Identifying discrepancies between clinical practice and evidence-based guideline in recurrent pregnancy loss care, a tool for clinical guideline implementation.

BACKGROUND: Practice variation in recurrent pregnancy loss (RPL) care is common. International guidelines vary in their recommendations for the management of RPL couples, which could lead to an increase of cross border reproductive care. Currently, the Dutch RPL guideline is being adapted from the European Society for Human Reproduction and Embryology (ESHRE) guideline. We aim to identify discrepancies between RPL guidelines and RPL practice. These discrepancies could be considered in the development of a new guideline and implementation strategies to promote adherence to new recommendations. METHODS: A nationwide survey on the management of RPL patients was conducted across all 107 hospital-based obstetrics and gynaecology practices in the Netherlands. The survey was sent via the Dutch Society for Obstetricians and Gynaecologists to all affiliated clinicians. The questionnaire consisted of 36 questions divided in four sections: clinician's demographics, RPL definition, investigations and therapy. The data were compared to the recommendations given by the Dutch national guideline and the most recent guideline of the ESHRE. RESULTS: All hospital-based practices (100%; n = 107) filled in the online questionnaire. The majority of respondents defined RPL similarly, as two or more pregnancy losses (87.4%), not obligatory consecutive (93.1%). More than half of respondents routinely perform thrombophilia screening ( 58%), although not advised by the ESHRE, while thyroid function (57%), thyroid auto-immunity (27%) and ß2-glycoprotein antibodies (42%) in the context of antiphospholipid syndrome (APS) are recommended but investigated less often. Regarding parental karyotyping, 20% of respondents stated they always perform parental karyotyping, without prior risk assessment. because of RPL. Treatment for hereditary thrombophilia was frequently (43.8% (n = 137)) prescribed although not recommended. And finally, a considerable part (12-16%) of respondents prescribe medication in case of unexplained RPL. CONCLUSION: While many clinicians perform investigations recommended by the ESHRE, there is a considerable variation of RPL practice in the Netherlands. We identified discrepancies between RPL guidelines and RPL practice, providing possibilities to focus on multifaceted implementation strategies, such as educational intervention, local consensus processes and auditing and feedback. This will improve the quality of care provided to RPL patients and may diminish the necessity felt by patients to turn to multiple opinions or cross border reproductive care.

External validation of a frequently used prediction model for ongoing pregnancy in couples with unexplained recurrent pregnancy loss.

STUDY QUESTION: What is the predictive performance of a currently recommended prediction model in an external Dutch cohort of couples with unexplained recurrent pregnancy loss (RPL)? SUMMARY ANSWER: The model shows poor predictive performance on a new population; it overestimates, predicts too extremely and has a poor discriminative ability. WHAT IS KNOWN ALREADY: In 50-75% of couples with RPL, no risk factor or cause can be determined and RPL remains unexplained. Clinical management in RPL is primarily focused on providing supportive care, in which counselling on prognosis is a main pillar. A frequently used prediction model for unexplained RPL, developed by Brigham et al. in 1999, estimates the chance of a successful pregnancy based on number of previous pregnancy losses and maternal age. This prediction model has never been externally validated. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study consisted of 739 couples with unexplained RPL who visited the RPL clinic of the Leiden University Medical Centre between 2004 and 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS: Unexplained RPL was defined as the loss of two or more pregnancies before 24 weeks, without the presence of an identifiable cause for the pregnancy losses, according to the ESHRE guideline. Obstetrical history and maternal age were noted at intake at the RPL clinic. The outcome of the first pregnancy after intake was documented. The performance of Brigham's model was evaluated through calibration and discrimination, in which the predicted pregnancy rates were compared to the observed pregnancy rates. MAIN RESULTS AND THE ROLE OF CHANCE: The cohort included 739 women with a mean age of 33.1 years (±4.7 years) and with a median of three pregnancy losses at intake (range 2-10). The mean predicted pregnancy success rate was 9.8 percentage points higher in the Brigham model than the observed pregnancy success rate in the dataset (73.9% vs 64.0% (95% CI for the 9.8% difference 6.3-13.3%)). Calibration showed overestimation of the model and too extreme predictions, with a negative calibration intercept of -0.46 (95% CI -0.62 to -0.31) and a calibration slope of 0.42 (95% CI 0.11-0.73). The discriminative ability of the model was very low with a concordance statistic of 0.55 (95% CI 0.51-0.59). Recalibration of the Brigham model hardly improved the c-statistic (0.57; 95% CI 0.53-0.62). LIMITATIONS, REASONS FOR CAUTION: This is a retrospective study in which only the first pregnancy after intake was registered. There was no time frame as inclusion criterium, which is of importance in the counselling of couples with unexplained RPL. Only cases with a known pregnancy outcome were included. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study externally validating the Brigham prognostic model that estimates the chance of a successful pregnancy in couples with unexplained RPL. The results show that the frequently used model overestimates the chances of a successful pregnancy, that predictions are too extreme on both the high and low ends and that they are not much more discriminative than random luck. There is a need for revising the prediction model to estimate the chance of a successful pregnancy in couples with unexplained RPL more accurately. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used and no competing interests were declared. TRIAL REGISTRATION NUMBER: N/A.

