Placental Methylglyoxal in Preeclampsia: Vascular and Biomarker Implications.

BACKGROUND: Preeclampsia is a multifaceted syndrome that includes maternal vascular dysfunction. We hypothesize that increased placental glycolysis and hypoxia in preeclampsia lead to increased levels of methylglyoxal (MGO), consequently causing vascular dysfunction. METHODS: Plasma samples and placentas were collected from uncomplicated and preeclampsia pregnancies. Uncomplicated placentas and trophoblast cells (BeWo) were exposed to hypoxia. The reactive dicarbonyl MGO and advanced glycation end products (Nε-(carboxymethyl)lysine [CML], Nε-(carboxyethyl)lysine [CEL], and MGO-derived hydroimidazolone [MG-H]) were quantified using liquid chromatography-tandem mass spectrometry. The activity of GLO1 (glyoxalase-1), that is, the enzyme detoxifying MGO, was measured. The impact of MGO on vascular function was evaluated using wire/pressure myography. The therapeutic potential of the MGO-quencher quercetin and mitochondrial-specific antioxidant mitoquinone mesylate (MitoQ) was explored. RESULTS: MGO, CML, CEL, and MG-H2 levels were elevated in preeclampsia-placentas (+36%, +36%, +25%, and +22%, respectively). Reduced GLO1 activity was observed in preeclampsia-placentas (-12%) and hypoxia-exposed placentas (-16%). Hypoxia-induced MGO accumulation in placentas was mitigated by the MGO-quencher quercetin. Trophoblast cells were identified as the primary source of MGO. Reduced GLO1 activity was also observed in hypoxia-exposed BeWo cells (-26%). Maternal plasma concentrations of CML and the MGO-derived MG-H1 increased as early as 12 weeks of gestation (+16% and +17%, respectively). MGO impaired endothelial barrier function, an effect mitigated by MitoQ, and heightened vascular responsiveness to thromboxane A2. CONCLUSIONS: This study reveals the accumulation of placental MGO in preeclampsia and upon exposure to hypoxia, demonstrates how MGO can contribute to vascular impairment, and highlights plasma CML and MG-H1 levels as promising early biomarkers for preeclampsia.

Quantification of left ventricular myocardial strain: Comparison between MRI tagging, MRI feature tracking, and ultrasound speckle tracking.

Ultrasound speckle tracking is frequently used to quantify myocardial strain, and magnetic resonance imaging (MRI) feature tracking is rapidly gaining interest. Our aim is to validate cardiac MRI feature tracking by comparing it with the gold standard method (i.e., MRI tagging) in healthy subjects and patients. Furthermore, we aim to perform an indirect validation by comparing ultrasound speckle tracking with MRI feature tracking. Forty-two subjects (17 formerly preeclamptic women, three healthy women, and 22 left bundle branch block patients of both sexes) received 3-T cardiac MRI and echocardiography. Cine and tagged MRI, and B-mode ultrasound images, were acquired. Intrapatient global and segmental left ventricular circumferential (MRI tagging vs. MRI feature tracking) and longitudinal (MRI feature tracking vs. ultrasound speckle tracking) peak strain and time to peak strain were compared between the three techniques. Intraclass correlation coefficient (ICC) (< 0.50 = poor, 0.50-0.75 = moderate, > 0.75-0.90 = good, > 0.90 = excellent) and Bland-Altman analysis were used to assess correlation and bias; p less than 0.05 indicates a significant ICC or bias. Global peak strain parameters showed moderate-to-good correlations between methods (ICC = 0.71-0.83, p < 0.01) with no significant biases. Global time to peak strain parameters showed moderate-to-good correlations (ICC = 0.56-0.82, p < 0.01) with no significant biases. Segmental peak strains showed significant biases in all parameters and moderate-to-good correlation (ICC = 0.62-0.77, p < 0.01), except for lateral longitudinal peak strain (ICC = 0.23, p = 0.22). Segmental time to peak strain parameters showed moderate-to-good correlation (ICC = 0.58-0.74, p < 0.01) with no significant biases. MRI feature tracking is a valid method to examine myocardial strain, but there is bias in absolute segmental strain values between imaging techniques. MRI feature tracking shows adequate comparability with ultrasound speckle tracking.

DEcreased Cognitive functiON, NEurovascular CorrelaTes and myocardial changes in women with a history of pre-eclampsia (DECONNECT): research protocol for a cross-sectional pilot study.

