Manfred Moertl

An automated method for the determination of the sFlt-1/PIGF ratio in the assessment of preeclampsia

OBJECTIVE The angiogenic and antiangiogenic factors soluble fms-like tyrosine kinase (sFlt)-1 and placental growth factor (PIGF) have been implicated in the mechanisms of disease responsible for preeclampsia (PE). Moreover, it has been proposed that the concentrations of these markers in maternal serum/plasma may have predictive value. This study evaluates a newly developed Elecsys (Roche, Penzberg, Germany) assay for sFlt-1 and PIGF and tests the value of the sFlt-1/PIGF ratio in the assessment of PE. STUDY DESIGN This multicenter case-control study included 351 patients: 71 patients with PE and 280 gestational age-matched control subjects from 5 European study centers. A total of 595 serum samples were measured for sFlt-1 and PIGF using an automated platform. RESULTS Maternal serum concentrations of sFlt-1 and PIGF significantly separated healthy women and women with PE. The sFlt-1/PIGF ratio had an area under the receiver operating characteristic curve of 0.95. The best performance was obtained in the identification of early-onset PE (area under the receiver operating characteristic curve of 0.97). CONCLUSION Measurement of sFlt-1 and PIGF and calculation of sFlt-1/PIGF ratio can be performed quickly and in a platform available in clinical laboratories. This is a substantial step forward in bringing the determination of these analytes to clinical practice in obstetrics. We propose that sFlt-1, PIGF, and sFlt-1/PIGF ratio may be of value in the prediction of PE and in the differential diagnosis of patients with atypical presentations of PE, and perhaps in the differential diagnosis of women with chronic hypertension suspected to develop superimposed PE.

The sFlt-1/PlGF ratio in different types of hypertensive pregnancy disorders and its prognostic potential in preeclamptic patients

OBJECTIVE The soluble fms-like tyrosine kinase (sFlt-1)/placental growth factor (PlGF) ratio is a reliable tool in the assessment of preeclampsia. We tested the hypothesis that the sFlt-1/PlGF ratio is able to identify women at risk for imminent delivery. We characterized the sFlt-1/PlGF ratio in different types of hypertensive pregnancy disorders. STUDY DESIGN We investigated 388 singleton pregnancies with normal pregnancy outcome, 164 with PE, 36 with gestational hypertension, and 42 with chronic hypertension. sFlt-1 and PlGF were measured in serum samples. RESULTS Patients with preeclampsia had a significantly increased sFlt-1/PlGF ratio as compared with controls and with patients with chronic and gestational hypertension in <34 weeks and ≥34 weeks (P < .001). Time to delivery was significantly reduced in women with preeclampsia in the highest quartile of the sFlt-1/PlGF ratio (P < .001). CONCLUSION The sFlt-1/PlGF ratio allows the identification of women at risk for imminent delivery and is a reliable tool to discriminate between different types of pregnancy-related hypertensive disorders.

Haemodynamic effects of carbetocin and oxytocin given as intravenous bolus on women undergoing caesarean delivery: a randomised trial

Please cite this paper as: Moertl M, Friedrich S, Kraschl J, Wadsack C, Lang U, Schlembach D. Haemodynamic effects of carbetocin and oxytocin given asintravenous bolus on women undergoing caesarean delivery: a randomised trial. BJOG 2011;118:1349–1356.

Changes in haemodynamic and autonomous nervous system parameters measured non-invasively throughout normal pregnancy

OBJECTIVE To examine non-invasively haemodynamic and autonomous parameters throughout normal pregnancy. STUDY DESIGN We used the Task Force Monitor 3040i system to retrieve, record, and calculate haemodynamic as well as autonomous parameters. 20 healthy women were included and scheduled for longitudinal examinations throughout normal pregnancy. Heart rate (HR), blood pressure (BP), stroke volume (SV), cardiac output (CO), systemic vascular resistance (SVR), heart rate variability (HRV), blood pressure variability (BPV), and baroreceptor sensitivity (BRS) were measured. Measurements were performed at gestational week 10(+0)-13(+6), 15(+0)-18(+6), 20(+0)-22(+6), and >30(+0). RESULTS HR increased during gestation showing a significant increase at III versus I trimester (74 bpm vs. 88 bpm, P<.05). Mean arterial pressure remained stable until III trimester, when a significant increase compared to I trimester could be noted (78 mm Hg vs. 86 mm Hg, P<.05). SV and CO remained relatively stable in I and II trimester, and in III trimester significant decreases were observed. In contrast, SVR increased significantly at III trimester (P<.001). Whereas HRV and BPV did not change at different gestational ages, BRS was significantly lower in III trimester compared to I trimester values (P<.05). CONCLUSION The non-invasive determination of cardiovascular and autonomous parameters throughout pregnancy is possible and the results of this pilot study can serve as basic parameters for classifying and assessing cardiovascular and autonomous changes in pathological conditions in pregnancy such as hypertensive disorders.

