Dysregulation of Complement Activation and Placental Dysfunction:A Potential Target to Treat Preeclampsia?

Preeclampsia is one of the leading causes of maternal and neonatal mortality and morbidity worldwide, affecting 2-8% of all pregnancies. Studies suggest a link between complement activation and preeclampsia. The complement system plays an essential role in the innate immunity, leading to opsonization, inflammation, and elimination of potential pathogens. The complement system also provides a link between innate and adaptive immunity and clearance of immune complexes and apoptotic cells. During pregnancy there is increased activity of the complement system systemically. However, locally at the placenta, complement inhibition is crucial for the maintenance of a normal pregnancy. Inappropriate or excessive activation of the complement system at the placenta is likely involved in placental dysfunction, and is in turn associated with pregnancy complications like preeclampsia. Therefore, modulation of the complement system could be a potential therapeutic target to prevent pregnancy complications such as preeclampsia. This review, based on a systematic literature search, gives an overview of the complement system and its activation locally in the placenta and systemically during healthy pregnancies and during complicated pregnancies, with a focus on preeclampsia. Furthermore, this review describes results of animal and human studies with a focus on the complement system in pregnancy, and the role of the complement system in placental dysfunction. Various clinical and animal studies provide evidence that dysregulation of the complement system is associated with placental dysfunction and therefore with preeclampsia. Several drugs are used for prevention and treatment of preeclampsia in humans and animal models, and some of these drugs work through complement modulation. Therefore, this review further discusses these studies examining pharmaceutical interventions as treatment for preeclampsia. These observations will help direct research to generate new target options for prevention and treatment of preeclampsia, which include direct and indirect modulation of the complement system

Vitamins C and E and the risks of preeclampsia and perinatal complications

Copyright © 2006 Massachusetts Medical Society.Background: Supplementation with antioxidant vitamins has been proposed to reduce the risk of preeclampsia and perinatal complications, but the effects of this intervention are uncertain. Methods: We conducted a multicenter, randomized trial of nulliparous women between 14 and 22 weeks of gestation. Women were assigned to daily supplementation with 1000 mg of vitamin C and 400 IU of vitamin E or placebo (microcrystalline cellulose) until delivery. Primary outcomes were the risks of maternal preeclampsia, death or serious outcomes in the infants (on the basis of definitions used by the Australian and New Zealand Neonatal Network), and delivering an infant whose birth weight was below the 10th percentile for gestational age. Results: Of the 1877 women enrolled in the study, 935 were randomly assigned to the vitamin group and 942 to the placebo group. Baseline characteristics of the two groups were similar. There were no significant differences between the vitamin and placebo groups in the risk of preeclampsia (6.0 percent and 5.0 percent, respectively; relative risk, 1.20; 95 percent confidence interval, 0.82 to 1.75), death or serious outcomes in the infant (9.5 percent and 12.1 percent; relative risk, 0.79; 95 percent confidence interval, 0.61 to 1.02), or having an infant with a birth weight below the 10th percentile for gestational age (8.7 percent and 9.9 percent; relative risk, 0.87; 95 percent confidence interval, 0.66 to 1.16). Conclusions: Supplementation with vitamins C and E during pregnancy does not reduce the risk of preeclampsia in nulliparous women, the risk of intrauterine growth restriction, or the risk of death or other serious outcomes in their infants. (Controlledtrials.com number, ISRCTN00416244 [controlled-trials.com] .)Alice R. Rumbold, Caroline A. Crowther, Ross R. Haslam, Gustaaf A. Dekker and Jeffrey S. Robinso

Clinical risk prediction for pre-eclampsia in nulliparous women: development of model in international prospective cohort

Objectives To develop a predictive model for pre-eclampsia based on clinical risk factors for nulliparous women and to identify a subgroup at increased risk, in whom specialist referral might be indicated

Decidual killer immunoglobulin-like receptor (kir)2dl1 expression and the onset of preeclampsia, birth weight and placental weight in early and late onset preeclampsia

