Validation of the modern concept of the development of preeclampsia

Sidorova I.S., Nikitina N.A.

I.M. Sechenov First Moscow State Medical University of Minzdrav of Russia (Sechenov University), Moscow, Russia
The article presents a modern, scientifically validated concept of the development and progression of preeclampsia. The destructive character of gestational endothelial damage in this pregnancy complication is associated with immune complex diseases. The pathogenesis of immune complex diseases involves an abnormal (excessive) activation of the complement system with the development of thrombotic microangiopathy. The authors emphasize the relationship between the time of preeclampsia onset (after 22 weeks of pregnancy) and the features of fetal organogenesis and systemogenesis, which allowed an assumption of the role of neuron-specific proteins of the developing fetal brain in immune damage to the maternal endothelium. The study findings imply the possibility of new therapeutic approaches to managing patients with preeclampsia, provide a rationale for targeted treatment modalities aimed at the most important link in the pathogenesis, which is essential in preserving maternal and child health and life.


complement system
neuron-specific proteins

According to the annual Maternal Deaths Surveillance Report produced by the Ministry of Health of the Russian Federation, the maternal mortality rate in the country has been on a downward trend decreasing (per 100,000 live births) as follows: 2013 - 12.9, 2014 - 11.9, 2015 - 10.7, 2016 - 10,5 [1].

Preeclampsia and eclampsia are major pregnancy complications ranking third and fourth among the top causes of maternal mortality. According to the Ministry of Health of the Russian Federation, the decline in maternal mortality from preeclampsia and eclampsia is extremely unstable: in 2014 it increased by almost 50% (from 1.21 to 1.8 per 100,000 live births), in 2015 decreased by 40% (up to 1.08 per 100,000 live births), in 2016 again increased by 27.8% (up to 1.38 per 100,000 live births), compared with each previous year [1, 2].

Among deaths associated with severe complications of preeclampsia and eclampsia, the proportion of severe brain damage and eclampsia also remained high (34.8% in 2013, 34.3% in 2014, 33.3% in 2015, 26.9% - in 2016), as well as a major obstetric hemorrhage with disseminated intravascular coagulation (30.4% - in 2013, 37.1% - in 2014, 42.9% - in 2015, 42.3% in 2016); there was an increase in the rates of liver disorders such as acute liver failure, acute fatty liver of pregnancy, and HELLP syndrome (34.8% in 2013, 40% in 2014 , 61% - in 2015, 80.8% - in 2016) [1, 2].

At the same time, the preventability and conditional preventability of maternal mortality from preeclampsia and eclampsia remain high, from 85 to 69% in different years [1].

The current concepts of preeclampsia is very vague: preeclampsia is considered a complication (syndrome, multisystem pathological condition) that occurs in the second half of pregnancy (after 20 weeks’ gestation) and diagnosed by new-onset arterial hypertension (BP ≥ 140/90 mm Hg), proteinuria (≥ 0.3 g/l in a 24-hour urine collection), edema (optional), and manifested by multi-organ /poly-systemic insufficiency associated with endothelial dysfunction.

It is not clear what this process is - inflammatory, infectious, immune, hemodynamic? What is the exact cause of endotheliocyte damage? What is the nature of the damage?

The causes of preeclampsia are still unknown; pathogenesis is not well understood; clinical and laboratory signs of preeclampsia do not reflect the true severity of this condition. The incidence rates of preeclampsia and associated maternal mortality do not decrease. Many issues related to terminology, classification, assessment of severity of preeclampsia have long been a subject of debate and change. The treatment of preeclampsia is neither pathogenetic nor etiologically based, and evidence-based prevention is lacking.

To date, the only known cure for pre-eclampsia is termination of pregnancy/delivery of the fetus to save the mother regardless of gestational age. The most dangerous complications of pre-eclampsia and eclampsia are the damage to cerebral vessels, intracerebral hemorrhages, edema, and dyscirculatory disorders, acute renal and hepatic failure, placental abruption, massive obstetric hemorrhages caused by damage to the endothelium and impairment of the hemostatic system. In the fetus, placental insufficiency results in growth restriction, hypoxic, ischemic and hemorrhagic organ damage.

Many human diseases including vascular and cerebrovascular disorders initially develop antenatally. The rates of disability and mortality from cerebrovascular diseases in Russia have reached some of the highest rates worldwide and tend to increase. Over the past 15 years, they have grown by 18% [3].

At present, according to the generally accepted concept, preeclampsia is considered systemic endotheliosis [4-6], since it involves the vascular endothelial lining, and also (and first of all) the placenta. The role of placental disorders has been repeatedly proven, starting from the early stages of pregnancy; insufficiency of gestational transformations of the uterine-placental site vessels, which develop from early pregnancy; but pre-eclampsia and eclampsia occur only after 20-21 weeks’ gestation, in the second half of pregnancy, and never in the first [7-10]. Why?

