thawing and transferring them into the uterine cavity at a later stage (freeze-all), instead of fresh-embryo transfer may lead to improved pregnancy rates and fewer complications during in vitro fertilisation and pregnancies resulting from it. OBJECTIVE: We aimed to evaluate if a policy of freeze-all results in a higher healthy baby rate than the current policy of transferring fresh embryos. DESIGN: This was a pragmatic, multicentre, two-arm, parallel-group, non-blinded, randomised controlled trial. SETTING: Eighteen in vitro fertilisation clinics across the UK participated from February 2016 to April 2019. PARTICIPANTS: Couples undergoing their first, second or third cycle of in vitro fertilisation treatment in which the female partner was aged < 42 years. INTERVENTIONS: If at least three good-quality embryos were present on day 3 of embryo development, couples were randomly allocated to either freeze-all (intervention) or fresh-embryo transfer (control). OUTCOMES: The primary outcome was a healthy baby, defined as a live, singleton baby born at term, with an appropriate weight for their gestation. Secondary outcomes included ovarian hyperstimulation, live birth and clinical pregnancy rates, complications of pregnancy and childbirth, health economic outcome, and State-Trait Anxiety Inventory scores. RESULTS: A total of 1578 couples were consented and 619 couples were randomised. Most non-randomisations were because of the non-availability of at least three good-quality embryos (n = 476). Of the couples randomised, 117 (19%) did not adhere to the allocated intervention. The rate of non-adherence was higher in the freeze-all arm, with the leading reason being patient choice. The intention-to-treat analysis showed a healthy baby rate of 20.3% in the freeze-all arm and 24.4% in the fresh-embryo transfer arm (risk ratio 0.84, 95% confidence interval 0.62 to 1.15). Similar results were obtained using complier-average causal effect analysis (risk ratio 0.77, 95% confidence interval 0.44 to 1.10), per-protocol analysis (risk ratio 0.87, 95% confidence interval 0.59 to 1.26) and as-treated analysis (risk ratio 0.91, 95% confidence interval 0.64 to 1.29). The risk of ovarian hyperstimulation was 3.6% in the freeze-all arm and 8.1% in the fresh-embryo transfer arm (risk ratio 0.44, 99% confidence interval 0.15 to 1.30). There were no statistically significant differences between the freeze-all and the fresh-embryo transfer arms in the live birth rates (28.3% vs. 34.3%; risk ratio 0.83, 99% confidence interval 0.65 to 1.06) and clinical pregnancy rates (33.9% vs. 40.1%; risk ratio 0.85, 99% confidence interval 0.65 to 1.11). There was no statistically significant difference in anxiety scores for male participants (mean difference 0.1, 99% confidence interval -2.4 to 2.6) and female participants (mean difference 0.0, 99% confidence interval -2.2 to 2.2) between the arms. The economic analysis showed that freeze-all had a low probability of being cost-effective in terms of the incremental cost per healthy baby and incremental cost per live birth. LIMITATIONS: We were unable to reach the original planned sample size of 1086 and the rate of non-adherence to the allocated intervention was much higher than expected. CONCLUSION: When efficacy, safety and costs are considered, freeze-all is not better than fresh-embryo transfer. TRIAL REGISTRATION: This trial is registered as ISRCTN61225414. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 25. See the NIHR Journals Library website for further project information.

During in vitro fertilisation, eggs and sperm are mixed in a laboratory to create embryos. An embryo is placed in the womb 2­5 days later (fresh-embryo transfer) and the remaining embryos are frozen for future use. Initial research suggested that freezing all embryos followed by thawing and replacing them a few weeks later could improve treatment safety and success. Although these data were promising, the data came from small studies and were not enough to change practice and policy. We conducted a large, multicentre, clinical trial to evaluate the two strategies: fresh-embryo transfer compared with later transfer of frozen embryos. We also compared the costs of both strategies during in vitro fertilisation treatment, pregnancy and delivery. This study was conducted across 18 clinics in the UK from 2016 to 2019, and 619 couples participated. Couples were allocated to one of two strategies: immediate fresh-embryo transfer or freezing of all embryos followed later by transfer of frozen embryo. The study's aim was to find out which type of embryo transfer gave participants a higher chance of having a healthy baby. We found that freezing all embryos followed by frozen-embryo transfer did not lead to a higher chance of having a healthy baby. There were no differences between strategies in the number of live births, the miscarriage rate or the number of pregnancy complications. Fresh-embryo transfer was less costly from both a health-care and a patient perspective. A routine strategy of freezing all embryos is not justified given that there was no increase in success rates but there were extra costs and delays to embryo transfer.

