ESHRE guideline: number of embryos to transfer during IVF/ICSI†.

STUDY QUESTION: Which clinical and embryological factors should be considered to apply double embryo transfer (DET) instead of elective single embryo transfer (eSET)? SUMMARY ANSWER: No clinical or embryological factor per se justifies a recommendation of DET instead of eSET in IVF/ICSI. WHAT IS KNOWN ALREADY: DET is correlated with a higher rate of multiple pregnancy, leading to a subsequent increase in complications for both mother and babies. These complications include preterm birth, low birthweight, and other perinatal adverse outcomes. To mitigate the risks associated with multiple pregnancy, eSET is recommended by international and national professional organizations as the preferred approach in ART. STUDY DESIGN, SIZE, DURATION: The guideline was developed according to the structured methodology for development and update of ESHRE guidelines. Literature searches were performed in PUBMED/MEDLINE and Cochrane databases, and relevant papers published up to May 2023, written in English, were included. Live birth rate, cumulative live birth rate, and multiple pregnancy rate were considered as critical outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS: Based on the collected evidence, recommendations were discussed until a consensus was reached within the Guideline Development Group (GDG). A stakeholder review was organized after the guideline draft was finalized. The final version was approved by the GDG and the ESHRE Executive Committee. MAIN RESULTS AND THE ROLE OF CHANCE: The guideline provides 35 recommendations on the medical and non-medical risks associated with multiple pregnancies and on the clinical and embryological factors to be considered when deciding on the number of embryos to transfer. These recommendations include 25 evidence-based recommendations, of which 24 were formulated as strong recommendations and one as conditional, and 10 good practice points. Of the evidence-based recommendations, seven (28%) were supported by moderate-quality evidence. The remaining recommendations were supported by low (three recommendations; 12%), or very low-quality evidence (15 recommendations; 60%). Owing to the lack of evidence-based research, the guideline also clearly mentions recommendations for future studies. LIMITATIONS, REASONS FOR CAUTION: The guideline assessed different factors one by one based on existing evidence. However, in real life, clinicians' decisions are based on several prognostic factors related to each patient's case. Furthermore, the evidence from randomized controlled trials is too scarce to formulate high-quality evidence-based recommendations. WIDER IMPLICATIONS OF THE FINDINGS: The guideline provides health professionals with clear advice on best practice in the decision-making process during IVF/ICSI, based on the best evidence currently available, and recommendations on relevant information that should be communicated to patients. In addition, a list of research recommendations is provided to stimulate further studies in the field. STUDY FUNDING/COMPETING INTEREST(S): The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, the literature searches, and the dissemination of the guideline. The guideline group members did not receive payment. DPB declared receiving honoraria for lectures from Merck, Ferring, and Gedeon Richter. She is a member of ESHRE EXCO, and the Mediterranean Society for reproductive medicine and the president of the Croatian Society for Gynaecological Endocrinology and Reproductive Medicine. CDG is the past Chair of the ESHRE EIM Consortium and a paid deputy member of the Editorial board of Human Reproduction. IR declared receiving reimbursement from ESHRE and EDCD for attending meetings. She holds an unpaid leadership role in OBBCSSR, ECDC Sohonet, and AER. KAR-W declared receiving grants for clinical researchers and funding provision to the institution from the Swedish Cancer Society (200170F), the Senior Clinical Investigator Award, Radiumhemmets Forskningsfonder (Dnr: 201313), Stockholm County Council FoU (FoUI-953912) and Karolinska Institutet (Dnr 2020-01963), NovoNordisk, Merck and Ferring Pharmaceuticals. She received consulting fees from the Swedish Ministry of Health and Welfare. She received honoraria from Roche, Pfizer, and Organon for chairmanship and lectures. She received support from Organon for attending meetings. She participated in advisory boards for Merck, Nordic countries, and Ferring. She declared receiving time-lapse equipment and grants with payment to institution for pre-clinical research from Merck pharmaceuticals and from Ferring. SS-R received research funding from Roche Diagnostics, Organon/MSD, Theramex, and Gedeo-Richter. He received consulting fees from Organon/MSD, Ferring Pharmaceuticals, and Merck Serono. He declared receiving honoraria for lectures from Ferring Pharmaceuticals, Besins, Organon/MSD, Theramex, and Gedeon Richter. He received support for attending Gedeon Richter meetings and participated in the Data Safety Monitoring Board of the T-TRANSPORT trial. He is the Deputy of ESHRE SQART special interest group. He holds stock options in IVI Lisboa and received equipment and other services from Roche Diagnostics and Ferring Pharmaceuticals. KT declared receiving payment for honoraria for giving lectures from Merck Serono and Organon. She is member of the safety advisory board of EDQM. She holds a leadership role in the ICCBBA board of directors. ZV received reimbursement from ESHRE for attending meetings. She also received research grants from ESHRE and Juhani Aaltonen Foundation. She is the coordinator of EHSRE SQART special interest group. The other authors have no conflicts of interest to declare. DISCLAIMER: This guideline represents the views of ESHRE, which were achieved after careful consideration of the scientific evidence available at the time of preparation. In the absence of scientific evidence on certain aspects, a consensus between the relevant ESHRE stakeholders has been obtained. Adherence to these clinical practice guidelines does not guarantee a successful or specific outcome, nor does it establish a standard of care. Clinical practice guidelines do not replace the need for application of clinical judgement to each individual presentation, nor variations based on locality and facility type. ESHRE makes no warranty, express or implied, regarding the clinical practice guidelines and specifically excludes any warranties of merchantability and fitness for a particular use or purpose (full disclaimer available at https://www.eshre.eu/Guidelines-and-Legal).

