Perinatal and maternal outcome after vitrification of blastocysts: a Nordic study in singletons from the CoNARTaS group.

Is transfer of vitrified blastocysts associated with higher perinatal and maternal risks compared with slow-frozen cleavage stage embryos and fresh blastocysts? Transfer of vitrified blastocysts is associated with a higher risk of preterm birth (PTB) when compared with slow-frozen cleavage stage embryos and with a higher risk of a large baby, hypertensive disorders in pregnancy (HDPs) and postpartum hemorrhage (PPH) but a lower risk of placenta previa when compared with fresh blastocysts. Transfer of frozen-thawed embryos (FETs) plays a central role in modern fertility treatment, limiting the risk of ovarian hyperstimulation syndrome and multiple pregnancies. Following FET, several studies report a lower risk of PTB, low birth weight (LBW) and small for gestational age (SGA) yet a higher risk of fetal macrosomia and large for gestational age (LGA) compared with fresh embryos. In recent years, the introduction of new freezing techniques has increased treatment success. The slow-freeze technique combined with cleavage stage transfer has been replaced by vitrification and blastocyst transfer. Only few studies have compared perinatal and maternal outcomes after vitrification and slow-freeze and mainly in cleavage stage embryos, with most studies indicating similar outcomes in the two groups. Studies on perinatal and maternal outcomes following vitrified blastocysts are limited. This registry-based cohort study includes singletons born after frozen-thawed and fresh transfers following the introduction of vitrification in Sweden and Denmark, in 2002 and 2009, respectively. The study includes 3650 children born after transfer of vitrified blastocysts, 8123 children born after transfer of slow-frozen cleavage stage embryos and 4469 children born after transfer of fresh blastocysts during 2002-2015. Perinatal and maternal outcomes in singletons born after vitrified blastocyst transfer were compared with singletons born after slow-frozen cleavage stage transfer and singletons born after fresh blastocyst transfer. Main outcomes included PTB, LBW, macrosomia, HDP and placenta previa. Data were obtained from the CoNARTaS (Committee of Nordic ART and Safety) group. Based on national registries in Sweden, Finland, Denmark and Norway, the CoNARTaS cohort includes all children born after ART treatment in public and private clinics 1984-2015. Outcomes were assessed with logistic multivariable regression analysis, adjusting for the country and year of birth, maternal age, body mass index, parity, smoking, parental educational level, fertilisation method (IVF/ICSI), single embryo transfer, number of gestational sacs and the child's sex. A higher risk of PTB (<37 weeks) was noted in the vitrified blastocyst group compared with the slow-frozen cleavage stage group (adjusted odds ratio, aOR [95% CI], 1.33 [1.09-1.62]). No significant differences were observed for LBW (<2500 g), SGA, macrosomia (≥4500 g) and LGA when comparing the vitrified blastocyst with the slow-frozen cleavage stage group. For maternal outcomes, no significant difference was seen in the risk of HDP, placenta previa, placental abruption and PPH in the vitrified blastocyst versus the slow frozen cleavage stage group, although the precision was limited.When comparing vitrified and fresh blastocysts, we found higher risks of macrosomia (≥4500 g) aOR 1.77 [1.35-2.31] and LGA aOR 1.48 [1.18-1.84]. Further, the risks of HDP aOR 1.47 [1.19-1.81] and PPH aOR 1.68 [1.39-2.03] were higher in singletons born after vitrified compared with fresh blastocyst transfer while the risks of SGA aOR 0.58 [0.44-0.78] and placenta previa aOR 0.35 [0.25-0.48] were lower. Since vitrification was introduced simultaneously with blastocyst transfer in Sweden and Denmark, it was not possible to explore the effect of vitrification per se in this study. The results from the change of strategy to vitrification of blastocysts are reassuring, indicating that the freezing technique per se has no major influence on the perinatal and maternal outcomes. The higher risk of PTB may be related to the extended embryo culture rather than vitrification. The study is part of the ReproUnion Collaborative study, co-financed by the European Union, Interreg V ÖKS. The study was also financed by grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF agreement (LUA/ALF 70940), Hjalmar Svensson Research Foundation and NordForsk (project 71 450). There are no conflicts of interest to declare. ISRCTN11780826.

