Introduction

Background

Preeclampsia is a disorder of widespread vascular endothelial malfunction and vasospasm that occurs after 20 weeks’ gestation and can present as late as 4-6 weeks postpartum. It is clinically defined by hypertension and proteinuria, with or without pathologic edema.

Preeclampsia is part of a spectrum of hypertensive disorders that complicate pregnancy. These include chronic hypertension, preeclampsia superimposed on chronic hypertension, gestational hypertension, preeclampsia, and eclampsia. Although each of these disorders can appear in isolation, they are thought of as progressive manifestations of a single process and are believed to share a common etiology.

The diagnostic criteria for preeclampsia focus on measurement of elevated blood pressure and proteinuria that develop after 20 weeks’ gestation. This must be differentiated from gestational hypertension, which is more common and may present with symptoms similar to preeclampsia, including epigastric discomfort or thrombocytopenia, but is not characterized by proteinuria. Additionally, patients with preexisting chronic hypertension may present with superimposed preeclampsia presenting as new-onset proteinuria after 20 weeks’ gestation.

Consensus is lacking among the various national and international organizations about the values that define the disorder, but a reasonable limit in a woman who was normotensive prior to 20 weeks’ gestation is a systolic blood pressure (BP) greater than 140 mm Hg and a diastolic BP greater than 90 mm Hg on 2 successive measurements 4-6 hours apart. Preeclampsia in a patient with preexisting essential hypertension is diagnosed if systolic BP has increased by 30 mm Hg or if diastolic BP has increased by 15 mm Hg.

Proteinuria is defined as 300 mg or more of protein in a 24-hour urine sample. In the emergency department, a urine protein-to-creatinine ratio of 0.19 or greater is somewhat predictive of significant proteinuria (negative predictive value [NPV], 87%).^{[1 ]}Serial confirmations 6 hours apart increase the predictive value. Although more convenient, a urine dipstick value of 1+ or more (30 mg/dL) is not reliable.

For the purposes of guiding management, a distinction can be made between mild preeclampsia and severe preeclampsia.

Diagnostic criteria for severe preeclampsia include at least one of the following:

• Systolic BP greater than 160 mm Hg or diastolic BP greater than 110 mm Hg on 2 occasions 6 hours apart with the patient at bed rest
• Proteinuria greater than 5000 mg in a 24-hour collection or more than 3+ on 2 random urine samples collected at least 4 hours apart
• Oliguria with less than 500 mL per 24 hours
• Persistent maternal headache or visual disturbance
• Pulmonary edema or cyanosis
• Concerning abdominal pain
• Impaired liver function test findings
• Thrombocytopenia
• Oligohydramnios, decreased fetal growth, or placental abruption

Eclampsia is defined as seizures in a patient with preeclampsia.

For more information, see Medscape’s Pregnancy Resource Center

Pathophysiology

The mechanism by which preeclampsia occurs is not certain, and a number of maternal, paternal, and fetal factors have been implicated in its development. The factors currently considered to be the most important include abnormal placental implantation; maternal immunological intolerance; cardiovascular and inflammatory changes; and genetic, nutritional, and environmental factors.^{[2 ]}

Placental implantation with abnormal trophoblastic invasion of uterine vessels is a major cause of hypertension associated with the preeclampsia syndrome.^{[3 ]}Normally, uterine invasion by endovascular trophoblasts cause extensive remodeling of uterine spiral arteries, resulting in enlarged vessel diameter. In preeclampsia, there is only shallow invasion, and the deeper uterine arterioles do not widen appropriately. Studies have shown that the degree of incomplete trophoblastic invasion of the spiral arteries is directly correlated with the severity of subsequent maternal hypertension. Subsequently, the resulting placental hypoperfusion leads by an unclear pathway to the release of systemic vasoactive compounds that cause an exaggerated inflammatory response, vasoconstriction, endothelial damage, capillary leak, hypercoagulability, and platelet dysfunction, all of which contribute to organ dysfunction and the various clinical features of the disease.

Immunological factors have long been considered to be key players in preeclampsia. One important component is a poorly understood dysregulation of maternal tolerance to paternally derived placental and fetal antigens.^{[4 ]}This maternal-fetal immune maladaptation is characterized by defective cooperation between uterine natural killer (NK) cells and fetal HLA-C, and results in histological changes similar to those seen in acute graft rejection. The endothelial cell dysfunction that is characteristic of preeclampsia may be partially due to an extreme activation of leukocytes in the maternal circulation, as evidenced by an upregulation of type 1 helper T cells.

Genetics have long been understood to play an important role, and preeclampsia has been shown to involve multiple genes. Importantly, the risk of preeclampsia is positively correlated between close relatives; a recent study showed that 20-40% of daughters and 11-37% of sisters of preeclamptic women also develop preeclampsia.^{[4 ]}Twin studies have also shown a high correlation, approaching 40%. Over a hundred maternal and paternal genes have been studied for their association with the syndrome, including those known to play a role in vascular diseases, blood pressure regulation, diabetes, and immunological functions. Because preeclampsia is genetically and phenotypically a complex disease, it is unlikely that any one gene will be shown to play a dominant role in its development.

