Author: Mary Hughes, DO, FACEP, FACOEP, Professor, Emergency Medicine, Michigan State University College of Osteopathic Medicine (MSU-COM); Program Director, MSU-COM Emergency Medicine Residency, East Lansing, MI.
Peer Reviewers: Charles Emerman, MD, Chairman, Emergency Medicine, Case Western Reserve University, Cleveland, OH; and Gary Hals, MD, PhD, Department of Emergency Medicine, Palmetto Richland Hospital, Columbia, SC.
Hypertensive disorders of pregnancy range from chronic pre-existing disease to life-threatening conditions such as HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) and eclampsia. They often represent a continuum from bad to worse. The emergency department (ED) physician is likely to evaluate a pregnant patient for many conditions unrelated to the pregnancy itself, and knowledge of abnormalities that warrant further assessment and follow-up is essential. Abnormal vital signs must be addressed even if the patient’s chief complaint is a sprained ankle or sore throat. This article will identify those conditions related to hypertensive disorders of pregnancy and their evaluation and treatment, specifically preeclampsia, eclampsia, and the HELLP syndrome. Although the ED physician often does not provide definitive care for these disorders, a working knowledge of abnormalities that may portend adverse outcomes for the mother and/or the fetus is essential. The number of times an ED physician diagnoses the HELLP syndrome, preeclampsia, or eclampsia may be small, but a missed opportunity for diagnosis may be catastrophic for all involved. Management of the variety of hypertensive pregnancy disorders is similar in many respects. Where appropriate, diagnostic pitfalls likely to present to the ED will be discussed. —The Editor
The mechanism by which pregnancy-induced hypertension (PIH) occurs is unclear,1,2 and the primary complication of this disorder is the later development of preeclampsia or eclampsia, both of which have significant fetal and maternal morbidity and mortality.1,3-6 Hypertensive disorders of pregnancy affect 7-10% of all pregnancies in the United States and are responsible for 15% of all maternal deaths, most commonly from cerebral hemorrhage.1,4,5,7,8 They are the second most common cause of maternal death in the United States, behind only thromboembolic disease.9 Preeclampsia complicates 2-3% of pregnancies and may complicate up to 30% of pregnancies if the woman has pre-existing insulin dependent diabetes mellitus, hypertension, or kidney disease.1,3,10-12 Hypertensive disorders of pregnancy cause significant perinatal morbidity and mortality as well, including abruptio placentae, fetal growth restriction, and pre-term delivery.6
Currently, as defined by the American College of Obstetrics and Gynecology (ACOG), PIH exists if the blood pressure is equal to or greater than 140/90 in the seated patient, using the appropriate size cuff, and defining the diastolic as the point at which no more sound is heard (Korotkoff Phase V).13 In the pregnant patient with pre-existing hypertension, a rise of 30/15 above her baseline blood pressure is cause for concern.14,15
Blood pressure measurements may be inaccurate for a variety of reasons, including operator error, improper cuff size, and failure to calibrate equipment. Ambulatory high blood pressure monitoring may be useful in determining "white coat hypertension" and for ongoing follow-up in the patient with hypertension, but is not without error, either. Two readings six hours apart that are elevated are necessary to support the diagnosis of hypertension.16-18
The diagnosis of hypertensive disorders of pregnancy and preeclampsia has varied over the years and begs for a standard definition.19 Currently, hypertensive pregnant patients are divided into two subgroups: those with pre-existing disease, and those who develop hypertension in the second half of pregnancy. (See Table 1.) Those who are found to be hypertensive in the first 20 weeks probably have pre-existing undiagnosed disease (chronic hypertension) because it is usual for the blood pressure to fall during the first 20 weeks.20 Blood pressure measurements that are elevated and occur after the gestational age of 20 weeks are part of the continuum of PIH. These include:
- hypertension without proteinuria or edema (gestational hypertension) (PIH);
- hypertension with associated proteinuria and/or edema (preeclampsia);
- hypertension with seizures (eclampsia);
- new onset proteinuria in the hypertensive patient (superimposed preeclampsia on chronic hypertension); and
- chronic hypertension.15 (See Table 1.)
