Preventing Recurrent Preeclampsia by Tailored Treatment of Nonphysiologic Hemodynamic Adjustments to Pregnancy.

[Figure: see text].

Cardiac dysfunction after preeclampsia; an overview of pro- and anti-fibrotic circulating effector molecules.

Preeclampsia (PE) is strongly associated with heart failure (HF) later in life. The aberrant cardiac remodelling is likely initiated or amplified during preeclamptic pregnancy. Aberrant remodelling often persists after delivery and is known to relate strongly to cardiac fibrosis. This review provides an overview of pro- and anti- fibrotic circulating effector molecules that are involved in cardiac fibrosis and their association with PE. Women with PE complicated pregnancies show increased ANG-II sensitivity and elevated levels of the pro-fibrotic factors IL-6, TNF-α, TGs and FFAs compared to uncomplicated pregnancies. In the postpartum period, PE pregnancies compared to uncomplicated pregnancies have increased ANG-II sensitivity, elevated levels of the pro-fibrotic factors IL-6, TNF-α, LDL cholesterol and leptin, as well as decreased levels of the anti-fibrotic factor adiponectin. The review revealed several profibrotic molecules that associate to cardiac fibrosis during and after PE. The role that these fibrotic factors have on the heart during and after PE may improve the understanding of the link between PE and HF. Furthermore they may provide insight into the pathways in which the relation between both diseases can be understood as potential mechanisms which interfere in the process of cardiovascular disease (CVD). Unravelling the molecular mechanism and pathways involved might bring the diagnostic and therapeutic abilities of those factors a step closer.

Obesity in pregnancy causes a volume overload in third trimester.

BACKGROUND: Obesity is a major risk factor for cardiovascular diseases. In this study, we aimed to investigate the maternal circulatory differences during pregnancy between obese and normal weight women. MATERIALS AND METHODS: The functioning of the maternal circulation (arteries, veins, heart and body fluid) was assessed by ECG-Doppler ultrasound, impedance cardiography (ICG) and bio-impedance during pregnancy in obese women (BMI ≥30 kg/m2 ) and normal weight, nonobese women (BMI 20-25 kg/m2 ). In this observational study, 232 assessments were performed in the obese group, whereas 919 assessments were performed in the nonobese group. RESULTS: Relative to nonobese women, the overall cardiovascular function in obese women during first and second trimester is consistent with a high volume/low-resistance circulation. In third trimester, cardiac output of obese women decreases from 9.2 (8.2-10.7) L/min to 8.5 (7.6-9.6) L/min (P = .037) whereas this is not true in the nonobese women (from 7.8 (7-8.5) L/min to 7.8 (6.8-8.9) L/min, P = .536). Simultaneously, the persistently lower peripheral vascular resistance in obese vs nonobese women disappears (880 (761-1060) dyn.sec/cm5 vs 928 (780-1067). CONCLUSIONS: The circulatory gestational adaptations between nonobese and obese women were generally similar. The findings in the third trimester suggest that a pregnancy in obese women start as a state of high volume/low resistance, gradually shifting to a volume overload with decrease of cardiac output and disappearance of low vascular resistance. This evolution makes obese women vulnerable for gestational hypertensive diseases.

Accuracy and precision of USCOM versus transthoracic echocardiography before and during pregnancy.

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.

Development of a biophysical screening model for gestational hypertensive diseases.

BACKGROUND: To investigate the possibility of using maternal biophysical parameters only in screening for the different types of gestational hypertensive diseases. METHODS: A total of 969 pregnant women were randomly screened in first and second trimester, of which 8 developed Early-onset Preeclampsia, 29 Late-onset Preeclampsia, 35 Gestational Hypertension and 897 women had a normal outcome. An observational maternal hemodynamics assessment was done via standardized electrocardiogram-Doppler ultrasonography, Impedance Cardiography and bio-impedance, acquiring functional information on heart, arteries, veins and body fluid. Preliminary prediction models were developed to test the screening potential for early preeclampsia, late preeclampsia and gestational hypertension using a Partial Least Square Discriminant Analysis. RESULTS: A combined model using maternal characteristics with cardiovascular parameters in first and second trimester offers high screening performance with Area Under the Curve of 99,9% for Early-onset Preeclampsia, 95,3% for Late-onset Preeclampsia and 94% for Gestational Hypertension. CONCLUSIONS: Using biophysical parameters as fundament for a new prediction model, without the need of biochemical parameters, seems feasible. However, validation in a large prospective study will reveal its true potential.