Effect of frozen-thawed embryo transfer with a poor-quality embryo and a good-quality embryo on pregnancy and neonatal outcomes.

BACKGROUND: To evaluate the impact of embryo quality and quantity, specifically a poor quality embryo (PQE) in combination with a good quality embryo (GQE), by double embryo transfer (DET) on the live birth rate (LBR) and neonatal outcomes in patients undergoing frozen-thawed embryo transfer (FET) cycles. METHODS: A study on a cohort of women who underwent a total of 1462 frozen-thawed cleavage or blastocyst embryo transfer cycles with autologous oocytes was conducted between January 2018 and December 2021. To compare the outcomes between single embryo transfer (SET) with a GQE and DET with a GQE and a PQE, propensity score matching (PSM) was applied to control for potential confounders, and a generalized estimating equation (GEE) model was used to determine the association between the effect of an additional PQE and the outcomes. Subgroup analysis was also performed for patients stratified by female age. RESULTS: After PS matching, DET-GQE + PQE did not significantly alter the LBR (adjusted odds ratio [OR] 1.421, 95% CI 0.907-2.228) compared with SET-GQE in cleavage-stage embryo transfer but did increase the multiple birth rate (MBR, [OR] 3.917, 95% CI 1.189-12.911). However, in patients who underwent blastocyst-stage embryo transfer, adding a second PQE increased the live birth rate by 7.8% ([OR] 1.477, 95% CI 1.046-2.086) and the multiple birth rate by 19.6% ([OR] 28.355, 95% CI 3.926-204.790), and resulted in adverse neonatal outcomes. For patients who underwent cleavage-stage embryo transfer, transferring a PQE with a GQE led to a significant increase in the MBR ([OR] 4.724, 95% CI 1.121-19.913) in women under 35 years old but not in the LBR ([OR] 1.227, 95% CI 0.719-2.092). The increases in LBR and MBR for DET-GQE + PQE compared with SET-GQE in women older than 35 years were nonsignificant toward. For patients who underwent blastocyst-stage embryo transfer, DET-GQE + PQE had a greater LBR ([OR] 1.803, 95% CI 1.165-2.789), MBR ([OR] 24.185, 95% CI 3.285-178.062) and preterm birth rate (PBR, [OR] 4.092, 95% CI 1.153-14.518) than did SET-GQE in women under 35 years old, while no significant impact on the LBR ([OR] 1.053, 95% CI 0.589-1.884) or MBR (0% vs. 8.3%) was observed in women older than 35 years. CONCLUSIONS: The addition of a PQE has no significant benefit on the LBR but significantly increases the MBR in patients who underwent frozen-thawed cleavage-stage embryo transfer. However, for patients who underwent blastocyst-stage embryo transfer, DET-GQE + PQE resulted in an increase in both the LBR and MBR, which may lead to adverse neonatal outcomes. Thus, the benefits and risks of double blastocyst-stage embryo transfer should be balanced. In patients younger than 35 years, SET-GQE achieved satisfactory LBR either in cleavage-stage embryo transfer or blastocyst-stage embryo transfer, while DET-GQE + PQE resulted in a dramatically increased MBR. Considering the low LBR in women older than 35 years who underwent single cleavage-stage embryo transfer, selective single blastocyst-stage embryo transfer appears to be a more promising approach for reducing the risk of multiple live births and adverse neonatal outcomes.

Pregnancy outcomes of fetal reduction in patients with intrauterine haematoma following double embryo transfer.

RESEARCH QUESTION: Is there an association between intrauterine haematoma (IUH) and pregnancy outcomes in patients who undergo fetal reduction after double embryo transfer (DET), and if so, what is the relationship between IUH-related characteristics and pregnancy outcomes? DESIGN: Clinical information and pregnancy outcomes of women who underwent fetal reduction after DET were analysed. Patients with other systematic diseases, ectopic pregnancy or heterotopic pregnancy, monochorionic twin pregnancies and incomplete data were excluded. Stratification of IUH pregnancies was undertaken based on IUH-related characteristics. The main outcome was incidence of fetal demise (<24 weeks), with other adverse pregnancy outcomes considered as secondary outcomes. RESULTS: Thirty-four IUH patients and 136 non-IUH patients who underwent fetal reduction after DET were included based on a 1:4 match for age, cycle type and fertilization method. IUH patients had a higher incidence of early fetal demise (20.6% versus 7.4%, P = 0.048), threatened abortion (48.1% versus 10.3%, P<0.001) and postpartum haemorrhage (PPH; 14.8% versus 4.0%, P = 0.043) compared with non-IUH patients. IUH was an independent risk factor for early fetal demise [adjusted OR (aOR) 3.34, 95% CI 1.14-9.77] and threatened abortion (aOR 8.61, 95% CI 3.28-22.61) after adjusting for potential confounders. IUH pregnancies undergoing fetal reduction that resulted in miscarriage had larger IUH volumes and earlier diagnosis (both P < 0.03). However, IUH characteristics (i.e. volume, changing pattern, presence or absence of cardiac activity) were not associated with threatened abortion or PPH. CONCLUSIONS: Fetal reduction should be performed with caution in IUH pregnancies after DET as the risk of fetal demise is relatively high. Particular attention should be given to IUH patients with early signs of threatened abortion and inevitable fetal demise.

