Dr. Mario López-Llera M.

Medical Hypotheses. 1995;45:591-601.

ABSTRACT

The etiology of preeclampsia-eclampsia remains largely unclarified in spite of over 100 years of systematic study. The assumption that the triggering event is lineal and amenable to reductionist techniques has charac-terized these efforts. The main purpose of this paper is to show that complexity and complicity characterize most pathophysiological processes in preeclampsia- eclampsia, a situation suggesting that similar mechanisms must exist at the origin of the disease.

The unique configuration of the intervillous space and the intensity of energy transference through the feto-maternal interface offer many dysfunctional possibilities, even in clinically normal pregnancies. The most characteristic seem to be; the shedding and deportation of trophoblast, the fragmentation of villi, the escape of fetal blood, and events associated with trophoblast damage, degeneration and death. The pathogenic potential of these natural processes seems to depend of the association with amplifiers and permissive factors, that vary from person to person and from time to time.

Thus, considering the convergence of multiple factors and the presence of non-linearity in some of their interactions as a plausible working hypothesis, further exploration on this subject should adhere to the rules of this different reality. To find the best possible method of inquiry and to recognize its limitations will be the surest way to avoid failure.

Key Words: Eclampsia; Etiology of Eclampsia; Complexity; Complicity; Trophoblast; Placental intervillous

COMPLEXITY AND COMPLICITY IN ECLAMPSIA. BARRIERS OR BRIDGES.

The information about the pathophysiology of the hypertensive complications of pregnancy has increased substantially in the last thirty years. However and in spite of many outstanding contributions, the unveiling of the main triggering mechanism has not been possible. Actually, the utilization of strictly reductionist tech-niques, while exponentially expanding the data have also encumbered their interpretation and seem to be leading to an endless dispersive reductionist fragmentation.

Since the etiology of preeclampsia-eclampsia could very well fall into the category of complex phenomena, it would appear only reasonable to study it according to the basic principles of this new branch of the scientific method. The terms used in the title clearly express the basic nature of the problem; complexity meaning invol-ving many parts and complicity the state or condition of being a complice or accomplice. With more technical propriety, J. Cohen and I. Stewart clarify that complicity arises when simple systems interact in a way that changes both and erases their dependence on initial conditions.[1]

Accordingly, the main purpose of the present paper is to propose that complexity and complicity charac-terize most pathophysiological processes known to occur in preeclampsia-eclampsia; a situation suggesting that similar type of interactions must exist at the origin of the disease. Due to space constraints, only the most relevant processes will be considered; the concept of eco-genetic interdependence, the potentially chaotic natural phenomena within the intervillous space, the existence of amplifiers and permissive factors, and the possible conversion of linearity into non-lineal type of relations. For similar reasons, quotations will be limited to data directly involved in the main thesis, while those related to widely accepted or secondary topics can be obtained by request.

However, since there is no precise or complete agreement on the definition, terminology, classification or grading of these diseases, an indispensable first step is to define the gestational pathology to be addressed in this paper as clearly as possible in order to avoid unwarranted generalizations.

DEFINITION OF THE PRE-ECLAMPSIA-ECLAMPSIA SYNDROME.

Most diseases are subject to change due to seasonal, geographical, cyclical, social and other less clear fac-tors, such as the level of public awareness and the depth and character of overall medical progress. Changes in terminology, classification and grading of some diseases reflect the conceptual evolution of the health and disease equation. The case of the hypertensive disorders of pregnancy is a good example of this process. During the first half of the XX Century, the concept of a "toxic" background generated the corresponding terminology [2]. As this idea fell into disrepute, it was replaced by a symptomatic definition centered around the single and most prominent clinical sign, hypertension [3]. However, the older term of pre-eclampsia- eclampsia continued in use to designate the most important type of hypertensive complication of pregnancy [4]. Furthermore, the results of several recent studies have brought back the "toxic" element for consideration [5-9].

In order to overcome the problems posed by this conceptual fluctuations, we will define this gestational pathology according to four basic criteria, as follows.

