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This study aimed to investigate the influence of hormonal treatment on the vaginal microbiome during fertility treatments. Bacterial vaginosis (BV) could affect fecundity, particularly in the in vitro fertilization (IVF) population, where negative effects on pregnancy outcomes have been reported. It is hypothesized that the hormone treatment during fertility treatments could influence the abundance of Lactobacilli, with negative effects on the pregnancy results. A total of 53 couples attending a fertility clinic in the Netherlands between July 2019 and August 2022 were included in this prospective cohort study. Vaginal samples were collected at start of treatment, oocyte retrieval or insemination from subjects undergoing intra uterine insemination (IUI) with mild ovarian stimulation, and IVF or intra cytoplasmatic sperm injection (ICSI) with controlled ovarian hyperstimulation. AmpliSens® Florocenosis/Bacterial vaginosis-FRT qPCR and 16S rRNA gene-based amplicon sequencing were performed on all samples. In total, 140 swabs were analyzed, with a median of two swabs per person. 33 (24%) tested qPCR BV positive. Lactobacilli percentage decreased during fertility treatments, leading to changes in the vaginal microbiome. Shannon diversity index was not significantly different. Of the total of 53 persons, nine switched from qPCR BV negative to positive during treatment. The persons switching to qPCR BV positive had already a (not significant) higher Shannon diversity index at start of treatment. If the vaginal microbiome of persons deteriorates during fertility treatments, timing of following treatments, lifestyle modifications, or a freeze all strategy could be of possible benefit. [ABSTRACT FROM AUTHOR]

HLA-G expressed by trophoblasts at the fetal-maternal interface and its soluble form have immunomodulatory effects. HLA-G expression depends on the combination of DNA polymorphisms. We hypothesized that combinations of specific single nucleotide polymorphisms (SNPs) in the 3′untranslated region (3′UTR) of HLA-G play a role in unexplained recurrent miscarriage. In a case control design, 100 cases with at least three unexplained consecutive miscarriages prior to the 20th week of gestation were included. Cases were at time of the third miscarriage younger than 36 years, and they conceived all their pregnancies from the same partner. The control group included 89 women with an uneventful pregnancy. The association of HLA-G 3′UTR SNPs and specific HLA-G haplotype with recurrent miscarriage was studied with logistic regression. Odds ratios (OR) and 95% confidence intervals (95% CI) were reported. Individual SNPs were not significantly associated with recurrent miscarriage after correction for multiple comparisons. However, the presence of the UTR-4 haplotype, which included +3003C, was significantly lower in women with recurrent miscarriage (OR 0.4, 95% CI 0.2–0.8, p  = 0.015). In conclusion, this is the first study to perform a comprehensive analysis of HLA-G SNPs and HLA-G haplotypes in a well-defined group of women with recurrent miscarriage and women with uneventful pregnancy. The UTR-4 haplotype was less frequently observed in women with recurrent miscarriage, suggesting an immunoregulatory role of this haplotype for continuation of the pregnancy without complications. Thus, association of HLA-G with recurrent miscarriage is not related to single polymorphisms in the 3′UTR, but is rather dependent on haplotypes. [ABSTRACT FROM AUTHOR]

Therapeutic plasma exchange (TPE) is indicated as a treatment for a wide array of diseases, extensively addressed in the Guidelines of the American Society for Apheresis. In pregnancy, TPE is an uncommon event and application is largely based on extrapolation of efficacy and safety in a non-pregnant population. This review intends to describe the currently available experience of TPE in pregnancy to help clinicians recognise indications during pregnancy and to support current guideline recommendations with literature-based experiences. In order to identify the clinical indications for which TPE is applied in pregnant women, we performed a literature search including studies till November 2019, without a start date restriction. Data extraction included medical indication for TPE and safety of TPE in pregnant women. 279 studies were included for analysis. Nowadays, TPE is predominantly applied for thrombotic microangiopathies, lipid disorders and a variety of autoimmune diseases. The application of TPE during pregnancy remains largely empiric and relies on individual case reports in the absence of high-quality studies and definitive evidence-based guidelines. Safety profile of TPE during pregnancy appears to be comparable to application of TPE in non-pregnant patients. In conclusion, based on the limited evidence that we found in literature with a high risk of publication bias, TPE procedures can be used safely during pregnancy with the appropriate preparation and experience of a multidisciplinary team. [ABSTRACT FROM AUTHOR]

