Preeclampsia is a clinical condition associated with hyper tension and proteinuria, with or without edema, that occurs in the second half of pregnancy, no earlier than the 20th week of gestation, in previously normotensive, non-proteinuric women and usually disappears after delivery, within 6–12 weeks. Hypertension is a systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg in two successive measurements at least 4 hours apart. Proteinuria is defined as an excretion ≥ 300 mg/24 h or a urinary protein/ creatinine ratio ≥ 0.3 mg/mg (30 mg/mmol) on the extemporaneous sample, or, if quantitative measurement is not avail able, a dipstick finding of ≥ 1+ proteinuria. Preeclampsia can also be defined by the concomitant finding of hypertension without proteinuria if thrombocytopenia, increased serum creatinine, transaminases, pulmonary edema, and neurological symptoms such as headache and/or visual disturbances are present (Table 1).
Table1. Diagnostic criteria of preeclampsia
A recent meta-analysis estimated that approximately 4.6% of pregnancies worldwide are complicated by preeclampsia. Preeclampsia is defined as severe if the signs and/ or symptoms listed in Table 2 are present.
Table2. Conditions associated with severe preeclampsia
Preeclampsia can have significant maternal–fetal consequences such as placental abruption, preterm delivery, low birth weight, and fetal death; the most severe complication of preeclampsia is eclampsia, or gestosis, characterized by convulsive seizures and/or maternal coma. Preeclampsia is the result of an altered function of the placenta, the etiology of which is not yet fully known but could be linked to various factors such as poor development of the uterine placental spiral arterioles (which reduces uteroplacental blood flow in late pregnancy), immunological alterations, and placental ischemia or infarction. Preeclampsia may also be asymptomatic or cause edema associated with excessive weight gain. Identifying risk factors for preeclampsia is essential to initiating appropriate prophylaxis by week 20.
The main risk factors for preeclampsia are:
• Preeclampsia in previous pregnancies, especially those with adverse outcomes
• Pre-existing chronic hypertension
• Diabetes
• Multiple pregnancies
• Chronic kidney disease
• Autoimmune diseases (antiphospholipid antibody syn drome, systemic lupus erythematosus)
Moderate risk factors include nulliparity, obesity, maternal age <20 or >35 years, family history of preeclampsia, thrombophilia, or other thrombotic conditions. Right from the beginning of pregnancy, it is advisable to carefully assess the individual risk conferred by clinical and anamnestic fac tors and, if necessary, to start the pregnant woman with more stringent surveillance or pharmacological prophylaxis.
The monitoring of women at risk of preeclampsia includes the assessment of blood pressure, platelet count, serum creatinine, liver function indexes, and proteinuria within 24 h. These evaluations should be carried out from the beginning of pregnancy and help in more advanced gestational periods to identify new onset preeclampsia concerning preexisting pathological conditions.
Given the clinical relevance of preeclampsia for its com plications on mother and fetus and the absence of adequate diagnostic screening tools, in recent years has been con ducted an intense research activity aimed at identifying potential biomarkers predictive of preeclampsia.
Studies on the pathogenesis of preeclampsia have highlighted the importance of an aberrant synthesis of angiogenesis modulators in determining the endothelial damage and increased capillary permeability that underlie the pathogenesis. Angiogenetic factors of significant interest in this area include vascular endothelial growth factor (VEGF) and placental growth factor, along with some proteins with known anti-angiogenic activity such as Soluble Endoglin (sEng), the truncated form of the receptor for VEGF (Flt-1), known as soluble FMS-like Tyrosine Kinase-1 (sFlt-1). In the ischemic trophoblast, a characteristic feature of eclampsia, the production of anti-angiogenic factors (sEng and sFlt-1) increases, and that of angiogenic factors (VEGF, PIGF) is reduced. Alterations in the levels of these factors in the mother’s plasma or urine precede the onset of preeclampsia by a few weeks, correlate with the severity of the disease, and normalize after delivery. These tests seem to be useful, especially in more advanced gestational periods, while they seem to be of little help before the 20th week. In particular, a recent meta-analysis has shown that the sFlt-1/PIGF ratio has the best diagnostic performance in predicting preeclampsia if used in the second-third trimester of pregnancy (after 20 weeks), with a sensitivity of 80% and a specificity of 92%. Growing scientific evidence has shown that increases in circulating proteins, such as pregnancy-associated plasma protein-A (PAPP-A), or changes in circulating free DNA in the first and second trimester predict adverse outcomes, including preeclampsia. However, this association is not strong enough to justify routine clinical use of these tests and, more importantly, to modify the clinical care pathway of women at risk for preeclampsia.