The concept developed by academician Sidorova I.S. with pupils offers a fresh look at this problem, considering preeclampsia not only, and not so much as hypertensive disorder during pregnancy, but as gestational immune complex, complement-mediated endotheliosis, in which purposefully targeted therapy is possible, instead of premature early delivery. And today this possibility exists. The presented concept of the author is the only one that allows understanding and explaining specific features, presenting a new definition of preeclampsia, changing the focus of scientific research and justifying the use of targeted therapy.

Material and methods

The proposed new concept of preeclampsia is the result of a large number of clinical and special studies:

A confidential audit of maternal mortality associated with preeclampsia, eclampsia and their complications in 2013-2015 in the regions of the Russian Federation (retrospective analysis of primary medical documentation of 97 deceased women, including outpatient medical records, individual pregnant and puerperal cards, birth histories, inpatient medical cards, and anatomic pathology reports). A detailed analysis of the documentation in the framework of the audit enables investigating the modern features of the development and progression of the most severe forms of preeclampsia, identify organizational flaws and medical errors. Based on the audit materials, three federal methodological letters were published for regional authorities, chief doctors of the perinatal centers and maternity homes.

A prospective cohort study comprising 504 pregnant women, who were divided into 3 groups: Group I (risk group) included 150 pregnant women at risk for developing pre-eclampsia (subsequently 42 and 108 of them did and did not develop preeclampsia, respectively); Group II (study group) comprised 254 patients with preeclampsia; 100 somatically healthy patients with normal pregnancy and an uncomplicated reproductive history made up Group III (control group).

Clinical evaluation included patients’ history taking, physical examination, laboratory and functional testing, evaluation of pregnancy and birth outcomes, measurements of biomarkers of endothelial and placental dysfunction and damage to the blood-brain barrier (tumor necrosis factor (TNF) -α, cell adhesion molecules VCAM, ICAM, vascular endothelial growth factor (VEGF), placental growth factor (PIGF), antiangiogenic factor (sFlt-1), neuron-specific proteins (NSP) (NSE, GFAP)). Biomarkers were measured in the control group and risk group at 10-14 weeks, 18-24 weeks, 30-34 weeks’ gestation, before giving birth and in the first 3-5 days after birth; in the study group before the start of therapy, 5-7 days during treatment and in the first 3-5 days after delivery (with moderate pre-eclampsia). In severe pre-eclampsia, biomarker levels were assessed twice – on the hospital admission to and in the first 3-5 days after delivery. The markers were determined using ELISA.

Comparative pathological and immunohistochemical analysis was conducted based on autopsy material of 10 women who died from severe pre-eclampsia/eclampsia (study group) and 3 women in the comparison group who died from other causes (uterine scar rupture massive hemorrhage, anaphylactic reaction to ketamine and acute leukemia without clinical signs of preeclampsia and cerebral symptoms). The antibodies from Novocastra (Germany) were used for deparaffinized tissue sections: 1) γ-NSE (γ- neuron-specific enolase, clone 5E2) is a marker of neurons and neuroendocrine cells; 2) cytokeratin-8 (clone TS1) - a marker of invasive cells (interstitial cytotrophoblast, multinuclear cells); 3) CD-34 (clone QBend / 10) is a marker of endothelial cells in capillaries and other vessels. A unified Kit Detection System (NCL-RTV) using standard technology was applied.

Electron microscopy of umbilical cord vessels in women with preeclampsia and in the control group (ultrathin 25 nm tissue sections, prepared using an LKB ultramicroscope (Sweden), contrasted with 4% alcohol solution of uranyl acetate and 0.4% aqueous solution of lead citrate, under a Philips electronic microscope (Netherlands) at different magnifications.

An immunochemical analysis was conducted in the Laboratory of Neurochemistry of the Department of Fundamental and Applied Neurobiology of Serbsky State Scientific Center for Social and Forensic Psychiatry of Minzrav of Russia (Head of Department: Academician of the RAS, Dr.Med.Sci., Professor V. Chekhonin), at the Laboratory of Biocatalysis of the M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry of the RAS (Head of the Laboratory - Academician of the RAS, Dr.Chem.Sci., Professor A. Gabibov).

Pathological and immunohistochemical studies were performed in the Laboratory of the Female Reproductive System Pathology of the Research Institute of Human Morphology (head - Dr.Med.Sci., Professor A.P. Milovanov).

General clinical and special research methods, as well as electron microscopy of umbilical cord vessels, were carried out in the laboratories of Sechenov University.


