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.

Clinical value and cost analysis of the sFlt-1/PlGF ratio in addition to the spot urine protein/creatinine ratio in women with suspected pre-eclampsia: PREPARE cohort study.

BACKGROUND: This study investigated the clinical value of adding the sFlt-1/PlGF ratio to the spot urine protein/creatinine ratio (PCr) in women with suspected pre-eclampsia. METHODS: This was a prospective cohort study performed in a tertiary referral centre. Based on the combination of PCr (< 30) and sFlt-1/PlGF (≤38) results, four groups were described: a double negative result, group A-/-; a negative PCr and positive sFlt-1/PlGF, group B-/+; a positive PCr and negative sFlt-1/PlGF, group C+/-; and a double positive result, group D+/+. The primary outcome was the proportion of false negatives of the combined tests in comparison with PCr alone in the first week after baseline. Secondary, a cost analysis comparing the costs and savings of adding the sFlt-1/PlGF ratio was performed for different follow-up scenarios. RESULTS: A total of 199 women were included. Pre-eclampsia in the first week was observed in 2 women (2%) in group A-/-, 12 (26%) in group B-/+, 4 (27%) in group C+/-, and 12 (92%) in group D+/+. The proportion of false negatives of 8.2% [95% CI 4.9-13.3] with the PCr alone was significantly reduced to 1.6% [0.4-5.7] by adding a negative sFlt-1/PlGF ratio. Furthermore, the addition of the sFlt-1/PlGF ratio to the spot urine PCr, with telemonitoring of women at risk, could result in a reduction of 41% admissions and 36% outpatient visits, leading to a cost reduction of €46,- per patient. CONCLUSIONS: Implementation of the sFlt-1/PlGF ratio in addition to the spot urine PCr, may lead to improved selection of women at low risk and a reduction of hospital care for women with suspected pre-eclampsia. TRIAL REGISTRATION: Netherlands Trial Register (NL8308).

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.

Impact of extracardiac pathology on head growth in fetuses with congenital heart defect.

OBJECTIVE: Neurodevelopmental delay is frequently encountered in children with a congenital heart defect (CHD). Fetuses with major CHD have a smaller head circumference (HC), irrespective of altered cerebral flow or brain oxygenation. This cohort study compared head growth in cases with isolated vs those with non-isolated CHD to evaluate the effect of additional pathology on head size in these fetuses. METHOD: All CHD cases diagnosed prenatally in the period January 2002-July 2014 were selected from our regional registry, PRECOR. Cases of multiple pregnancy, and those affected by maternal diabetes, severe fetal structural brain anomalies or functional CHD were excluded. Subjects were divided into groups according to whether the CHD was isolated, and the non-isolated group was subdivided into three groups: cases with genetic anomaly, extracardiac malformation or placental pathology. In both isolated and non-isolated CHD groups, CHDs were also grouped according to their potential effect on aortic flow and oxygen saturation. Mean HC Z-scores at 20 weeks and increase or decrease (Δ) of HC Z-scores over the course of pregnancy were compared between isolated and non-isolated groups, using mixed linear regression models. RESULTS: Included were 916 cases of CHD diagnosed prenatally, of which 378 (41.3%) were non-isolated (37 with placental pathology, 217 with genetic anomaly and 124 with extracardiac malformation). At 20 weeks, non-isolated cases had significantly lower HC Z-scores than did isolated cases (Z-score = -0.70 vs -0.03; P < 0.001) and head growth over the course of pregnancy showed a larger decrease in this group (Δ HC Z-score = -0.03 vs -0.01 per week; P = 0.01). Cases with placental pathology had the lowest HC Z-score at 20 weeks (Z-score = -1.29) and the largest decrease in head growth (Δ HC Z-score = -0.06 per week). In CHD subjects with a genetic diagnosis (Z-score = -0.73; Δ HC Z-score = -0.04 per week) and in those with an extracardiac malformation (Z-score = -0.49; Δ HC Z-score = -0.02 per week), HC Z-scores were also lower compared with those in subjects with isolated CHD. CHDs that result in low oxygenation or flow to the brain were present more frequently in isolated than in non-isolated cases. CONCLUSIONS: Smaller HC in fetuses with CHD appears to be associated strongly with additional pathology. Placental pathology and genetic anomaly in particular seem to be important contributors to restricted head growth. This effect appears to be irrespective of altered hemodynamics caused by the CHD. Previously reported smaller HC in CHD should, in our opinion, be attributed to additional pathology. Neurodevelopment studies in infants with CHD should, therefore, always differentiate between isolated and non-isolated cases. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Why are congenital heart defects being missed?