INTRODUCTION: Pre-eclampsia is a hypertensive disorder affecting up to 8% of pregnancies. After pre-eclampsia, women are at increased risk of cognitive problems, and cerebrovascular and cardiovascular disorders. These sequelae could result from microvascular dysfunction persisting after pre-eclampsia. This study will explore differences in cerebral and myocardial microvascular function between women after pre-eclampsia and women after normotensive gestation. We hypothesise that pre-eclampsia alters cerebral and myocardial microvascular functions, which in turn are related to diminished cognitive and cardiac performance. METHODS AND ANALYSIS: The cross-sectional 'DEcreased Cognitive functiON, NEurovascular CorrelaTes and myocardial changes in women with a history of pre-eclampsia' (DECONNECT) pilot study includes women after pre-eclampsia and controls after normotensive pregnancy between 6 months and 20 years after gestation. We recruit women from the Queen of Hearts study, a study investigating subclinical heart failure after pre-eclampsia. Neuropsychological tests are employed to assess different cognitive domains, including attention, processing speed, and cognitive control. Cerebral images are recorded using a 7 Tesla MRI to assess blood-brain barrier integrity, perfusion, blood flow, functional and structural networks, and anatomical dimensions. Cardiac images are recorded using a 3 Tesla MRI to assess cardiac perfusion, strain, dimensions, mass, and degree of fibrosis. We assess the effect of a history of pre-eclampsia using multivariable regression analyses. ETHICS AND DISSEMINATION: This study is approved by the Ethics Committee of Maastricht University Medical Centre (METC azM/UM, NL47252.068.14). Knowledge dissemination will include scientific publications, presentations at conferences and public forums, and social media. TRIAL REGISTRATION NUMBER: NCT02347540.

Active plasma renin concentration throughout healthy and complicated pregnancy: a systematic review and meta-analysis.

BACKGROUND: Pregnancy is characterized by profound circulatory changes and compensatory adjustments in the renin-angiotensin-aldosterone system (RAAS). Differences in regulatory response may antedate or accompany vascular complicated pregnancy. We performed a systematic review and meta-analysis to delineate the trajectory of active plasma renin concentration (APRC) in healthy pregnancy and compare this to complicated pregnancy. METHODS: We performed a systematic review and meta-analysis on APRC during normotensive and hypertensive pregnancies, using PubMed (NCBI) and Embase (Ovid) databases. We included only studies reporting measurements during pregnancy together with a nonpregnant reference group measurement. Risk of bias was assessed with QUIPS. Ratio of the mean (ROM) and 95% confidence intervals (CI) of APRC values between pregnant and nonpregnant women were estimated for predefined intervals of gestational age using a random-effects model. Meta-regression was used to analyze APRC over time. RESULTS: In total, we included 18 studies. As compared to nonpregnant, APRC significantly increased as early as the first weeks of healthy pregnancy and stayed increased throughout the whole pregnancy (ROM 2.77; 95% CI 2.26-3.39). APRC in hypertensive complicated pregnancy was not significantly different from nonpregnancy (ROM 1.32; 95% CI 0.97-1.80). CONCLUSION: Healthy pregnancy is accompanied by a profound rise in APRC in the first trimester that is maintained until term. In hypertensive complicated pregnancy, this increase in APRC is not observed.

Impact of cannula diameter on pregnancy outcomes after minimally invasive fetal laser surgery in the treatment of twin-to-twin transfusion syndrome: A systematic review and meta-analysis.

INTRODUCTION: Preterm prelabor rupture of membranes (PPROM) remains a major complication of fetal laser surgery in the treatment of twin-to-twin transfusion syndrome (TTTS). The aim of the study was to determine the impact of cannula size on pregnancy outcomes, with a particular focus on PPROM. MATERIAL AND METHODS: The protocol was developed and registered in the PROSPERO database under registration number CRD42022333630. The PubMed, Web of Science, and EMBASE databases were searched electronically on May 18, 2022, and updated on March 2, 2023, utilizing a combination of the relevant MeSH terms, keywords, and word variants for "TTTS" and "laser". Randomized controlled trials, prospective and retrospective cohorts, case-control studies, and case reports/series with more than five participants were considered eligible for inclusion. Studies reporting the cannula diameter and PPROM rate after laser surgery in the treatment of monochorionic pregnancies affected by TTTS between 16- and 26 weeks' gestation were included. Data was extracted independently, and when appropriate, a random-effects meta-analysis was undertaken to calculate pooled estimates and their confidence intervals. Heterogeneity in the effect estimates of the individual studies was calculated using the I2 statistic. The primary outcome was PPROM rate. Secondary outcomes were survival rate, preterm birth, and incomplete surgery. The quality of the included studies was assessed using a modified quality in prognosis study tool. RESULTS: We included a total of 22 studies, consisting of 3426 patients. Only one study was scored as low quality, seven as moderate quality, and the remaining 14 as high quality. The mean PPROM rate after laser surgery treating TTTS was 22.9%, ranging from 11.6% for 9 French (Fr) to 54.0% for 12 Fr. Subsequent meta-regression for the clinically relevant PPROM rate before 34 weeks of gestation, showed increased PPROM rates for increased cannula size (p-value 0.01). CONCLUSIONS: This systematic review confirmed PPROM as a frequent complication of fetal laser surgery, with a mean PPROM rate of 22.9%. A larger cannula diameter relates to a significant higher PPROM risk for PPROM before 34 weeks gestation. Hence, the ideal balance between optimal visualization requiring larger port diameters and shorter operation time and more complete procedures that benefit from larger diameters is crucial to reduce iatrogenic PPROM rates.