The validation of the new concept was initially supported by the specific features of preeclampsia that cannot be explained by the current concepts of preeclampsia; the authors highlighted the following features:

  1. Preeclampsia occurs only in the second half of pregnancy, after 22 weeks’ gestation. According to the WHO, if the major preeclampsia symptoms of (edema, proteinuria, high blood pressure) before 20-21 week’s gestation, the diagnosis of pre-eclampsia cannot be made. If the same symptoms occur after this gestational age, in the second half of pregnancy, pre-eclampsia is the first choice diagnosis.
  2. Preeclampsia is characterized by a relentlessly progressive course. It is impossible to stop, cure, or slow its development.
  3. Symptomatic treatment is ineffective, and polypragmasia is dangerous because the drugs may negatively affect a developing fetus. The effectiveness of prevention has not been proven.
  4. The only known cure for pre-eclampsia is termination of pregnancy/delivery of the fetus regardless of gestational age (usually premature, aimed to save the mother and/or fetus).
  5. Eclampsia is the most reliable evidence of preceding severe pre-eclampsia. Not a single case of eclampsia is manifesting before 20-22 weeks’ gestation has been reported by the world medical literature, including Cochrane reviews.
  6. Preeclampsia is a condition that occurs only during pregnancy and is inherent only to humans. It is not found in the animal world. It cannot be produced experimentally (only a gestosis-like model, but not eclampsia).

Preeclampsia is a serious complication of the perinatal period. This period coincides with the manifestation of pre-eclampsia, which occurs only after 22 weeks’ gestation until the end of pregnancy or early delivery (removal of the fetus and placenta).

In the first half of pregnancy - the prenatal period - the main events of the new life take place: the general organization, the construction of organs and systems of the fetus and placenta, the formation of the fetal-placental unit. But the fetus, born before 22 weeks’ gestation cannot live not only because of functional and anatomical immaturity, and most importantly, due to the absence of a higher structure of the human fetal brain - new cortex (neocortex).

The neocortex and other higher brain structures develop in the second half of pregnancy, reaching functional activity from 22 weeks’ gestation and until the end of the perinatal period. The neocortex is an associative center of a new type, controlling the interaction of organs and systems. Cortical representation is the tip of the iceberg of the subcortical specialization of the human brain. And all this is conceived in the mother’s womb; provided by the mother’s genome, determined by the father’s genome.

The development of the neocortex, a unified system of regulation and interaction, is ensured by the fetal NSP, which are divided into species-specific and stage-specific, in accordance with the gestational age.

The perinatal period commences at 22 completed weeks of gestation (the time when birth weight is normally 500 g, body length is at least 25 cm, and a brain weight is at least 72-82 g), and ends seven completed days after birth (WHO). From now on, the prematurely born fetus is capable of surviving, subject to medical care and assistance.

For the first time, we present the findings of our research on the characteristics of fetal NSP, their products in different gestational ages, their significance and dynamics during normal pregnancy and pregnancy complicated by pre-eclampsia. The study investigated neuron-specific enolase (NSE), which is intensively produced by neurons, and glial fibrillary acidic protein (GFAP), which is expressed by astrocytes during their development (gliogenesis).

The specific activity of neuronal proteins is aimed at maintaining the structure and ensuring the stability of the cytoskeleton of neurons and glial cells, maintaining spatial orientation and the formation of the blood-brain barrier, which by this time separates the neocortex from the cerebral blood flow and, most importantly, from the effects of immunocompetent cells.

From this gestational age and until 38-40 weeks’ gestation (and further after birth) the higher structures of the central nervous system of the human fetus are formed. At 28-34 weeks’ gestation, the structure of the fetal brain is much more complicated and gradually becomes similar to the brain of an adult. Although in the postnatal period the brain development continues, neurons are no longer formed.

By the middle of pregnancy (20-22 weeks), a dense blood-brain barrier is formed, and only substances necessary for the fetal brain can pass.

Fetal NSPs have the following characteristics [11]:

  • They are strong immunogens since they do not induce immunological tolerance (“barrier proteins”);
  • NSPs are produced in each fetus, but normally they do not penetrate the blood-brain and placental barriers; and if they pass them in trace amounts, the resulting immune complex activates the complement via the classical pathway, and the immune complexes are destroyed;
  • When the NSPs cross from the brain into the blood, an immune reaction develops: the formation of antibodies is followed by the formation of circulating immune complexes that activate complement and induce the formation of the membrane attack complex (MAC) C5b-9. The penetration of fetal NSPs into the maternal bloodstream, vessels, endothelial and other tissues containing Fc and C receptors, activates the complement via an abnormal pathway.

The main obstacles for fetal NSP to cross into the maternal bloodstream are blood-brain and placental barriers.