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.

Comparison and appraisal of (inter)national recurrent pregnancy loss guidelines.

Investigations and treatment options of recurrent pregnancy loss (RPL) differ internationally. This manuscript reviews the similarities and differences between international guidelines. The European Society of Human Reproduction and Embryology (ESHRE) guideline (2017), the American Society for Reproductive Medicine (ASRM) Committee Opinion (2013) and the Royal College of Obstetricians and Gynaecologists (RCOG) guideline (2011) were appraised using the AGREE II criteria. The guidelines were checked for definitions, risk factors, investigations and therapeutic options. The guidelines agreed on acquired thrombophilia analysis. All guidelines agreed on a regimen for the treatment of antiphospholipid antibody syndrome consisting of aspirin and heparin, but only the ESHRE guideline specified the order of starting these medications. Treatment of thrombophilia and uterine anomalies was advised against; all guidelines recommended supportive care for unexplained RPL. The guidelines did not agree on the definition of RPL and differed in investigations regarding lifestyle, karyotype analysis of parents and/or pregnancy tissue, and the diagnostic tool for uterine anomalies. All three guidelines indicate an association between lifestyle and RPL; the ESHRE recommends health behaviour changes. Couples suffering from RPL should be informed about possible investigations and treatment options, and whether those are evidence-based. It is important for clinicians to realize that the guidelines differ internationally.

Oocyte donation pregnancies with high fetal-maternal immunogenetic dissimilarity show alterations in the maternal peripheral immunoregulatory response.

Oocyte donation (OD) pregnancies result in increased fetal-maternal immunogenetic dissimilarity due to paternal and donor-derived genes. Higher fetal-maternal HLA mismatches are correlated with preeclampsia. Therefore, this study explored the maternal immune response, focusing on regulatory T cells (Tregs) during low versus high allogeneic pregnancies, and healthy versus preeclamptic OD pregnancies. Ten healthy and five preeclamptic OD pregnancies were included. Maternal peripheral blood was collected at different stages of pregnancy. Fetal-maternal HLA mismatches were determined, and immunophenotyping of peripheral blood mononuclear cells was conducted using a 22-colour spectral flow cytometry panel. Cytokines and hormones were detected in maternal plasma using ELISA and Luminex assays. The findings show similarities, but also distinct differences between low and high allogeneic healthy OD pregnancies. Early high allogeneic OD pregnancy showed reduction in Tregs, and CD8+ T cells, alongside lower percentage of effector/memory Tregs expressing PD-1 and Helios. Additionally, high allogeneic OD pregnancies showed increased IL-6 and progesterone in the first trimester. These variations suggest a different mode of immune regulation in early high allogeneic OD pregnancies, possibly to maintain healthy pregnancy. Further comparative analyses revealed reduced CD45RO+CTLA-4+ Tregs and increased latent TGF-ß1 and -ß2 levels in early preeclamptic compared to healthy OD pregnancy. Late-stage preeclamptic OD pregnancies exhibited higher frequencies of CD45RO+TIGIT+ Tregs and higher levels of TNFα, indicating both a regulatory and pro-inflammatory environment. Overall, this study sheds light on the course of various immunoregulatory key players in OD pregnancy, and expands knowledge on maternal tolerance in this particular type of pregnancy.

