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Time-lapse imaging of embryos has been widely introduced to fertility laboratories worldwide with the aim of identifying the best quality embryos to transfer that will ultimately improve IVF success rates. In this opinion paper, we explore the lack of evidence of benefit of this novel intervention, analyse the methodological flaws of current studies, offer ideal study designs that assess the various features of time-lapse imaging, and discuss forthcoming studies. In particular, we emphasize the ethical aspects of hastily adopting a costly technology without current high level evidence of improved live birth rates, safety and cost effectiveness.

Background Thyroid hormone disorders and thyroid peroxidase autoantibodies (TPO-Ab) in women are associated with subfertility and early pregnancy loss. Here, we aim to provide a comprehensive overview of the literature on the pathophysiology of these associations. Methods A review of the literature in the English language was carried out. Relevant studies were identified by searching Medline, EMBASE and the Cochrane Controlled Trials Register from 1975 until March 2014. Results From a total of 6108 primary selected articles from the literature search, 105 articles were selected for critical appraisal. Observational data indicate that altered thyroid hormone levels are associated with disturbed folliculogenesis, spermatogenesis, lower fertilization rates and lower embryo quality. Triiodothyronine (T3) in combination with FSH enhances granulosa cell proliferation and inhibits granulosa cell apoptosis by the PI3K/Akt pathway. T3 is considered a biological amplifier of the stimulatory action of gonadotrophins on granulosa cell function. T3 increases the expression of matrix metalloproteinases (MMP), MMP-2, MMP-3, fetal fibronectin and integrin α5β1T3 in early placental extravillous trophoblasts. Thyroid hormone transporters and receptors are expressed in the ovary, early embryo, endometrium, uterus and placenta. No other data explaining the associations could be retrieved from the literature. The presence of TPO-Ab is negatively associated with spermatogenesis, fertilization and embryo quality, but no data are available on the potential pathophysiological mechanisms. Conclusions Thyroid hormone disorders and TPO-Ab are associated with disturbed folliculogenesis, spermatogenesis, fertilization and embryogenesis. The pathophysiology of these associations remains largely unknown, as evidence is limited and includes studies using small sample sizes, and often restricted to animal models. There are no studies on the pathophysiology underlying the association between TPO-Ab and reproduction. The available evidence, although limited, supports a role of thyroid hormone in fertility and early pregnancy. This justifies clinical intervention studies on the effects of thyroid hormone supplementation in women with subclinical hypothyroidism and in women prone to develop hypothyroidism due to the presence of TPO-Ab. In addition, more research is needed to identify the underlying mechanisms. This would be of particular interest in women undergoing IVF to pinpoint the effects of thyroid hormone on different parameters of reproduction.

This is the protocol for a review and there is no abstract. The objectives are as follows: To determine whether IVF with frozen-thawed embryo transfers only (freeze-all strategy) has a positive effect on fertility outcomes, including live birth rate, compared to standard IVF with fresh and frozen-thawed embryo transfers.

In in vitro fertilization (IVF), the selection of embryos for transfer is generally based on the morphology of the available embryos. However, not all embryos with good morphology implant and on average only one in four treatments are successful. This has driven a quest for alternative selection methods. The best known alternative selection method is preimplantation genetic screening (PGS), which has been used for over a decade before it was shown to be inferior to morphological selection. Now, new forms of PGS (performing biopsy at another stage of development and new methods for analysis) are emerging, just like alternative noninvasive embryo selection methods. However, the concept that better selection will lead to improved IVF results is not so certain anymore. Evidence is accumulating that all available embryos in an IVF cycle can be cryopreserved and transferred in subsequent cycles without impairing pregnancy rates or maybe even with an improvement in pregnancy rates. Embryo selection will then no longer be able to improve the live birth rate in IVF; it could even lower the live birth rate. Embryo selection will only be able to improve the time to pregnancy, if embryos with the highest implantation potential are transferred first.

