Criteria
Needed
1. Hypertension
Systolic ≥160 or diastolic ≥110 on two occasions at least 4 h apart while patient is on bed rest (unless antihypertensive therapy is initiated before this time
2. Thrombocytopenia
Platelet count <100,000
3. Impaired liver function
Elevated liver transaminases to twice the normal values, severe persistent right upper quadrant or epigastric pain unresponsive to medication and not accounted for by alternative diagnoses, or both.
4. New development of renal insufficiency
Elevated serum creatinine greater than 1.1 mg/dl, or doubling of serum creatinine in absence of other renal disease.
5. Pulmonary edema
6. New onset cerebral or visual disturbances
Some symptoms are considered to be ominous. Headaches or visual disturbances such as scotoma can be premonitory symptoms of eclampsia. Epigastric pain or right upper quadrant pain accompanies hepatocellular necrosis, ischemia, and edema that stretches Glisson’s capsule. This characteristic pain is frequently associated with elevated serum hepatic transaminases. Thrombocytopenia signifies platelet activation, aggregation and microangiopathic hemolysis. Other features of severe preeclampsia include renal or cardiac involvement. Importantly, fetal growth restriction has been removed as a finding indicative of severe preeclampsia.
1.4 Eclampsia
Preeclampsia when complicated with convulsions and/or coma is called eclampsia. Seizures are generalized tonic clonic type. They may occur before, during and after onset of labour and termed as antepartum, intapartum or postpartum eclampsia. Postpartum usually tend to occur within 48 h of delivery. However in 10 % of cases fits can occur after 48 h of delivery, termed as delayed postpartum eclampsia (Sibai 2005).
1.5 Chronic Hypertension
Chronic hypertension is defined as presence of hypertension of any cause antedating pregnancy or before 20th week of pregnancy and its presence beyond 12 weeks after delivery. The condition poses a difficult problem regarding diagnosis and management because there is fall in blood pressure during the second and early third trimesters in both normotensive and chronically hypertensive women. Even a careful search for systemic changes of hypertension may turn futile, as many of these do not have ventricular, retinal or renal changes.
1.6 Preeclampsia Superimposed on Chronic Hypertension
If baseline hypertension is accompanied by worsening, new-onset proteinuria or other symptoms listed in Table 1, then superimposed preeclampsia is diagnosed. Superimposed preeclampsia tend to occur earlier in pregnancy, more severe and often accompanied by fetal – growth restriction (Fig. 1).
Fig. 1
Massive vulval edema in a woman with severe preeclampsia
2 Incidence
The incidence varies markedly with race and ethnicity e.g. in Maternal-Fetal Medicine Units (MFMU) Network study, the incidence of preeclampsia was 5 % in white, 9 % in Hispanic, and 11 % in African-American women (Myatt et al. 2012a, b). Staff and coworkers reported incidence in nulliparous women as 3–10 % (Staff et al. 2014) and somewhat lower in multiparous 1.4–4 % (Roberts et al. 2011). Incidence of eclampsia has decreased over the years in areas where prenatal care is readily available. In countries with adequate resources, incidence averages 1 in 2000 deliveries (Royal College of Obstetricians and Gynaecologists 2006).
3 Risk Factors
Hypertensive disorders are more likely to develop in women with following characteristics
Are exposed to chorionic villi for the first time- young or elderly primigravida
Are exposed to superabundance of chorionic villi – multiple pregnancy, hydatidiform mole
Have preexisting conditions of endothelial activation or inflammation such as diabetes or renal or cardiovascular disease
Are genetically predisposed to hypertension developing during pregnancy – family history of preeclampsia or hypertension, race and ethnicity
Obesity – BMI >35 kg/m2
Hereditary thrombophilias – antiphospholipid antibody syndrome, protein C, protein S deficiency, Factor V Leiden mutation
Ironically, smoking has consistently been associated with a reduced risk for hypertension during pregnancy, possible mechanism may be upregulation of placental adrenomedullin expression, which regulates volume homeostasis.
4 Etiopathogenesis
Various theories have been proposed to explain pathogenesis of preeclampsia. Those currently considered important include:
- 1.
Abnormal trophoblastic invasion of uterine vessels – Normal implantation is characterized by extensive remodeling of spiral arterioles within decidua basalis as well as myometrium. Endovascular trophoblasts replace the vascular endothelial and muscular lining to result in low resistance vessels. In preeclampsia, however, there is incomplete invasion, only the decidual vessels but not myometrial vessels are lined with trophoblasts resulting in high resistance vessels. Mc Mohan et al have provided evidence that decreased soluble antiangiogenic factors may be involved in faulty endovascular remodelling (McMohan et al. 2014). Nelson et al. in their study on 1200 women reported that vascular lesions including spiral arterioles narrowing, atherosis, and infarcts were common in placentas of women diagnosed with preeclampsia before 34 weeks (Nelson et al. 2014).