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-ß 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.

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-1α, IL-1ß, 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. 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.

The development of preeclampsia in oocyte donation pregnancies is related to the number of fetal-maternal HLA class II mismatches.

In oocyte donation (OD) pregnancy, a fetus can be completely allogeneic to the recipient. Consequently, the maternal immune system has to cope with greater immunogenetic dissimilarity compared to naturally conceived pregnancy. Previously, we showed an association between successful OD pregnancy and lower immunogenetic dissimilarity, reflected by the number of fetal-maternal Human Leukocyte Antigen (HLA) mismatches, than expected by chance. In this study we aimed to determine whether the development of preeclampsia in OD pregnancies is related to the number of fetal-maternal HLA mismatches. A retrospective, nested case-control study was performed within a cohort of 76 singleton OD pregnancies. Maternal and fetal umbilical cord blood was typed for HLA-A, -B, -C, -DR and -DQ, and the number of fetal-maternal HLA mismatches was calculated. In addition, the incidence of child-specific HLA antibodies was determined. 13 pregnancies were complicated by preeclampsia. To demonstrate an influence of HLA mismatches on the development of preeclampsia, a univariate logistic regression analysis was performed adjusted for maternal age and socio-economic status. A significant association between the number of fetal-maternal HLA class II mismatches and the development of preeclampsia was observed (OR = 3.8, 95 % CI: 1.6-9.0; p = 0.003). This association was not linked to the development of HLA class II antibodies. According to our findings, an increased number of HLA class II mismatches is a risk factor for the development of preeclampsia in OD pregnancies. The effect of HLA class II mismatches might be explained by the induction of a cellular rather than a humoral immune response.

[Effectiveness of progesterone in pregnancy complications]. / Effect van progesteron bij zwangerschapscomplicaties.

This commentary reflects on the effectiveness of progesterone in early pregnancy complications. Several studies have investigated the role of progesterone in women with bleeding in early pregnancy and in women with recurrent miscarriages. These publications suggests that first trimester use of progesterone is not effective to prevent miscarriages when there is blood loss in the first trimester, and that it is also not effective to prevent new miscarriages in women with recurrent miscarriages in their history. However, subgroup analysis tells us it might be effective to prevent new miscarriages in women with blood loss in the first trimester and three earlier miscarriages. Expert groups in the Netherlands are currently considering recommendations on the prescription of progesterone for women with early pregnancy complications.

[Pulmonary sequestrum--not infiltrate--in a 45-year-old woman]. / Geen pulmonaal infiltraat, maar een longsekwester bij een 45-jarige vrouw.

A 45-year-old woman presented at the emergency room with acute dyspnoea and slight fever, without coughing. The chest radiography showed a consolidation in the lower left lobe. The CT scan revealed a consolidation in the posterior-basal segment of the lower left lobe without an air bronchogram but with various densities. Based on these findings, the possibility of pulmonary sequestration was considered. A CT scan showed an arterial branch arising from the aorta that supplied the consolidation, confirming pulmonary sequestration. The patient underwent resection of the intralobar sequestrum, after which she recovered and was asymptomatic. Pulmonary sequestration should be considered in any patient with pneumonia or recurrent pneumonia in the lower lobes of the lung, especially in the absence of an air bronchogram or signs of endobronchial obstruction. The treatment ofchoice is surgical resection.

What are people really eating? The relation between energy intake derived from estimated diet records and intake determined to maintain body weight.

Two hundred sixty-six free-living human volunteers, 21-64 y old, were trained by dietitians to record daily their food intake for at least 7 d. Subsequently, they were fed diets of conventional foods adjusted in amounts to maintain their body weight for greater than or equal to 45 d. Comparing their estimated energy intake with the intake determined to maintain weight yielded mean differences of 2365 and 1792 kJ (565 and 428 kcal) in men and women, respectively, representing an underreporting of 18%. Twenty-two individuals (8%) overestimated and 29 (11%) were accurate to within 419 kJ (100 kcal) of their maintenance requirement. The remaining 215 individuals (81%) reported their habitual intake at 2930 +/- 1586 kJ (700 +/- 379 kcal) below that subsequently determined as their maintenance requirement. These findings suggest caution in the interpretation of food-consumption data.