No evidence for a diminished ovarian reserve among patients with hypertensive disorders of pregnancy: a case control study.

BACKGROUND: Existing evidence suggests a relation between cardiovascular dysfunction and diminished ovarian reserve. While it is known that pre-existent cardiovascular dysfunction is also associated with the development of preeclampsia (PE) during pregnancy, we hypothesize that signs of diminished ovarian reserve may occur more frequently among women with a history of hypertensive disorders of pregnancy (HDP). The aim of our study was therefore to analyse if women with a history of HDP show signs of diminished ovarian reserve, represented by lower anti-Mullarian hormone (AMH) levels, compared to controls. For this retrospective observational case control study, patients included women with a history of HDP, whereas controls constituted of women with a history of an uncomplicated pregnancy. The study was conducted in a tertiary referral centre in which all women underwent a one-time cardiovascular and metabolic assessment. Ovarian reserve and markers of cardiovascular function were evaluated, adjusted for age and body mass index (BMI) using linear regression analyses. RESULTS: 163 patients and 81 controls were included over a time span of 3 years. No signs of diminished ovarian reserve i.e. lower AMH level were observed in the patient group versus controls. A subgroup analysis even showed higher AMH levels in late onset HDP as compared to controls (2.8 vs. 2.0 µg/L, p = 0.025). As expected, cardiovascular function markers were significantly less favourable in the patient group compared to controls; higher levels of systolic blood pressure (BP) (5%), diastolic BP (4%), triglycerides (29%), glucose (4%) and insulin levels (81%) (all p < 0.05), whereas high density lipid (HDL) cholesterol was 12% lower (NS). CONCLUSIONS: Despite unfavourable cardiovascular risk profile, the present study does not substantiate the hypothesis that women with HDP show accelerated ovarian ageing as compared to healthy parous controls. Although HDP patients should be warned about their cardiovascular health, they shouldn't be concerned about unfavourable ovarian reserve status.

Unexplained recurrent pregnancy loss and markers of arterial vascular health: An experimental case-control study.

OBJECTIVE: To investigate whether women with unexplained recurrent pregnancy loss have impaired arterial vascular health compared with controls, and to evaluate whether this is modifiable by exercise. DESIGN: Experimental case-control pilot study. SETTING: University medical centre in the Netherlands. POPULATION: Twelve women with unexplained recurrent pregnancy loss, 11 nulliparous women and 19 primiparous women with a history of uncomplicated pregnancies. METHODS: In all three groups we measured baseline characteristics, metabolic components and arterial vascular health, and repeated this in women with unexplained recurrent pregnancy loss after 1 month of protocolled and supervised cycle training. MAIN OUTCOME MEASURES: Differences in arterial vascular health between women with unexplained recurrent pregnancy loss and controls, and the effect of exercise on arterial vascular health in women with unexplained recurrent pregnancy loss. RESULTS: Women with unexplained recurrent pregnancy loss have a significantly increased carotid intima media thickness in comparison with both controls (both P < 0.01), a significantly decreased brachial endothelial dependent flow-mediated vasodilation in comparison with both controls (nulliparous: P < 0.01; primiparous: P = 0.05) and a significantly decreased femoral endothelial dependent flow-mediated vasodilation in comparison with primiparous women (P = 0.01). The endothelium independent glyceryl trinitrate response was similar in all groups. With 1 month of exercise, the carotid intima media thickness decreased significantly by 7% (P = 0.05) and the femoral FMD increased significantly by 10% (P = 0.01) in women with unexplained recurrent pregnancy loss. CONCLUSIONS: Women with unexplained recurrent pregnancy loss have an impaired vascular health in comparison with controls. This impaired arterial vascular health can be improved by exercise.

