To trigger or not to trigger ovulation in a natural cycle for frozen embryo transfer: a randomized controlled trial.

STUDY QUESTION: Is the clinical pregnancy rate (CPR) following a frozen embryo transfer (FET) in a natural cycle (NC) higher after spontaneous ovulation than after triggered ovulation [natural cycle frozen embryo transfer (NC-FET) versus modified NC-FET]? SUMMARY ANSWER: The CPR did not vary significantly between the two FET preparation protocols. WHAT IS KNOWN ALREADY: Although the use of FET is continuously increasing, the most optimal endometrial preparation protocol is still under debate. For transfer in the NC specifically, conflicting results have been reported in terms of the outcome following spontaneous or triggered ovulation. STUDY DESIGN, SIZE, DURATION: In a tertiary hospital setting, subjects were randomized with a 1:1 allocation into two groups between January 2014 and January 2019. Patients in group A underwent an NC-FET, while in group B, a modified NC-FET was performed with a subcutaneous hCG injection to trigger ovulation. In neither group was additional luteal phase support administered. All embryos were vitrified-warmed on Day 3 and transferred on Day 4 of embryonic development. The primary outcome was CPR at 7 weeks. All patients were followed further until 10 weeks of gestation when the ongoing pregnancy rate (OPR) was defined by the observation of foetal cardiac activity on ultrasound scan. Other secondary outcomes included biochemical pregnancy rate, early pregnancy loss and the number of visits, blood samples and ultrasonographic examinations prior to FET. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 260 patients (130 per study arm) were randomized, of whom 12 withdrew consent after study arm allocation. A total of 3 women conceived spontaneously before initiating the study cycle and 16 did not start for personal or medical reasons. Of the 229 actually commencing monitoring for the study FET cycle, 7 patients needed to be switched to a hormonal replacement treatment protocol due to the absence of follicular development, 12 had no embryo available for transfer after warming and 37 had a spontaneous LH surge before the ovulation trigger could be administered, although they were allocated to group B. Given the above, an intention-to-treat (ITT) analysis was performed taking into account 248 patients (125 in group A and 123 in group B), as well as a per protocol (PP) analysis on a subset of 173 patients (110 in group A and 63 in group B). MAIN RESULTS AND THE ROLE OF CHANCE: Demographic features were evenly distributed between the study groups, as were the relevant fresh and frozen ET cycle characteristics. According to the ITT analysis, the CPR and OPR in group A (33.6% and 27.2%, respectively) and group B (29.3% and 24.4%, respectively) did not vary significantly [relative risk (RR) 0.87, 95% CI (0.60;1.26), P = 0.46 and RR 0.90, 95% CI (0.59;1.37), P = 0.61, respectively]. Biochemical pregnancy rate and early pregnancy loss were also found to be not statistically significantly different between the groups. In contrast, more clinic visits and blood samplings for cycle monitoring were required in the NC-FET group (4.05 ± 1.39) compared with the modified NC-FET group (3.03 ± 1.16, P = <0.001), while the number of ultrasound scans performed were comparable (1.70 ± 0.88 in group A versus 1.62 ± 1.04 in group B). The additional PP analysis was in line with the ITT results: CPR in group A was 36.4% versus 38.1% in group B [RR 1.05, 95% CI (0.70;1.56), P = 0.82]. LIMITATIONS, REASONS FOR CAUTION: The results are limited by the high drop-out rate for the PP analysis in the modified NC-FET group as more than one-third of the subjects allocated to this group ovulated spontaneously before ovulation triggering. Nonetheless, this issue is inherent to routine clinical practice and is an important observation of an event that can only be avoided by performing a very extensive monitoring that limits the practical advantages associated with modified NC-FET. Furthermore, although this is the largest randomized controlled trial (RCT) investigating this specific research question so far, a higher sample size would allow smaller differences in clinical outcome to be detected, since currently they may be left undetected. WIDER IMPLICATIONS OF THE FINDINGS: This RCT adds new high-quality evidence to the existing controversial literature concerning the performance of NC-FET versus modified NC-FET. Based on our results showing no statistically significant differences in clinical outcomes between the protocols, the treatment choice may be made according to the patient's and treating physician's preferences. However, the modified NC-FET strategy reduces the need for hormonal monitoring and may therefore be considered a more patient-friendly and potentially cost-effective approach. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was available for this study. None of the authors have a conflict of interest to declare with regard to this study. TRIAL REGISTRATION NUMBER: NCT02145819. TRIAL REGISTRATION DATE: 8 January 2014. DATE OF FIRST PATIENT'S ENROLMENT: 21 January 2014.