Low Volume Circulation in Normotensive Women Pregnant with Neonates Small for Gestational Age.

BACKGROUND: Pregnancies complicated with small for gestational age (SGA) neonates are reported with maternal circulatory maladaptations. OBJECTIVES: We aimed to understand the pathophysiology of the maternal circulation in normotensive SGA pregnancies and to point out the trimestral differences from those with appropriate-to-large (non-SGA [NGA]) neonates. METHODS: An observational study was conducted in 3 trimestral cohorts of normotensive pregnancies, categorized after birth according to neonatal birth weight percentile (BW%) as SGA (BW% ≤10, n = 158) or NGA (BW% > 10, n = 1,038). Standardized electrocardiogram-Doppler ultrasound, impedance cardiography, and bio-impedance were used to assess the maternal heart, arteries, veins, and fluid. RESULTS: Diastolic blood pressure and mean arterial pressure were not significantly different, unless in the third trimester. In SGA compared to NGA pregnancies, total peripheral resistance (TPR) was higher and total arterial compliance, cardiac output (CO), and total body water (TBW) were lower throughout pregnancy. Venous return-enhancing functions were activated. In NGA but not SGA pregnancies, a positive correlation was found between BW% and CO + TBW and a negative correlation between BW% and TPR. CONCLUSIONS: SGA pregnancies are characterized by lower maternal body fluid volume and CO, while normal blood pressures are maintained via increased TPR already from the first trimester onwards. Pregnancy-induced hemodynamic changes are superimposed on these characteristics.

Gestational hypertensive disorders show unique patterns of circulatory deterioration with ongoing pregnancy.

A combined assessment of heart, arteries, veins, and body fluid content throughout pregnancy has not yet been reported. We hypothesized that a gradual aggravation of circulatory dysfunction exists from the latent to the clinical phase of gestational hypertensive disease (GHD), and that pathways are unique for preeclampsia with early onset < 34 wk (EPE) and late onset ≥ 34 wk (LPE), and gestational hypertension (GH). Women with singleton pregnancy and no known diseases were invited for a prospective, observational study and had standardized sphygmomanometric blood pressure measurement, bioimpedance body water spectrum analysis, impedance cardiography for cardiac and arterial assessment, and combined Doppler-ECG of hepatic and renal interlobar veins and uterine arteries. Outcome was categorized as uncomplicated (UP, n = 1,700), EPE ( n = 87), LPE ( n = 218), or GH ( n = 188). A linear mixed model for repeated measurements, corrected for age, parity, and body mass index, was employed in SAS 9.4 to analyze trimestral changes within and between groups. From the first to the third trimester, body water increased in all groups, and an increasing number of abnormal parameters relative to UP occurred in all GHD. First-trimester blood pressure and peripheral resistance were higher in GHD than UP, together with increased uterine flow resistance and extracellular water in EPE, and with lower heart rate and aorta flow velocity in LPE. An overall gestational rise of body water volumes coexists with a gradual worsening of cardiovascular dysfunction in GHD, of which pathophysiological pathways are unique for EPE, LPE, and GH, respectively.

Body fluid volume homeostasis is abnormal in pregnancies complicated with hypertension and/or poor fetal growth.

OBJECTIVES: To evaluate body water volumes and cardiac output in each trimester of pregnancies complicated with hypertension and/or poor fetal growth, relative to uncomplicated pregnancy. METHODS: In this semi-longitudinal cohort study, a standardised non-invasive maternal hemodynamics assessment in first, second or third trimester was performed in 1068 women with uncomplicated pregnancy (UP), 75 with early onset (EPE) and 117 with late onset preeclampsia (LPE), 139 with gestational hypertension (GH), 129 with small for gestational age (SGA) neonates and 43 with essential hypertension (EH). Women with hypertension or SGA were included prior to onset of symptoms or at diagnosis of disease; 46% of women (758/1631) were assessed in ≥ 2 trimesters. Impedance cardiography and spectrum analysis were used to measure cardiac output, total body water (TBW), extracellular (ECW) and intracellular water (ICW). A linear mixed model was used for inter-trimestrial comparison of parity-, age- and BMI-corrected values within and between groups. RESULTS: For all pregnancies, TBW is higher in each consecutive trimester, mainly due to increasing fraction of ECW (ECW%). Compared to first trimester UP, ECW and ECW% are higher in EPE whereas TBW, ECW and ICW are lower in SGA. Compared to inter-trimestrial differences in UP, abnormal changes for body water volumes are observed in GH, EPE and LPE and for CO in EPE and LPE. Changes in EH are not different from UP. CONCLUSIONS: This study is the first to show that concomitant gestational changes of ECW and CO are different from UP already in preclinical stages of pregnancies complicated with hypertension and/or poor fetal growth, except EH. This finding highlights the relevance of early gestational assessment of maternal body fluid status in pregnancies at risk for hypertension or poor fetal growth.