Prediction Model Based on Easily Available Markers for Aberrant Cardiac Remodeling in Women After Pregnancy.

BACKGROUND: Preeclampsia is strongly associated with left ventricular concentric remodeling (LVCR) and left ventricular hypertrophy (LVH) up to 10 years after delivery. This predisposes to heart failure later in life. Adequate detection and prediction of LVCR or LVH is expected to decrease the risk of developing clinical heart failure within this high-risk female population. Therefore, we developed and internally validated a prediction model for aberrant cardiac remodeling in formerly pregnant women. METHODS: This large cohort study included women with a history of preeclampsia or normotensive pregnancy within a postpartum interval of 6 months to 30 years. Cardiovascular assessment was performed, including echocardiography, 30-minute blood pressure measurements, and circulating biomarkers. Aberrant cardiac remodeling based on echocardiographic findings was defined as either LVCR or LVH. Discriminative performance was evaluated by the area under the receiver operating characteristic curve. RESULTS: A total of 1397 women were included, of which 139 (10%) with LVCR or LVH (mean±SD age, 43±9 years) and 1258 (90%) without LVCR or LVH (40±8 years). The final prediction model was established based on the predictors age, waist circumference, systolic blood pressure, glycated hemoglobin, antihypertensive medication use, and early onset preeclampsia (yes/no). After internal validation, the prediction model showed accurate discriminative ability with an area under the receiver operating characteristic curve of 0.702 (95% CI, 0.657-0.756). CONCLUSIONS: Based on the conventional predictors, we developed a prediction model for women who are on average 8 to 12 years postpartum. Internal validation showed accurate discriminative ability. Upon external validation, this model may aid clinicians to initiate further diagnostic testing or clinical follow-up. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02347540.

Sex Differences in the Anti-Hypertensive Effect of Calcium-Channel Blockers: A Systematic Review and Meta-Analysis.

Cardiovascular disease (CVD) is the number one cause of death worldwide, with hypertension as the leading risk factor for both sexes. As sex may affect responsiveness to antihypertensive compounds, guidelines for CVD prevention might necessitate divergence between females and males. To this end, we studied the effectiveness of calcium channel blockers (CCB) on blood pressure (BP), heart rate (HR) and cardiac function between sexes. We performed a systematic review and meta-analysis on studies on CCB from inception to May 2020. Studies had to present both baseline and follow-up measurements of the outcome variables of interest and present data in a sex-stratified manner. Mean differences were calculated using a random-effects model. In total, 38 studies with 8202 participants were used for this review. In females as compared to males, systolic BP decreased by -27.6 mmHg (95%CI -36.4; -18.8) (-17.1% (95%CI -22.5;-11.6)) versus -14.4 mmHg (95%CI -19.0; -9.9) (-9.8% (95%CI -12.9;-6.7)) (between-sex difference p < 0.01), diastolic BP decreased by -14.1 (95%CI -18.8; -9.3) (-15.2%(95%CI -20.3;-10.1)) versus -10.6 mmHg (95%CI -14.0; -7.3) (-11.2% (95%CI -14.8;-7.7)) (between-sex difference p = 0.24). HR decreased by -1.8 bpm (95%CI -2.5; -1.2) (-2.5% (95%CI -3.4; -1.6)) in females compared to no change in males (0.3 bpm (95% CI -1.2; 1.8)) (between-sex difference p = 0.01). In conclusion, CCB lowers BP in both sexes, but the observed effect is larger in females as compared to males.

The Representation of Females in Studies on Antihypertensive Medication over the Years: A Scoping Review.

BACKGROUND: The leading global risk factor for cardiovascular-disease-related morbidity and mortality is hypertension. In the past decade, attention has been paid to increase females' representation. The aim of this study is to investigate whether the representation of females and presentation of sex-stratified data in studies investigating the effect of antihypertensive drugs has increased over the past decades. METHODS: After systematically searching PubMed and Embase for studies evaluating the effect of the five major antihypertensive medication groups until May 2020, a scoping review was performed. The primary outcome was the proportion of included females. The secondary outcome was whether sex stratification was performed. RESULTS: The search resulted in 73,867 articles. After the selection progress, 2046 studies were included for further analysis. These studies included 1,348,172 adults with a mean percentage of females participating of 38.1%. Female participation in antihypertensive studies showed an increase each year by 0.2% (95% CI 0.36-0.52), p < 0.01). Only 75 (3.7%) studies performed sex stratification, and this was the highest between 2011 and 2020 (7.2%). CONCLUSION: Female participation showed a slight increase in the past decade but is still underrepresented compared to males. As data are infrequently sex-stratified, more attention is needed to possible sex-related differences in treatment effects to different antihypertensive compounds.

