BACKGROUND

Assisted hatching (AH) is a manipulation of zona pellucida aiming to facilitate embryo implantation.

METHODS

Systematic review and meta-analysis of medical literature was used to evaluate the effect of AH on assisted reproduction outcomes: clinical pregnancy, live birth, multiple pregnancy and miscarriage. Additional analysis was performed in these subgroups: (i) fresh embryos transferred to unselected or non-poor prognosis women; (ii) fresh embryos transferred to women with previous repeated failure; (iii) fresh embryos transferred to women of advanced age; (iv) frozen-thawed embryos transferred to unselected or non-poor prognosis women. Analyses were based on risk ratio and 95% confidence intervals (RR, 95% CIs) using Mantel–Haenszel random effects model.

RESULTS

There were 28 studies (5507 participants) included. AH was related to a trend toward increased clinical pregnancy for all participants (RR = 1.11, 95% CI = 1.00–1.24), with a significant increase in subgroups 2 (RR = 1.73; 95% CI = 1.37–2.17) and 4 (RR = 1.36; 95% CI = 1.08–1.72, P< 0.01), but not for subgroups 1 and 3. For multiple pregnancy, a significant increase was observed for all participants (RR = 1.45; 95% CI = 1.11–1.90) and for subgroups 2 (RR = 2.53; 95% CI = 1.23–5.21) and 4 (RR = 3.40; 95% CI = 1.93–6.01). No significant heterogeneity was observed in subgroup analysis.

CONCLUSIONS

AH was related to increased clinical pregnancy and multiple pregnancy rates in women with previous repeated failure or frozen-thawed embryos. However, AH is unlikely to increase clinical pregnancy rates when performed in fresh embryos transferred to unselected or non-poor prognosis women or to women of advanced age. Due to the small sample evaluated by the pool of included studies, no proper conclusions could be drawn regarding miscarriage or live birth.

BACKGROUND

Preimplantation genetic screening (PGS) has increasingly been used in the past decade. Here we present a systematic review and meta-analysis of RCTs on the effect of PGS on the probability of live birth after IVF.

METHODS

PubMed and trial registers were searched for RCTs on PGS. Trials were assessed following predetermined quality criteria. The primary outcome was live birth rate per woman, secondary outcomes were ongoing pregnancy rate, miscarriage rate, multiple pregnancy rate and pregnancy outcome.

RESULTS

Nine RCTs comparing IVF with and without PGS were included in our meta-analysis. Fluorescence in situ hybridization was used in all trials and cleavage stage biopsy was used in all but one trial. PGS significantly lowered live birth rate after IVF for women of advanced maternal age (risk difference: –0.08; 95% confidence interval: –0. 13 to –0.03). For a live birth rate of 26% after IVF without PGS, the rate would be between 13 and 23% using PGS. Trials where PGS was offered to women with a good prognosis and to women with repeated implantation failure suggested similar outcomes.

CONCLUSIONS

There is no evidence of a beneficial effect of PGS as currently applied on the live birth rate after IVF. On the contrary, for women of advanced maternal age PGS significantly lowers the live birth rate. Technical drawbacks and chromosomal mosaicism underlie this inefficacy of PGS. New approaches in the application of PGS should be evaluated carefully before their introduction into clinical practice.

BACKGROUND

Preimplantation  genetic diagnosis (PGD) has been stated to improve live birth rates compared with natural conception in couples with recurrent miscarriage (RM) carrying a structural chromosome abnormality. It is unclear to what extent this claim can be substantiated by evidence. A systematic review of the literature was performed on the reproductive outcome of these couples after natural conception or after PGD.

METHODS

MEDLINE, EMBASE and the Cochrane database were searched until April 2009. Trials, patient series and case reports describing reproductive outcome in couples with RM carrying a structural chromosome abnormality after natural conception and/or after PGD were included. Since no randomized controlled trials or non-randomized comparative studies were found, separate searches for both groups were conducted. Primary outcome measure was live birth rate per couple. Secondary outcome measure was miscarriage rate per couple.

RESULTS

Four observational studies reporting on the reproductive outcome of 469 couples after natural conception and 21 studies reporting on the reproductive outcome of 126 couples after PGD were found. After natural conception, live birth rate per couple varied between 33 and 60% (median 55.5%) after parental chromosome analysis; miscarriage rate ranged from 21 to 40% (median 34%). After PGD, live birth rate per couple varied between 0 and 100% (median 31%) after parental chromosome analysis; miscarriage rate ranged from 0 to 50% (median 0%).

CONCLUSIONS

Currently, there are insufficient data indicating that PGD improves the live birth rate in couples with RM carrying a structural chromosome abnormality.

BACKGROUND

Complex chromosomal rearrangements (CCRs) describe structural rearrangements, essentially translocations, involving at least three breakpoints on two or more chromosomes. Although they are rare in humans, their clinical identification is important since CCR carriers can display various phenotypes which include phenotypically normal subjects, infertile males and patients with mental retardation and/or congenital abnormalities. The rearrangement can be de novo or familial. The use of fluorescent in situ hybridization assays and molecular techniques for the characterization of CCRs have indicated that the rearrangements could be more complex than initially assumed. Accumulating data have revealed that the mechanisms underlying the genesis of CCRs remain elusive.