• At population level, women with unexplained recurrent miscarriage had less oral sex. • Oral sex seems to influence pregnancy outcome in a proportion of the women. • Oral sex might induce maternal tolerance towards paternal antigens of the fetus. A possible way of immunomodulation of the maternal immune system before pregnancy would be exposure to paternal antigens via seminal fluid to oral mucosa. We hypothesized that women with recurrent miscarriage have had less oral sex compared to women with uneventful pregnancy. In a matched case control study, 97 women with at least three unexplained consecutive miscarriages prior to the 20th week of gestation with the same partner were included. Cases were younger than 36 years at time of the third miscarriage. The control group included 137 matched women with an uneventful pregnancy. The association between oral sex and recurrent miscarriage was assessed with conditional logistic regression, odds ratios (ORs) were estimated. Missing data were imputed using Imputation by Chained Equations. In the matched analysis, 41 out of 72 women with recurrent miscarriage had have oral sex, whereas 70 out of 96 matched controls answered positive to this question (56.9% vs. 72.9%, OR 0.50 95%CI 0.25−0.97, p = 0.04). After imputation of missing exposure data (51.7%), the association became weaker (OR 0.67, 95%CI 0.36–1.24, p = 0.21). In conclusion, this study suggests a possible protective role of oral sex in the occurrence of recurrent miscarriage in a proportion of the cases. Future studies in women with recurrent miscarriage explained by immune abnormalities should reveal whether oral exposure to seminal plasma indeed modifies the maternal immune system, resulting in more live births. [ABSTRACT FROM AUTHOR]

Objective: The aim of our study is to explore whether the cerebral growth is delayed in fetuses with congenital heart defects (CHD) in the second and early third trimester.Methods: A prospective cohort study was conducted in 77 CHD cases, with 75 healthy controls. 3D cerebral volume acquisition was performed sequentially. The volumes of the fetal hemicerebrum and extracerebral fluid were compared by linear regression analysis, and the Sylvian fissure was measured.Results: Between 19 and 32 weeks of gestation, 158 measurements in cases and 183 measurements in controls were performed (mean 2.2/subject). The volume growth of the hemicerebrum (R2 = 0.95 vs. 0.95; p = 0.9) and the extracerebral fluid (R2 = 0.84 vs. 0.82, p = 0.9) were similar. Fetuses with abnormal oxygen delivery to the brain have a slightly smaller brain at 20 weeks of gestation (p = 0.02), but this difference disappeared with advancing gestation. CHD cases demonstrated a slightly shallower Sylvian fissure (mean ratio 0.146 vs. 0.153; p = 0.004).Conclusions: Our study shows no differences in cerebral growth, studied in an unselected cohort, with successive cases of isolated CHD. Even in the severest CHD cases, cerebral size is similar in the early third trimester. The cause and meaning of a shallower Sylvian fissure is unclear; possibly, it is a marker for delayed cerebral maturation or it might be an expression of decreasing amount of extracerebral fluid. [ABSTRACT FROM AUTHOR]

HLA-C is the only polymorphic classical HLA I antigen expressed on trophoblast cells. It is known that higher incidence of C4d deposition on trophoblast cells is present in women with recurrent miscarriage. C4d is a footprint of antibody-mediated classical complement activation. Therefore, this study hypothesize that antibodies against HLA-C may play a role in the occurrence of unexplained consecutive recurrent miscarriage. Present case control study compared the incidence of HLA-C specific antibodies in 95 women with at least three consecutive miscarriages and 105 women with uneventful pregnancy. In the first trimester of the next pregnancy, presence and specificity of HLA antibodies were determined and their complement fixing ability. The incidence of HLA antibodies was compared with uni- and multivariate logistic regression models adjusting for possible confounders. Although in general a higher incidence of HLA antibodies was found in women with recurrent miscarriage 31.6% vs. in control subjects 9.5% (adjusted OR 4.3, 95% CI 2.0–9.5), the contribution of antibodies against HLA-C was significantly higher in women with recurrent miscarriage (9.5%) compared to women with uneventful pregnancy (1%) (adjusted OR 11.0, 95% CI 1.3–89.0). In contrast to the control group, HLA-C antibodies in the recurrent miscarriage group were more often able to bind complement. The higher incidence of antibodies specific for HLA-C in women with recurrent miscarriage suggests that HLA-C antibodies may be involved in the aetiology of unexplained consecutive recurrent miscarriage. [ABSTRACT FROM AUTHOR]