OBJECTIVE: Congenital heart defects (CHD) are still missed frequently in prenatal screening programs, which can result in severe morbidity or even death. The aim of this study was to evaluate the quality of fetal heart images, obtained during the second-trimester standard anomaly scan (SAS) in cases of CHD, to explore factors associated with a missed prenatal diagnosis. METHODS: In this case-control study, all cases of a fetus born with isolated severe CHD in the Northwestern region of The Netherlands, between 2015 and 2016, were extracted from the PRECOR registry. Severe CHD was defined as need for surgical repair in the first year postpartum. Each cardiac view (four-chamber view (4CV), three-vessel (3V) view and left and right ventricular outflow tract (LVOT, RVOT) views) obtained during the SAS was scored for technical correctness on a scale of 0 to 5 by two fetal echocardiography experts, blinded to the diagnosis of CHD and whether it was detected prenatally. Quality parameters of the cardiac examination were compared between cases in which CHD was detected and those in which it was missed on the SAS. Regression analysis was used to assess the association of sonographer experience and of screening-center experience with the cardiac examination quality score. RESULTS: A total of 114 cases of isolated severe CHD at birth were analyzed, of which 58 (50.9%) were missed and 56 (49.1%) were detected on the SAS. The defects comprised transposition of the great arteries (17%), aortic coarctation (16%), tetralogy of Fallot (10%), atrioventricular septal defect (6%), aortic valve stenosis (5%), ventricular septal defect (18%) and other defects (28%). No differences were found in fetal position, obstetric history, maternal age or body mass index (BMI) or gestational age at examination between missed and detected cases. Ninety-two cases had available cardiac images from the SAS. Compared with the detected group, the missed group had significantly lower cardiac examination quality scores (adequate score (≥ 12) in 32% vs 64%; P = 0.002), rate of proper use of magnification (58% vs 84%; P = 0.01) and quality scores for each individual cardiac plane (4CV (2.7 vs 3.9; P < 0.001), 3V view (3.0 vs 3.8; P = 0.02), LVOT view (1.9 vs 3.3; P < 0.001) and RVOT view (1.9 vs 3.3; P < 0.001)). In 49% of missed cases, the lack of detection was due to poor adaptational skills resulting in inadequate images in which the CHD was not clearly visible; in 31%, the images showed an abnormality (mainly septal defects and aortic arch anomalies) which had not been recognized at the time of the scan; and, in 20%, the cardiac planes had been obtained properly but showed normal anatomy. Multivariate regression analysis showed that the volume of SAS performed per year by each sonographer was associated significantly with quality score of the cardiac examination. CONCLUSIONS: A lack of adaptational skills when performing the SAS, as opposed to circumstantial factors such as BMI or fetal position, appears to play an important role in failure to detect CHD prenatally. The quality of the cardiac views was inadequate significantly more often in undetected compared with detected cases. Despite adequate quality of the images, CHD was not recognized in 31% of cases. A high volume of SAS performed by each sonographer in a large ultrasound center contributes significantly to prenatal detection. In 20% of undetected cases, CHD was not visible even though the quality of the images was good. © 2019 Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Values and beliefs on trainee selection: What counts in the eye of the selector? A qualitative study exploring the program director's perspective.

OBJECTIVES: Postgraduate trainee selection is a high-stakes process. While many studies focused on selection methods and psychometrics, little is known about the influence of selectors' personal values and beliefs in the judgment and decision-making process. A better understanding of these factors is vital since selectors determine the future workforce. METHODS: We interviewed programme directors (PDs) from 11 specialties in one University Hospital. Thematic analysis was conducted with a combined approach of generic and in-vivo coding. RESULTS: PDs value excellence, 'fit' and personal characteristics. The content of these values are subject to personal interpretation and differ between PDs. PDs use various 'proxies' as alternative indicators of performance. They consider intuition, teamwork and autonomy important in judgement and decision-making. PDs find selection challenging and feel great accountability towards candidates and society. CONCLUSIONS: Selectors criteria of judgement- and decision-making often remain implicit and focus on prior achievements and 'fit' with the current trainee-pool, possibly compromising the workforce's diversity. Implicit 'proxies' and intuitive decision-making may be an unwitting source of judgemental bias. 'Making the implicit explicit', by increasing awareness of personal values and beliefs and structuring the selection interview, may improve the quality of trainee selection.

