Werner Rath

Genes and the preeclampsia syndrome.

Abstract Preeclampsia is specific to pregnancy and is still a leading cause of maternal and perinatal mortality and morbidity, affecting about 3% of women, but the underlying pathogenetic mechanisms still remain unclear. Immune maladaptation, placental ischemia and increased oxidative stress represent the main components discussed to be of etiologic importance, and they all may have genetic implications. Since the familial nature of preeclampsia is known for many years, extensive research on the genetic contribution to the pathogenesis of this severe pregnancy disorder has been performed. In this review, we will overview the linkage and candidate gene studies carried out so far as well as summarize important historical notes on the genetic hypotheses generated in preeclampsia research. Moreover, the influence of maternal and fetal genes and their interaction as well as the role of genomic imprinting in preeclampsia will be discussed.

Interleukin-1beta and interleukin-8 concentrations in the Lower uterine segment during parturition at term

Objective To assess the roles of interleukin-1β, interleukin-8, and fibroblasts in the lower uterine segment during parturition. Methods Lower uterine segment biopsy specimens were obtained from 36 women undergoing cesarean delivery at various stages of cervical dilation (less than 2 cm, n = 8; 2 to less than 4 cm, n = 9; 4-6 cm, n = 10; more than 6 cm, n = 9). The concentrations of interleukin-1β and interleukin-8 in protein extracts prepared from the tissue samples were measured by enzyme immunoassays. The effect of incubation with interleukin-1β (30 U/mL) on interleukin-8 secretion by lower uterine segment fibroblasts in vitro also was determined. Results The median interleukin-1β concentration in the specimens increased from 1.3 pg/mg of total protein at less than 2 cm of dilation to 22.2 pg/mg of total protein at 4-6 cm of dilation (P < .05). No further increase was detectable after 6 cm of dilation. The interleukin-8 concentration increased from 17.2 pg/mg of total protein at less than 2 cm of dilation to 2080.7 pg/mg of total protein at 4-6 cm of dilation (P < .05), thus paralleling the increase in interleukin-1β concentration. Interleukin-1β induced a significant increase in interleukin-8 secretion by fibroblasts in vitro, from 0.8 ng/106 cells to 35.6 ng/106 cells. Conclusion The increase in interleukin-8 concentration in the lower uterine segment during parturition may be induced by interleukin-1β and fibroblasts may be one of the sources of this interleukin-8.

Elevated soluble adhesion molecules in women with pre-eclampsia: Do cytokines like tumour necrosis factor-α and interleukin-1β cause endothelial activation?

OBJECTIVE The purpose of the present study was to evaluate the clinical significance of tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) for endothelial cell activation in pre-eclampsia. Therefore, we determined and compared the correlations between these cytokines and circulating adhesion molecules in the sera of pre-eclamptic pregnant women, normotensive pregnant women and nonpregnant women. METHODS The soluble adhesion molecules VCAM-1, ICAM-1, E-selectin, and P-selectin were determined in the serum of 38 pre-eclamptic pregnant women and 40 normotensive pregnant and nonpregnant controls using ELISA-techniques. We correlated these serum concentrations with the serum levels of TNF-alpha and IL-1beta, respectively, also determined by ELISA. RESULTS Elevated serum levels of VCAM-1 and E-selectin could be detected in pre-eclamptic patients, with and without HELLP-syndrome. In contrast, no increased serum concentration of ICAM-1, P-selectin, TNF-alpha and IL-1beta were found in these patients. While significant correlation between VCAM-1 and E-selectin could be determined (r=0.604; p<0.001) no unambiguous correlations, however, were found between TNF-alpha or between IL-1beta and the examined adhesion molecules or the selectins. CONCLUSIONS In contrast to in vitro investigations on cultured umbilical vein endothelium, our experimental results indicate that the cytokines TNF-alpha and IL-1beta can not explain endothelial cell activation, and that their measurement in serum is not useful for the detection of pre-eclampsia.

Interplay between Vascular Endothelial Growth Factor (VEGF) and Nuclear Factor Erythroid 2-related Factor-2 (Nrf2) IMPLICATIONS FOR PREECLAMPSIA

