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OBJECTIVES: Overwhelming clinical evidence exists on disturbed vascular and endothelial function in the pathophysiology of preeclampsia (PE). In a non-pregnant (NP) population, L-FMC (low-flow mediated constriction) provides insight in the 'resting' endothelial capacity in contrast to the gold standard of flow mediated dilatation (FMD), reflecting endothelial nitric oxide bioavailability.STUDY DESIGN: Longitudinal follow-up of 100 healthy pregnant (HP) women, 33 PE women and 16 NP controls with non-invasive vascular assessments. HP women were evaluated at 12 and 35 weeks of gestation and at 6 months postpartum. PE patients were assessed at diagnosis (mean 30 weeks) and 6 months postpartum.MAIN OUTCOME MEASURES: Endothelial function (L-FMC, FMD, peripheral arterial tonometry (PAT)) and arterial stiffness (pulse wave velocity (PWV) and analysis (PWA)) were measured at the different visits and compared between groups.RESULTS: Overall endothelial dysfunction is present in PE (FMD HP 9.09 ± 4.20 vs PE 5.21 ± 4.47, p = 0.0004; L-FMC HP -1.90 ± 2.66 vs PE -0.40 ± 2.09, p = 0.03). L-FMC gradually elevates during the course of a HP (1st trim -0.31 ± 1.75 vs 3rd trim -1.97 ± 3.02, p 0.05).CONCLUSION: PE is characterized by dysfunction of both resting and recruitable endothelial capacity. This study offers new insights in different aspects of endothelial function in pregnancy, since L-FMC reflects an adaptation in HP that is absent in PE.

Objective: Monitoring hemodynamic status throughout pregnancy may help in identifying women with maladaptation predisposing to hypertensive complications. The Ultrasonic Cardiac Output Monitor (USCOM) is an easy-to-operate device for measuring cardiac output (CO) quickly. Our aim was to assess agreement between USCOM and transthoracic echocardiography (TTE) in: 1) non-pregnant women to correct for possible sources of discrepancy; 2) women longitudinally over the course of the pregnancy.Study design: High-risk women admitted for cardiovascular risk factor evaluation before pregnancy and multiple times during pregnancy, were included. CO was measured by TTE directly followed by USCOM measurements.Main outcome measures: Bias, limits of agreement (LOA) and percentage error between the two methods by Bland-Altman analysis.Results: Despite comparable non-pregnant CO levels (4.6 L/min), LOA and percentage error between the two methods improved moderately by optimizing the measurements using only the highest quality USCOM recordings in 132 non-pregnant women (percentage error of 39% and 30%, respectively). During pregnancy, in total 83, 106, 96 and 77 measurements were evaluated at respectively 12, 16, 20 and 30 weeks gestational age. Mean CO in USCOM was about 0.6 L/min higher compared to TTE in all trimesters; percentage error ranged from 35% to 45%. Linear mixed model analysis showed no association between bias and moment of measurement.Conclusion: Agreement between USCOM and TTE in pregnancy was outside our a priori determined level of acceptability and therefore absolute values of USCOM and TTE cannot be used interchangeably. Future research should focus on the agreement of USCOM and TTE in clinical decision-making.

Introduction Recurrence rates of preeclampsia vary based on severity of disease in the complicated pregnancy together with presence of risk factors consistent with the metabolic syndrome. Several efforts to reduce recurrent disease have been implemented in clinical practice in the past decades. Objective To assess whether recurrence rates of preeclampsia and related foetal complications decreased in the past 20 years in women who received tailored preventive advices after an extensive non-pregnant assessment on cardiovascular risk factors. Methods In this observational cohort study, we included 752 women who had their first pregnancy complicated by preeclampsia between 1996 and 2012, and who participated in a non-pregnant cardiovascular and metabolic assessment at least 4 months after delivery. A questionnaire was sent to women to follow-up on their next pregnancy outcome. We divided the study population in three groups based on year of their second delivery (1) 1996–2004; (2) 2005–2009; and (3) 2010–2016. We compared recurrence rates of preeclampsia and related foetal complications between the groups with the chi-square test. Results In total, 467 (62%) women responded to the questionnaire of which two-thirds had a subsequent ongoing pregnancy. The overall recurrence rate of preeclampsia was 24%. Preeclampsia recurred in 29% (29/99) of women who delivered between 1996 and 2004, compared to recurrence rates of 20% (20/99) in 2005–2009 and 24% (28/119) in 2010–2016 (p-value .319). Related offspring complications, including small for gestational age, decreased significantly over time (p-value .016). Discussion Recurrence rates of preeclampsia did not decrease over the past 20 years in women who have been extensively assessed on cardiovascular risk factors. In the same period, foetal and neonatal outcomes improved substantially. Efforts to extend and improve strategies to reduce recurrence risk of preeclampsia still seem to be necessary.

