Preeclampsia: a view through the danger model

Classical thinking suggests that the immune system undergoes activation on the basis of discrimination between ‘self’ and ‘non-self’. Accordingly, the fetus activates the mother's immune system because the fetus is in part ‘non-self’. Thus, successful pregnancy depends on constraint of maternal immunity. Preeclampsia is an outcome of lost constraint.Instead, the danger model suggests that normal pregnancy, regardless of the expression of ‘non-self’ antigens, does not activate the maternal immune system unless that pregnancy expresses danger signals. Thus, preeclampsia stems from stress or abnormal cell death in pregnancy-related tissues. This compels expression of specific danger signals and potential activation of anti-fetal immunity, which secondarily feeds the syndrome.Study of preeclampsia from this perspective may bring forth novel mechanisms and indicators of vascular and metabolic dysfunction during pregnancy.     

Preeclampsia,insulin signalling and immunological dysfunction: a fetal,maternal or placental disorder?

An inappropriate glycogen accumulation in preeclamptic placentas was described as secondary to biochemical alterations. Insulin resistance is widely accepted to be associated with preeclampsia, although its basis remain unclear. A family of putative insulin mediators, namely inositol phosphoglycans, were described to exert many insulin-like effects on lipid and glucose metabolism. A definite association between the P-type mediator (P-IPG) and preeclampsia was reported, being increased in placenta, urine, amniotic fluid and cord blood from human preeclamptic pregnancies. A strong link exists between insulin resistance and inflammation. Clear features of insulin resistance and systemic inflammatory activation were described in preeclampsia. It may be a consequence of the immunological dysfunction that occurs in preeclampsia that is temporized during sperm exposure and co-habitation which confuses the maternal immune network to perceive ‘danger’. The over-expression of P-IPG during preeclampsia may be a counter-regulatory mechanism to insulin resistance since these molecules mimic insulin action. Besides, the lipidic form of P-IPG was reported to be similar to endotoxins, and may represent the ‘danger signa’. We propose here a novel working theory on insulin resistance and preeclampsia.     

Poissons,grenouilles, femmes et hommes: The appropriation and retention of archetypal systems for reproduction

In contradistinction to other biological systems, the reproductive mechanisms in sexually reproducing species are unique in that their success relies upon a synchronous interaction between two separate individuals. Reproduction has become increasingly more efficient as higher forms have developed internal fertilization and gestation. Although our anthropomorphic perspective has dominated the understanding of reproductive processes, ‘recent discoveries’ make it clear that this reproductive efficiency has been gained by retention of previously present biological mechanisms whose origins are in the vestigial excretory tracts and ducts which are the precursors of the reproductive tract. We refer to these as ‘archetypal systems’. They include the interaction between sex steroid sensitive tissues and sex steroids, the renin-angiotensin system and the macrophage/monokine response to infection. Through these mechanisms the reproductive tracts have maintained control over the microenvironment in which the reproductive processes occur. Thus, gamete development in male and female, and fertilization and early embryonic existence in the female tract prior to implantation still occur in compartments which are extracorporeal, i.e., separated from blood or subendothelial spaces, and are controlled by cellular mechanisms found in ancient excretory tracts. Since the majority of the changes between lower forms and contemporary mammals are anatomical modifications which have favoured the success of these extracorporeal events within the developing, generally land-based mammals, we should take special note of lower animals, understanding the evolutionary appropriation of mechanisms designed to furnish the suitable microenvironment from the surrounding tissues. Our ability to integrate these into a meaningful approach to the control of reproduction and to the diagnosis and treatment of reproductive disorders will be much enhanced if we are able to break intellectual barriers and view reproduction from the perspective of those lower forms to which we owe so much of our present reproductive efficiency.     

Preeclampsia: A review of the pathogenesis and possible management strategies based on its pathophysiological derangements

This review is divided into three parts. The first part briefly describes the pathogenesis of preeclampsia. This is followed by reviewing previously reported management strategies of the disease based on its pathophysiological derangements. Finally, the author defines the safe and acceptable methods/medications that may be used to ‘prevent’ preeclampsia (in high risk patients) and those that may be used to ‘treat’ preeclampsia (meant to prolong the pregnancy in patients with established preeclampsia). The review concludes that multi-center trials are required to include multiple drugs in the same management protocol.     