Clinically, it is a condition complicating the second half of pregnancy and early puerperium of a previously healthy woman, characterized by hypertension, proteinuria and some times by sudden generalized edema. Severe cases may present generalized convulsions and/or a comatous state. A similar picture may occur in patients with underlying cardiovascular, metabolic or renal disease, in which case it is known as superimposed pre-eclampsia-eclampsia.

Hemodynamically, this problem is characterized by diminished blood volume with hemoconcentration and consequent rheological changes [10-15] and by vasoconstriction with increased peripheral vascular resistance [13,16-20]. This vasoconstriction seems to begin regionally affecting the utero-placental and renal vascula- tures.

Hematologically, there are significant changes in platelet physiology that lead to increased consumption and turn-over rate [21-30], associated to de-regulation of the prostacyclin/ thromboxane balance [31-36]. Advan-ced cases will show various degrees of hemolysis and/or fibrinogen consumption [37-39].

Morphologically, there is a defective utero-placental interface (incomplete trophoblast-spiral arteries union) [40-45], changes in the vascular endothelium ( capillary glomerular endotheliosis) [46-48] and, in severe cases, hepatic peri-portal hemorrhagic necrosis, multi-systemic vascular damage and parenchymatous hemorrhages [49].

None of these abnormalities is specific but their convergence during a human pregnancy produce a unique pathological process. Furthermore, each one of these four criteria carry a different weight in the validation of the diagnosis. Their significance grows ascendingly from the clinical to the morphological category. Thus, in our opinion, if a patient shows incomplete or doubtful clinical features, but meets the requirements of any two of the remaining three criteria, the presence of a pre-eclamptic condition should be accepted.

GENES AND ENVIRONMENT.

All living organisms possess a complete and very precise genetic program in charge of their biological cycles. Similarly, all active biological systems cannot exist, nor have they existed, independently of a given "milieu". The separation of these two fundamental and complementary structures, required by current methods of study and analysis, does never take place in their natural settings.

In this respect, some information obtained in the study of essential or primary hypertension may help expose how difficult it is to dissect cultural, environmental and genetic influences involved in apparently simple final phenotypes [50]. For example, K. Lindpainter [51] expressed the view that the genetic background of essential hypertension is both polygenic and heterogeneous and that it is likely to involve both specific gene-gene and gene-environment interactions, making their investigation a very difficult task. Furthermore, Wu and Berecek [52] reported that the administration of an angiotensin converting enzyme inhibitor during early pregnancy of spontaneously hypertensive rats prevented the development of hypertension in their offspring and also in succeeding untreated generations.

As far as eclampsia is concerned, the finding that it occurs oftener in daughters, sisters and granddaughters of eclamptic patients suggested a hereditary and possibly genetic origin [53-55]. Nevertheless, other studies have linked some hostile intrauterine conditions, that lead to fetal growth retardation and very premature birth, with the development of chronic hypertension in adult life [56-62]. Since early antepartum eclampsia is associated with this unfavorable intrauterine environment [63,64], and since any functional impairment of the cardiovascular system in adulthood becomes a significant predisposing factor for eclampsia [65], the type of inheritance involved must be extremely complex. In addition, a very low birth-weight infant with a conflictive neonatal recovery also inherits a particular cultural and socioeconomic structure that will affect her future reproductive performance.

Thus, at present, it seems justified to accept that the general nature of any biological system is genetically determined, but that the unfolding of the program is conditioned by interactions with its environment. The stimuli provided by this environment during some critical stages of growth and development will, to a certain degree, confirm or reprogram the genetic information and lead, within strict limits, to other phenotypical variants. Consequently and irrespective of the true character, penetrance and number of inherited maternal factors, the existence of permissive or accessory components must be considered, since many epidemiological data and clinical features of eclampsia are not explained through the mechanism of orthodox maternal genetic inheritance [66].

THE CENTRAL POINT AND MAIN COMMON PATHWAY.