An investigation into the effect of potential confounding patient and treatment parameters on human embryo morphokinetics.

OBJECTIVE: To determine the effect of patient and treatment parameters on 19 embryo morphokinetic parameters using pronuclear fading as time zero. DESIGN: Single-site, retrospective cohort analysis. SETTING: Fertility treatment center. PATIENTS(S): Patients undergoing treatment between September 2014 and January 2016 (n = 639) whose embryos were cultured in the EmbryoScope for 6 days (n = 2,376). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Multiple regression analysis of body mass index; maternal age; infertility diagnosis; treatment type; suppression protocol on time to each cellular division (tn): t2, t3, t4, t5, t6, t7, t8, t9, time to start of compaction (tM), start of blastulation (tSB), full blastocyst (tB); and interval measurements: s2, s3, cc2, cc3, cc4, t9-tM, tM-tSB, and tSB-tB. Beta coefficients were analyzed to quantify any significant effects. RESULT(S): Embryos appeared to be subtly affected by patient and treatment parameters, exhibiting complex relationships between various morphokinetic parameters and specific patient and treatment factors, rather than a systemic effect. CONCLUSION(S): These findings outline the need for the consideration of confounding factors when assessing an embryo's ability to achieve implantation. Although morphokinetic parameters have been related to embryo viability, it is likely that this will vary depending on the embryo's origin.

Examining the efficacy of six published time-lapse imaging embryo selection algorithms to predict implantation to demonstrate the need for the development of specific, in-house morphokinetic selection algorithms.

OBJECTIVE: To study the efficacy of six embryo-selection algorithms (ESAs) when applied to a large, exclusive set of known implantation embryos. DESIGN: Retrospective, observational analysis. SETTING: Fertility treatment center. PATIENT(S): Women undergoing a total of 884 in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment cycles (977 embryos) between September 2014 and September 2015 with embryos cultured using G-TL (Vitrolife) at 5% O2, 89% N2, 6% CO2, at 37°C in EmbryoScope instruments. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Efficacy of each ESA to predict implantation defined using specificity, sensitivity, positive predictive value (PPV), negative predictive value (NPV), area under the receiver operating characteristic curve (AUC), and likelihood ratio (LR), with differences in implantation rates (IR) in the categories outlined by each ESA statistically analyzed (Fisher's exact and Kruskal-Wallis tests). RESULT(S): When applied to an exclusive cohort of known implantation embryos, the PPVs of each ESA were 42.57%, 41.52%, 44.28%, 38.91%, 38.29%, and 40.45%. The NPVs were 62.12%, 68.26%, 71.35%, 76.19%, 61.10%, and 64.14%. The sensitivity was 16.70%, 75.33%, 72.94%, 98.67%, 51.19%, and 62.33% and the specificity was 85.83%, 33.33%, 42.33%, 2.67%, 48.17%, and 42.33%, The AUC were 0.584, 0.558, 0.573, 0.612, 0.543, and 0.629. Two of the ESAs resulted in statistically significant differences in the embryo classifications in terms of IR. CONCLUSION(S): These results highlight the need for the development of in-house ESAs that are specific to the patient, treatment, and environment. These data suggest that currently available ESAs may not be clinically applicable and lose their diagnostic value when externally applied.

Embryos cultured in a time-lapse system result in superior treatment outcomes: a strict matched pair analysis.

A retrospective strict matched-pair analysis of 728 treatment cycles between January 2011 and September 2014 was performed. A total of 364 treatment cycles, where all embryos were cultured and examined in EmbryoScope®, were matched to treatment cycles where all the embryos were cultured in a standard incubator with conventional morphological examination. Matching was performed for patient age, number of oocytes collected, treatment type and date of oocyte collection (± six months). The clinical (CPR), implantation (IR), live birth (LBR) and miscarriage rates (MR) were calculated and considered significant when p < 0.05 (Chi-square test). CPR, IR and LBR were found to be significantly higher in the time-lapse system (TLS) group compared to the standard incubation group (CPR = 44.8% versus 36.5%, p = 0.02; IR = 39.3% versus 32.2%, p = 0.03; and LBR = 43.1% versus 33.8%, p = 0.01). Although there was a 5.5% decrease in the MR for the TLS group when compared to the standard incubation group, this result was not statistically significant (18.9% versus 24.4%, p = 0.19). There is a paucity of well-designed studies to confirm that embryos cultured and examined in TLS can result in superior treatment outcomes, and this strict-matched pair analysis with a large cohort of treatment cycles indicates the advantage of using TLS.

Reproductive potential of fresh and cryopreserved epididymal and testicular spermatozoa in consecutive intracytoplasmic sperm injection cycles in the same patients.