Exploring Sex Differences of Beta-Blockers in the Treatment of Hypertension: A Systematic Review and Meta-Analysis.

AIMS: In the prevention of cardiovascular morbidity and mortality, early recognition and adequate treatment of hypertension are of leading importance. However, the efficacy of antihypertensives may be depending on sex disparities. Our objective was to evaluate and quantify the sex-diverse effects of beta-blockers (BB) on hypertension and cardiac function. We focussed on comparing hypertensive female versus male individuals. METHODS AND RESULTS: A systematic search was performed for studies on BBs from inception to May 2020. A total of 66 studies were included that contained baseline and follow up measurements on blood pressure (BP), heart rate (HR), and cardiac function. Data also had to be stratified for sex. Mean differences were calculated using a random-effects model. In females as compared to males, BB treatment decreased systolic BP 11.1 mmHg (95% CI, -14.5; -7.8) vs. 11.1 mmHg (95% CI, -14.0; -8.2), diastolic BP 8.0 mmHg (95% CI, -10.6; -5.3) vs. 8.0 mmHg (95% CI, -10.1; -6.0), and HR 10.8 beats per minute (bpm) (95% CI, -17.4; -4.2) vs. 9.8 bpm (95% CI, -11.1; -8.4)), respectively, in both sexes' absolute and relative changes comparably. Left ventricular ejection fraction increased only in males (3.7% (95% CI, 0.6; 6.9)). Changes in left ventricular mass and cardiac output (CO) were only reported in males and changed -20.6 g (95% CI, -56.3; 15.1) and -0.1 L (95% CI, -0.5; 0.2), respectively. CONCLUSIONS: BBs comparably lowered BP and HR in both sexes. The lack of change in CO in males suggests that the reduction in BP is primarily due to a decrease in vascular resistance. Furthermore, females were underrepresented compared to males. We recommend that future research should include more females and sex-stratified data when researching the treatment effects of antihypertensives.

Associations of periconceptional oral contraceptive use with pregnancy complications and adverse birth outcomes.

BACKGROUND: Periconceptional use of oral contraceptives (OCs) has been reported to increase risks of pregnancy complications and adverse birth outcomes, but risks are suggested to differ depending on the timing of discontinuation, amount of oestrogen and progestin content. METHODS: Prospective cohort study among 6470 pregnancies included in the PRegnancy and Infant DEvelopment (PRIDE) Study in 2012-19. Exposure was defined as any reported use of OCs within 12 months pre-pregnancy or after conception. Outcomes of interest were gestational diabetes, gestational hypertension, pre-eclampsia, pre-term birth, low birthweight and small for gestational age (SGA). Multivariable Poisson regression using stabilized inverse probability weighting estimated relative risks (RRs) with 95% CIs. RESULTS: Any periconceptional OC use was associated with increased risks of pre-eclampsia (RR 1.38, 95% CI 0.99-1.93), pre-term birth (RR 1.38, 95% CI 1.09-1.75) and low birthweight (RR 1.45, 95% CI 1.10-1.92), but not with gestational hypertension (RR 1.09, 95% CI 0.91-1.31), gestational diabetes (RR 1.02, 95% CI 0.77-1.36) and SGA (RR 0.96, 95% CI 0.75-1.21). Associations with pre-eclampsia were strongest for discontinuation 0-3 months pre-pregnancy, for OCs containing ≥30 µg oestrogen and for first- or second-generation OCs. Pre-term birth and low birthweight were more likely to occur when OCs were discontinued 0-3 months pre-pregnancy, when using OCs containing <30 µg oestrogen and when using third-generation OCs. Associations with SGA were observed for OCs containing <30 µg oestrogen and for third- or fourth-generation OCs. CONCLUSIONS: Periconceptional OC use, particularly those containing oestrogen, was associated with increased risks of pre-eclampsia, pre-term birth, low birthweight and SGA.

The efficacy of emergency cervical cerclage in singleton and twin pregnancies: a systematic review with meta-analysis.

