R. Faber

Predictive Value of Maternal Angiogenic Factors in Second Trimester Pregnancies With Abnormal Uterine Perfusion

Angiogenic factors like placental growth factor and its antiangiogenic antagonist soluble fms-like tyrosine kinase 1 (sFlt1) are closely related to the pathogenesis of preeclampsia and intrauterine growth restriction. Because it is known that altered maternal sFlt1 and placental growth factor levels are detectable weeks before the onset of these pregnancy complications, it was the aim of the study to investigate the predictive value of these markers in high-risk second trimester pregnancies characterized by abnormal uterine perfusion. This prospective study includes 63 second trimester pregnant women with abnormal uterine perfusion. Twenty five of them developed a later complication (12 with preeclampsia, 11 with intrauterine growth restriction, and 2 with intrauterine death), whereas 38 had a normal course of pregnancy. Pregnancies with adverse pregnancy outcome showed in the second trimester significantly higher sFlt1 (1403.6±555 versus 451.8±42 pg/mL; P<0.05) and lower placental growth factor (139.6±24 versus 184.1±21 pg/mL) levels compared with those with normal outcome. These alterations were more pronounced in pregnancies with subsequent preeclampsia compared with intrauterine growth restriction and early onset diseases (delivery <34 weeks) compared with late-onset diseases. The combination of Doppler and sFlt1 increases the sensitivity of Doppler alone for iatrogenic preterm delivery from 64% up to 79% and the specificity from 63% up to 80%. Using both factors, sFlt1 and placental growth factor, early onset preeclampsia can be predicted with 83% sensitivity and 95% specificity. We conclude that the concurrent measurement of uterine perfusion and angiogenic factors allows an efficient prediction of early onset pregnancy complications, particularly preeclampsia.

Angiotensin II Type 1 Receptor Agonistic Antibodies Reflect Fundamental Alterations in the Uteroplacental Vasculature

Abnormal uterine perfusion detected by Doppler sonography reflects impaired trophoblast invasion, a factor involved in the pathogenesis of pregnancy complications such as preeclampsia or intrauterine growth retardation. Recent studies have demonstrated an autoantibody against the angiotensin type 1 (AT1) receptor in pregnant women with preeclampsia. Our aim was to determine whether the AT1 autoantibody precedes the clinical symptoms and is thus predictive of preeclampsia. We therefore detected this antibody in serum from second trimester pregnancies with abnormal uterine perfusion because these women show an indirect sign of inadequate trophoblast invasion. Then the AT1 autoantibody distribution/concentration was compared with that of women at term with or without pregnancy pathology. The AT1 autoantibody was already detectable in second trimester pregnant women with abnormal uterine perfusion before the clinical manifestation of preeclampsia (80%). However, it was also found in second trimester pregnant women with abnormal uterine perfusion who later developed intrauterine growth retardation (60%) or even had a normal course of pregnancy (62%). In the third trimester, the AT1 autoantibody was demonstrated in 89% of patients with manifest preeclampsia, 86% of those with manifest intrauterine growth retardation, and even in healthy pregnant women at term with a history of abnormal uterine perfusion in the second trimester. We conclude that the AT1 autoantibody is an early but nonspecific marker for preeclampsia. The generation of this antibody seems to be associated with distinct types of pregnancy disorders resulting from impaired placental development. The AT1 autoantibody may thus be causative for pathological uteroplacental perfusion.

Circulatory soluble endoglin and its predictive value for preeclampsia in second-trimester pregnancies with abnormal uterine perfusion

OBJECTIVE Soluble endoglin (sEng) is increased dramatically in preeclampsia and acts synergistically with soluble fms-like tyrosine kinase 1 (sFlt1) to promote the preeclamptic phenotype. The aim of this study was to investigate whether the sEng increase was present already in second-trimester pregnancies with abnormal uterine perfusion and whether the pregnancy was at risk for preeclampsia. STUDY DESIGN This prospective study includes 77 second-trimester pregnant women with abnormal uterine perfusion. sEng and sFlt1 were measured with an enzyme-linked immunosorbent assay. RESULTS Adverse pregnancy outcome was associated with higher sEng levels in the second trimester. SEng was highest in those pregnancies with early-onset preeclampsia. Combined analysis of sEng and sFlt1 is able to predict early-onset preeclampsia with a sensitivity of 100% and a specificity of 93.3%. CONCLUSION Elevated sEng levels are detectable in second-trimester pregnancies with abnormal uterine perfusion and subsequent pregnancy complications. The concurrent measurement of uterine perfusion and angiogenic factors allows a highly efficient prediction of early-onset preeclampsia.

Joint symbolic dynamic analysis of beat-to-beat interactions of heart rate and systolic blood pressure in normal pregnancy.

Pregnancy induces important changes in the autonomic control. Measures of heart rate (HR) variability and systolic blood pressure (SP) variability are sensitive to those changes. The interactions between HR and SP are complex and strongly non-linear. Therefore they cannot be completely described by linear analysis techniques. A study of joint symbolic dynamics is presented as a new short-term non-linear analysis method to investigate the interactions between HR and SP. Continuous, non-invasive 30 min blood pressure recordings (Portapres) of 25 pregnant and 14 non-pregnant women were analysed. Time series of beat-to-beat HR and SP were extracted. Using the concept of joint symbolic dynamics, HR and SP changes were transformed into a bivariate symbol vector. Subsequently, this symbol vector was transformed into a word series (words consisting of three successive symbols), and the probability of occurrence of each word type was calculated and compared between both groups. Significant differences were found in five word types between pregnant and non-pregnant women: w0,4(0.021±0.011 against 0.008±0.006; p=0.022), w4,6(0.020±0.010 against 0.007±0.003; p=0.001), w3,2(0.004±0.003 against 0.007±0.003; p=0.038), w6,5(0.009±0.007 against 0.023±0.008; p<0.001) and w3,6(0.011±0.007 against 0.023±0.008; p=0.001). Joint symbolic dynamics provides an efficient non-linear representation of HR and SP interactions that offers simple physiological interpretations.