Calcium Supplementation During Pregnancy for Preventing Hypertensive Disorders Is not Associated with Changes in Platelet Count,Urate, and Urinary Protein: a Randomized Control Trial

Objective. To test the hypothesis that calcium supplementation inhibits the underlying pathological processes in women with preeclampsia. Methods. Seven hundred and eight nulliparous women were enrolled in a WHO randomized double-blind trial, who received 1.5 g of calcium or placebo from 20 weeks of pregnancy or earlier. Platelet count, serum urate, and urinary protein/creatinine ratio were measured at or near 35 gestational weeks. Results. No difference was detected in rates of abnormal platelet count (relative risk [RR] 1.18; 95% confidence interval [CI], 0.63 to 2.18), serum urate level (1.0; 0.64 to 1.57) or urine protein/creatinine ratio (1.01; 0.76 to 1.34). This was consistent with the main trial finding of no difference in the incidence of ‘dipstick’ proteinuria between women receiving calcium and those receiving placebo (8312 women; RR, 1.01; 95% CI, 0.88 to 1.15). Conclusions. An effect of calcium supplementation in the second half of pregnancy on the rate of abnormal laboratory measures associated with preeclampsia was not demonstrated.     

Role of nuclear receptors and their ligands in human trophoblast invasion

Human implantation involves a major invasion of the uterine wall and complete remodelling of uterine arteries by extravillous cytotrophoblasts (EVCT). Abnormality in these early steps of placental development leads to poor placentation, fetal growth defects and is often associated with preeclampsia, a major and frequent complication of human pregnancy. To study the mechanisms that control trophoblast invasion during early placental development and provide new insight in the understanding of preeclampsia, we have developed in vitro models of human invasive trophoblasts. We have shown that activation of the ligand-activated nuclear receptor PPARgamma with synthetic (rosiglitazone) or natural (15deoxyPGJ(2)) agonists inhibits the trophoblastic invasion process. Analysis of PPARgamma-target genes revealed that placental growth hormone and the protease PAPP-A might be involved in the PPARgamma-mediated effect in an autocrine manner. We next investigated PPARgamma ligands at the materno-fetal interface and have shown that oxidized LDLs are present in EVCT in situ and decrease trophoblast invasion in vitro. Analysis of oxidized LDLs revealed that they contain potent PPARgamma agonists such as eicosanoids and also high levels of oxysterols, which are specific ligands for the liver X receptor (LXR). The isoform beta of LXR was found in EVCT in situ, and activation of LXRbeta with synthetic or natural ligands inhibits trophoblast invasion in vitro. Together, our data underscore a major role for PPARgamma and LXRbeta in the control of human trophoblast invasion and suggest that excess ligands such as oxidized LDLs at the implantation site might contribute to the development of preeclampsia.     

Cardiovascular Research in Pregnancy: The Role of Animal Models

Because of ethical constraints upon research during human pregnancy, animal species have been used to model both the physiological adaptation to pregnancy and the pathophysiology of preeclampsia. This review examines these applications in animals such as rats, guinea pigs, rabbits, dogs, and sheep. However, the main thrust of this review is to look at studies in the baboon and explore the contribution of this large Old World primate in furthering our understanding of human pregnancy.     

Association between gamete source,exposure and preeclampsia: A review of literature

Preeclampsia complicates 3%-5% of pregnancies and is one of the major causes of maternal morbidity and mortality. The pathologic mechanisms are well described but despite decades of research, the exact etiology of preeclampsia remains poorly understood. For years it was believed that the etiology of preeclampsia was the result of maternal factors, but recent evidence suggests that preeclampsia may be a couple specific disease where the interplay between both female and male factors plays an important role. Recent studies have suggested a complex etiologic mechanism that includes genetic imprinting, immune maladaptation, placental ischemia and generalized endothelial dysfunction. The immunological hypothesis suggests exaggerated maternal response against fetal antigens. While the role of maternal exposure to new paternal antigens in the development of preeclampsia was the initial focus of research in this area, studies examining pregnancy outcomes in pregnancies from donor oocytes provide intriguingly similar findings. The pregnancies that resulted from male or female donor gametes or donor embryos bring new insight into the role of immune response to new antigens in pathogenesis of preeclampsia. The primary goal of the current review is the role of exposure to new gametes on the development of preeclampsia. The objective was therefore to provide a review of current literature on the role of cohabitation length, semen exposure and gamete source in development of preeclampsia.     