Cryopreservation of human embryos is now a routine procedure in assisted reproductive technologies laboratories. There is no consensus on the superiority of any protocol, and substantial differences exist among centers in day of embryo cryopreservation, freezing method, selection criteria for which embryos to freeze, method of embryo thawing, and endometrial preparation for transfer of frozen-thawed embryos. In the past decade, the number of frozen-thawed embryo transfer cycles per started in vitro fertilization (IVF) cycle increased steadily, and at the same time the percentage of frozen-thawed embryo transfers that resulted in live births increased. Currently, cryopreservation of human embryos is more important than ever for the cumulative pregnancy rate after IVF. Interestingly, success rates after frozen-thawed embryo transfer are now nearing the success rates of fresh embryo transfer. This supports the hypothesis of so called freeze-all strategies in IVF, in which all embryos are frozen and no fresh transfer is conducted, to optimize success rates. High-quality randomized controlled trials should be pursued to find out which cryopreservation protocol is best and whether the time has come to completely abandon fresh transfers.

Chromosome aneuploidy is naturally occurring, typically sporadic and generally leads to non-viable offspring. The use of PGS has the potential to select the best embryos for transfer and reduce the risk of losing a much wanted pregnancy. However there is no high-level clinical evidence from randomized control trials to demonstrate a beneficial effect of PGS on the live birth rate after IVF, and for women of advanced age, PGS using cleavage stage biopsy and FISH may lead to a significant decrease in live birth rates. Technical limitations and chromosomal mosaicism confound the effectiveness of PGS, but a test that could identify aneuploidy with 100 % accuracy would be a significant advance; no such test has yet been developed. New approaches in the application of PGS should be evaluated carefully before their introduction into clinical practice.

Mitotic errors during early development of human preimplantation embryos are common, rendering a large proportion of embryos chromosomally mosaic. It is also known that the percentage of diploid cells in human diploid-aneuploid mosaic embryos is higher at the blastocyst than at the cleavage stage. In this study, we examined whether there is temporal and/or developmental-stage variation in the occurrence of mitotic errors in human preimplantation embryos from the first day of development onward using mitotically stable digynic tripronuclear human embryos as a model system. All the cells of the 114 digynic tripronuclear human preimplantation embryos included were analyzed by fluorescence in situ hybridization for chromosomes 1, 13, 16, 17, 18, 21, X, and Y. Embryos were grouped according to day of development (1–6) and developmental stage (2-cell to blastocyst stage). The possibility of a mitotic error was highest in the first and second mitotic divisions. The percentage of cells with mitotic error...

Mitotic errors during early development of human preimplantation embryos are common, rendering a large proportion of embryos chromosomally mosaic. It is also known that the percentage of diploid cells in human diploid-aneuploid mosaic embryos is higher at the blastocyst than at the cleavage stage. In this study, we examined whether there is temporal and/or developmental-stage variation in the occurrence of mitotic errors in human preimplantation embryos from the first day of development onward using mitotically stable digynic tripronuclear human embryos as a model system. All the cells of the 114 digynic tripronuclear human preimplantation embryos included were analyzed by fluorescence in situ hybridization for chromosomes 1, 13, 16, 17, 18, 21, X, and Y. Embryos were grouped according to day of development (1-6) and developmental stage (2-cell to blastocyst stage). The possibility of a mitotic error was highest in the first and second mitotic divisions. The percentage of cells with mitotic errors increased during preimplantation development and was highest at the 9-16 cell stage (76%, P = 0.027). Thereafter, the percentage of cells with mitotic errors decreased to 64% at the morula and 56% at the blastocyst stage. The pattern found correlates with the activation of the embryonic genome at the 8-16 cell stage. A better insight in the timing of occurrence of mitotic errors in human preimplantation embryos could help in understanding and prevention of these errors and is relevant in the context of PGS.

