Preeclampsia

Etiology

Although there is an extensive understanding of the clinical presentation, diagnostic criteria, and management of preeclampsia currently routinely utilized, the underlying etiology of preeclampsia is poorly understood. The principal mechanism of disease implicated in the etiology of preeclampsia and eclampsia is uteroplacental ischemia. This theory was based on the observation of placental infarctions in patients with eclampsia and on animal studies showing that subcutaneous injections of autolyzed human placental extracts into guinea pigs elicited convulsions, hepatic focal necrosis, and renal lesions, similar to those observed in women who died of eclampsia.[4][8][9] The pathophysiology of preeclampsia, therefore, can be likened to the release and progression of a particular toxin, leading to a diffuse vasculopathy, which, if sustained, ultimately leads to severe complications such as the development of seizures seen in eclampsia.[8]

While there are numerous supporting research investigations, the following evidence supports, and is the most widely accepted to support, a causal link between placental ischemia and the development of preeclampsia:

• experimentally induced ischemia in several animal models leads to hypertension and proteinuria [10][11][12]                                                                                                                                                    
• uterine blood flow is lower in patients with preeclampsia than in pregnant women without preeclampsia [13][14]                                                                                                                                        
• placental histopathologic lesions indicative of ischemia are frequent and consistent findings in preeclampsia and eclampsia [15]                                                                                                                                       
• failure of physiologic transformation of the spiral arteries and atherosis are typical features of preeclampsia [16]                                                                                                                                            
• the pulsatility index of the uterine artery (a parameter to assess resistance to flow) is higher in patients with preeclampsia than in women with unaffected pregnancies [17]

While there is a certain consensus on this proposed main etiology, further research aims to clarify this primary mechanism of uteroplacental ischemia implicated in PIH and preeclampsia.

Epidemiology

Preeclampsia and eclampsia account for >50,000 maternal deaths yearly worldwide. Like hypertensive disorders, the incidence of preeclampsia is correlated to ethnicity and race, most prevalent among black and Hispanic patients, resulting in approximately 26% of maternal deaths among this population in the US.[4][18][2][19] Worldwide, preeclampsia affects 2% to 8% of pregnancies, but varies among race groups, as mentioned, but also among those groups within different countries.[20] Recent studies suggest morbidity is higher in developing countries, particularly in Africa and Latin America, and that Asians may be a low-risk population.[21][22] Several studies have reported similar observations and a low incidence of preeclampsia in patients in China, New Zealand, and Asian Americans in comparison to Native Americans, black Americans, and Europeans.[23][24][4]

There are several risk factors and predeterminants of preeclampsia. Several risk factors associated with preeclampsia include prior chronic hypertension, diabetes mellitus, renal disease, obesity, short stature, nutritional deficiencies, gestational hypertension in previous pregnancies, heredity, autoimmune disorders (systemic lupus erythematosus and antiphospholipid antibody syndrome), hydatidiform mole, multiple pregnancies, fetal macrosomia, nulliparity, advanced maternal age, high BMI and assisted reproduction.[4][5][25][26]

Pathophysiology

Preeclampsia can be broadly categorized into 2 subtypes: early-onset ( or placental) and late-onset (or maternal) preeclampsia. Both appear to have distinguished etiologies and phenotypes.[27] Regarding the early-onset type, the defective placenta is attributed to the development of preeclampsia. Examination of the preeclamptic placenta reveals numerous placental infarcts and arterial sclerosis. This is accompanied by placental hypoperfusion due to altered trophoblast invasion and, thus, placental ischemia.[28] 

Maternal preeclampsia arises due to the interaction between a healthy placenta and maternal factors that would ultimately cause microvascular damage. This might be due to maternal endothelial dysfunction. Since maternal preeclampsia occurs later in the gestation period, this can be managed expectantly until 37 weeks of gestation. Maternal preeclampsia occurs during the later stages of pregnancy, causing little or no change in the arterial conversion, and thus, the placental perfusion is maintained.[29]

Histopathology

The histopathology of preeclampsia involves a complex interplay of maternal and placental factors. Examination of placental tissue from individuals with preeclampsia often reveals distinct features such as maternal vascular malperfusion (MVM) lesions characterized by abnormalities in the maternal blood supply to the placenta. These lesions may manifest as fibrinoid necrosis, atherosis, and increased syncytial knots. Abnormalities in the trophoblasts, such as increased syncytial knot formation and reduced invasion into the maternal spiral arteries, are commonly observed. Inflammatory responses, including infiltration of immune cells and alterations in the placental vasculature, are evident.

While categorical histopathologic associations between the placenta and preeclampsia are still evolving, a comprehensive study revealed a higher prevalence of MVM lesions and placental weight <10th percentile during the initial onset of preeclampsia compared to subsequent occurrences. Additionally, the incidence of small for gestational age neonates and composite adverse neonatal outcomes was significantly greater during the first occurrence of preeclampsia.[30]

Diffuse vasculopathy, if sustained, ultimately leads to severe complications such as the development of seizures seen in eclampsia. As such, the definitive treatment for preeclampsia to stop this progression is delivery to remove the inciting factors from the defective placenta.

