Dysregulation of the interleukin-17A pathway in endometrial tissue from women with unexplained infertility affects pregnancy outcome following assisted reproductive treatment.

STUDY QUESTION: Which transcriptomic alterations in mid-luteal endometrial scratch biopsies, taken prior to the assisted reproductive treatment (ART) treatment cycle are associated with unsuccessful pregnancy? SUMMARY ANSWER: Dysregulated interleukin-17 (IL-17) pathway components are demonstrated in women who fail to become pregnant after ART. WHAT IS KNOWN ALREADY: Implantation failure is now recognised as a critical factor in unexplained infertility and may be an important component of failed ART. STUDY DESIGN, SIZE, DURATION: Using a prospective longitudinal study design, 29 nulliparous women with unexplained infertility undergoing ART were recruited between October 2016 and February 2018. Mid-luteal stage endometrium and matched serum samples were collected, and patients underwent a single embryo transfer in the subsequent cycle. RNA-seq analysis of endometrial biopsies was performed on the discovery cohort (n = 20). PARTICIPANTS/MATERIALS, SETTING, METHODS: Gene set enrichment analysis of the differentially expressed genes (DEGs) was performed. Endometrium and serum were then prepared for IL-17A analysis by ELISA. MAIN RESULTS AND THE ROLE OF CHANCE: There were 204 differentially expressed protein-coding genes identified in tissue from women who became pregnant (n = 9) compared with tissue from women who failed to become pregnant (n = 11) (false discovery rate; P < 0.05). Of the 204 DEGs, 166 were decreased while 38 were increased in the pregnant compared to the non-pregnant groups. Gene set enrichment analysis of the DEGs identified an over-representation of IL-17 and Pl3K-Akt signalling pathways. All the DEGs within the IL-17 signalling pathway (MMP3, MMP1, IL1ß, LCN2, S100A9 and FOSL1) demonstrated decreased expression in the pregnant group. Serum IL-17 protein levels were increased in the non-pregnant discovery cohort (n = 11) and these findings were confirmed a validation cohort (n = 9). LIMITATIONS, REASONS FOR CAUTION: Limitations of our study include the cohort size and the lack of aneuploidy data for the embryos; however, all embryos transferred were single good or top-quality blastocysts. WIDER IMPLICATIONS OF THE FINDINGS: These findings demonstrate dysregulated IL-17 pathway components in women who fail to become pregnant after ART. Elevated serum levels of the pro-inflammatory cytokine IL-17 may predict failure of ART in women with unexplained infertility. Future trials of anti-IL-17 therapies in this cohort warrant further investigation. STUDY FUNDING/COMPETING INTEREST(S): Funding from the UCD Wellcome Institutional Strategic Support Fund, which was financed jointly by University College Dublin and the SFI-HRB-Wellcome Biomedical Research Partnership (ref 204844/Z/16/Z), is acknowledged. The authors have no competing interests. TRIAL REGISTRATION NUMBER: NA.

CA125 measured during menstruation can be misleading.

The aim of these case reports and literature review is to report the importance of cyclical variation of serum CA-125 levels in two patients with endometriosis. Two case reports and a literature review of cyclical variation in serum CA-125 levels are discussed. There was significant variation in serum CA-125 levels taken during menses and mid-cycle in these two cases. Serum CA-125 levels increase dramatically during menstruation in women with endometriosis. This is important when assessing disease status.

Uptake of the Influenza Vaccination in Pregnancy.

Influenza is caused by a highly infectious RNA virus, which usually occurs in a seasonal pattern with epidemics in the winter months. The objective of this study was to determine the uptake of the influenza vaccine in a pregnant population and ascertain the reasons why some women did not receive it. A prospective cohort study was conducted over a two-week period in January 2016 in the National Maternity Hospital Dublin, a tertiary referral maternity hospital delivering over 9000 infants per year. There were 504 women studied over the 2-week period. Overall, 197(39.1%) women received the vaccine at a mean gestational age 20.9 weeks (SD 7.0). Given the increased rates of influenza in the community and the associated implications for mother and infant, it is important that pregnant women are educated regarding the risks of influenza in pregnancy and encourage this cohort to be vaccinated.

Probiotic therapy in couples with infertility: A systematic review.

The reproductive microbiome is becoming increasingly recognised for its influence on fertility. While there has been much work to investigate the treatment of bacterial vaginosis and disordered microbiomes in optimizing outcomes in Assisted Reproductive Technology (ART), the role of routinely prescribed probiotics is yet to be established. The therapeutic potential of probiotic therapy remains an exciting opportunity in ART and this review endeavours to summarise its evidence to date. A systematic review of MEDLINE (Pubmed), Allied Health Literature (CINAHL), EMBASE, Web of Science and the Cochrane database was performed on 7th May 2019, and repeated on 26th August 2019. The search was built using the terms 'subfertility;' 'probiotic therapy;' 'clinical pregnancy rate' and 'assisted reproductive outcomes.' The primary outcome was change in clinical pregnancy rate. Secondary outcomes included improvements in male and female fertility parameters and microbial assessment. The initial search found 882 articles, of which 26 full manuscripts were reviewed. Four articles were eligible for inclusion. Of the two studies that reported the primary outcome, only one study found probiotics increased the clinical pregnancy rate non-significantly (48.0%-58.8%, p = 0.47). It also found higher miscarriage rate (30 % vs 16.6 %, p = 0.47) in the group treated with probiotics. Both studies on males with oral probiotic found significantly improved sperm motility. While benefit in sperm motility has been observed with male probiotic therapy, there is conflicting evidence on the efficacy of probiotic therapy for women undergoing assisted reproduction. High quality randomized studies are needed to definitively examine probiotic therapy and establish its benefit for couples undergoing assisted reproduction.

