Is the probability of pregnancy after ovarian stimulation for IVF associated with serum estradiol levels on the day of triggering final oocyte maturation with hCG? A systematic review and meta-analysis.

PURPOSE: The objective of this systematic review and metaanalysis was to examine if the probability of pregnancy after ovarian stimulation for in vitro fertilization (IVF), using GnRH analogues and gonadotrophins is associated with serum estradiol level (Ε2) on the day of triggering final oocyte maturation with human chorionic gonadotrophin (hCG). METHODS: Twenty-one studies were eligible for this systematic review, including 19,598 IVF cycles, whereas three studies were eligible for metaanalysis, including 641 IVF cycles. The main outcome measure was achievement of ongoing pregnancy/live birth and, if not available, clinical pregnancy or biochemical pregnancy. RESULTS: Pooling of data showed no differences in the probability of clinical pregnancy between patients with high and low Ε2 levels on the day of triggering final oocyte maturation. The pooled effect sizes for the Ε2 thresholds groups constructed, regarding clinical pregnancy were 2000-3000 pg/mL-OR 0.91, 95% CI 0.55 to 1.50, (fair quality/moderate risk of bias, n = 1 study), 3000-4000 pg/mL-OR 0.89, 95% CI 0.46 to 1.70, (fair quality/moderate risk of bias, n = 1 study, good quality/no information on which to base a judgement about risk of bias n = 2 studies), 4000-5000 pg/mL-OR 0.74, 95% CI 0.37 to 1.49 fair quality/moderate risk of bias, n = 1 study), 5000-6000 pg/mL-OR 0.62, 95% CI 0.19 to 1.98, (fair quality/moderate risk of bias, n = 1 study). In addition, no difference was observed in the probability of ongoing pregnancy for the Ε2 threshold group of 3000-4000 pg/mL OR 0.85, 95% CI 0.40 to 1.81(good quality/no information on which to base a judgement about risk of bias, n = 1 study). CONCLUSION: Currently, there is insufficient evidence to support or deny the presence of an association between the probability of pregnancy and serum Ε2 levels on the day of triggering final oocyte maturation with hCG in women undergoing ovarian stimulation for IVF.

Higher probability of live-birth in high, but not normal, responders after first frozen-embryo transfer in a freeze-only cycle strategy compared to fresh-embryo transfer: a meta-analysis.

STUDY QUESTION: Does the outcome of the comparison of live birth rates between the first frozen embryo transfer (ET) (in a freeze-only cycles strategy, i.e. frozen ET group) and a fresh embryo transfer (fresh ET group) differ considering the type of ovarian response? SUMMARY ANSWER: Α significantly higher probability of live birth is present in high, but not normal, responders, after the first frozen ET in a freeze-only cycle strategy as compared to a fresh ET. WHAT IS KNOWN ALREADY: It has been hypothesised that freezing all good embryos in a fresh in-vitro fertilisation (IVF) cycle and deferring embryo transfer in subsequent cycles may provide a more physiological endometrial environment for embryo implantation when compared to a fresh ET. However, currently, three relevant meta-analyses have been published with conflicting results, while none of them has taken into consideration the type of ovarian response. Recently, the publication of additional, large relevant randomised controlled trials (RCTs) in patients with different types of ovarian response makes possible the comparative evaluation of the first frozen ET (in a freeze-only cycle strategy) versus fresh ET, considering the type of ovarian response. STUDY DESIGN, SIZE, DURATION: A systematic review and meta-analysis was performed aiming to identify RCTs comparing the first frozen ET (in a freeze-only cycle strategy) to a fresh ET. The main outcome was live birth, while secondary outcomes included ongoing pregnancy, clinical pregnancy, moderate/severe ovarian hyperstimulation syndrome (OHSS) and miscarriage. PARTICIPANTS/MATERIALS, SETTING, METHODS: We identified eight eligible RCTs, including 5265 patients, which evaluated the first frozen ET in a freeze-only cycle strategy versus a fresh ET either in high responders (n = 4) or in normal responders (n = 4). No relevant RCTs were present in poor responders. Meta-analysis of weighted data using fixed and random effects model was performed. Results are reported as relative risk (RR) with 95% confidence interval (CI). MAIN RESULTS AND THE ROLE OF CHANCE: Eligible RCTs were published between 2011 and 2018. Four RCTs (n = 3255 patients) compared the first frozen ET (in a freeze-only cycle strategy) to a fresh ET in normal responders and four RCTs (n = 2010 patients) did the comparison in high responders. In high responders, a significantly higher probability of live birth was observed in the frozen ET group when compared with the fresh ET group (RR: 1.18, 95% CI: 1.06-1.31; fixed effects model; heterogeneity: I2 = 0%; three studies; n = 3398 patients). However the probability of live birth was not significantly different between the frozen ET group and the fresh ET group in normal responders (RR: 1.13, 95% CI: 0.90-1.41; random effects model; heterogeneity: I2 = 77%; three studies; n = 1608 patients). The risk of moderate/severe OHSS was significantly lower in the frozen ET group when compared with the fresh ET group both in high (RR: 0.19, 95% CI: 0.10-0.37; fixed effects model; heterogeneity: not applicable; a single study; n = 1508 patients) and normal responders (RR: 0.39, 95% CI: 0.19-0.80; fixed effects model; heterogeneity: I2 = 0%; two studies; n = 2939 patients). LIMITATIONS, REASONS FOR CAUTION: Considerable heterogeneity was present among the studies, regarding ovarian stimulation protocols and the triggering signal used for inducing final oocyte maturation as well as the cryopreservation methods, while the quality of evidence was poor for the live birth rate in high responders. Moreover, the analysis did not apply a standard for determining 'high' or 'normal' responders since the type of ovarian response followed the characterisation of populations as reported by the authors of the eligible studies. WIDER IMPLICATIONS OF THE FINDINGS: A freeze-only cycle strategy should be the preferred option in high responders since it enhances the probability of live birth, while reducing the chance of moderate/severe OHSS. In normal responders, the same strategy could be applied, in the interest of patient safety or clinic convenience, without compromising the chances of live birth. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used and there were no competing interests. PROSPERO REGISTRATION NUMBER: PROSPERO registration number: CRD42018099389.

