The freeze-all strategy versus agonist triggering with low-dose hCG for luteal phase support in IVF/ICSI for high responders: a randomized controlled trial.

STUDY QUESTION: Does the freeze-all strategy in high-responders increase pregnancy rates and improve safety outcomes when compared with GnRH agonist triggering followed by low-dose hCG intensified luteal support with a fresh embryo transfer? SUMMARY ANSWER: Pregnancy rates after either fresh embryo transfer with intensified luteal phase support using low-dose hCG or the freeze-all strategy did not vary significantly; however, moderate-to-severe ovarian hyperstimulation syndrome (OHSS) occurred more frequently in the women who attempted a fresh embryo transfer. WHAT IS KNOWN ALREADY: Two strategies following GnRH agonist triggering (the freeze-all approach and a fresh embryo transfer attempt using a low-dose of hCG for intensified luteal phase support) are safer alternatives when compared with conventional hCG triggering with similar pregnancy outcomes. However, these two strategies have never been compared head-to-head in an unrestricted predicted hyper-responder population. STUDY DESIGN, SIZE, DURATION: This study included women with an excessive response to ovarian stimulation (≥18 follicles measuring ≥11 mm) undergoing IVF/ICSI in a GnRH antagonist suppressed cycle between 2014 and 2017. Our primary outcome was clinical pregnancy at 7 weeks after the first embryo transfer. Secondary outcomes included live birth and the development of moderate-to-severe OHSS. PARTICIPANTS/MATERIALS, SETTING, METHODS: Following GnRH agonist triggering, women were randomized either to cryopreserve all good-quality embryos followed by a frozen embryo transfer in an subsequent artificial cycle or to perform a fresh embryo transfer with intensified luteal phase support (1500 IU hCG on the day of oocyte retrieval, plus oral estradiol 2 mg two times a day, plus 200 mg of micronized vaginal progesterone three times a day). MAIN RESULTS AND THE ROLE OF CHANCE: A total of 212 patients (106 in each arm) were recruited in the study, with three patients (one in the fresh embryo transfer group and two in the freeze-all group) later withdrawing their consent to participate in the study. One patient in the freeze-all group became pregnant naturally (clinical pregnancy diagnosed 38 days after randomization) prior to the first frozen embryo transfer. The study arms did not vary significantly in terms of the number of oocytes retrieved and embryos produced/transferred. The intention to treat clinical pregnancy and live birth rates (with the latter excluding four cases lost to follow-up: one in the fresh transfer and three in the freeze-all arms, respectively) after the first embryo transfer did not vary significantly among the fresh embryo transfer and freeze-all study arms: 51/105 (48.6%) versus 57/104 (54.8%) and 41/104 (39.4%) versus 42/101 (41.6%), respectively (relative risk for clinical pregnancy 1.13, 95% CI 0.87-1.47; P = 0.41). However, moderate-to-severe OHSS occurred solely in the group that received low-dose hCG (9/105, 8.6%, 95% CI 3.2% to 13.9% vs 0/104, 95% CI 0 to 3.7, P < 0.01). LIMITATIONS, REASONS FOR CAUTION: The sample size calculation was based on a 19% absolute difference in terms of clinical pregnancy rates, therefore smaller differences, as observed in the trial, cannot be reliably excluded as non-significant. WIDER IMPLICATIONS OF THE FINDINGS: This study offers the first comparative analysis of two common strategies applied to women performing IVF/ICSI with a high risk to develop OHSS. While pregnancy rates did not vary significantly, a fresh embryo transfer with intensified luteal phase support may still not avoid the risk of moderate-to-severe OHSS and serious consideration should be made before recommending it as a routine first-line treatment. Future trials may allow us to confirm these findings. STUDY FUNDING/COMPETING INTEREST(S): The authors have no conflicts of interest to disclose. No external funding was obtained for this study. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT02148393. TRIAL REGISTRATION DATE: 28 May 2014. DATE OF FIRST PATIENT'S ENROLMENT: 30 May 2014.