Table 1. Definition of Hypertensive Disorders
of Pregnancy in Adult Patients15,22,34,35
Non-proteinuric hypertension, now termed gestational hypertension or previously termed PIH, is estimated to occur in 8-10% of nulliparous women; preeclampsia in 2-3%; and eclampsia in 5-6/10,000 pregnancies that progress beyond 20 weeks.4,5
It is important for the ED physician to keep in mind that in the normal gravid patient, the blood pressure drops during the second trimester of pregnancy. Any reading over 140 mmHg systolic or 90 mmHg diastolic is abnormal. Close attention should be paid to blood pressure readings in any pregnant patient presenting to the ED, regardless of the reason for the visit. All abnormal values should be rechecked, and if persistent elevation is noted, contact should be made with the patient’s obstetrician. Significant blood pressure elevation, especially in the absence of proteinuria, should prompt a urine drug screen for cocaine.14
It is not uncommon for an ED physician to encounter a pediatric patient who is pregnant; therefore, a brief mention of definitions is given, as they differ from those in adults. In females younger than 18 years, hypertension is defined by the American Academy of Pediatrics as a blood pressure consistently greater than the 95th percentile of pressures, corrected for age and height. These levels often are much lower than the 140/90 pressure used for adults. For example, in females 16 years of age, the 95th percentile is 125-132/83-86 mmHg.21
Many women choose to delay pregnancy until their 30s or 40s, which allows for a concomitant rise in pre-existing hypertension or chronic hypertension. Chronic hypertension also causes an increase in the prevalence of abruptio placenta, which occurs in approximately 10% of such pregnancies.22 Pregnancies with pre-existing hypertension also are at increased risk for superimposed preeclampsia, with a reported rate of 25% in one study.23 The risk for small for gestational age infants, premature delivery, and perinatal death also increases.24
Blood Pressure Control in Pregnancy, Preeclampsia, Eclampsia, and HELLP
Identification of hypertension in a pregnant patient visiting the ED for any reason warrants re-evaluation of the vital signs, a urine dip for protein, a complete physical examination, and obstetrical consult. (See Figure 1.) Patients who have pre-existing disease, are currently receiving antihypertensive therapy, do not have proteinuria and who come back to their baseline on recheck after lying down for 30 minutes, may be managed for their initial presenting problem without further attention to the hypertension. However, if the patient’s blood pressure remains elevated on recheck, even in the absence of proteinuria, adjustment should be made to her antihypertensive regimen in consult with her obstetrician. The management of the patient with a hypertensive disorder of pregnancy varies with the disorder being treated. Patients should not be discharged from the ED if their blood pressure is not controlled to less than 140/90. (See Figure 1.)
If the patient presents to the ED without a prior history of hypertension and has a painful condition, pain management may be all that is necessary to control the blood pressure. Unless otherwise indicated, these patients may be discharged from the ED.
Over the years, numerous recommendations have been put forth for the management of the pregnant hypertensive patient so as to decrease maternal morbidity and mortality and allow for the delivery of a viable newborn as close to maturity as possible. The threshold for beginning antihypertensive therapy is a diastolic blood pressure of 100 mmHg or greater. Antihypertensive choices in pregnancy are predicated on fetal safety and maintenance of uteroplacental blood flow. Studies have demonstrated that treatment of diastolic blood pressures greater than 110 mmHg with medication decreases the incidence of maternal cerebral and cardiac events.25 Blood pressure control, however, does not prevent or cure preeclampsia.18
Bed rest is the primary non-pharmacologic treatment of PIH, which results in lower blood pressure and often diuresis. Strict bed rest may place the patient at increased risk for thromboembolic events, and should be avoided.26 In addition, avoidance of alcohol and tobacco may help.10 The choice of an antihypertensive agent depends on the urgency with which the blood pressure must be controlled. For patients who purely have hypertension, there are a variety of medications that may be used. (See Table 2.)10,14,27-29
Treatment of mild hypertension (less than 150/100) has not been shown to produce significant maternal or fetal benefits in most studies, and referral to obstetrics for further monitoring, once preeclampsia has been ruled out by the absence of proteinuria, is appropriate.10 For moderate hypertension (diastolic 100-110 mmHg) that does not resolve with 30 minutes of rest without proteinuria or evidence of end organ involvement, methyldopa (Aldomet) 250-500 mg PO may be used to begin therapy. An alternative would be nifedipine (Procardia, Adalat) 10 mg PO, repeated in 30-60 minutes if blood pressure is greater than 150/100. Labetolol (Normodyne, Trandate) also may be used with a starting dose of 100 mg twice daily. When the blood pressure has been controlled to less than 150/100 and the patient’s obstetrician has been consulted for follow-up within 24 hours, the patient may be discharged from the ED from a hypertensive standpoint with a prescription for the antihypertensive agent used. (See Table 2.)
Once preeclampsia develops (see next section) there often is a need to prevent the development of eclampsia, and initially hospital admission or in-patient observation in an obstetrical special care unit is warranted. An initial dose of dexamethasone (Decadron) 10 mg should be given if the patient is fewer than 34 weeks gestation.