Phase Synchronization of Hemodynamic Variables at Rest and after Deep Breathing Measured during the Course of Pregnancy

Background The autonomic nervous system plays a central role in the functioning of systems critical for the homeostasis maintenance. However, its role in the cardiovascular adaptation to pregnancy-related demands is poorly understood. We explored the maternal cardiovascular systems throughout pregnancy to quantify pregnancy-related autonomic nervous system adaptations. Methodology Continuous monitoring of heart rate (R-R interval; derived from the 3-lead electrocardiography), blood pressure, and thoracic impedance was carried out in thirty-six women at six time-points throughout pregnancy. In order to quantify in addition to the longitudinal effects on baseline levels throughout gestation the immediate adaptive heart rate and blood pressure changes at each time point, a simple reflex test, deep breathing, was applied. Consequently, heart rate variability and blood pressure variability in the low (LF) and high (HF) frequency range, respiration and baroreceptor sensitivity were analyzed in resting conditions and after deep breathing. The adjustment of the rhythms of the R-R interval, blood pressure and respiration partitioned for the sympathetic and the parasympathetic branch of the autonomic nervous system were quantified by the phase synchronization index γ, which has been adopted from the analysis of weakly coupled chaotic oscillators. Results Heart rate and LF/HF ratio increased throughout pregnancy and these effects were accompanied by a continuous loss of baroreceptor sensitivity. The increases in heart rate and LF/HF ratio levels were associated with an increasing decline in the ability to flexibly respond to additional demands (i.e., diminished adaptive responses to deep breathing). The phase synchronization index γ showed that the observed effects could be explained by a decreased coupling of respiration and the cardiovascular system (HF components of heart rate and blood pressure). Conclusions/Significance The findings suggest that during the course of pregnancy the individual systems become increasingly independent to meet the increasing demands placed on the maternal cardiovascular and respiratory system.

Heart rate variability and baroreceptor reflex sensitivity in early- versus late-onset preeclampsia

Objective To determine whether there are differences in autonomic nervous system function in early- versus late-onset preeclampsia. Methods Matched case-control study. Cases were defined as singleton pregnancies with preeclampsia at < 34+0 weeks of gestation (early-onset preeclampsia) and ≥ 34+0 weeks of gestation (late-onset preeclampsia). For each case in each of the preeclampsia subgroups, three „control”uncomplicated singleton pregnancies were matched by maternal age, height, and week of gestation. Blood pressure and heart rate were measured continuously for 30 minutes in each participant. Baroreceptor reflex sensitivity (assessed using sequence technique), time and frequency domain heart rate variability measures, as SDNN, RMSSD, LFRRI, HFRRI and LF/HFRRI of R-R intervals, were compared between groups (p<0.05 significant). Results 24 women with preeclampsia (10 with early-onset and 14 with late-onset preeclampsia) and 72 controls were included in the study. SDNN, RMSSD and HFRRI were significantly higher in the late-onset preeclampsia group compared to gestational age matched controls (p = 0.033, p = 0.002 and p = 0.018, respectively). No significant differences in SDNN RMSSD and HFRRI between early-onset preeclampsia group and gestational age matched controls were observed (p = 0.304, p = 0.325 and p = 0.824, respectively). Similarly, baroreceptor reflex sensitivity was higher in late-onset preeclampsia compared to controls at ≥ 34 weeks (p = 0.037), but not different between early-onset preeclampsia compared to controls at < 34 weeks (p = 0.50). Conclusions Heart rate variability and baroreceptor reflex sensitivity are increased in late- but not early-onset preeclampsia compared to healthy pregnancies. This indicates a better autonomic nervous system mediated adaptation to preeclampsia related cardiovascular changes in late-onset disease.