Interpreting a normal pregnancy as a successful exchange of information between the conceptus and the mother, the crucial importance of an adequate specialized structure to control it becomes self-evident. During the first few days of the conceptus' life this exchange occurs freely, but as soon as nidation takes place and placentation begins, most of the information is channeled through the utero-placental interface. For practical purposes, the intervillous space (IVS) becomes the central point of the gestational process and acquires a unique significance; it becomes the site of maximal energy transfer of the complete materno-fetal supersystem.

The IVS is limited by fetal trophoblast on one side and by maternal decidua on the other, and it is occupied by maternal blood in continuous renovation. Even though the whole area is dependent of the major circulatory system and has no clear mechanisms of autoregulation, its effectiveness depends mainly of the adequacy of the trophoblast and spiral arterioles union, since this will determine its internal hemodynamics. However, the condition of advanced abdominal pregnancy and the incidence of pre-eclampsia in these cases [67-69], prove that the spiral arterioles with their trophoblastic penetration are not indispensable for an almost complete gestation nor for the pathogenesis of the pre-eclamptic syndrome. On the other hand, the high incidence of fetal growth retardation and of fetal death in these patients indicate that the efficacy of such fetomaternal

interface is minimal, but at the same time show the extraordinary capacity for adaptation. In addition, the facts that 85.4 per cent of the mothers were 25 years of age or more and 42.3 per cent were multigravidas [70] strongly suggest that some type of underlying disease was partly responsible for the pre-eclamptic syndrome, in spite of the report of one case validated with renal biopsy findings [71].

The characterization of primary or of superimposed preeclampsia does not depend of differences in the fetomaternal interface, but on the condition of other external functions. Actually, both types seem to share common processes occurring within this unique structure. Thus, an incomplete trophoblast and spiral arterioles union or the presence of underlying disease in the vascular, renal or metabolic systems, may simply act as amplifiers of internal conflicts in the IVS. In other words, the IVS has several specific local processes that can be amplified by various factors and become pathogenic after reaching a critical point.

In spite of its apparent structural simplicity, several very complex processes take place within the fetomaternal interface. They can be grouped in the following categories; hemodynamic, rheological, metabolic, hematological, hormonal, biochemical, immunological, morphologic, and purely mechanical, such as the vibrator effects of the fetal systole, the massage-like action of the uterine contractions, and the maternal posture and type of physical activity. Their harmonious performance is essential to keep the gestational process within ample physiological bounds. However, the very nature of these events and their multiple interactions also offer many dysfunctional possibilities. As far as the pre-eclamptic syndrome is concerned, the most characteristic and with more pathogenic potentials seem to be; the shedding and deportation of trophoblast, the fragmentation of villi, the escape of fetal blood, and events associated with trophoblastic damage, degeneration and death.[9,72-84]

In this regard, it must be emphasized that the primary aims of the utero-placental interface are; to provide an immunological buffer zone compatible with the acceptance and growth of foreign fetal tissues; to allow and favor the exchange of vital substances between mother and fetus, and to keep the formed elements of the fetal blood separated from those of the mother. However, the nature of the processes involved and the structural characteristics of the IVS entail a certain degree of entropy. The leakage of fetal blood into the maternal circulatory system signals the appearance of fissures along this otherwise continuous lining.

Although the existence of some particular constitutional deficiencies cannot be ruled out, the mechanisms of villous rupture most likely depend of conditions occurring on the maternal side and intimately related to hemodynamic and physical factors, including increased fragility of its fractal structure as its mass grows less than the surface in successive ramifications. Furthermore, if Simpsom and Elias [78] are correct in that even bimanual examination of a pregnant uterus can cause transient passage of fetal cells into the maternal circulation, then, other mechanical events inside and outside the uterus, such as sudden pressure changes on the placenta caused by some fetal movements, can also increase the leakage of fetal cells.

Based on accepted knowledge about vascular tissue repair in general, the sequence of events could be as follows. First, the action of conflicting hemodynamic forces leading to turbulences and pressure changes around a particularly exposed and possibly debilitated villous structure create a rent on its trophoblastic

lining followed by rupture of fetal capillaries with expulsion of blood elements and fragments of trophoblast into the IVS. Next, a sealing and reconstructive process begins on both sides of the lining; fetal blood components occlude the opening and repair the endothelium, assisted on the outside by maternal platelets and

fibrinogen molecules. Then, the continuity of the trophoblast is regenerated and the functionality of the villous unit may be recovered or lost. However, since the initial repair mechanisms consist mainly of thrombotic processes, inside and outside the villous proper, they can extend to nearby zones, enlarge the affected area of intervillous thrombosis, and increase the activation of maternal blood coagulation factors.