For oral use, methyldopa has a very long track record of safety and is the only agent whose effects have been studied in children exposed in-utero. If this agent cannot be tolerated or is ineffective, alternatives should be chosen based on mechanism of action and age of the pregnancy. In all cases, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists are contraindicated. If a patient becomes pregnant while on these agents, she should have her medication changed.10,15 As many pregnancies are first diagnosed in the ED, once this diagnosis is made, a review of the patient’s current medications should be undertaken for safe use in pregnancy, with modifications made in consultation with the patient’s primary care physician or obstetrician.
If the patient has severe hypertension, (greater than 180/110) or evidence of preeclampsia or end organ involvement, intravenous medications such as hydralazine (Apresoline) 5 mg IV, followed in 10 minutes by a repeat dose of 5 mg and then 10 mg every 30 minutes to a total dose of 30 mg, should be used. Fluid loading with 500-1000 cc normal saline may be necessary to prevent placental hypoperfusion. An alternative in the non-asthmatic patient would be the use of IV labetolol, beginning with 20 mg IV, followed by 40-80 mg IV every 10 minutes to a total dose of 300 mg or a blood pressure less than 140/90. Labetalol also can be administered as a continuous infusion of 0.5-2 mg/minute. This does not require fluid loading. In addition, loading with magnesium sulfate to prevent the development of eclampsia in the severely pre-eclamptic patient should be started in the ED if rapid admission is not possible. (See discussion on magnesium sulfate therapy.) (See Table 2 and Table 3.) Alternatively, 1 g of methyldopa may be given orally, followed by 250-500 mg every 6 hours. The maximum dose is 4 g/day.29
Table 2 lists several antihypertensives that may be of use in pregnancy-related hypertension. Both IV hydralazine and IV labetolol have been used parenterally to manage the acute hypertensive emergency in pregnancy. Hydralazine IV has been associated with decreased blood flow in the placenta causing fetal distress, especially if the mother is not pre-treated with volume expansion. Women with preeclampsia often are at risk for pulmonary edema, and excessive fluid loading can be problematic.30 Labetolol has become more popular as an IV agent to control severe hypertension because it hasn’t been shown to require fluid loading, but it is problematic and often contraindicated in patients with underlying lung disease such as asthma.10,31
Although not directly related to the management of hypertension in pregnancy, the ED physician often is queried as to the safety of medications while breast-feeding. Occasionally blood pressure control must be initiated, or often maintained, once the patient has delivered the baby. This may have a direct impact on the breast-feeding mother and her infant. All antihypertensives studied have been found in breast milk.31 Long-term neonatal effects have not been studied.24 Methyldopa as a first-line oral agent is reasonable unless contraindicated, and then labetolol may become first-line therapy. If the patient has renal disease, then calcium channel blockers are the drugs of choice. ACE inhibitors and angiotensin II receptor antagonists should not be used due to neonatal renal effects. Diuretics may decrease milk production.24 Certain beta blockers are concentrated in breast milk (atenolol [Tenormin] and metoprolol [Lopressor, Toprol]) while others are not (labetolol and propranolol [Inderal]).32
Preeclampsia and Hypertension with Superimposed Preeclampsia
Introduction. Preeclampsia is defined as the condition where hypertension and proteinuria, with or without generalized edema, develops after 20 weeks gestation.33-34 (See Table 1.) This condition also may be superimposed on pre-existing hypertension, and thus the name superimposed preeclampsia. Preeclampsia complicates 2-3% to 2-8% of pregnancies, and 75-80% of preeclampsia patients are primigravidas.4,5,33,35 Maternal complications of preeclampsia include eclampsia, but also disseminated intravascular coagulation (DIC), HELLP, pulmonary edema, renal failure, cerebral edema and hemorrhage, and liver failure with potential for hepatic rupture and hemorrhage.10,25 Fetal complications are related to the severity of the decreased perfusion and may include intrauterine growth restriction, premature delivery, hypoxemia, acidosis, and death.10
Pathophysiology and Classification. The precise etiology of preeclampsia remains an enigma, with multiple unproven theories being offered.36 Evidence of increased platelet and endothelial activation has been noted to precede preeclampsia in some women. Abnormal placentation causing ischemia of the placenta and release of toxic factors that result in endothelial damage is thought to cause vascular constriction, increased capillary leakage, and platelet aggregation leading to preeclampsia and, in more severe cases, the HELLP syndrome and eclampsia.37,38 Immunologic factors also may be the instigator of preeclampsia and HELLP, with tumor necrosis factor (alpha) being cited as one possible cause of both disorders.37 Oxidative stress, in which there is a preponderance of oxidants, has been postulated as yet another cause of endothelial damage in preeclampsia and HELLP. N-acetylcysteine has been proposed to help tip the balance in the direction of anti-oxidation, thus helping prolong the pregnancy and decreasing fetal and maternal morbidity and mortality.39 Lastly, in normal pregnancies, cytotrophoblast cells invade the uterine spiral arteries and replace the normal endothelial lining of these vessels. This allows for the development of a low resistance arteriolar system to supply the growing fetus.40 Due to unknown causes, this trophoblastic remodeling is limited to the proximal vessels in patients with preeclampsia, causing a decreased uteroplacental perfusion and leading to hypoxia of the placenta, causing regions of placental infarction.40 Regardless of the underlying cause, patients with preeclampsia have increased vascular reactivity when compared to normal healthy pregnant controls or patients with HELLP syndrome.41,42