Is ovarian response associated with adverse perinatal outcomes in GnRH antagonist IVF/ICSI cycles?

RESEARCH QUESTION: Is there an association between ovarian response and perinatal outcomes? DESIGN: A retrospective, single-centre cohort study including all women undergoing their first ovarian stimulation cycle in a gonadotrophin releasing hormone antagonist protocol, with a fresh embryo transfer that resulted in a singleton live birth from January 2009 to December 2015. Patients were categorized into four groups according to the number of oocytes retrieved: one to three (category 1), four to nine (category 2), 10-15 (category 3), or over 15 oocytes (category 4). RESULTS: The overall number of patients analysed was 964. No relevant statistical difference was found among neonatal outcomes across the four ovarian response categories. Neonatal weight (in grams) was comparable between all groups (3222 ± 607 versus 3254 ± 537 versus 3235 ± 575 versus 3200 ± 622; P = 0.85, in categories 1, 2, 3 and 4, respectively). No statistically significant differences were found among the ovarian response categories for birth weight z-scores (taking into account neonatal sex and delivery term). The incidence of pre-term birth and low birth weight was comparable across the different ovarian response groups (P = 0.127 and P = 0.19, respectively). Finally, the occurrence of adverse obstetric outcomes did not differ among the ovarian response categories. Multivariate regression analysis revealed that the number of oocytes was not associated with neonatal birth weight. CONCLUSIONS: No association was found between ovarian response and adverse perinatal outcomes in antagonist IVF and intracytoplasmic sperm injection cycles. Future, larger scale and prospectively designed investigations are needed to validate these results.

Impact of Serum Estradiol Levels Prior to Progesterone Administration in Artificially Prepared Frozen Embryo Transfer Cycles.

Background: The need for endocrine monitoring in artificial cycles for frozen embryo transfer (FET) remains unclear and, more specifically, the value of the late-proliferative phase serum estradiol (E2) levels is with conflicting evidence in current literature. Objective: To investigate whether artificial FET cycles require endocrine monitoring for the serum E2 level prior to initiation of exogenous progesterone administration after an endometrial thickness of 6.5 mm has been reached. Design: One thousand two hundred and twenty-two (n = 1,222) artificial FETs performed in a tertiary center between 2010 and 2015 were subdivided into 3 groups according to the following late-proliferative serum E2 level percentiles: ≤p10 (E2 ≤144 pg/ml; n = 124), p11-p90 (E2 from 145 to 438 pg/ml; n = 977) and >p90 (E2 >439 pg/ml; n = 121). A mixed-effects multilevel multivariable regression analysis was performed to assess the potential effect of the late-proliferative E2 level on the live birth rate (LBR). Results: The level of late-proliferative circulating E2 showed no significant difference in terms of LBR after FET. Specifically, the multivariable regression model demonstrated a LBR of 19.5% for the p11-p90 reference group, compared to 24.4% for the ≤p10 (p = 0.251) and 19.5% for the >p90 group (p = 0.989). Conclusion: In this large retrospective dataset, no association was observed between late-proliferative phase serum E2 levels and LBR following FET in artificially prepared cycles. Although, caution is warranted due to the retrospective nature of the analysis and the potential for unmeasured confounding, we argue that monitoring of the late-proliferative serum E2 levels and using them to guide clinical decision-making (e.g., medication step-up, cycle prolongation or cancelation) may be of questionable value.

Modified natural cycle IVF versus conventional stimulation in advanced-age Bologna poor responders.