Frozen embryo transfer: a review on the optimal endometrial preparation and timing.

STUDY QUESTION: What is the optimal endometrial preparation protocol for a frozen embryo transfer (FET)? SUMMARY ANSWER: Although the optimal endometrial preparation protocol for FET needs further research and is yet to be determined, we propose a standardized timing strategy based on the current available evidence which could assist in the harmonization and comparability of clinic practice and future trials. WHAT IS KNOWN ALREADY: Amid a continuous increase in the number of FET cycles, determining the optimal endometrial preparation protocol has become paramount to maximize ART success. In current daily practice, different FET preparation methods and timing strategies are used. STUDY DESIGN, SIZE, DURATION: This is a review of the current literature on FET preparation methods, with special attention to the timing of the embryo transfer. PARTICIPANTS/MATERIALS, SETTING, METHODS: Literature on the topic was retrieved in PubMed and references from relevant articles were investigated until June 2017. MAIN RESULTS AND THE ROLE OF CHANCE: The number of high quality randomized controlled trials (RCTs) is scarce and, hence, the evidence for the best protocol for FET is poor. Future research should compare both the pregnancy and neonatal outcomes between HRT and true natural cycle (NC) FET. In terms of embryo transfer timing, we propose to start progesterone intake on the theoretical day of oocyte retrieval in HRT and to perform blastocyst transfer at hCG + 7 or LH + 6 in modified or true NC, respectively. LIMITATIONS REASONS FOR CAUTION: As only a few high quality RCTs on the optimal preparation for FET are available in the existing literature, no definitive conclusion for benefit of one protocol over the other can be drawn so far. WIDER IMPLICATIONS OF THE FINDINGS: Caution when using HRT for FET is warranted since the rate of early pregnancy loss is alarmingly high in some reports. STUDY FUNDING/COMPETING INTEREST(S): S.M. is funded by the Research Fund of Flanders (FWO). H.T. and C.B. report grants from Merck, Goodlife, Besins and Abbott during the conduct of the study. TRIAL REGISTRATION NUMBER: Not applicable.

Vitrified-warmed blastocyst transfer on the 5th or 7th day of progesterone supplementation in an artificial cycle: a randomised controlled trial.

Prospective studies comparing different durations of progesterone supplementation before transfer of vitrified-warmed blastocysts in an artificial cycle are lacking. However, in oocyte donation programmes, the sporadic available evidence demonstrates considerable differences in clinical pregnancy rates according to the duration of progesterone administration. This randomised controlled trial (RCT), included 303 patients undergoing a frozen-thawed embryo transfer (FET) of one or two vitrified-warmed blastocyst(s) in an artificial cycle. Randomisation was performed when the endometrial thickness reached ≥7 mm after oestrogen supplementation. One hundred and fifty two patients in group A received 7 d of vaginal micronised progesterone tablets and 151 patients in group B received 5 d of micronised vaginal progesterone before FET. No differences were seen in clinical pregnancy rate between both groups: 42/152 (27.6%) in group A versus 49/151 (32.5%) in group B. Although no statistically significant difference was observed in clinical pregnancy rates, our study was powered to detect an absolute difference of 16%. In this regard, we cannot exclude that smaller, clinically relevant differences might exist and our study did not have the power to detect this. Patients were also not blinded for the intervention, causing a potential bias.

Frozen-thawed embryo transfers in natural cycles with spontaneous or induced ovulation: the search for the best protocol continues.