Preeclampsia and even eclampsia can occur under all socio-economic conditions, and risk factors are listed in Table 4.24,43,44
Table 4. Risk Factors for Preeclampsia24,43,44
Preeclampsia is classified as either mild or severe; there is no moderate level. Severe is defined in a pregnant patient past 20 weeks gestation with new onset proteinuria, hypertension, and one or more of the following complicating signs, symptoms, or lab values: central nervous system (CNS) dysfunction, liver capsule distention, hypertension, proteinuria, oliguria or renal failure, pulmonary edema, HELLP syndrome or any of its lab components separately.10,18,22 (Table 5.) Absence of these classifies the preeclampsia as mild.33 However, preeclampsia by nature has an unpredictable course and, therefore, all patients, whether labeled mild or severe, should be managed cautiously. Rapid progression from mild disease to an eclamptic seizure is not uncommon.18,45 HELLP syndrome is a form of severe preeclampsia, and approximately 4-12% of cases of preeclampsia manifest as HELLP syndrome.46-49 (See section on HELLP.)
Table 5. Signs, Symptoms, or Lab Values Associated
with Severe Preeclampsia10,18,22
Clinical Presentation. The signs and symptoms of preeclampsia can be variable. Patients presenting with CNS dysfunction, including headache, visual disturbances, or evidence of a cerebrovascular accident (CVA), should be evaluated for preeclampsia. In addition, right upper quadrant pain may be the presenting complaint, and preeclampsia may be the final diagnosis when other etiologies are ruled out. Occasionally, preeclampsia patients will present in pulmonary edema or acute renal failure. At times, hypertension will be an incidental finding in the ED patient seeking care for another problem. Because preeclampsia may be abrupt in onset or the patient may be devoid of prior prenatal care, hypertension and/or peripheral edema noted on physical exam should prompt the treating physician to obtain a urine specimen to evaluate for proteinuria. If the systolic blood pressure is greater than 160 mmHg or the diastolic blood pressure is greater than 100 mmHg, obstetrical consult should be sought from the ED and an antihypertensive agent begun. (See discussion on management of hypertension.) If preeclampsia is diagnosed based on hypertension, proteinuria, +/- peripheral edema, then hospital admission is the norm, at least for a period of observation to further evaluate and monitor the mother and fetus.
Imitators of preeclampsia may include hemolytic uremic syndrome (HUS), thrombotic thrombocytopenia (TTP), acute fatty liver of pregnancy, autoimmune diseases such as system lupus erythematosis (SLE), and sepsis.32,50 The same organ systems can be affected in all diseases in this differential, and preeclampsia may be superimposed on any of them, making the final diagnosis difficult and one that takes many tests and often much time to delineate. In the ED, ordering the initial battery of tests, namely a complete blood count (CBC) with peripheral smear, prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, blood urea nitrogen (BUN), creatinine, glucose, electrolytes, uric acid, and hepatic panel to include bilirubin, LDH, AST, and ALT as well as a urinalysis will help begin the process. Obstetrics should be involved early, and a hematology consult may be necessary for plasma exchange in the patient with TTP. TTP and HUS are less common than HELLP syndrome, and often present with bleeding, bruising, or epistaxis. Mental status changes including seizures may occur, and abdominal pain is frequent. Fever and elevated creatinine occur in half of patients, and most demonstrate microscopic proteinuria and hematuria. However, DIC is uncommon with TTP and HUS, and, therefore, fibrinogen, PT, and PTT are normal. In addition, more than 50% of cases of TTP occur before 24 weeks gestation, and plasma transfusions and exchanges markedly have increased the survival, thus the need for urgent hematology consultation if TTP or HUS is suspected.50
Acute fatty liver of pregnancy usually develops in the third trimester and carries a 90% mortality if untreated. Presenting symptoms include headache, nausea, vomiting, abdominal pain, or malaise, with 50% of patients demonstrating hypertension and thrombocytopenia. Hypoglycemia and hyperammonemia suggest the disease. Abnormal coagulation studies in the form of decreased fibrinogen and abnormal PT and PTT are present 70-80% of the time. Elevation of bilirubin and hepatic transaminases is typical.50
Autoimmune diseases will share common findings with preeclampsia, but serologic testing for disorders such as SLE and antiphospholipid antibody syndrome should help differentiate the disorders. Finally, sepsis may mimic preeclampsia and/or HELLP syndrome. Often the vital signs will help make the diagnosis. Blood cultures and early broad spectrum antibiotics are essential for treatment of sepsis.50