Objectives High resistance utero-placental circulation leads to placenta insufficiency related complications for both mother and fetus. The objective of this study was to evaluate the relationship between abnormal uterine artery pulsatility index (UtAPI) Doppler measurements, neonatal outcome and placental histological findings in placenta syndrome (PS) pregnancies. Methods A retrospective pilot study was performed on singleton pregnancies complicated by PS (pre-eclampsia and/or foetal growth restriction). UtA, umbilical (UmbA) and middle cerebral artery (MCA) Doppler measurements were collected within the last two weeks prior to delivery. Patients were divided into two groups according to UtAPI values, in which UtAPI > p95 was considered abnormal. Histological lesions were classified according to the criteria of the Society for Pediatric Pathology. Statistical analysis was performed using independent T-, Mann-Whitney U- and Fisher’s exact test. Multivariate analysis was used to correct UtAPI for gestational age (GA) at delivery and parity. Results The UtA-PI > p95 group (n = 25) showed a higher rate of premature delivery (p = 0,025), caesarean section (p = 0,007) and NICU-admission (p = 0,001) compared to the UtA-PIp95 group showed a significantly higher UmbA-PI (p = 0,004) with absent or reversed flow (p = 0,002), a lower MCA-PI (p = 0,010) and cerebro-placental ratio (p Conclusions In pregnancies complicated by PS, UtA-PI > p95 showed a moderate predictive ability for placental underperfusion independently of GA at delivery and parity. Furthermore, neonatal outcome and Doppler measurements were poorer.

Introduction During pregnancy, left ventricular (LV) diastolic function is of utmost importance to accommodate the increased preload in order to maintain increased cardiac output without triggering excessive sympathetic-tone-regulated reliance on heart rate. Insight in the physiological adaptation of diastolic function during pregnancy may enable the identification of women with impaired cardiac compliance, maladaptive to the pregnancy associated volume overload. Objective To meta-analytically determine the pattern of diastolic function indices during singleton normotensive pregnancies and hypertensive complicated pregnancies. Methods We performed a systematic review and meta-analysis on diastolic function during pregnancy using PubMed and Embase. We included studies that reported a non-pregnant reference measurement. Indices of interest were: mitral E-wave velocity, mitral A-wave velocity, E/A ratio, and left atrial volume (LAV). Mean differences between pregnant and reference measurements were calculated for predefined gestational age intervals using a random-effects model. Results We included 29 eligible studies. Normotensive pregnancies were characterized by a larger increase in passive LV filling (E-wave, 12%) compared to active LV filling during diastole (A-wave, 5%) resulting in a 17% increase of the E/A ratio in the first trimester. The E/A ratio progressively decreased during advancing gestation with 18%, resulting from normalized E-waves and increased A-waves. Hypertensive complicated pregnancies had a tendency of a larger decrease of the E/A ratio although not statistically significant (31%, p = 0.74). LAV increased more in hypertensive pregnancies compared to normotensive pregnancies (30% vs. 112% respectively, p Discussion Diastolic function in normotensive pregnancy is mainly dominated by passive filling in the first trimester while more by active filling later on in pregnancy. The E/A ratio therefore increases in the first trimester, to eventually progressively decrease in the second half of pregnancy. Stronger decline in E/A ratio along with concomitant increase in LAV in hypertensive pregnancies suggest fortified loss in cardiac diastolic function.

