Preeclampsia and eclampsia are grave complications
of pregnancy responsible for morbidity and mortality.
National Eclampsia Registry of the FOGSI has helped in
quantifying the magnanimity and also the clinical relevant
pointers which can help in improving the health care
delivery. Many complex pathogenic mechanisms are now
implicated to be responsible for this disease rightfully called
the GESTOSIS which means pregnancy going abnormal.
Many preventive strategies have been suggested but only a
few are scientifically proved to be useful. Early antenatal
care, clinical risk assessment, biomarkers, close vigilance,
calcium and nutritional supplementation are useful.
Keywords : Preeclampsia, Eclampsia, GESTOSIS, Hypertension in pregnancy, Registry
Hypertensive disorders of pregnancy constitute a perplexing and clinically challenging group of pregnancy complications that are responsible for a substantial burden of illness in developed as well as underdeveloped countries of the world. They are a leading cause of maternal and perinatal mortality and morbidity worldwide.
Approximately 72,000 pregnant women die every year
because of eclampsia and severe preeclampsia. That
amounts to nearly 200 women every day. Preeclampsia–
eclampsia ranks second only to hemorrhage as a specific, direct cause of maternal death. The risk that a woman in a developing country will die of preeclampsia or eclampsia is about 300 times that of a woman in a developed country [1].
Preeclampsia is defined as a systemic syndrome that is typically characterized by new-onset hypertension and proteinuria in pregnancy. Urinary excretion of 300 mg of protein in 24 h is defined as significant proteinuria. The syndrome is characterized by poor placental perfusion and a general disease process which may affect multiple organ systems.
Eclampsia is a complex phenomenon as a result of cerebral dysrhythmia due to the multifarious pathogenesis started by abnormal trophoblastic invasion initiating vasospasm, endothelial dysfunction, and platelet aggregation.
Globally hypertensive disorders of pregnancy complicate
approximately 5–10 % of pregnancies [2]. In Africa and Asia, hypertensive diseases accounted for 9 % maternal
deaths, whereas, in Latin America and the Carribean, the figure is over 25 % [3].
Incidence of hypertensive disorders in India is found to be
10.08 % as observed through the data collected by the
National Eclampsia Registry (NER) (11,266 out of
1,11,725 deliveries) over the past 3 years with 2,554
patients out of this presenting with eclampsia.
The FOGSI-ICOG NER has brought forth some
revealing trends. Eclampsia prevalence among registry
patients is 1.9 %. National sample surveys in the past have
shown prevalence to be 1–5 %. This is out of the 11,725
deliveries analyzed from the cases reported by 175
reporting centers. Number of cases of eclampsia is more
than cases of imminent eclampsia. This points to the lost
opportunities of prevention. 17 % of preeclampsia patients
are actually in the adolescent age group reflecting the very
early age at marriage in spite of several awareness programs
and legal guidelines. 76.34 % of the patients were
between 21 and 30 years of age thus rendering a very
young population morbid and at risk of mortality. It also is
a disease of the first-time pregnant woman as 81 % of the
patients with preeclampsia were primigravid.
Antenatal care has been identified as the single intervention
which could influence the maternal mortality of our
country. Many women still seem to be unreached with this
basic pregnancy evaluation. Most of the patients reported
by the registry were registered for antenatal care either in
the second (40.98 %) or the third trimester (46.28 %). Very
few (12.54 %) booked in the first trimester.
As per the NER data most of the times preeclampsia was found not to be associated with any symptoms (57 %); 22 % had headache and very few had vomiting, epigastric pain, giddiness, etc. (Table 1). Antenatal eclampsia is noted to be common (76.78 %); however, post-partum convulsions (13.72 %) are also significant. 40.5 % mothers had 1–4 convulsions before admission, while 23 % had just one. Greater numbers of convulsions prior to care may be due to lack of reachable facilities (Table 2). Time spent in access to care is crucial and may alter maternal and fetal outcome. Convulsions post admission (76.6 %) indicate lack of standardized care protocol for eclampsia which is mandatory. Time spent between the first episode of convulsion and access to care is between 1 and 4 h in majority (48.33 %) of patients. This indicates the severe need to train medical officers, birth attendants, and paramedical personnel in remote interiors as well as better transport facilities to handle obstetric emergencies (Table 3). Magnesium sulfate was used only in 44 % cases of patients before admission (Table 4).
