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Freeze-all versus fresh blastocyst transfer strategy during in vitro fertilisation in women with regular menstrual cycles: multicentre randomised controlled trial.

ABSTRACT: OBJECTIVE:To compare the ongoing pregnancy rate between a freeze-all strategy and a fresh transfer strategy in assisted reproductive technology treatment. DESIGN:Multicentre, randomised controlled superiority trial. SETTING:Outpatient fertility clinics at eight public hospitals in Denmark, Sweden, and Spain. PARTICIPANTS:460 women aged 18-39 years with regular menstrual cycles starting their first, second, or third treatment cycle of in vitro fertilisation or intracytoplasmic sperm injection. INTERVENTIONS:Women were randomised at baseline on cycle day 2 or 3 to one of two treatment groups: the freeze-all group (elective freezing of all embryos) who received gonadotropin releasing hormone agonist triggering and single frozen-thawed blastocyst transfer in a subsequent modified natural cycle; or the fresh transfer group who received human chorionic gonadotropin triggering and single blastocyst transfer in the fresh cycle. Women in the fresh transfer group with more than 18 follicles larger than 11 mm on the day of triggering had elective freezing of all embryos and postponement of transfer as a safety measure. MAIN OUTCOME MEASURES:The primary outcome was the ongoing pregnancy rate defined as a detectable fetal heart beat after eight weeks of gestation. Secondary outcomes were live birth rate, positive human chorionic gonadotropin rate, time to pregnancy, and pregnancy related, obstetric, and neonatal complications. The primary analysis was performed according to the intention-to-treat principle. RESULTS:Ongoing pregnancy rate did not differ significantly between the freeze-all and fresh transfer groups (27.8% (62/223) v 29.6% (68/230); risk ratio 0.98, 95% confidence interval 0.87 to 1.10, P=0.76). Additionally, no significant difference was found in the live birth rate (27.4% (61/223) for the freeze-all group and 28.7% (66/230) for the fresh transfer group; risk ratio 0.98, 95% confidence interval 0.87 to 1.10, P=0.83). No significant differences between groups were observed for positive human chorionic gonadotropin rate or pregnancy loss, and none of the women had severe ovarian hyperstimulation syndrome; only one hospital admission related to this condition occurred in the fresh transfer group. The risks of pregnancy related, obstetric, and neonatal complications did not differ between the two groups except for a higher mean birth weight after frozen blastocyst transfer and an increased risk of prematurity after fresh blastocyst transfer. Time to pregnancy was longer in the freeze-all group. CONCLUSIONS:In women with regular menstrual cycles, a freeze-all strategy with gonadotropin releasing hormone agonist triggering for final oocyte maturation did not result in higher ongoing pregnancy and live birth rates than a fresh transfer strategy. The findings warrant caution in the indiscriminate application of a freeze-all strategy when no apparent risk of ovarian hyperstimulation syndrome is present. TRIAL REGISTRATION:Clinicaltrials.gov NCT02746562.

SUBMITTER: Stormlund S

PROVIDER: S-EPMC7399608 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Freeze-all versus fresh blastocyst transfer strategy during in vitro fertilisation in women with regular menstrual cycles: multicentre randomised controlled trial.

Stormlund Sacha S Sopa Negjyp N Zedeler Anne A Bogstad Jeanette J Prætorius Lisbeth L Nielsen Henriette Svarre HS Kitlinski Margaretha Laczna ML Skouby Sven O SO Mikkelsen Anne Lis AL Spangmose Anne Lærke AL Jeppesen Janni Vikkelsø JV Khatibi Ali A la Cour Freiesleben Nina N Ziebe Søren S Polyzos Nikolaos P NP Bergh Christina C Humaidan Peter P Andersen Anders Nyboe AN Løssl Kristine K Pinborg Anja A

BMJ (Clinical research ed.) 20200805

<h4>Objective</h4>To compare the ongoing pregnancy rate between a freeze-all strategy and a fresh transfer strategy in assisted reproductive technology treatment.<h4>Design</h4>Multicentre, randomised controlled superiority trial.<h4>Setting</h4>Outpatient fertility clinics at eight public hospitals in Denmark, Sweden, and Spain.<h4>Participants</h4>460 women aged 18-39 years with regular menstrual cycles starting their first, second, or third treatment cycle of in vitro fertilisation or intracy ...[more]