Identification of the causes of intrauterine death during 310 consecutive autopsies

OBJECTIVE Evaluation of causes of death in stillborn infants. METHODS During a five-year period, 310 consecutive autopsies of stillborn infants were performed using a standardized protocol with systematic examination of all major cranial, thoracic and abdominal organs including microscopic examination. RESULTS In 71%, the intrauterine death (ID) occurred up to the end of the 37th week of gestation. Thirty-seven percent (115/310) stillbirths represented with maceration and about one-half with minor or major malformations. Thirty-one percent (53/171) of them were responsible for intrauterine death. In 83% (44/53), the intrauterine death of the malformed fetus occurred before the end of 37th week of gestation, most of them (48/53, 90.6%) were small for gestational age infants. In 75.5% (234/310), the placental villous tree and the umbilical cord represented pathologic conditions. In 191 cases (61.1%), utero-placental pathology was responsible for intrauterine death. Intrauterine infections and traumatic lesions were accompanied by intrauterine death in 2.2 and 1.3%, respectively. In 15.2%, unexplained intrauterine death (because of severe maceration, the placenta was not available for autopsy or insufficient clinical data) occurred. CONCLUSIONS Perinatal autopsy may be valuable in three ways: the confirmation of ante-mortem diagnoses; the identification of unexpected disorders; and exclusion of other (perhaps inheritable) conditions which might be have caused the intrauterine death. Clinically valuable information, obtained from the autopsy, can be improved by high autopsy rate and performing perinatal necropsies by specially trained pathologists.

Baroreflex sensitivity, heart rate, and blood pressure variability in normal pregnancy

Heart rate variability is a relevant predictor of cardiovascular risk in humans. However, to use heart and blood pressure (BP) variability or baroreflex sensitivity as markers for hypertensive pregnancy disorders, it is first necessary to describe these parameters in normal pregnancy. To accommodate the complexities of autonomic cardiovascular control we added parameter domains of nonlinear dynamics to conventional linear methods of time and frequency domains. The BP of 27 women with normal pregnancy and 14 nonpregnant women were monitored at a high resolution (200 Hz sampling frequency) using a Portapres for 30 min. The pregnant women were divided into groups of 32 or less or greater than 32 weeks of gestation. Pregnant and nonpregnant women were classified into subclasses of maternal age of less than 28 or 28 or more years. Except for two single parameter domains, we found no significant differences in heart rate and BP variability for pregnant women with different gestational age or different maternal age. Moreover, no significant differences in spontaneous baroreflex sensitivity could be found between pregnant women regardless of either their age or gestational age. In contrast, all measures of nonlinear dynamics of heart rate variability as well as all parameter domains of spontaneous baroreflex sensitivity showed significant changes between pregnant and nonpregnant women, whereas BP variability did not differ between those groups. This complex assessment of autonomic cardiovascular regulation has shown that the parameters tested are stable in the second half of normal pregnancy, and might have the potential to be excellent indicators of pathophysiologic conditions.

Differential regulation of visfatin and adiponectin in pregnancies with normal and abnormal placental function

Objective   There is compelling evidence that insulin resistance may play a pivotal role in the development of pregnancy complications including pre‐eclampsia and intrauterine growth restriction (IUGR). As dysregulation of visfatin and adiponectin is found in insulin resistance, both adipokines might contribute to pregnancy disorders.

Serum levels of the adipokine visfatin are increased in pre‐eclampsia

Objective  Pre‐eclampsia (PE) is a serious cardiovascular complication in pregnancy which shares risk factors with the metabolic syndrome including insulin resistance and obesity. Recently, visfatin was introduced as a novel insulin‐mimetic adipokine which is up‐regulated when weight is gained. In the current study, we investigated visfatin serum levels in pre‐eclamptic patients as compared to healthy gestational age‐matched controls.

Soluble fms-like Tyrosine Kinase 1

To the Editor: Soluble fms-like tyrosine kinase 1 (sFlt1), a splice variant of the vascular endothelial growth factor receptor Flt1 and a potent inhibitor of vascular endothelial growth factor, has...

New insights into the biology of preeclampsia

Abstract Despite recent research progress, the biology of preeclampsia is still poorly understood and neither effective prediction nor causal therapy have yet emerged. Nevertheless, recent studies have documented new and exciting pathophysiological mechanisms for the origin and development of preeclampsia. These studies provide a more differentiated view on alterations of particular peptide systems with strong impact on angiogenesis and cardiovascular regulation in this pregnancy disorder. With the identification of the antiangiogenic factor soluble fms-like tyrosine kinase 1 and the agonistic autoantibody to the angiotensin II type 1 receptor, two factors have been described with a clear linkage to the development of the disease. This review focuses on the most recent and relevant insights into the biology of preeclampsia and develops hypotheses regarding possible links between the reported aspects of preeclampsia.