Abnormally narrow spiral arterioles likely impair placental blood flow. Diminished perfusion and a hypoxic environment lead to release of placental micro particles that incite an inflammatory response.
- 2.
Immunological maladaptation between maternal, fetal and placental tissues-
Maternal immune system produces blocking antibodies against fetal and placental antigens in normal pregnancy which prevents immune rejection of fetus. Immune dysregulation is another theory cited to account for preeclampsia syndrome. Some of the factors associated with dysregulation include “Human leukocyte antigen (HLA), Natural killer (NK)- cells receptor haplotypes, and possibly shared susceptibility genes with diabetes and hypertension.
Immune dysregulation may explain an increased risk in the first pregnancy and when paternal antigenic load is increased e.g. in molar pregnancy. Conversely, women previously exposed to paternal antigens, such as a prior pregnancy with same partner, are immunized against preeclampsia and hence protected.
- 3.
Endothelial Cell Activation –
Inresponse to placental factors released by ischemic changes, a cascade of events begins. Cytokines released from activated leukocytes such as tumour necrosis factor-α (TNF-α) and interleukins (IL) contribute to oxidative stress associated with preeclampsia. It is characterized by reactive oxygen species and free radicals that lead to formation of self- propagating lipid peroxides which in turn generate highly toxic radicals that injure endothelial cells, modify nitric oxide production, and interfere with prostaglandin balance.
- 4.
Maternal genetic predisposition –
Preeclampsia is a multifactorial, polygenic disorder. Ward and Taylor cite a 20–40 % risk of preeclampsia in daughters of preeclamptic mothers; 11–37 % in sisters of preeclamptic mothers and 22–47 % for twins (Ward and Taylor 2014).
Various genes with possible association with preeclampsia syndrome are listed in Table 2.
Table 2
Genes with possible association with preeclampsia syndrome
Gene
Function affected
MTHFR
Methylene tetrahydrofolate reductase
F5
Factor V leiden
AGT
Angiotensinogen
HLA
Human Leukocyte antigens
NOS3
Endothelial nitric oxide
F2
Prothrombin (factor II)
ACE
Angiotensin converting enzyme
CTLA4
Cytotoxic T-lymphocyte associated protein
LPL
Lipoprotein lipase
SERPINE 1
Serine peptidase inhibitor
- 5.
Nutritional factors
Role of antioxidants like vit C, vit E and Calcium have been evaluated in various studies in causation of preeclampsia. According to Task force 2013, supplementation with antioxidants vitamins C or E showed no benefits. Also, there is no role of calcium supplementation in population without deficiency of dietary calcium (American College of Obstetricians and Gynecologists, Task Force on Hypertension in Pregnancy 2013).
4.1 Pathogenesis
4.1.1 Vasospasm
Endothelial activation causes vascular constriction with increased resistance and subsequent hypertension. At the same time, endothelial damage causes interstitial leakage through which blood constituents, including platelets and fibrinogen are deposited subendothelially. With diminished blood flow ischemia of surrounding tissues causes necrosis, hemorrhage, and end organ disturbance.
4.1.2 Endothelial Cell Injury
Intact endothelium has anticoagulant properties, and endothelial cells blunt response of smooth muscle to agonists by releasing nitric oxide. In preaclampsia, placental factors are secreted into maternal circulation and provoke dysfunction of endothelium. Damaged endothelium produces less nitric oxide and secretes substances that promote coagulation and increase sensitivity to vasopresssors.
Pregnant women normally develop refractoriness to infused vasopressors. Women with preeclampsia, however have increased reactivity to infused norepinephrine and angiotensin II.
Similarly, in normal pregnancy vascular responsiveness is decreased due to endothelial prostacyclin (PGI2) production. Its synthesis is decreased in preeclampsia. At the same time thromboxane A2, a potent vasoconstrictor, secretion is increased by platelets and PGI2: TXA2 ratio decreases which favors increased sensitivity to infused angiotensin II and ultimately, vasoconstriction.
Nitric oxide, a potent vasodilator is synthesized by endothelial cells. Inhibition of nitric oxide synthesis in preeclampsia, increases mean arterial blood pressure, decreases heart rate, and reverses pregnancy associated refractoriness to vasopressors.