History and Physical

Although preeclampsia typically presents with a hallmark history and physical signs and symptoms, several atypical presentations exist. This section will review the most common presentations of preeclampsia and those that should prompt further investigation and diagnostic testing. 

The most common history findings in patients with preeclampsia are patient complaints of a new-onset headache not accountable by any other alternative diagnosis (ie, history of headaches or migraines) that is unresponsive to medication. This complaint may or may not be accompanied by additional complaints of visual disturbance. Patients may also endorse right upper quadrant or epigastric pain with associated nausea or vomiting. Shortness of breath and a perceived increase in swelling, both worsening from baseline pregnancy-related symptoms, may also be reported. 

In patients with preeclampsia, prevalent historical indicators often include the emergence of a new-onset headache resistant to conventional medications, distinct from pre-existing headache conditions or migraines. Visual disturbances may accompany this complaint. Patients may report discomfort in the right upper quadrant or epigastric region, coupled with feelings of nausea or vomiting. Shortness of breath and an escalation in swelling, exceeding baseline pregnancy-related symptoms, may also be articulated by affected individuals.

Patients who present with any single feature or combination of these complaints should undergo a thorough physical exam. This begins with an evaluation of vital signs, specifically blood pressure. Patients with a SBP  ≥140 mmHg or a DBP ≥90 mmHg should raise suspicion for preeclampsia. In patients at or further than 20 weeks gestation, blood pressure readings on 2 measurements at least 4 hours apart should be evaluated with further diagnostic workup.

Recent reevaluation of diagnostic blood pressure readings had expanded to include sustained severe hypertensive readings within minutes of repeat readings to allow for timely intervention with antihypertensive therapy. These blood pressure readings include SBP ≥160 mmHg or DBP ≥110 mmHg. Per ACOG, patients previously diagnosed with gestational hypertension presenting with these severe range blood pressures should be diagnosed with preeclampsia with severe features, regardless of the presence of other diagnostic criteria. When patients present with shortness of breath, auscultation and percussion of the lungs should be undertaken to examine for pulmonary disturbances. Palpation of the right upper quadrant and epigastric areas should be performed to evaluate for tenderness. An evaluation for edema should also be completed, specifically evaluating areas of dependent (gravity-related) edema, such as the lower extremities, or independent edema, such as in the face or hands.[4]

Evaluation

Following a detailed history and physical examination, patients with signs and symptoms of preeclampsia should undergo timely diagnostic testing. This includes pregnancy-induced hypertension laboratory testing, consisting of a urinalysis to evaluate the presence of proteinuria (either with a urine dipstick result ≥2+ if other methods are not readily available, a 24-hour urine collection sample significant for ≥300 mg, or a urine protein to creatinine ratio significant of 0.3 or greater), complete blood count to evaluation for thrombocytopenia (defined as a platelet count <100 K/mm), a complete metabolic panel to assess for impaired liver function (with liver enzymes more than 2 times the upper limit of normal), and renal insufficiency (defined as a serum concentration ≥1.1 mg/dL, or levels 2 times greater than baseline). All abnormal laboratory findings must exclude any preexisting aberrations or secondary causes for abnormalities to be significant for diagnosis.

Although elevated blood pressure with companying proteinuria is typically thought to be required for the diagnosis of preeclampsia, it may not be present in every case. In such cases, where the absence of proteinuria and new-onset hypertension is discovered, other new-onset symptoms such as thrombocytopenia, renal insufficiency, pulmonary edema, impaired liver function, or new-onset headache with or without visual disturbance may be used for diagnosis. This typically is referred to as preeclampsia without severe features, including new-onset severe range blood pressures (SBP ≥160 mmHg, DBP ≥110 mmHg on 2 readings at least 4 hours apart), without the findings previously mentioned.[4][31]

Treatment / Management

Management of preeclampsia begins with early diagnosis and intervention, focusing on adequate blood pressure control and seizure prevention.

Antihypertensive Management:

Blood pressure control includes both immediate antihypertensive management in cases of severe hypertension (ie, ≥160 mm Hg systolic and/or ≥110 mm Hg diastolic) as well as maintenance antihypertensive management either in the antepartum or postpartum periods depending on the particular diagnosis of preeclampsia.

Antihypertensive medications, which are efficacious and without adverse effects on the fetus, include the following medications:

• Beta-blockers, such as labetalol
• Calcium-channel blockers, such as nifedipine
• Alpha-2 agonists, such as clonidine
• Vasodilators, such as hydralazine

Medications commonly used in the treatment of severe hypertension include IV labetalol, IV hydralazine, or PO immediate-release nifedipine. While there is no evidence to suggest a benefit of either IV medications as an initial choice for antihypertensive management, the decision of medication is usually dictated by the presence of IV access at the time of diagnosis, with PO nifedipine being favored in cases where IV access is either unavailable or not possible.[32](A1)

Medications commonly used to treat blood pressure maintenance include PO labetalol, extended-release nifedipine, and extended-release clonidine.[33] As with the IV antihypertensive medications, there is no evidence to suggest a benefit of either PO medication as an initial choice in terms of efficacy. Nifedipine and clonidine offer less frequent dosing options, which may benefit noncompliant patients where extended-release nifedipine is a daily dosed medication and clonidine is usually administered as a weekly patch.