Preeclampsia is a multisystemic disorder with profound implications for both the mother and the fetus. Abnormal interactions between fetal trophoblast and maternal decidua, including the cells of the maternal immune system, lead to inadequate placental invasion and maternal vascular remodeling. Thus, the origins of preeclampsia lie in the earliest stages of pregnancy. Preeclampsia generallymanifests during late pregnancy and remits after delivery attributing the critical role of its appearance to placenta. Generally, preeclampsia is considered a disorder with two components: 1. An unidentified signal from the placenta associated either with defective implantation or greater placental mass as in multifetal pregnancies or vesicular mole. 2. The aberrant maternal response to this signal is determined by her genotype and phenotype and influenced by physiological and metabolic changes in pregnancy and also causes endothelial dysfunction with multisystemic affliction.
The pathogenesis is result of multifactorial origin which can grossly be understood under following components:
Many possibilities have been speculated to give rise to preeclampsia. But, the novel and unifying theory about the pathophysiology of preeclampsia which is more convincing is the one originally proposed by Feinberg et al. from USA in 2005. It is the GESTOSIS theory which states that there is excess of immune complexes produced because of placental antigenicity which are not cleared by maternal immune system. Hence, they are deposited in the various endothelial layers causing pro-inflammatory cytokines and oxidative stress. This results in clinical preeclampsia which is inflammatory response of pregnancy. Support for this theory comes from the fact that this disorder is more frequent in primigravidas, adaptive protection is acquired in subsequent pregnancies of the same paternity, and baseline risk returns with first pregnancies of a new partner. Higher incidence is seen in oocyte donation pregnancy, is common in pregnancy with hyper placentation, and is cured after placenta is removed. The natural mechanisms in the body cannot curb the inflammatory response, and the overwhelming inflammatory response is a clinical turning point in the disease process. This maternal oxidative stress in turn stimulates further placental apoptosis and necrosis generating, an auto-amplification process. This leads to varying severity of clinical preeclampsia. Neutrophils accumulated in the inflammatory site are activated by the immune complexes. They release proteases and toxic oxygen radicals which cause further damage to the so called ‘‘oxidative stress’’ seen in preeclampsia. The main immune complex clearance mechanism in the humans is via the erythrocyte complement receptor type1 (CR1).
Erythrocytes express approximately 500 CR1 receptors per cell. A decreased expression of erythrocyte CRI in preeclamptic patients correlates with severity of disease—as happens in anemia. If low CR1 is matched with low immune complex production, no adverse sequel would be anticipated. Hence, all anemic patients don’t get preeclampsia. This is where other factors such genetic, lifestyle, nutrition, etc., could be implicated.
The degree of complement activation reflects the
severity of the disease. Pregnancies complicated by
HELLP syndrome have increased plasma levels of C3a and
C5a as compared to women with preeclampsia without
HELLP syndrome.
The common pathophysiology of preeclampsia results from: 1. Vasoconstriction with exaggerated response to vasoactive substances. 2. Plasma volume reduction due to capillary leakage and redistribution and shift of the extracellular volume from the intravascular to the interstitial compartments 3. Platelet aggregation triggered by endothelial dysfunction which leads to intravascular thrombosis. These three factors cause reduced perfusion of the brain, liver, kidneys, and the utero-placental complex reflected in the clinical syndrome.
Renal Dysfunction
The renal lesion typical of preeclampsia is ‘‘glomerular
endotheliosis’’. This is a variant of thrombotic micorangiopathy
and is characterized by endothelial cell swelling,
obliteration of the endothelial cell fenestrae, and occlusion
of the capillary lumens. Excess amounts of sFlt-1 and
decreased VEGF production by the podocytes cause proteinuria.
VEGF deficiency causes disruption of the glomerular
endothelium leading to proteinuria, oliguria, and
increased creatinine which imply severe disease. Increased
uric acid is a marker of sodium reabsorption which occurs
due to reduced renal blood flow and Angiotensin II. Uric
acid also is produced by placental trophoblasts and is a
marker of apoptosis and senescence of these cells. Uric
acid, therefore, is a marker of severity of the disease at both
renal and placental levels.