RESEARCH QUESTION: Do ongoing pregnancy rates (OPR) differ between modified natural cycle IVF (MNC-IVF) and conventional high-dose ovarian stimulation (HDOS) in advanced-age Bologna poor responders? DESIGN: This was a retrospective cohort study including patients with poor ovarian response (POR) attending a tertiary referral university hospital from 1 January 2011 to 1 March 2017. All women who fulfilled the Bologna criteria for POR and aged ≥40 years who underwent their first intracytoplasmic sperm injection (ICSI) cycle in the study centre were included. RESULTS: In total, 476 advanced-age Bologna poor responder patients were included in the study: 189 in the MNC-IVF group and 287 in the HDOS group. OPR per patient were significantly lower in the MNC-IVF group (5/189, 2.6%) compared with the HDOS group (29/287, 10.1%) (P = 0.002). However, after adjustment for relevant confounders (number of oocytes and presence of at least one top-quality embryo), the multivariate logistic regression analysis showed that the type of treatment strategy (HDOS versus MNC-IVF) was not significantly associated with OPR (odds ratio 2.56, 95% confidence interval 0.9-7.6). CONCLUSIONS: In advanced-age Bologna poor responders, MNC-IVF, which is a more patient-friendly approach, could be a reasonable alternative in this difficult-to-treat group of women.

Added value today of hormonal measurements in ovarian stimulation in gonadotropin-releasing hormone antagonist treatment cycle.

PURPOSE OF REVIEW: Traditional approach of ovarian stimulation monitoring for in-vitro fertilization involves transvaginal sonography and serum estradiol measurements. Accumulating evidence has shown that hormonal evaluations during ovarian stimulation allow individual cycle optimization, moving away from only predicting the risk of ovarian hyperstimulation syndrome, but in addition assessing the impact of ovarian stimulation on endometrial receptivity, quality of oocytes, and subsequently embryos. The purpose of this review is to discuss the relevance and added value of hormonal monitoring during ovarian stimulation in gonadotropin-releasing hormone antagonist cycles where most of the advances have occurred. RECENT FINDINGS: Basal hormonal status, particularly estradiol, progesterone, and luteinizing hormone are instrumental in prediction of the patients with poor prognosis. Estradiol levels on the day of trigger are less sensitive in predicting ovarian hyperstimulation syndrome then the number of follicles more than 11 mm in diameter. Progesterone elevation on the day of trigger is associated with lower pregnancy rates. The gold standard treatment for progesterone elevation is to adopt a freeze-all strategy when the threshold of 1.50 ng/ml is exceeded. The effect of progesterone elevation on embryo quality remains to be confirmed by more trials. SUMMARY: Endocrine monitoring during ovarian stimulation allows fine-tuning of the physiology of the stimulated cycle and thereby increases the chances of successful treatment outcome.

Processing and selection of surgically-retrieved sperm for ICSI: a review.

Although the technique of intracytoplasmic sperm injection (ICSI) has been a revolution in the alleviation of male infertility, the use of testicular sperm for ICSI was a formerly unseen breakthrough in the treatment of the azoospermic man with primary testicular failure. At the clinical level, different procedures of testicular sperm retrieval (conventional TESE, micro-TESE, FNA/TESA, MESA, PESA) are being performed, the choice is mainly based on the cause of azoospermia (obstructive versus non-obstructive) and the surgeon's skills. At the level of the IVF laboratory, mechanical procedures to harvest the sperm from the tissue may be combined with enzymatic treatment in order to increase the sperm recovery rates. A number of techniques have been developed for viable sperm selection in males with only immotile testicular sperm available. However, large, well-designed studies on the benefit and safety of one over the other technique are lacking. Despite all the available methods and combinations of laboratory procedures which have a common goal to maximize sperm recovery from testicular samples, a large proportion of NOA patients fail to father a genetically own child. Advanced technology application may improve recovery rates by detection of the testicular foci with active spermatogenesis and/or identification of the rare individual sperm in the testicular suspensions. On the other hand, in vitro spermatogenesis or sperm production from embryonic stem cells or induced pluripotent stem cells might be future options. The present review summarizes the available strategies which aim to maximize sperm recovery from surgically retrieved samples.