Introduction Successful remodelling of spiral artery ensures adequate uteroplacental perfusion and sufficient nutrient supply to the fetus. HLA-C interaction with maternal KIR determines the outcome of spiral artery remodelling. Strong inhibitory KIR2DL1 lower the expression of cytokines and angiogenic factors affecting uteroplacental perfusion and nutrient supply. Material and methods We analysed the decidual expression of KIR2DL1 in early and late preeclampsia groups by quantitative immunohistochemistry using anti human-KIR2DL1/CD158a antibody and its correlation with preeclampsia onset, birth weight and placental weight. 35 patients, 14 patients with early onset preeclampsia (EO-PE) and 21 with late preeclampsia (LO-PE) were analysed. Result There was a significant difference between the expression of KIR2DL1 between the EO-PE and LO-PE group (p < 0,001) with a strong negative correlation between decidual expression of KIR2DL1 and preeclampsia onset (p < 0,001, r = −0,723), birth weight (p < 0,001, r = −0,770) and placental weight (p < 0,001, r = −0,770). Conclusion In patients with EO-PE, the higher placental of KIR2DL1 and inhibitory KIR2DL1 contributes to earlier onset of preeclampsia, lower birth weight of the baby and low placental weight. The strong negative correlation might be due to much lower expression of cytokines and angiogenic factors in higher KIR2DL1 expression samples. The different expression of KIR2DL1 between EO-PE and LO-PE is in line with current concepts on different pathophysiologic pathway leading to these different PE phenotypes

Decidual killer immunoglobulin-like receptor (kir)2dl1 expression and the onset of preeclampsia, birth weight and placental weight in early and late onset preeclampsia

Introduction Successful remodelling of spiral artery ensures adequate uteroplacental perfusion and sufficient nutrient supply to the fetus. HLA-C interaction with maternal KIR determines the outcome of spiral artery remodelling. Strong inhibitory KIR2DL1 lower the expression of cytokines and angiogenic factors affecting uteroplacental perfusion and nutrient supply. Material and methods We analysed the decidual expression of KIR2DL1 in early and late preeclampsia groups by quantitative immunohistochemistry using anti human-KIR2DL1/CD158a antibody and its correlation with preeclampsia onset, birth weight and placental weight. 35 patients, 14 patients with early onset preeclampsia (EO-PE) and 21 with late preeclampsia (LO-PE) were analysed. Result There was a significant difference between the expression of KIR2DL1 between the EO-PE and LO-PE group (p < 0,001) with a strong negative correlation between decidual expression of KIR2DL1 and preeclampsia onset (p < 0,001, r = −0,723), birth weight (p < 0,001, r = −0,770) and placental weight (p < 0,001, r = −0,770). Conclusion In patients with EO-PE, the higher placental of KIR2DL1 and inhibitory KIR2DL1 contributes to earlier onset of preeclampsia, lower birth weight of the baby and low placental weight. The strong negative correlation might be due to much lower expression of cytokines and angiogenic factors in higher KIR2DL1 expression samples. The different expression of KIR2DL1 between EO-PE and LO-PE is in line with current concepts on different pathophysiologic pathway leading to these different PE phenotypes

Differential item functioning of the Functional Independence Measure in higher performing neurological patients

OBJECTIVE: When comparing outcomes of the Functional Independence Measure (FIM ) between patient groups, item characteristics of the FIM should be consistent across groups. The purpose of this study was to compare item difficulty of the FIM in 3 patient groups with neurological disorders. SUBJECTS: Patients with stroke (n=295), multiple sclerosis (n=150), and traumatic brain injury (n=88). METHODS: FIM scores were administered in each group. The FIM consists of a motor domain (13 items) and a cognitive domain (5 items). Rasch rating scale analysis was performed to investigate differences in item difficulty (differential item functioning) between groups. RESULTS: Answering categories of the FIM items were reduced to 3 (from the original 7) because of disordered thresholds and low answering frequencies. Two items of the motor domain ("bladder" and "bowel") did not fit the Rasch model. For 7 out of the 11 fitting motor items, item difficulties were different between groups (i.e. showed differential item functioning). All cognitive items fitted the Rasch model, and 4 out of 5 cognitive items showed differential item functioning. CONCLUSION: Differential item functioning is present in several items of both the motor and cognitive domain of the FIM. Adjustments for differential item functioning may be required when FIMdata will be compared between groups or will be used in a pooled data analysi

Therapeutic potential of regulatory T cells in preeclampsia-opportunities and challenges