Frequency

United States

Preeclampsia occurs in approximately 5-7% of all pregnancies. The incidence of preeclampsia is 23.6 cases per 1,000 deliveries in the United States. The incidence of eclampsia is estimated to be 1 in 2000 deliveries.

International

The global incidence of preeclampsia has been estimated at 5-14% of all pregnancies. In developing countries, hypertensive disorders were the second most common obstetrical cause of stillbirths and early neonatal deaths, accounting for 23.6%.^{[5 ]}

Mortality/Morbidity

Preeclampsia is the third leading pregnancy-related cause of death, after hemorrhage and embolism. Preeclampsia is the cause in an estimated 790 maternal deaths per 100,000 live births.

Morbidity and mortality is related to systemic endothelial dysfunction; vasospasm and small-vessel thrombosis leading to tissue and organ ischemia; CNS events such as seizures, strokes, and hemorrhage; acute tubular necrosis; coagulopathies; and placental abruption in the mother.

Hemolysis, elevated liver enzyme levels, and low platelets (HELLP) syndrome may be an outcome of severe preeclampsia, although some authors believe it to have an unrelated etiology.

In the fetus, ischemic encephalopathy, growth retardation, and the various sequelae of premature birth can occur.

Race

The frequency of mortality differs among race and ethnicity, with African Americans having a worse mortality rate than white women.

Age

Preeclampsia occurs more frequently in women at the extremes of reproductive age.

• Younger women (<20 y) have a slightly increased risk. Primigravid patients in particular seem to be predisposed.
• Older women (>35 y) have a markedly increased risk.

Clinical

History

Mild-to-moderate preeclampsia may be asymptomatic. Many cases are detected through routine prenatal screening. Patients with severe preeclampsia display end-organ effects and may complain of the following:

• CNS
  • Headache
  • Visual disturbances – Blurred, scintillating scotomata
  • Altered mental status
  • Blindness – May be cortical^{[6 ]}or retinal
• Dyspnea
• Edema: This exists in many pregnant women but sudden increase in edema or facial edema is more concerning for preeclampsia. The edema of preeclampsia occurs by a distinct mechanism that is similar to that of angioneurotic edema.
• Epigastric or right upper quadrant (RUQ) abdominal pain: Hepatic involvement occurs in 10% of women with severe preeclampsia. This pain is frequently accompanied by elevated serum hepatic transaminase levels.
• Weakness or malaise: This may be evidence of hemolytic anemia.

Preeclampsia in a prior pregnancy is strongly associated with recurrence in subsequent pregnancies. A history of gestational hypertension or preeclampsia should strongly raise clinical suspicion. Uncommonly, patients can have antepartum preeclampsia treated with delivery that then recurs in the postpartum period.^{[7 ]}Although this is highly unusual, recurrent preeclampsia does occur and should be considered in postpartum patients who present with hypertension and proteinuria.

Physical

Findings on physical examination may include the following:

• Increased BP compared with the patient’s baseline or greater than 140/90 mm Hg
• Altered mental status
• Decreased vision or scotomas
• Papilledema
• Epigastric or RUQ abdominal tenderness
• Peripheral edema: Edema can be normal in pregnancy, and a gradual increase in dependent edema is not necessarily ominous. However, a sudden increase in edema or swelling of the face is more suggestive of preeclampsia and should be promptly investigated.
• Hyperreflexia or clonus: Although deep tendon reflexes are more useful in assessing magnesium toxicity, the presence of clonus may indicate an increased risk of convulsions.
• Seizures
• Focal neurologic deficit

Causes

• Pregnancy-associated risk factors
  • Chromosomal abnormalities
  • Hydatidiform mole
  • Multifetal pregnancy: Incidence is increased in twin gestations but is unaffected by their zygosity.
  • Oocyte donation or donor insemination
  • Urinary tract infection
• Maternal-specific risk factors
  • Extremes of age
  • Black race: In the United States, the incidence of preeclampsia is 1.8% among white women and 3% in African Americans.
  • Family history of preeclampsia
  • Nulliparity
  • Preeclampsia in a previous pregnancy
  • Diabetes
  • Obesity: Body weight is strongly correlated with progressively increased risk, ranging from 4.3% for women with a BMI <20 kg/m to 13.3% in those with a BMI >35 kg/m. A United Kingdom study on obesity showed that 9% of extremely obese women were preeclamptic compared with 2% of matched controls.^{[8 ]}
  • Chronic hypertension
  • Renal disease
  • Collagen vascular disease
  • Antiphospholipid syndrome
  • Periodontal disease^{[9 ]}
  • Vitamin D deficiency: One literature review suggests that maternal vitamin D deficiency may increase the risk of preeclampsia and fetal grown restriction.

Recent studies have suggested that smoking during pregnancy is associated with a reduced risk of gestational hypertension and preeclampsia; however, this is controversial.^{[10 ]}Placenta previa has also been correlated with a reduced risk of preeclampsia.