Ginström Ernstad E ，Spangmose AL ，Opdahl S ，Henningsen AA ，Romundstad LB ，Tiitinen A ，Gissler M ，Wennerholm UB ，Pinborg A ，Bergh C ，Malchau SS ... -  《-》

Obstetric and perinatal risks in 4601 singletons and 884 twins conceived after fresh blastocyst transfers: a Nordic study from the CoNARTaS group.

Are obstetric and perinatal outcomes in pregnancies after fresh blastocyst transfer (BT) comparable with those born after fresh cleavage stage transfer (CT) and spontaneous conception (SC)? Fresh BT is associated with a higher risk of placental and perinatal complications. BT optimizes the selection of top-quality embryos and increases pregnancy and live birth rates per transfer compared to CT. However, concerns have been raised as extended culture duration may increase obstetric complications and impair perinatal outcomes. Previous studies have shown a higher risk of preterm birth (PTB) among infants born after BT compared with CT. Pregnancies after BT are also prone to a higher risk of same-sex twins after single embryo transfer (SET). A retrospective register-based cohort study used data from Denmark, Norway and Sweden including three cohorts: 56 557 singletons and 16 315 twins born after fresh IVF/ICSI cycles and 2 808 323 SC singletons in Denmark (birth years 1997-2014), Norway (2010-2015) and Sweden (2002-2015). Of the fresh IVF/ICSI singletons, 4601 were born after BT and 51 956 after CT. The twin cohort consisted of 884 fresh IVF/ICSI children born after BT and 15 431 fresh IVF/ICSI children born after CT. Data were obtained from a large Nordic cohort of children born after ART and SC initiated by the Committee of Nordic ART and Safety (CoNARTaS). The CoNARTaS cohort was established by cross-linking National ART-, Medical Birth-, and National Patients Registers using the unique personal identification number, allocated to every citizen in the Nordic countries. Obstetric and perinatal outcomes after BT, CT and SC were compared using logistic regression analysis. For perinatal outcomes, we calculated gestational age based on the date of oocyte pick-up (OPU) and in sensitivity analyses on data from Denmark and Norway, we also calculated gestational age based on the second-trimester ultrasonography (US) scan. Risk of pregnancies with same-sex twins after SET was used as a proxy for risk of monozygotic twins. Adjustments were made for child's sex, birth year, parity (0 or >1), maternal age, body mass index, smoking, educational level, fertilization method (IVF/ICSI), the number of aspirated oocytes, SET and country. Information on educational level and the number of aspirated oocytes was not available for Norway. Children born after frozen embryo transfer were not included. The birth cohorts were restricted according to the year in which BT was introduced in the different countries. A higher risk of placenta previa was found in singleton pregnancies after BT compared with CT (adjusted odds ratio [aOR] 2.11 [95% CI 1.76; 2.52]). Singletons born after BT had a higher risk of PTB (aOR 1.14 [95% CI 1.01; 1.29]) compared with CT singletons, when estimated based on OPU. Furthermore, an altered male/female ratio (aOR 1.13 [95% CI 1.06; 1.21]) with more males following BT compared with CT was seen. Risk of same-sex twins after SET was higher after single BT compared with single CT (aOR 1.94 [95% CI 1.42; 2.60]). Residual confounding cannot be excluded, in particular related to duration and cause of infertility that we could not adjust for due to lack of reliable data. Extended embryo culture to the blastocyst stage has the potential to compromise obstetric and perinatal outcomes in fresh cycles. These results are important since an increasing number of IVF/ICSI treatments are performed as BT. NORDFORSK (project no: 71450). The Research Fund of Rigshospitalet, Copenhagen University Hospital. ReproUnion Collaborative study, co-financed by the European Union, Interreg V ÖKS. Grants from Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (LUA/ALF 70940), Hjalmar Svensson Research Foundation. The Research Council of Norway through its Centres of Excellence funding scheme, project number 262700. None of the authors has any conflicts of interests to declare regarding this study. ISRCTN11780826.