Implantationsst?rungen, Pr?eklampsie und intrauterine Wachstumsrestriktion

Preeclampsia and intrauterine growth restriction (IUGR) are major pregnancy pathologies and the leading causes of maternal and perinatal mortality and morbidity. Interestingly the etiologies of both syndromes are still unclear which is why a large number of hypotheses have been developed. The joint occurrence of both syndromes in a single pregnancy has deleterious effects on both mother and child. Studies dealing with such severe cases of preeclampsia with associated IUGR have led to the development of hypotheses attempting to explain all clinical and morphological alterations in a single hypothesis. This in turn has resulted in the general misconception that a failure in invasion of the placental trophoblast is directly linked with the etiology of preeclampsia. However, recent progress in the identification of new biomarkers to predict preeclampsia has changed views on the etiology of preeclampsia. It has become clear that a failure in trophoblast invasion is directly linked to IUGR while a defect of the villous trophoblast precedes preeclampsia.     

Increased cranial capacity in hominid evolution and preeclampsia

One of the major trends in primate evolution generally and hominid evolution in particular, is cranio-facial contraction accompanied by an increase in cranial capacity. Landmark-based morphometric methods are applied to adult skulls of great apes (Gorilla, Pan), australopithecines (Australopithecus and Paranthropus), and humans (Homo eragster, erectus, neanderthalensis, and sapiens). Morphological changes quantified by vector fields (Procrustes methods) indicate that these skull plans are characterized by distinctive degrees of cranio-facial contraction. These suggest the existence of three discrete skull organization plans: "great ape", "australopithecine" and "Homo". This paper focuses on the "Homo" skull bauplan and discusses the possible relationships between greatly increased cranial capacity and preeclampsia. The earliest species of the human lineage exhibit less cranio-facial contraction and smaller cranial capacity than Homo neanderthalensis and modern Homo sapiens. Neandertalization introduces a posterior elongation of the skull and leads to a large increase in cranial capacity in the last Neandertals, with values as large as in present-day H. sapiens. Consequently, a new biological hypothesis is proposed to account for the unexplained disappearance of H. neanderthalensis some 30000 years ago related to the possible appearance of preeclampsia as a factor affecting the survival of the species.     

Severe Preeclampsia Associated with Coinheritance of Factor V Leiden Mutation and Protein S Deficiency

Background: Inherited thrombophilic disorders are associated with an increased risk of venous thromboembolism during pregnancy. Preliminary research suggests that these disorders might also increase the risk for preeclampsia.Case: A 29-year-old primigravida developed severe, early onset preeclampsia and postpartum deep venous thrombosis. Subsequent testing revealed coinheritance of the factor V Leiden mutation and protein S deficiency. Heparin prophylaxis was administered during two subsequent pregnancies without recurrence of either preeclampsia or venous thromboembolism.Conclusion: Our patient’s inherited thrombophilia may have played a role in the development of preeclampsia, and anticoagulation during subsequent pregnancies may have prevented preeclampsia recurrence. An association between inherited thrombophilic disorders and preeclampsia is biologically plausible.     

IFPA Award in Placentology Lecture: Complicated interactions between genes and the environment in placentation,pregnancy outcome and long term health

Most research on the developmental origins of health and disease has implicated poor nutrition in the fetus, most often conferred by deficiencies in maternal nutrition, as an important causal factor that programmes offspring physiology for adult disease. Emerging evidence implicates interactions between genes and the environment that may help to explain why poor growth before birth is associated with a variety of adult onset diseases that appear in different individuals of the same birthweight. However, it is underappreciated that the placenta, particularly trophoblast invasion, is key to health of both the mother and child in both the short and long term and that the role of the father is more important than perhaps ever expected. Intrauterine growth restriction (IUGR) is but one of a continuum of several pregnancy complications that may be related and that may reflect the long term health of both parents and offspring. These include preeclampsia, pre-term birth and gestational diabetes, as well as IUGR. Polymorphisms in genes that regulate how the placenta invades maternal tissues, differentiates and functions and how the mother adapts to pregnancy have been identified as candidates that confer risk to pregnancy success. Potentially, pregnancy provides a window that gives clues to modifiable risk factors that should be addressed early to ameliorate late adult disease. Placentation and trophoblast invasion and its inhibitors in other species may provide new ideas for understanding what goes wrong in human pregnancy. Placentologists and clinicians may usefully collaborate to identify factors that predict risk for pregnancy complications and poor health later in life.     