Prevention. In recent years, several attempts to prevent preeclampsia have given mixed results. Low-dose aspirin therapy, vitamin and mineral supplements, calcium supplements, nutritional supplements such as fish oil, and various antihypertensive regimens have been studied, with none proven to be effective in all groups.1,51-54 Aspirin given at 100 mg/day ingested eight hours after arising demonstrated a significant decrease in blood pressure when compared to the effect when taken immediately upon arising, and an even stronger effect was noted if the aspirin was taken at bedtime.54 Until the pathogenesis of preeclampsia is defined more accurately, no accurate prevention is likely.52
Management of Preeclampsia. Over the years, many management strategies have been used to treat the preeclampsia patient. Definitive therapy is delivery, with the first priority being the safety of the mother, and the second priority the delivery of a mature live newborn.55 Initial evaluation of the preeclamptic patient usually is performed as an in-patient and, following a thorough evaluation of the mother and fetus, a variety of options may be chosen, including at-home monitoring, day units, or continued hospitalization.15 Therapy with at-home monitoring by the mother and frequent out-patient clinic visits now has become the standard in reliable patients without co-morbid diseases.26
Despite the fact that delivery is the definitive treatment for preeclampsia, increased efforts have been instituted to manage severe preeclampsia remote from term to increase fetal viability and decrease long-term sequelae associated with premature birth. This should be done only in a tertiary center with the ability to monitor the mother and fetus appropriately. The precise age of the fetus is most important in making clinical decisions that may have long-ranging consequences. In selected patients, hospital admission, careful monitoring, corticosteroid administration to encourage fetal lung maturation, and prophylaxis with magnesium sulfate26, 56-64 (see Table 3) to prevent seizures, along with oral antihypertensives to control blood pressure in the 130-150/80-100 mmHg range (see Table 1) has been used with some success.65 The frequency of eclampsia was decreased in patients with severe preeclampsia by the use of magnesium sulfate.15,66,67
Introduction. Eclampsia is a disorder confined exclusively to the pregnant or newly delivered patient up to two weeks postpartum and still accounts for significant fetal and maternal morbidity and mortality, with approximately 50,000 maternal deaths annually worldwide.4 It is defined as cerebral involvement resulting in convulsions in association with pre-eclampsia. It is further divided into antepartum, intra-partum, and postpartum, depending on when convulsions occur in relation to labor.26 Eclampsia complicates approximately 1 in 2000 pregnancies in developed countries, but may rise as high as 1 in 100 pregnancies in developing countries.35,56,57,68 It complicates 0.2-0.5% of all deliveries.10 Up to 30% of women with eclampsia will have HELLP syndrome, which results in a greater number of pre-term infants and higher mortalities than in patients with eclampsia alone.69
The frequency of eclamptic seizures in women with preeclampsia is fewer than 1%.70,71 Approximately 40% of seizures occur antepartum before women receive medical attention, and nearly 50% occur at a gestational age fewer than 36 weeks. Sixteen percent of eclamptic seizures occur more than 48 hours post-partum. Unfortunately, this means only 45-50% of all seizures will occur during a time when the patient actually is in the hospital being monitored, severely limiting efforts at seizure prophylaxis.71,72 Ten percent of women who suffer an eclamptic seizure will develop some form of blindness, which usually resolves within a week and often is due to retinal detachment or occipital lobe involvement with edema, ischemia, or infarct.26 The pathophysiology of eclampsia is an extension of preeclampsia, and predicting which patients will progress to this most severe form remains a mystery.
Clinical Presentation and ED Management. Eclampsia should be the ED working diagnosis in any pregnant patient past 20 weeks who presents with a new onset grand mal seizure. Although the differential should be sufficiently broad to include underlying epilepsy, intracerebral events such as a CVA, tumor or subarachnoid hemorrhage, as well as drug ingestions, the initial work up needs to include an urgent dipstick urine analysis to rule in or out proteinuria. By definition, eclampsia is a seizure in conjunction with preeclampsia. However, the patient may not be aware of her preeclamptic state due to rapid onset of preeclampsia in some patients, rapid progression from preeclampsia to eclampsia in some, and lack of prenatal care prior to the onset of seizure in others. The ED physician also should be suspicious of this diagnosis in the newly post-partum patient (up to 2 weeks) who presents with a grand mal seizure. Although eclampsia often is a diagnosis of exclusion, the work-up is fairly straightforward and should include a thorough history and physical with attention to the neurologic exam and fetal monitoring for signs of distress. This is followed by basic metabolic studies, a urine analysis, non-contrast head CT scan, and a urine drug screen. The differential for the pregnant patient with hypertension, proteinuria, and edema is broad and includes many conditions other than preeclampsia or eclampsia.10,17,50,73 (See Table 6.) However, with appropriate lab tests and a non-contrast head CT scan, the ED physician should be able to rapidly rule out most other causes of these disorders.