Endothelin 1 (Et 1) levels are increased in pregnancy but even more in preeclamptic women likely as a result of endothelial activation.
4.1.3 Angiogenic and Antiangiogenic Proteins
Angiogenic imbalance is another hypothesis to describe pathogenesis of preeclampsia. Trophoblasts of women destined to develop preeclampsia over produces anti angiogenic peptides that enter maternal circulation:
- 1.
Soluble Fms-like tyrosine kinase-1 (sFlt-1) is a variant of Flt-1 receptor for placental growth factor (PIGF) and vascular endothelial growth factor (VEGF). Increased sFlt 1 levels inactivate and decrease PIGF and VEGF concentration leading to endothelial dysfunction.
- 2.
Soluble endoglin (sEng), a placenta derived molecule that blocks endoglin which is a surface coreceptor for TGFβ family. It inhibits various TGFβ isoforms from binding to endothelial receptors resulting in decreased endothelial nitric oxide dependent vasodilatation.
5 Pathophysiology
5.1 Cardiovascular System
Normal cardiovascular function is severely compromised in preeclampsia. Following changes are observed
- 1.
Increased cardiac afterload caused by hypertension
- 2.
Pathologically diminished hypervolemia of pregnancy
- 3.
Endothelial activation causing interendothelial extravasation of intravascular fluid into extravascular space, especially lungs.
5.2 Myocardial Function
There is a ventricular remodellingas evidenced by diastolic dysfunction as an adaptive response to maintain normal contractility with increased afterload in preeclampsia. When combined with underlying ventricular dysfunction like concentric hypertrophy from chronic hypertension- further diastolic dysfunction may cause cardiogenic pulmonary edema.
5.3 Ventricular Function
Both normal pregnant women and women with preeclampsia syndrome can have normal or slightly hyperdynamic ventricular function. Left ventricular filling pressures are dependent on the volume of intravenous fluids infused. Specifically, aggressive hydration results in overtly hyperdynamic ventricular function accompanied by elevated capillary wedge pressures resulting in pulmonary edema. This was compounded by endothelial- epithelial leak and decreased serum oncotic pressures from low serum albumin concentration.
5.4 Blood Volume
Hemoconcentration is a hallmark of eclampsia. Normal expected hypervolemia is severely curtailed with eclampsia. It results from generalized vasoconstriction that follows endothelial activation and leakage of plasma into interstitial space due to increased permeability. This vasospasm and endothelial leakage may persist for variable duration after delivery as endothelium is restored to normalcy. As this takes place, vasoconstriction reverses, the blood volume increases and hematocrit usually falls.
Women with preeclampsia are thus,
- 1.
Unduly sensitive to vigorous fluid therapy resulting in pulmonary edema.
- 2.
Are sensitive to blood loss at delivery considered normal for a normotensive woman.
5.5 Hematological Changes
5.5.1 Platelet Abnormalities
Thrombocytopenia
Overt thrombocytopenia defined by a platelet count <100,000/uL indicates severe disease. Lower the platelet count higher the fetal and maternal morbidity and mortality. In most cases delivery is advisable as thrombocytopenia continues to worsen. After delivery platelet count declines for first 24 h but returns to normal thereafter within 3–5 days. Other causes like thrombotic microangiopathy should be ruled out if these do not reach a nadir until 48–72 h after delivery.
Other Platelet Abnormalities
Platelet bound and circulating platelet- bind ableimmunoglobulin are increased suggesting surface alteration. Platelet aggregation is decreased, compared with normal increase as in normal pregnancy, as a result of immunological processes or platelet deposition at the site of endothelial damage. Importantly, neonatal thrombocytopenia does not develop despite severe maternal thrombocytopenia so maternal thrombocytopenia is not a fetal indication of cesarean delivery.
Hemolysis
It is seen as elevated serum lactate dehydrogenase levels and decreased haptoglobin levels, schizocytosis, spherocytosis, and reticulocytosis in peripheral blood film. These changes result from microangiopathic hemolysis caused by endothelial disruption with platelet adherence and fibrin deposition. Erythrocytic membrane changes, increased adhesiveness, and aggregation may also promote hypercoagulable state.
Coagulation Changes
Increased intravascular coagulation and intravascular destruction are commonly found in preeclampsia syndrome. There is increased factor VII consumption, increased fibrinopeptides A and B, D dimers, and decreased anti thrombin III and protein C and S levels. Unless there is placental abruption, plasma fibrinogen levels do not differ remarkably from levels in normal pregnancy. Routine laboratory assessments of coagulation, including prothrombin time, activated partial thromboplastin time, and plasma fibrinogen levels are unnecessary in management of preeclampsia.