Vitamin D supplementation in pregnancy-a survey of compliance with recommendations.

BACKGROUND: Vitamin D deficiency in pregnancy has important maternal and fetal implications, with increased risk of developing gestational diabetes, preeclampsia, preterm birth and small for gestational age birthweight. It is recommended that every pregnant woman should take 5 µg (200 IU) of vitamin D per day during pregnancy and lactation. AIMS: This study aimed to determine the prevalence of women taking vitamin D supplementation and to identify the reasons for patients not taking supplementation within women attending an antenatal clinic in Dublin. METHODS: Survey of women attending the antenatal clinic of the National Maternity Hospital Dublin during 2 weeks in January 2017. Women were asked to record demographics, medical comorbidities and use of vitamin D supplementation or any other supplements in pregnancy, as well as reasons for non-use if appropriate. RESULTS: Three hundred women were invited to participate and 175 completed the questionnaire (58%). Overall, 38.9% (n = 68) reported to be taking vitamin D supplementation. Of the women that reported not to be taking vitamin D supplementation, 57.9% (n = 62) were taking a pregnancy multivitamin that contained vitamin D, and 28.0% (n = 30) did not know that it was recommended in pregnancy. Therefore, a total of 45 women (25.7%) in our cohort were taking no vitamin D supplementation during pregnancy. There was no difference in non-use based on maternal age, BMI, parity, or country of origin. CONCLUSIONS: Of the women surveyed, 74.3% reported supplementation with vitamin D, either knowingly or unknowingly. Public health initiatives need to utilize this relatively safe, low-cost intervention to maximize maternal and fetal health. This could reduce the rates of antenatal conditions with associated high morbidity and healthcare burden such as gestational diabetes and preeclampsia.

Maternal body mass index and spontaneous contractility of human myometrium in pregnancy.

OBJECTIVE: There is controversy as to whether maternal body mass index (BMI) influences the contractility of human myometrium in pregnancy. The aim of this study was to examine spontaneous contractile activity of human pregnant myometrium in vitro, with respect to maternal BMI. STUDY DESIGN: Myometrial tissue specimens were obtained at cesarean delivery from 74 women with BMI values ranging from 19 to 50.1 kg m-2. By recording in vitro from eight strips per donor (590 strips in total), several parameters of spontaneous contractile activity were monitored. The relationship between BMI and contractility was evaluated using linear regression analysis. RESULTS: There was a significant correlation between maximum amplitude (P=0.007) and mean contractile force (P=0.001) with increasing BMI. However, the time to onset of contractions (P=0.009), and time taken to reach maximal amplitude (P=0.020) also increased with increasing BMI. No significant correlation was observed with BMI for other parameters studied. The mean maximum amplitude value for spontaneous contractions was 37±1 mN, the mean contractile force for spontaneous contractions was 4.1±0.1 mN, the average time to the first spontaneous contraction was 11.3±0.6 min and the average frequency of contractions was 6.5±0.2 per hour. CONCLUSIONS: These results suggest that the time to onset of contractions is increased with increasing maternal BMI, but that the force developed is greater. In all other respects, human uterine contractility is unaffected by increasing BMI. These findings underline the complexity of regulation of uterine contractility in labor with elevated maternal BMI.

An international assessment of trainee experience, confidence, and comfort in operative vaginal delivery.

AIM: The aim of this study was to assess Irish and Canadian obstetricians in training ("trainees") experience, confidence, and comfort in performing operative vaginal delivery (OVD). STUDY DESIGN: Trainees in Obstetrics and Gynaecology in the University of Toronto and the Royal College of Physicians of Ireland (RCPI) were invited to participate in an anonymous online survey reviewing experience as primary operator of OVD. Trainee confidence and comfort was self-assessed based upon their last few OVDs. RESULTS: The response rate was 55% amongst Canadian trainees (31/56) and 44% amongst Irish trainees (21/48). When comparing Irish with Canadian trainee experience, the median numbers of vacuum and forceps deliveries performed by Irish trainees as primary operator were reported to be higher [125 (range 10-150) vs 20 (range 5-40); p < 0.0001 (ventouse), 45 (range 10-150) vs 6 (range 1-12); p = 0.0001 (forceps)]. Despite this, trainee confidence between the groups did not differ [confidence score: 18.7 (SD 3.2) vs 17.8 (SD 3.5), p = 0.3]. There were some differences regarding comfort in certain aspects of OVD, most notably increased comfort in Irish trainees in pre-procedure assessment skills of OVD. CONCLUSION: With falling OVD rates worldwide, training experience is declining. Despite higher numbers of OVD within the Irish trainee group, there was no difference in trainee confidence between the two groups. These results suggest that a high number of cases as primary operator may not be required to establish operator confidence in performing a procedure. Irish trainees self-reported more comfort in non-technical skills of OVD, suggesting a step-wise effect of experience on first technical and then non-technical skills.

Thrombin-induced association of SHP-2 with multiple tyrosine-phosphorylated proteins in human platelets.

SH2 domain containing phosphatase-2 (SHP-2) has an important regulatory role in a variety of cell types. However, little is known concerning its function in platelets. We show here that, in thrombin-stimulated human platelets, SHP-2 undergoes a time-dependent association with platelet endothelial cell adhesion molecule-1 (PECAM-1) and four low molecular weight phosphoproteins which are attenuated by the Src kinase inhibitor PP1. The low molecular weight proteins, which may be transmembrane proteins, are shown to bind exclusively to the N-terminal SH2 domain of SHP-2 and are therefore possible activators of the phosphatase. In addition, SHP-2 phosphatase activity is shown to be increased following thrombin stimulation or cross-linking of PECAM.