We emphasize that the main factors for the development of pre-eclampsia are not just pregnancy, the presence of a developing living fetus, the second half of its gestational growth, increased permeability of the blood-brain and placental barriers, but the presence of sensitization (the so-called «reinforcing loop»).

In healthy pregnant women, who do not have traumatic injuries, degenerative, or oncological diseases of the brain, NSPs in the peripheral bloodstream are not detected in significant quantities.

The blood-brain and placental barriers have similar morphological structures, and, accordingly, common factors influencing their permeability. Ischemia and hypoxia, chronic placental insufficiency, infectious processes, metabolic disorders (especially mitochondrial), intoxication of any etiology, systemic immune, hematological and extragenital diseases of the mother, chronic kidney diseases, mutation and polymorphism of regulatory genes lead to increased permeability of both barriers, disruption of cytoarchitectonic organization of the fetal cortex, and focal dystrophic, destructive and functional changes in neurons [12-14].

Summarizing the above, it should be emphasized that preeclampsia is an immunocomplex general biological specific gestational process of damage to the endothelium, the inner lining of the microcirculatory system, which Fc and C receptors located at the membrane. Such receptors contain red blood cells, platelets, neutrophils, and other blood and tissue cells.

It small and medium-sized vessels, the blood flow velocity slows; they have multiple branches, where the blood flow is turbulent, which may impede fixation of circulating immune complexes containing antigens in the form of fetal NSP, specific antibodies and proteins of the complement system.

Gestational damage to the vascular endothelium is characterized by specific features of the antigen in immune complexes, including foreign NSP of an allogeneic fetus, which is not present in any other diseases. Interestingly, an experimental deletion of the NSP gene results in rapid brain destruction. The human brain is a potential center of auto-aggression. Its foreign nature is attributable to a variety of extremely diverse cells, tissues, neuronal species, and stage-specific proteins. The blood-brain barrier was formed during evolution to separate these complex specific structures from the immune system (similar protection is seen in the organs of the visual system and female genital glands).

To test the hypotheses of the neuroimmune origin of preeclampsia, we determined serum levels of NSP (NSE, GFAP) of pregnant women, newborns, parturient and puerperal women, fetuses (during cordocentesis), women with preeclampsia of varying severity, women with normal pregnancy, and in non-pregnant healthy women of reproductive age.

The findings indicated that:

  • All pregnant women with preeclampsia had significantly higher levels of antigens (NSE and GFAP) and neuro antibodies to them, compared with women without preeclampsia;
  • The earliest gestational age associated with a significant increase in NSP concentrations was 22-24 weeks;
  • Of note is the scale of increase in antibody levels: compared with the control group, women with severe pre-eclampsia had a 15- and 8-fold increase in serum levels of NSE and GFAP, respectively;
  • The levels of NSPs (antigens and antibodies to them) increased along with increasing severity of preeclampsia, its duration, highest blood pressure, proteinuria, and maternal anasarca;
  • Impairment of uteroplacental and fetal-placental blood flow, deterioration of the fetus is accompanied by elevation of NSP concentrations.
  • Fetuses at 18-22 weeks’ gestation of (cordocentesis) of mothers with the subsequent development of severe pre-eclampsia had the highest serum NSP levels, while the mother had the highest levels of anti-NSP antibodies;
  • In the control groups (non-pregnant women and, pregnant without preeclampsia), NSP was not found in significant quantities;
  • No significant levels of NSP were found in any group of patients before 22 weeks’ gestation.

Analysis of modern clinical features of preeclampsia and eclampsia showed that pathophysiological changes in these pregnancy complications often do not correlate with the severity of clinical manifestations; there may be multidirectional changes in laboratory and functional parameters. In this regard, it is of practical interest to investigate the levels of biochemical markers at the earliest stages of preeclampsia, their changes as it progresses, and also after delivery. All women, both with early and late preeclampsia, showed significant changes in biomarkers compared with the control group, most pronounced in pregnant women with early severe preeclampsia (a 3- and 2-fold decrease in PIGF and VEGF, respectively, 4-fold increase in sFlt, 10-fold reduction in PIGF/sFlt-1, 1.6-fold increase inTNFα by, 2.7-and1.7-fold increase in VCAM and ICAM, respectively, 2-and 3.4-fold increase NSE and GFAP, respectively, as compared with the control group).

