Introduction:
Hypertension complicates about 8% of pregnancies in developed countries, significantly more in some areas. For a quarter of these young women, it is pre-eclampsia, the severity of which can be extreme. Hypertension in pregnancy is thus the leading cause of fetal death, and the second or third leading cause of maternal mortality worldwide.
The mechanisms responsible for these hypertensions, which disappear once the pregnancy is over, have given rise to a considerable number of successive theories. Preeclampsia has thus received the sobriquet of “disease of hypotheses”, as a tribute to the remarkable inventiveness of those who have preoccupied themselves with it. Over time, however, a few cornerstones have been put in place, allowing to sketch a physiopathological construction that we hope more sustainable than the previous ones. In any case, some fundamental points now seem to have been acquired.
The importance of this construction lies in the fact that it conditions all therapeutic hope. Indeed, the inanity of symptomatic treatment is obvious, and naive hypertension / antihypertensive reasoning is, at best, ineffective. Only the termination of pregnancy currently allows the end of the disease when it becomes threatening. Not only is this solution unsatisfactory, but its price in terms of prematurity can be unreasonable. This is why prevention strategies, based on pathophysiology, have been put in place among young women considered to be high-risk, and some have allowed significant progress.
Definitions:
Symptoms:
The hypertensive disorders of pregnancy revolve around two main symptoms: hypertension and proteinuria. The National High Blood Pressure Education Program (NHBPEP) updated their definitions in 2000.
Hypertension:
It is defined by values greater than or equal to 140 mmHg for the systolic or 90 mmHg for the diastolic, several times.
Measurements of blood pressure are delicate in pregnant women because of their lability (remember that the cardiac output is increased by 30%), so they must be iterative.
It is essential to practice these measurements on a subject as relaxed as possible, and at a distance from the gynecological examination.
The most used position is the sitting position, after a few minutes of calm and conversation. The diastolic pressure should be assessed by phase V of Korotkoff.
Ambulatory Blood Pressure Measurement (ABPM) is not recognized as a diagnostic criterion. In some cases, it can nevertheless help to recognize the so-called white coat hypertension. No predictive value has been attributed to it so far.
Proteinuria:
Proteinuria is said to be “significant” if it exceeds 0.3 g in the urine of 24 hours, in the absence of any urinary infection.
Such proteinuria is superadded to hypertension in about 10% of cases. It does not precede it, but follows it almost always, constituting the picture of preeclampsia.
Edema:
This third element of the symptomatic triad that classically characterized preeclampsia is no longer a pathological definition today. Nevertheless, diffuse oedemas, affecting the lower limbs, but also the hands (sign of the ring) and the face, can be a warning sign, especially if they are major and brutal constitution.
Classification:
The “official” classification of hypertensive disorders of pregnancy has hardly evolved since that of the American College of Obstetricians and Gynecologists (ACOG) in the 1970s, and its clinical relevance remains limited. It separates pregnancy hypertension into four broad categories.
Pre-eclampsia-eclampsia:
It is a specific syndrome of the gravid state. It appears after the 20th week, and associates hypertension and proteinuria, according to the threshold values indicated above.
The authors recognize that threshold values, the specificity of this definition is mediocre. “Certainty level of diagnosis” is higher for systolic BP of 160 mmHg or greater, diastolic BP of 110 mmHg or greater, proteinuria of 2 g / 24 hours or more, creatinine of 12 mg / l or more, thrombocytopenia, headache or visual disturbances, epigastric bar pain. These criteria actually define the severe forms of preeclampsia.
Eclampsia consists of the occurrence, in a preeclamptic woman or not, of convulsions without any other individualizable cause.
Gestational Hypertension (or Pregnancy):
It is a hypertension noted for the first time after the 20th week. Since proteinuria can always appear secondarily, this diagnosis is definitively established only postpartum. If, in addition, the hypertension decreases completely within 12 weeks after delivery, it is a transient hypertension of the pregnancy.
Chronic hypertension:
It is hypertension that is present before pregnancy, or found before the 20th week of pregnancy. Any hypertension found during pregnancy that does not disappear postpartum falls under the same heading.
Pre-eclampsia added:
This is the appearance of significant proteinuria in a woman with chronic hypertension. The prognosis then matches that of preeclampsia. The same diagnosis is admitted in the event of a sudden increase in previously safe hypertension, thrombocytopenia or hepatic cytolysis.
“HELLP syndrome”:
In 1982, Weinstein described an essentially biological syndrome called HELLP (Hemolysis, Elevated Liver Enzymes, Low Platelet Count), combining moderate intravascular hemolysis, elevated transaminases, and thrombocytopenia.
Clinical signs occur in the third trimester and are associated with general malaise (90%), epigastric bar pain or limited to the right hypochondrium (90%), nausea and vomiting (50%). This syndrome is associated with a very poor fetal prognosis, even maternal and, despite some heroic therapeutic attempts (immunoglobulins, plasma exchanges, etc.), most authors agree to consider as a single outcome a rapid termination of pregnancy .
This syndrome is mentioned here because it is often (but not always) associated with hypertension and proteinuria. It has been considered alternatively either as a complication of preeclampsia, or as a symptomatic variant of it.
Epidemiology:
Frequency:
The estimated frequency of hypertensive disorders of pregnancy is largely due to the definitions used. Recent estimates are fairly consistent. The ACOG has evaluated between 6 and 8% of pregnancies. The NHLBI retains the value of 8%. In a database of some 300,000 births (representative sample of 39 million births) in the United States, Zhang found a frequency of 5.9%.
The frequency of preeclampsia is between 2 and 3% according to the studies. Zhang separates modest preeclampsia (2%) from severe preeclampsia (0.6%). As for eclampsia, its frequency is 0.56 to 1 ‰.