BACKGROUND The media that are used to culture human preimplantation embryos are considered to be an important factor for the success rates of IVF/ICSI. Here, we present a systematic review of randomized controlled trials (RCTs) on the effect of culture media on IVF/ICSI success rates. METHODS RCTs published between January 1985 and July 2012 were eligible for inclusion. The primary outcome was live birth. Secondary outcomes were health of babies born, ongoing pregnancies, clinical pregnancies, miscarriages, multiple pregnancies, implantation rate, cryopreservation rate, embryo quality and fertilization rate. For those media that were evaluated in more than one comparison, an unconventional meta-analysis was performed by pooling the data of the media they were compared to. RESULTS Twenty-two RCTs were included that evaluated 31 different comparisons. Conventional meta-analysis was not possible for any of the outcomes as nearly all trials compared different culture media. Only four trials reported on live birth, and one of them reported a significant difference. Nine trials reported on ongoing and/or clinical pregnancy rates, of which four showed a significant difference. Pooling the data did not reveal a superior culture medium. CONCLUSIONS It is yet unknown what culture medium leads to the best success rates in IVF/ICSI. Given the potential importance of culture media for treatment outcome, rigorously designed RCTs are needed for currently available, as well as newly introduced culture media.

Background During in vitro fertilisation (IVF) procedures, human preimplantation embryos are cultured in the laboratory. While some laboratories culture in an atmospheric oxygen concentration (similar to 20%), others use a lower concentration (similar to 5%) as this is more comparable to the oxygen concentration observed in the oviduct and the uterus. Animal studies have shown that high oxygen concentration could have a negative impact on embryo quality via reactive oxygen species causing oxidative stress. In humans, it is currently unknown which oxygen concentration provides the best success rates of IVF procedures, eventually resulting in the hightest birth rate of healthy newborns. Objectives To determine whether embryo culture at low oxygen concentrations improves treatment outcome (better embryo development and more pregnancies and live births) in IVF and intracytoplasmic sperm injection (ICSI) as compared to embryo culture at atmospheric oxygen concentrations. Search methods The Menstrual Disorders and Subfertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and PsycINFO electronic databases were searched (up to 4th November 2011) for randomised controlled trials on the effect of low oxygen concentrations for human embryo culture. Furthermore, reference lists of all obtained studies were checked and conference abstracts handsearched. Selection criteria Only truly randomised controlled trials comparing embryo culture at low oxygen concentrations (similar to 5%) with embryo culture at atmospheric oxygen concentrations (similar to 20%) were included in this systematic review and meta-analysis. Data collection and analysis Two review authors selected the trials for inclusion according to the above criteria. After that two authors independently extracted the data for subsequent analysis, and one author functioned as a referee in case of ambiguities. The statistical analysis was performed in accordance with the guidelines developed by The Cochrane Collaboration. Main results Seven studies with a total of 2422 participants were included in this systematic review. Meta-analysis could be performed with the data of four included studies, with a total of 1382 participants. The methodological quality of the included trials was relatively low. Evidence of a beneficial effect of culturing in low oxygen concentration was found for live birth rate (OR 1.39; 95% CI 1.11 to 1.76; P = 0.005; I-2 = 0%); this would mean that a typical clinic could improve a 30% live birth rate using atmospheric oxygen concentration to somewhere between 32% and 43% by using a low oxygen concentration. The results were very similar for ongoing and clinical pregnancy rates. There was no evidence that culturing embryos under low oxygen concentrations resulted in higher numbers of adverse events such as multiple pregnancies, miscarriages or congenital abnormalities. Authors' conclusions The results of this systematic review and meta-analysis suggest that culturing embryos under conditions with low oxygen concentrations improves the success rates of IVF and ICSI, resulting in the birth of more healthy newborns

Preimplantation genetic screening (PGS) was introduced into clinical practice to improve the disappointingly low ongoing pregnancy rates in subfertile couples in assisted reproduction, based on the assumption that the high rates of chromosomal aneuploidy in the cleavage stage embryos of these couples were the underlying cause. However, despite its wide availability and usage during the past 10 years, PGS has never been shown to actually increase ongoing pregnancy rates after assisted reproduction. In fact, meta-analysis of all properly designed studies conducted for the indication advanced maternal age shows a significant reduction in ongoing pregnancy rates. This lack of evidence for the efficacy of PGS and the accumulating evidence for its harm for the indication advanced maternal age, means that PGS should not be offered as a routine treatment in clinical practice.