Table 6. Differential of Patients
Presenting with Hypertension,
Proteinuria, and Edema10,17,50,73
Patients with eclamptic seizures are at risk for status seizures. In antepartum eclampsia, labor may ensue and delivery may be rapid, at times before the post-ictal period is resolved.57 Continuous fetal monitoring in the ED is warranted, with emergent obstetric consultation. Patients may not present to the hospital of planned delivery with their eclamptic seizure; therefore, regardless of the level of obstetrical care available at the institution, the ED physician must be adept at making this diagnosis and begin rapid emergent treatment of the mother and monitoring of the fetus. (See below.) Overall, 6.5% of patients with eclampsia develop multiple neurological complications, including cortical blindness, aphasia, paresis, psychosis, coma, or cerebrovascular accidents.74 CT scans in patients with eclampsia often yield relevant diagnoses. Approximately 43% are normal, 44% have hypodensities, 6% reveal intracerebral hemorrhages, and 6% hydrocephalus.74 There are two reported cases in the literature of eclamptic seizures precipitated by the administration of the anticholinergic drug scopolamine for epigastric pain in the patient with HELLP syndrome. The proposed mechanism is unopposed sympathetic nervous system activity due to inhibition of the parasympathetic system, exacerbating vasospasm, and hypertension.75
Management of Eclampsia. Management of eclampsia is multifaceted and must include management of hypertension (see previous section), prevention of further seizures, and safe delivery of the fetus once the mother is stabilized. The majority of eclamptic seizures will resolve in 60-90 seconds, and delivery should be planned as soon as the mother’s condition permits.70 Magnesium therapy is designed to prevent further seizures and has been established as the most effective drug to prevent recurrent seizures in the eclamptic patient.72 Intravenous and IM regimens exist and are effective for magnesium sulfate therapy, but the IM route is more painful, associated with abscess formation in 0.5% of cases, and very risky in patients with HELLP syndrome and a platelet count of fewer than 100,000.76 (See discussion below.)
Use of Magnesium Sulfate. Magnesium sulfate first was administered intrathecally in 1906 to prevent eclamptic seizures. It first was used IM in 1926 to prevent recurrent seizures, and in 1933 it was given IV to women with preeclampsia and eclampsia.59 Worldwide, the use of magnesium sulfate for eclampsia is variable. The Collaborative Eclampsia Trial has established magnesium sulfate as superior to diazepam or phenytoin for the prevention of recurrent seizures in eclampsia. In addition, it may have benefits to the fetus, and in preeclamptic females may reduce the risk of first convulsions.57,67,77,78 Both the IM and IV regimens begin with 4 g of a 20% solution of magnesium sulfate IV over 4 minutes. In the IM regimen, this immediately is followed by 5 g IM of a 50% solution of magnesium sulfate in each buttock, followed by 5 g IM every 4 hours, alternating buttocks. In the IV regimen, the initial loading dose is followed by a continuous infusion of 2 g/hour—generally mixed as 20 g in a liter of IV solution and run at 100 cc/hour. The IV maintenance dose should be cut in half in the presence of renal insufficiency. In either case, if seizures persist after 15 minutes, an additional load of 2-4 g of magnesium sulfate is given IV, depending on maternal size. If the seizure persists, 250 mg of amobarbital (Amytal) should be given slowly IV. The patient receiving magnesium therapy must be monitored closely. Patellar reflexes, respiratory rate, and hourly urine output should be monitored in each patient, and magnesium therapy should be halted in the absence of patellar reflexes, a respiratory rate less than 16/min, or urine output less than 100 cc/4-hour period. Magnesium levels should be monitored every 4-6 hours, and the dose adjusted to maintain levels between 4 and 7 mEq/liter (4.8 - 8.4 mg/dL; 2-4 mmol/L). (See Table 3.)26,56-64 The conversion of magnesium levels from mEq/L to mg/dL is as follows: 1.2 times magnesium level in mEq/L = magnesium level in mg/dL.64
Table 7 lists the common signs/symptoms of magnesium toxicity. Early signs and symptoms include nausea, somnolence, a sensation of warmth, diplopia, dysarthria, and weakness. Further increases in levels lead to loss of patellar reflexes, followed by respiratory depression, muscle paralysis, prolonged PR and QRS on ECG, respiratory arrest, followed by cardiac arrest and death.26,58,59,64,77,79 In addition to being cautious with magnesium sulfate in patients on calcium channel blockers, the ED physician needs to give consideration to other drug/drug interactions that may occur, especially with paralytics. When performing rapid sequence intubation, the ED physician should not give a defasiculating dose of a non-depolarizing blocker. A single dose of succinylcholine (Anectine) 1 mg/kg may be used without difficulty. If paralytics need to be continued, the succinylcholine should be allowed to wear off, and then the dose of the non-depolarizing neuromuscular blocking agent should be decreased due to its potentiation with magnesium sulfate.80,81