Preeclampsia is associated with maternal mortality of 0.1 to 5 per 1,000 cases, much more in less favored areas. This mortality is largely concentrated in patients with HELLP syndrome. Even though eclampsia has become a rare occurrence in our climate, it remains a particularly serious event.
Gestational hypertensions appear readily from the first pregnancy, the age of the latter being not fundamentally different from that of normal pregnancies. In France, the frequency of hypertension and preeclampsia does not seem to differ according to the ethnic groups. In the United States, the findings are more divergent. The differences between socio-professional categories are modest, and disadvantaged groups are not necessarily more exposed than others to pre-eclampsia. It is, however, its complications that are more frequent and severe, for obvious reasons, in all countries where access to care is highly unequal.
Risk factors:
We find the very classic factors that are primiparity, twinning, obesity (and associated hyperinsulinism), as well as all the underlying vascular pathologies (hypertension, diabetes …).
The greatly increased incidence of anterior preeclampsia contradicts the old notion that preeclampsia, the disease of the primiparous, does not recur.
Smoking appears as a “protective” factor,
inversely correlated with the frequency of preeclampsia, whose frequency is reduced by 30 to 50% among smokers.This apparent paradox has not been satisfactorily explained.
Note that nicotine induces angiogenesis and opposes its inhibitors whose rate is lower in early pregnancy in women smokers.
Other contributing factors:
Antipatient immunization:
It has been recognized since the 1970s that tolerance of the fetal “graft” requires prior immunization of the mother against paternal determinants. This immunization occurs by contact of maternal mucous membranes with sperm.
The risk of preeclampsia is thus higher in the case of early conception in a recent couple than in the case of later conception in a couple that has been established for a longer time. In case of artificial insemination, the risk of preeclampsia is higher if the sperm comes from a foreign donor rather than the spouse. The use of barrier contraception such as condoms would also be associated with an increased incidence of preeclampsia.
It appears that an essential factor in this process is the spermatic transforming growth factor b 1 (TGF- b 1), which initiates a postcoital mucosal inflammatory reaction, increases the recognition of HLA soluble sperm antigens, and deflects the maternal immune response. to type Th2, thus preparing maternal tolerance for paternal antigens expressed by the fetus.
Thrombophilies:
Several authors have reported an increased frequency of thrombophilic diseases in young women with early and severe preeclampsia. It is mainly an antiphospholipid, a C or S protein deficiency, a Leiden factor V or II mutation.Enthusiasm for this etiological factor has been rapidly tempered by conflicting studies, and recent meta-analyzes are limited to a weak association with the factor V or factor II Leiden mutation.
Genetics:
Some familial aggregation of preeclampsia cases is known, and cohort studies do suggest genetic transmission. Thus, a family history of preeclampsia (mother or sister) increases the risk (relative risk [RR]: 3.4, 95% confidence interval [CI] 1.5-7.6) of having the same pathology. In the offspring of women with severe pre-eclampsia or eclampsia, preeclampsia is more common (23%) in girls than in daughters-in-law (10%), with the predisposition being transmitted by both men and women. by women. Cnattingius et al. have calculated that a genetic factor accounts for more than 50% of the probability of preeclampsia, that maternal genes contribute more (35%) than fetal genes (20%), and that there is an interaction between paternal and maternal genes. Family transmission is much more common in severe or early pre-eclampsia. Moreover, studies of monozygotic twin pairs do not generally show concordance for preeclampsia.
The research strategy based on candidate genes has paid off. The M235T variant of the angiotensinogen gene, the Leiden factor V or II mutation, a NO synthase gene, were incriminated but unconfirmed. The GOPEC study tested seven plausible candidate genes in more than 600 women with preeclampsia and their families.
None of these genes appeared with a significantly higher frequency.
Genomic studies have been somewhat more fruitful, but have underlined the extreme complexity of the situation, due to the heterogeneity of this pathology and the diversity of possible genetic mechanisms. Pre-eclampsia “maternal” and “placental” (see below) do not seem to be associated with the same loci, the HELLP syndrome has a particular gene, epigenetics would intervene in a major way in certain loci associated with “placental” preeclampsia, with a “parent of origin” effect.
Different loci have been found consistently in different populations (Australia, Finland, Norway, Netherlands).Exploration of the 10q22 region has revealed a gene (STOX1) or perhaps a pair of genes that seem directly involved in the proliferation and invasiveness of the extravillous trophoblast.
“Dangerous father”:
Preeclampsia is not just the problem of an individual, it is that of a couple. The father can intervene in his genesis in two ways: an immunological “conflict” or the transmission of a paternal gene contributing to placental dysfunction.Many findings led to the idea that this pathology could be of paternal origin, and gave birth to the expression “dangerous father”.
When a pregnancy has been pre-eclamptic in a couple, a new procreation between the same father and a different woman doubles the risk of preeclampsia for the latter.
In subjects whose mother was preeclamptic, the relative risk of preeclampsia is 2.1 in men and 3.3 in women. This induced risk is identical for the girl from preeclamptic pregnancy and her sisters from normal pregnancies. In men, the risk is increased only for the one resulting from preeclamptic pregnancy, which raised the hypothesis of a double gene.
The Leiden factor V mutation in the mother does not increase the frequency of preeclampsia, but increases when the fetus is a carrier, especially in African American or Hispanic women. The discordance between monozygotic binoculars has also been interpreted as a witness to a crucial paternal role.
Pathophysiology:
Hemodynamics of normal pregnancy:
Normal pregnancy is a state of profound vasodilation.
Cardiac output increases by about 30%. Systemic vascular resistance decreases, as well as arterial pressure.