International audience; The recent debate on preimplantation genetic screening (PGS) has raised questions about its routine use in clinical practice. It has been suggested that the most effective way to resolve the debate about the usefulness of PGS is to perform more well-designed and well-executed randomized controlled trials (RCTs). However, in view of the lack of evidence for the effectiveness of PGS and the accumulating evidence for its harmfulness, it is our opinion that it is unethical to perform additional RCTs for the indication advanced maternal age using cleavage stage biopsy.

BACKGROUND: Human preimplantation embryos generated through in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatments show a variable rate of numerical chromosome abnormalities or aneuploidies. Preimplantation genetic screening (PGS) has been designed to screen for aneuploidies in high risk patients, with the aim of improving live birth rates in IVF/ICSI. We assessed whether the effect of PGS on live births rates differs in women of advanced maternal age with variable risks for embryonic aneuploidy, and weighed these effects against the results obtained after IVF/ICSI without PGS. METHODS: The effect of PGS on live birth rates was compared between groups defined by maternal age, number of previous miscarriages, semen quality, total amount of recombinant FSH (rFSH) administered during ovarian stimulation and total number of top-quality embryos, using data from a randomized controlled trial among women of advanced maternal age (35-41 years). RESULTS: There was no significant differential effect of PGS in groups based on maternal age (P-value of interaction 0.16), the number of previous miscarriages (P-value of interaction 0.93), semen quality (P-value of interaction 0.26), rFSH dose (P-value of interaction 0.15) or the number of top-quality embryos (P-value of interaction 0.59). Live birth rates after IVF/ICSI with PGS were lower in all groups when compared with live birth rates after IVF/ICSI without PGS. CONCLUSIONS: The paradigm that the effect of PGS is determined by a woman's risk for embryonic aneuploidy seems incorrect. In fact, PGS has no clinical benefit over standard IVF/ICSI in women of advanced maternal age regardless of their risk for embryonic aneuploidy.

Chromosome aneuploidy is naturally occurring, typically sporadic and generally leads to non-viable offspring. The use of PGS has the potential to select the best embryos for transfer and reduce the risk of losing a much wanted pregnancy. However there is no high-level clinical evidence from randomized control trials to demonstrate a beneficial effect of PGS on the live birth rate after IVF, and for women of advanced age, PGS using cleavage stage biopsy and FISH may lead to a significant decrease in live birth rates. Technical limitations and chromosomal mosaicism confound the effectiveness of PGS, but a test that could identify aneuploidy with 100 % accuracy would be a significant advance; no such test has yet been developed. New approaches in the application of PGS should be evaluated carefully before their introduction into clinical practice.

Background In both in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI), selection of the most competent embryo(s) for transfer is generally based on morphological criteria. However, many women fail to achieve a pregnancy after transfer of good quality embryos. One of the presumed causes is that such morphologically normal embryos show an abnormal number of chromosomes (aneuploidies). In preimplantation genetic screening (PGS), embryos are analysed for aneuploidies and only embryos that are euploid for the chromosomes tested are transferred. This technique has been suggested and used to improve pregnancy rates for the following indications: (i) advanced maternal age, (ii) repeated IVF failure, (iii) repeated miscarriage and (iv) testicular sperm extraction (TESE)-ICSI. Although PGS is used more and more often, its effectiveness is still unclear. Objectives To assess the effectiveness of PGS in terms of live births in women undergoing IVF or ICSI treatment. Search strategy We searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library Issue 1, 2005), MEDLINE (1966 to present) and EMBASE (1980 to present) (searched March 2005) and reference lists of articles. We also contacted authors for providing additional data when necessary. Selection criteria Trials for all four suggested indications as mentioned above were sought. All relevant published randomised controlled trials were selected. They were eligible for inclusion if the comparison dealt with IVF/ICSI with PGS versus IVF/ICSI without PGS. Data collection and analysis Relevant data were extracted independently by two authors. All trials were screened and analysed according to predetermined quality criteria. Validity was assessed in terms of method of randomisation, completeness of follow-up, intention-to-treat analysis and presence or absence of blinding. The primary outcome measure was live birth rate per woman. Secondary outcome measures were the proportion of women reaching embryo transfer, mean number of embryos transferred per transfer, clinical pregnancy rate, multiple pregnancy rate, miscarriage rate, ongoing pregnancy rate, proportion of women reaching embryo transfer after cryopreservation and proportion of women whose child has a congenital malformation. Main results Two randomised controlled trials met our predetermined eligibility criteria. These trials used PGS for advanced maternal age. The primary outcome of live birth rate per woman was not significantly different in the PGS and control groups, though data were only available from one study. The live birth rate was 11% (21 out of 199) in the PGS group, versus 15% (29 out of 190) in the control group (OR 0.65; 95% CI 0.36 to 1.19). For a control group rate of 15%, these data suggest a live birth rate using PGS of between 4% and 17%. Ongoing pregnancy rate was provided in both studies. This was not significantly different with a combined odds ratio of 0.64 (95% CI 0.37 to 1.09). For a control group rate of 20%, this suggests an ongoing pregnancy rate using PGS of between 8% and 21%. Authors' conclusions To date there is insufficient data to determine whether PGS is an effective intervention in IVF/ICSI for improving live birth rates. Available data on PGS for advanced maternal age showed no difference in live birth rate and ongoing pregnancy rate. However, only two randomised trials were found, of which one included only 39 patients. For both studies comments on their methodological quality can be made. Therefore more properly conducted randomised controlled trials are needed. Until such trials have been performed PGS should not be used in routine patient care.