Predictors of twin pregnancy in in vitro fertilization with intracytoplasmic sperm injection cycles with day 3 double embryo transfer.

OBJECTIVE: The purpose of this study was to identify factors associated with twin pregnancy following day 3 double embryo transfer (DET). METHODS: This retrospective cohort study incorporated data from 16,972 day 3 DET cycles. The participants were women aged between 18 and 45 years who underwent in vitro fertilization with intracytoplasmic sperm injection (IVF/ICSI) at My Duc Assisted Reproduction Technique Unit (IVFMD), My Duc Hospital, located in Ho Chi Minh City, Vietnam. RESULTS: Of the 16,972 day 3 DET cycles investigated, 8,812 (51.9%) resulted in pregnancy. Of these, 6,108 cycles led to clinical pregnancy, with 1,543 (25.3% of clinical pregnancies) being twin pregnancies. Factors associated with twin pregnancy included age under 35 years (odds ratio [OR], 1.5; 95% confidence interval [CI], 1.32 to 1.71; p<0.001) and cycles involving the transfer of at least one grade I embryo. Relative to the transfer of two grade III embryos, the risk of twin pregnancy was significantly elevated following the transfer of two grade I embryos (OR, 1.40; 95% CI, 1.16 to 1.69; p<0.001) or a combination of one grade I and one grade II embryo (OR, 1.27; 95% CI, 1.05 to 1.55; p=0.001). CONCLUSION: By analyzing a large number of IVF/ICSI cycles, we identified several predictors of twin pregnancy. These findings can assist medical professionals in tailoring treatment strategies for couples with infertility.

Transfer of a poor-quality along with a good-quality embryo on in vitro fertilization/intracytoplasmic sperm injection-embryo transfer clinical outcomes: a systematic review and meta-analysis.

OBJECTIVE: To investigate the effect on the pregnancy rate of transfer of a good-quality embryo (GQE) and a poor-quality embryo (PQE) in comparison with a single GQE transfer. DESIGN: Systematic review and meta-analysis. SETTING: Not applicable. PATIENT(S): Infertility patients undergoing in vitro fertilization/intracytoplasmic sperm injection- embryo transfer. INTERVENTION(S): Three major electronic databases (PubMed, Embase, and Cochrane Library) for studies those compared single GQE transfer to double embryo transfer of a GQE + PQE were searched. The Newcastle-Ottawa Quality Assessment Scale was used to evaluate the study quality. Random-effect meta-analysis was performed on all data for an overall analysis, followed by a subgroup analysis (fresh cleavage-stage embryos, fresh blastocysts, frozen-thawed blastocysts, and the same assessment criteria for blastocyst quality). MAIN OUTCOME MEASURE(S): The primary outcome was clinical pregnancy rate (CPR). RESULT(S): A total of 17 studies with 17,612 cycles for GQE transfer and 6,431 cycles for GQE + PQE transfer were included in the meta-analysis. No significant differences were found in CPR (relative risk [RR] = 1.02; 95% confidence interval [CI], 0.91-1.14) and live birth rate (RR = 0.96; 95% CI, 0.87-1.07) between GQE + PQE and GQE transfers. However, the transfer of GQE + PQE increased multiple pregnancy rate (RR = 0.14; 95% CI, 0.09-0.20) and multiple birth rate (RR = 0.08; 95% CI, 0.06-0.12), when compared with the patients undergoing a single GQE transfer. Subgroup analyses by type of embryo for transfer and assessment criteria for embryo quality showed similar trends. CONCLUSION(S): Double embryo transfer with GQE + PQE does not result in increased or decreased CPR and live birth rate when compared with a single GQE transfer but leads to a higher multiple pregnancy rate and multiple birth rate. CLINICAL TRIAL REGISTRATION NUMBER: Prospero CRD42022296681 (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=296681) registered on January 7, 2022.

Effectiveness and Safety of Two Consecutive Cycles of Single Embryo Transfer Compared With One Cycle of Double Embryo Transfer: A Systematic Review and Meta-Analysis.