OBJECTIVE: An emergency (rescue) cervical cerclage can be offered to pregnant women presenting with dilatation and prolapsed membranes in the second trimester of pregnancy because of cervical insufficiency. This study aimed to investigate the effectiveness of an emergency cerclage in both singleton and twin pregnancies in the prevention of extreme premature birth. DATA SOURCES: We performed a systematic literature search in PubMed and Embase from inception to June 2022 for transvaginal cervical emergency cerclages. STUDY ELIGIBILITY CRITERIA: All studies on transvaginal cervical emergency cerclages with at least 5 patients and reporting survival were included. METHODS: Included studies were assessed for quality and risk of bias with an adjusted Quality In Prognosis Studies tool. Random-effects meta-analyses and meta-regressions were performed for the primary outcome: survival. RESULTS: Our search yielded 96 studies, incorporating 3239 women, including 14 studies with an expectant management control group, incorporating 746 women. Overall survival after cervical emergency cerclage was 74%, with a fetal survival of 88% and neonatal survival of 90%. Singleton and twin pregnancies showed similar survival, with a pregnancy prolongation of 52 and 37 days and a gestational age at delivery of 30 and 28 weeks, respectively. Meta-regression analyses indicated a significant inverse association between mean gestational age at diagnosis and pregnancy prolongation and no association between dilatation or gestational age at diagnosis and gestational age at delivery. Compared with expectant management, emergency cerclage significantly increased overall survival by 43%, fetal survival by 17% and neonatal survival by 22%, along with a significant pregnancy prolongation of 37 days and reduction in delivery at <28 weeks of gestation of 55%. These effects were more profound in singleton pregnancies than in twin pregnancies. CONCLUSION: This systematic review indicates that, in pregnancies threatened by extreme premature birth because of cervical insufficiency, emergency cerclage leads to significantly higher survival, accompanied by significant pregnancy prolongation and reduction in delivery at <28 weeks of gestation, compared with expectant management. The mean gestational age at delivery was 30 weeks, independent of dilatation or gestational age at diagnosis. Survival was similar for singleton and twin pregnancies, implying that emergency cerclage should be considered in both.

Attenuated cognitive functioning decades after preeclampsia.

BACKGROUND: Preeclampsia, a hypertensive pregnancy disorder, is a leading cause of maternal and fetal morbidity and mortality, with remote cardio- and cerebrovascular implications. After preeclampsia, women may report serious disabling cognitive complaints, especially involving executive function, but the extent and time course of these complaints are unknown. OBJECTIVE: This study aimed to determine the impact of preeclampsia on perceived maternal cognitive functioning decades after pregnancy. STUDY DESIGN: This study is part of a cross-sectional case-control study named Queen of Hearts (ClinicalTrials.gov Identifier: NCT02347540), a collaboration study of 5 tertiary referral centers within the Netherlands investigating long-term effects of preeclampsia. Eligible participants were female patients aged ≥18 years after preeclampsia and after normotensive pregnancy between 6 months and 30 years after their first (complicated) pregnancy. Preeclampsia was defined as new-onset hypertension after 20 weeks of gestation along with proteinuria, fetal growth restriction, or other maternal organ dysfunction. Women with a history of hypertension, autoimmune disease, or kidney disease before their first pregnancy were excluded. Attenuation of higher-order cognitive functions, that is, executive function, was measured with the Behavior Rating Inventory of Executive Function for Adults. Crude and covariate-adjusted absolute and relative risks of clinical attenuation over time after (complicated) pregnancy were determined with moderated logistic and log-binomial regression. RESULTS: This study included 1036 women with a history of preeclampsia and 527 women with normotensive pregnancies. Regarding overall executive function, 23.2% (95% confidence interval, 19.0-28.1) of women experienced clinically relevant attenuation after preeclampsia, as opposed to 2.2% (95% confidence interval, 0.8-6.0) of controls immediately after childbirth (adjusted relative risk, 9.20 [95% confidence interval, 3.33-25.38]). Group differences diminished yet remained statistically significant (P < .05) at least 19 years postpartum. Regardless of history of preeclampsia, women with lower educational attainment, mood or anxiety disorders, or obesity were especially at risk. Neither severity of preeclampsia, multiple gestation, method of delivery, preterm birth, nor perinatal death was related to overall executive function. CONCLUSION: After preeclampsia, women were 9 times more likely to experience clinical attenuation of higher-order cognitive functions as opposed to after normotensive pregnancy. Despite overall steady improvement, elevated risks persisted over decades after childbirth.