Differential Diagnoses

Abdominal Trauma, Blunt	Ovarian Torsion
Abruptio Placentae	Pregnancy, Eclampsia
Aneurysm, Abdominal	Status Epilepticus
Appendicitis, Acute	Stroke, Hemorrhagic
Cholecystitis and Biliary Colic	Stroke, Ischemic
Cholelithiasis	Subarachnoid Hemorrhage
Congestive Heart Failure and Pulmonary Edema	Subdural Hematoma
Domestic Violence	Thrombotic Thrombocytopenic Purpura
Early Pregnancy Loss	Toxicity, Amphetamine
Encephalitis	Toxicity, Sympathomimetic
Headache, Tension	Toxicity, Thyroid Hormone
Hypertensive Emergencies	Transient Ischemic Attack
Hyperthyroidism, Thyroid Storm, and Graves Disease	Urinary Tract Infection, Female
Migraine Headache	Withdrawal Syndromes

Workup

Laboratory Studies

• CBC count and peripheral smear
  • Microangiopathic hemolytic anemia (HELLP)
  • Thrombocytopenia <100,000
  • Hemoconcentration may occur in severe preeclampsia.
  • Schistocytes on peripheral smear
• Liver function tests: Transaminase levels are elevated from hepatocellular injury and in HELLP syndrome.
• Serum creatinine level: Levels are elevated due to decreased intravascular volume and decreased glomerular filtration rate (GFR).
• Urinalysis
  • Proteinuria is one of the diagnostic criteria for preeclampsia.
  • Significant proteinuria defining preeclampsia is 300 mg or more of protein in a 24-hour urine sample.
  • Proteinuria suggestive of preeclampsia is greater than or equal to 1+ protein on urine dipstick or 300 mg/L or more on urine dipstick.
  • Microalbuminuria and urine albumin: Creatinine ratios have been shown to have poor clinical predictive values and should not be used.
• Abnormal coagulation profile: PT and aPTT are elevated.
• Disseminated intravascular coagulopathy testing will show fibrin split products and decreased fibrinogen levels.
• Uric acid
  • Hyperuricemia is one of the earliest laboratory manifestations of preeclampsia. It has a low sensitivity, ranging from 0-55%, but a relatively high specificity, ranging from 77-95%.^{[11 ]}
  • Serial levels may be useful to indicate disease progression.

Imaging Studies

• Head CT: This study is used to detect intracranial hemorrhage in selected patients with sudden severe headaches, focal neurologic deficits, or seizures with a prolonged post-ictal state.
• Ultrasonography: This is used to assess the status of the fetus as well as to evaluate for growth restriction (typically asymmetrical — use abdominal circumference). Aside from transabdominal ultrasonography, umbilical artery Doppler ultrasonography should be performed to assess blood flow. The value of Doppler ultrasonography in other fetal vessels has not been demonstrated.
• Cardiotocography: This is the standard fetal nonstress test and the mainstay of fetal monitoring. Although it gives continuing information about fetal well being, it has little predictive value.

Other Tests

A study at Yale University has shown preliminary results that Congo Red, a dye currently used to locate atypical amyloid aggregates in Alzheimer’s disease, may also be effective in the early diagnosis of preeclampsia.^{[12 ]}This finding may lead to a spot urine test that can be used in emergency departments and internationally, especially in resource-poor countries where preeclampsia continues to be underdiagnosed and accounts for a large percentage of maternal and fetal mortality.

Treatment

Prehospital Care

Prehospital care for pregnant patients with suspected preeclampsia includes the following:

• Oxygen via facemask
• Intravenous access
• Cardiac monitoring
• Transportation of patient in left lateral decubitus position
• Seizure precautions

Emergency Department Care

In the emergency setting, control of BP and seizures should be priorities. Definitive therapy is delivery of the fetus,^{[13 ]}although preeclampsia may paradoxically emerge in postpartum patients. In general, the further the pregnancy is from term, the greater the impetus to manage the patient medically.

BP control

• The goal is to lower BP to prevent cerebrovascular and cardiac complications while maintaining uteroplacental blood flow.
• Control of mildly increased BP does not appear to improve perinatal morbidity or mortality, and, in fact, it may reduce birth weight.
• Antihypertensive treatment is indicated for diastolic blood pressure above 105 mm Hg and systolic pressure above 160 mm Hg, though patients with chronic hypertension may tolerate higher values.
• Patients with severe preeclampsia who have BP below 160/105 mm Hg may benefit from antihypertensives because of the possibility of unpredictable acceleration of the disease and sudden increases in hypertension.
• The goal is to maintain diastolic blood pressure between 90 and 100 mm Hg and systolic pressure between 140 and 155 mm Hg.
• First-line medications are labetalol, given orally or IV; nifedipine, given orally or IV; or hydralazine IV. Doses are as noted below.
• Atenolol, ACE inhibitors, ARBs, and diuretics should be avoided.