Objective: To date, evidence regarding the effectiveness and safety of two consecutive cycles of single embryo transfer (2SETs) compared with one cycle of double embryo transfer (DET) has been inadequate, particularly considering infertile women with different prognostic factors. This study aimed to comprehensively summarize the evidence by comparing 2SETs with DET. Methods: PubMed, Embase, Cochrane Library databases, ClinicalTrails.gov, and the WHO International Clinical Trials Registry Platform were searched up to March 22, 2022. Peer-reviewed, English-language randomized controlled trials (RCTs) and observational studies (OS) comparing the outcomes of 2SETs with DET in infertile women with their own oocytes and embryos were included. Two authors independently conducted study selection, data extraction, and bias assessment. The Mantel-Haenszel random-effects model was used for pooling RCTs, and a Bayesian design-adjusted model was conducted to synthesize the results from both RCTs and OS. Main Results: Twelve studies were finally included. Compared with the DET, 2SETs were associated with a similar cumulative live birth rate (LBR; 48.24% vs. 48.91%; OR, 0.97; 95% credible interval (CrI), 0.89-1.13, τ2 = 0.1796; four RCTs and six observational studies; 197,968 women) and a notable lower cumulative multiple birth rate (MBR; 0.87% vs. 17.72%; OR, 0.05; 95% CrI, 0.02-0.10, τ2 = 0.1036; four RCTs and five observational studies; 197,804 women). Subgroup analyses revealed a significant increase in cumulative LBR (OR, 1.33; 95% CrI, 1.29-1.38, τ2 = 0) after two consecutive cycles of single blastocyst transfer compared with one cycle of double blastocyst transfer. Moreover, a lower risk of cesarean section, antepartum hemorrhage, preterm birth, low birth weight, and neonatal intensive care unit admission but a higher gestational age at birth and birth weight were found in the 2SETs group. Conclusion: Compared to the DET strategy, 2SETs result in a similar LBR while simultaneously reducing the MBR and improving maternal and neonatal adverse outcomes. The 2SETs strategy appears to be especially beneficial for women aged ≤35 years and for blastocyst transfers.

The effect of transferring a poor-quality embryo together with a good-quality embryo on the singleton birth weight: A retrospective cohort study.

Background: Embryo quality may affect birth weight among neonates born through assisted reproductive technology. There are very limited studies assessing the adverse effect of transferring a poor-quality embryo with a good-quality one on neonatal outcomes. Objective: The aim of this study was to evaluate the effect of double embryo transfer (DET) with one good-quality embryo (GQE) plus a poor-quality one on the birth weight of newborns conceived by in vitro fertilization in both fresh and frozen-thawed embryo transfer cycles. Materials and Methods: This study was conducted at Yazd Reproductive Sciences Institute, Yazd, Iran. A total of 626 women were classified into three groups according to the embryo quality: single embryo transfer with a GQE (group A); DET using two GQEs (group B); and DET using one good-quality and one poor-quality embryo (group C). The primary outcome was singleton birth weight which was compared between the three groups among fresh and frozen-embryo transfer cycles. A comparative analysis was also performed regarding the effect of vitrification procedures on neonatal birth weight within each of the three embryo quality-based groups. Results: The mean birth weight and the rate of preterm birth were similar between the three groups (p = 0.45 and 0.32, respectively). There were also no significant differences found in the vitrification comparative analysis between and within the groups with regard to birth weight. Conclusion: Our results showed that a poor-quality embryo did not have a significant influence on a good-quality one regarding neonatal birth weight when transferred together.

Comparisons of benefits and risks of single embryo transfer versus double embryo transfer: a systematic review and meta-analysis.

BACKGROUND: Evidence referring to the trade-offs between the benefits and risks of single embryo transfer (SET) versus double embryo transfer (DET) following assisted reproduction technology are insufficient, especially for those women with a defined embryo quality or advanced age. METHODS: A systematic review and meta-analysis was conducted according to PRISMA guidelines. PubMed, EMBASE, Cochrane Library and ClinicalTrials.gov were searched based on established search strategy from inception through February 2021. Pre-specified primary outcomes were live birth rate (LBR) and multiple pregnancy rate (MPR). Odds ratio (OR) with 95% confidence interval (CI) were pooled by a random-effects model using R version 4.1.0. RESULTS: Eighty-five studies (14 randomized controlled trials and 71 observational studies) were eligible. Compared with DET, SET decreased the probability of a live birth (OR = 0.78, 95% CI: 0.71-0.85, P < 0.001, n = 62), and lowered the rate of multiple pregnancy (0.05, 0.04-0.06, P < 0.001, n = 45). In the sub-analyses of age stratification, both the differences of LBR (0.87, 0.54-1.40, P = 0.565, n = 4) and MPR (0.34, 0.06-2.03, P = 0.236, n = 3) between SET and DET groups became insignificant in patients aged ≥40 years. No significant difference in LBR for single GQE versus two embryos of mixed quality [GQE + PQE (non-good quality embryo)] (0.99, 0.77-1.27, P = 0.915, n = 8), nor any difference of MPR in single PQE versus two PQEs (0.23, 0.04-1.49, P = 0.123, n = 6). Moreover, women who conceived through SET were associated with lower risks of poor outcomes, including cesarean section (0.64, 0.43-0.94), antepartum haemorrhage (0.35, 0.15-0.82), preterm birth (0.25, 0.21-0.30), low birth weight (0.20, 0.16-0.25), Apgar1 < 7 rate (0.12, 0.02-0.93) or neonatal intensive care unit admission (0.30, 0.14-0.66) than those following DET. CONCLUSIONS: In women aged < 40 years or if any GQE is available, SET should be incorporated into clinical practice. While in the absence of GQEs, DET may be preferable. However, for elderly women aged ≥40 years, current evidence is not enough to recommend an appropriate number of embryo transfer. The findings need to be further confirmed.

Determining the cause of intrauterine fetal death in monochorionic twins: A case report.