Pregnant women at increased risk of adverse perinatal outcomes: A combination of less healthy behaviors and adverse psychosocial and socio-economic circumstances.

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.

Fetuses with Isolated Congenital Heart Defects Show Normal Cerebral and Extracerebral Fluid Volume Growth: A 3D Sonographic Study in the Second and Third Trimester.

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.

Head growth in fetuses with isolated congenital heart defects: lack of influence of aortic arch flow and ascending aorta oxygen saturation.

OBJECTIVES: Congenital heart defects (CHDs) are reported to be associated with a smaller fetal head circumference (HC) and neurodevelopmental delay. Recent studies suggest that altered intrauterine brain hemodynamics may explain these findings. Our objectives were to evaluate the pattern of head growth in a large cohort of fetuses with various types of CHD, analyze these patterns according to the type of CHD and estimate the effect of cerebral hemodynamics with advancing gestation in the second and third trimesters. METHODS: Singleton fetuses with an isolated CHD were selected from three fetal medicine units (n = 436). Cases with placental insufficiency or genetic syndromes were excluded. CHD types were clustered according to the flow and oxygen saturation in the aorta. Z-scores of biometric data were constructed using growth charts of a normal population. HC at different gestational ages was evaluated and univariate and multivariate mixed regression analyses were performed to examine the patterns of prenatal HC growth. RESULTS: Fetuses with severe and less severe types of CHD demonstrated statistically significant HC growth restriction with increasing gestational age (slope of -0.017/day); however, there was no statistically significant effect of fetal hemodynamics on HC growth. Fetuses with CHD but normal brain oxygenation and normal aortic flow showed a significant decrease in HC growth (slope of -0.024/day). Only fetuses with isolated tetralogy of Fallot demonstrated a smaller HC z-score at 20 weeks of gestation (-0.67 (95% CI, -1.16 to -0.18)). CONCLUSIONS: Despite the decline in head growth in fetuses with a prenatally detected isolated CHD, HC values were within the normal range, raising the question of its clinical significance. Furthermore, in contrast to other studies, this large cohort did not establish a significant correlation between aortic flow or oxygen saturation and HC growth. Factors other than altered fetal cerebral hemodynamics may contribute to HC growth restriction with increasing gestational age, such as (epi)genetic or placental factors. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

The Vaginal Microbiome Changes During Various Fertility Treatments.

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.

The addition of the sFlt-1/PlGF ratio to the protein/creatinine ratio in multiple pregnancy: Post-hoc analysis of the PREPARE cohort study.

OBJECTIVE: To assess the predictive accuracy of the sFlt-1/PlGF ratio cut-off 38 in addition to the standard-of-care spot urine protein/creatinine ratio (PCr) for multiple pregnancies in women with suspected pre-eclampsia. STUDY DESIGN: Post-hoc analysis of a prospective cohort study. MAIN OUTCOME MEASURES: Primary outcome was the occurrence of pre-eclampsia in one and four weeks after presentation with suspected pre-eclampsia. Test characteristics with 95% confidence intervals (CI) were calculated on pre-eclampsia development in one and four weeks. RESULTS: Twenty-three multiple pregnancies with suspected pre-eclampsia between 20 and 37 weeks gestation were included for analysis. Women who eventually developed pre-eclampsia had a significantly higher PCr (34.0 vs. 16.5, p = 0.015), sFlt-1 (17033 vs. 5270 pg/ml, p = 0.047) and sFlt-1/PlGF ratio (99 vs. 25, p = 0.033) at baseline. Furthermore, PCr ≥ 30 and sFlt-1/PlGF ratio > 38 was respectively seen in 1/16 (6.3 %) and 3/16 (18.8 %) of the women who did not develop pre-eclampsia. For predicting pre-eclampsia within one week the sFlt-1/PlGF ratio sensitivity was 75.0 % [95 % CI 19.4-99.4] and the negative predictive value 93.8 % [73.0-98.8], while no pre-eclampsia developed when PCr was < 30. Consequently, the combination of these tests did not lead to an improvement in test characteristics, with non-significant differences in positive predictive value (50.0 % [29.5-70.5] versus 80.0 % [37.3-96.4]) compared to PCr alone for pre-eclampsia development in one week. CONCLUSIONS: In addition to standard-of-care spot urine PCr measurements, this study has not been able to demonstrate that the sFlt-1/PlGF ratio cut-off 38 is of added value in the prediction of pre-eclampsia in multiple pregnancy. TRIAL REGISTRATION: Netherlands Trial Register (NL8308).