Spangmose AL ，Ginström Ernstad E ，Malchau S ，Forman J ，Tiitinen A ，Gissler M ，Opdahl S ，Romundstad LB ，Bergh C ，Wennerholm UB ，Henningsen AA ，Pinborg A ... -  《-》

Perinatal outcomes of singletons following vitrification versus slow-freezing of embryos: a multicenter cohort study using propensity score analysis.

Is embryo vitrification associated with a higher risk of adverse perinatal outcomes than slow-freezing? Embryo vitrification was not associated with increased risks of adverse perinatal outcomes of pre-term birth (PTB), low birthweight (LBW), small for gestational age (SGA), large for gestational age (LGA) and macrosomia, as compared to slow-freezing. Vitrification is becoming a widely adopted technology for embryo cryopreservation with higher embryo survival rate and live birth rate than the slow-freezing technique. However, limited data are currently available on risks of adverse perinatal outcomes following vitrification as compared to that of slow-freezing. The impact of vitrification on perinatal outcomes remains further to be elucidated. Six large reproductive medical centers in Guangdong province, Southeast of China, took part in this multicenter retrospective cohort study. Cohorts of 3199 live born singletons after Day 3 frozen-thawed embryo transfer (FET) cycles with either vitrification or slow-freezing between January 2011 and December 2015 were included in the study. Each patient only contributed one cycle per cohort and vanishing twins were excluded. Propensity score (PS) matching was used to control for potential confounding factors. All live-born singletons following either a vitrified or a slow-frozen cleavage FET cycle during the period from 2011 to 2015 were analyzed. Perinatal outcomes of PTB, LBW, macrosomia, SGA and LGA were compared. The vitrified and slow-frozen cohorts were matched by propensity scores with a 1:1 ratio accounting for potential confounding factors associated with perinatal outcomes. These variables included baseline demographics (maternal age, BMI, education level, parity, type of infertility and cause of infertility), as well as IVF characteristics (insemination method, endometrial preparation protocol and embryo cryopreservation duration). A total of 2858 cases from vitrified embryo transfer (ET) and 341 babies from the slow-freezing group were included. After PS matching, 297 pairs of newborns were generated for comparison. The median gestational age was 39 weeks for both cohorts and the birthweights were comparable (3187.7 ± 502.1 g in the vitrified group vs. 3224.6 ± 483.6 in the slow-freezing group, P>0.05). There were no significant differences between the two groups on the incidence of PTB (5.4% vs. 7.7%), LBW (6.7% vs. 5.7%), macrosomia (5.7% vs. 6.1%), SGA (12.5% vs. 8.4%) and LGA (6.4% vs. 8.1%). Parallel logistic regression analysis indicated that vitrification was non-inferior to slow-freezing method in terms of the occurrence of PTB (OR, 0.68 [95% CI, 0.35, 1.31]), LBW (OR, 1.19[0.61-2.32]), macrosomia (OR, 0.94 [0.48-1.86]), SGA (1.55[0.91-2.64]) and LGA (0.78[0.42-1.45]), P>0.05. Sex-stratified PS matching models with multivariable regression analysis further confirmed that vitrification did not increase the risks of above-mentioned adverse perinatal outcomes in either the male or female infant cohort. Although the analysis was adjusted for a number of important confounders, the hospital dataset did not contain other potential confounders such as the medical history and obstetrics outcomes of women during pregnancy to allow adjustment. In addition, the current findings are only applicable to cleavage stage FET, but not pronuclei stage or blastocyst stage ET. Vitrified ET, in comparison with slow-frozen ET, was not associated with increased risks of adverse neonatal outcomes. With its superiority on live birth rates and non-inferiority on safety perinatal outcomes, transition from slow-freezing to the use of vitrification for embryo cryopreservation is reassuring. Nonetheless, future research is needed for the long-term effects of vitrification method on offspring's health outcomes. The study was funded by the National Key Research and Development Program (2016YFC100205), Guangzhou Science and Technology Project (201804020087), Guangdong Province Science and Technology Project (2016A020218008) and Guangdong Provincial Key Laboratory of Reproductive Medicine (2012A061400003). The authors have no conflicts of interest to declare.

