HLA-C antibodies in women with recurrent miscarriage suggests that antibody mediated rejection is one of the mechanisms leading to recurrent miscarriage

AbstractHLA-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

Microarrays as a diagnostic tool in prenatal screening strategies: ethical reflection

Obstetric

Assessment of human fetal cardiac autonomic nervous system development using color tissue Doppler imaging

ObjectivesFunctional development of the fetal cardiac autonomic nervous system (cANS) plays a key role in fetal maturation and can be assessed through fetal heart rate variability (fHRV)-analysis, with each HRV parameter representing different aspects of cANS activity. Current available techniques, however, are unable to assess the fHRV parameters accurately throughout the whole pregnancy. This study aims to test the feasibility of color tissue Doppler imaging (cTDI) as a new ultrasound technique for HRV analysis. Secondly, we explored time trends of fHRV parameters using this technique.Methods18 healthy singleton fetuses were examined sequentially every 8 weeks from 10 weeks GA onwards. From each examination, 3 cTDI recordings of the four-chamber view of 10 seconds were retrieved to determine accurate beat-to-beat intervals. The fHRV parameters SDNN, RMSSD, SDNN/RMSSD, and pNN10, each representing different functional aspects of the cANS, were measured, and time trends during pregnancy were explored using spline functions within a linear mixed-effects model.ResultsIn total, 77% (95% Cl 66–87%) of examinations were feasible for fHRV analysis from the first trimester onwards, which is a great improvement compared to other techniques. The technique is able to determine different maturation rates of the fHRV parameters, showing that cANS function, presumably parasympathetic activity, establishes around 20 weeks GA and matures rapidly until 30 weeks GA.ConclusionsThis is the first study able to assess cANS function through fHRV analysis from the first trimester onwards. The use of cTDI to determine beat-to-beat intervals seems feasible in just 3 clips of 10 seconds, which holds promise for future clinical use in assessing fetal well-being.Research into fetal development and medicin

Advanced paternal age is associated with an increased risk of spontaneous miscarriage: a systematic review and meta-analysis

BACKGROUND: Although spontaneous miscarriage is the most common complication of human pregnancy, potential contributing factors are not fully understood. Advanced maternal age has long been recognised as a major risk factor for miscarriage, being strongly related with fetal chromosomal abnormalities. The relation between paternal age and the risk of miscarriage is less evident, yet it is biologically plausible that an increasing number of genetic and epigenetic sperm abnormalities in older males may contribute to miscarriage. Previous meta-analyses showed associations between advanced paternal age and a broad spectrum of perinatal and paediatric outcomes. This is the first systematic review and meta-analysis on paternal age and spontaneous miscarriage.OBJECTIVE AND RATIONALE: The aim of this systematic review and meta-analysis is to evaluate the effect of paternal age on the risk of spontaneous miscarriage.SEARCH METHODS: PubMed, Embase and Cochrane databases were searched to identify relevant studies up to August 2019. The following free text and MeSH terms were used: paternal age, father's age, male age, husband's age, spontaneous abortion, spontaneous miscarriage, abortion, miscarriage, pregnancy loss, fetal loss and fetal death. PRISMA guidelines for systematic reviews and meta-analysis were followed. Original research articles in English language addressing the relation between paternal age and spontaneous miscarriage were included. Exclusion criteria were studies that solely focused on pregnancy outcomes following artificial reproductive technology (ART) and studies that did not adjust their effect estimates for at least maternal age. Risk of bias was qualitatively described for three domains: bias due to confounding, information bias and selection bias.OUTCOMES: The search resulted in 975 original articles. Ten studies met the inclusion criteria and were included in the qualitative synthesis. Nine of these studies were included in the quantitative synthesis (meta-analysis). Advanced paternal age was found to be associated with an increased risk of miscarriage. Pooled risk estimates for miscarriage for age categories 30-34, 35-39, 40-44 and >= 45 years of age were 1.04 (95% CI 0.90, 1.21), 1.15 (0.92, 1.43), 1.23 (1.06, 1.43) and 1.43 (1.13, 1.81) respectively (reference category 25-29 years). A second meta-analysis was performed for the subgroup of studies investigating first trimester miscarriage. This showed similar pooled risk estimates for the first three age categories and a slightly higher pooled risk estimate for age category >= 45 years (1.74; 95% CI 1.26, 2.41).WIDER IMPLICATIONS: Over the last decades, childbearing at later ages has become more common. It is known that frequencies of adverse reproductive outcomes, including spontaneous miscarriage, are higher in women with advanced age. We show that advanced paternal age is also associated with an increased risk of spontaneous miscarriage. Although the paternal age effect is less pronounced than that observed with advanced maternal age and residual confounding by maternal age cannot be excluded, it may have implications for preconception counselling of couples comprising an older aged male.Cervix cance

Therapeutic plasma exchange in pregnancy: A literature review

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.Research into fetal development and medicin

Exploring gender differences among couples with unexplained recurrent pregnancy loss regarding preferences for supportive care