The volume of systolic ejection is increased, as well as the heart rate. Overall arterial compliance increases by 30% while the reflection wave is delayed. Vasodilation appears to be dependent on the endothelium. It is probably the main cause of the increase in plasma volume (+ 50%) that occurs during pregnancy, which is “perceived” as a situation of underfilling, with recruitment of the renin-angiotensin system.
The mechanism of this endothelial-dependent vasodilatation in pregnant women is not fully clarified. A major role is attributed to relaxin, a hormone produced by the corpus luteum and abundantly secreted during pregnancy. The administration of relaxin makes it possible to reproduce all the hemodynamic changes observed during pregnancy.Growth factors such as vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF) potentiate endothelium-dependent vasodilatation, as do TGF-b1. We will discuss further these factors whose function is essential.
This vasodilation also affects the kidney. The glomerular filtration rate (GFR) increases by 40 to 60% while the renal blood flow (FSR) increases by 50 to 80%. The increase in DFG is considered entirely due to that of the FSR, because of a profound reduction in the tone of afferent and efferent arterioles. This phenomenon is very early, occurring within 2 to 3 weeks of conception. An amino acid infusion further increases GFR, indicating that the renal functional reserve is not depleted.
Expansion of plasma volume probably plays an important role in this mechanism. Again, relaxin and endothelium have been implicated. Relaxin would increase gelatinase activity, converting “big endothelin” (ET) to E (1-32), and thus inducing renal vasodilatation, hyperfiltration, and decreased myogenic activity via the E-receptor (B) and the NO system. Inhibition of relaxin by antibodies or ovariectomy completely suppresses renal vasodilatation.
Preeclampsia:
Hemodynamically, the main feature of preeclampsia is the abolition of vasodilatation. In severe forms there is on the contrary a vasoconstriction explaining the increase in blood pressure, as well as an increased reactivity to vasopressors, mainly angiotensin. The speed of the pulse wave is increased while the arterial compliance is decreased. The entire hemodynamic picture suggests a transition to a state of lower cardiac output and high vascular resistance.
Flow-dependent vasodilation is impaired or abolished during preeclampsia. This anomaly precedes the first clinical manifestations, it is already patent in patients with uterine Doppler “notches” in the second trimester, as well as an increase in the asymmetric dimethylarginine (ADMA), natural inhibitor of NO synthase. A reduction in NO production has been shown. Some studies also suggest that endothelial progenitors may be fewer and less active during preeclampsia.
The other classic elements of endothelial dysfunction are also present in preeclampsia, including the activation of hemostasis. It is at this level that a thrombophilia could, without being the etiological factor, represent an important aggravating factor.
The plasma volume is not “expandu” as it is normally, there may even be an absolute hypovolemia.
This is directly correlated with the delay of fetal growth.
Nephropathy:
Impaired renal function has a significant reduction in GFR more than RPF, usually at the level observed outside pregnancy, with a decreased filtration fraction. Some fine studies of glomerular hemodynamics have made it possible to specify the nature of these anomalies. The ultrafiltration coefficient Kf is reduced by 50%. The postconcentric oncotic pressure is decreased.
Hemodynamic impairment is not the only cause. Subendothelial fibrinoid deposits and mesangial interposition also limit the filtration area. Proteinuria can be several grams or even tens of grams per 24 hours. The study of fractional clearance of dextrans shows that they are associated with a loss of glomerular barrier selectivity both for particle size and (probably) for their charge.
Renal damage is not only functional, it is also anatomical, although reversible. Glomerular lesions were initially described in a classic article by Pollack and Nettles, and termed endotheliosis by Spargo. They were considered pathognomonic, although this absolute specificity was discussed later. They consist of an increase in the volume of glomeruli, with dilation of the flocculus and an almost occlusive “swelling” of the endothelial cells. The walls are thickened by numerous double contours and there is a discreet mesangial proliferation.
The search for immunoglobulin and complement immunofluorescence deposits has been almost always futile or inconsistent, while fibrin deposition is constant and important.
These lesions are reversible and will have completely disappeared 3 months after delivery. Moreover, the renal biopsy may eventually reveal other lesions, indicating underlying glomerular nephropathy, or vascular involvement that the normotension of patients did not suggest. Such lesions are obviously not reversible. The de novo constitution of segmental and focal hyalinosis has also been reported.
Pathogenesis:
Animal models:
Preeclampsia is non-existent spontaneously outside the human species. Early on, it was shown that creating hypertension in the pregnant animal by a renal arterial stenosis or angiotensin infusion pattern did not lead to any other symptoms of preeclampsia, and no fetal repercussions. Conversely, achieving uterine ischemia can reproduce all the symptoms of preeclampsia.
It is therefore the models of uteroplacental ischemia that dominate the experimental field on the subject. All converge towards endothelial dysfunction, the determinants of which are analyzed in many experimental works.
Note, however, that other models have been developed, such as the injection of low doses of bacterial endotoxin triggering an inflammatory reaction, or the BPH / 5 mouse line. Takimoto et al. reported a model of preeclampsia in transgenic mice for components of the human renin-angiotensin system. The crossing of a female carrier of the transgene of angiotensinogen with a male carrying that of renin (nothing happens if it is the opposite) leads to the complete picture of preeclampsia, regressive after parturition. This is the only model in which an imprinting phenomenon is probably involved.
Pathology of the placenta:
No clinical picture comparable to that of preeclampsia is observed outside pregnancy. Preeclampsia is specific to pregnancy, and stops with it. It can occur during abdominal pregnancies, which innocent uterine distention long incriminated. It also occurs in molar pregnancies, making it unlikely to involve the embryo. The only common denominator is the existence of a placenta and trophoblastic tissue. Piering et al. reported the case of a woman who had preeclampsia during an abdominal pregnancy. Fetal extraction was performed by leaving part of the functional placenta in place. Preeclampsia persisted until 99 days later, ablation of all remaining placental tissue, which definitively ended the maternal symptoms.