Control of seizures

• The basic principles of airway, breathing, circulation (the ABCs) should always be followed as a general principle of seizure management.
• Active seizures should be treated with intravenous magnesium sulfate as a first-line agent.^{[14,15 ]}A loading dose of 4 g should be given by an infusion pump over 5-10 minutes, followed by an infusion of 1 g/h maintained for 24 hours after the last seizure. Recurrent seizures should be treated with an additional bolus of 2 g or an increase in the infusion rate to 1.5 g or 2 g per hour.
• Prophylactic treatment with magnesium sulfate is indicated for all patients with severe preeclampsia.^{[14 ]}No consensus exists about whether patients with mild preeclampsia (elevated blood pressure without evidence of end-organ damage) need to be on magnesium seizure prophylaxis.
• Magnesium levels, respiratory rate, reflexes, and urine output must be monitored to detect magnesium toxicity. Magnesium sulfate is mostly excreted in the urine, and therefore urine output needs to be closely monitored. If urine output falls below 20 mL/h, the magnesium infusion should be stopped. Magnesium toxicity can be easily assessed by clinical examination; the first sign of toxicity is often a loss of deep tendon reflexes, followed by respiratory depression. If signs of toxicity are present, the magnesium sulfate infusion should be stopped. Calcium gluconate 1 g (10 mL) can be given over 10 minutes to reverse the effects.^{[11,16 ]}
• Be aware of the risk of seizures following delivery — up to 44% of eclampsia cases have been reported to occur postnatally. This risk is especially elevated 48 hours postpartum, but it can occur at any time up to 4 weeks after delivery.^{[11 ]}
• For seizure refractory to magnesium sulfate therapy, benzodiazepines and/or phenytoin may be considered.

Fluid management^{[17 ]}

• Little clinical evidence exists in the published literature on which to base decisions regarding the management of fluids during preeclampsia. Currently, no prospective studies are available, and guidelines are largely based on consensus and retrospective review.
• Despite the peripheral edema, patients with preeclampsia are intravascularly volume depleted with high peripheral vascular resistance. Diuretics should be avoided.
• Aggressive volume resuscitation may lead to pulmonary edema, which is a common cause of maternal morbidity and mortality. Pulmonary edema occurs most frequently 48-72 hours postpartum, probably due to mobilization of extravascular fluid. Because volume expansion has no demonstrated benefit, patients should be fluid restricted when possible, at least until the period of postpartum diuresis.
• Volume expansion has not been shown to reduce the incidence of fetal distress and should be used judiciously, as discussed.
• Central venous or pulmonary artery pressure monitoring may be indicated in critical cases. A central venous pressure (CVP) of 5 mm Hg in women with no heart disease indicates sufficient intravascular volume, and maintenance fluids alone are sufficient. Total fluids should generally be limited to 80 mL/h or 1 mL/kg/h.
• Careful measurement of fluid input and output is advisable, particularly in the immediate postpartum period. Many patients will have a brief (up to 6 h) period of oliguria following delivery; this should be anticipated and not overcorrected.

Delivery

• Delivery is the definitive treatment for antepartum preeclampsia. Obstetrical consultation should be sought early to coordinate transfer to an obstetrical floor, as appropriate.
• Patients with mild preeclampsia are often induced after 37 weeks’ gestation. Prior to this, the immature fetus is treated with expectant management with corticosteroids to accelerate lung maturity in preparation for early delivery.
• In patients with severe preeclampsia, induction of delivery should be considered after 34 weeks’ gestation. In these cases, the severity of disease must be weighed against the risks of prematurity.
• Eclampsia is common after delivery and has occurred up to 6 weeks after delivery. Patients at risk for eclampsia should be carefully monitored postpartum.^{[18 ]}Additionally, patients with preeclampsia successfully treated with delivery may present with recurrent preeclampsia up to 4 weeks postpartum.

Consultations

Immediate obstetric consultation is warranted for all patients who present with preeclampsia.

Medication

Magnesium sulfate is the first-line treatment of prevention of primary and recurrent eclamptic seizures. For eclamptic seizures refractory to magnesium sulfate, lorazepam and phenytoin may be used as second-line agents.

In the setting of severe hypertension (systolic BP, >160 mm Hg; diastolic BP, >110 mm Hg), antihypertensive treatment is recommended. Antihypertensive treatment decreases the incidence of cerebrovascular problems but does not alter the progression of preeclampsia.

Traditionally, hydralazine has been used for control of severe hypertension in women with preeclampsia. However, the evidence regarding the side effects and maternal/fetal outcomes when compared with labetalol and nifedipine is conflicting.

Anticonvulsants

Agents that inhibit smooth muscle contractions are used.

Magnesium sulfate

First-line therapy for seizure prophylaxis. Antagonizes calcium channels of smooth muscle. Indicated in severe preeclampsia, eclampsia, and preeclampsia in the near term. Administer IV/IM for seizure prophylaxis in preeclampsia. Use IV for quicker onset of action in true eclampsia.