Hepatic Dysfunction
Intravascular fibrin deposits block the hepatic sinusoids, leading to hepatic dysfunction which is a component of the HELLP syndrome. Clinically epigastric or upper quadrant pain is sign of hepatic affliction. Biochemically elevated liver enzymes and coagulopathy are associated extreme consequences of subcapsular hematoma and hepatic rupture.
Hematological Abnormalities
Microangiopathic hemolysis and thrombocytopenia are the main hematological components. Hemolysis is the result of microvascular endothelial injury and activation. Initial platelet activation is followed by increased consumption leading to thrombocytopenia with increased risk of hemorrhage and further reduction in the organ perfusion [6].
Effects on the Brain
Eclampsia and other neurological abnormalities are associated with preeclampsia, and their pathogenesis is poorly understood. There are two theories postulated: 1. Hypertension and vasospasm result in vascular disregulation which leads to reduced cerebral perfusion, cytotoxic edema, ischemia, and infarction. 2. Autoregulatory mechanism of the cerebral vasculature is overcome by sudden increases in the blood pressure. This results in the development of areas of vasoconstriction and forced vasodilatation. Vasogenic edema and hyperperfusion and extravasation of erythrocytes and plasma ensue in patches. The latter entity is also called the posterior reversible leucoencephalopathy syndrome (PRES). Transient cortical blindness and intracranial hemorrhages are also associated with preeclampsia.
Cardiopulmonary Effects
Exaggerated capillary permeability and decreased plasma colloid osmotic pressure predispose the woman to pulmonary edema. It can occur spontaneously or secondary to fluid overload. Also, the left ventricular dysfunction leading to cardiac under filling is commonly associated with preeclampsia.
None of the tests proposed to predict the at-risk population for preeclampsia have risen to the level that they can be recommended for general population screening. Uterine artery Doppler (UAD) can be of help in predicting preeclampsia in the at-risk population. Doppler ultrasonography of the uterine arteries at 20–24 weeks’ gestation, to detect abnormal trophoblast invasion, predicts about 40 % of subsequent preeclampsia, however, its success in predicting severe early onset preeclampsia approaches 80 % [7]. Recently, several predictive biochemical markers— including placental growth factor, soluble fms-like tyrosine kinase-1 (sFlt-1), plasma protein 13, and pregnancy-associated plasma protein-A (PAPP-A)—have been evaluated, but none is as yet in routine clinical use [8].
In the absence of effective screening modalities, clinical risk factors can help us to be more vigilant. These factors are chronic hypertension/renal disease (15–40 %), Pregestational diabetes (10–35 %), connective tissue disease (lupus, rheumatoid arthritis) (10–20 %), thrombophilia (acquired or congenital) (10–40 %), obesity/insulin resistance (10–15 %), age older than 40 years (10–20 %), limited sperm exposure (10–35 %), family history of preeclampsia/ cardiovascular disease (10–15 %), woman born as SFGA (1.5 fold), adverse outcome in a previous pregnancy: IUGR, abruptio placentae, and IUFD (2–3 fold).
Specific inquiry of signs and symptoms mentioned below can help early diagnosis and reduce the adverse outcomes of preeclampsia. Weight gain (more than 600 g/week), increasing edema (especially sudden onset), persistent headache (needs attention), blurred vision (Immediate attention needed as can be a sign of cerebral edema), malaise, nausea (prolonged or severe first-trimester emesis), epigastric discomfort (may be mistaken as dyspepsia), and right upper quadrant discomfort (can be due to Glisson’s subcapsular bleed and hepatic hemorrhage) are these clinical clues. Several measurements of blood pressure including systolic blood pressure, diastolic blood pressure, pulse, mean arterial pressure, and 24-h ambulatory pressure have been studied in early pregnancy as predictors of preeclampsia [9]. The mid-trimester mean arterial pressure has been found to be the best predictor of preeclampsia in low-risk women, but the authors admit that the low positive likelihood ratio makes it unlikely that this measure would have a clinical effect in isolation [10].