Systemic vascular resistance and endogenous inhibitors of nitric oxide synthesis in early- compared to late-onset preeclampsia: preliminary findings

ABSTRACT Objective: To examine systemic vascular resistance index (SVRI), asymmetric (ADMA) and symmetric dimethylarginine (SDMA) levels in preeclampsia at different gestations. Methods: Twenty-four preeclamptic patients (14 at ≥ 34 weeks’) and 72 matched healthy controls were included. SVRI was calculated from impedance cardiography measurements. ADMA and SDMA levels were determined using enzyme-linked immunosorbent assay. Results: SVRI and SDMA were higher in preeclampsia overall, in early onset and late onset compared to controls. SVRI was correlated with ADMA and SDMA, respectively. Conclusions: Early-onset and late-onset preeclampsia are both characterized by increased systemic vascular resistance and elevated levels of nitric oxide synthesis inhibitors.

Maternal cardiovascular and endothelial function from first trimester to postpartum

Objective To explore noninvasively the complex interactions of the maternal hemodynamic system throughout pregnancy and the resulting after-effect six weeks postpartum. Methods Eighteen women were tested beginning at the 12th week of gestation at six time-points throughout pregnancy and six weeks postpartum. Heart rate, heart rate variability, blood pressure, pulse transit time (PTT), respiration, and baroreceptor sensitivity were analyzed in resting conditions. Additionally, hemoglobin, asymmetric and symmetric dimethylarginine and Endothelin (ET-1) were obtained. Results Heart rate and sympathovagal balance favoring sympathetic drive increased, the vagal tone and the baroreflex sensitivity decreased during pregnancy. Relative sympathetic drive (sympathovagal balance) reached a maximum at 6 weeks postpartum whereas the other variables did not differ compared to first trimester levels. Postpartum diastolic blood pressure was higher compared to first and second trimester. Pulse transit time and endothelial markers showed no difference throughout gestation. However, opposing variables PTT and asymmetric dimethylarginine (ADMA) were both higher six weeks postpartum. Conclusions The sympathetic up regulation throughout pregnancy goes hand in hand with a decreased baroreflex sensitivity. In the postpartum period, the autonomic nervous system, biochemical endothelial reactions and PTT show significant and opposing changes compared to pregnancy findings, indicating the complex aftermath of the increase of blood volume, the changes in perfusion strategies and blood pressure regulation that occur in pregnancy.

History of Preeclampsia Adds to the Deleterious Effect of Chronic Stress on the Cardiac Ability to Flexibly Adapt to Challenge

Preeclampsia, a pregnancy-specific disorder, presents a major health problem during gestation, but is also associated with increased risk for cardiovascular complications in later life. We aimed to investigate whether chronic stress experience and preeclampsia may have additive adverse effects on the cardiac ability to flexibly adapt to challenge, that is, to mount an appropriately vigorous heart rate response to an acute psychological challenge, or whether they may perhaps have synergistic effects (e.g., mutual augmentation of effects). Blunted cardiac responding to challenge has been linked to poor health outcomes in the longer term. Women previously affected by preeclampsia and women after uncomplicated pregnancies were tested 15–17 weeks post-partum in a standardized stress-reactivity protocol, while cardiovascular variables were simultaneously recorded. Changes in heart rate and blood pressure in response to the stressor were analyzed with regard to the effects of history of preeclampsia and chronic stress experience. Findings indicated blunted cardiac responses in women with higher chronic stress experience (p = 0.020) and, independently from that, in women with a history of preeclampsia (p = 0.018), pointing to an additive nature of the effects of preeclampsia and chronic stress on impaired cardiovascular functioning. Consequently, if both are present, a history of preeclampsia may add to the already deleterious effects of the experience of chronic stress. The additive nature of the effects suggests that stress-reducing interventions, albeit they will not eliminate the heightened cardiovascular risk in patients with a history of preeclampsia, may improve their overall prognosis by avoiding further accumulation of risk.