Dosing

Adult

4-6 g IV over 20 min with maintenance of 1-2 g/h

Pediatric

Not established

Interactions

Concurrent use with nifedipine may cause hypotension and neuromuscular blockade; may increase neuromuscular blockade seen with aminoglycosides and potentiate neuromuscular blockade produced by tubocurarine, vecuronium, and succinylcholine; may increase CNS effects and toxicity of CNS depressants, betamethasone, and cardiotoxicity of ritodrine

Contraindications

Documented hypersensitivity; heart block; Addison disease; myocardial damage; severe hepatitis

Precautions

Pregnancy

A – Fetal risk not revealed in controlled studies in humans

Precautions

Magnesium sulfate may alter cardiac conduction leading to heart block in digitalized patients; respiratory rate, deep tendon reflex, and renal function should be monitored when electrolyte is administered parenterally; caution when administering magnesium sulfate dose since may produce significant hypotension or asystole; in overdose, calcium gluconate, 10-20 mL IV of 10% solution, can be given as antidote for clinically significant hypermagnesemia

Lorazepam (Ativan)

Sedative hypnotic with short onset of effects and relatively long half-life. By increasing the action of gamma-aminobutyric acid (GABA), which is a major inhibitory neurotransmitter in the brain, may depress all levels of CNS, including limbic and reticular formation.
Important to monitor patient’s blood pressure after administering dose. Adjust as necessary.

Dosing

Adult

4 mg/dose IV slowly over 2-5 min and repeat in 10-15 min prn; cumulative dose of 8 mg/d typically considered maximum
1-10 mg/d PO/IV/IM divided bid/tid

Pediatric

Infants and children: 0.1 mg/kg IV slowly over 2-5 min; repeat prn in 10-15 min at 0.05 mg/kg; not to exceed 4 mg/dose
Adolescents: 0.07 mg/kg IV slowly over 2-5 min and repeat in 10-15 min prn; not to exceed 4 mg/dose

Interactions

Toxicity of benzodiazepines in CNS increases when used concurrently with alcohol, phenothiazines, barbiturates, and MAO inhibitors

Contraindications

Documented hypersensitivity; preexisting CNS depression, hypotension, and narrow-angle glaucoma; reversal agents (eg, flumazenil) contraindicated when lorazepam used for life-threatening conditions (eg, control of intracranial pressure or status epilepticus)

Precautions

Pregnancy

D – Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in renal or hepatic impairment, myasthenia gravis, organic brain syndrome, or Parkinson disease

Phenytoin (Dilantin)

Phenytoin has been used successfully in eclamptic seizures, but cardiac monitoring is required secondary to associated bradycardia and hypotension.
Central anticonvulsant effect of phenytoin is by stabilizing neuronal activity by decreasing the ion flux across depolarizing membranes.
Some benefits to using phenytoin are that it can be continued orally for several days until the risk of eclamptic seizures has subsided, it has established therapeutic levels that are easily tested, and no known neonatal adverse effects are associated with short-term usage.

Dosing

Adult

10 mg/kg loading dose infused IV no faster than 50 mg/min, followed by maintenance dose started 2 h later at 5 mg/kg

Pediatric

Administer as in adults

Interactions

Amiodarone, benzodiazepines, chloramphenicol, cimetidine, fluconazole, isoniazid, metronidazole, miconazole, phenylbutazone, succinimides, sulfonamides, omeprazole, phenacemide, disulfiram, ethanol (acute ingestion), trimethoprim, and valproic acid may increase phenytoin toxicity
Phenytoin effects may decrease when taken concurrently with barbiturates, diazoxide, ethanol (chronic ingestion), rifampin, antacids, charcoal, carbamazepine, theophylline, and sucralfate
Phenytoin may decrease effects of acetaminophen, corticosteroids, dicumarol, disopyramide, doxycycline, estrogens, haloperidol, amiodarone, carbamazepine, cardiac glycosides, quinidine, theophylline, methadone, metyrapone, mexiletine, oral contraceptives, valproic acid

Contraindications

Documented hypersensitivity; sinoatrial block; second- and third-degree AV block; sinus bradycardia; Adams-Stokes syndrome

Precautions

Pregnancy

D – Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Perform blood counts and urinalyses when therapy is begun and at monthly intervals for several months thereafter to monitor for blood dyscrasias; discontinue use if a rash appears, and do not resume use if rash is exfoliative, bullous, or purpuric; rapid IV infusion may result in death from cardiac arrest, marked by QRS widening; caution in acute intermittent porphyria and diabetes (may elevate blood sugar levels); discontinue use if hepatic dysfunction occurs

Antihypertensives

These agents are used to decrease systemic resistance and to help reverse uteroplacental insufficiency.

Hydralazine (Apresoline)

First-line therapy against preeclamptic hypertension. Decreases systemic resistance through direct vasodilation of arterioles, resulting in reflex tachycardia. Reflex tachycardia and resultant increased cardiac output helps reverse uteroplacental insufficiency, a key concern when treating hypertension in a patient with preeclampsia. Adverse effects to the fetus are uncommon.

Dosing

Adult

5-10 mg IV; repeat q20min to maximum of 60 mg

Pediatric

Not established

Interactions

MAO inhibitors and beta-blockers may increase hydralazine toxicity; pharmacologic effects of hydralazine may be decreased by indomethacin

Contraindications

Documented hypersensitivity; mitral valve rheumatic heart disease

Precautions

Pregnancy

C – Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Hydralazine has been implicated in myocardial infarction; caution in suspected coronary artery disease

Labetalol (Normodyne)

Second-line therapy that produces vasodilatation and decreases in systemic vascular resistance. Has alpha-1 and beta-antagonist effects and beta2-agonist effects. Has more rapid onset than hydralazine and less overshoot hypotension. Dosage and duration of labetalol is more variable. Adverse effects to fetus are uncommon.