Investigation of organs, tissues, and vessels of the women, who died from severe pre-eclampsia and eclampsia of women revealed the following specific signs of gestational immune complex endotheliosis:

  • Manifest damage to endotheliocytes, capillary microthrombi;
  • Hydrops, swelling of endotheliocytes with an abnormal monolayer of the endothelial lining;
  • Separation of endothelial cells from the basement membrane up to «de-endothelialization» in some areas of the vessels, where a «turbulence» of blood flow occurs; reduced blood supply to tissues;
  • Increased permeability of subcellular membranes;
  • Vacuolization and destruction of mitochondria, endoplasmic reticulum, cytoskeleton elements, and other cellular organelles, which ultimately leads to microangiopathy, loss of endothelial receptivity, the ineffectiveness of the medications, and multi-organ failure;
  • Antiangiogenic damage - a decrease in the number of capillaries and rarefaction of the capillary network.

The degree of damage to endotheliocytes correlates with the severity of preeclampsia.

Edema and swelling of endotheliocytes in the brain and kidney vessels, the formation of microthrombi in the places of micro-vessel «de-endothelialization» results in an occlusion of vascular lumen, organ and tissue hypo-perfusion with the development of foci of necrosis in target organs. In a normal pregnancy, the endothelium is intact and retains its physiological structure.

Therefore, for the first time we have clearly shown the destructive nature of endothelial damage, much more markedly pronounced in severe preeclampsia, which can be associated with the formation of the membrane attack complex C5b-C9 (MAK), which is formed during an abnormal pathway of the activation of complement system proteins in autoimmune, complement-mediated, immune complex diseases and leads to cell lysis.

The results of the audit of maternal mortality from preeclampsia/eclampsia and the analysis of autopsy material of deceased women revealed the clinical and morphological similarity of this pregnancy complication with thrombotic microangiopathy, in which the microvascular immune damage is associated with excessive activation of the complement system.

The traditional morphological study of the brain showed pronounced perivascular and pericellular edema, foci of ischemia and necrosis, and brain tissue hemorrhages. Immunohistochemical studies using markers of neurons NSE and endothelial cells CD-34 revealed a marked decrease in the density of capillary distribution in the cerebral cortex during preeclampsia and eclampsia, in contrast to the comparison group (who died from other causes), which indicates pronounced hypoperfusion in this brain area resulting from a severe and prolonged anti-angiogenic condition characteristic of preeclampsia.

The use of markers of differentiated neurons and astrocytes (NSE, GFAP) showed severe damage to the neurons of the cerebral cortex and other cells to the point of their death with the release of NSE from neurons into the brain extracellular space. Total and subtotal desquamation of endotheliocytes in some areas, which were «lumped» in the vessel lumen, was observed in the cerebral capillaries.

An important fact, not previously described in the literature, was the detection of NSE-positive granules in dendritic masses and edematous desquamated endothelial cells of the cerebral capillaries only in women who died of preeclampsia. This finding may be viewed as a morphological equivalent of the NSE release from neurons and its concentration in the zone damage to the blood-brain barrier (in the basement membrane and endothelial cells of the cerebral capillaries).

The eclamptic liver was detected only in 40% of cases. Findings acquired using a marker of endotheliocytes CD-34 showed a sharp decrease in the density of the capillary network, unlike the comparison group, which explains the necrotic changes in the liver in severe pre-eclampsia. Besides, there was a sharp increase in stellate reticuloendothelial cells (Kupffer cells) with the presence of NSE expression in women who died from preeclampsia. This fact indicates decompensation of the liver detoxification function, impaired elimination of NSE (including those in immune complexes) in severe pre-eclampsia and eclampsia.

A new fact was the increase in the number of mesangial and juxtaglomerular cells, which play a role in synthesizing renin. Apparently, this mechanism supports treatment-refractory hypertension in patients with preeclampsia. An extreme degree of damage and total desquamation of endotheliocytes in some areas of arterioles was found only women who died from severe pre-eclampsia and eclampsia. Such a pronounced destructive endotheliosis was not seen in the comparison group, including those who died from chronic arterial hypertension (without pre-eclampsia).

The same morphological pattern was found in the heart: reduction in myocardial vascularization, desquamation of endotheliocytes in some areas of microvessels.

Changes in the vascular endothelium in the microcirculation system in women who died from severe pre-eclampsia and eclampsia are, in essence, a phenomenon of immune complex gestational destructive endotheliosis, which is confirmed by electron microscopy studies of the vessels and pathological studies of organs and tissues. This process leads to multiple organ failure and the ineffectiveness of symptomatic therapy. Dysfunction of the receptors of the damaged endothelium blocks the action of injected medications, thus determining the specific features of this complication.

The histological «portrait» of the gestational destructive endotheliosis is in many ways similar to the morphological changes in thrombotic microangiopathy (TMA). As an extremely rare (1: 1,000,000) pathology (in particular, the atypical hemolytic-uremic syndrome (aHUS)), this disease was previously not well known in obstetric practice, although the severe course of preeclampsia and HELLP syndrome seemed consistent with preexisting (co-occurring) immune TMA-type pathology.