Outcome of Epithelial Ovarian Cancer: Time for Strategy Trials to Resolve the Problem of Optimal Timing of Surgery.

INTRODUCTION: The standard treatment of ovarian cancer is the combination of debulking surgery and chemotherapy. There is an ongoing discussion on which treatment is best: primary debulking surgery (PDS) or neoadjuvant chemotherapy with interval debulking (NACT-IDS). Even a large randomized trial has not settled this issue. We examined whether comparing a specified treatment protocol would not be a more logical approach to answer this type of discussions. METHODS: A retrospective study of 142 consecutively treated patients according to a fixed protocol between 2000 and 2012 was conducted. Disease-free survival and overall survival were calculated by univariate and multivariate analyses for the whole group and for advanced stages separately. Specific differences between PDS and NACT-IDS were studied. Comparison of results from large databases was made. RESULTS: Disease-free survival and overall 5-year survival for the whole group were 35% and 50%. For the advanced stages, disease-free survival and overall 5-year survival were 14% and 36%, with a median disease-free and overall survival of 16 and 44 months. Of the 98 women with advanced ovarian carcinoma, 54% of operable patients underwent PDS and 44% underwent NACT-IDS. More patients in the PDS group were optimally (<1 cm) debulked: 80% vs 71%. There was no significant difference in survival between PDS or NACT-IDS. Optimally debulked patients had a significant better overall survival in multivariate analysis with a hazard ratio of 2.1. DISCUSSION: Outcome of treatment according to a fixed protocol with a mixture of PDS and NACT-IDS was similar to results from large databases. We hypothesize that comparison of a specific strategy may yield more useful results than awaiting the perfect randomized trial.

Maternal venous hemodynamics assessment for prediction of preeclampsia should be longitudinal.

OBJECTIVE: To address the question whether maternal venous abnormalities exist at the onset of, or develop during the course of pregnancy. METHODS: We present five case reports of patients with early onset preeclampsia (EPE), late onset preeclampsia (LPE), gestational hypertension (GH), essential hypertension (EH) and an uncomplicated pregnancy (UP). Maternal renal and hepatic vein Doppler waves and maternal venous pulse transit times (VPTT) were assessed in early pregnancy and again shortly before delivery. RESULTS: In all cases, maternal VPTT were normal in early pregnancy and changed to abnormal values in EPE and LPE, which was not true for UP and GH or EH. CONCLUSION: These observations support the view that venous hemodynamic dysfunction of preeclampsia (PE) develops during the course of pregnancy. Therefore, assessment of an individual's venous function for prediction of PE should be serial and longitudinal.

Is there a correlation between maternal venous hemodynamic dysfunction and proteinuria of preeclampsia?