In the light of abnormal blood pressure reading existence of severe preeclampsia should be assessed. Persistent blood pressure above 160/110 mmHg, proteinuria, refractory oliguria (\500 cc over 24 h), renal function compromise (minimal criterion would be a rise in serum creatinine of 1 mg/dl above baseline), persistent right upper quadrant or epigastric pain or both, persistent headache, scotomata or blurred vision, shortness of breath with reduced oxygen saturation or pulmonary edema, thrombocytopenia (platelets \100,000/cu.mm), hemolysis (based on peripheral smear analysis or increased bilirubin), impaired liver function of unclear etiology, and estimated fetal weight below 5th percentile for gestational age are important parameters to be noted.
The correct diagnosis and classification of hypertension in pregnancy are essential for proper management of the mother and the baby. The classification proposed by the International Society for the Study of Hypertension in Pregnancy (ISSHP) is easy to use in clinical settings (Table 5). It also is self-explanatory and practical.
Atypical Preeclampsia
Hypertension and proteinuria before 20 weeks (e.g., in
gestational trophoblastic disease), preeclampsia with
hypertension but without proteinuria, or preeclampsia with
proteinuria without hypertension when associated with
above-mentioned systemic involvement is designated at
atypical preeclampsia. Preeclampsia arising first time after
48 h of delivery can also be included in this definition. This
is an important entity for diagnosis and management of
unusual cases.
Classification as early onset preeclampsia and late onset preeclampsia is clinically useful. Appearance of preeclampsia before 34 weeks is called as early onset preeclampsia (EOPET). EOPET is associated with greater morbidity and fourfold increased risk of stillbirth in a subsequent pregnancy, and higher recurrence risk in subsequent pregnancy than when the disorder presents later. It is suggested to subdivide preeclampsia into two groups by time (gestation) of onset because of differences in prognosis and management. This distinction is held important as there is a suspicion that these two are separate entities with distinct predisposing factors. The early onset disease may be associated with the underlying genetic or environmental factors leading to abnormal placentation. The late onset disease called the late onset preeclampsia (LOPET) may be the result of obesity, diabetes, cardiovascular abnormalities (Table 6), or multifetal pregnancy.
Mild preeclampsia can be managed expectantly until fetal maturity of 37 weeks of gestation and also till spontaneous onset of labor if well controlled. A day’s hospitalization may be undertaken for blood pressure monitoring, fetal evaluation, assessing 24-h proteinuria, and assessing any other systemic involvement. Also, the patient can be offered dietary advice and the correct categorization after her blood pressure has been monitored round the clock. Any serious presentations such as severe edema, ascites, high blood pressure, severe proteinuria, headache, pain, severe growth restriction, convulsions, etc., demand a hospital care.
The primary evaluation in the presence of abnormal blood pressure should include non-stress testing (if gestational age more than 32 weeks), amniotic fluid index, serial blood pressure (4 h.) determination, and 24-h urine collection (if dipstick proteinuria is negative). Initial laboratory evaluation comprising a complete blood count with platelets (\100,000/ll: severe disease repeat after 6–12 h) (coagulation profile essential if platelets less), liver enzymes such as AST, ALT, serum creatinine levels (0.9 mg/dl [1.2 denotes renal impairment), and LDH levels (600 IU is the cutoff) should be undertaken.
WHO and FOGSI guidelines are now formulated and should be followed to manage these patients. In short, the principles of management as per WHO guidelines are [12]: Interventions that are recommended for prevention or treatment of preeclampsia & eclampsia
Simple algorithm which is recommended for management is as follows (Table 7).
Vaginal delivery is less hemodynamically stressful than cesarean delivery for the mother. To accomplish vaginal delivery, it is necessary to provide optimal anesthesia and analgesia. Also, caution must be observed while using intravenous infusions. The system of fluid restriction should be maintained until there is a postpartum diuresis, as oliguria is common with severe preeclampsia. Women who have preeclampsia are volume depleted. As such, they are prone to hypotension after administration of regional anesthesia if the block sets up too rapidly. For this reason, epidural anesthesia or some of the newer combined techniques offer optimal analgesia by allowing for slower implementation of the regional block.
Fluid overload can pose a serious threat to the mother in the form of pulmonary edema, and close vigilance is essential. Epidural anesthesia is a preferred choice of anesthesia, and spinal anesthesia is not entirely contraindicated. General anesthesia poses a challenge, and its actions with anticonvulsants need to be considered Whether a vaginal delivery or a CS, active management with oxytocics should be practiced to prevent PPH. It is safe to use Oxytocin 5 U bolus equally diluted over 2–3 min or prostaglandin injections. Prostaglandins can be used also as misoprostol sublingually or transvaginally. Due to hemoconcentration, even average loss may not be well tolerated by these patients. All attempts to reduce blood loss should be undertaken. The fluids used should be liberal but judicious. Recommendation is 80 ml/kg/h as over infusion can cause pulmonary edema in these women.