Background: Several studies have suggested that decreasing VEGF levels might result in placental oxidative stress in preeclampsia. Results: VEGF activates Nrf2 in an ERK1/2-dependent manner, protecting against oxidative stress, and, in turn, up-regulates VEGF expression. Conclusion: Reduced VEGF bioavailability may lead to aggregation of oxidative stress and result in preeclampsia. Significance: Nrf2 activation might be considered as an adjunct therapeutic strategy to combat preeclampsia. Several recently published studies have suggested that decreasing VEGF levels result in placental oxidative stress in preeclampsia, although the question as to how decreased VEGF concentrations increase oxidative stress still remains unanswered. Here, we show that VEGF activated Nrf2, the main regulating factor of the intracellular redox balance, in the cytotrophic cell line BeWo. In turn, this activated the production of antioxidative enzymes thioredoxin, thioredoxin reductase, and heme oxygenase-1, which showed a decrease in their expression in the placentas of preeclamptic women. Nevertheless, this activation occurred without oxidative stress stimulus. As a consequence, the activation of Nrf2 protected BeWo cells against H2O2/Fe2+-induced oxidative damage. We further show that VEGF up-regulated the expression of itself. A positive feedback loop was described in which VEGF activated Nrf2 in an ERK1/2-dependent manner; the up-regulation of HO-1 expression by Nrf2 augmented the production of carbon monoxide, which in turn up-regulated VEGF expression. In conclusion, VEGF induces the Nrf2 pathway to protect against oxidative stress and, via a positive feedback loop, to elevate VEGF expression. Therefore, decreased VEGF bioavailability during preeclampsia may result in higher vulnerability to placental oxidative cell damage and a further reduction of VEGF bioavailability, a vicious circle that may end up in preeclampsia.

Pregnancy complications in women with childhood sexual abuse experiences

OBJECTIVE Childhood sexual abuse (CSA) has an estimated prevalence of 20% and has a constantly growing list of known long-term consequences on physical as well as psychological health which may also influence obstetrical care attributed to it. However, scientific data on the association of CSA and pregnancy are sparse. Therefore, the study investigated pregnancy complications in women exposed to CSA. METHODS The study was designed as a cohort study comparing 85 women exposed to CSA with 170 matched unexposed women. CSA was identified by interview using modified questions from Wyatt [Child Abuse Negl 9 (1985) 507-519]. Data on pregnancy complications were collected by questionnaire and based on entries in a booklet (Mutterpass) in which all relevant data on pregnancy are documented at each prenatal consultation for any women attending prenatal care in Germany. Statistical analysis was performed with chi square, Fishers Exact Test, and multiple logistic regression analysis to control the association between CSA and pregnancy complications for confounders significant in univariate analysis, i.e., physical abuse, other adverse experiences during childhood, abuse during pregnancy, substance abuse, and occupation. RESULTS Women exposed to CSA were significantly more often hospitalized during pregnancy (41.2%/19.4%; OR 2.91, CI 1.64-5.17). They presented more often complications such as premature contractions (38.8%/20%; OR 2.54 CI 1.43-4.51), cervical insufficiency (25.9%/9.4%; OR 3.36, CI 1.65-6.82), and premature birth (18.8%/8.2%; OR 2.58, CI 1.19-5.59). CONCLUSION Therefore, health care providers should adapt prenatal care to the specific needs of women exposed to CSA.

Diagnosis and treatment of peripartum bleeding

Abstract Severe peripartum hemorrhage (PPH) contributes to maternal morbidity and mortality and is one of the most frequent emergencies in obstetrics, occurring at a prevalence of 0.5–5.0%. Detection of antepartum risk factors is essential in order to implement preventive measures. Proper training of obstetric staff and publication of recommendations and guidelines can effectively reduce the frequency of PPH and its resulting morbidity and mortality. Therefore, an interdisciplinary expert committee was formed, with members from Germany, Austria, and Switzerland, to summarize recent scientific findings. An up-to-date presentation of the importance of embolization and of the diagnosis of coagulopathy in PPH is provided. Furthermore, the committee recommends changes in the management of PPH including new surgical options and the off-label use of recombinant factor VIIa.

Anal sphincter injury during vaginal delivery--an argument for cesarean section on request?

Abstract Aims: Fear of damage to the pelvic floor from vaginal delivery and long-term sequelae (urinary and anal incontinence) sometimes being cited as an indication for cesarean section on request. The aim of the present study was to compare the effects of vaginal delivery versus elective cesarean section on anal sphincter function. Material and methods: We studied 71 consecutive women six weeks before delivery, 52 of them 4–6 weeks after delivery, and all patients with occult sphincter lesions 3months after delivery. A bowel function questionnaire was completed, and anal endosonography, manometry, and measurement of the pudendal-nerve terminal motor latency were performed. Results: Forty-two (80,8 percent) patients were delivered vaginally, ten (19,2 percent) by elective cesarean section at term. Clinically recognized anal sphincter injuries occurred in 9.5 percent (4) of patients, two of them developed incontinence for gas. The overall incidence of anal incontinence after vaginal delivery was 4.8 percent. Occult sphincter defects were identified endosonographically in 19 percent (8) of women, there was no reported case of any anal incontinence 3 months after delivery. No woman delivered by cesarean section had altered anal continence or any significant change in anal pressures, rectal sensibility, and PNTML. Conclusion: Severe sphincter tear is the single most important factor leading to anal incontinence in women, whereas occult sphincter defects are rarely associated with short-term sequelae, but may predispose to the development of anal incontinence later on in life. Elective cesarean section should be recommended for women at increased risk for anal incontinence.