Heterogeneous pathology:
Preeclampsia is clearly not an unambiguous mechanism disease, and it is not the purely descriptive classifications in use that can help its dismemberment. One of the dominant ideas is to distinguish “maternal preeclampsia” from “placental preeclampsia”.
If the maternal vessels are pathological (hypertension, prehypertensive vascular anomalies, diabetes …), the maternal hemodynamic resources have no possibility to increase and ensure the significant increase in flow required by the fetal unit at the end of pregnancy. The consequence is placental ischemia occurring at this critical time, and creating the conditions for preeclampsia.
On the contrary, there is a peculiar disease, absolutely specific to the gravid state, occurring on healthy vessels.
It has its origin in a very early anomaly of implantation and trophoblastic invasion, resulting in placental dysfunction, and therefore ischemia. Its prognosis is more threatening, its phenotypic expression very diverse, but often rich.
The common core leading to the pre-eclampsia phenotype is therefore placental ischemia, but with different upstream determinisms, leading to no less different manifestations. Maternal preeclampsia is late, almost or completely, without fetal growth retardation, its risk factors are mainly vascular, placental morphology is normal. In contrast, placental preeclampsia is early, associated with growth retardation, with a pathological placenta and a marked genetic component.
It is she who is most often announced by abnormalities of uterine doppler in the second trimester.
Antiangiogenic factors:
The recent discovery of these factors represented a major advance in understanding the mechanisms of preeclampsia. On the one hand, placentation presupposes a powerful angiogenesis. On the other hand, angiogenic factors have a vasodilating systemic action and stimulate the endothelial production of prostacyclin. They are considered essential for the vasodilatation described above. During pregnancy, VEGF and PlGF are largely produced by the placenta, and appear at a high rate in the maternal circulation.
Both act by binding to a membrane receptor called Flt-1.
There is a soluble form of this receptor, called sFlt-1. This form results from a particular splicing resulting in a receptor comprising the extracellular ligand-binding part, but lacking the transmembrane and intracellular domain.
Thus, this receptor binds to the ligands, but prevents their biological activity. Normally, sFlt-1 is present throughout pregnancy, and its production increases in late pregnancy, thus constituting a kind of physiological barrier to placental vascular growth.
Maynard et al. have shown that sFlt-1 messenger ribonucleic acid (mRNA) is overexpressed in the placenta in preeclampsia. SFlt-1 passes into the maternal circulation, and its circulating level is greatly increased in case of preeclampsia, then associated with a very low level of VEGF and free PlGF.
SFlt-1 is stimulated by hypoxia, via hypoxia inducible transcription factors 1 (HIF-1). This stimulation of sFlt-1 appears to be a unique property of the cytotrophoblast, and it has been suggested that this would have a specific splicing factor, directing the response to hypoxia to the soluble and inhibitory form of the receptor instead of the transmembrane form produced by the endothelial cells. In fact, cytotrophoblasts under hypoxia conditions lose their invasiveness. SFlt-1 inhibits placental growth in vitro and inhibits trophoblastic invasion. Its suppression by immunoprecipitation restores the angiogenic capacities.
In vivo, the introduction of sFlt-1 in pregnant rats causes hypertension, proteinuria, and glomerular endotheliosis.
In the human clinic, Levine et al. found a rise in sFlt-1 levels several weeks before the onset of preeclampsia, with a low level of free PlGF.
The excess of sFlt-1, however, only reproduces part of the pre-eclampsia phenotype, which has led the same researchers in the Karumanchi group to seek a second factor.
Venkatesha et al. have rapidly implicated another soluble receptor, said s-Endoglin (s-Eng), co-receptor modulating the activity of TGF-b1. It is also produced by the placenta, increased in preeclampsia, and directly responsible in vivo for a hypertension and an increase in vascular permeability.
S-Eng potently inhibits endothelium-dependent vasodilatation. Its rate is particularly high in case of HELLP syndrome.
The coadministration of these two substances increases the intensity of the signs of preeclampsia, and also creates the equivalent of a HELLP syndrome, which is not the case of sFlt-1 alone.
Anti-AT1 Antibody:
Wallukat et al. showed that preeclamptic pregnant women had circulating antibodies capable of activating the AT1 receptor of angiotensin II. These antibodies appear after the 20th week and disappear after delivery, that is, they are almost synchronous with maternal symptoms. They create hypertension, activate tissue factor, initiator of the extrinsic pathway of hemostasis, and PAI-1, all effects blocked by losartan. They inhibit placental growth. These antibodies are associated with a lack of uterine perfusion even more than at the clinical prognosis of pregnancy. They could act as a stimulus for the production of sFlt-1 by the trophoblast.
Pathology in two phases:
First phase: abnormal placentation
Trophoblastic Invasion:
During implantation, the extracellular cytotrophoblast colonizes the syncitial mass, and invades the decidua to the spiral arteries. This is the first interstitial phase of trophoblastic invasion. A crucial role is attributed to the differentiation mechanisms of the trophoblast, on which its invasive properties depend. Activin induces this differentiation, and causes growth of trophoblasts which therefore express the HLA-G and the metalloprotease MMP-9, characteristics of the invasive trophoblast. The second phase is the endovascular invasion of the spiral arteries of the myometrium, which will go up to about one-third of it. This process leads to the destruction of the endothelium and muscularis, with dilation of these vessels. The endovascular trophoblastic cells undergo a deep transformation giving them an endothelial phenotype.
The invasion is done through proteolytic enzymes, including plasmin, which degrades the extracellular matrix and activates various metalloproteases. The plasminogen activator (urokinase type, uPA) seems to play a vital role. An excess of its PAI-1 inhibitor is associated with a defective trophoblastic invasion.