Dosing

Adult

50-100 mg IV; repeat q30min to a maximum of 300 mg

Pediatric

Not established

Interactions

Decreases effect of diuretics and increases toxicity of methotrexate, lithium, and salicylates; may diminish reflex tachycardia, resulting from nitroglycerin use, without interfering with hypotensive effects; cimetidine may increase labetalol blood levels; glutethimide may decrease labetalol effects by inducing microsomal enzymes

Contraindications

Documented hypersensitivity; cardiogenic shock; pulmonary edema; bradycardia; atrioventricular block; uncompensated congestive heart failure; reactive airway disease; severe bradycardia

Precautions

Pregnancy

C – Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in impaired hepatic function; discontinue therapy if signs of liver dysfunction; in elderly patients, a lower response rate and higher incidence of toxicity may be observed

Nifedipine (Procardia)

Relaxes coronary smooth muscle and produces coronary vasodilation, which, in turn, improves myocardial oxygen delivery. Sublingual administration is generally safe, despite theoretical concerns.

Dosing

Adult

10-30 mg IR cap PO tid; not to exceed 120-180 mg/d
30-60 mg SR tab PO qd; not to exceed 90-120 mg/d

Pediatric

0.25-0.5 mg/kg/dose PO tid/qid prn

Interactions

Fentanyl and alcohol may increase hypotensive effects; calcium channel blocker may increase cyclosporine levels; H2 blockers (cimetidine), erythromycin, nafcillin, and azole antifungals may increase toxicity (avoid combination or monitor closely); carbamazepine may reduce bioavailability (avoid this combination); rifampin may decrease levels (monitor and adjust dose of calcium channel blocker)

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C – Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May cause lower extremity edema; allergic hepatitis has occurred but is rare

Follow-up

Further Inpatient Care

Hospitalization is indicated for all women with severe preeclampsia. The goals of hospitalization include the following:

• Daily weigh-ins
• Blood pressure readings every 4 hours
• Prophylactic anticonvulsive therapy
• Corticosteroids to enhance fetal lung maturity

Further Outpatient Care

Outpatient management of preeclampsia has a limited role. The decision to treat on an outpatient basis must be made in consultation with an obstetrician. Detailed instructions on signs and symptoms of progression of disease, including headache, visual changes, abdominal pain, vaginal bleeding, or decreased fetal movement, as well as strict bed rest is recommended.

Transfer

Patients with severe preeclampsia must be stabilized in the ED as much as possible prior to transfer to a tertiary care facility.

Complications

Complications of preeclampsia may include the following:

• Abruptio placentae with disseminated intravascular coagulopathy
• Renal insufficiency or failure
• Hemolysis, elevated liver enzyme levels, and low platelet count (or HELLP syndrome)
• Eclampsia
• Cerebral hemorrhage
• Maternal death and/or fetal demise

Prognosis

• Early detection and frequent obstetric assessment markedly improves prognosis.
• A history of preeclampsia increases a woman’s subsequent risk of vascular disease, including hypertension, thrombosis, ischemic heart disease, myocardial infarction, and stroke.^{[19 ]}

Patient Education

For excellent patient education resources, visit eMedicine’s Pregnancy and Reproduction Center and Circulatory Problems Center. Also, see eMedicine’s patient education articles Pregnancy and High Blood Pressure.

Miscellaneous

Medicolegal Pitfalls

• Immediate obstetric consultation is required for all patients who present with preeclampsia.
• Maintain a high index of suspicion for preeclampsia when evaluating any complaint in a pregnant patient with abnormally elevated BP.
• Any pregnant patient, regardless of age, is at risk for preeclampsia.