METHODS

We performed a large PubMed search in order to summarize the current knowledge in this field and address important aspects of CCR formation and meiotic behavior, highlighting the complexity of these rearrangements at the chromosomal and genomic level.

RESULTS

The review of published data indicates that the complexity of CCRs is becoming increasingly known, thanks to the application of more and more efficient molecular techniques. These approaches have allowed the precise sequence analysis of breakpoints and the identification of insertions, deletions, inversions and recombination events. New models have been proposed for the formation of CCRs, based on replication-based mechanisms and specific sequence elements. Their meiotic behavior has been discussed in the light of these new molecular data.

CONCLUSIONS

Despite the increasing understanding of the mechanisms involved in their genesis, CCRs arise as unique, complex events for which the genetic and reproductive counseling of carriers remains a challenge.

BACKGROUND

Patients with polycystic ovary syndrome (PCOS) are at risk of arterial disease. We examined the risk of (non)fatal coronary heart disease (CHD) or stroke in patients with PCOS and ovulatory women without PCOS, and assessed whether obesity might explain a higher risk of CHD or stroke.

METHODS

We performed a systematic review and meta-analysis of controlled observational studies. Four definitions of PCOS were considered: World Health Organization type II anovulation, National Institutes of Health criteria, Rotterdam consensus and Androgen-excess criteria. Obesity was defined as BMI > 30 kg/m² and/or waist circumference >88 cm. Study quality was assessed using the Newcastle–Ottawa Scale. Primary outcome was fatal/non-fatal CHD or stroke. Definitions of CHD and stroke were based on criteria used by the various authors. The effect measure was the pooled relative risk in a random effects model. Risk ratios and rate ratios were combined here.

RESULTS

After identifying 1340 articles, 5 follow-up studies published between 2000 and 2008 were included. The studies showed heterogeneity in design, definitions and quality. In a random effects model the relative risk for CHD or stroke were 2.02 comparing women with PCOS to women without PCOS (95% confidence interval 1.47, 2.76). Pooling the two studies with risk estimates adjusted for BMI showed a relative risk of 1.55 (1.27, 1.89).

CONCLUSIONS

This meta-analysis showed a 2-fold risk of arterial disease for patients with PCOS relative to women without PCOS. BMI adjustment did not affect this finding, suggesting the increased risk for cardiovascular events in PCOS is not completely related to a higher BMI in patients with PCOS.

BACKGROUND

Aspirin is believed to improve the outcome of IVF, but previous conventional meta-analyses on the subject are conflicting. Therefore, we performed a meta-analysis with individual patient data (IPD MA) of randomized clinical trials (RCTs) on the subject.

METHODS

A systematic literature search was conducted to identify RCTs assessing the effectiveness of aspirin in IVF. Authors were asked to share their original data. In a one step meta-analytic approach, the treatment effect of aspirin was estimated with odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression, based on the intention to treat principle.

RESULTS

Ten studies fulfilled the inclusion criteria. Authors of six studies provided IPD, including 1119 patients (562 placebo and 557 aspirin). There were 160 clinical pregnancies in the aspirin (28.8%) and 179 (31.9%) in the placebo group [OR 0.86, 95% CI (0.69–1.1)]. There were 129 ongoing pregnancies in the aspirin (23.6%) and 147 in the placebo group (26.7%) [OR 0.85, 95% CI (0.65–1.1)]. Whereas the conventional meta-analysis limited to studies that could provide IPD showed an OR of 0.89 (95% CI 0.69–1.2), the conventional meta-analysis limited to the eight studies of which method of randomization could be confirmed showed an OR of 0.94 (95% CI 0.76–1.17) and the conventional meta-analysis including all 10 eligible RCTs identified with our search changed the OR to 1.07 (95% CI 0.81–1.41). This difference in direction of effect, derived from the studies not able to share IPD of which quality of randomization could not be confirmed.

CONCLUSIONS

Aspirin does not improve pregnancy rates after IVF.

BACKGROUND

GnRH agonist (GnRHa) triggering has been shown to significantly reduce the occurrence of ovarian hyperstimulation syndrome (OHSS) compared with hCG triggering; however, initially a poor reproductive outcome was reported after GnRHa triggering, due to an apparently uncorrectable luteal phase deficiency. Therefore, the challenge has been to rescue the luteal phase. Studies now report a luteal phase rescue, with a reproductive outcome comparable to that seen after hCG triggering.

METHODS

This narrative review is based on expert presentations and subsequent group discussions supplemented with publications from literature searches and the authors’ knowledge. Moreover, randomized controlled trials (RCTs) were identified and analysed either in fresh IVF cycles with embryo transfer (ET), oocyte donation cycles or cycles without ET; risk differences were calculated regarding pregnancy rate and OHSS rate.