Is oocyte maturation rate associated with triptorelin dose used for triggering final oocyte maturation in patients at high risk for severe ovarian hyperstimulation syndrome?

STUDY QUESTION: Are oocyte maturation rates different among 0.1, 0.2 and 0.4 mg triptorelin used for triggering final oocyte maturation in patients at high risk for ovarian hyperstimulation syndrome (OHSS) undergoing ICSI? SUMMARY ANSWER: A dose of 0.1 mg triptorelin results in similar oocyte maturation rates compared to higher doses of 0.2 and 0.4 mg in patients at high risk for OHSS undergoing ICSI. WHAT IS KNOWN ALREADY: The GnRH agonist triptorelin is widely used instead of hCG for triggering final oocyte maturation, in order to eliminate the risk of severe OHSS in patients undergoing ovarian stimulation for IVF/ICSI. However, limited data are currently available regarding its optimal dose use for this purpose in patients at high risk for OHSS. STUDY DESIGN, SIZE, DURATION: A retrospective study was performed between November 2015 and July 2017 in 131 infertile patients at high risk for severe OHSS undergoing ovarian stimulation for ICSI. High risk for severe OHSS was defined as the presence of at least 19 follicles ≥11 mm in diameter on the day of triggering final oocyte maturation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Ovarian stimulation was performed with recombinant FSH and GnRH antagonists. Patients received 0.1 (n = 42), 0.2 (n = 46) or 0.4 mg (n = 43) triptorelin for triggering final oocyte maturation. Hormonal evaluation of FSH, LH, estradiol (E2) and progesterone (PRG) was carried out on the day of triggering final oocyte maturation, 8 and 36 hours post triggering and 3, 5, 7, and 10 days after triptorelin administration. During this period, all patients were assessed for symptoms and signs indicative of severe OHSS development. Primary outcome measure was oocyte maturation rate, defined as the number of metaphase II (MII) oocytes divided by the number of cumulus-oocyte-complexes retrieved per patient. Results are expressed as median (interquartile range). MAIN RESULTS AND THE ROLE OF CHANCE: No significant differences in patient baseline characteristics were observed among the 0.1 mg, the 0.2 mg and the 0.4 mg groups. Regarding the primary outcome measure, no differences were observed in oocyte maturation rate among the three groups compared [82.6% (17.8%) versus 83.3% (18.8%) versus 85.1% (17.2%), respectively, P = 0.686].In addition, no significant differences were present among the 0.1 mg, 0.2 mg and 0.4 mg groups, regarding the number of mature (MII) oocytes [21 (13) versus 20 (6) versus 20 (11), respectively; P = 0.582], the number of oocytes retrieved [25.5 (13) versus 24.5 (11) versus 23 (12), respectively; P = 0.452], oocyte retrieval rate [81.0% (17.7%) versus 76.5% (23.5%) versus 75.0% (22.5), respectively; P = 0.088], the number of fertilized (two pronuclei) oocytes [12.5 (9) versus 14.5 (7) versus 14.0 (8), respectively; P = 0.985], fertilization rate [71.7% (22%) versus 77.1% (19.1%) versus 76.6% (23.3%), respectively; P = 0.525] and duration of luteal phase [7 (1) versus 8 (2) versus 7 (1) days, respectively; P = 0.632]. Moreover, no significant differences were present among the three triptorelin groups regarding serum levels of LH, FSH, E2 and PRG at any of the time points assessed following triggering of final oocyte maturation. LIMITATIONS, REASONS FOR CAUTION: This is a retrospective study, and although there were no differences in the baseline characteristics of the three groups compared, the presence of bias cannot be excluded. WIDER IMPLICATIONS OF THE FINDINGS: Based on the results of the current study, it appears that triggering final oocyte maturation with a lower (0.1 mg) or a higher dose (0.4 mg) of triptorelin, as compared to the most commonly used dose of 0.2 mg, does not confer any benefit in terms of oocyte maturation rate in patients at high risk for severe OHSS. STUDY FUNDING/COMPETING INTEREST(S): No external funding was obtained for this study. There are no conflicts of interest.