Women at high risk of developing preeclampsia (previous preeclampsia, prepregnancy diabetes, prepregnancy hypertension, and renal disease) should receive low-dose aspirin prophylaxis. Most risk factors are not modifiable, so interventions to reduce the likelihood of preeclampsia are limited to pharmacological prophylaxis and weight gain during pregnancy.
Prophylaxis aims to prevent severe and potentially fatal complications; uncomplicated preeclampsia is reversible and begins to resolve spontaneously after childbirth.
In the absence of maternal and/or fetal complications requiring immediate termination of pregnancy, the most important factor in the treatment decision is the gestational age. The safest treatment for the mother is delivery, but it may not be safe for the fetus, depending on the gestational age. In early gestational periods, conservative treatment aims to achieve fetal maturity (especially respiratory maturity) while keeping the maternal clinical condition under constant and careful control.
Pharmacological control of hypertension allows to avoid maternal complications directly related to blood pressure values, such as placental abruption, heart failure, and maternal cerebral hemorrhage. However, it cannot modify the disease’s progression.
Eclampsia, or gestosis, consists of generalized tonic-clonic seizures in women with preeclampsia. It represents the convulsive manifestation of preeclampsia and is considered one of its most severe clinical manifestations.
Eclampsia most frequently occurs before delivery (almost always after the 28th week) but can also occur afterward (after 48 h and up to 4 weeks) or during labor. In the hours preceding the onset of convulsions, the woman may present signs and symptoms such as hypertension, headache, visual disturbances, and epigastric pain; in 25–40% of cases, there are no prodromal signs.
Eclampsia occurs in 2–3% of women with severe preeclampsia who do not receive prophylaxis and up to 0.6% of women with non-severe preeclampsia. In industrialized countries, it has an incidence ranging from 1.5 to 10 cases/10,000 deliveries. It is difficult to predict the eclampsia onset; the only way to reduce its incidence is to administer prophylaxis with magnesium sulfate in cases at risk, that is, in cases of severe preeclampsia, and especially when a headache, visual disturbances, and epigastric pain are present. Prophylaxis is not recommended in all other cases (moderate or mild preeclampsia). The diagnosis of eclampsia is essentially clinical and is based on the above-mentioned neurological symptoms. If the neurological deficit is not persistent, investigations are limited to those for screening for preeclampsia. Vice versa, it is appropriate to consider a differential diagnosis aimed at excluding other causes incidental to pregnancy (brain tumors, brain aneurysms) or conditions exacerbated by the gravid state (thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome, cerebral venous thrombosis).
The therapeutic approach is based on maintaining maternal oxygenation and protection from accidental trauma during the acute crisis and treating hypertension and seizures with magnesium sulfate. Delivery is the only curative treatment.
Once eclampsia has been established, it is helpful to maintain intensive monitoring for 24–48 h after the convulsive crisis has ceased. Concerning the clinical condition, it is necessary to frequently monitor hemoglobinemia, hematocrit and platelets, liver function indexes (transaminases, lactate dehydrogenase, and bilirubin), and renal function indexes (creatininemia and serum electrolytes). Coagulation investigations are indicated in the case of hemolysis elevated liver enzymes, low platelet syndrome or disseminated intra vascular coagulation.
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