PMID: 32759285

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Project description:BackgroundUterine adenomyosis is a benign disease, common among women in their 40 and 50 s, characterised by ectopic endometrial tissue in the uterine myometrial layer. Adenomyosis causes infertility and has a negative effect on the outcomes of in vitro fertilisation (IVF)/intracytoplasmic sperm injection (ICSI) embryo transfer (ET) cycles. It has also been reported to have different characteristics depending on the adenomyotic lesion localisation. The effect of its localisation on IVF/ICSI-ET outcomes is unclear. This study aimed to investigate whether adenomyotic lesion localisation, assessed using magnetic resonance imaging (MRI), was associated with outcomes of IVF/ICSI-ET cycles.MethodsThis multicentre, joint, retrospective cohort study analysed the medical records of 67 infertile patients with adenomyosis who underwent IVF/ICSI with fresh and frozen-thawed ET at five participating facilities from January 2012 to December 2016 and for whom MRI data were available. Fifteen patients were excluded; therefore, the MRI data of 52 patients were evaluated by two radiologists. We assessed the localisation of and classified adenomyotic lesions into advanced (invades the full thickness of the uterine myometrium), extrinsic (localised on the serosal side), and intrinsic (localised on the endometrial side) subtypes.ResultsThere were 40 advanced, nine extrinsic, and three intrinsic cases, and the outcomes of 100, 27, and nine ET cycles, respectively, were analysed. Pregnancy loss/clinical pregnancy and live birth rates of the advanced, extrinsic, and intrinsic groups were 64 % (16/25) and 9 % (9/100), 33.3 % (3/9) and 22.2 % (6/27), and 50 % (1/2) and 11.1 % (1/9), respectively. A logistic regression analysis adjusted for age, prior miscarriage, and body mass index showed that the extrinsic group had fewer pregnancy losses (odds ratio 0.06; 95 % confidence interval [CI]: 0.00-0.54, p = 0.026) and more live births (odds ratio 6.05; 95 % CI: 1.41-29.65, p = 0.018) than the advanced group.ConclusionsAdenomyotic lesions exert different effects on IVF/ICSI-ET outcomes. Thus, MRI assessments of adenomyosis in infertile patients are beneficial. Establishment of treatment plans based on adenomyotic lesion localisation should be considered.

Project description:STUDY QUESTION:Are there any differences in live birth rates (LBR) following fresh blastocyst transfer in natural or clomiphene-stimulated cycles, or after elective blastocyst freezing in clomiphene-stimulated cycles followed by thawing and transfer at different time-points? SUMMARY ANSWER:Clomiphene citrate (CC) administration adversely affected the LBR after single fresh blastocyst transfer (SBT) in CC cycles compared with that in natural cycles, while this adverse effect of CC is not present when a single vitrified-warmed blastocyst transfer (SVBT) is performed in subsequent natural ovulatory cycles, regardless of the duration between CC administration and the day of SVBT. WHAT IS KNOWN ALREADY:CC affects uterine receptivity associated with a thinning of the uterine endometrium through an antioestrogenic effect. However, the duration that this adverse effect of CC on uterine endometrium persists after initial use is still unknown. STUDY DESIGN SIZE DURATION:A retrospective cohort study of 157 natural cycle IVFs followed by SBT and 1496 minimal ovarian stimulation with CC IVF cycles followed by SBT (n = 24) or SVBT (n = 1472) from January 2010 to December 2014 was conducted. SVBT cycles were classified into two groups according to the period between the last day of CC administration and the day of SVBT (A: ≤60 d and B: ≥61 d). All groups were then compared based on pregnancy outcomes (natural-SBT group: n = 157, CC-SBT group: n = 24, SVBT-A: n = 1143, SVBT-B: n = 329). PARTICIPANTS/MATERIALS SETTING METHODS:Women were aged 30-39 years at oocyte retrieval. In SVBT cycles, blastocysts were vitrified and warmed using a Cryotop safety kit. SVBT was performed in subsequent natural ovulatory cycles. The main outcomes were LBR and neonatal outcome, and both were compared among the groups. MAIN RESULTS AND THE ROLE OF CHANCE:The LBR in the CC-SBT group (29.2%, 7/24) was significantly lower compared with the natural-SBT (56.1%, 88/157) (P = 0.01) and SVBT-A (50.0%, 572/1143) (P = 0.04), but not SVBT-B (47.4%, 156/329), groups. Furthermore, multivariate logistic regression analysis revealed that the LBR was comparable among the natural-SBT and SVBT groups, but was significantly lower in the CC-SBT group (adjusted odds ratio: 0.324, 95% CI: 0.119-0.800, P = 0.01). No significant differences among all groups were observed for gestational age (P = 0.19), birthweight (P = 0.41) and incidence of malformation (P = 0.53). LIMITATIONS REASONS FOR CAUTION:In this study we analysed a biased sample, based on clinical judgement regarding endometrial thickness, and the study was limited by its retrospective nature. The low statistical power caused by the group size disparity was also a limitation, especially in the CC-SBT group. Although the outcome showing inferiority of CC-SBT compared to natural-SBT is consistent with general findings in the literature, further large-scale clinical studies, ideally RCTs, are necessary to validate our results and clarify the prolonged effect of CC in SVBT cycles on pregnancy and neonatal outcomes. WIDER IMPLICATIONS OF THE FINDINGS:Our observation suggests that CC administered in minimal ovarian stimulation cycles affects adversely the pregnancy outcomes when SBT is performed. Therefore, for a CC-based minimal stimulation IVF cycle, we suggest that frozen embryo transfer should be performed in a subsequent natural ovulatory cycle to avoid the possibility of implantation failure associated with CC administration. STUDY FUNDING/COMPETING INTERESTS:The authors have no conflicts of interest to declare. No external funding was either sought or obtained.