STUDY QUESTION: Is natural cycle frozen-thawed embryo transfer (NC-FET) associated with better clinical pregnancy rates (CPR) when compared to modified natural cycle frozen-thawed embryo transfer (mNC-FET)? SUMMARY ANSWER: NC-FET is associated with a higher CPR compared to mNC-FET. WHAT IS KNOWN ALREADY: There is conflicting evidence regarding the impact of hCG triggering on clinical outcomes after frozen-thawed embryo transfer (FET), and information on the effect of luteal phase support (LPS) is lacking. STUDY DESIGN, SIZE, DURATION: This retrospective study included all (n = 2353) consecutive cycles with FET of vitrified cleavage and blastocyst stage embryos warmed between January 2010 and April 2015 in a tertiary centre. The FET cycles were grouped by type as follows: NC (n = 501), NC + LPS (n = 828) or mNC + LPS (n = 1024). Artificial cycles were excluded from the analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: We performed mixed-effect multilevel multivariable regression analysis to account for the clustering of FETs using embryos derived from the same patient and/or ovarian stimulation cycle. Adjustment for the following potential confounders was also performed: female age at oocyte retrieval, number of oocytes retrieved, fresh cycle pregnancy outcome, embryo transfer rank, number of embryos transferred, embryo stage and grade and endometrial thickness. Bonferroni adjustment for multiple comparisons was performed whenever indicated. MAIN RESULTS AND THE ROLE OF CHANCE: The unadjusted CPR per cycle was significantly higher in the NC-FET group (46.9%) when compared with the mNC-FET + LPS groups (29.7%, P < 0.001) but not the NC-FET + LPS group (39.9%, P = 0.069). The lower clinical performance of mNC-FET + LPS remained significant even after adjusting for potential confounders [adjusted odds ratio (95% CI) compared to the NC-FET groups: 2.18 (1.64-2.90) and 1.67 (1.31-2.12) for the NC-FET and NC-FET + LPS groups, respectively]. A sensitivity analysis restricting the sample only to the first FET performed by the couple in our centre was also performed. The predicted CPR in this multivariable logistic regression model remained significantly higher in the NC-FET (53.9%) and NC-FET + LPS (44.9%) groups when compared to mNC-FET + LPS (34.2%, all Bonferroni-adjusted pairwise comparisons with P ≤ 0.01). LIMITATIONS, REASONS FOR CAUTION: The interpretation of the findings of this study is limited by the retrospective nature of the analysis and the potential for unmeasured confounding. WIDER IMPLICATIONS OF THE FINDINGS: The use of mNC-FET, using hCG triggering or progesterone supplementation, should be reconsidered in light of the potential negative effect on pregnancy outcome. STUDY FUNDING/COMPETING INTERESTS: None. TRIAL REGISTRATION NUMBER: N/A.

Long term results after bipolar radial head arthroplasty.

Radial head fractures are common injuries, occurring mostly in active young people 85%. Treatment of the more complex radial head fractures (Mason type III and IV), appear to be challenging and remain a subject of controversy. Replacement of the radial head with a metal prosthesis imitates the stabilizing role of the radial head and has been considered as the treatment of choice. However, long-term results are scarce. We report our mid to long-term (mean 9.4 year) clinical and radiographic results after insertion of a Judet Bipolar Radial Head prosthesis. 34 patients were treated with the Judet Bipolar Head prosthesis between 2000 and 2008. In this study, 21 patients were re-examined after a mean period of 113 months (range, 174-84), ie, 9.4 years (range, 14.5-7). Follow-up examinations included both the Mayo Elbow Performance Index (MEPI) and Dis- abilities of the arm, shoulder and hand (DASH) score. Range of motion was measured with a hand goniometer. X-rays were evaluated for peri-articular ossifications, radiolucent lines and signs of proximal erosion, capitellar erosion. Mean Mayo Elbow Performance Index was 88.6 (Range 100-50). According to the MEPI score we had 14 excellent, 1 good, 5 fair results and one poor result. One patient reported severe pain, 3 patients reported moderate pain, one patient reported mild pain and 16 patients reported no pain at all. Difference between pronation-suppination range was noted between primary or secondary indication of the radial head, no other significant differences were found. Mean DASH score was 23.1° (Range 0-63) without difference between primary and secondary indication. Mean flexion was 121.8° (Range : 110-140), mean extension deficit was 24.8° (Range 15-40), mean pronation was 62.4° (Range : 50-80) and suppination 58.8° (Range : 45-80). Ten patients showed signs of ulnohumeral joint degenerative arthritis. One patient developed symptomatic ulna plus. One patient showed radiolucent lines surrounding the prosthesis with proximal bone erosion. There were no reports of dislocations of the prosthesis. One case of radiological signs of overlenghtening was noted. Mainly good clinical results are achieved with the -Judet bipolar radial head implant. Functional results after long term follow-up are, however less optimistic then the excellent results achieved after short- to mid-term follow-up. No clear link between radiological signs and functional results can be found.

What is the optimal duration of progesterone administration before transferring a vitrified-warmed cleavage stage embryo? A randomized controlled trial.

