Not applicable.

Background/Aims: To determine the composition of the vaginal wall and to explore the connective tissue layer, muscularis and basement membrane in relation to the pathogenesis of pelvic organ prolapse (POP). Methods: We performed a histopathological study with respect to the composition of the vaginal wall of 33 patients and 9 controls. Tissue samples from the vaginal wall were analysed for collagens II and IV, desmin, elastin, fibronectin, smooth muscle actin (SMA) and transforming growth factor (TGF)-β1 using (immuno)histochemistry. Morphometric analyses were also performed. Results: Morphometric characteristics and expression of SMA, TGF-β1, elastin and collagen II were significantly altered in women with POP. Conclusion: Our results suggest that there could be an altered tissue composition of the vaginal wall in women with POP. SMA expression could play a role in the pathogenesis of POP. The alterations in elastin and TGF-β1 expression are likely a result of POP.

Microdeletions of the Y chromosome (YCMs), Klinefelter syndrome (47,XXY), and CFTR mutations are known genetic causes of severe male infertility, but the majority of cases remain idiopathic. Here, we describe a novel method using single molecule Molecular Inversion Probes (smMIPs), to screen infertile men for mutations and copy number variations affecting known disease genes. We designed a set of 4,525 smMIPs targeting the coding regions of causal (n = 6) and candidate (n = 101) male infertility genes. After extensive validation, we screened 1,112 idiopathic infertile men with non-obstructive azoospermia or severe oligozoospermia. In addition to five chromosome YCMs and six other sex chromosomal anomalies, we identified five patients with rare recessive mutations in CFTR as well as a patient with a rare heterozygous frameshift mutation in SYCP3 that may be of clinical relevance. This results in a genetic diagnosis in 11-17 patients (1%-1.5%), a yield that may increase significantly when more genes are confidently linked to male infertility. In conclusion, we developed a flexible and scalable method to reliably detect genetic causes of male infertility. The assay consolidates the detection of different types of genetic variation while increasing the diagnostic yield and detection precision at the same or lower price compared with currently used methods.

Not applicable.

A retrospective cohort study was performed with the followings aims: to evaluate the influence of paternal age on best embryo quality available for embryo transfer on the third day; biochemical pregnancy rate; miscarriage rate and ongoing pregnancy rate at 8 weeks' gestational age, after IVF or intracytoplasmic sperm injection (ICSI) treatment, respectively, including treatment with non-ejaculated spermatozoa. In total, 7051 first IVF/ICSI cycles in Radboud university medical center, between 1 January 2001 and 1 June 2013 were included in this study. A statistical model was used to analyse the effect of paternal age and maternal age. No statistically significant differences between the paternal age groups were found with respect to the probability of an ongoing pregnancy after the first cycle (35-44 years: odds ratio [OR] = 0.97 [95% confidence interval [CI]: 0.86 to 1.10] and ≥45 years: OR = 1.01 [95% CI: 0.82 to 1.26]), respectively, compared with <35 years of age (control). Similar results were found with respect to paternal age and the availability of a top quality embryo for transfer, biochemical pregnancy and miscarriage. However, live birth was not taken into account. In conclusion, paternal age did not affect ongoing pregnancy rates in first IVF/ICSI cycles.

STUDY QUESTION Are there more de novo mutations (DNMs) present in the genomes of children born through medical assisted reproduction (MAR) compared to spontaneously conceived children? SUMMARY ANSWER In this pilot study, no statistically significant difference was observed in the number of DNMs observed in the genomes of MAR children versus spontaneously conceived children. WHAT IS KNOWN ALREADY DNMs are known to play a major role in sporadic disorders with reduced fitness such as severe developmental disorders, including intellectual disability and epilepsy. Advanced paternal age is known to place offspring at increased disease risk, amongst others by increasing the number of DNMs in their genome. There are very few studies reporting on the effect of MAR on the number of DNMs in the offspring, especially when male infertility is known to be affecting the potential fathers. With delayed parenthood an ongoing epidemiological trend in the 21st century, there are more children born from fathers of advanced age and more children born through MAR every day. STUDY DESIGN, SIZE, DURATION This observational pilot study was conducted from January 2015 to March 2019 in the tertiary care centre at Radboud University Medical Center. We included a total of 53 children and their respective parents, forming 49 trios (mother, father and child) and two quartets (mother, father and two siblings). One group of children was born after spontaneous conception (n = 18); a second group of children born after IVF (n = 17) and a third group of children born after ICSI combined with testicular sperm extraction (ICSI-TESE) (n = 18). In this pilot study, we also subdivided each group by paternal age, resulting in a subgroup of children born to younger fathers (&lt;35 years of age at conception) and older fathers (&gt;45 years of age at conception). PARTICIPANTS/MATERIALS, SETTING, METHODS Whole-genome sequencing (WGS) was performed on all parent-offspring trios to identify DNMs. For 34 of 53 trios/quartets, WGS was performed twice to independently detect and validate the presence of DNMs. Quality of WGS-based DNM calling was independently assessed by targeted Sanger sequencing. MAIN RESULTS AND THE ROLE OF CHANCE No significant differences were observed in the number of DNMs per child for the different methods of conception, independent of parental age at conception (multi-factorial ANOVA, f(2) = 0.17, P-value = 0.85). As expected, a clear paternal age effect was observed after adjusting for method of conception and maternal age at conception (multiple regression model, t = 5.636, P-value = 8.97 × 10−7), with on average 71 DNMs in the genomes of children born to young fathers (&lt;35 years of age) and an average of 94 DNMs in the genomes of children born to older fathers (&gt;45 years of age). LIMITATIONS, REASONS FOR CAUTION This is a pilot study and other small-scale studies have recently reported contrasting results. Larger unbiased studies are required to confirm or falsify these results. WIDER IMPLICATIONS OF THE FINDINGS This pilot study did not show an effect for the method of conception on the number of DNMs per genome in offspring. Given the role that DNMs play in disease risk, this negative result is good news for IVF and ICSI-TESE born children, if replicated in a larger cohort. STUDY FUNDING/COMPETING INTEREST(S) This research was funded by the Netherlands Organisation for Scientific Research (918-15-667) and by an Investigator Award in Science from the Wellcome Trust (209451). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER N/A.

The long-term effects on development and health in children born after TESE-ICSI procedures seem to be reassuring.

We found a similar overall prevalence of birth defects in newborns born after PESA-ICSI and TESE-ICSI. The maternal and treatment-related factors investigated did not show a significantly increased cumulative risk of birth defects.