Trophoblast progression is controlled by various vascular growth factors and cytokines. NO production seems to play an important role, perhaps as well as direct hemodynamic factors. The oxygen tension has also been questioned, and it has been shown that HIF-1a and HIF-2a (hypoxia inducible transcription factors) are electively increased in preeclampsia, following a pattern similar to that observed in the placenta of women having given birth at high altitude.
Nevertheless, the spiral arteries of the myometrium are colonized around 15 to 18 weeks by the trophoblast, which replaces the endothelium (acquisition of specific cadherins) after destroying the muscular structures. These arteries are thus transformed into channels whose diameter is multiplied by 4 to 6, and which no longer have a resistive function, but only a conductive one. This “transformation” of the spiral arteries is a prerequisite for adequate irrigation of the placenta and the fetus.
The existence of an anomaly of this trophoblastic invasion was a major step in the physiopathological understanding of preeclampsia. It was shown in placental bed biopsies in the 1970s that trophoblastic invasion is defective when preeclampsia occurs in the third trimester or isolated fetal growth delays. This anomaly consists of an absence of transformation of the spiral arteries, or an incomplete transformation over an insufficient length. Characteristic is also the lack of acquisition of the endothelial phenotype by trophoblasts.
The mechanism leading to this defective trophoblastic invasion is unclear. The factors currently put forward are a lack of cooperation between maternal immune cells and trophoblastic antigens, an inhibition of angiogenesis, and insufficient proteolysis.
Immunological factors:
There are two successive interfaces between the mother and the fetus.
The first, very early, brings together the maternal decidua and extravillous fetal cytotrophoblast. When the placenta is formed the second interface, which prevails until the end of pregnancy, between the syncytiotrophoblast which forms the surface of this placenta and the immune cells of the circulating maternal blood. Neither of these two interfaces express the transplantation antigens (HLA A, B and D). In addition, the decidua is poor in T cells. There are therefore no potential actors of transplant rejection. There is also a deviation of maternal immunity from Th1 to Th2 (IL-3, IL-4, IL-10), limiting the risk of cytotoxicity.
Fifty to 90% of the leucocytes of the decidua are NK cells with high expression of “bright” CD 56, the remainder consisting essentially of monocytes / macrophages. These are uterine NK (uNK), significantly different from circulating NK by a different cytokine repertoire and a low cytotoxic potential. B and T lymphocytes are rare in decidua, with the exception of so-called regulatory Treg (CD4 + / CD25 +) T cells, producing interleukin (IL) -4 and TGF-b1, and considered as essential to immune tolerance. The extravillous cytotrophoblast (and it alone) expresses HLA antigens, all class 1 (C, E and G), which are the preferred ligands for NK cell receptors.
HLA-C, highly polymorphic, binds on NK cells to killer cell immunoglobulin-like receptors (KIR).
This interaction modifies the cytokine repertoire of NK, and activates various adhesion molecules and metalloproteases, as well as the production of VEGF, all direct agents of the invasion. There is therefore cooperation between NK cells and the extravillous cytotrophoblast to invade and reshape the spiral arteries. Certain combinations between a KIR haplotype and an HLA-C epitope are inhibitory and increase the risk of preeclampsia.
HLA-G, which is totally trophoblast-specific and highly monomorphic, has mainly an immunomodulatory function by inhibiting the cytotoxicity of NK cells, and thus, in a way, protecting the fetus against an immune reaction. In addition, it is able to destroy cytotoxic T lymphocytes, or to direct them towards a tolerance profile. The circulating level of soluble HLA-G is lower at the beginning of pregnancy in women who will subsequently have preeclampsia. HLA-G polymorphisms have also been implicated.
This immune interaction therefore hardly concerns adaptive immunity, but rather the “innate” immunity linked to NK cells. It essentially comprises non-specific immunomodulation with HLA-G and a strong interaction with HLA-C which is considered today as the prime driving force of the invasion. A lack of this interaction, qualified for want of better “maternofoetal maladaptation”, is responsible for a defective invasion, and an increased apoptosis of trophoblasts.
Angiogenesis and its inhibition:
Placental growth very much depends on angiogenesis.
We have described above the antiangiogenic factors that are sFlt-1 and s-Eng. Although the role of these receptors in preeclampsia has been very strongly argued in a few years, their involvement in the earliest anomalies of trophoblastic invasion remains unclear, especially since their production is stimulated by hypoxia, whose cause always escapes. It has never been shown elevation of these factors in the first few weeks of pregnancy. At 11 weeks, their rate is not different between women whose pregnancy is normal and those who develop preeclampsia.
The gradient appears only between 13 and 17 weeks.
An initiating role of the antiangiogenic factors is thus for the moment improbable. On the other hand, it is clear that they play a major role in slowing down placental growth and increase the pathological process in the critical period following the first invasion phase. The discussion is of the same order regarding anti-AT1 antibodies.
Second phase: from placenta to clinical disease
The clinical phase of preeclampsia is initiated by placental ischemia, which leads to maternal symptoms. We have seen above that this ischemia can have different origins.
The dominant role of the placenta in this phase is attested by the fact that its disappearance (because of the termination of pregnancy) puts an end to all the symptoms. The link between placental ischemia and preeclampsia can not, however, be purely mechanical, and we must admit a particular maternal receptivity to the consequences of placental ischemia. It would otherwise be impossible to explain that with identical placental abnormalities, some pregnancies carry the complete picture of preeclampsia, while others are limited to isolated intrauterine growth restriction (IUGR), without hypertension or proteinuria. The recent observation of a normal pregnancy in a “surrogate mother” after in vitro fertilization (IVF) of an embryo from a pair affected by iterative preeclampsia is another argument.