OBJECTIVE: To determine if the cryopreservation of epididymal and testicular spermatozoa alters their reproductive potential by examination of patients who underwent consecutive cycles of ICSI using fresh and then cryopreserved spermatozoa. DESIGN: Retrospective review. SETTING: Tertiary care university hospital. PATIENT(S): One hundred sixty-two consecutive cycles of ICSI were analyzed. Thirteen patients were identified as having undergone treatment with freshly retrieved epididymal spermatozoa; these patients subsequently underwent treatment with spermatozoa cryopreserved from that cycle. Eighteen patients underwent ICSI with freshly retrieved testicular spermatozoa; these patients subsequently underwent treatment with spermatozoa cryopreserved from that cycle. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Fertilization rates and pregnancy rates. RESULT(S): The fertilizing capacity of epididymal spermatozoa remained unchanged after cryopreservation and subsequent thawing, with fertilization rates of 58% and 57% for fresh and cryopreserved spermatozoa, respectively. Testicular spermatozoa, however, showed a significant decrease in fertilizing capacity after cryopreservation when compared with freshly retrieved spermatozoa (52% and 71%, respectively). Pregnancy rates appeared unaffected by the cryopreservation of epididymal spermatozoa (fresh, 3/13; frozen, 2/13) or testicular spermatozoa (fresh, 2/18; frozen, 5/18). CONCLUSION(S): This study offers further evidence that motile epididymal spermatozoa retain their fertilizing capacity after cryopreservation. The data presented on testicular spermatozoa suggest that although cryopreservation may reduce the fertilizing capacity of testicular spermatozoa, there is no decrease in pregnancy rates.

Postoperative pain, complications, and satisfaction rates in patients who undergo surgical sperm retrieval.

OBJECTIVE: To determine patients' experiences with surgical sperm retrieval and its common complications. DESIGN: A questionnaire based survey using visual analogue scales (VAS) and closed questions to analyze complication, pain, and satisfaction rates. SETTING: Tertiary care university hospital. PATIENT(S): One hundred consecutive males undergoing surgical sperm retrieval by percutaneous epididymal sperm aspiration (PESA) or testicular sperm extraction (TESE). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): We surveyed for pain perception complication rates and satisfaction scores. RESULT(S): Of the 85 patients who replied, 21 underwent retrieval for nonobstructive causes, 37 following failed reversal of vasectomy, and 27 for other obstructive causes. Retrieval was successful in 100% of obstructive causes and in 61% for nonobstructive azoospermia. Epididymal retrieval was successful in 23 patients, 30 patients underwent TESE after failed PESA, and 23 had TESE only. There were significant increases in pain perception scores and reported complications with TESE over PESA (31 vs. 16; and 21 out of 63 vs. 2 out of 22, respectively), but no difference in satisfaction rate. The cause of azoospermia did not affect pain perception or satisfaction in TESE. Complication rates were increased in larger testes (3 out of 22 vs. 24 out of 63). Unsuccessful sperm retrieval did not significantly affect patients' pain perception or satisfaction. Surgical sperm retrieval was rated as significantly less painful than both vasectomy and reversal (21% vs. 42% vs. 57%, respectively) and was associated with significantly fewer days absent from work (3.0 vs. 8.5). CONCLUSION(S): Surgical sperm retrieval by PESA or TESE is a safe procedure with only minor complications that is tolerated well by patients.

Effect on clinical outcome of the interval between collection of epididymal and testicular spermatozoa and intracytoplasmic sperm injection in obstructive azoospermia.

We wished to determine whether the interval between surgical retrieval of epididymal and testicular spermatozoa in obstructive azoospermia and their subsequent use in intracytoplasmic sperm injection (ICSI) has an effect on their fertilizing capacity and pregnancy rates in patients undergoing ICSI. This was a retrospective review of 164 consecutive cycles of ICSI in partners of men undergoing surgical sperm retrieval for obstructive azoospermia. Seventy-three cycles used fresh testicular spermatozoa; in 35 cycles ICSI was performed within 4 hours of sperm retrieval, and in 38 cycles spermatozoa were incubated overnight before ICSI. Epididymal spermatozoa were used in 29 cycles; 22 cases within 4 hours of retrieval and 7 cases following overnight culture. Cyropreserved testicular and epididymal spermatozoa were used in 42 and 20 ICSI cycles, respectively. Fertilization and clinical pregnancy rates were calculated for each treatment group. Fertilization rates for epididymal spermatozoa were 67% at 4 hours, 56% at 24 hours, and 63% for cryopreserved spermatozoa (P =.52). Fertilization rates for testicular spermatozoa were 63% at 4 hours, 71% at 24 hours, and 60% for cryopreserved spermatozoa (P =.16). Unlike testicular spermatozoa, cryopreserved epididymal spermatozoa showed a significant increase in clinical pregnancy rates with cryopreservation, with rates of 4 of 22, 1 of 7, and 10 of 20 at 4 hours, 24 hours, and cryopreservation, respectively (P =.049). This study confirms that fertilization and pregnancy rates following ICSI with motile spermatozoa are unaffected by the duration between surgical retrieval of spermatozoa and their injection into oocytes. It also demonstrates that of all treatment modalities, the use of frozen epididymal spermatozoa was associated with the greatest pregnancy rates.