Acute hemorrhage in monochorionic twins with ruptured velamentous vessels: anemic twin resuscitated by its co-twin through placental vascular anastomoses?

Monochorionic (MC) twin pregnancies are at increased risk of several complications including acute or chronic twin-twin transfusion syndrome (TTTS) and twin anemia-polycythemia sequence (TAPS). Both TTTS and TAPS result from inter-twin fetofetal transfusion through the placental vascular anastomoses. In addition, MC twin pregnancies are at increased risk of having a velamentous cord insertion, which has been linked with poor perinatal outcome due to risk of rupture of the velamentous vessels. In sporadic cases, these vascular connections may have a positive effect instead of a deleterious effect. We present a case of acute fetal distress in a MC twin pregnancy caused by acute hemorrhage following rupture of velamentous vessels. An emergency cesarean section delivery was performed at 29+2 weeks' gestation. One infant was severely anemic at birth and required immediate treatment with volume expansion and blood transfusion. Acute fetal blood loss through the ruptured vessels led to an acute fetofetal transfusion from the co-twin through the placental vascular anastomoses. Delayed intervention could have resulted in severe hypovolemic shock and acute anemia in both fetuses. Instead, in the current case, placental vascular anastomoses had a transient protective role and allowed transfusion of blood from one co-twin into the circulation of the anemic twin.

A clinical prediction model to assess the risk of operative delivery.

OBJECTIVE: To predict instrumental vaginal delivery or caesarean section for suspected fetal distress or failure to progress. DESIGN: Secondary analysis of a randomised trial. SETTING: Three academic and six non-academic teaching hospitals in the Netherlands. POPULATION: 5667 labouring women with a singleton term pregnancy in cephalic presentation. METHODS: We developed multinomial prediction models to assess the risk of operative delivery using both antepartum (model 1) and antepartum plus intrapartum characteristics (model 2). The models were validated by bootstrapping techniques and adjusted for overfitting. Predictive performance was assessed by calibration and discrimination (area under the receiver operating characteristic), and easy-to-use nomograms were developed. MAIN OUTCOME MEASURES: Incidence of instrumental vaginal delivery or caesarean section for fetal distress or failure to progress with respect to a spontaneous vaginal delivery (reference). RESULTS: 375 (6.6%) and 212 (3.6%) women had an instrumental vaginal delivery or caesarean section due to fetal distress, and 433 (7.6%) and 571 (10.1%) due to failure to progress, respectively. Predictors were age, parity, previous caesarean section, diabetes, gestational age, gender, estimated birthweight (model 1) and induction of labour, oxytocin augmentation, intrapartum fever, prolonged rupture of membranes, meconium stained amniotic fluid, epidural anaesthesia, and use of ST-analysis (model 2). Both models showed excellent calibration and the receiver operating characteristics areas were 0.70-0.78 and 0.73-0.81, respectively. CONCLUSION: In Dutch women with a singleton term pregnancy in cephalic presentation, antepartum and intrapartum characteristics can assist in the prediction of the need for an instrumental vaginal delivery or caesarean section for fetal distress or failure to progress.

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.

Fetal blood sampling in addition to intrapartum ST-analysis of the fetal electrocardiogram: evaluation of the recommendations in the Dutch STAN® trial.