Placental debris:
Apoptosis of trophoblasts, a phenomenon present in normal pregnancy, is much more intense in preeclampsia.
This results in increased maternal clearance of syncytiotrophoblast debris in the form of microparticles, as well as an increase in fetal deoxyribonucleic acid (DNA) and cytokeratin.
Inflammatory syndrome:
This apoptotic or necrotic placental debris is the main stimulus of a generalized maternal inflammatory reaction. The intermediate mechanism could be the binding of circulating monocytes to these debris, enhancing the production of pro-inflammatory cytokines. There is also a wide activation of polymorphonuclear cells.
If a moderate inflammatory reaction is present in the normal pregnancy, this reaction appears considerably increased, and more diffuse still, in preeclampsia. According to Redman, this is an inflammatory “decompensation” linked to the excess of substances of trophoblastic origin released into the circulation. Interestingly, Goswami et al. Found that syncytiotrophoblast debris is in large excess in the blood of women with pre-eclampsia, especially early, but not in those with fetal growth retardation without hypertension.
One of the major implications of this inflammatory process is the development of generalized endothelial dysfunction.
Endothelial dysfunction:
The maternal preeclampsia syndrome has all the elements of generalized endothelial dysfunction: vasoconstriction and hypertension, activation of hemostasis, imbalance between prostacyclin and thromboxane in favor of the latter. It has been directly shown that in the presence of preeclamptic women serum, endothelial cells in culture produce less prostacyclin, and more free radicals (reviewed in).
The antiangiogenic factors discussed above are obviously implicated in this endothelial dysfunction, irrespective of inflammation. VEGF acts directly on endothelial function, induces NO and prostacyclin, is vasodilatory and lowers blood pressure. We have seen that the administration of antiangiogenic factors alone can reproduce the entire preeclamptic syndrome and the HELLP syndrome.
The main source of these substances during pregnancy is placental, and experimental induction of placental ischemia alone triggers overexpression of sFlt-1 mRNA. The production of sFlt-1 and s-Eng is massively increased in the weeks before and during the clinical symptoms of preeclampsia.
Some studies suggest that sFlt-1 is specific for these clinical symptoms. Thus, circulating sFlt-1 is elevated in preeclampsia, but not in isolated growth failure without hypertension, even though placental lesions are identical.Similarly, sFlt-1 would not be increased in pregnancies with retroplacental hematoma (HRP) alone without hypertension (HTA). This factor would therefore be very specific to maternal endothelial symptomatology. The idea that the hypoxic placenta creates maternal symptoms by interfering with NO-mediated vasodilatation mediated by TGF- btherefore appears to be essential.
Antibodies to the AT1 receptor of angiotensin II activate the functions of angiotensin II, of which severe hypertension and endothelial dysfunction are an integral part. They also activate AT1 receptors in the glomerular mesangium.
Finally, anti-AT1 antibodies activate tissue factor, initiator of the coagulation cascade and also promote the production of free radicals.
Clinic:
The clinical pictures are of different presentation and severity. These tables are not fixed at the onset of symptoms, and the situation is still potentially evolving. This instability requires constant monitoring as soon as the diagnosis of hypertension is made.
Simple hypertension:
Isolated hypertension during pregnancy only modestly obtains its prognosis, with a relative risk ranging from 1 to 3. According to the classifications mentioned above, this hypertension may be “gravid” or “chronic”, the difference is not always easy to make at the moment, even if the standard 20 week criterion is usually used as a marker. These hypertensions are almost always asymptomatic. However, it is important to remember that at any time proteinuria can be added to the picture, thereby substantially increasing the risk. In addition, very severe hypertension, even without proteinuria, share the prognosis of preeclampsia.
“Moderate” pre-eclampsia:
When significant proteinuria is associated with hypertension, the risk is much higher. It remains modest when the blood pressure is low and easily controlled, usually coexisting with proteinuria of less than 1 g / 24 h. In these cases, however, enhanced surveillance is necessary. The increase of symptoms or the appearance of a HELLP syndrome is indeed always possible.
Preeclampsia “serious”:
All different is the picture of “severe” preeclampsia.
Hypertension is then major, threatening, and remarkably insensitive to antihypertensive treatments. Proteinuria is several grams, even tens of grams per 24 hours, with a nephrotic syndrome. There are diffuse oedemas, infiltrating the upper and lower limbs, the loins, the face. Fetal growth slows down and stops. Patients are often cephalalgic and photophobic. It is in such cases that a HELLP syndrome often comes to complete the picture, and rapidly progressive thrombocytopenia creates a major threat in the short term. In this situation, the only way out is the termination of pregnancy, almost always by cesarean section. This decision, which is delicate when preeclampsia is early, requires balancing the risk of prematurity with that of a perilous prolongation of pregnancy.
It is, of course, in such cases that maternal complications or acute renal failure appear most readily, and that the maternal vital prognosis is most severely threatened.
Inaugural accident:
There are also circumstances in which a pregnancy that seemed normal (or so pathological) suddenly turns to drama when retroplacental hematoma or eclampsia occur, often doubled by fetal death. It is then after the accident that hypertension, proteinuria, and the whole procession of maternal complications occur which will increase the gravity.Note also that about one third of HELLP syndrome and a quarter of eclampsia occur in the postpartum.
Complications:
The risk is both maternal and fetal. For the mother, it is the possible occurrence of a retroplacental hematoma, or eclampsia. Recall that they may be accompanied by major disseminated intravascular coagulation (DIC), especially in cases of HELLP syndrome, and may be followed by acute renal failure, or even cortical necrosis. This means that they retain a very serious, even dramatic, prognostic meaning. Thus, in a series of 442 pregnancies with HELLP syndrome, Sibai et al. report DIC in 21% of cases, HRP in 16%, acute renal failure in 7.7%, pulmonary edema in 6%. In addition, 55% of patients required transfusions, and 2% had laparotomy because of a bleeding syndrome. Maternal mortality was 1.1%.