Are singleton pregnancies after assisted reproduction technology (ART) associated with a higher risk of placental anomalies compared with non-ART singleton pregnancies? A systematic review and meta-analysis.

BACKGROUND: Placental anomalies (placenta praevia, placental abruption, morbidly adherent placenta and cord insertion anomalies) are associated with maternal and fetal morbidity and mortality. It has been suggested these might be more prevalent in pregnancies after assisted reproduction technology (ART). OBJECTIVES: To determine whether ART singleton pregnancies are associated with an increased risk of placental anomalies compared with non-ART singleton pregnancies. SEARCH STRATEGY: MEDLINE, EMBASE, CENTRAL, Web of Science and Scopus (January 2018). SELECTION CRITERIA: Cohort studies reporting placental anomalies in ART and non-ART singleton pregnancies. DATA COLLECTION AND ANALYSIS: We report pooled odds ratios (OR) for the comparisons: (1) ART versus SC (spontaneously conceived), (2) ART versus non-ART (unspecified), (3) FET-ART (frozen-embryo transfer) versus SC, (4) ART versus non-ART (subfertile patients). Study quality was assessed using a modified Newcastle -Ottawa scale. MAIN RESULTS: 33 low/moderate quality studies evaluated 124 215 ART and 6 054 729 non-ART singleton pregnancies. Risk of placenta praevia, placental abruption and morbidly adherent placenta was higher in ART than SC pregnancies: odds ratio (OR) (OR 3.76, 95% CI 3.09-4.59); (OR 1.87, 95% CI 1.70-2.06) and (OR 2.27, 95% CI 1.79-2.87) respectively. Risk of placenta praevia and placental abruption was higher in ART than in non-ART (subfertile patients): (OR 2.51, 95% CI 2.12-2.98) and (OR 1.61, 95% CI 1.33-1.95) respectively. Results were similar when comparing ART with unspecified non-ART pregnancies. Risk of placenta praevia was higher, but not significantly so, in FET-ART than in SC pregnancies (OR 2.42, 95% CI 0.63-9.30). CONCLUSIONS: Singleton ART pregnancies are associated with an increased risk of placental anomalies compared with non-ART singleton pregnancies. TWEETABLE ABSTRACT: A review of over 6 million singleton pregnancies finds increased risk of placental anomalies after ART.

Ultrasound and hematological changes during early luteal phase in women at high risk for developing ovarian hyperstimulation syndrome.

OBJECTIVE: To assess ultrasound and hematological changes during the early luteal phase following triggering of final oocyte maturation with human chorionic gonadotropin (hCG) in women at high risk for developing ovarian hyperstimulation syndrome (OHSS). METHODS: This was a retrospective cohort study of 319 women undergoing in-vitro fertilization who were at high risk for OHSS following administration of hCG for the triggering of final oocyte maturation. Patients were treated with a gonadotropin-releasing hormone agonist or antagonist protocol and were monitored for 5 days post-oocyte retrieval (early luteal phase). Severe OHSS was diagnosed in the presence of at least moderate ascites and two or more of the following: maximum ovarian diameter (MOD) > 100 mm, hematocrit (Ht) > 45%, white blood cell count (WBC) > 15 000/mm3 , hydrothorax, dyspnea and oliguria. Outcome measures included change in Ht, ascites grade, WBC and MOD, as well as the association between these changes during the early luteal phase. RESULTS: Ascites grade, Ht and WBC increased significantly (P ≤ 0.001) during the early luteal phase, both in patients who developed and in those who did not develop severe early OHSS. MOD increased significantly (P = 0.001) only in patients who developed severe early OHSS. On multivariable analysis, both time following oocyte retrieval and whether severe early OHSS developed were significantly associated with ascites grade, Ht, WBC and MOD; furthermore, there was also a significant interaction between time and development of severe early OHSS for all four variables (P ≤ 0.001). CONCLUSIONS: In women at high risk of OHSS, ascites grade, Ht and WBC significantly increased with time over the 5-day observation period, in line with the pathophysiology of the syndrome. Our data support the use of MOD in the diagnosis of severe early OHSS, and provide novel evidence for the role of change in Ht as a patient-specific hemoconcentration marker during development of OHSS. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Transdermal testosterone pretreatment in poor responders undergoing ICSI: a randomized clinical trial.