References

1. Rodriguez-Thompson D, Lieberman ES. Use of a random urinary protein-to-creatinine ratio for the diagnosis of significant proteinuria during pregnancy. Am J Obstet Gynecol. Oct 2001;185(4):808-11. [Medline].
2. Cunningham FG, Veno KJ, Bloom SL, et al. Pregnancy Hypertension. In: Williams Obstetrics. 23e. 2010:[Full Text].
3. Zhou Y, Damsky CH, Fisher SJ. Preeclampsia is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype. One cause of defective endovascular invasion in this syndrome?. J Clin Invest. May 1 1997;99(9):2152-64. [Medline]. [Full Text].
4. Madejczyk M, Kruszynski G, Breborowicz G. Etiopathology of preeclampsia. Arch Perinat Med. 2009;15(3):144-151. [Full Text].
5. Ngoc NT, Merialdi M, Abdel-Aleem H, Carroli G, Purwar M, Zavaleta N, et al. Causes of stillbirths and early neonatal deaths: data from 7993 pregnancies in six developing countries. Bull World Health Organ. Sep 2006;84(9):699-705. [Medline]. [Full Text].
6. Llovera I, Roit Z, Johnson A, Sherman L. Cortical blindness, a rare complication of pre-eclampsia. J Emerg Med. Oct 2005;29(3):295-7. [Medline].
7. Andrus SS, Wolfson AB. Postpartum preeclampsia occurring after resolution of antepartum preeclampsia. J Emerg Med. Feb 2010;38(2):168-70. [Medline].
8. Knight M, Kurinczuk JJ, Spark P, Brocklehurst P. Extreme obesity in pregnancy in the United Kingdom. Obstet Gynecol. May 2010;115(5):989-97. [Medline].
9. [Best Evidence] Conde-Agudelo A, Villar J, Lindheimer M. Maternal infection and risk of preeclampsia: systematic review and metaanalysis. Am J Obstet Gynecol. Jan 2008;198(1):7-22. [Medline].
10. Wikstrom AK, Stephansson O, Cnattingius S. Tobacco use during pregnancy and preeclampsia risk: effects of cigarette smoking and snuff. Hypertension. May 2010;55(5):1254-9. [Medline].
11. [Guideline] Tuffnell DJ, Shennan AH, Waugh JJ, Walker JJ. Royal College of Obstetricians and Gynaecologists. The management of severe pre-eclampsia/eclampsia. 2006. [Full Text].
12. Larson, NF. Congo Red Dot Urine Test Can Predict, Diagnose Preeclampsia. Medscape Medical News. Available at http://www.medscape.com/viewarticle/716741?src=rss. Accessed Apr 22, 2010.
13. Wagner LK. Diagnosis and management of preeclampsia. Am Fam Physician. Dec 15 2004;70(12):2317-24. [Medline].
14. Lew M, Klonis E. Emergency management of eclampsia and severe pre-eclampsia. Emerg Med (Fremantle). Aug 2003;15(4):361-8. [Medline].
15. McCoy S, Baldwin K. Pharmacotherapeutic options for the treatment of preeclampsia. Am J Health Syst Pharm. Feb 15 2009;66(4):337-44. [Medline].
16. Lindheimer MD, Taler SJ, Cunningham FG. Hypertension in pregnancy. J Am Soc Hypertens. April 2010;4(2):68-78. [Medline].
17. Engelhardt T, MacLennan FM. Fluid management in pre-eclampsia. Int J Obstet Anesth. Oct 1999;8(4):253-9. [Medline].
18. Yancey LM, Withers E, Bakes K, Abbott J. Postpartum preeclampsia: Emergency department presentation and management. J Emerg Med. Sep 22 2008;[Medline].
19. [Best Evidence] Bellamy L, Casas JP, Hingorani AD, Williams DJ. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. BMJ. Nov 10 2007;335(7627):974. [Medline].
20. Doan-Wiggins L. Hypertensive disorders of pregnancy. Emerg Med Clin North Am. Aug 1987;5(3):495-508. [Medline].
21. Frakes MA, Richardson LE 2nd. Magnesium sulfate therapy in certain emergency conditions. Am J Emerg Med. Mar 1997;15(2):182-7. [Medline].
22. Lipstein H, Lee CC, Crupi RS. A current concept of eclampsia. Am J Emerg Med. May 2003;21(3):223-6. [Medline].
23. Ogle ME, Sanders AB. Preeclampsia. Ann Emerg Med. May 1984;13(5):368-70. [Medline].
24. Powers DR, Papadakos PJ, Wallin JD. Parenteral hydralazine revisited. J Emerg Med. Mar-Apr 1998;16(2):191-6. [Medline].
25. Probst BD. Hypertensive disorders of pregnancy. Emerg Med Clin North Am. Feb 1994;12(1):73-89. [Medline].
26. Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet. Feb 26-Mar 4 2005;365(9461):785-99. [Medline].
27. Witlin AG, Sibai BM. Magnesium sulfate therapy in preeclampsia and eclampsia. Obstet Gynecol. Nov 1998;92(5):883-9. [Medline].

Keywords

preeclampsia, preeclampsia treatment, preeclampsia diagnosis, preeclampsia symptoms, preeclampsia causes, hypertensive disease in pregnancy, pregnancy-induced hypertension, toxemia of pregnancy, hypertension, proteinuria, eclampsia, seizure in pregnancy, microangiopathic hemolytic anemia, HELLP syndrome

Contributor Information and Disclosures

Author

Zina Semenovskaya, MD, Resident Physician, Department of Emergency Medicine, Kings County Hospital, State University of New York Downstate Medical Center College of Medicine
Disclosure: Nothing to disclose.

Coauthor(s)

Mert Erogul, MD, Assistant Professor of Emergency Medicine, University Hospital of Brooklyn: Consulting Staff, Department of Emergency Medicine, Kings County Hospital Center
Mert Erogul, MD is a member of the following medical societies: American College of Emergency Physicians, American Medical Association, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Medical Editor

Assaad J Sayah, MD, Chief, Department of Emergency Medicine, Cambridge Health Alliance
Assaad J Sayah, MD is a member of the following medical societies: National Association of EMS Physicians
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Mark Zwanger, MD, MBA, Assistant Professor, Department of Emergency Medicine, Thomas Jefferson University
Mark Zwanger, MD, MBA is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, and American Medical Association
Disclosure: Pfizer Salary Employment

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

Pamela L Dyne, MD, Professor of Clinical Medicine/Emergency Medicine, David Geffen School of Medicine at UCLA; Attending Physician, Department of Emergency Medicine, Olive View-UCLA Medical Center
Pamela L Dyne, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Acknowledgments

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Dawn C Jung, MD, to the development and writing of this article.