For the fetus, the risk is that of a delay, or even a stop of the growth by default of perfusion, resulting in the maximum in utero death.
Surveillance:
The surveillance of a hypertensive pregnant woman is first clinical: changes in blood pressure figures, weight curve, appearance of edema … These data are quite discriminating.
Biological monitoring is also needed. The first element is the screening for proteinuria. A positive test with the strip justifies a dosage on the urine of the 24 hours. This is crucial, and shifts the patient from one level of risk to another. A blood test should also be performed monthly except in special cases: a blood count ensures the good quality of hemoconcentration and the absence of thrombocytopenia. The determination of transaminases makes it possible to detect the appearance of a HELLP syndrome. We will not dwell here on screening for gestational diabetes.
The monitoring of serum uric acid has long been part of these biological elements, before falling into disuse. Indeed, if a rise in serum uric acid (above 350 μmol / l) indicates a very high risk of developing preeclampsia, this is not an early warning, and the negative predictive value of Urea is low. Recent work has, however, put this parameter in the spotlight. A direct role of uric acid has even been evoked in the endothelial dysfunction that characterizes preeclampsia.
In reality, the centerpiece of the surveillance of a pregnant woman, hypertensive or not, is today the ultrasound, with Doppler examination on different sites. We will not detail these exams here.
The meaning of these different elements of surveillance is not only to provide a prognostic index. Together they allow an increasingly precise adjustment of the treatment, and the obstetric decision, guaranteeing an outcome as favorable as possible.
Treatment:
Medical treatment of high blood pressure:
Referring to what has been said above about the initiating role of placental ischemia, it is not clear that antihypertensive therapy is beneficial for either placenta or fetal growth. On the contrary, it can be suspected that a lowering of the pressure within a resistive circuit leads to a decrease in the flow rate, which would be the opposite of the goal sought.
This is what is observed in experimentation.
Many doubts persist on the indications and the modalities of antihypertensive treatment. These are actually different depending on the type and severity of hypertension.
Chronic Hypertension or Moderate Pregnancy:
These are situations in which the obstetric prognosis is most often favorable. Thirty controlled studies of antihypertensive therapy in these situations have been reported. Their meta-analysis shows that, overall, the treatment has some positive effects in the mother: fewer hypertensions exceeding 160/100 and fewer hospitalizations.
On the other hand, it has no effect on the prognosis of pregnancy, and on the fetal prognosis in particular. On the contrary, the incidence of fetal hypotrophy is higher under treatment. This fact may be more marked with beta-blockers than with other antihypertensives. However, it must be agreed with Sibai that the numbers of studies have never been sufficient for a modest effect on fetal death or HRP (incidence of the order of 2%) can be highlighted, or completely excluded .
Note also that no dietary measures (sodium, unsaturated fatty acids, calcium) or lifestyle (rest …) has shown therapeutic or preventive value of anything. Hospitalization, a sort of sacred rite not long ago, is not more beneficial.
Severe hypertension:
The case here is even less simple in that there have been no controlled studies, for obvious reasons. The benefit of treatment for short-term hypertension in a young woman is probably not major. It is nevertheless likely to avoid maternal complications,
in the first rank of which pulmonary edema. The classic assertion of the risk of stroke is not very credible. Cases are rare, and the accountability of blood pressure figures has never been adequately substantiated. The general practice is to treat these hypertension when the figures regularly exceed 160 to 180 and / or 110 mmHg. It is certainly as important as before, or even more so, to act sensitively, and not to lower the numbers below 140 and 90 mmHg.
Which antihypertensive drugs?
While it is clear that blood pressure should not be lowered too fast or too deep to avoid a detrimental loss of uterine perfusion, the effect of antihypertensive drugs on the fetoplacental side of the circulation remains poorly understood.
Most of these drugs cross the placental barrier, all the more easily as their protein binding is weak. In the absence of good pharmacological studies, their use in pregnancy remains empirical. Doppler umbilical artery tests are too limited in sensitivity to draw solid conclusions. No oral antihypertensive drug has a specific Marketing Authorization (MA) for this indication.
Some antihypertensives can be used without restriction, first and foremost central antihypertensives, and mainly methyldopa, which has the longest recoil and the most established safety. It alone has benefited from long-term pediatric studies after maternal use. An in vitro study on umbilical artery fragments also showed that of all the antihypertensive agents tested, methyldopa was the only one to have neutral behavior on umbilical resistance.
Beta-blockers, with the aforementioned reservations about fetal growth, are also widely used, and have benefited from sound clinical studies. They are part of the first line therapeutic arsenal. Less bradycardic products such as labetalol or pindolol are often preferred. They could run a lower risk of stunting.
Calcium blockers, and especially nicardipine, are widely used, at least in France, in pregnant women.
Yet their record is poor. None have marketing authorization for this indication, and they are “not recommended” in the SPC. There is little certainty about their lack of teratogenicity. Their tocolytic action, which is invaluable in the event of a threat of premature delivery, can be a source of difficulty during delivery, even postpartum. Nevertheless their absence of contraindications and their generally good tolerance made it the easy drug for many obstetric units. This broad experience, coupled with a decline that is starting to be important, partly compensates for a limited level of proof.
Simultaneous administration of a calcium channel blocker and magnesium sulfate (MgSO4) has been discouraged following the publication of isolated cases of severe neuromuscular blockage and possibly maternal death. Although the danger of this association has recently been questioned, caution should remain in place.