Preeclampsia and human reproduction. An essay of a long term reflection

Hypertensive disorders of pregnancy (HDP: pregnancy-induced hypertension, preeclampsia, eclampsia) affect approximately 10% of human births. Women are at increased risk for HDP during their first conception; and/or when the conception is with a new partner (new paternity); when conception occurs very shortly after the beginning of their sexual relationship. A primary cause of preeclampsia is the defect of the normal human-specific deep endovascular invasion of trophoblast, which is a consequence of the nutritional demands of growth of the human fetal brain. The occurrence of preeclampsia represents a reproductive disadvantage unique to humans compared with other mammals. As such, it may have played a significant role in shaping human reproduction and, therefore, human sexuality. This deep implantation/preeclampsia phenomenon may explain many anthropological mysteries of human sexuality that do not exist in other mammalian species (and primates). These include: very low fertility rate, concealed ovulation, all year long 'apparent-waste-of-efficiency' sexuality, absence of sperm competition in human females at the time of conception, and the unexplained testicle size in human males compared with relevant primates. Further, this deep trophoblastic implantation (and its failure in preeclampsia) in humans might be a decisive condition of hominization between great apes and all the other Homo genuses. This frontier might even have occurred inside these Homo lineages: because of their relatively small brains, the first species of Homo might not have presented the deep trophoblastic invasion described in Homo sapiens.     

妊娠早期子痫前期的预测

子痫前期是发病率和病死率较高的产科并发症,以滋养细胞浅侵入母体子宫螺旋动脉为特征.尽管对子痫前期的病理生理改变已有较多的了解,但有效及时的预测是非常困难的.虽然不同检测方法均认为胎盘功能不良与妊娠不良结局有关,但用单一指标做预测的效果很差.超声技术的提高对预测十分有利,但需要标准化.妊娠早期母亲生化标记物结合子宫动脉多普勒筛查可能是很有前途的筛查工具.     

Atherosis revisited: current concepts on the pathophysiology of implantation site disorders

There are two distinct histological manifestations of impaired placental implantation in humans--incomplete trophoblastic vascular invasion and atherosis. Both have been described to occur in pregnancies affected by a variety of disorders such as preeclampsia, fetal growth restriction, systemic lupus erythematosus, and diabetes. Our purpose was to integrate recent developments in the understanding of implantation site disorders into a pathophysiological scenario that interrelates these placentation disorders and associated pregnancy complications. Sources were identified from a MEDLINE search of English-language articles published from 1966 to 1997. Additional sources were identified from references cited in relevant reports. We selected articles relating to the following topics: atherosis, implantation site disorders, trophoblastic invasion, preeclampsia, fetal growth restriction, implantation site development, atherosclerosis, and endothelial activation-damage. A contemporary version of normal placentation, including vascular adaptation, was reviewed with comments on normal trophoblastic differentiation and vascular invasion. Specific abnormalities of the implantation site, including atherosis and incomplete trophoblastic invasion, were discussed in the context of placental site hypoperfusion and the association with pregnancy complications. It was concluded that atherosis and incomplete trophoblastic invasion may be both a consequence and a cause of placental site hypoperfusion resulting in the development of preeclampsia and a variety of other pregnancy disorders.     

基质金属蛋白酶与子痫前期发病关系的研究

目的 探讨基质金属蛋白酶(MMP)2、9在子痫前期患者胎盘绒毛中的表达及其与子痫前期发病的关系.方法 采用免疫组化链霉亲和素-生物素-过氧化物酶复合物(SABC)法检测20例子痫前期患者(病例组)和20例正常孕妇(对照组)胎盘绒毛MMP-2、9的表达,实时荧光定量RT-PCR检测两组孕妇胎盘绒毛MMP-2、9 mRNA的表达水平.因提取后的mRNA部分降解,用于RT-PCR检测的胎盘绒毛病例组13份,对照组10份.采用2-△△Ct相对定量表示PCR结果.结果 对照组孕妇胎盘绒毛MMP-2、9的染色强度均高于病例组,两组比较,差异有统计学意义(P＜0.05);对照组胎盘绒毛MMP-2 mRNA的平均表达水平为7.6±2.8,病例组胎盘绒毛MMP-2 mRNA的平均表达水平为5.6±1.5,两组比较,差异有统计学意义(P＜0.05).对照组胎盘绒毛MMP-9 mRNA的平均表达水平为2.2±2.6,高于病例组的-0.9±2.0,两组比较,差异也有统计学意义(P＜0.05).对照组胎盘绒毛MMP-2的平均表达水平高于MMP-9,两者比较,差异有统计学意义(P＜0.05).结论 MMP-2、9表达降低导致的滋养细胞侵袭能力的下降,可能与子痫前期的发病相关.     