Bien que la technique d'injection intra cytoplasmique d'un spermatozoïde (ICSI) ait constitué une révolution dans le soulagement de l'infertilité masculine, l'utilisation de spermatozoïdes testiculaires lors de l'ICSI fut une découverte capitale auparavant inaperçue du traitement de l'homme azoospermique par altération testiculaire primaire. Au plan clinique, différentes procédures de recueil des spermatozoïdes testiculaires sont réalisées (TESE conventionnelle, micro-TESE, FNA/TESA, MESA, PESA) dont le choix dépend principalement de la cause de l'azoospermie (obstructive versus non obstructive) et des compétences du chirurgien. Au plan du laboratoire de fécondation in vitro, des procédures mécaniques d'extraction des spermatozoïdes du tissu peuvent être combinées avec un traitement enzymatique dans l'objectif d'accroitre le taux de récupération de spermatozoïdes. Plusieurs techniques ont été développées pour sélectionner des spermatozoïdes vivants chez les hommes n'ayant que des spermatozoïdes testiculaires immobiles. Toutefois, il manque des études bien construites et à effectifs consistants portant sur le bénéfice et l'innocuité d'une technique par rapport aux autres. Malgré toutes les méthodes et combinaisons de procédures de laboratoire disponibles qui ont comme objectif commun d'accroitre au maximum la récupération de spermatozoïdes dans les échantillons testiculaires, un grand nombre de patients avec NOA échouent à obtenir un enfant qui soit génétiquement leur. L'utilisation d'une technologie de pointe devrait améliorer les taux de récupération par la détection de foyers testiculaires ayant une spermatogenèse active et/ou l'identification de rare spermatozoïde isolé dans les suspensions testiculaires. D'autre part, la spermatogenèse in vitro ou la production de spermatozoïdes à partir de cellules souches embryonnaires ou de cellules souches pluripotentes induites pourraient constituer de futures options. Le présent article de revue résume les stratégies disponibles qui visent à maximiser la récupération de spermatozoïdes dans des échantillons extraits chirurgicalement.

Bien que la technique d'injection intra cytoplasmique d'un spermatozoïde (ICSI) ait constitué une révolution dans le soulagement de l'infertilité masculine, l'utilisation de spermatozoïdes testiculaires lors de l'ICSI fut une découverte capitale auparavant inaperçue du traitement de l'homme azoospermique par altération testiculaire primaire. Au plan clinique, différentes procédures de recueil des spermatozoïdes testiculaires sont réalisées (TESE conventionnelle, micro-TESE, FNA/TESA, MESA, PESA) dont le choix dépend principalement de la cause de l'azoospermie (obstructive versus non obstructive) et des compétences du chirurgien. Au plan du laboratoire de fécondation in vitro, des procédures mécaniques d'extraction des spermatozoïdes du tissu peuvent être combinées avec un traitement enzymatique dans l'objectif d'accroitre le taux de récupération de spermatozoïdes. Plusieurs techniques ont été développées pour sélectionner des spermatozoïdes vivants chez les hommes n'ayant que des spermatozoïdes testiculaires immobiles. Toutefois, il manque des études bien construites et à effectifs consistants portant sur le bénéfice et l'innocuité d'une technique par rapport aux autres. Malgré toutes les méthodes et combinaisons de procédures de laboratoire disponibles qui ont comme objectif commun d'accroitre au maximum la récupération de spermatozoïdes dans les échantillons testiculaires, un grand nombre de patients avec NOA échouent à obtenir un enfant qui soit génétiquement leur. L'utilisation d'une technologie de pointe devrait améliorer les taux de récupération par la détection de foyers testiculaires ayant une spermatogenèse active et/ou l'identification de rare spermatozoïde isolé dans les suspensions testiculaires. D'autre part, la spermatogenèse in vitro ou la production de spermatozoïdes à partir de cellules souches embryonnaires ou de cellules souches pluripotentes induites pourraient constituer de futures options. Le présent article de revue résume les stratégies disponibles qui visent à maximiser la récupération de spermatozoïdes dans des échantillons extraits chirurgicalement.

Severe ovarian hyperstimulation syndrome after gonadotropin-releasing hormone (GnRH) agonist trigger and "freeze-all" approach in GnRH antagonist protocol.