BMI : new aspects of a classical risk factor for hypertensive disorders in pregnancy

HDP (hypertensive diseases in pregnancy) are one of the leading causes of maternal and fetal mortality and morbidity. BMI (body mass index) is an established risk factor for pre-eclampsia, but its role in HELLP syndrome is unknown. We therefore investigated BMI as a risk factor in the development of HELLP syndrome. At the beginning of pregnancy, BMI was measured in 1067 women with a history of HDP and 1063 controls. Diagnoses of HDP were classified according to ISSHP (International Society for the Study of Hypertension in Pregnancy) and BMI according to WHO (World Health Organization) criteria. After verification of exclusion criteria and matching for confounders, 687 women with hypertensive diseases in pregnancy and 601 controls remained for statistical evaluation by chi(2) test and multiple logistic regressions. As a continuous variable, the increase in BMI was associated with an increase in the development of gestational hypertension {OR (odds ratio), 1.1 [95% CI (confidence interval) 1.062-1.197]} and pre-eclampsia [OR, 1.1 (95% CI, 1.055-1.144)]}, but not for HELLP syndrome. According to WHO definitions, overweight women (BMI > or =25 and <30 kg/m(2)) had a 2-fold (95% CI, 1.365-2.983) risk and obese women (BMI > or =30 kg/m(2)) had a 3.2-fold (95% CI, 1.7-5.909) risk of developing pre-eclampsia when compared with women of normal weight (BMI > or =15.5 and <25 kg/m(2)). Being overweight or having obesity had no effect on the risk of HELLP syndrome. As an increased BMI is correlated with the risk of developing pre-eclampsia but not HELLP syndrome, both diseases have a different risk profile. This finding supports that underlying physiological mechanisms in pre-eclampsia vary from those in HELLP syndrome.

Emotional stress and the risk to develop hypertensive diseases in pregnancy.

Objective: Cardiovascular diseases are strongly influenced by stress and do share several risk factors with hypertensive diseases in pregnancy (HDP). The aim of the study is to investigate the correlation between emotional stress during pregnancy and the risk for HDP. Methods: A self-administered questionnaire comprising obstetrical and psychosocial questions was completed by 725 patients and 880 controls matched for age, parity, nationality, and educational level. Results: Emotional stress during pregnancy was associated with a 1.6-fold increased risk for HDP. Conclusion: Psychosocial interventions to reduce emotional stress during pregnancy may help to decrease the risk to develop HDP.

The role of soluble adhesion molecules in evaluating endothelial cell activation in preeclampsia.

OBJECTIVE Adhesion molecules, such as vascular cell adhesion molecule 1, are known to be increased in the serum of patients with preeclampsia, indicating that these molecules are possible markers of endothelial cell activation. We investigated the influence of serum from women with preeclampsia on the expression of adhesion molecules by cultured endothelial cells. STUDY DESIGN Human umbilical vein endothelial cells were cultured in Ham/Iscove modified Dulbeccos medium containing 20% pooled human serum, l -glutamine (200 mmol/L), penicillin, and streptomycin. We stimulated these cells for 24 hours with sera from patients with preeclampsia and then determined the levels of vascular cell adhesion molecule 1, intercellular cell adhesion molecule 1, E-selectin, and P-selectin in the supernatant and in the maternal serum by means of enzyme-linked immunosorbent assay. These results were compared with those of sera obtained from normotensive pregnant and nonpregnant women. In addition, the expressions of these adhesion molecules on the endothelial surface were determined by immunofluo-rescence microscopy. RESULTS Only for vascular cell adhesion molecule 1 and E-selectin were elevated plasma levels found in hypertensive patients, whereas intercellular cell adhesion molecule 1 and P-selectin showed similar plasma levels in all the patients. No differences in the levels of the adhesion molecules were found between the supernatants of endothelial cell cultures after stimulation with sera from patients with preeclampsia and those after stimulation with normotensive control sera. In contrast, with immunofluorescence microscopy we could detect higher amounts of vascular cell adhesion molecule 1, intercellular cell adhesion molecule 1, and E-selectin on the endothelial surface after stimulation with sera from women with preeclampsia. CONCLUSION Although vascular cell adhesion molecule 1 and E-selectin were elevated in maternal serum samples from women with preeclampsia and on the endothelial surface after stimulation with such sera, there were no detectable increases in the levels of both of these adhesion molecules in the supernatant of cultured endothelial cells. We therefore assume that sera from women with preeclampsia may cause endothelial cell activation. Because we could not detect elevated concentrations of any of the investigated adhesion molecules in the supernatant of endothelial cells, we believe that factors other than sera from women with preeclampsia seem to play a major role in the release of soluble forms of adhesion molecules from the endothelial membrane.