STUDY QUESTION: Does pretreatment with transdermal testosterone increase the number of cumulus-oocyte complexes (COCs) retrieved by more than 1.5 in poor responders undergoing intracytoplasmic sperm injection (ICSI), using recombinant follicle stimulating hormone (FSH) and gonadotrophin releasing hormone agonists (GnRHa)? SUMMARY ANSWER: Testosterone pretreatment failed to increase the number of COCs by more than 1.5 as compared with no pretreatment in poor responders undergoing ICSI (difference between medians: 0.0, 95% CI: -1.0 to +1.0). WHAT IS KNOWN ALREADY: Androgens are thought to play an important role in early follicular development by enhancing ovarian sensitivity to FSH. In a recent meta-analysis, testosterone pretreatment resulted in an increase of 1.5 COCs as compared with no pretreatment. However, this effect was based on the analysis of only two randomized controlled trials (RCTs) including 163 patients. Evidently, there is a need for additional RCTs that will allow firmer conclusions to be drawn. STUDY DESIGN, SIZE, DURATION: The present RCT was designed to detect a difference of 1.5 COCs (sample size required = 48 patients). From 02/2014 until 04/2015, 50 poor responders fulfilling the Bologna criteria have been randomized (using a randomization list) to either testosterone pretreatment for 21 days ( ITALIC! n = 26) or no pretreatment ( ITALIC! n = 24). PARTICIPANTS/MATERIALS, SETTING, METHODS: All patients underwent a long follicular GnRHa protocol. Recombinant FSH stimulation was started on Day 22 following GnRHa initiation. In the testosterone pretreatment group, a daily dose of 10 mg of testosterone gel was applied transdermally for 21 days starting from GnRHa initiation. Results are expressed as median (interquartile range). MAIN RESULTS AND THE ROLE OF CHANCE: No differences in baseline characteristics were observed between the two groups compared. Testosterone levels [median (interquartile range)] were significantly higher in the testosterone pretreatment on the day of initiation of FSH stimulation [114 (99.5) ng/dl versus 20 (20) ng/dl, respectively, ITALIC! P < 0.001]. Duration of FSH stimulation [median (interquartile range)] was similar between the groups compared [12.5 (3.0) days versus 12 (3.0) days, respectively, ITALIC! P = 0.52]. The number of COCs retrieved [median (interquartile range)] was not different between the testosterone pretreatment and the no pretreatment groups [3.5 (4.0) versus 3.0 (3.0), 95% CI for the median: 2.0-5.0 versus 2.7-4.3, respectively; difference between medians: 0.0, 95% CI: +1.0 to -1.0). Similarly no differences were observed regarding fertilization rates [median (interquartile range)] [66.7% (32.5) versus 66.7% (42.9), respectively, ITALIC! P = 0.97] and live birth rates per randomized patient (7.7% versus 8.3%, respectively, rate difference: -0.6%, 95% CI: -19.0 to +16.9). LIMITATIONS, REASONS FOR CAUTION: The study was not powered to detect differences less than 1.5 COCs, although it is doubtful whether these differences would be clinically relevant. Moreover, due to sample size restrictions, no conclusions can be drawn regarding the probability of live birth. WIDER IMPLICATIONS OF THE FINDINGS: The results of this randomized clinical trial, suggesting that pretreatment with 10 mg of transdermal testosterone for 21 days does not improve ovarian response by more than 1.5 oocytes, could be used to more accurately consult patients with poor ovarian response. However, an improvement in IVF outcome using a higher dose of testosterone or a longer pretreatment period cannot be excluded. STUDY FUNDING/COMPETING INTEREST: The study was partially funded by a Scholarship from the Academy of Athens. C.A.V. reports personal fees and non-financial support from Merck, Sharp and Dome, personal fees and non-financial support from Merck Serono, personal fees and non-financial support from IPSEN Hellas S.A., outside the submitted work. B.C.T. reports grants from Merck Serono, grants from Merck Sharp & Dohme, personal fees from Merck Serono, personal fees from Merck Sharp & Dohme, personal fees from IBSA & Ferring, outside the submitted work. TRIAL REGISTRATION NUMBER: NCT01961336. TRIAL REGISTRATION DATE: 10 October 2013. DATE OF FIRST PATIENT'S ENROLLMENT: 02/2014.

Corifollitropin alfa compared with follitropin beta in poor responders undergoing ICSI: a randomized controlled trial.