Experiences of Peri-partum Urinary Incontinence from a Women's and Health Care Perspective: A Qualitative Study.

OBJECTIVES: Urinary incontinence (UI) is highly prevalent peri-partum. To gain more understanding regarding the gap between the prevalence of UI and actual help seeking behaviour of peri-partum women, this study aims to understand, (1) how peri-partum women experience UI and which factors influence these experiences and (2) the perspective of health care professionals on UI during pregnancy, and the first year after childbirth. METHODS: A qualitative approach was used, using semi-structured interviews with adult pregnant and up to 1 year post-partum women and a focus group with health care professionals (HCP's) involved in the care of pregnant and post-partum women. Thematic analysis was used to analyse the data. RESULTS: Six pregnant and seven post-partum women were included. Nearly all of these women expressed to be not, or only slightly bothered by their UI and accept it as a result of pregnancy and/or delivery. They were surprised because they were unaware that UI could be a problem. None of the HCP's routinely asked about the presence of UI during pregnancy. At the post-natal check at 6 weeks post-partum, UI is still not a standard question for the majority of the gynecologists and registrars in contrast to the midwives. CONCLUSIONS FOR PRACTICE: The interviewed women with UI during pregnancy and the first year after childbirth were surprised but hardly bothered by their UI and accept it as part of being pregnant or as a result of the delivery. HCP's do not routinely discuss UI during pregnancy or post-partum.

What is already known on this subject? Peri-partum women with urinary incontinence often believe it is normal and will resolve by itself over time. Health care professionals in peri-partum care, although knowledgeable on urinary incontinence, do not standardly discuss urinary incontinence in The Netherlands. A majority of peri-partum women do not seek professional help.What this study adds? The beliefs peri-partum women have on urinary incontinence probably originates from information from a health care professional, friend or the internet. To disclose their urinary incontinence, women need to be timely and structurally asked by their health care professional. A lack of time is one of the reasons why health care professionals do not standardly discuss this topic.

Analysis of FCGR3A-p.176Val variants in women with recurrent pregnancy loss and the association with CD16a expression and anti-HLA antibody status.

Natural Killer (NK) cells have been implicated in recurrent pregnancy loss (RPL). The p.Val176Phe (or Val158Phe) Single Nucleotide Polymorphism (SNP) in the FCGR3A gene encoding the FcγRIIIA or CD16a receptor has been associated with an enhanced affinity for IgG and stronger NK-mediated antibody-dependent cellular cytotoxicity. We hypothesized that the presence of at least one p.176Val variant associates with RPL and increased CD16a expression and alloantibodies e.g., against paternal human leukocyte antigen (HLA). In 50 women with RPL, we studied frequencies of the p.Val176Phe FCGR3A polymorphisms. Additionally, CD16a expression and anti-HLA antibody status were analyzed by flowcytometry and Luminex Single Antigens. In woman with RPL, frequencies were: 20% (VV), 42% (VF) and 38% (FF). This was comparable to frequencies from the European population in the NCBI SNP database and in an independent Dutch cohort of healthy women. NK cells from RPL women with a VV (22,575 [18731-24607]) and VF (24,294 [20157-26637]) polymorphism showed a higher expression of the CD16a receptor than NK cells from RPL women with FF (17,367 [13257-19730]). No difference in frequencies of the FCGR3A-p.176 SNP were detected when comparing women with or without class I and class II anti-HLA antibodies. Our study does not provide strong evidence for an association between the p.Val176Phe FCGR3A SNP and RPL.

[Female physicians and pregnancy. Does the working climate discourage starting a family?] / Vrouwelijke artsen en zwangerschap.

Female physicians, especially those in surgical subspecialties, have an increased risk on subfertility and pregnancy complications, amongst preterm birth, compared to the general population. Long hours and unpredictable work weeks in a working climate that seems to discourage to start a family are contributing to these increased risks. Many physicians were unaware of the negative impact of delayed family planning and often regretted their decision to postpone pregnancy. Although differences between countries exist, also in the Netherlands, despite paid pregnancy and maternity leave, we also may not create the right working climate and truthful pregnancy-protective circumstances for female doctors to be able to work as safely as possible on something that could conceivably be viewed upon as their most important life's work. This American study with provocative title makes worrisome generic matters visible to us as profession, but also to employers in a labor market predominantly staffed by women.

Maternal anxiety forecasts shorter prolongation of pregnancies complicated by early-onset preeclampsia.