5.5.2 Fluid and Electrolyte changes
In preeclampsia the volume of extracellular fluid is much greater than that in normal pregnant women. The mechanism is thought to be endothelial injury. In addition, these women have decreased plasma oncotic pressure as a result of proteinuria.
Following a convulsion, serum pH and bicarbonate are lowered due to lactic acidosis and compensatory respiratory loss of carbon dioxide.
5.5.3 Kidney
As a result of preeclampsia renal perfusion and glomerular filtration are reduced but not much less than normal nonpregnant values. The mechanism may be due to increased renal afferent arteriolar resistance and to some extent reduced plasma volume.
Morphological changes include glomerular endotheliosis blocking filtration barrier. As already discussed these women are sensitive to intravenous fluid therapy due to risk of pulmonary edema, intensive fluid therapy for oliguria is not indicated except in diminished urine output due to hemorrhage or fluid loss from vomiting or fever.
Plasma uric acid concentration is typically elevated likely due to enhanced tubular reabsorption, increased placental urate production compensatory to increased oxidative stress.
Detection of proteinuria adds to diagnosis of preeclampsia. Proteinuria may develop late e.g. Zwart et al. did not find proteinuria in 17 % of women by the time of seizures (Zwart et al. 2008). Various methods for its estimation have already been discussed previously.
Rarely acute tubular necrosis occurs as a result of preeclampsia alone but more commonly it is induced by severe obstetrical hemorrhage for which adequate blood replacement is not given. Rarely, irreversible renal cortical necrosis develops.
5.5.4 Liver
Symptomatic involvement is considered to be a sign of severe disease. It typically manifests as moderate to severe right upper quadrant or epigastric pain and tenderness. Such women commonly have elevated levels of serum aminotransferases namely aspartate (AST) or alanine transferase (ALT). Asymptomatic elevations of serum transaminases- ALT and AST- are also considered markers for severe preeclampsia. Values seldom exceed 500 U/L but have been reported to be greater than 2000 U/L.
The characteristic lesions are periportal hemorrhage in liver periphery. Sheehan and Lynch described some degree of hepatic infarction accompanied hemorrhage in almost half of the women who died of eclampsia (Sheehan and Lynch 1973). Constellation of hemolysis, hepatocallular necrosis and thrombocytopenia was termed as HELLP syndrome by Weinstein in 1985 (Weinstein 1985).
Hemorrhagic infarction may extend to form a hepatic hematoma which in turn may extend to form a hepatic hematoma that may extend to form sub capsular rupture. Computed tomography (CT) scanning or magnetic resonance (MR) imaging may be used to identify these. Management usually consists of observation and conservative approach unless hemorrhage is ongoing where prompt surgical intervention may be lifesaving.
5.5.5 Brain
Cerebrovascular Pathophysiology
Auto regulation is the mechanism by which cerebral blood flow remains relatively constant despite alterations in cerebral perfusion pressure. This mechanism protects brain from hyper perfusion when mean arterial pressures increase to as high as 160 mm Hg, which is far greater thanthose seen in most women with eclampsia. Therefore, it was theorized that auto regulation must be altered by pregnancy.
Two theories have been proposed for the cerebrovascular changes seen in eclampsia. In the first, in response to acute and severe hypertension, cerebrovascular overregulation leads to vasospasm, diminished blood flow results in ischemia, cytotoxic edema and eventually tissue infarction. The second theory proposes that sudden elevations in systemic blood pressure exceed normal cerebrovascular autoregulatory capacity. Regions of forced vasodilation and vasoconstriction develop, especially in arterial bound zones. At the capillary level, disruption of end-capillary pressure causes increased hydrostatic pressure, hyperperfusion, and extravasation of plasma and red cells through endothelial tight-junction openings, leading to vasogenic edema. Very few eclamptic women have mean arterial pressures that exceed limits of autoregulation.
Most likely mechanism is the combination of the two. Thus, preeclampsia associated cell leak develops at a blood pressure levels much lower than those usually causing vasogenic edema and is coupled with a loss of upper-limit of autoregulation. To conclude eclampsia occurs when cerebral hyperperfusion forces capillary fluid interstitially because of endothelial damage, which leads to perivascular edema.
Manifestations
There are several neurological manifestations of preeclampsia syndrome, signifying severe involvement and immediate attention.
Headache and Scotomas
Fifty to Sixty percent of women have headaches and 20–30 % have visual changes preceding eclampsia (Sibai 2005). These are usually unresponsive to analgesic, but show improvement with magnesium sulphate therapy.
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