OBJECTIVES: To evaluate in early and late preeclampsia a correlation of maternal venous Doppler flow characteristics with biochemical parameters in maternal serum and urine, or with gestational outcome. STUDY DESIGN: In this observational cross-sectional study, renal interlobar vein impedance index (RIVI) was measured according to a standardised protocol for combined electrocardiogram-Doppler ultrasonography in 86 women with uncomplicated pregnancy, 78 women with late onset preeclampsia (≥34w) and 67 with early onset preeclampsia (<34w). For each group, maternal age, pre-gestational BMI and parity were recorded together with birth weight and -percentile. For both early onset and late onset preeclampsia, maternal serum was analysed for thrombocyte count and concentrations of creatinine, ASAT, ALAT and uric acid and 24h urine collections were analysed for creatinine clearance and proteinuria (mg/24h). A non-parametric Mann-Whitney U-tests was performed for continuous data and a Fisher's exact tests for categorical data. Significant linear dependence between variables was identified using Pearson's correlation coefficient at nominal level a=0.05. RESULTS: Proteinuria was higher in early onset than in late onset preeclampsia (1756mg [838-6116mg] versus 877mg [416-1696mg], p<0.001), and this was also true for RIVI in both left (0.45 [0.40-0.55] versus 0.41 [0.35-0.45], p=0.001) and right kidney (0.45 [0.39-0.55] versus 0.38 [0.30-0.43], p<0.001). In our data set, there was a significant correlation between proteinuria and RIVI of left (correlation coefficient=0.172, p=0.036) and right kidney (correlation coefficient=0.218, p=0.009) in late onset but not early onset preeclampsia. CONCLUSION: Maternal RIVI may correlate with proteinuria of late onset preeclampsia.

Maternal venous hemodynamics in gestational hypertension and preeclampsia.

BACKGROUND: To evaluate characteristics of venous hemodynamics, together with cardiac and arterial function, in uncomplicated pregnancies (UP), non-proteinuric gestational hypertension (GH) and preeclampsia (PE). METHODS: In this observational cross-sectional study, venous hemodynamics was assessed using a standardised protocol for combined electrocardiogram (ECG)-Doppler ultrasonography, together with a non-invasive standardised cardiovascular assessment using impedance cardiography (ICG) in 13 women with UP, 21 with GH, 34 with late onset PE ≥ 34 w (LPE) and 22 with early onset PE < 34 w (EPE). ECG-Doppler parameters were impedance index at the level of hepatic veins (HVI) and renal interlobar veins (RIVI) together with venous pulse transit times (VPTT), as well as resistive and pulsatility index, and arterial pulse transit time (APTT) at the level of uterine arcuate arteries. ICG parameters were aortic flow velocity index (VI), acceleration index (ACI) and thoracic fluid content. Mann Whitney U-test, Kruskall-Wallis test and linear regression analysis with heteroskedastic variance was used for statistical analysis. RESULTS: RIVI in both kidneys was >15% higher (P ≤ .010) in LPE and EPE, as compared to GH and UP. Next to this, >30% lower values for VI and ACI (P ≤ .029), and > 15% lower values for APTT (P ≤ .012) were found in GH, LPE and EPE, as compared to GH. CONCLUSION: In comparison to UP, similar abnormalities of central arterial function and APTT were found in GH, EPE and LPE. Proteinuria of LPE and EPE was associated with increased RIVI, this was not observed in GH.

Improving the reliability of venous Doppler flow measurements: relevance of combined ECG, training and repeated measures.

The nature of venous Doppler waves is highly variable. An additional electrocardiogram (ECG) improves the interpretation of venous Doppler wave characteristics and allows measurement of venous pulse transit time. The purpose of this study was to assess the reproducibility of ECG-guided repeated measurements of venous Doppler flow characteristics before and after sonographer training and the inter- and intra-observer variability. In four groups of 25 healthy women, venous Doppler flow measurements were performed at the level of the kidneys and liver according to a standardized protocol. Intra-observer Pearson correlation coefficients of the renal interlobar vein Doppler indices were ≥ 0.80 with the addition of the ECG, which are higher than the results of a former study. The inter-observer correlation between an experienced ultrasonographer and an inexperienced ultrasonographer improved from ≥ 0.71 to ≥ 0.91 after training. The correlation range of all parameters between two independent observers improved when values were based on repeated measures. The addition of an ECG to the Doppler image, training and repeated measurements are helpful in improving venous Doppler wave interpretation.

Maternal cardiovascular profiling in the first trimester of pregnancies complicated with gestation-induced hypertension or fetal growth retardation: a pilot study.