At a finer level of events, the partial or complete detachment of villi create a transient disruption of the immunological buffer zone. Various fetal antigenic materials become exposed to the maternal milieu, while others are carried away by the maternal blood flow, where they are recognized and neutralized. In both cases, antigen-antibody reactions take place, even though most authors concede limited immunogenic properties to trophoblastic cells [85].

As relevant as these processes of fracture and deportation might be, one must not lose sight of the much bigger issue of in situ trophoblastic damage and dysfunction associated with placental infarction [79-84]. Both are intimately related, but quantitatively the latter clearly outweighs the first one. Nevertheless, from the point of view of timing, placental infarction must be considered a late manifestation of IVS dysfunction.

Finally, the breakdown of damaged or detached trophoblast is associated with the release of substances that may have vasoactive properties, be potentially noxious to the vascular endothelium, and capable of affecting the mechanisms of hemostasis and prostanoids production and balance [5-9,31-36].

In spite of their ominous character, these processes occur in all pregnancies, they are inevitable events in human hemochorial placentation. The difference between clinical normality or a pre-eclamptic syndrome depends of a balance equation with the intensity of the phenomena on one side, and the regulatory capacity of the host organism on the other. For the final results of this equation, we have to consider also the presence of amplifying circumstances and permissive conditions.

AMPLIFIERS AND PERMISSIVE FACTORS.

In this context, an amplifier is any biological or biologically related circumstance that effectively increases the IVS natural conflicts. They may consist entirely of local features contained within the pregnant uterus or be the local expression of systemic maternal handicaps or, in some cases, have a dual character. Factors associated with multiple pregnancy, molar pregnancy, polyhydramnios, and labor contractions are examples of

the first category, while several conditions characterized by systemic endothelial or arteriolar involvement, like chronic hypertension, and some chronic renal or collagen diseases belong to the second type. Diabetes mellitus is a condition with a dual character since, if untreated, leads to macrosomia, hyperplacentosis and polyhydramnios, while at the same time affects the vascular endothelium systemically. (Table 1.)

A permissive factor is any particular aspect of the maternal organism that allows a normal intensity of the IVS conflicts to generate evident pathological responses at a local or systemic level. Possible examples of these factors are; some nutritional deficiencies [86-93], unfavorable genetic combinations[53,94-98], immunological incompetences [99-105], and various ecological influences [106-110].

The possibility that a certain amplifier could also contain permissive factors increases the complexity of the processes and makes their identification a very difficult task. Also, if the underlying medical conditions responsible for the amplifiers or permissive factors are in a very early stage, their existence can be very difficult to prove with conventional means and be missed entirely.

The experience of a first term or near-term pregnancy in a healthy woman is a good example of amplifiers and permissive factors combined. Since this is the first time the maternal organism will be subjected to such radical changes, both locally and systemically, the lack of a biological phenotypical memory may stunt the regulatory responses with an increase of the IVS conflicts. On the contrary, the whole process of a potentially successful first pregnancy should improve their effectiveness for the next one.

The gross facts that a second pregnancy and delivery are easier than the first one or that the weight, volume and shape of a parous uterus is significantly different from a nulligravid one, indicate that the reproductive process imprints lasting changes to the maternal organism. These morphologic and macroscopic changes are the visible part of much finer features at a cellular, biochemical and immunological levels that may operate somewhat as a temporal biological memory.

Although the gestational changes involve practically the complete maternal organism, there are three areas where the lack of a temporal memory becomes particularly important. The maternal milieu together with the trophoblast must provide an immunological buffer zone to cope with changing immunogenic characteristics from early to late types of fetal cells. The maternal hemodynamics must secure an increasing blood flow to a completely new unit while preserving or even improving preexisting regional blood flows, and, the myometrium with its intertwined vasculature must experience an enlargement and growth process of unique proportions, while establishing a highly functional uteroplacental connection.