Background: Determining the cause of intrauterine fetal death is essential for patients to manage their next pregnancy. However, in the majority of cases of fetal death, the cause remains unexplained despite comprehensive evaluation, especially in the cases of twins. Among twin pregnancies, conditions of monochorionic twinning, commonly regarded as monozygotic, are more complicated than dichorionic ones. Case summary: We systematically evaluated the cause of fetal death for a Han Chinese woman with monochorionic twinning following in vitro fertilization/embryo transfer. Discrepant karyotypes were unexpectedly discovered between the twins. One fetus had an aneuploid male karyotype (46, XY), dup (9) (p24.3-q13), and the other had a normal female karyotype (46, XX). We considered that the male died of aberration of chromosome 9 and the female died of subsequent acute exsanguination through vascular anastomosis. Conclusion: This study demonstrated the importance of recognizing the presence of monochorionic dizygotic twinning and the challenges of clinical management for twins following in vitro fertilization/double embryo transfer.

Multivariate analysis of the factors associated with live births during in vitro fertilisation in Southeast Asia: a cross-sectional study of 104,015 in vitro fertilisation records in Taiwan.

PURPOSE: To investigate the factors associated with live births and the interaction between age and the number of embryos transferred after in vitro fertilisation (IVF) treatment. METHODS: This study analyses data from a population-based-assisted reproductive database of all registered artificial reproduction institutions (n = 80) from 2010 to 2016 in Taiwan. The probability of a live birth in correlation with the treatment parameters was measured with multivariate logistic regression analyses using the generalised additive model (GAM) and Pearson's chi-square exact test. RESULTS: A total of 104,015 IVF treatments performed between 2010 and 2016 were included in our analysis. From these treatments, 31,467 (30.3%) were successfully delivered, and 40,565 test-tube babies were born. Pearson's chi-square exact test indicated that parents' age, cause of infertility, type of ovarian stimulation, additional assisted reproductive technology techniques, donated egg or sperm, fresh or frozen embryo, presence or absence of ovarian hyperstimulation syndrome, and day of embryo transfer were significantly associated with live births after an IVF cycle (p < 0.05). Multiple logistic regression analysis with the GAM revealed that the odds of a live birth with IVF treatment in patients < 34 years of age were 2.55 times higher than that in patients ≥ 45 years of age (odds ratio = 2.55, 95% confidence interval = 1.69-2.90) for patients who underwent a single-embryo transfer (SET); a similar pattern was observed when two or more embryos were transferred. Egg donation, the assisted hatching technique, oral ovarian stimulation agents, and implantation of frozen embryos during SET were shown to improve the chance of a live birth by 29-90%. Implantation of the embryo after the 5th day of culture yielded the highest odds of a live birth. The interaction plot revealed that maternal age, especially < 40 years, was associated with the probability of a live birth. SET and double-embryo transfer showed similar associations with the probability of a live birth across age groups. Transferring more than two embryos might reduce the probability of a live birth during IVF treatment for women ≥ 40 years of age. CONCLUSIONS: Implanting a greater number of embryos did not improve the age-related decrease in fertility for patients undergoing IVF. Therefore, we suggested that ≤ 2 blastocysts could be transferred during IVF treatments for women ≥ 40 years. Transferring a blastocyst on day 5 of culture was associated with a significant increase in the odds of a live birth resulting from IVF.

Cerebral palsy in ART children has declined substantially over time: a Nordic study from the CoNARTaS group.

STUDY QUESTION: Are the decreasing multiple birth rates after ART associated with a simultaneous drop in the incidence of cerebral palsy (CP) in ART children over time? SUMMARY ANSWER: The relative odds of CP in ART children have declined in the Nordic countries over the past two decades concurrently with declining multiple birth rates. WHAT IS KNOWN ALREADY: In the Nordic countries, the rate of twin pregnancies after ART has decreased from 30% in the early 1990s to 4-13% in 2014, following the implementation of elective single embryo transfer (SET). Consequently, preterm birth rates have declined substantially in ART pregnancies. However, whether the risk of CP, a known consequence of preterm birth, has decreased correspondingly is still unknown. STUDY DESIGN, SIZE, DURATION: Retrospective register-based cohort study based on data on all singletons, twins, and higher-order multiples born in Denmark (birth year 1994-2010), Finland (1990-2010), and Sweden (1990-2014), corresponding to 111 844 ART children and 4 679 351 spontaneously conceived children. PARTICIPANTS/MATERIAL, SETTING, METHODS: Data were obtained from a large Nordic cohort of children born after ART and spontaneous conception initiated by the Committee of Nordic ART and Safety-CoNARTaS. The CoNARTaS cohort was established by cross-linking national register data using the unique personal identification number, allocated to every citizen in the Nordic countries. Data from the National Medical Birth Registers, where information on maternal, obstetric, and perinatal outcomes is recorded, were cross-linked to data from the National ART- and Patients Registers to obtain information on fertility treatments and CP diagnoses. Relative risks of CP for ART compared to spontaneous conception were estimated as odds ratios from multivariate logistic regression analyses across all birth years, as well as for the following birth year categories: 1990-1993, 1994-1998, 1999-2002, 2003-2006, 2007-2010, and 2011-2014. Analyses were made for all children and for singletons and twins, separately. MAIN RESULTS AND THE ROLE OF CHANCE: The main outcome measure was the relative odds of CP in different time periods for ART versus spontaneously conceived children. CP was diagnosed in 661 ART children and 16 478 spontaneously conceived children born between 1990 and 2014. In 1990-1993, the relative odds of CP were substantially higher in all ART children (adjusted odds ratio (aOR) 2.76 (95% CI 2.03-3.67)) compared with all spontaneously conceived children, while in 2011-2014, it was only moderately higher (aOR 1.39 (95% CI 1.01-1.87)). In singletons, the higher relative odds of CP in ART children diminished over time from 1990 to 1993 (aOR 2.02 (95% CI 1.22-3.14)) to 2003-2006 (aOR 1.18 (95% CI 0.91-1. 49)) and was not significantly increased for birth cohorts 2007-2010 and 2011-2014. For ART twins versus spontaneously conceived twins, the relative odds of CP was not statistically significantly increased throughout the study period. LIMITATIONS, REASONS FOR CAUTION: The main limitation of the study was a shorter follow-up time and younger age at first CP diagnosis for ART children compared with spontaneously conceived children. However, analyses ensuring a minimum of bias from differences in age at CP diagnosis and follow-up time confirmed the results, hence, we do not consider this to cause substantial bias. WIDER IMPLICATIONS OF THE FINDINGS: A SET policy in ART treatments has the potential to reduce the increased risk of cerebral palsy in the ART population due to lower rates of multiple deliveries. At a time with high survival rates of frozen/thawed embryos, this study provides a strong argument against the continued use of multiple embryo transfer in most ART settings. Larger cohort studies including also the number of gestational sacs in early pregnancy will be preferable to show an effect of vanishing twins on the risk of CP in the ART population. STUDY FUNDING/COMPETING INTEREST(S): The study was financed by grants from NordForsk (grant number 71450), Elsass Foundation (19-3-0444), the ALF-agreement (ALFGBG 70940), and The Research Fund of Rigshospitalet, Copenhagen University Hospital. There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: ISRCTN11780826.