OBJECTIVE: In this study, we determine whether maternal cardiovascular (CV) profiling can detect first trimester differences between women with uncomplicated pregnancies (UP) and those who will develop gestational hypertensive disorders (GHD) or normotensive fetal growth retardation (FGR). METHODS: Cardiac, arterial, and venous function were evaluated in 242 pregnant women around 12 weeks of gestation, using impedance cardiography (ICG) and combined electrocardiogram - Doppler ultrasonography. After postnatal determination of gestational outcome, first trimester measurements were compared between groups using Mann-Whitney U test for continuous data or Fisher's Exact test for categorical variables (SPSS 20.0). RESULTS: Compared to UP, first trimester aortic flow velocity index [71 ± 0.96 versus 61 ± 4.91 1/1000/s (p = 0.016)], acceleration index [133 ± 2.25 versus 106 ± 11.26 1/100/s(2) (p = 0.023)] and Heather index [23.1 ± 0.35 versus 19.2 ± 1.70 Ω/s(2) (p = 0.019)] were lower in GHD pregnancies, and first trimester stroke volume [77 ± 1.16 versus 67 ± 3.97 ml (p = 0.033)] and cardiac output [7.3 ± 0.10 versus 6.2 ± 0.31 l/min (p = 0.025)] were lower in FGR pregnancies. CONCLUSIONS: Maternal CV function in the first trimester of pregnancy differs between UP and those destined to develop GHD or FGR. This can be assessed with non-invasive maternal CV profiling, opening perspectives for the application of this technique in early gestational screening for GHD and FGR.

Non-invasive assessment of gestational hemodynamics: benefits and limitations of impedance cardiography versus other techniques.

To obtain data for maternal stroke volume and cardiac output during pregnancy, it is preferable to use a non-invasive, accurate and reproducible method. In this aspect, impedance cardiography is an excellent technique which is also highly accessible and easy to perform. This paper is a comprehensive review on the published literature about impedance cardiography and highlights the strengths and limitations of its applications in obstetrics.

PP070. Maternal cardiovascular profiling in the first trimester ofpregnancies complicated with gestation induced hypertension or fetal growth restriction.

INTRODUCTION: Maternal cardiovascular (CV) profiling is useful in the assessment of gestational hypertensive disorders (GHD)(1). The onset of GHD occurs during the first weeks of gestation(2). OBJECTIVE: To evaluate whether CV profiling can detect first trimester differences between women with uncomplicated pregnancies (UP) and those who will develop GHD or fetal growth restriction (FGR). METHODS: CV function was evaluated according to standardised protocols in 242 pregnant women around 12 weeks of gestation, using impedance cardiography (ICG) and combined ECG - Doppler ultrasonography. Outcome was evaluated after delivery and categorized as UP (n=218), GHD with or without proteinuria (n=13), and pregnancies complicated with FGR (n=11). Measurements were compared between groups using Mann-Whitney U test for continuous data or Fisher's Exact test for categorical variables. RESULTS: As compared to UP, women destined to develop GHD showed increased systolic blood pressure, diastolic blood pressure and mean arterial pressure; and decreased ICG aortic velocity - and acceleration index. Pregnancies complicated with FGR showed decreased stroke volume and cardiac output when compared to UP. No differences were found concerning the maternal veins. CONCLUSION: First trimester maternal CV function differs between women with uncomplicated pregnancies and those destined to develop GHD or FGR. Non-invasive CV profiling enables the identification of these differences.

PP078. The influence of maternal position on gestational hemodynamics.

INTRODUCTION: Cardiovascular profiling is useful for gestational hemodynamic studies. Conflicting results of cardiac output evolution from third trimester pregnancy to term are frequently reported. OBJECTIVES: To stress the effect of maternal position in the assessment of maternal cardiac and arterial parameters during normal pregnancy. METHODS: Impedance cardiography measurements were executed during 16 normal pregnancies using a standard protocol with known reproducibility. Gestational evolution of stroke volume, cardiac output, cardiac cycle time intervals, aortic flow parameters and total peripheral vascular resistance was measured in supine, standing and sitting positions. SAS procedure MIXED for linear mixed models was used for each parameter separately. RESULTS: Evolution of stroke volume and cardiac output in supine position differed from standing (p<0.01) and sitting positions (p<0.05). Next to this, pre-ejection period, left ventricular ejection time index, systolic time ratio and total peripheral vascular resistance also showed a different evolution between supine and standing positions (p<0.05); no differences were observed between standing and sitting positions (p⩾0.19). CONCLUSION: Next to the frequently reported cardiac output, gestational evolutions of other pre-load dependent parameters are influenced by maternal position. This study shows the importance of a standardized protocol for the measurement of cardiovascular parameters in pregnancy.