Introduction Insights in the adaptation of cardiac output (CO) and peripheral systemic vascular resistance in normal pregnancy may aid in identifying women with deviant adaptation. These women are thought to be at risk for hypertensive related complications during pregnancy. Objectives First, to describe the pattern of CO and peripheral resistance changes in normotensive singleton pregnancies. Second, to explore the adaptation of these variables in pregnancies complicated by hypertension, pre-eclampsia and/or foetal growth restriction. Methods We performed a meta-analysis of systematically reviewed literature on CO and peripheral resistance throughout normotensive and complicated pregnancies, using PubMed (NCBI) and Embase (Ovid) databases. Only studies reporting measurements during pregnancy and non-pregnant reference values were included. Pooled mean differences between pregnant and non-pregnant women were calculated for predefined intervals of gestational age using a random-effects model. Results In total, 92 studies were included in this meta-analysis. In uncomplicated pregnancies, CO progressively increased from the first weeks on. After peaking in the early third trimester (+1.47 L/min, over 30% increase as compared to the non-pregnant reference group), CO declined slightly until term. Next to that, peripheral resistance decreased progressively until early third trimester (−316 dyn · s · cm−5, −24% as compared to the non-pregnant group), after which it increased a little. In the first trimester of complicated pregnancies, an augmented increase in CO was observed (+1.36 L/min versus +0.73 L/min in the uncomplicated pregnancies, p Discussion During normal pregnancy, CO increases and peripheral resistance decreases by 30% and 24% respectively, reaching their maximum measure in the second half of pregnancy. Deviant hemodynamic adaptations showing an initial augmented increase with a cross-over to a low cardiac output might identify pregnancies that will be complicated by hypertension and/or growth restriction.

Objectives Although pregnancy rates of artificial reproductive techniques (ART) pregnancies have been optimized, these pregnancies have a higher risk of pregnancy complications due to impaired placentation during early pregnancy and thereby affecting placental vascularization, -structure and later on fetal growth. The aim of this study is to investigate if there are placental ultrasonographic differences between ART- and naturally conceived pregnancies. Methods A cross-sectional pilot study included 35 ART- and 30 naturally conceived (NC) pregnancies at the Maastricht University Medical Centre, between October 2017 and March 2018. Inclusion criteria were singleton pregnancies (NC, IVF/ICSI), maternal age ⩾18 years and body-mass-index (BMI) Results Placental calcifications at 12 and 16 weeks of gestation showed no significant difference between the ART and NC-group. However, placental lakes at 16 weeks were more prominent in the ART-group (59.5%) compared to the NC-group (26.1% (p = 0.017). Vascularization index at the umbilical cord insertion (UCI) and in the peripheral parts of the placenta was measured. At 12 weeks, the ART-group compared to the NC-group, showed a lower VI at the UCI (0.73 ± 0.81% vs. 2.00 ± 2.46%, p = 0.156) and in the peripheral parts of the placenta (1.73 ± 3.43% vs. 4.14 ± 4.92%, p = 0.023). At 16 weeks, no significant differences were found. Conclusions Reduced early placental vascularisation in ART-compared to NC-pregnancies may reflect the underlying aetiology of impaired placentation. These results provide promising possibilities for a more extended prospective trial and using placental ultrasonography as a predictor in the future.

Introduction Data on blood pressure (BP) adaptation in pregnancy show conflicting results on the occurrence of a mid-pregnancy BP drop. These inconsistent findings may contribute to delayed recognition of maladaptation in women at risk for a hypertensive complicated pregnancy. Objective To meta-analytically describe the pattern of BP adaptation in singleton normotensive pregnancies and hypertensive pregnancies. Methods We performeda systematic review and meta-analysis using PubMed and Embase. Studies included, needed to report a reference non-pregnant measurement. Mean differences between pregnant and reference measurements were calculated for systolic BP (SBP) and diastolic BP (DBP) in predefined gestational intervals using a random-effects model. Results In total, 110 studies were included (23079 BP readings). In normotensive pregnancy, both SBP and DBP started to decrease early in pregnancy, reaching their maximum reduction of −3.3% (−3.7 mmHg, (95% CI, −5.1 to −2.3)) and −5.6% (−3.9 mmHg, (95% CI, −4.8 to −3.0)) respectively in the late second trimester. In the third trimester, SBP and DBP gradually increased to reference values. In hypertensive complicated pregnancies, SBP did not decrease, while DBP initially decreased with −7.2% (−5.8 mmHg, (95% CI, −8.3 to −3.4)) in the early second trimester. From the second half of pregnancy onwards, BP increased to values higher than reference. SBP and DBP increased with 35% (38.2 mmHg, (95% CI, 27.3–49.2)) and 37% (26.1 mmHg, (95% CI, 18.4–33.8)) respectively in the hypertensive group, statistically significantly higher than normotensive pregnancies (p Discussion This is the first meta-analysis on BP adaptation during pregnancy. In normotensive pregnancy, both SBP and DBP initially decrease, reaching their nadir in the late second trimester showing a clinically moderate, but statistically significant mid-pregnancy drop. Hypertensive complicated pregnancies lack a SBP decrease in early pregnancy which might reflect impaired vascular compliance in these women.