OBJECTIVE: To report two cases with GnRH agonist triggering and a freeze-all approach in a GnRH antagonist protocol resulting in the development of severe ovarian hyperstimulation syndrome (OHSS), requiring hospitalization and peritoneal drainage. DESIGN: Two case reports. SETTING: A tertiary referral center and an obstetrics and gynecology department of a hospital. PATIENT(S): Case 1 and case 2: severe OHSS with abdominal distension, ascites development, and hemoconcentration. INTERVENTION(S): Case 1 and case 2: diagnosed by clinical, hematologic, and ultrasound findings. Hospitalization, IV infusion, and peritoneal drainage. MAIN OUTCOME MEASURE(S): Symptomatic treatment and prevention of further complication. RESULT(S): Complete recovery. CONCLUSION(S): Two cases of severe OHSS after GnRH agonist trigger in a GnRH antagonist protocol without the administration of any hCG for luteal-phase support. Clinicians have to be aware that even the sequential approach to ovarian stimulation with a freeze-all attitude does not completely eliminate OHSS in all patients.

Vaginal progesterone supplementation has no effect on ongoing pregnancy rate in hCG-induced natural frozen-thawed embryo transfer cycles.

OBJECTIVE: The purpose of this study is to assess the effect of luteal phase supplementation (LPS) on pregnancy rates in human chorionic gonadotropin (hCG)-induced natural frozen-thawed (FET) cycles. STUDY DESIGN: All performed hCG-induced natural FET cycles from January 2006 until August 2007 were retrospectively identified. The study group consisted of 452 cycles: 243 supplemented with progesterone administration (600 mg natural micronized progesterone in three separate doses) and 209 without progesterone. Analysis was limited to cycles where embryos were cryopreserved on day 3. Final oocyte maturation was achieved by hCG when endometrial thickness of >or=7 mm and a follicle of 17 mm were present on ultrasound. RESULTS: No statistically significant differences were observed in ongoing pregnancy rate between the two groups (22% versus 21%, p=0.8; difference +1%; 95% confidence interval (CI): -6.5 to +8.7). The non-significant effect of the presence or not of luteal support on pregnancy rate was confirmed by logistic regression (odds ratio (OR): 0.9, 95% CI: 0.54-1.47, P=0.64). A previous pregnancy following fresh embryo transfer (OR: 6.04, 95% CI: 3.63-10.02, P=0.001) and increased endometrial thickness (OR: 1.25, 95% CI: 1.11-1.41, P=0.001) significantly affected the achievement of ongoing pregnancy, whereas the association between embryo score and achievement of pregnancy was marginally significant (OR:0.28, 95% CI: 0.08-0.97, P=0.05). CONCLUSION: There is no convincing evidence to support the use of LPS in hCG-induced natural FET cycles, since there is no luteal phase defect. Further prospective randomized studies are necessary to confirm these findings.

Corifollitropin alfa in a long GnRH agonist protocol: proof of concept trial.

Fifty healthy women, aged 18-39 years with no known risk of ovarian hyperstimulation were treated with 100 or 150 µg corifollitropin alfa (dependent on body weight) in a long GnRH agonist protocol. At these doses, corifollitropin alfa initiated and supported growth of a large cohort of follicles during the first week of ovarian stimulation.

In vitro fertilization pregnancy in a patient with proven chronic endometritis.

OBJECTIVE: To report an in vitro fertilization (IVF) pregnancy in a patient with histologically confirmed chronic endometritis before the IVF treatment without prior antibiotherapy. DESIGN: Case report. SETTING: Academic reproductive medicine unit. PATIENT(S): A 30-year-old woman with primary infertility due to mild oligoasthenoteratospermia of the male partner. INTERVENTION(S): Diagnostic hysteroscopy and endometrial biopsy. MAIN OUTCOME MEASURE(S): Delivery after the first IVF. RESULT(S): Histologic examination of the endometrium revealed chronic endometritis. The patient delivered a healthy boy at 40 weeks' gestation after the first IVF treatment. CONCLUSION(S): Our findings suggest that the impact of chronic endometritis on infertility and IVF outcome should be further investigated in prospective randomized studies.