Gestational carrier pregnancy outcomes from frozen embryo transfer depending on the number of embryos transferred and preimplantation genetic testing: a retrospective analysis.

OBJECTIVE: To compare gestational age, birth weight (BW), and live birth rates in gestational carriers (GC) after the transfer of 1 or 2 frozen embryo(s) with or without preimplantation genetic testing for aneuploidy (PGT-A), with the understanding that several social and economic factors may motivate intended parents to request the transfer of 2 embryos and/or PGT-A when using a GC. DESIGN: Retrospective cohort study SETTING: An assisted reproductive technology practice. PATIENT(S): All frozen blastocyst transfers with GCs from 2009-2018. INTERVENTION(S): One or 2 embryo frozen embryo transfers with and without PGT-A. MAIN OUTCOME MEASURE(S): Live birth, preterm birth, and low BW. RESULTS: A total of 583 frozen embryo transfer cycles with vitrified high-grade blastocysts (grade BB or higher) to GCs were analyzed. Although the live birth rate was significantly greater in frozen embryo transfers with 2 embryos, after single embryo transfer (SET), the mean gestational age and BW of live births were statistically significantly greater than those of double embryo transfer (DET). The rate of multiple births was 1.9% for SET compared to 20.0% for DET per transfer. Only 3.8% of live births from SET experienced low BW and 0.6% had very low or extremely low BW. By comparison, 12.5% of DET live births were low BW and 5% were very low BW. After SET, 13.4% of live births were preterm, compared with 40% in DET. The analysis also included a total of 194 transfers with PGT-A compared to 389 cycles without. Overall, live births per transfer were not significantly different between these latter 2 subgroups. CONCLUSION: Frozen embryo transfer cycles in GCs with DET were associated with more preterm births and lower birth weights compared with those of SET. Intended parents and GCs should be counseled that DET is associated with greater risks of adverse pregnancy and perinatal outcomes, which mitigates higher live birth rates. The use of PGT-A did not appear to improve the live birth rate.

What Are the Live Birth and Multiple Pregnancy Rates When 1 Versus 2 Low-Quality Blastocysts Are Transferred in a Cryopreserved Cycle? a Retrospective Cohort Study, Stratified for Age, Embryo Quality, and Oocyte Donor Cycles.

Outcomes among women who transferred only Gardner's grade BB or lower quality frozen embryos transferred (FET) are not well known. Our objective is to study whether transferring 2 versus 1 frozen low-quality blastocysts will increase the live birth rate (LBR) and the multiple pregnancy rate (MPR). This is a retrospective cohort study including 1104 FET cycles. Only day 5-6 blastocysts of grade BB or lower quality were included. Clinical pregnancy rate (CPR), MPR, and LBR per cycle were compared between single embryo transfer (SET) (n = 969) and double embryo transfer (DET) (n = 135). CPR and MPR were compared between SET and DET in grade BB, BC, CB, and CC individually. Among SET, BB blastocysts had higher CPR 34% (P = 0.0001) and a sub-significant increase in LBR 19% (P = 0.059) in comparison to other grade SET. Among all BB, MPR was significantly higher when transferring two versus one (5.9 vs. 1.9, P = 0.009). If age at egg collection ≥ 40 years (n = 97), no difference was found in CPR (11.1 vs. 11.7, P = 0.9), MPR (0 vs. 0), and LBR (6.3 vs. 0,P = 0.13) when SET or DET was performed. If age was < 40 years (n = 818), the MPR was significantly higher in DET than SET (6.7 vs. 1.63, P = 0.004). In egg donor cycles (n = 189), there was no difference in CPR, MPR, and LBR between SET and DET. Single embryo transfer should be offered even in women ≥ 40 years of age or transferring lower quality embryos since transferring more did not increase outcomes in this group, and SET is likely the safest path.