STUDY QUESTION: What is the impact on clinical pregnancy rates when vitrified cleavage stage Day 3 embryos, warmed and cultured overnight to Day 4, are transferred on the 3rd or 5th day of progesterone administration in an artificial cycle? SUMMARY ANSWER: Clinical pregnancy rates are similar when transferring a vitrified-warmed cleavage stage Day 3 embryo after overnight culture on the 3rd or 5th day of progesterone administration. WHAT IS KNOWN ALREADY: In artificially prepared cycles, progesterone supplementation is generally started 3 days before embryo transfer, although the optimal length of exposure to progesterone before frozen embryo transfer (FET) has not been established. However, in a natural cycle, serum progesterone levels start to rise before ovulation, due to the LH-stimulated production by the peripheral granulosa cells. Hence, it could be postulated that progesterone supplementation before embryo transfer in an artificial cycle should start earlier or even later. STUDY DESIGN, SIZE, DURATION: Prospective, randomized controlled trial, encompassing 300 patients who had embryos frozen on Day 3 and who underwent FET in an artificial cycle. Between 1 November 2012 and 31 December 2014, 300 patients were allocated to one of two groups as soon as endometrial thickness reached ≥7 mm on ultrasound after estrogen supplementation. A computer-generated randomization list was used, not concealed to the physicians. Each patient was enrolled into the study only once. FET was performed on the fifth day of progesterone supplementation in Group A, whereas in Group B, FET was performed on the third day of vaginal micronized progesterone administration. Embryos were thawed the day before transfer and after overnight culture, one or two Day 4 embryos were transferred. PARTICIPANTS/MATERIALS, SETTING, METHODS: One hundred and fifty patients in Group A received 5 days of vaginal micronized progesterone tablets and one hundred and fifty patients in Group B received 3 days of micronized progesterone vaginally before FET. In Group A, 13 patients did not have an embryo transfer, compared with 12 patients in Group B. MAIN RESULTS AND THE ROLE OF CHANCE: Clinical pregnancy rates did not differ significantly between both groups (37/137 (27.0%) in Group A versus 26/138 (18.8%) in Group B (OR 1.6 (CI 0.9-2.82), ITALIC! P = 0.11). However, early pregnancy loss was significantly higher in Group B (32/58 (55.2%)) compared with Group A (21/58 (36.2%)) (OR 0.46 (CI 0.22-0.97), ITALIC! P = 0.04). LIMITATIONS, REASONS FOR CAUTION: Although no statistically significant difference was seen in the primary outcome, the study may have been underpowered to detect smaller differences. The study was also not blinded and patients were aware of the exact duration of progesterone supplementation. WIDER IMPLICATIONS OF THE FINDINGS: This is the first randomized controlled trial to show that duration of progesterone administration in an artificially prepared FET cycle may modulate cycle outcome and that too short progesterone supplementation might be deleterious. STUDY FUNDING/COMPETING INTERESTS: No external finance was involved in this study. All authors declare to have no conflict of interest with regard to this trial. TRIAL REGISTRATION NUMBER: The trial was registered at clinicaltrials.gov (NCT01940653). TRIAL REGISTRATION DATE: 9 September 2013. DATE OF FIRST PATIENT'S ENROLLMENT: 1 November 2012.

Cryopreserved embryo transfer in an artificial cycle: is GnRH agonist down-regulation necessary?

The use of GnRH agonist downregulation in artificial endometrium priming cycles for cryopreserved embryo transfer was retrospectively investigated to establish whether higher live birth rates resulted. Six hundred and ninety-nine patients underwent 1129 artificial endometrium priming cycles for the transfer of cryopreserved embryos between 1 July 2009 and 1 June 2012. Hormonal supplementation with (group A, n = 280 cycles) or without (group B, n = 849 cycles) GnRH agonist co-treatment was given. Live birth rates were comparable between the two groups per started cycle (14.9% [41/275] in group A versus 15.1% [127/839] in group B) or per embryo transfer (17.5% [41/234] in group A versus 17.6% [127/723] in group B). After logistic regression analysis, the only variables that were significantly associated with live birth rates were day of embryo transfer (OR 0.69; 95% CI 0.48 to 0.98) for day 3 versus day 5 embryos, the number of embryos transferred (OR 2.13; 95% CI 1.58 to 2.86) for two embryos versus one embryo transferred and the endometrial thickness on the day of embryo transfer (OR 1.15; 95% CI 1.05 to 1.25). Live birth rates after cryopreserved embryo transfer in artificial cycles did not increase when a GnRH agonist was administered.

Administration of corifollitropin alfa on Day 2 versus Day 4 of the cycle in a GnRH antagonist protocol: a randomized controlled pilot study.