STUDY QUESTION: Does substituting 150 µg corifollitropin alfa for 450 IU follitropin beta during the first 7 days of ovarian stimulation in proven poor responders, result in retrieval of a non-inferior number (<1.5 fewer) of cumulus oocyte complexes (COCs)? SUMMARY ANSWER: A single s.c. dose of 150 µg corifollitropin alfa on the first day of ovarian stimulation, followed if necessary, from Day 8 onwards, with 450 IU of follitropin beta/day, is not inferior to daily doses of 450 IU follitropin beta. The 95% CI of the difference between medians in the number of oocytes retrieved was -1 to +1 within the safety margin of 1.5. WHAT IS KNOWN ALREADY: Recent data from retrospective studies suggest that the use of corifollitropin alfa in poor responders is promising since it could simplify ovarian stimulation without compromising its outcome. STUDY DESIGN, SIZE, DURATION: Seventy-nine women with previous poor ovarian response undergoing ICSI treatment were enrolled in this open label, non-inferiority, randomized clinical trial (RCT). PARTICIPANTS/MATERIALS, SETTING, METHODS: Inclusion criteria were: previous poor response to ovarian stimulation (≤4 COCs) after maximal stimulation, age <45 years, regular spontaneous menstrual cycle, body mass index: 18-32 kg/m(2) and basal follicle stimulating hormone ≤20 IU/l. On Day 2 of the menstrual cycle, patients were administered either a single s.c dose of 150 µg corifollitropin alfa (n = 40) or a fixed daily dose of 450 IU of follitropin beta (n = 39). In the corifollitropin alfa group, 450 IU of follitropin beta were administered from Day 8 of stimulation until the day of human chorionic gonadotrophin (hCG) administration, if necessary. To inhibit premature luteinizing hormone surge, the gonadotrophin releasing hormone antagonist ganirelix was used. Triggering of final oocyte maturation was performed using 250 µg of recombinant hCG, when at least two follicles reached 17 mm in mean diameter. MAIN RESULTS AND THE ROLE OF CHANCE: The number of COCs retrieved was not statistically different between the corifollitropin alfa and the follitropin beta groups [Median 3 versus 2, 95% CI 2-4, 2-3, respectively, P = 0.26]. The 95% CI of the difference between medians in the number of oocytes retrieved was -1 to +1. A multivariable analysis adjusting for all the potential baseline differences confirmed this finding. No significant difference was observed regarding the probability of live birth between the corifollitropin alfa and the follitropin beta group (live birth per patient reaching oocyte retrieval: 7.9 versus 2.6%, respectively, difference +5.3%, 95% CI: -6.8 to +18.3). LIMITATIONS, REASONS FOR CAUTION: The present study was not powered to test a smaller difference (e.g. 1 COC) in terms of COCs retrieved as well as to show potential differences in the probability of pregnancy. Moreover, it would be interesting to assess whether the continuation of stimulation in the long acting FSH arm, where necessary, with 200 IU instead of 450 IU of follitropin beta would have altered the direction or the magnitude of the effect of the type of FSH, observed on the number of COCs retrieved. WIDER IMPLICATIONS OF THE FINDINGS: Corifollitropin alfa simplifies IVF treatment because it is administered in a GnRH antagonist protocol and replaces seven daily FSH injections with a single one of a long acting FSH without compromising the outcome. It could greatly reduce the burden of treatment for poor responders and this deserves further investigation.

Novasure impedance control system versus microwave endometrial ablation for the treatment of dysfunctional uterine bleeding: a double-blind, randomized controlled trial.

PURPOSE OF INVESTIGATION: To compare the efficacy and safety of two different second-generation ablation devices, Novasure impedance control system and microwave endometrial ablation (MEA), in cases of abnormal uterine bleeding (AUB). MATERIALS AND METHODS: This is a randomized controlled trial that took place in a single Gynecological Department of a University Hospital. Sixty-six women with dysfunctional uterine bleeding (DUB), unresponsive to medical treatment, were included in the trial. The ratio of women allocated to bipolar radio-frequency ablation or MEA was 1:1. Follow-up assessments were carried out at three and 12 months post-ablation. The present main outcome measure was amenorrhea rates 12-months post-treatment. RESULTS: The rate of amenorrhea at 12-months post-ablation was significantly higher in women treated by Novasure (25/33; 75.8%) as compared to those treated by MEA (8/33; 24.2%) (rate difference: +51.5%, 95% CI: +27.8 to +67.7). CONCLUSION: In women with DUB, endometrial ablation with Novasure bipolar radiofrequency impedance-controlled system is associated with increased rates of amenorrhea at 12-months post-treatment as compared to the MEA method.

What is the optimal GnRH antagonist protocol for ovarian stimulation during ART treatment? A systematic review and network meta-analysis.