Antiseizure Management:

The first choice for seizure prophylaxis in patients with preeclampsia with severe features is IV magnesium sulfate therapy.[4][25][31] In cases where magnesium sulfate IV is contraindicated, leviteracetam can be used for prophylaxis.(B3)

Management of eclampsia (ie, development of seizure activity) is discussed in a separate article, but includes seizure treatment initially with an IV benzodiazepine medication.[34]

For recurrent seizures despite magnesium sulfate IV (or if it is contraindicated), alternative medications include:

• Lorazepam: 2-4 mg IV x 1, may repeat x 1 after 10-15 min
• Diazepam: 5-10 mg IV every 5-10 min to max dose 30 mg
• Phenytoin: 15-20 mg/kg IV x 1, may repeat 10 mg/kg IV after 20 min if no response
• Levetiracetam: 500 mg IV or orally, may repeat in 12 hours

Antepartum Management and Delivery Timing:

Fetal evaluation should include ultrasonography of the amniotic fluid index, estimated fetal weight, and antenatal testing, such as non-stress tests and biophysical profiles. Fetal status may also play a major role in determining delivery versus expectant management in preeclamptic patients. 

Ultimately, the definitive treatment of preeclampsia is the delivery of the fetus. While continued observation is permissible for preterm gestations in patients with either well-controlled gestational hypertension or preeclampsia without severe features in the setting of normal antepartum testing, risks of expectant management exist (see “Complications” section). If expectant management is undertaken in stable patients, serial ultrasonography, weekly antepartum testing, and close observation of symptoms, blood pressure, and laboratory values should be employed. As per ACOG, it is recommended that patients at 37 0/7 weeks gestation diagnosed with gestational hypertension or preeclampsia without severe features should undergo delivery rather than expectant management.

It is also recommended that patients diagnosed with preeclampsia with severe features at or beyond 34 0/7 weeks gestation undergo delivery after maternal stabilization and should not be delayed to accommodate steroid administration. In cases where patients less than 34 0/7 weeks gestation are diagnosed with preeclampsia with severe features, proper stabilization of both maternal and fetal well-being should be initiated, with management usually continued in the inpatient or outpatient setting expectantly. However, there is little evidence to suggest a benefit to this practice, and this is mainly based upon expert opinion and individualized treatment plans between patient and provider.[35][36](A1)

While neonatal and maternal outcomes may benefit from delivery or expectant management, informed decision-making regarding benefits and risks must be discussed with the patient. Antepartum admission with close monitoring of maternal and fetal conditions may be employed with a low threshold for delivery if maternal or fetal deterioration is suspected. Findings that indicate expeditious delivery after stabilization, regardless of gestational age, can be described as fetal and maternal factors.

Fetal factors include abnormal antepartum testing and sustained reversed end-diastolic flow of the umbilical artery. Maternal factors include uncontrolled blood pressure, continued headaches/visual disturbance or right upper quadrant/epigastric pain despite repeated medical management, myocardial infarction, stroke, pulmonary edema, HELLP syndrome, eclampsia, or suspicion of placental abruption or bleeding with no other diagnosis. Delivery before 34 0/7 weeks gestation, if indicated, should prompt the administration of antenatal steroids for fetal lung maturation, but this should not delay delivery. This also applied to the late preterm period of 34 0/7 through 36 6/7 weeks gestation. 

Differential Diagnosis

The differential diagnosis for preeclampsia may include chronic hypertension, gestational hypertension, antiphospholipid antibody syndrome, thrombotic microangiopathies, lupus, epilepsy or seizure disorder, chronic renal disease,  chronic liver disease, or other significant medical conditions (ie, pheochromocytoma or other endocrinopathies).[4][37]

Prognosis

Early diagnosis, timely medical intervention, and appropriate maternal and fetal surveillance significantly improve maternal and fetal outcomes. As preeclampsia continues to be responsible for up to a quarter of maternal deaths in certain ethnic backgrounds (the Caribbean and Latin American populations, followed by Asian and black populations), prompt care and routine monitoring decrease morbidity and mortality.[4][25]

Complications

Delayed delivery of the fetus in preeclamptic patients in the late preterm period increases the risk of severe hypertension, with severe consequences such as eclampsia, HELLP syndrome, pulmonary edema, myocardial infarction, acute respiratory distress syndrome, stroke, renal and retinal injury, and fetal complications including fetal growth restrictions, placental abruption, or fetal or maternal death.[4][37]

Common complications exist with the initiation of medical management for adequate blood pressure control. These include tachycardia, hypotension, headaches, and fetal heart tracing abnormalities when using labetalol, hydralazine, or nifedipine. The use of magnesium sulfate for seizure prophylaxis also carries additional adverse effects and complication risks, such as respiratory depression and cardiac arrest. Thus, frequent laboratory testing of serum magnesium levels and physical examinations every 4 to 6 hours for magnesium sulfate therapy patients is recommended.[4]