Inflammation is a central feature and is implicated as a causal factor in preeclampsia and other hypertensive disorders of pregnancy. Inflammatory mediators and leukocytes, which are elevated in peripheral blood and gestational tissues, contribute to the uterine vascular anomalies and compromised placental function that characterize particularly the severe, early onset form of disease. Regulatory T (Treg) cells are central mediators of pregnancy tolerance and direct other immune cells to counteract inflammation and promote robust placentation. Treg cells are commonly perturbed in preeclampsia, and there is evidence Treg cell insufficiency predates onset of symptoms. A causal role is implied by mouse studies showing sufficient numbers of functionally competent Treg cells must be present in the uterus from conception, to support maternal vascular adaptation and prevent later placental inflammatory pathology. Treg cells may therefore provide a tractable target for both preventative strategies and treatment interventions in preeclampsia. Steps to boost Treg cell activity require investigation and could be incorporated into pregnancy planning and preconception care. Pharmacological interventions developed to target Treg cells in autoimmune conditions warrant consideration for evaluation, utilizing rigorous clinical trial methodology, and ensuring safety is paramount. Emerging cell therapy tools involving in vitro Treg cell generation and/or expansion may in time become relevant. The success of preventative and therapeutic approaches will depend on resolving several challenges including developing informative diagnostic tests for Treg cell activity applicable before conception or during early pregnancy, selection of relevant patient subgroups, and identification of appropriate windows of gestation for intervention.Sarah A. Robertson, Ella S. Green, Alison S. Care, Lachlan M. Moldenhauer, Jelmer R. Prins, M. Louise Hull, Simon C. Barry and Gustaaf Dekker

Comparison of chop chemotherapy with autologous bone marrow transplantation for slowly responding patients with aggressive non-Hodgkin's lymphoma

High-dose chemoradiotherapy combined with autologous bone marrow transplantation can cure patients with disseminated, aggressive non-Hodgkin's lymphoma in whom first-line chemotherapy has failed. In contrast, cure is rare with second-line chemotherapy. It has been suggested that patients with slow responses to the initial phase of first-line chemotherapy are at high risk for relapse. Therefore, such patients are potential candidates for early bone marrow transplantation

The antenatal causes of cerebral palsy - Genetic and viral associations

Cerebral palsy is the most common neurological disorder in children. Epidemiological evidence suggests that antenatal origins are a major cause. Currently there is no antenatal test for cerebral palsy, no proven preventable measures in late pregnancy, and no known cure. Cerebral palsy affects not only the diagnosed child, but also their family and the community, requiring considerable social and financial resources to assist these children in their daily lives.Catherine S. Gibson, Alastair H. MacLennan, Paul N. Goldwater, and Gustaaf A. Dekker for The South Australian Cerebral Palsy Research Grou

Single-nucleotide polymorphism associations with preterm delivery: a case-control replication study and meta-analysis

BackgroundThe aim of this study was to replicate single-nucleotide polymorphism (SNP) associations with preterm birth (PTB; birth at MethodsSpontaneous PTB cases and controls were selected from an existing cohort. Candidate SNPs were taken from an existing genotype panel. A systematic review was conducted for each SNP in the panel to determine suitability as a PTB candidate. Those with significant associations previously reported in Caucasians were selected for replication. Candidate SNPs were already genotyped in cases and controls and clinical data were accessed from state perinatal and cerebral palsy databases. Association analysis was conducted between each SNP and PTB, and meta-analysis was conducted if there were ≥ 3 studies in the literature. Maternal and fetal SNPs were considered as separate candidates.ResultsA cohort of 170 cases and 583 controls was formed. Eight SNPs from the original panel of genotyped SNPs were selected as PTB candidates and for replication on the basis of systematic literature review results. In our cohort, fetal factor V Leiden (FVL) was significantly associated with PTB (odds ratio (OR): 2.6, 95% confidence interval (CI): 1.31-5.17), and meta-analysis confirmed this association (OR: 2.71, 95% CI: 1.15-6.4).ConclusionReplication and meta-analysis support an increased risk of PTB in Caucasians with the fetal FVL mutation.Michael E. O’Callaghan, Alastair H. MacLennan, Gai L. McMichael, Eric A. Haan and Gustaaf A. Dekke