The impact of a poor quality embryo on the implantation chance of a good quality one when transferred together: A study on double blastocyst transfers.

OBJECTIVE: Embryo quality assessment with morphological evaluation remains the first-line method of assessment to select the best embryo for transfer. We aimed to determine if an effect of poor quality embryos on good quality ones exists, whether by a paracrine effect or an adverse endometrial influence, when they are transferred together. MATERIALS AND METHODS: We included 412 couples, who underwent intracytoplasmic sperm injection (ICSI) cycles in a tertiary IVF center. Single embryo transfer with a good quality embryo and double embryo transfers with a good + poor quality embryo were evaluated. Overall pregnancy (PR) and live birth rates (LBR) were our main outcome measures. RESULTS: When PR and LBR are compared, there was no statistical significance between single embryo transfer (SET) and double embryo transfer (DET) groups (51.7 % vs 53.7 %, p = 0.620 and 47 % vs 43.1 %, p = 0.117). When the PR and LBRs were compared between SET from poor cohort and DET group, the outcomes were better in DET group (22.1 % vs 53.7 %, p < 0.001 and 22.1 % vs 43.1 %, p < 0.001). The PR and LBRs of SET from good cohort were significantly better than those of DET (64.4 % vs 53.7 %, p < 0.001 and 57.7 % vs 43.1, p < 0.001). When the PR and LBRs of SET from good cohort and SET from poor cohort were compared, better results were obtained in SET from good cohort. CONCLUSION: The addition of poor quality embryo even is of benefit to the LBR, in the setting of when there is only one good quality blastocyst available for the transfer.

Impact of Transferring a Poor Quality Embryo Along with a Good Quality Embryo on Pregnancy Outcomes in IVF/ICSI Cycles: a Retrospective Study.

Background The number and the quality of embryos transferred are important predictors of success in in vitro fertilization (IVF) cycles. In the presence of more than one good quality embryo on the transfer day, double-embryo transfer (DET) can be performed with these embryos, but generally, different quality embryos are present in the available transfer cohort. We aimed to investigate the effect of transferring a poor quality embryo along with a good quality embryo on IVF outcomes. Methods In this study, 2298 fresh IVF/intracytoplasmic sperm injection (ICSI) cycles with two good quality embryos (group A), one good and one poor quality embryo (group B), and single good quality embryo (group C) transfers were examined. All groups were divided into two subgroups according to the transfer day as cleavage or blastocyst stage. Clinical pregnancy and live birth rates were the primary outcomes. Results In the cleavage stage transfer subgroups, the clinical pregnancy rates were lower in the single-embryo transfer (SET) subgroup compared with DET subgroups, but the difference was not statistically significant compared with DET with mixed quality embryos. The live birth rates were comparable between the three groups. In the blastocyst transfer subgroups, the clinical pregnancy and live birth rates were significantly higher in DET with two good quality embryos than DET with mixed quality embryos and SET groups. Multiple pregnancy rates were higher in both DET groups in terms of transfer day (p = 0.001). Conclusion DET with mixed quality embryos results with lower clinical pregnancy and live birth rates compared with DET with two good quality embryos at the blastocyst stage. At cleavage stage transfer, there is no difference in live birth rates between the two groups.

Is transferring a lower-quality embryo with a good-quality blastocyst detrimental to the likelihood of live birth?

OBJECTIVE: To determine if transferring a lower-quality embryo with a good-quality blastocyst is detrimental, given that evidence suggests that embryos can signal the endometrium and that embryo quality may affect negatively endometrial receptivity. DESIGN: Retrospective cohort study. SETTING: In vitro fertilization center. INTERVENTION(S): Single- versus double-embryo transfer. PATIENT(S): Patients with a double-embryo transfer of a good-quality blastocyst plus a lower-quality blastocyst, early blastocyst, or morula were compared with patients receiving a single good-quality blastocyst. MAIN OUTCOME MEASURE(S): Live birth, multiple gestation. RESULT(S): In this study, 4,640 in vitro fertilization cycles were analyzed. In none of the analyses did transferring a second lower-quality embryo negatively affect birth rate. In the primary analysis, transferring a second lower-quality embryo increased live birth by 10% and the multiple birth rate by 15%. The addition of a fair- or poor-quality blastocyst or early blastocyst markedly increased the twin birth rate by 22%-27% with an 8%-12% increase in live birth. The addition of a morula did not increase live birth but resulted in 12% more multiples. In women younger than 38 years, adding a lower-quality embryo increased the birth rate by 7% but resulted in 18% increase in multiples. In women 38 years or older, adding a lower-quality embryo increased the live birth rate by 9% with a 15% increase in multiples. CONCLUSION(S): Addition of a lower-quality embryo does not have a detrimental effect on a good-quality blastocyst and results in a small increase in live births. However, this is at the expense of a marked increase in the likelihood of multiple gestations.

Is guided, targeted information about the risks of twin pregnancy able to increase the acceptance of single embryo transfer among IVF couples? A prospective study.