TMA is a fairly heterogeneous group of diseases with a morphological picture and clinical manifestations similar to preeclampsia [15-18]. They are characterized by the development of microangiopathic hemolytic anemia, thrombocytopenia, microthrombosis and multi-organ dysfunction - clinical manifestations in which severe preeclampsia and HELLP syndrome are easily distinguished. Mortality in aHUS, in the absence of specific therapy, previously reached 90%, has now decreased to 10% (due to the use of special therapy blocking aggressive MAC), which implies the possibility of therapeutic intervention by blocking the destructive MAK molecule [19].

Preeclampsia, eclampsia, and HELLP syndrome are, in fact, TMA [19]. According to the results of our audit, thrombocytopenia was noted in 77.5% of deceased patients, and 40.8% had very severe thrombocytopenia. HELLP syndrome was diagnosed in more than half of the deceased, but other possible variants of TMA were not investigated.

Of note is sometimes an atypical course of severe pre-eclampsia and eclampsia: worsening after delivery with the development of oliguria/anuria, unexpected complications such as placental abruption, antenatal fetal demise, and sudden development of eclampsia in patients with moderate arterial hypertension and mild clinical manifestations of preeclampsia.

It was shown for the first time that the clinical, laboratory and morphohistochemical changes in severe preeclampsia, eclampsia, HELLP syndrome have a close resemblance to diseases classified as TMA (edema of endotheliocytes, their detachment from the basal membrane, the presence of deposits in the subendothelial layer, vascular occlusion, reduced ability to adaptive dilatation, loss of vascular tone autoregulation, etc.). Involvement of the blood cells in the pathological process: erythrocytes (schistocytes, reduced deformability), platelets (adhesion, aggregation, micro thrombogenesis), desquamation of the endothelium, microangiopathy are also characteristic of the immune (immune complex) pathology.

During pregnancy, patients with genetically determined autoimmune diseases (aHUS, thrombotic thrombocytopenic purpura, antiphospholipid syndrome, etc.) have similar mechanisms for MAC formation, but complement may be activated via an abnormal pathway not only by polymorphism of genes encoding the proteins of complement components, lack of enzymes, bacteria that produce Shiga-toxin, but also immune complexes.

Thus, it is not the pregnancy itself causes gestational damage to the vascular endothelium, but the presence of dual trigger stimulants sensitizing and activating the maternal complement system in an abnormal way.

The pathophysiological basis of some autoimmune immune complex diseases is well known: an abnormal way of activating complement proteins has been proven; uncontrolled formation of destructive MAC (C5b-C9), which, embedded in the bi-lipid layer of the endotheliocyte cell wall, contributes to their lysis resulting in TMA-type damage to the endothelium. Women with severe pre-eclampsia were found to have significantly higher levels of MAC than pregnant women without this complication [20-22].

There is evidence that in severe preeclampsia, the levels of sC5b-9 correlate with an increase in the anti-angiogenic factor sFlt-1 and a decrease in the level of PlGF and VEGF, i.e., with changes characteristic of preeclampsia [23].

In women with severe preeclampsia and HELLP syndrome, early delivery is recommended. However, it is extremely important to investigate the possibility and effectiveness of targeted pathogenetically directed therapy, blocking the stereochemical process of activation of the complement system, which plays a key role in the development of gestational endotheliosis. Such agents have been developed for HUS and paroxysmal nocturnal hemoglobinuria (variants of TMA). Targeting at C5 complement component, they prevent C5 from being cleaved into С5а and С5b and result in the formation of the terminal complex. Further research in this direction will finally allow the development of methods and means for treating and preventing pre-eclampsia.


The specific features of preeclampsia, their clinical and morphological similarities with immune and genetic diseases, as well as differences in the manifestation of co-morbidities, allow us to present a different definition of preeclampsia:

«Preeclampsia is a gestational neuro-immune complex endotheliosis that develops in the perinatal period of pregnancy as a fundamental stereochemical process, in which NSPs of the fetal neocortex trigger the activation of the complement via an abnormal pathway.»

Based on world literature, the audit of maternal mortality in Russia, our clinical observations for more than 20 years, clinical, laboratory, immunochemical, morphological, immunohistochemical, electron microscopy studies, findings in research on biomarkers of fetal and placental barrier, endothelial and placental dysfunction, we present a different concept of the essence and nature of preeclampsia. It is not only a hypertensive state secondary to placental insufficiency, but a significantly more severe gestational general pathological specific neuro-immune complex endotheliosis, in which NSP of the developing fetal brain during the formation, construction, active growth and isolation of the neocortex, was for the first time considered as an antigen that disrupts the activation of complement proteins.