Background International guidelines recommend to offer supportive care during a next pregnancy to couples affected by recurrent pregnancy loss (RPL). In previous research, several options for supportive care have been identified and women's preferences have been quantified. Although it is known that RPL impacts the mental health of both partners, male preferences for supportive care have hardly been explored. Methods A cross-sectional study was conducted in couples who visited a specialized RPL clinic in the Netherlands between November 2018 and December 2019. Both members of the couples received a questionnaire that quantified their preferences for supportive care in a next pregnancy and they were asked to complete this independently from each other. Preferences for each supportive care option were analysed on a group level (by gender) and on a couple level, by comparing preferences of both partners. Results Ninety-two questionnaires (completed by 46 couples) were analysed. The overall need for supportive care indicated on a scale from 1 to 10 was 6.8 for men and 7.9 for women (P = 0.002). Both genders preferred to regularly see the same doctor with knowledge of their obstetric history, to make a plan for the first trimester and to have frequent ultrasound examinations. A lower proportion of men preferred a doctor that shows understanding (80% of men vs. 100% of women, P = 0.004) and a doctor that informs on wellbeing (72% vs. 100%, P = <= 0.000). Fewer men preferred support from friends (48% vs. 74%, P = 0.017). Thirty-seven percent of men requested more involvement of the male partner at the outpatient clinic, compared to 70% of women (P = 0.007). In 28% of couples, partners had opposing preferences regarding peer support. Conclusions While both women and men affected by RPL are in need of supportive care, their preferences may differ. Current supportive care services may not entirely address the needs of men. Health care professionals should focus on both partners and development of novel supportive care programs with specific attention for men should be considered.Gynecolog

Impaired immunomodulatory effects of seminal plasma may play a role in unexplained recurrent pregnancy loss: results of an in vitro study

Background: 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).Methods: 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. Results: 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-beta and VEGF in the seminal plasma. Conclusion: 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.Clinical epidemiolog

Identification of distinct seminal plasma cytokine profiles associated with male age and lifestyle characteristics in unexplained recurrent pregnancy loss

Background: 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). Methods: 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. Results: 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-1 alpha, IL-1 beta, IL-6, IL-8, IL-12, IL-18 and TNF-alpha, 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. Conclusion: 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.Research into fetal development and medicin

Effectiveness of a multidisciplinary clinical pathway for women with systemic lupus erythematosus and/or antiphospholipid syndrome

Objectives SLE and/or antiphospholipid syndrome (SLE/APS) are complex and rare systemic autoimmune diseases that predominantly affect women of childbearing age. Women with SLE/APS are at high risk of developing complications during pregnancy. Therefore, clinical practice guidelines recommend that patients with SLE/APS should receive multidisciplinary counselling before getting pregnant. We investigated the clinical effectiveness of implementing a multidisciplinary clinical pathway including prepregnancy counselling of patients with SLE/APS. Methods A clinical pathway with specific evaluation and prepregnancy counselling for patients with SLE/APS was developed and implemented in a tertiary, academic hospital setting. Patients were prospectively managed within the clinical pathway from 2014 onwards and compared with a retrospective cohort of patients that was not managed in a clinical pathway. Primary outcome was a combined outcome of disease flares for SLE and thromboembolic events for APS. Secondary outcomes were maternal and fetal pregnancy complications. Results Seventy-eight patients with 112 pregnancies were included in this study. The primary combined outcome was significantly lower in the pathway cohort (adjusted OR (aOR) 0.20 (95% CI 0.06 to 0.75)) which was predominantly determined by a fivefold risk reduction of SLE flares (aOR 0.22 (95% CI 0.04 to 1.09)). Maternal and fetal pregnancy complications were not different between the cohorts (respectively, aOR 0.91 (95% CI 0.38 to 2.17) and aOR 1.26 (95% CI 0.55 to 2.88)). Conclusions The outcomes of this study suggest that patients with SLE/APS with a pregnancy wish benefit from a multidisciplinary clinical pathway including prepregnancy counselling.Research into fetal development and medicin

Evaluating the role of paternal factors in aetiology and prognosis of recurrent pregnancy loss: Study protocol for a hospital-based multicentre case-control study and cohort study (REMI III project)

Introduction Recurrent pregnancy loss (RPL) is defined as the spontaneous demise of two or more pregnancies before the fetus reaches viability. Despite investigation of multiple known maternal risk factors, in more than 50% of couples, this condition remains unexplained. Studies focusing on paternal factors in RPL are scarce, and therefore, paternal evaluation in RPL is currently very limited. However, regarding single miscarriage, there are multiple publications suggesting a contributive role of paternal factors. In this project, we aim to identify paternal factors associated with RPL and to improve couple-specific prediction of future pregnancy outcomes by developing a prediction model containing both maternal and paternal factors. Methods and analysis In a case-control design, the relation between unexplained RPL and paternal age, lifestyle factors, sperm DNA damage and immunomodulatory factors in peripheral blood and semen will be studied. Prospectively, 135 couples with naturally conceived unexplained RPL (cases) and 135 fertile couples without a history of pregnancy loss (controls) will be included, with collection of paternal blood and semen samples and documentation of clinical and lifestyle characteristics. In addition, 600 couples from both groups will be included retrospectively. To adjust for confounders, multivariate logistic regression will be used. The predictive value of paternal and maternal factors will be studied in the total RPL cohort consisting of approximately 735 couples. The primary outcome of the cohort study is live birth within 5 years after initial visit of the clinic. Secondary outcomes are ongoing pregnancy, time interval until next pregnancy and pregnancy complications. Ethics and dissemination This project is approved by the Medical Research Ethics Committee