OBJECTIVES: To evaluate the recommendations for additional fetal blood sampling (FBS) when using ST-analysis of the fetal electrocardiogram. DESIGN: Prospective cohort study. SETTING: Three academic and six non-academic teaching hospitals in the Netherlands. POPULATION: Labouring women with a high-risk singleton pregnancy in cephalic position beyond 36 weeks of gestation. METHODS: In labouring women allocated to the STAN® arm of a previously published randomised controlled trial who underwent one or more FBS during delivery, we assessed whether FBS was performed according to the trial protocol and how fetal acidosis, defined as an FBS pH < 7.20, was related to ST-waveform analysis. MAIN OUTCOME MEASURES: The number of FBS showing fetal acidosis, related to the different STAN® criteria where additional FBS is recommended. RESULTS: Among 2827 women monitored with STAN®, 297 underwent FBS, of whom 171 (57.6%) were performed according to the predefined criteria and 126 were performed in absence of these criteria. In the first group, rates of fetal acidosis (pH < 7.20) were two of 18, none of nine, 12 of 111 and three of 33 when FBS was taken for abnormal cardiotocogram (CTG) at the start, intermediary CTG at the start, abnormal CTG >60 minutes, and poor electrocardiogram quality, respectively. When the predefined criteria were not met and ST-analysis showed no ST-events, only two incidents of fetal acidosis were seen. CONCLUSIONS: The performance of FBS is valuable in the advised STAN® criteria. When these criteria are not met, performance of FBS does not seem helpful in the detection of fetal acidosis.

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.

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.

Individualized choice in prenatal diagnosis: the impact of karyotyping and standalone rapid aneuploidy detection on quality of life.

OBJECTIVE: To assess the reasons and perceptions of women who are offered a choice between karyotyping and standalone rapid aneuploidy detection (RAD) and to compare the impact of both tests on anxiety and health-related quality of life. METHODS: In this prospective comparative study, women undergoing amniocentesis on behalf of their age or for an increased Down syndrome risk were offered a choice between karyotyping (group 1, n = 68) and standalone RAD (group 2, n = 61). Follow-up was 9 weeks post amniocentesis. RESULTS: The most commonly cited reason for choosing karyotyping was obtaining as much information as possible, while for choosing standalone RAD, it was the short waiting time. Prenatal screening (OR 7.09), no knowledge of karyotyping (OR 4.2), and an intermediate perceived risk for chromosomal abnormalities (OR 3.6) were associated with choosing standalone RAD. There were no systematic differences in time of karyotyping and standalone RAD in terms of anxiety (P = 0.11), generic physical and mental health (P = 0.94, 0.52; P = 0.66, 0.07), personal perceived control (PPC; P = 0.69), and stress (P = 0.66). CONCLUSION: Offering a choice between karyotyping and standalone RAD does not influence anxiety, stress, PPC, or generic health. Individual choice in prenatal diagnosis meets individual needs and thereby could reduce anxiety and stress.

The impact of rapid aneuploidy detection (RAD) in addition to karyotyping versus karyotyping on maternal quality of life.

OBJECTIVE: To assess the impact of rapid aneuploidy detection (RAD) combined with fetal karyotyping versus karyotyping only on maternal anxiety and health-related quality of life. METHODS: Women choosing to undergo amniocentesis were selected into group 1, i.e. receiving a karyotype result only (n = 132) or to group 2, i.e. receiving both the result of RAD and karyotyping (n = 181). RESULTS: There were no systematic differences in time of RAD combined with karyotyping versus karyotyping only in terms of anxiety (P = 0.91), generic physical health (P = 0.76, P = 0.46), generic mental health (P = 0.52, P = 0.72), personal perceived control (P = 0.91) and stress (P = 0.13). RAD combined with karyotyping reduced anxiety and stress two weeks earlier compared to karyotyping only. CONCLUSION: RAD as add-on to karyotyping reduces anxiety and stress in the short term but it does not influence overall anxiety, stress, personal perceived control, and generic mental and physical health when compared to a karyotype-only strategy.

Karyotyping or rapid aneuploidy detection in prenatal diagnosis? The different views of users and providers of prenatal care.

Developments in prenatal diagnosis raise the question which test strategy should be implemented. However, preferences of women and caregivers are underexposed. This study investigates what kind of prenatal test pregnant women and caregivers prefer and if differences between the groups exist, using self-report questionnaires. Women preferred either karyotyping (50%) or rapid aneuploidy detection (43%). Caregivers opted for the latter (78%). A test targeted on Down syndrome was the least preferred in both groups. We recommend the use of individualised choice for genetic test in prenatal diagnosis, overcoming the existing differences in preferences between women and caregivers.