Project description:BackgroudThis study's objectives were to compare the clinical, perinatal, and obstetrical outcomes of patients with different estradiol (E2) levels in fresh single-blastocyst-transfer (SBT) cycles under an early follicular phase prolonged regimen on the day of trigger.MethodsWe recruited patients in fresh SBT cycles (n = 771) undergoing early follicular phase prolonged protocols with β-hCG values above 10 IU/L between June 2016 and December 2018. Patients who met the inclusion and exclusion criteria were divided into four groups according to their serum E2 level percentages on the day of trigger: <25th, 25th-50th, 51st-75th, and >75th percentile groups.ResultsAlthough the rates of clinical pregnancy (85.57% (166/194)), embryo implantation 86.60% (168/194), ongoing pregnancy (71.13% (138/194)), and live birth (71.13% (138/194)) were lowest in the >75th percentile group, we did not observe any significant differences (all P > 0.05). We used this information to predict the rate of severe ovarian hyperstimulation syndrome (OHSS) area under the curve (AUC) = 72.39%, P = 0.029, cut off value of E2 = 2,893 pg/ml with the 75% sensitivity and 70% specificity. The 51st-75th percentile group had the highest rates of low birth weight infants (11.73% (19/162), P = 0.0408), premature delivery (11.43% (20/175), P = 0.0269), admission to the neonatal intensive care unit (NICU) (10.49% (17/162), P = 0.0029), twin pregnancies (8.57% (15/175), P = 0.0047), and monochorionic diamniotic pregnancies (8.57% (15/175); P = 0.001). We did not observe statistical differences in obstetrics complications, including gestational diabetes mellitus (GDM), gestational hypertension, placenta previa, premature rupture of membranes (PROM), and preterm premature rupture of membranes (PPROM).ConclusionWe concluded that serum E2 levels on the day of trigger were not good predictors of live birth rate or perinatal and obstetrical outcomes. However, we found that high E2 levels may not be conducive to persistent pregnancies. The E2 level on the day of trigger can still be used to predict the incidence of early onset severe OHSS in the fresh SBT cycle.