OBJECTIVE: To assess whether receiving information about twin pregnancy in the form of oral presentation given by a physician could affect the acceptance of single embryo transfer (SET) by couples undergoing IVF. STUDY DESIGN: Prospective interventional study. SETTING: University hospital IVF unit. PATIENTS: One hundred and forty patients (70 couples) undergoing IVF. INTERVENTIONS: A questionnaire to measure patients' emotions about twin pregnancy was administered to IVF patients just before and immediately after attending a slide presentation in which the risks of twin pregnancy were explained. Patients scored (1 to 6) ten adjectives linked either to positive or negative emotions; scores before and after presentation were compared. The patients' preference between double embryo transfer (DET) and SET was also registered before and after the presentation. RESULTS: The presentation about twin pregnancy caused a significant (p < 0.001) shift of the score distribution toward lower values for positive adjectives referred to twin pregnancy and higher values for negative adjectives. Information impacted similarly on women and men. Despite the relevant change in the emotional attitude, after presentation, 45.7% of women and 48.6% of men were still favorable to DET, whereas 24.3% of women and 37.1% of men preferred SET. CONCLUSIONS: Oral information on the risks of twin pregnancy can affect the emotional attitude of patients toward twin pregnancy, but the wish of getting pregnant after fresh embryo transfer overcomes all rational consideration, and the majority of patients still prefer DET.

Single and double embryo transfer provide similar live birth rates in frozen cycles.

Research question: Do live birth rates (LBRs) differ in frozen cycles of women who received single versus double embryo transfer?Design: Retrospective cohort study including women who underwent their first frozen embryo transfer (FET) in a tertiary referral University Hospital between 2009-2014.Results: 3601 patients were included in the analysis with 1936 (53.8%) having a single embryo transfer (SET) and 1665 (46.2%) having a double embryo transfer (DET). Overall, 657/3601 (18.24%) had a live birth. LBR were similar between SET and DET either for cleavage [100/757 (13.1%) versus 153/1032 (14.8%), p = .33] or blastocyst stage FET [256/1179 (21.7%) versus 148/633 (23.4%), p = .4). Ongoing pregnancy rates were comparable between DET and SET [316/1665 (18.9%) versus 359/1936 (18.5%)]. Multiple delivery rates were significantly higher in women with DET compared to SET [53/316 (16.7%) versus 7/359 (1.9%), p < .001]. Multivariate logistic regression analysis allowing adjustment for relevant confounders showed that the number of embryos transferred in the frozen cycle was not related to LBR.Conclusions: This is the largest study providing evidence that both SET and DET may result in similar LBR, albeit multiple pregnancy rates are significantly lower in case of SET. Therefore, SET should be the main strategy in women undergoing FET.

The effect on twinning rate of transferring double vitrified-warmed embryos in women of advanced reproductive age: a retrospective study.

Twin pregnancies are associated with greater risk of neonatal morbidity and mortality than a singleton. This study was performed to investigate the twin pregnancy rate when two vitrified-warmed embryos are transferred in women of advanced reproductive age (≥35 years at the time of oocyte retrieval) and to evaluate the implications of findings in selecting candidates for elective single embryo transfer (eSET). A retrospective analysis of data which included 2,038 women aged 35-45 years, who underwent vitrified-warmed double embryo transfer (DET), from January 2013 to December 2016 was undertaken. Pregnancy and twin rates were estimated after stratifying by prognostic profile. The twin pregnancy rate was lower in women with poor prognosis (12/96, 12.5%) as compared with that in women with favorable prognosis (102/374, 27.3%) and average prognosis (78/346, 22.5%) with significant differences (P < 0.05). The twin rate for women with favorable prognosis was 29.2% (70/240) in the cycles of women aged 35-37 years, 26.8% (26/97) in the cycles of women aged 38-40 years and 16.2% (6/37) in the cycles of women >40 years. The twin rate for women with average prognosis was 25.8% (51/198) in the cycles of women aged 35-37 years, 22.0% (22/100) in the cycles of women aged 38-40 years and 10.4% (5/48) in the cycles of women >40 years. The twin rate for women with poor prognosis was 15.3% (9/59) in the cycles of women aged 35-37 years, 10.3% (3/29) in the cycles of women aged 38-40 years and 0% (0/8) in the cycles of women >40 years. From these results, it was concluded that women with a favorable or average prognosis have a high risk of twin pregnancies. The finding can be used to guide future practice: that is, performing eSET in women with favorable or average prognosis and DET in women with poor prognosis.

Single or double embryo transfer? Decision-making process in patients participating in an oocyte donation program.

In IVF/ICSI programs, after receiving the information about the success results of single embryo transfer (SET) vs double embryo transfer (DET) and the risks of multiple pregnancy, a significant number of patients opt for SET. Up to date, no comparable studies have been published in oocyte recipients. The aim of this study was to evaluate if the counseling provided to oocyte recipients influence their decision on the number of embryos to be transferred. Fifty-five recipients expressed their preference and the relevance for the decision-making process that they attribute to certain factors through an anonymous questionnaire completed pre and post-counseling. Before counseling, 32 out of 55 recipients preferred DET, 13 preferred SET and 10 were undecided. From the 32 recipients who preferred DET, 16 (50%) maintained their preference after counseling, 13 (40.6%) changed their decision to SET and 3 (9.4%) changed to undecided (McNemar's test: p < .05). After counseling, the patients attached less importance to the probability of pregnancy and more importance to maternal and perinatal risks (p < .05). We conclude that after counseling, a significant number of recipients changed their preferences from DET to SET.