We used on-line microdialysis measurements of dopamine and noradrenaline extracellular concentrations in the medial prefrontal cortex of awake, freely moving rats during the dark and the light period of the day to study whether (i) basal efflux would be higher in the active, dark period than in the inactive, light period; (ii) the activation induced by environmental stimuli would be dependent on these conditions. When determined one day after cannula placement, noradrenaline and dopamine levels were higher during the dark. Maximal relative increases induced by novelty and handling were 150% and 175-200%, respectively, and were very similar in the light and the dark, but the net increases were higher in the dark. Separate groups were tested one week after cannula placement to ensure recovery of possibly disturbed circadian rhythms. While basal levels in the dark were now approximately twice those in the light, the maximal relative and net increases after both novelty and handling were very similar. Basal levels of dopamine in the nucleus accumbens (one day after cannula placement) were not different in the light or dark, but were increased by novelty and handling to about 130% only in the light period, not in the dark. Thus, in the prefrontal cortex, dopamine strongly resembles noradrenaline, in that basal efflux was state dependent, whereas activation by stimuli was not. In the nucleus accumbens, basal dopamine efflux was not state dependent, but activation by stimuli was. These results suggest that there are differential effects of circadian phase on basal activity and responsiveness of the mesolimbic vs the mesocortical dopamine system. (C) 2000 IBRO. Published by Elsevier Science Ltd. All rights reserved

Background and aims: Increased risk for chromosomal abnormalities in embryos is considered as a cause of low pregnancy rate with advanced maternal age. PGS has been suggested to improve pregnancy outcome. Since PGS includes extensive embryo manipulation, PGS could have an effect on morphological outcome in children. A follow-up study of a RCT comparing IVF/ICSI with PGS (PGS+) and without (PGS-) was performed to evaluate morphological abnormalities of live born children at 2 years of age. Methods: 408 women were included in a multicenter RCT on the efficacy of PGS. There were 120 women with ≥1 live births, 119 mothers with 142 children alive (57 PGS+; 85 PGS-) were available for follow-up. A reference group of 67 children conceived naturally was formed. At 2 years of age a body-surface examination and anthropometry was performed. Morphological abnormalities were classified as major abnormalities, minor anomalies or common variants according to Merks (Am J Med Genet 2003;123A:211-230). Results: No significant association was found between PGS and any specific minor anomaly or major abnormality. The proportions [95% CI] of children with ≥1 minor anomalies and ≥1 major abnormalities for PGS+ versus PGS- were 64 % [50 -76] vs 67 % [55 - 77] and 28 % [18 - 42] vs 35 % [25 - 46], respectively. No significant differences were found between the randomized and reference groups. Conclusions: This study found no differences in morphological abnormalities between children conceived after IVF/ICSI with PGS and children conceived after regular treatment.