Our concept of ​​preeclampsia allows us to offer a pathogenetic approach to the choice of active or expectant management for patients with this pregnancy complication. The development of new (other) ideas about the pathogenesis of pre-eclampsia is a real opportunity to stop its further and inevitable progression; prevent serious maternal, fetal and neonatal morbidity, develop a system for the protection of the fetal physiological development, apply targeted agents that block the uncontrolled formation of MAC and the abnormal pathway of complement activation.


  1. Филиппов О.С., Гусева Е.В., Малышкина А.И., Михайлов А.В., Зубенко Н.В., Фаткуллин И.Ф., Башмакова Н.В., Артымук Н.В., Пестрикова Т.Ю., Палиева Н.В. Материнская смертность в Российской Федерации в 2016 году. Методическое письмо Министерства здравоохранения Российской Федерации №15-4/10/2-7339 от 23.10.17. [Filippov O.S., Guseva E.V., Malyshkina A.I., Mikhailov A.V., Zubenko N.V. and etc. Maternal mortality in the Russian Federation in 2016. Methodological letter of the Ministry of Health of the Russian Federation No. 15-4 / 10 / 2-7339 of 10.23.17. (in Russian)].
  2. Филиппов О.С., Гусева Е.В., Сидорова И.С., Никитина Н.А. Результаты конфиденциального аудита материнской смертности в Российской Федерации в 2015 году. Методическое письмо Министерства здравоохранения Российской Федерации № 15-4/10/2-7955 от 14.12.2016. [Filippov O.S., Guseva E.V., Sidorova I.S., Nikitina N.A. The results of a confidential audit of maternal mortality in the Russian Federation in 2015. Methodical letter of the Ministry of Health of the Russian Federation No. 15-4 /10 / 2-7955 of 12/14/2016. (in Russian)].
  3. Здравоохранение в России 2017. Статистический сборник / Росстат. М.; 2017. [Zdravookhranenie v Rossii. 2017. Statisticheskii sbornik / Rosstat. – Moskva; 2017. 170 s. (in Russ)]
  4. Anderson U.D., Olsson M.G., Kristensen K.H., Akerström B., Hansson S.R. Review: Biochemical markers to predict preeclampsia. Placenta. 2012; 33(Suppl.):S42-7.
  5. Lamarca B. Endothelial dysfunction. An important mediator in the pathophysiology of hypertension during pre-eclampsia. Minerva Ginecol. 2012; 64(4): 309-20.
  6. Young B.C., Levine R.J., Karumanchi S.A. Pathogenesis of preeclampsia. Annu. Rev. Pathol. 2010; 5: 173-92.
  7. Милованов А.П. Патология системы мать-плацента-плод. М.: Медицина; 1999. [Milovanov A.P. Pathology of the mother-placenta-fetus system. M .: Meditsina; 1999; 1999. 448 p. (in Russian)].
  8. Brosens I., Pijnenborg R., Vercruysse L., Romero R. The “Great Obstetrical Syndromes” are associated with disorders of deep placentation. Am. J. Obstet. Gynecol. 2011; 204(3): 193-201.
  9. Roberts J.M. Pathophysiology of ischemic placental disease. Semin. Perinatol. 2014; 38(3): 139-45.
  10. Urato A.C., Norwitz E.R. A guide towards pre-pregnancy management of defective implantation and placentation. Best Pract. Res. Clin. Obstet. Gynaecol. 2011; 25(3): 367-87.
  11. Чехонин В.П., Дмитриева Т.Б., Жирков Ю.А. Иммунохимический анализ нейроспецифических антигенов. М.: Медицина; 2000. [Chekhonin V.P., Dmitrieva T.B., Zhirkov Yu.A. Immunochemical analysis of neurospecific antigens. M: Meditsina; 2000. 415 p. (in Russian)].
  12. Berger R., Garnier Y. Perinatal brain injury. J. Perinat. Med. 2000; 28(4): 261-85.
  13. Brunel H., Girard N., Confort-Gouny S., Viola A., Chaumoitre K., D’ercole C. et al. Fetal brain injury. J. Neuroradiol. 2004; 31(2): 123-37.
  14. Chekhonin V.P., Lebedev S.V., Dmitrieva T.B., Blinov D.V., Gurina O.I., Semenova A.V., Volodin N.N. Enzyme immunoassay of NSE and GFAP as the criterion of dynamic evaluation of the rat blood-brain barrier in perinatal hypoxic ischemic injury of the CNS. Bull. Exp. Biol. Med. 2003; 136(3): 261-5.
