Does conventional blastocyst morphological evaluation correlate with euploidy (as assessed by comprehensive chromosome screening (CCS) of trophectoderm (TE) biopsies) and implantation potential? A moderate relation between blastocyst morphology and CCS data was observed but the ability to implant seems to be mainly determined by the chromosomal complement of preimplantation embryos rather than developmental and morphological parameters conventionally used for blastocyst evaluation. Combined with improving methods for cryopreservation and blastocyst culture, TE biopsy and CCS is considered to be a promising approach to select euploid embryos for transfer. Understanding the role of morphology in blastocyst stage preimplantation genetic screening (PGS) cycles may help in further optimizing the cycle management and clinical outcomes. This is a multicenter retrospective observational study performed between January 2009 and August 2013. The study includes the data analysis of 956 blastocysts with conclusive CCS results obtained from 213 patients following 223 PGS cycles. Single frozen embryo transfer (FET) cycles of 215 euploid blastocysts were performed where it was possible to track the implantation outcome of each embryo transferred. PGS was offered to infertile patients of advanced maternal age (>35 years) and/or with a history of unsuccessful IVF treatments (more than two failed IVF cycles) and/or previous spontaneous abortion (more than two spontaneous miscarriages). Prior to TE biopsy for CCS, blastocyst morphology was assessed and categorized in four groups (excellent, good, average and poor quality). The developmental rate of each embryo reaching the expanded blastocyst stage was defined according to the day of biopsy post-fertilization. Day 5 and Day 6 biopsied blastocysts were defined as faster and slower growing embryos, respectively. A novel blastocyst biopsy method, not requiring the opening of the zona pellucida at the cleavage stage of embryo development, was used. Linear regression models were used to test the relationship between blastocyst morphology and developmental rate CCS data and FET cycle outcomes of euploid blastocysts. Among the embryological variables assessed (morphology and developmental rate), only blastocyst morphology was predictive of the CCS data. The euploidy rate was 56.4, 39.1, 42.8 and 25.5% in the excellent, good, average and poor blastocyst morphology groups, respectively. A diagnosis of complex aneuploidy was also associated with blastocyst morphology (P < 0.01) with 6.8, 15.2, 17.4 and 27.5% of excellent, good, average and poor quality embryos, respectively, showing multiple chromosome errors. Faster and slower growing embryos showed a similar aneuploidy rate. Regression logistic analysis showed that none of the parameters used for conventional blastocyst evaluation (morphology and developmental rate) was predictive of the implantation potential of euploid embryos. The implantation potential of euploid embryos was the same, despite different morphologies and developmental rates. The study is limited by its retrospective nature. A higher sample size or a prospective randomized design could be used in future studies to corroborate the current findings. This study provides knowledge for a better laboratory and clinical management of blastocyst stage PGS cycles suggesting that the commonly used parameters of blastocyst evaluation are not good enough indicators to improve the selection among euploid embryos. Accordingly, all poor morphology and slower growing expanded blastocysts should be biopsied and similarly considered for FET cycles. This knowledge will be of critical importance to achieve similar cumulative live birth rates in PGS programs compared with conventional IVF, avoiding the potential for exclusion of low quality but viable embryos from the biopsy and transfer procedures. Future research to identify non-invasive biomarkers of reproductive potential may further enhance selection among euploid blastocysts. No funding was obtained for the study. All authors have no conflicts to declare. None.

Understanding fertility in young and old: Fertility in humans follows a U-curve, with low rates in both teenagers and women of advancing maternal age (mid-30s and above). Gruhn et al. found that this distinct shape originates from chromosomal errors in human eggs, which result in genomic imbalance and pregnancy loss. The error types and chromosomes affected in the young and advanced age groups were different, suggesting that two distinct chromosome-based mechanisms balance risk associated with pregnancy and evolutionary fitness as women enter and exit their reproductive life span. The authors show that chromosome structure erodes only with advancing age, acting as a “molecular clock” for reproductive senescence. Science , this issue p. 1466