It involves close vigilance for eclampsia, PPH, HELLP, Pulmonary edema, and thromboembolic complications. 72 h post-delivery are an important period when hemodynamic transition is occurring in the mother, which need close observation and early detection of eclampsia. The NER data have shown a high index of postpartum eclampsia (13 %), and it has to be remembered that such an occurrence leading to morbidity has to be avoided by all means.
Post-partum every patient of preeclampsia should be monitored closely for 6 weeks with proper advice regarding the use of antihypertensive medication and should report at regular intervals. They should be guided and encouraged to use contraception at least for a period of 2–3 years. The preferred method would be an IUCD. They should be counseled regarding the importance of preconceptional checkup counseling and the necessary care periconceptionally in the subsequent pregnancy.
Long term sequelae such as cardiovascular and metabolic diseases are observed. Women with preeclampsia have a three–four fold increased risk of developing chronic hypertension and an approximately two-fold increased risk of ischemic heart disease, stroke, and venous thromboembolism [8].
There is an increased risk of still births and neonatal death associated with preeclampsia. Preterm delivery incidence is high with iatrogenic preterm delivery before 33 weeks being 80 fold more and between 33 and 36 weeks being about 40 fold. There is a twofold increased risk of neonatal mortality associated with preeclampsia.
Preeclampsia in previous pregnancy is an important risk factor for recurrence in the subsequent pregnancy with 7–15 % 9 chance, while it is 1 % for women with no preeclampsia in their antecedent pregnancy.
Unfortunately, very few measures can be taken to prevent preeclampsia, which are as follows. (1) Non pharmacological: daily bed rest, life-style changes, smoking, and regular prenatal exercise. (2) Nutritional: higher total dietary fiber intake, dietary protein and energy, garlic, dietary sodium restriction, weight reduction, and fish oil supplementation. (3) Pharmacological: vitamin D, magnesium, folic acid and other B-vitamins, zinc supplementation, nitric oxide, progesterone, low-dose aspirin, low-dose aspirin/heparin, calcium supplementation, antihypertensive drugs, diuretics, antioxidant supplementation, and concomitant vitamin C and E supplementation.
All these above have been recommended, but none of them are proved to be useful. Low-dose aspirin is associated with a 10–19 % reduction in preeclampsia risk and a 10–16 % decrease in perinatal morbidity and mortality. This risk reduction was seen in women who were in the ‘‘moderate to high risk category’’ [13]. Antiplatelet agents for preventing PE and its complications [14] and calcium supplementation reduce the risk of preeclampsia, particularly in populations that have diets deficient in calcium (level 1 evidence) [15]. Good quality studies have shown that calcium supplementation of at least 1 g daily started around mid-pregnancy is associated with a modest reduction in PE and a more notable reduction in its severe manifestations among women with low dietary calcium intake [15]. If prevention is not possible, then at least early detection and better management should be the aim. Presently unfortunately when we so called ‘‘TREAT’’ preeclampsia, we are only treating the symptoms and not the cause and that must be clearly borne in mind.
Things that can be done at a grass-roots level include early referral from medical officer to specialist especially in the circumstances like multiple pregnancy, preeclampsia in any previous pregnancy, underlying medical conditions, preexisting hypertension or booking diastolic BP C90 mm of Hg, preexisting renal disease or booking proteinuria (C 1? on more than one occasion or quantified at C0.3 g/24 h), preexisting diabetes, presence of antiphospholipid antibodies, first pregnancy, age of 40 years or more, BMI of 35 kg/m2 or more, family history of preeclampsia, and booking diastolic BP C80 mm of Hg \90 mm of Hg. Immediate admission should be arranged for a woman whose diastolic BP C110 mm of Hg and new proteinuria C1? on dipstick, systolic BP C170 mm of Hg and new proteinuria C1? on dipstick, diastolic BP C90 mm of Hg and new proteinuria C1? on dipstick and significant symptoms.