BACKGROUND: Several GnRH antagonist protocols are currently used during COS in the context of ART treatments; however, questions remain regarding whether these protocols are comparable in terms of efficacy and safety. OBJECTIVE AND RATIONALE: A systematic review followed by a pairwise and network meta-analyses were performed. The systematic review and pairwise meta-analysis of direct comparative data according to the PRISMA guidelines evaluated the effectiveness of different GnRH antagonist protocols (fixed Day 5/6 versus flexible, ganirelix versus cetrorelix, with or without hormonal pretreatment) on the probability of live birth and ongoing pregnancy after COS during ART treatment. A frequentist network meta-analysis combining direct and indirect comparisons (using the long GnRH agonist protocol as the comparator) was also performed to enhance the precision of the estimates. SEARCH METHODS: The systematic literature search was performed using Embase (Ovid), MEDLINE (Ovid), Cochrane Central Register of Trials (CENTRAL), SCOPUS and Web of Science (WOS), from inception until 23 November 2021. The search terms comprised three different MeSH terms that should be present in the identified studies: GnRH antagonist; assisted reproduction treatment; randomized controlled trial (RCT). Only studies published in English were included. OUTCOMES: The search strategy resulted in 6738 individual publications, of which 102 were included in the systematic review (corresponding to 75 unique studies) and 73 were included in the meta-analysis. Most studies were of low quality. One study compared a flexible protocol with a fixed Day 5 protocol and the remaining RCTs with a fixed Day 6 protocol. There was a lack of data regarding live birth when comparing the flexible and fixed GnRH antagonist protocols or cetrorelix and ganirelix. No significant difference in live birth rate was observed between the different pretreatment regimens versus no pretreatment or between the different pretreatment protocols. A flexible GnRH antagonist protocol resulted in a significantly lower OPR compared with a fixed Day 5/6 protocol (relative risk (RR) 0.76, 95% CI 0.62 to 0.94, I2 = 0%; 6 RCTs; n = 907 participants; low certainty evidence). There were insufficient data for a comparison of cetrorelix and ganirelix for OPR. OCP pretreatment was associated with a lower OPR compared with no pretreatment intervention (RR 0.79, 95% CI 0.69 to 0.92; I2 = 0%; 5 RCTs, n = 1318 participants; low certainty evidence). Furthermore, in the network meta-analysis, a fixed protocol with OCP resulted in a significantly lower OPR than a fixed protocol with no pretreatment (RR 0.84, 95% CI 0.71 to 0.99; moderate quality evidence). The surface under the cumulative ranking (SUCRA) scores suggested that the fixed protocol with no pretreatment is the antagonist protocol most likely (84%) to result in the highest OPR. There was insufficient evidence of a difference between fixed/flexible or OCP pretreatment/no pretreatment interventions regarding other outcomes, such as ovarian hyperstimulation syndrome and miscarriage rates. WIDER IMPLICATIONS: Available evidence, mostly of low quality and certainty, suggests that different antagonist protocols should not be considered as equivalent for clinical decision-making. More trials are required to assess the comparative effectiveness of ganirelix versus cetrorelix, the effect of different pretreatment interventions (e.g. progestins or oestradiol) or the effect of different criteria for initiation of the antagonist in the flexible protocol. Furthermore, more studies are required examining the optimal GnRH antagonist protocol in women with high or low response to ovarian stimulation.

Prevention of intra-peritoneal adhesions in gynaecological surgery: theory and evidence.

Post-operative adhesions are a significant complication of all abdominal surgical procedures. The major strategies for adhesion prevention in gynaecological surgery are focused on the optimization of surgical technique and use of anti-adhesive agents, which fall into two main categories: pharmacological agents and barriers. Surgical technique that minimizes peritoneal trauma can reduce, but cannot prevent post-operative adhesion formation. Various local and systemic drugs that can alter the local inflammatory response, inhibit the coagulation cascade and promote fibrinolysis have been evaluated. Limited data support the administration of post-operative corticosteroids in addition to systemic intra-operative corticosteroids for the prevention of adhesions after gynaecological surgery. None of the remaining pharmacological agents have been found effective for the reduction of post-operative adhesions. Barriers are currently considered the most useful adjuncts, which may reduce adhesion formation. They act by separating the traumatized peritoneal surfaces during the healing period. The separation can be achieved by solid barriers or fluids. There is limited evidence from randomized clinical trials that support the beneficial effect of most of these barrier agents in the prevention of intra-peritoneal adhesions after gynaecological surgery. However, the evidence is not adequate for definite conclusions to be drawn and further research in this field is warranted.

Parity: A key measure of confounding in data-linkage studies of outcomes after medically assisted reproduction.

Parity is a potential confounder of the association between medically assisted reproduction (MAR) and health outcomes. This concept paper describes a population-based record linkage study design for selecting MAR-unexposed women matched to the parity of MAR-exposed women, at the time of the first exposure to MAR. Women exposed to MAR were identified from claims for government subsidies for relevant procedures and prescription medicines, linked to perinatal records. Women unexposed to MAR were identified from linked perinatal and death records, matched to exposed women by age, rurality, age of first child (if any) and parity at the date of first MAR. The availability of a longitudinal, whole-of-population dataset ("population spine") based on enrolments in Australia's universal health insurance scheme was a critical design element. The example application examines cancer risk in women after exposure to MAR. Parity is a confounder in this setting because it is associated with MAR and hormone-sensitive cancers.