PURPOSE: In early-onset preeclampsia, each additional day of pregnancy prolongation reduces offspring infant mortality about 9%. We evaluated if maternal stress at admission to hospital for early-onset preeclampsia predicted admission-to-delivery intervals in days. METHODS: This prospective, longitudinal cohort-study involved 15 singleton pregnancies with a diagnosis of preeclampsia before 34 weeks gestation with intended expectant management. Upon hospital admission, maternal psychological stress was assessed with questionnaires and physiological stress with hair cortisol. Hair samples were analyzed in three hair segments representing the preconception period, and the first and second trimester of pregnancy. RESULTS: Mean pregnancy prolongation was 16.2 days. Higher maternal anxiety at hospital admission significantly correlated with shorter admission-to-delivery intervals (r = - 0.54, p = 0.04). Chronically increased hair cortisol concentrations (i.e. from preconception through the second trimester) of pregnancy tended to be related to shorter admission-to-delivery intervals (p <. 10). CONCLUSION: Higher reported anxiety is, and chronically high hair cortisol tended to be, related with fewer days of prolongation from admission to delivery in women with early-onset preeclampsia. These findings suggest that maternal stress might be a potential determinant of disease progression. Future research into early innovative stress-reducing interventions for early-onset preeclampsia may shed more light on the etiology and treatment of this disease.

Working conditions in women with multiple pregnancy-the impact on preterm birth and adherence to guidelines: a prospective cohort study.

BACKGROUND: Women with multiple pregnancies are at risk for maternal complications such as preterm birth. Hazardous working conditions, such as physically demanding work and long and irregular working hours, might increase the risk of preterm birth. OBJECTIVE: This study primarily aimed to determine whether certain working conditions up to 20 weeks of pregnancy increase the risk of preterm birth in multiple pregnancies. The secondary objective was to evaluate whether the working conditions of Dutch women with multiple pregnancy have been adjusted to the guidelines of the Netherlands Society of Occupational Medicine. STUDY DESIGN: We performed a prospective cohort study alongside the ProTWIN trial, a multicenter randomized controlled trial that assessed whether cervical pessaries could effectively prevent preterm birth. Women with paid work of >8 hours per week completed questionnaires concerning general health and working conditions between 16 and 20 weeks of pregnancy. Univariable and multivariable logistic regression analyses were performed to identify work-related factors associated with preterm birth (32-36 weeks' gestation) and very preterm birth (<32 weeks' gestation). We analyzed a subgroup of participants who worked for more than half of the week (>28 hours). We calculated the proportion of women who reported work-related factors not in accordance with guidelines. RESULTS: We studied 383 women, of whom 168 (44%) had been randomized to pessary, 142 (37%) to care as usual, and 73 (19%) did not participate in the randomized part of the study. After adjusting for confounding variables, working >28 hours was associated with very preterm birth (n=33; 78%) (adjusted odds ratio, 3.0; 95% confidence interval, 1.1-8.1), and irregular working times were associated with preterm birth (n=26, 17%) (adjusted odds ratio, 2.0; 95% confidence interval, 1.0-4.1) and very preterm birth (n=10; 24%) (adjusted odds ratio, 2.7; 95% confidence interval, 1.0-7.3). Within a subgroup of 213 participants working >28 hours per week, multivariable analysis showed that irregular working times (n=16; 20%) (adjusted odds ratio, 3.5; 95% confidence interval, 1.2-10.1) and no/little freedom in performance of tasks (n=23; 28%) (adjusted odds ratio, 3.0; 95% confidence interval, 1.3-7.3) were associated with preterm birth. Irregular working times (n=9; 27%) (adjusted odds ratio, 3.4; 95% confidence interval, 1.0-11.1), requiring physical strength (n=9; 27%) (adjusted odds ratio, 5.3; 95% confidence interval, 1.6-17.8), high physical workload (n=7; 21%) (adjusted odds ratio, 3.9; 95% confidence interval, 1.1-13.9), and no/little freedom in performing tasks (n=10; 30%) (adjusted odds ratio, 3.2; 95% confidence interval, 1.1-9.6) were associated with very preterm birth. Before 20 weeks of pregnancy, 224 (58.5%) women with multiple pregnancy continued to work under circumstances that were not in accordance with the guidelines. CONCLUSION: In our cohort study, nearly 60% of women with multiple pregnancy continued to work under circumstances not in accordance with the guidelines to avoid physical and job strain and long and irregular working hours. Irregular hours were associated with preterm and very preterm birth, and long hours were associated with preterm birth.