Antibodies to Oxidized Low-Density Lipoprotein,Cardiolipin, and Phosphatidyl Serine Fail to Predict the Risk of Preeclampsia

Objective: To test the hypothesis that variants in the angiotensinogen gene are a major genetic cause of preeclampsia (PE).

Methods: Ten families with a high incidence of PE were typed for alleles at a microsatellite repeat within the angiotensinogen gene (AGT). Logarithm of odds (LODs) scores were used to examine for cosegregation of AGT alleles with the disease under several models of inheritance. Both recessive and dominant modes of inheritance with penetrances ranging from 0.9 to 0.5 were considered for a range of disease gene frequencies. A model-independent analysis, affected pedigree member method (AFFPED), was also used.

Results: There was no indication of cosegregation between preeclampsia and angiotensinogen alleles under any model. Under most dominant models the preeclampsia gene was excluded from a 5 centimorgan region around angiotensinogen (LOD < -2). AFFPED also does not support close linkage of AGT and the preeclampsia gene.

Conclusions: Variants at the angiotensinogen gene are not responsible for the preeclampsia in these families. We are unable to verify the reports of two groups suggesting that susceptibility to preeclampsia is correlated with variation at the angiotensinogen locus. Distinguishing preeclampsia from other hypertensive disorders of pregnancy has long been a difficult problem, and still remains to be solved. Raised blood pressure is almost certainly a secondary event in the PE causal chain. The pathophysiology of preeclampsia suggests that genes involved in specifying products which affect the interaction of trophoblast and decidua are better candidates for the origin of the fundamental lesion than are genes involved in controlling blood pressure.     

Review: hCG, preeclampsia and regulatory T cells

Human chorionic gonadotropin (hCG) is crucial for successful pregnancy. Its many functions include angiogenesis and immune regulation. Despite years of research, the etiology of preeclampsia remains unknown. Marked by insufficient trophoblast invasion and poor spiral artery remodeling, preeclampsia has also been linked to immune dysregulation. Here we discuss the roles of hCG in the context of endovascular cross-talk between trophoblasts and endothelial cells and immune tolerance. We propose that functional and glycosylation modifications of hCG may contribute to the pathogenesis of preeclampsia.     

The prefrontal-limbic system: development, neuroanatomy, function, and implications for socioemotional development

The knowledge that neonatal emotional experience and associated learning processes are critical in the maturation of prefronto-limbic circuits emphasizes the importance of preterm and neonatal care. The further improvement of care and intervention strategies requires a deeper understanding of epigenetic mechanisms mediating experience-induced synaptic reorganization underlying the emergence of emotional and cognitive behavioral traits. Interdisciplinary research efforts are needed in which pediatricians and developmental biologists and psychologists merge their knowledge, concepts, and methodology. The hope is that the translational relevance of research efforts can be improved through a greater interaction between basic and clinical scientists.     

Markers for endothelial injury,clotting and platelet activation in preeclampsia

Summary The etiology of disseminated intravascular coagulation (DIC) in preeclampsia is not well understood. We measured plasma levels of fibronectin (FN), which may reflect endothelial cell injury, fibrinopeptide A (FPA), a specific marker of clotting, platelet counts (PLC) and mean platelet volumes (MPV), as well as β-thromboglobulin (βTG) and platelet factor 4 (Pf4), products of irreversible platelet activation in 24 preeclamptic patients and 24 controls matched for age, gestational age, labor status, and parity. In preeclampsia, FN and FPA were significantly elevated while PLC were significantly decreased (P<0.0001, <0.05 and <0.01, respectively). βTG, Pf4, and MPV values did not show significant differences. These findings support the hypothesis that endothelial injury, clotting activation and platelet consumption are increased in preeclampsia. However, the much closer association of preeclampsia with FN levels as compared to FPA, βTG, Pf4, suggests that endothelial injury is a more basic mechanism of preeclampsia than clotting or platelet activation.