Gu F ，Li S ，Zheng L ，Gu J ，Li T ，Du H ，Gao C ，Ding C ，Quan S ，Zhou C ，Li P ，Xu Y ... -  《-》

Clinical outcomes following cryopreservation of blastocysts by vitrification or slow freezing: a population-based cohort study.

What are the clinical efficacy and perinatal outcomes following transfer of vitrified blastocysts compared with transfer of fresh or of slow frozen blastocysts? Compared with slow frozen blastocysts, vitrified blastocysts resulted in significantly higher clinical pregnancy and live delivery rates with similar perinatal outcomes at population level. Although vitrification has been reported to be associated with significantly increased post-thaw survival rates compared with slow freezing, there has been a lack of general consensus over which method of cryopreservation (vitrification versus slow freezing) is most appropriate for blastocysts. A population-based cohort of autologous fresh and initiated thaw cycles (a cycle where embryos were thawed with intention to transfer) performed between January 2009 and December 2011 in Australia and New Zealand was evaluated retrospectively. A total of 46 890 fresh blastocyst transfer cycles, 12 852 initiated slow frozen blastocyst thaw cycles and 20 887 initiated vitrified blastocyst warming cycles were included in the data analysis. Pairwise comparisons were made between the vitrified blastocyst group and slow frozen or fresh blastocyst group. A Chi-square test was used for categorical variables and t-test was used for continuous variables. Cox regression was used to examine the pregnancy outcomes (clinical pregnancy rate, miscarriage rate and live delivery rate) and perinatal outcomes (preterm delivery, low birthweight births, small for gestational age (SGA) births, large for gestational age (LGA) births and perinatal mortality) following transfer of fresh, slow frozen and vitrified blastocysts. The 46 890 fresh blastocyst transfers, 11 644 slow frozen blastocyst transfers and 19 978 vitrified blastocyst transfers resulted in 16 845, 2766 and 6537 clinical pregnancies, which led to 13 049, 2065 and 4955 live deliveries, respectively. Compared with slow frozen blastocyst transfer cycles, vitrified blastocyst transfer cycles resulted in a significantly higher clinical pregnancy rate (adjusted relative risk (ARR): 1.47, 95% confidence intervals (CI): 1.39-1.55) and live delivery rate (ARR: 1.41, 95% CI: 1.34-1.49). Compared with singletons born after transfer of fresh blastocysts, singletons born after transfer of vitrified blastocysts were at 14% less risk of being born preterm (ARR: 0.86, 95% CI: 0.77-0.96), 33% less risk of being low birthweight (ARR: 0.67, 95% CI: 0.58-0.78) and 40% less risk of being SGA (ARR: 0.60, 95% CI: 0.53-0.68). A limitation of this population-based study is the lack of information available on clinic-specific cryopreservation protocols and processes for slow freezing-thaw and vitrification-warm of blastocysts and the potential impact on outcomes. This study presents population-based evidence on clinical efficacy and perinatal outcomes associated with transfer of fresh, slow frozen and vitrified blastocysts. Vitrified blastocyst transfer resulted in significantly higher clinical pregnancy and live delivery rates with similar perinatal outcomes compared with slow frozen blastocyst transfer. Comparably better perinatal outcomes were reported for singletons born after transfer of vitrified blastocysts than singletons born after transfer of fresh blastocysts. Elective vitrification could be considered as an alternative embryo transfer strategy to achieve better perinatal outcomes following Assisted Reproduction Technology (ART) treatment. No specific funding was obtained. The authors have no conflicts of interest to declare.

Li Z ，Wang YA ，Ledger W ，Edgar DH ，Sullivan EA ... -  《-》

Perinatal outcomes of children born after frozen-thawed embryo transfer: a Nordic cohort study from the CoNARTaS group.

Wennerholm UB ，Henningsen AK ，Romundstad LB ，Bergh C ，Pinborg A ，Skjaerven R ，Forman J ，Gissler M ，Nygren KG ，Tiitinen A ... -  《-》