Diuretics have been discontinued as antihypertensives in pregnancy because they decrease plasma volume and may worsen chronic fetal distress. It goes without saying that their indications remain intact in other circumstances, such as heart failure.
Antihypertensives, contraindicated in pregnancy, are primarily the ACE inhibitors and angiotensin receptor antagonists (ARBs).
Administered beyond the first trimester, they may be responsible for fetopathies, especially potentially fatal anthurias.These products do not have the reputation of being teratogens strictly speaking, nevertheless a recent study reports an abnormally high number of malformations, notably cardiac and neurological, in case of taking of an IEC during the first trimester, compared to women who used the same or another antihypertensive drug or no antihypertensive drug.Although this study is unique and requires confirmation, such treatment should be avoided in a young woman wanting a pregnancy, and in any case be substituted for the known pregnancy.
Severe preeclampsia:
The treatment of severe preeclampsia is the responsibility of specialized resuscitation units. The usual severity of hypertension makes its treatment necessary and urgent, and control of blood pressure is usually a prerequisite for fetal extraction in the very short term. This treatment is usually parenteral. The number of drugs that can be used is more limited here and the small number of suitable studies is hampering attempts at meta-analysis.
Nicardipine, given as an intravenous infusion, is the favorite in France. In fact, intravenous nicardipine has hardly been studied more than oral forms, and the experience acquired is the level of evidence. Labetalol has been the subject of more studies and has been compared to standard antihypertensives, particularly hydralazine. Its effectiveness as well as its safety can be held for some.
Urapidil has also given satisfactory results.
Hydralazine has kept an indication in France during pregnancy, but given its efficacy, which is no better than others, and its particularly poor tolerance, unless covered by a beta-blocker, its use tends to become scarce. .
In all cases, antihypertensive therapy should be conducted with gentleness. A plateau should be reached in a few hours to a diastolic not less than 100 mmHg. Decay at around 90 mmHg should only be done secondarily and more slowly. Aggressive treatment exposes both maternal complications and rapid fetal death.
Given the constant hypovolemia in severe forms, and its connection with fetal growth retardation, the temptation is strong to resort to volume expansion. Practical studies have shown no consistent benefit, and this practice is abandoned by most teams.
Preventing eclampsia is another controversial topic.
In the Magpie study, the use of magnesium sulphate reduced the risk of eclampsia by 50% compared with placebo.
This study was considered definitive as to the indication of this drug, even if it is not easy to handle. In reality, the need for prevention of eclampsia is not unanimous unless there is imminent threat.
The termination of pregnancy is the only measure that puts an end to the maternal hypertensive and proteinuric manifestations. The debate between an early extraction with the risk induced by prematurity, and an expectant attitude playing on medical treatment is still widely open between specialists.
Preventive treatments:
The logic, with regard to pathophysiology, would be to act early, before the placental lesions are formed and that appear the symptoms that are the consequence. This is why many hopes have turned to preventive treatments.
Studies of aspirin in prevention of preeclampsia have been widely reported and commented. As a result of our pilot study, several others came to corroborate the idea of a protective effect of aspirin against preeclampsia. Subsequently, other trials have questioned this benefit. Without going into the details of the argumentation, it appeared that these negative studies had suffered from heterogeneous selection, late start of treatment, and low doses of aspirin. Leitich’s meta-analysis showed that, despite these negative studies, the treatment is active, even more so if the aspirin dose is at least 100 mg / day and treatment is started before 17 weeks. Other metaanalyses only confirmed this efficacy in targeted indications. The recent PARIS study, a meta-analysis of patients’ individual data, confirmed this effect.
The main indications are historical, namely a history of early preeclampsia and / or fetal growth retardation. Overall, aspirin still appears today as the only preventive treatment that has proven effective. The optimal start of such treatment is probably earlier than that in the studies. The addition of low doses of corticosteroids is a possibility mentioned in some studies. The association or replacement of aspirin with heparin is also discussed, with a level of evidence that is still below the desirable minimum.
It has been suggested that heparin, like aspirin, would inhibit placental apoptosis. These attitudes are short series, and can not be recommended on a larger scale until more consistent evidence has been provided.
The importance of oxidative stress in preeclampsia has led to prevention trials with antioxidant vitamins (C and E for the most part). A first trial involving high-risk patients (17% PE in the control group) yielded encouraging results. In contrast, two larger trials in unselected patients or patients considered at risk but very heterogeneous were negative.
L-arginine supplementation was also tested.
Encouraging data have been reported on short series in prevention. In contrast, an experiment with pre-eclamptic women was negative.
Calcium supplementation was another hypothesis considered, especially in populations with insufficient spontaneous intake. The tests yielded discordant results. A recent study conducted under the aegis of the World Health Organization has been negative.
An action on antiangiogenic factors could be of great interest. It remains, however, to this day a theoretical hypothesis.
The future:
Space is lacking to address this important issue in detail. We will summarize it in a few points:
• recurrent preeclampsia in a subsequent pregnancy in 10 to 25% of cases;
• women who have had preeclampsia become more often hypertensive afterwards;
• they also have a generally increased cardiovascular and renal risk;
• the whole justifies a real follow-up of these young women.
Conclusion:
Conceptually, preeclampsia appears as a struggle for survival between maternal and fetopaternal genes.
Some authors have suggested that maternal hypertension in this context of defective placentation would aim to safeguard the blood supply to the fetus. This finalist vision emphasizes the derisory nature of symptomatic treatments, and especially reinforces the idea that any future treatment of this condition requires early protection of the best possible placental function.
Finally, if preeclampsia stops with pregnancy, the underlying ground it reveals will continue. It must be screened, and the primary prevention measures that it implies for the future are not the least of the therapeutic issues in this area.