A decision-making algorithm for performing or cancelling embryo transfer in patients at high risk for ovarian hyperstimulation syndrome after triggering final oocyte maturation with hCG.

STUDY QUESTION: Can the grade of ascites, haematocrit (Ht), white blood cell (WBC) count and maximal ovarian diameter (MOD) measured on Day 3 be used to construct a decision-making algorithm for performing or cancelling embryo transfer in patients at high risk for severe ovarian hyperstimulation syndrome (OHSS) after an hCG trigger? SUMMARY ANSWER: Using cut-offs of ascites grade>2, Ht>39.2%, WBC>12 900/mm3 and MOD>85 mm on Day 3, a decision-making algorithm was constructed that could predict subsequent development of severe OHSS on Day 5 with an AUC of 0.93, a sensitivity of 88.5% and a specificity of 84.2% in high-risk patients triggered with hCG. WHAT IS KNOWN ALREADY: Despite the increasing popularity of GnRH agonist trigger for final oocyte maturation as a way to prevent OHSS, ≥75% of IVF cycles still involve an hCG trigger. Numerous risk factors and predictive models of OHSS have been proposed, but the measurement of these early predictors is restricted either prior to or during the controlled ovarian stimulation. In high-risk patients triggered with hCG, the identification of luteal-phase predictors assessed post-oocyte retrieval, which reflect the pathophysiological changes leading to severe early OHSS, is currently lacking. STUDY DESIGN SIZE DURATION: A retrospective study of 321 patients at high risk for severe OHSS following hCG triggering of final oocyte maturation. High risk for OHSS was defined as the presence of at least 19 follicles ≥11 mm on the day of triggering of final oocyte maturation. PARTICIPANTS/MATERIALS SETTING METHODS: The study includes IVF/ICSI patients at high risk for developing severe OHSS, who administered hCG to trigger final oocyte maturation. Ascites grade, MOD, Ht and WBC were assessed in the luteal phase starting from the day of oocyte retrieval. Outcome measures were the optimal thresholds of ascites grade, MOD, Ht and WBC measured on Day 3 post-oocyte retrieval to predict subsequent severe OHSS development on Day 5. These criteria were used to construct a decision-making algorithm for embryo transfer, based on the estimated probability of severe OHSS development on Day 5. MAIN RESULTS AND THE ROLE OF CHANCE: The optimal Day 3 cutoffs for severe OHSS prediction on Day 5 were ascites grade>2, Ht>39.2%, WBC>12 900/mm3 and MOD>85 mm. The probability of severe OHSS with no criteria fulfilled on Day 3 is 0% (95% CI: 0-5.5); with one criterion, 0.8% (95% CI: 0.15-4.6); with two criteria, 13.3% (95% CI: 7.4-22.8); with three criteria, 37.2% (95% CI: 24.4-52.1); and with four criteria, 88.9% (95% CI, 67.2-98.1). The predictive model of severe OHSS had an AUC of 0.93 with a sensitivity of 88.5% and a specificity of 84.2%. LIMITATIONS REASONS FOR CAUTION: This is a retrospective study, and therefore, it cannot be excluded that non-apparent sources of bias might be present. In addition, we acknowledge the lack of external validation of our model. We have created a web-based calculator (http://ohsspredict.org), for wider access and usage of our tool. By inserting the values of ascites grade, MOD, Ht and WBC of high-risk patients on Day 3 after oocyte retrieval, the clinician instantly receives the predicted probability of severe OHSS development on Day 5. WIDER IMPLICATIONS OF THE FINDINGS: The present study describes a novel decision-making algorithm for embryo transfer based on ascites, Ht, WBC and MOD measurements on Day 3. The algorithm may be useful for the management of high-risk patients triggered with hCG and for helping the clinician's decision to proceed with, or to cancel, embryo transfer. It must be emphasized that the availability of the present decision-making algorithm should in no way encourage the use of hCG trigger in patients at high risk for OHSS. In these patients, the recommended approach is the use of GnRH antagonist protocols, GnRH agonist trigger and elective embryo cryopreservation. In addition, in patients triggered with hCG, freezing all embryos and luteal-phase GnRH antagonist administration should be considered for the outpatient management of severe early OHSS and prevention of late OHSS. STUDY FUNDING/COMPETING INTERESTS: NHMRC Early Career Fellowship (GNT1147154) to C.A.V. No conflict of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Steroid receptor expression in human endometrium during the follicular phase of stimulated cycles.