Seminal plasma contains signaling molecules capable of modulating the maternal immune environment to support implantation and pregnancy. Prior studies indicated that seminal plasma induces changes in gene transcription of maternal immune cells. Reduced immune suppressive capacity may lead to pregnancy loss. The aim of this study was to investigate the immunomodulating effects of seminal plasma on T cells and monocytes in the context of recurrent pregnancy loss (RPL). Female T cells and monocytes were incubated with seminal plasma of 20 males in unexplained RPL couples (RPL males) and of 11 males whose partners had ongoing pregnancies (control males). The effect of seminal plasma on messenger RNA (mRNA) expression of immune cells was measured. Levels of mRNA expression were related to key signaling molecules present in the seminal plasma. Agglomerative hierarchical cluster analysis was performed on seminal plasma expression profiles and on mRNA expression profiles. Expression of CD25 and anti-inflammatory IL-10 by female T cells was significantly lower after stimulation with seminal plasma of RPL males compared to control males. Female monocytes treated with seminal plasma of RPL males showed an immune activation signature of relatively elevated HLA-DR expression. Expression of these T cell and monocyte components was particularly correlated with the amounts of TGF-β and VEGF in the seminal plasma. Our findings indicate that seminal plasma has immunomodulating properties on female immune cells compatible with the induction of a more regulatory phenotype, which may be impaired in cases of unexplained RPL. • Seminal plasma (SP) induced changes in gene expression of female immune cells. • Changes in gene expression compatible with induction of more regulatory phenotype. • Immunomodulatory effects of SP impaired in unexplained recurrent pregnancy loss. • Immunomodulatory effects of SP correlated with immunological factors present in SP. [ABSTRACT FROM AUTHOR]

• A subgroup of men in couples with unexplained recurrent pregnancy loss (RPL) have high pro-inflammatory seminal plasma expression profiles. • Men with the high pro-inflammatory seminal plasma profile are significantly older and have more unfavorable lifestyle characteristics. • Cytokine expression profiles in the seminal plasma may be useful for diagnostic and prognostic purposes in couples with unexplained RPL. Seminal plasma contains a wide range of cytokines, chemokines and growth factors. Part of these signalling molecules assist in inducing a state of active maternal immune tolerance towards the fetus. Disbalances in seminal plasma content may contribute to pregnancy loss. This study investigated cytokine expression profiles in seminal plasma of male partners of couples with unexplained recurrent pregnancy loss (RPL) and the association with clinical and lifestyle characteristics, including smoking, alcohol consumption and body mass index (BMI). In the seminal plasma of 52 men who visited a specialised RPL clinic the levels of 25 pre-selected cytokines, chemokines and growth factors were measured by Bio-Plex assay or ELISA. Two-way hierarchical cluster analysis was performed. Identified patient clusters were compared on clinical and lifestyle characteristics. Two distinct cytokine expression profiles in the seminal plasma were revealed by cluster analysis. Patient cluster I showed relatively higher levels of pro-inflammatory cytokines, including IL-1α, IL-1β, IL-6, IL-8, IL-12, IL-18 and TNF-α, compared to Patient cluster II. Men belonging to Patient cluster I were significantly older and had significantly more lifestyle risk factors compared to men in Patient cluster II. Cluster analysis suggested the existence of a less favourable pro-inflammatory cytokine expression profile, being present in part of men affected by RPL and associated with advanced male age and lifestyle risk factors. These findings may serve as a starting point for further research into underlying mechanisms and ultimately lead to novel diagnostic and therapeutic approaches for couples with RPL. [ABSTRACT FROM AUTHOR]

Smoking during pregnancy is associated with a multitude of health behaviors and with the psychosocial and socio-economic circumstances of pregnant women. Limited research has so far been conducted on the clustering of these characteristics and on their effect on pregnancy outcomes. This study aimed to identify different groups of pregnant women based on their behavioral, psychosocial and socio-economic characteristics and their pregnancy outcomes. In total, 2455 women who were 12 weeks pregnant completed a questionnaire on smoking behavior, health behaviors and psychosocial and socio-economic characteristics. Neonatal and maternal outcomes were extracted from the Dutch perinatal registration. Subgroups were identified with latent class analysis and adverse pregnancy outcomes were compared between subgroups with logistic regression. Women were classified into four latent classes. Two classes represented the healthy higher-educated pregnant women who did not smoke: one group of multigravida women and one of primigravida women, also characterized by less pregnancy-specific knowledge and more pregnancy-related stress. The remaining women were grouped into two less healthy groups. One group frequently quit smoking, reported less healthy eating, less physical activity and comparable stress levels as the healthy higher-educated groups. The last group contained the most smokers, had the highest scores on psychosocial and pregnancy-related stress and the most adverse socio-economic circumstances. This group had an increased risk of adverse maternal outcomes, in particular developing diabetes during pregnancy. A comprehensive and integrated approach is needed to improve outcomes in pregnancies with a combination of adverse health, psychosocial, and socio-economic conditions. [ABSTRACT FROM AUTHOR]