  15. Краснопольский В.И., Шифман Е.М., Куликов А.В., Козловская Н.Л., Артымук Н.В., Белокриницкая Т.Е., Гурьева В.М., Упрямова Е.Ю., Смирнов Г.А., Степанюк В.А., Матковский А.А., Коротчаева Ю.В. Отчет о проведении Форума экспертов «Тромботические микроангиопатии и атипичный гемолитико-уремический синдром в акушерстве. Первый шаг к междисциплинарному консенсусу». Российский вестник акушера-гинеколога. 2017; 17(1): 118-25. [Krasnopol’skii V.I., Shifman E.M., Kulikov A.V., Kozlovskaya N.L., Artymuk N. V., Belokrinitskaya T.E., Gur’eva V.M., Upryamova E.Yu., Smirnov G.A., Stepanyuk V.A., Matkovskii A.A. Report on Experts Forum «Thrombotic microangiopathies and atypical hemolytic-uremic syndrome in obstetrics. The first step to cross-disciplinary consensus». Russian Bulletin of Obstetrician-Gynecologist/Rossiyskiy vestnik akushera-ginekologa. 2017; 1: 96–103. (in Russian)]. doi:
  16. Распопин Ю.С., Колесниченко А.П., Синявская Н.В., Миллер А.А., Шифман Е.М., Куликов А.В. Многоликая тромботическая микроангиопатия – «ожерелье смерти» осложнений беременности и родов. Клиническая нефрология. 2017; 2: 32-6. [Raspopin Yu.S., Kolesnichenko A.P.,Sinyavskaya N.V., Miller A.A., Shifman E.M., Kulikov A.V. Many-faced thrombotic microangiopatia – «necklace of death» of complications of pregnancy and childbirth. Klinicheskaya nefrologiya. 2017; 2: 32-36. (in Russian)].
  17. Tsai H.M., Kuo E. From gestational hypertension and preeclampsia to atypical hemolytic uremic syndrome. Obstet. Gynecol. 2016; 127(5): 907-10.
  18. Salmon J.E., Heuser C., Triebwasser M., Liszewski M.K., Kavanagh D., Roumenina L. et al. Mutations in complement regulatory proteins predispose to preeclampsia: a genetic analysis of the PROMISSE cohort. PLoS Med. 2011; 8(3): e1001013.
  19. Макацария А.Д., Бицадзе В.О., Хизроева Д.Х., Акиньшина С.В. Тромботические микроангиопатии в акушерской практике. М.: ГЭОТАР-Медиа; 2017. [Makatsariya A.D., Bitsadze V.O., Khizroeva D.Kh., Akin’shina S.V.Thrombotic microangiopathy in obstetric practice. M.: GEOTAR-Media; 2017. 304 s. (in Russian)].
  20. Burwick R.M., Fichorova R.N., Dawood H.Y., Yamamoto H.S., Feinberg B.B. Urinary excretion of C5b-9 in severe preeclampsia: tipping the balance of complement activation in pregnancy. Hypertension. 2013; 62(6): 1040-5.
  21. Regal J.F., Burwick R.M., Fleming S.D. The complement system and preeclampsia. Curr. Hypertens. Rep. 2017; 19(11): 87.
  22. Regal J.F., Gilbert J.S., Burwick R.M. The complement system and adverse pregnancy outcomes. Mol. Immunol. 2015; 67(1): 56-70.
  23. Guseh S.H., Feinberg B.B., Dawood H.Y., Yamamoto H.S., Fichorova R.N., Burwick R.M. Urinary excretion of C5b-9 is associated with the anti-angiogenic state in severe preeclampsia. Am. J. Reprod. Immunol. 2015; 73(5): 437-44. 10.1111/aji.12349.

Received 21.06.2018

Accepted 22.06.2018

About the Authors

Sidorova, Iraida S., MD, professor, academician of the RAS, merited scholar of the Russian Federation, merited doctor of the Russian Federation, professor
at the Department of Obstetrics and Gynecology №1, Medical Faculty, I.M. Sechenov First Moscow State Medical University of Minzdrav of Russia (Sechenov University).
119991, Russia, Moscow, Trubetskaya str. 8, bld. 2. Tel.: +74992486729. E-mail:
Nikitina, Natalia A., MD, professor, Department of Obstetrics and Gynecology №1, Medical Faculty, I.M. Sechenov First Moscow State Medical University of Minzdrav
of Russia (Sechenov University). 119991, Russia, Moscow, Trubetskaya str. 8, bld. 2. Tel.: +79169403934. E-mail: ORCID ID 0000-0001-8659-9963.

For citation: Sidorova I.S., Nikitina N.A. Validation of the modern concept of the development of preeclampsia. Akusherstvo i Ginekologiya/Obstetrics and Gynecology.2019; (4): 26-33. (in Russian)

Similar Articles

By continuing to use our site, you consent to the processing of cookies that ensure the proper functioning of the site.