RESULTS

In fresh IVF cycles with ET (9 RCTs) no OHSS was reported after GnRHa triggering [0% incidence in the GnRHa group: risk difference 5% (with 95% CI: –0.07 to 0.02)]. Importantly, the delivery rate improved significantly after modified luteal support [6% risk difference in favour of the HCG group (95% CI: –0.14 to 0.2)] when compared with initial studies with conventional luteal support [18% risk difference (95% CI: –0.36 to 0.01)]. In oocyte donation cycles (4 RCTs) the OHSS incidence is 0% [10% risk difference (95% CI: 0.02–0.40)].

CONCLUSIONS

GnRHa triggering is a valid alternative to hCG triggering, resulting in an elimination of OHSS. After modified luteal support there is now a non-significant difference of 6% in delivery rate in favour of hCG triggering.

BACKGROUND

A limitation to our ability to distinguish between developmentally competent and incompetent eggs is our still only partial knowledge of the critical features that are needed to make a good egg and when during oogenesis these specific characteristics are acquired. The main objective of this review is to summarize the results of areas of investigation that are contributing to our still inadequate understanding of the molecular aspects of making developmentally competent eggs.

METHODS

For each area discussed, a systematic search was made using PubMed. The search was without temporal limits but mainly yielded publications between 1982–1999 (23%) and 2000–2011 (77%).

RESULTS

Taking an oocyte-centred view, we describe throughout folliculogenesis: (i) the factors that regulate oocyte growth; (ii) the role of oocyte–cumulus cell dialogue; (iii) the epigenetic organization of the oocyte genome and (iv) the storage and regulation of maternal RNAs.

CONCLUSIONS

The multifaceted complex of factors involved in oocyte growth constitutes the backbone on which oocyte developmental competence is built up. Operating behind the expression of these factors is a specific epigenetic signature established during oogenesis, but our knowledge is only approximate and major efforts will be required for more accurate analyses at specific gene loci. The growing research on small silencing RNAs during oogenesis and early oocyte development is revealing these molecules’ critical role in mRNA degradation. Our next challenge will be to dissect the complex interactions among the different molecular players identified and to establish the presence of functional links among these factors.

BACKGROUND

The majority of research aimed at improving embryo development in vitro has focused on manipulation of the chemical environment, examining details such as energy substrate composition and impact of various growth factors or other supplements. In comparison, relatively little work has been done examining the physical requirements of preimplantation embryos and the role culture platforms or devices can play in influencing embryo development.

METHODS

Electronic searches were performed using keywords centered on embryo culture techniques using PUBMED through June 2010 and references were searched for additional research articles.

RESULTS

Various approaches to in vitro embryo culture that involve manipulations of the physical culture environment are emerging. Novel culture platforms being developed examine issues such as media volume and embryo spacing. Furthermore, methods to permit dynamic embryo culture with fluid flow and embryo movement are now available, and novel culture surfaces are being tested.

CONCLUSIONS

Although several factors remain to be studied to optimize efficiency, manipulations of the embryo culture microenvironment through novel culture devices may offer a means to improve embryo development in vitro. Reduced volume systems that reduce embryo spacing, such as the well-of-the-well approach, appear beneficial, although more work is needed to verify the source of their true benefit in human embryos. Emerging microfluidic technology appears to be a promising approach. However, along with the work on specialized culture surfaces, more information is required to determine the impact on human embryo development.

BACKGROUND

Approximately half recurrent miscarriage (RM) cases remain unexplained after standard investigations. Secondary RM (SRM) is, in contrast to primary RM, preceded by a birth, which increases the transfer of fetal cells into the maternal circulation. Mothers of boys are often immunized against male-specific minor histocompatibility (H-Y) antigens, and H-Y immunity can cause graft-versus-host disease after stem-cell transplantation. We proposed the H-Y hypothesis that aberrant H-Y immunity is a causal factor for SRM.

METHODS

This is a critical review of the H-Y hypothesis based on own publications and papers identified by systematic PubMed and EMBASE searches.

RESULTS

SRM is more common after the birth of a boy and the subsequent live birth rate is reduced for SRM patients with a firstborn boy. The male:female ratio of children born prior and subsequent to SRM is 1.49 and 0.76 respectively. Maternal carriage of HLA-class II alleles presenting H-Y antigens to immune cells is associated with a reduced live birth rate and increased risk of obstetric complications in surviving pregnancies in SRM patients with a firstborn boy. In early pregnancy, both antibodies against HLA and H-Y antigens are increased in SRM patients compared with controls. Presence of these antibodies in early pregnancy is associated with a lower live birth rate and a low male:female ratio in subsequent live births, respectively. Births of boys are also associated with subsequent obstetric complications in the background population.

CONCLUSIONS

Epidemiological, immunogenetic and immunological studies support the hypothesis that aberrant maternal H-Y immune responses have a pathogenic role in SRM.