Surgical sperm retrieval: a review of current practice.

Although pregnancies were achieved after surgical sperm retrieval and in vitro fertilization 8 years before the introduction of intracytoplasmic sperm injection (ICSI), it is the development of ICSI that has led to the rapid expansion of surgical procedures to obtain sperm from azoospermic males for use in assisted conception cycles. The natural desire for couples to achieve a pregnancy using their own gametes and a national shortage of donor sperm have driven the demand for an expansion of this service. Males who have previously been considered unable to father their own genetic child can now be offered treatment, which, in most cases, will lead to the recovery of sperm for use in treatment. This article considers the development of the techniques available to clinicians and provides an overview of the many treatments (and their acronyms) to assist clinicians unfamiliar with the practicalities of surgical sperm retrieval. In reviewing the current published studies, we also offer some guidelines as to the optimization of the potential future provisions of surgical sperm retrieval treatments for azoospermic males, either secondary to obstruction (particularly after vasectomy) or from non-obstructive causes.

Optimal treatment for poor responders to ovarian stimulation: does in vitro insemination offer any advantages to intrauterine insemination?

A retrospective study was performed of 1832 consecutive in vitro insemination (IVF)/intracytoplasmic sperm injection (ICSI) cycles over 18 months, to analyse the benefits or otherwise to the patient of continuing with in vitro treatment or converting the assisted conception cycle to intrauterine insemination (IUI). Two hundred and seventy cycles were identified in which three follicles or fewer were obtained after controlled ovarian hyperstimulation; in 143 of these cycles, the clinicians or patients elected to abandon all treatment, whereas treatment was continued in 127 patients. In 79 cycles, the patients proceeded with IVF/ICSI and in 48 patients, the cycles were converted to IUI. Data were analysed with regard to the clinical pregnancy rate. In addition, the data for IUI were compared with eight cycles of supraovulation IUI (S/IUI) performed over the same period. There were no significant differences in clinical pregnancy rates among any treatment modality 6/48 (12.5%), 6/79 (7.7%) and 1/8 (12.5%) for IUI, IVF and S/IUI, respectively (P = 0.64). The lowest total number of motile spermatozoa required to achieve pregnancy using IUI was 2.0 x 10(6). In conclusion, it appears that, if the treatment is suitable, patients who respond poorly to controlled hyperstimulation for IVF would not be disadvantaged in achieving a pregnancy by offering them conversion to the medically and financially less interventional IUI.

Development and in vitro testing of a new method of urine preparation for retrograde ejaculation; the Liverpool solution.

OBJECTIVE: To design a new method for oral preparation of urine for sperm retrieval after retrograde ejaculation (RE) and to test the motility of sperm exposed to prepared and unprepared urine. DESIGN: In vitro testing of urine conditions and sperm motility. SETTING: Assisted conception unit at a teaching hospital in the United Kingdom. PATIENT(S): Ten healthy volunteers to provide urine and sperm specimens from men attending the unit for semen analysis. INTERVENTION(S): Various solutions of sodium bicarbonate and sodium chloride were drunk by a single subject until a suitable regimen was achieved. This regimen (called the Liverpool solution) was then tested on 10 volunteers. Samples of sperm were then added to prepared urine, unprepared urine, and culture medium, and the motility was analyzed. MAIN OUTCOME MEASURE(S): Urinary pH and osmolarity, sperm motility. RESULT(S): Urine produced by the 10 volunteers had a mean pH of 7.47 (range, 7.23-7.79) and a mean osmolarity of 289 mOsmol/L (range, 225-412 mOsmol/L), similar to that of medium. The progressive motility of sperm exposed to the unprepared urine was reduced (42.4% of sperm in medium), whereas that in the prepared urine was similar to that in the control medium. CONCLUSION(S): Liverpool solution can be used in any unit treating couples with RE, and it is a noninvasive and inexpensive regimen that may optimize urine pH and osmolarity for sperm survival after RE.