A successful oocyte cryopreservation programme is of utmost importance where a limited number of oocytes can be inseminated per cycle, to overcome legal and ethical issues related to embryo storage, for oocyte donation programmes and for fertility preservation (especially for cancer patients). Vitrification has been recently proposed as an effective procedure for this purpose. In order to validate the effectiveness of oocyte vitrification a non-inferiority trial was started on sibling metaphase II (MII) oocytes. To demonstrate the non-inferiority based on an absolute difference of 17% in the fertilization rate per sibling oocyte, a minimum of 222 oocytes were required. After oocyte denudation, MII oocytes with normal morphology were randomly allocated to fresh ICSI insemination or to vitrification procedure. If pregnancy was not obtained a subsequent ICSI cycle was performed with warmed oocytes of the same cohort. In both groups, three oocytes were inseminated per cycle by ICSI procedure. Primary end-points were fertilization rates calculated per warmed and per injected oocytes. Secondary end-points were zygote and embryo morphology. A total of 244 oocytes were involved in this study. Of the 120 fresh sibling oocytes inseminated, 100 were fertilized (83.3%). Survival rate of sibling vitrified oocytes was 96.8% (120/124 oocytes). Fertilization rate after ICSI was 76.6% (95/124) per warmed oocyte and 79.2% (95/120) per survived/inseminated oocyte. No statistical difference in fertilization rates was observed between the two groups when calculated per sibling oocytes (absolute difference -6.73%; OR: 0.65; 95% CI = 0.33-1.29; P = 0.20) and per inseminated oocyte (absolute difference -4.17%; OR: 0.76; 95% CI = 0.37-1.53; P = 0.50). Embryo development was also similar in both treatment groups up till Day 2. The percentage of excellent quality embryos was 52.0% (52/100) in the fresh group and 51.6% (49/95) in the vitrification group (absolute difference -0.43%; OR: 0.98; 95% CI = 0.53-1.79; P = 0.9). The mean age of the 40 patients included in this study was 35.5 +/- 4.8 years (range 26-42). Fifteen clinical pregnancies were obtained in the vitrification cycles of 39 embryo transfers performed (37.5% per cycle, 38.5% per embryo transfer), with an implantation rate of 20.2% (19/94). Three spontaneous miscarriages occurred (20%). Twelve pregnancies are ongoing (30.0% per cycle, 30.8% per embryo transfer) beyond 12 weeks of gestation. Our results indicate that oocyte vitrification procedure followed by ICSI is not inferior to fresh insemination procedure, with regard to fertilization and embryo developmental rates. Moreover, ongoing clinical pregnancy is compatible with this procedure, even with a restricted number of oocytes available for insemination. The promising clinical results obtained, in a population of infertile patients, need to be confirmed on a larger scale. iSRCTN60158641.

Eva Hoffman, Alan Handyside and colleagues generate genome-wide maps of crossovers and chromosome segregation patterns by recovering all three products of single female human meioses. They detect a reverse chromosome segregation pattern and selection for higher recombination rates in the female germ line and report chromosomal drive against non-recombinant chromatids at meiosis II. Crossover recombination reshuffles genes and prevents errors in segregation that lead to extra or missing chromosomes (aneuploidy) in human eggs, a major cause of pregnancy failure and congenital disorders. Here we generate genome-wide maps of crossovers and chromosome segregation patterns by recovering all three products of single female meioses. Genotyping >4 million informative SNPs from 23 complete meioses allowed us to map 2,032 maternal and 1,342 paternal crossovers and to infer the segregation patterns of 529 chromosome pairs. We uncover a new reverse chromosome segregation pattern in which both homologs separate their sister chromatids at meiosis I; detect selection for higher recombination rates in the female germ line by the elimination of aneuploid embryos; and report chromosomal drive against non-recombinant chromatids at meiosis II. Collectively, our findings show that recombination not only affects homolog segregation at meiosis I but also the fate of sister chromatids at meiosis II.

Chromosome imbalance (aneuploidy) is the major cause of pregnancy loss and congenital disorders in humans. Analyses of small biopsies from human embryos suggest that aneuploidy commonly originates during early divisions, resulting in mosaicism. However, the developmental potential of mosaic embryos remains unclear. We followed the distribution of aneuploid chromosomes across 73 unselected preimplantation embryos and 365 biopsies, sampled from four multifocal trophectoderm (TE) samples and the inner cell mass (ICM). When mosaicism impacted fewer than 50% of cells in one TE biopsy (low-medium mosaicism), only 1% of aneuploidies affected other portions of the embryo. A double-blinded prospective non-selection trial (NCT03673592) showed equivalent live-birth rates and miscarriage rates across 484 euploid, 282 low-grade mosaic, and 131 medium-grade mosaic embryos. No instances of mosaicism or uniparental disomy were detected in the ensuing pregnancies or newborns, and obstetrical and neonatal outcomes were similar between the study groups. Thus, low-medium mosaicism in the trophectoderm mostly arises after TE and ICM differentiation, and such embryos have equivalent developmental potential as fully euploid ones.