BACKGROUND: No data are currently available regarding kinetics of human endometrial steroid receptors in stimulated cycles. METHODS: In 31 patients (age <39 years) stimulated with gonadotrophins and GnRH antagonists for intrauterine insemination (IUI) an endometrial biopsy was performed on the first day after the end of menstruation and a second biopsy was performed two (Group 0 + 2, n = 10) or four (Group 0 + 4, n = 11) days after the first biopsy, or on the day of hCG administration (Group 0 + hCG, n = 10). Expression of progesterone (PR) and estrogen (ER) receptor was investigated by immunohistochemistry using monoclonal antibodies. RESULTS: PR and ER levels were significantly increased in the second versus the first biopsy, in all groups analyzed (P = 0.01), in both stromal and glandular cells. Between the three groups compared, a significant increase in PR expression was observed for glandular cells (P = 0.03), with the highest value observed in Group 0 + 4. Moreover, the increase in PR expression in stromal cells differed between groups (P = 0.01), with the highest value observed in the Group 0 + hCG. CONCLUSIONS: In stimulated cycles for IUI, ER expression in both glandular and stromal endometrial cells, after an initial increase, does not appear to change significantly during the follicular phase. On the contrary, during the same period of time, following an initial rise, PR expression in glandular and stromal cells continues to increase.

Role of the endocrine profile for the achievement of pregnancy with IVF.

The predictive value of pre-ovulatory hormones for achievement of pregnancy has been extensively evaluated in assisted reproductive technologies. Currently, no high-quality evidence exists to support or deny an association between oestradiol levels on the day of human chorionic gonadotrophin (HCG) administration and pregnancy achievement in IVF cycles. Retrospective studies appear to support the lack of such an association. Progesterone elevation on the day of HCG administration does not appear to be associated with the probability of clinical pregnancy in women undergoing IVF. Finally, no retrospective studies exist to suggest that low endogenous midfollicular LH concentrations are associated with a significantly decreased probability of ongoing pregnancy beyond 12 weeks of gestation in IVF. In two prospective studies, high endogenous LH concentrations during down-regulation were associated with a decreased probability of ongoing pregnancy beyond 12 weeks of gestation. Existing studies evaluating the association between single measurements of pre-ovulatory hormones and the achievement of pregnancy are of low quality and cannot lead to solid conclusions. Based on the available literature, it appears that no association exists between single assessments of oestradiol, progesterone or LH, and pregnancy achievement.

Benefits of luteinizing hormone activity in ovarian stimulation for IVF.

Knowledge of the physiology of folliculogenesis has led to a better understanding of the role of LH activity in this process. This role has been investigated in the setting of ovarian stimulation and several treatment modalities have been proposed. LH activity can be provided in the forms of: (i) human menopausal gonadotrophins (HMG), (ii) recombinant LH (rLH), (iii) human chorionic gonadotrophin (HCG), and (iv) recombinant HCG (rHCG). Current evidence suggests that ovarian stimulation performed with HMG in patients treated with a long gonadotrophin releasing hormone (GnRH) agonist protocol seems to result in increased (3-4%) clinical pregnancy rates compared with recombinant FSH (rFSH). Data regarding the short GnRH agonist or GnRH antagonist protocol are scarce and firm conclusions cannot be drawn. Administration of rLH prior or during ovarian stimulation with rFSH does not seem to increase the probability of pregnancy. Existing data suggest that HCG is capable of partially or completely replacing FSH administration during the mid-to-late follicular phase of an ovarian stimulation cycle, leading to a decreased requirement for FSH, without compromising pregnancy rates. High quality evidence originating from randomized controlled trials regarding the potential value of rHCG administration during ovarian stimulation for IVF is not available.

Estrogen addition to progesterone for luteal phase support in cycles stimulated with GnRH analogues and gonadotrophins for IVF: a systematic review and meta-analysis.

BACKGROUND: The purpose of the present systematic review and meta-analysis was to examine whether the probability of pregnancy is increased by adding estrogen to progesterone for luteal phase support in patients treated by in vitro fertilization (IVF). METHODS: A literature search covering MEDLINE, EMBASE, CENTRAL, meeting proceedings and reference lists of published articles was performed to identify relevant RCTs. Data were extracted for meta-analysis yielding pooled relative risks (RR) and 95% confidence intervals (CI). Sensitivity analyses by including studies with pseudo-randomization or unclear method of randomization were also performed (n=1141 patients in total). RESULTS: Four RCTs (n=587 patients) were eligible for inclusion. No statistically significant differences were present between patients who received a combination of progesterone and estrogen for luteal support when compared with those who received only progesterone, in terms of positive hCG rate (RR: 1.02, 95% CI: 0.87-1.19), clinical pregnancy rate (RR: 0.94, 95% CI: 0.78-1.13) and live birth rate (RR: 0.96, 95% CI: 0.77-1.21) per woman randomized. These results did not materially differ in the sensitivity analyses performed. CONCLUSIONS: The currently available evidence suggests that the addition of estrogen to progesterone for luteal phase support does not increase the probability of pregnancy in IVF. However, there is an obvious need for further RCTs that will assess, with more confidence, the effect of estrogen addition to progesterone during the luteal phase on the probability of pregnancy.