STUDY QUESTION: Does the initiation of corifollitropin alfa administration on cycle day 4 instead of cycle day 2 result in a reduced total rFSH consumption in a GnRH antagonist protocol? SUMMARY ANSWER: Initiation of corifollitropin alfa on cycle day 4 compared with day 2 results in significantly reduced total rFSH consumption at the end of the follicular phase. WHAT IS KNOWN ALREADY: In vitro fertilization treatment is associated with significant physical, psychological and emotional stress in infertile patients. This notion has fuelled the search for simplified treatment approaches that may reduce the treatment burden. The introduction of corifollitropin alfa has provided a more patient-friendly treatment protocol because it obviates the need for daily hormonal injections. In addition, postponing the initiation of hormonal stimulation should also reduce the total gonadotrophin consumption and the number of injections needed. STUDY DESIGN, SIZE, DURATION: A prospective randomized controlled pilot study was conducted in a university centre in Belgium. Between December 2011 and March 2013, 59 patients were randomized in the study and 52 of these patients received the allocated intervention. PARTICIPANTS/MATERIALS, SETTING, METHODS: All patients were randomly assigned to the control group (CD2), with initiation of corifollitropin alfa on cycle day 2, or to the study group (CD4) with initiation of stimulation on day 4. The GnRH antagonist was administered from cycle day 7 onwards in both treatment arms. The main outcome measure was the total rFSH consumption at the end of the follicular phase after corifollitropin alfa treatment. MAIN RESULTS AND THE ROLE OF CHANCE: The total dose of rFSH at the end of the follicular phase was significantly reduced in the CD4 group compared with the CD2 group (324 (276) IU in the CD2 group versus 173 (255) IU in the CD4 group, P = 0.015, mean difference -151, 95% confidence interval (CI) -301 to -1). A significant reduction of total duration of rFSH stimulation in the CD4 group was also observed (8.6 (1.4) days in CD2 group versus 7.8 (1.2) days in the CD4 group, P = 0.008, mean difference -0.8, 95% CI -1.6 to -0.1). The number of cumulus-oocyte-complexes was comparable in both treatment groups (12.8 (7.3) in CD2 group versus 14.7 (8.8) in the CD4 group, P = 0.461, mean difference 1.8, 95% CI -2.7 to 6.4). Ongoing pregnancy rates of 48% in the CD2 group and 41% in the CD4 group were achieved (P = 0.60, relative risk (RR) 0.85, 95% CI 0.46-1.56). Final oocyte maturation was triggered with GnRH agonist instead of hCG in two patients in the CD2 group and in eight patients in the CD4 group, because of an increased risk of ovarian hyperstimulation syndrome (P = 0.078, RR 3.7 (95% CI 0.88-15.8). LIMITATIONS, REASONS FOR CAUTION: Before general implementation can be advised, this trial should be validated in a much larger randomized trial. WIDER IMPLICATIONS OF THE FINDINGS If the approach of starting ovarian stimulation on Day 4 of the cycle could be implemented in a large population of infertile patients, it would result in a significant reduction of gonadotrophin consumption. STUDY FUNDING/COMPETING INTEREST(S): No external finance was involved in this study. C.B and N.P.P. have received fees from MSD. Otherwise the authors declare no conflict of interest regarding this study. TRIAL REGISTRATION NUMBER: The trial was registered at clinicaltrials.gov (NCT01633580).

Pregnancy outcome after cervical conisation: a retrospective cohort study in the Leuven University Hospital.

OBJECTIVE: To assess pregnancy outcome after conisation. DESIGN: Retrospective cohort study. SETTING: Belgium, data from a university hospital. POPULATION: Fifty-five pregnancies in 34 women after conisation, and 55 pregnancies in 54 women without a history of conisation or cervical intraepithelial neoplasia (CIN). METHODS: Hospital data were reviewed and questionnaires were collected from 599 women who had a conisation in a 5-year period, among whom subsequent pregnancies were identified. The control group consisted of matched pregnancies of women without a history of conisation. MAIN OUTCOME MEASURES: Gestational age at delivery, neonatal biometry, neonatal condition at birth. RESULTS: Numbers of sexual partners (4.6 +/- 3.4 SD versus 2.5 +/- 2.5 SD) and ex-smokers were significantly higher in the study group compared with the control group. Gestational age at delivery (266 +/- 2 days versus 274 +/- 9 days), neonatal head circumference (33.9 +/- 2.5 cm, versus 34.6 +/- 2.5 cm) and birthweight (3088 +/- 754 g versus 3381 +/- 430 g) were significantly lower in the study group compared with the control group. Numbers of preterm [<37 weeks; 14/55 (25%) versus 2/55 (4%); P = 0.002] and severe preterm (<34 weeks; 6/55 (11%) versus 0/55 (0%); P = 0.031] deliveries in the study group were significantly higher. There were no cases of perinatal mortality. CONCLUSIONS: Conisation affects obstetrical outcome after conisation for CIN. Babies tend to be born earlier and are smaller. It is not clear whether this is related to the procedure or to factors linked with CIN.