The possible consequence of incomplete immunological adaptation may be a poorly structured trophoblast/spiral arteriole connection responsible for increased turbulence in the intracotiledonary space and neighboring areas of the IVS. In addition, this incomplete tolerance could also be involved in abnormal reactions in the microenvironment of villous rupture and trophoblast damage.

A circulatory or hemodynamic maladjustment with reduced uteroplacental blood flow could lead to trophoblastic hypoxia and relative ischemia followed by increased cellular damage and higher levels of IVS conflicts. An inertial myometrial resistance to stretch could be the cause of the relative increase in the spontaneous uterine contractility seen in pre-eclamptic patients. This contractility could hinder the arterial and venous uteroplacental circulation intermitently and favor trophoblastic hypoxia and dysfunction.

LINEARITY AND NON-LINEARITY.

It has become evident that most naturally occurring complex systems cannot be explored successfully with reductionist methods alone. The birth of non-linear science offers different perspectives and provides new tools for the study of complex behaviour [1,111-117]. Eclampsia seems to be a clear example of a movement from relative order into relative disorder, sometimes leading to total chaos.

Stability in biologic systems results from an almost infinite number of interactions regulated through feedback loops. Environmental influences and eco-genetic factors continuously threaten this stability at the macro and microscopic scales, but the threat of de-stabilization acquires special significance during periods of intense energy mobilization, such as the growth and development of a new super-system implies. During de-stabilization, some negative feedback loops become irregular and set their critical points outside physiological limits or change their cycles altogether into positive feedback loops and converge towards a catastrophic event due to the lack of adequate counterregulatory mechanisms.

Considering the anatomic and functional integrity of the fetomaternal interface as the pre-requisites of efficiency and stability for the gestational process, the primary feedback loops must somehow originate and exist within these particular structures. The number of main feedback loops and of loops within loops involved in the physiology of the fetomaternal interface depends on how far down in the microscopic scale our exploration is able to penetrate, but it must be quite large and only partially known.

In previous paragraphs, the IVS conflicts with their amplifiers and permissive factors were considered the central issue and main triggering events in the etiology of eclampsia. For illustration, in the following paragraphs, we will apply the concepts of turbulence and chaos only to the loops directly involved in the process of trophoblastic damage and its hemodynamic counterparts, but a similar basic interpretation can be given to all systems and sub-systems involved in the pathologic physiology of eclampsia, such as the processes of lipid peroxidation [32,118-123], the role of endothelins [124-130], and the participation of endothelium-derived relaxing factors [129-136].

Briefly, once the IVS conflicts with their associated trophoblastic damage pass a critical limit, the initially localized process becomes part of a wider web affecting the stability of many external regulatory mechanisms. The functions of the vascular endothelium and the balance of vaso-regulatory substances is tipped, slightly at first, in favor of constriction[13,17-20]. For a highly vascular organ with no known mechanisms of hemodynamic autoregulation, like the placenta, an increase in the systemic blood pressure could be interpreted deterministically as an attempt to improve IVS perfusion and attenuate trophoblast and fetal jeopardy. Thus, the early stages of this newly formed loop could be considered compensatory in principle. However, since the fundamental IVS conflicts have not disappeared and the demands of pregnancy advance, this highly unstable negative feedback loop is disrupted and a positive feedback loop takes its place; the higher the blood pressure the worse the IVS conflicts and the trophoblast and fetal damage. On the other hand, but also operating within this basic loop, the processes of trophoblast stress and villous fracture lead to activation of the blood coagulation cycle and intervillous thrombosis, tipping the balance in favor of increased platelet and fibrinogen consumption and turn-over rate [21-30,137-139]. In time, this local de-stabilization of the coagulation and fibrinolysis system becomes an accessory for the loops promoting vasoconstriction due to an increase in the thromboxane/prostacyclin ratio [31-36]. Here again, a necessary mechanism for the sealing of the points of feto-maternal interface disruption and designed to limit the consequences of IVS conflicts, becomes an agent of further aggression. The paradox of compensatory measures turning into pathogenic processes becomes a reality.