Objectives To evaluate the physiological adaptation of blood flow in human uterine spiral arteries throughout the course of normotensive and hypertensive pregnancies based on existing literature. Methods A systematic literature review and meta-analysis on the change of arterial uterine spiral arteries, measured by Doppler ultrasonography, was conducted. Literature search was performed in Pubmed, EMBASE and Cochrane Library. The search was limited to papers published in English. Both first and second selection were performed by two independent researchers. Weighted means of the Doppler indices were calculated for the three pregnancy trimesters. Results Seven longitudinal prospective and four cross-sectional studies were included with publication dates ranging from 1995 to 2015. Ultrasound measurements were performed at certain gestational ages using transvaginal or transabdominal transducers. In normotensive pregnancies, pulsatility index (PI) decreased from 0.76 (95% CI: 0.65–0.86) in the first trimester to 0.51 (95% CI: 0.45–0.57) (p Conclusions PI and RI in uterine spiral arteries both decreased with advancing gestational age with the largest decrease between the first and second trimester. This is in concordance with previous histological hypertrophic decidual vasculopathy- and Doppler uterine artery findings. Longitudinal studies examining comprehensively the predictive value of spiral artery Doppler for hypertensive pregnancies are yet to be determined.

Introduction In an earlier paper we reported on the development of a model aimed at the prediction of preeclampsia recurrence, based on variables obtained before the next pregnancy (fasting glucose, BMI, previous birth of a small-for-gestational-age infant, duration of the previous pregnancy, and the presence of hypertension). Objective To externally validate and recalibrate the prediction model for the risk of recurrence of early-onset preeclampsia. Methods We collected data about course and outcome of the next ongoing pregnancy in 229 women with a history of early-onset preeclampsia. Recurrence was defined as preeclampsia requiring delivery before 34 weeks. We computed risk of recurrence and assessed model performance. In addition, we constructed a table comparing sensitivity, specificity, and predictive values for different suggested risk-thresholds. Results Early-onset preeclampsia recurred in 6.6% of women. The model systematically underestimated recurrence risk. The model’s discriminative ability was modest, the area under the receiver operating characteristic curve was 58.9% (95% CI: 45.1 – 72.7). Using relevant risk-thresholds, the model created groups that were only moderately different in terms of their average risk of recurrent preeclampsia (Table 1). Conclusion Compared to an AUC of 65% in the development cohort, the discriminate ability of the model was diminished. It had inadequate performance to classify women into clinically relevant risk groups.

Objective To evaluate early-pregnancy levels of ADMA (asymmetric dimethylarginine) in recurrent hypertensive pregnancy. Study design In this retrospective observational study, blood samples from 35 normotensive women with a previous hypertensive pregnancy were obtained preconceptionally and at 12, 16 and 20weeks in their next pregnancy. We assessed ADMA, symmetric dimethylarginine (SDMA), l-arginine and l-citrulline. We analyzed differences in longitudinal patterns between normotensive (NT, n =18) and recurrent hypertensive (HT, n =17) pregnancies by linear mixed models, with a sub-analysis for preeclampsia (PE, n =6). Main outcome measures ADMA, SDMA, l-arginine and l-citrulline. Results Pre-pregnant SDMA and l-citrulline were lower in HT. At 12weeks, ADMA and ADMA/SDMA ratio correlated inversely with PAPP-A and β-hCG, respectively. In both groups, ADMA-related compounds changed inconsistently with advancing (mid-trimester) pregnancy, although in HT, l-arginine tended to decrease between 16 and 20weeks, a decline consistent in PE. Conclusion These data support a modest role for ADMA and related metabolites in the pathogenesis of hypertensive pregnancy.