Use of Other Anticonvulsants. In the patient in whom magnesium therapy is contraindicated (those with myasthenia gravis, cardiac conduction defects in the setting of cardiac muscle damage), or in those in whom it should be used cautiously if at all (those on calcium channel blockers or with renal insufficiency), phenytoin (Dilantin) or diazepam (Valium) may be used. It should be noted that in the myasthenic patient, phenytoin is not without risk, and therefore diazepam is probably the drug of choice. Initially diazepam should be used to control the seizure, beginning with 10 mg IV over 2 minutes, repeated if seizure recurs. Prevention of further seizures may continue with diazepam via infusion 40-80 mg/liter of D5/W over 24 hours titrated to seizure control and restlessness, followed by 20-40 mg/ liter D5W over the second 24 hours. Alternatively, once the seizure has been controlled, prevention may begin with phenytoin (or phenytoin equivalents) 1 g IV over 20 minutes, followed by one of the following: 100 mg IV every 6 hours for 24 hours; 500 mg orally 10 hours after initial dose; or an infusion of 500 mg in 200 cc of NS over four hours beginning immediately after the bolus, and repeated once 12 hours after the bolus. Phenytoin should be continued for 24 hours after delivery or after the last seizure, whichever is later.
Introduction. The HELLP syndrome is a severe form of preeclampsia that occurs in 0.2-0.8% of all pregnancies,46,73,82,83 carries a 1-2% maternal mortality rate when care is provided in a tertiary center,84,85 and an 11% perinatal mortality.86 It occurs in 20% of women with severe preeclampsia and 10% of women with eclampsia.84 The development of liver disease and a coagulopathy in association with hypertension portend a poorer fetal and maternal outcome in preeclampsia, as does a platelet count of fewer than 50,000.46,69 In contrast to non-HELLP preeclampsia, HELLP syndrome is more common in multiparous women who are Caucasian.84
HELLP syndrome has been further classified as follows:
Class I: maternal platelet count < 50,000/microliter
Class II: maternal platelet count >50,000 and < 100,000/microliter
Class III: maternal platelet count > 100,000 and < 150,000/microliter
In one study, all groups with HELLP syndrome had higher maternal and perinatal morbidity than a control group with severe preeclampsia without HELLP.69
Maternal morbidity may include premature delivery, an increased cesarean section rate, more use of blood products, multisystem organ failure, sepsis, adult respiratory distress syndrome (ARDS), pulmonary edema, ascites, pleural effusion, cerebral edema, retinal detachment, hemorrhage (both spontaneous and postpartum), DIC, or hepatic rupture. Given the severe nature of HELLP complications, HELLP can be fatal for both mother and fetus.46,84 The pathophysiology of HELLP is similar to preeclampsia. The reason certain patients go on to develop the HELLP syndrome while most do not is still an enigma and hinders definitive therapy.69
Clinical Presentation. The most common presenting complaints of this disorder are epigastric or right upper quadrant pain (65-90% of patients) believed to be secondary to liver capsule distention, often associated with nausea and vomiting.46,73,69 These symptoms worsen as the severity of HELLP worsens.83 The mother often has a shallow respiratory pattern due to diaphragmatic irritation, which may predispose her to atelectasis and pneumonia.25 In Class I HELLP syndrome, 35% reported nausea with or without vomiting, 50% reported epigastric pain, and 61% reported a headache. Mean blood pressures were lower in patients with Class I or II HELLP syndrome when compared to patients with severe preeclampsia alone. Although HELLP is a form of preeclampsia, be aware that the presence of proteinuria and hypertension are variable, with up to 14% of patients with HELLP having no proteinuria, and nearly 20% being normotensive.83,87 HELLP syndrome occurs most often before term, although up to one-third of cases may present post-partum, with development up to seven days post-partum reported.84,88 The differential is similar to preeclampsia and is listed in Table 6. (See previous discussion under pre-eclampsia section.) Coagulation studies will help differentiate acute fatty liver of pregnancy and DIC from the other disorders. Most other labs tests are somewhat variable, and the patient condition as well as clinical experience will be necessary to reach a final diagnosis.