In addition, the blood circulating through the maternal vasculature follows the rules of a basically orderly laminar flow all the way down to the end of the spiral arterioles, where it must abruptly change into an IVS turbulent flow. This sudden change in fluid dynamics may be somewhat softened by the muffling function of the distal portion of the arteriole [140,141], but it has to take place to comply with the new rules imposed by the unique configuration of the IVS [142].

The transition may be smoothed or roughened by the interplay of several cycles, but an elevation of the maternal systemic blood pressure and its oscillatory dynamics, that result in overlapping rythms that may compete against one another, is one of the main factors increasing turbulence at the exit of the spiral arterioles delivering blood to the immediate IVS. A turbulent non-laminar flow may favor a more homogeneous distribution of blood particles, components, and nutrients for the feto-maternal exchange, but it also increases friction in some areas alternating with relative stasis in others. At a certain limit, friction modifies platelet behavior and trophoblast integrity, and, on the other hand, stagnation favors thrombosis. These results tend to worsen the IVS conflicts, add more positive feedback loops, enlarge the web of affected factors and increase the instability of the whole system. It would seem as if the IVS and, more precisely, the hyper-active process of energy transfer through the feto-maternal interface, were acting as a strange attractor.

Accepting the convergence of multiple factors and the presence of non-linearity in some of their interactions as a plausible working hypothesis, the approach to the study of the etiology of pre-eclampsia-eclampsia would have to be redirected in order to adhere to the rules of this different reality. Three principles dominating this alternate space would inflict unprecedented changes to the research exploring this problem but they also could shed new light in many of its age old inconsistencies. The first one is the fact that some complex system cannot be simulated by experimental models simpler than the system itself; the second one is the concept of sensitive dependence of initial conditions, and the third one are the confounding effects of strange attractors that appear in the midst of turbulent processes.

With these facts in mind, attempting to predict the appearance of a pre-eclamptic condition by the observation of one or two separate variables early in pregnancy [143-149] or trying to prevent or cure the disease by acting upon a single variable or even a small group of variables [150-152] is proving as frustrating as the long-term prediction of the weather or the efforts for climate control. In both matters, there can be some degree of short-term approximation but uncertainty prevails.

CONCLUSIONS

Preeclampsia-eclampsia is the most complex condition of human reproduction that elemental and separate actions of all types have not clarified. Even though complex behavior can arise from the combination of relatively simple processes that a strictly lineal approach may help characterize, the study of multiple combinations and their intricate consequences requires the mentality and the tools of non-lineal science.

An overwhelming weight of reliable data signals some particular abnormality of the placenta as the origin of the pre-eclampsia-eclampsia syndrome. The histological simplicity of the fetomaternal interface coupled with the configurational complexity of the IVS provide the necessary requirements for the generation of non-linear relationships between groups of functions and between minisystems and macrosystems. Thus, given the natural presence of a limited and balanced disorder within the IVS, the turning point towards instability with pathological consequences depends of the associated amplifying and permissive factors that vary from person to person and from time to time. The main problem is that several types of "placental abnormalities" are taking place somewhat simultaneously confounding the sequence of events and obscuring the cause and effect relationship. However, in a non-lineal milieu the direct dependence of cause and effect ceases to exist. Instead, we have groups of causes followed by groups of consequences that behave like causes themselves that, in turn, give more consequences expanding the multidimensional web of involved actions to the point that the orderly sequence of first, second, third, loses all meaning.

This predicament does not mean that the search for its ultimate cause is fatally fruitless, it only stresses the fact that non-linear problems often have complex origins that cannot be identified with conventional reduc-tionist techniques nor with absolute mathematical precision. Furthermore, it is telling us that to find the best possible method of inquiry and to recognize its limitations is the surest way to avoid persistent failure. The encounters with complexity and complicity in the study of biological problems must not be considered barriers but bridges towards fertile grounds for creative scientific endeavors.

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