Vitamin E in foods from high and low linoleic acid diets.

As part of a human diet study, vitamin E activity was estimated in foods used in seven daily menus. Each menu was designed to contain 35% fat calories with either 10 or 30 gm/day of linoleic acid (18:2) and 500 mg/day of cholesterol. To estimate vitamin E activity, each food used in the menus was analyzed for alpha and gamma tocopherol content by high-pressure liquid chromatography with fluorescence detection. This article reports the alpha and gamma tocopherol contents of those foods, tocopherol contributions from each food in one sample 2,400-kcal menu, and the mean daily vitamin E activity (milligram alpha tocopherol equivalents) of all seven menus at five caloric levels. Major sources of alpha tocopherol (greater than 10% of the RDA) common to both diets (10 and 30 gm linoleic acid) were olive oil and a few fruits and vegetables. Additional major sources in the 30-gm linoleic acid diets were polyunsaturated fatty acid (PUFA) vegetable oils and margarine. Contrary to a common assumption, increasing the level of PUFA in the menus did not necessarily result in higher milligram equivalents of alpha tocopherol because soybean oil, with a tocopherol composition that is predominantly gamma tocopherol, was the major source of linoleic acid in the diets. Thus, vitamin E activity was not necessarily increased when soybean oil was substituted for a less saturated fat such as olive oil, which has mostly alpha tocopherol.

The value of hysteroscopy in the diagnostic approach to a rudimentary horn pregnancy.

A 33-year-old woman presented with an ectopic pregnancy without any complaints. Laparoscopy was performed since a tubal pregnancy was expected. However, both fallopian tubes appeared normal and it was not possible to differentiate accurately between a pregnancy in a non-communicating horn and a pregnancy in a bicornuate uterus. We therefore performed MRI which showed a thin myometrium around the pregnancy. In order to differentiate between a communicating and a non-communicating uterine horn the authors performed a hysteroscopy. Since there was only one cervical os, and an entrance to the second uterine cavity was not seen along the cervical canal, it was concluded that this pregnancy was situated in a non-communicating rudimentary horn. The non-communicating uterine horn, with the pregnancy in situ, was completely removed. Since a pregnancy in a bicornuate uterus is viable in contrast to a pregnancy in a non-communicating horn, accurate diagnosis is important.

Clinical and immunologic aspects of egg donation pregnancies: a systematic review.

BACKGROUND: Egg donation (ED) makes it possible for subfertile women to conceive. Pregnancies achieved using ED with unrelated donors are unique, since the entire fetal genome is allogeneic to the mother. The aims of this review were to evaluate the consequences of ED pregnancies and to place them in the special context of their atypical immunologic relationships. METHODS: This review comprised an online search of English language publications listed in Pubmed/Medline, up to 29 January 2010. Seventy-nine papers met inclusion criteria. Using the literature and the authors' own experience, the relevant data on pregnancy outcome and complications, placental pathology and immunology were evaluated. RESULTS: Multiple studies document that ED pregnancies are associated with a higher incidence of pregnancy-induced hypertension and placental pathology. The incidence of other perinatal complications, such as intrauterine growth restriction, prematurity and congenital malformations, is comparable to conventional IVF. During pregnancy, both local and systemic immunologic changes occur and in ED pregnancies these changes are more pronounced. There is almost no information in the literature on the long-term complications of ED pregnancies for the mother. CONCLUSIONS: ED pregnancies have a higher risk of maternal morbidity. Owing to the high degree of antigenic dissimilarity, ED pregnancies represent an interesting model to study complex immunologic interactions, as the fully allogeneic fetus is not rejected but tolerated by the pregnant woman. Knowledge of the immune system in ED pregnancies has broader significance, as it may also give insight into immunologic aspects of tolerance in solid organ transplantation.