The intensity of HELLP generally reaches a peak 24 hours after delivery, and lab values return to normal following this in most patients.73 Patients who do not demonstrate an increase in platelet count by 96 hours after delivery often have severe systemic, non-compensated disease.69 Patients with more severe HELLP have shorter times from admission to delivery and longer lengths of stay overall.83
ED Evaluation. The ED physician evaluating any pregnant or recently delivered woman with complaints of upper abdominal pain should consider and work up the patient for the HELLP syndrome. Even though this is a preeclampsia syndrome, not all patients have hypertension or proteinuria.84,89 This variability in patient presentation makes the possibility of misdiagnosis by the ED physician more likely. As with other hypertensive disorders of pregnancy, the criteria used to define HELLP vary somewhat. The most useful lab tests are a CBC with a peripheral smear, LDH and transaminases, creatinine, uric acid, fractionated bilirubin, and a urine analysis. Coagulation studies are useful in patients with platelets fewer than 100,000.69,73 Thrombocytopenia is defined as a platelet count fewer than 150,000, and liver enzymes (LDH and the transaminases) are mildly to moderately elevated in most cases. Evidence of hemolysis may be seen on a peripheral smear, or the hematocrit may be low without another etiology.46,49,82,90 A low threshold for admission to obstetrics from the ED should be maintained by the treating ED physician.
Misdiagnoses of HELLP syndrome include gastritis, cholelithiasis, appendicitis, pancreatitis, nephrolithiasis, pyelonephritis, viral gastroenteritis, and hepatitis. In the converse, severe diseases misdiagnosed as HELLP syndrome include dissecting aneurysms, cardiomyopathy, chronic hypertension with concomitant renal disease, acute fatty liver, alcoholic liver disease, cholecystitis, glomerulonephritis, and acute cocaine intoxication. As misdiagnosis may result in catastrophic maternal and fetal consequences, one should consider HELLP syndrome in patients diagnosed with the above conditions.69
In addition, it has been determined that on admission nausea, vomiting, or epigastric pain are all independent risk factors for increased maternal morbidity in patients with severe preeclampsia or HELLP syndrome. Laboratory values on admission that portend a high risk for significant maternal morbidity include; LDH greater than 1400 IU/L, AST greater than 150 IU/L, ALT greater than 100 IU/L, uric acid greater than 7.8 mg/dL, urinary protein of 4+, serum creatinine greater than 1.0 mg/dL. The LDH, AST, and uric acid have the strongest predictive value and are risk additive with worsening thrombocytopenia.91
Management of HELLP. Once the diagnosis of the HELLP syndrome has been established, consideration should be given to transfer to a tertiary care facility if available. Urgent delivery is the usual treatment, although under certain circumstances in a tertiary facility prepared for delivery 24 hours/day, expectant management may be considered to allow for steroid administration, especially if the gestational age is fewer than 34 weeks. In addition to fetal lung maturation, antenatal steroids and/or postpartum steroids have been shown to stabilize the maternal condition.85,92,93 The only contraindication to antenatal steroids is intrauterine infection or maternal tuberculosis.58,85,92,93 The current recommended protocol is dexamethasone 10 mg IV every 12 hours through delivery and into the postpartum period until the maternal blood pressure has stabilized, urine output is adequate without fluid boluses or diuretics, platelets are greater than 100,000, and the patient is clinically stable. Following this, two additional doses of 5 mg dexamethasone are given every 12 hours.85,92,93 Isler, in a double blind study, demonstrated that dexamethasone 10 mg IV every 12 hours was superior to 12 mg betamethasone IM every 24 hours for the stability of HELLP syndrome.94 Dexamethasone IV often allows a 48-hour window in the fetus fewer than 34 weeks gestational age for fetal lung maturation.95 The ED physician faced with a pregnant patient fewer than 34 weeks gestation who presents with preeclampsia or HELLP should administer the initial dose of dexamethasone, providing contraindications are absent (i.e., intrauterine infection, maternal TB).
In summary, if the ED physician suspects the HELLP syndrome, plans should be made to admit or transfer the patient to a tertiary care facility and, if the patient is fewer than 34 weeks gestation, dexamethasone 10 mg IV should be given. In addition, as eclamptic seizures frequently develop in the HELLP patient, magnesium sulfate therapy is indicated as a prophylactic measure to prevent the development of this most serious complication, and may need to be continued 48 hours into the puerperium until evidence of recovery is apparent.69 (See Table 3.) (See Table 8 for a summary of pitfalls in ED management of patients with preeclampsia, HELLP, or eclampsia.)
Table 8. Pitfalls in the ED Management of Patients
with Preeclampsia, HELLP, and Eclampsia
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