Project description:BACKGROUND:It is not known whether segmentation of an in vitro fertilisation (IVF) cycle, with freezing of all embryos prior to transfer, increases the chance of a live birth after all embryos are transferred. METHODS:In a prospective study of UK Human Fertilisation and Embryology Authority data, we investigated the impact of segmentation, compared with initial fresh embryo followed by frozen embryo transfers, on live birth rate and perinatal outcomes. We used generalised linear models to assess the effect of segmentation in the whole cohort, with additional analyses within women who had experienced both segmentation and non-segmentation. We compared rates of live birth, low birthweight (LBW <?2.5?kg), preterm birth (<?37?weeks), macrosomia (>?4?kg), small for gestational age (SGA <?10th centile), and large for gestational age (LGA >?90th centile) for a given ovarian stimulation cycle accounting for all embryo transfers. RESULTS:We assessed 202,968 women undergoing 337,148 ovarian stimulation cycles and 399,896 embryo transfer procedures. Live birth rates were similar in unadjusted analyses for segmented and non-segmented cycles (rate ratio 1.05, 95% CI 1.02-1.08) but lower in segmented cycles when adjusted for age, cycle number, cause of infertility, and ovarian response (rate ratio 0.80, 95% CI 0.78-0.83). Segmented cycles were associated with increased risk of macrosomia (adjusted risk ratio 1.72, 95% CI 1.55-1.92) and LGA (1.51, 1.38-1.66) but lower risk of LBW (0.71, 0.65-0.78) and SGA (0.64, 0.56-0.72). With adjustment for blastocyst/cleavage-stage embryo transfer in those with data on this (329,621?cycles), results were not notably changed. Similar results were observed comparing segmented to non-segmented within 3261 women who had both and when analyses were repeated excluding multiple embryo cycles and multiple pregnancies. When analyses were restricted to women with a single embryo transfer, the transfer of a frozen-thawed embryo in a segmented cycles was no longer associated with a lower risk of LBW (0.97, 0.71-1.33) or SGA (0.84, 0.61-1.15), but the risk of macrosomia (1.74, 1.39-2.20) and LGA (1.49, 1.20-1.86) persisted. When the analyses for perinatal outcomes were further restricted to solely frozen embryo transfers, there was no strong statistical evidence for associations. CONCLUSIONS:Widespread application of segmentation and freezing of all embryos to unselected patient populations may be associated with lower cumulative live birth rates and should be restricted to those with a clinical indication.

Project description:BackgroundInformation regarding the influence of cytoplasmic events during fertilisation on the clinical outcome remains limited. The cytoplasmic halo is one of these events. A previous study that used time-lapse technology found an association of the presence and morphokinetics of the cytoplasmic halo with cleavage patterns, development to the blastocyst stage, and the ongoing pregnancy rate after blastocyst transfer. Therefore, the cytoplasmic halo may be a useful predictor of the pregnancy outcome after cleaved embryo transfer. This study evaluated the ability of the cytoplasmic halo to predict a live birth after fresh cleaved embryo transfer on day 2, and sought to identify factors potentially influencing the presence and morphokinetics of the halo.MethodsA total of 902 embryos cultured in the EmbryoScope+® time-lapse system and subjected to single fresh cleaved embryo transfer were retrospectively analysed. The presence and duration of a cytoplasmic halo were annotated. The initial positions of the pronuclei were also observed. The correlation between the cytoplasmic halo and live birth was evaluated and the association of the cytoplasmic halo with patient, cycle, and embryonic characteristics was determined.ResultsAbsence of a cytoplasmic halo was associated with a significant decrease in the likelihood of a live birth after fresh cleaved embryo transfer. Prolongation of the halo, especially the duration of central repositioning of cytoplasmic granules, had an adverse impact on the live birth rate. The characteristics of the cytoplasmic halo were not affected by the ovarian stimulation method used, female age, the serum steroid hormone level on the day of trigger, or semen quality. However, the cytoplasmic halo was significantly affected by male age, oocyte diameter, and the initial position of the male pronucleus.ConclusionsAbsence or prolongation of the cytoplasmic halo was negatively correlated with the live birth rate after fresh cleaved embryo transfer. The characteristics of the cytoplasmic halo were strongly associated with oocyte diameter, male age, and the initial position of the male pronucleus. These findings indicate that the characteristics of the cytoplasmic halo can be used to select more competent embryos for transfer at the cleavage stage.

Dataset Information

Freeze-all versus fresh blastocyst transfer strategy during in vitro fertilisation in women with regular menstrual cycles: multicentre randomised controlled trial.

Publications

Freeze-all versus fresh blastocyst transfer strategy during in vitro fertilisation in women with regular menstrual cycles: multicentre randomised controlled trial.

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