Further Reading

The Geneva Foundation for Medical Education and Research has published a list of international links relevant to the diagnosis, prevention, and treatment of hypertension, preeclampsia, and eclampsia in pregnancy.

The World Health Organization has published guidelines on the management of preeclampsia and eclampsia that is especially useful for midwives and other mid-level providers and can be extrapolated for use in the developing world. It is available in English and Portuguese.

© 1994-// 2010 by Medscape.
All Rights Reserved
(http://www.medscape.com/public/copyright)

Introduction

The diagnosis of pregnancy requires a multifaceted approach using 3 main diagnostic tools. These are history and physical examination, laboratory evaluation, and ultrasonography. Currently, physicians may use all of these tools to diagnose pregnancy at early gestation and to help rule out other pathologies.

History and Physical Examination

The diagnosis of pregnancy has traditionally been made based on history and physical examination findings. Important aspects of the menstrual history must be obtained. The woman should describe her usual menstrual pattern, including date of onset of last menses, duration, flow, and frequency. Items that may confuse the diagnosis of early pregnancy are an atypical last menstrual period, contraceptive use, and a history of irregular menses. Additionally, as many as 25% of women bleed during their first trimester, further complicating the assessment.^{[1 ]}

Be alert for rising human chorionic gonadotropin (hCG) levels, an empty uterus observed on sonogram, abdominal pain, and vaginal bleeding because these may signal an ectopic pregnancy.^{[2,3 ]}Ectopic pregnancies are the primary cause of first trimester maternal mortality and should be diagnosed early, before the pregnancy ruptures or the patient becomes unstable (see Media file 1).^{[4 ]}

Pregnancy diagnosis. Sonogram showing a complex mass in the adnexa (labeled EP). It was found to be an ectopic pregnancy at the time of surgery.

Other historical factors related to ectopic pregnancies include prior tubal manipulation, pelvic inflammatory disease, previous ectopic pregnancy, tubal disease, use of an intrauterine device for contraception, fertility therapies, and tubal ligation.^{[3,5,6 ]}See Ectopic Pregnancy for a full description and details.The classic presentation of pregnancy is a woman with menses of regular frequency who presents with amenorrhea, nausea, vomiting, generalized malaise, and breast tenderness.

Upon physical examination, one may find an enlarged uterus after bimanual examination, breast changes, and softening and enlargement of the cervix (Hegar sign; observed at approximately 6 wk). The Chadwick sign is a bluish discoloration of the cervix from venous congestion and can be observed by 8-10 weeks. A gravid uterus may be palpable low in the abdomen if the pregnancy has progressed far enough, usually by 12 weeks. Currently, through the use of chemical assays and ultrasonography, physicians are capable of making the diagnosis of pregnancy before many of the physical signs and symptoms are evident.^{[7 ]}

Laboratory Evaluation

Several hormones can be measured and monitored to aid in the diagnosis of pregnancy. The most commonly used assays are for the beta subunit of hCG. Other hormones that have been used include progesterone and early pregnancy factor.

The cytotrophoblast and syncytiotrophoblast each secrete a variety of hormones that include, but are not limited to, corticotropin-releasing hormone, gonadotropin-releasing hormone, thyrotropin-releasing hormone, somatostatin, corticotropin, human chorionic thyrotropin, human placental lactogen, inhibin/activin, transforming growth factor-beta, insulinlike growth factors 1 and 2, epidermal growth factor, pregnancy-specific beta-1 glycoprotein, placental protein 5, and pregnancy-associated plasma protein-A. To date, no commercially feasible tests that use these hormones have been made available to aid in the diagnosis of pregnancy.

Beta-human chorionic gonadotropin

hCG is a glycoprotein similar in structure to follicle-stimulating hormone (FSH), luteinizing hormone (LH), and thyrotropin. hCG is composed of alpha and beta subunits. The alpha subunit of hCG is similar to the alpha subunit of FSH, LH, and thyrotropin. The free beta subunit of hCG differs from the others in that it has a 30–amino acid tailpiece at the COOH terminus. Free beta subunits are degraded by macrophage enzymes in the kidney to make a beta subunit core fragment, which is primarily detected in urine samples.

The beta-hCG subunit is present in the syncytial layer of the blastomere. Hyperglycosylated hCG is a form of hCG produced by invasive cytotrophoblast cells in early pregnancy and implantation. hCG messenger RNA is detectable in the blastomeres of 6- to 8-cell embryos at 2 days but cannot be isolated in culture medium until 6 days. Detection in maternal serum and urine is evident only after implantation and vascular communication has been established with the decidua by the syncytiotrophoblast 8-10 days after conception.

hCG is present in the maternal circulation as either an intact dimer, alpha or beta subunit, and degraded form, or beta core fragment. Intact and free beta subunit are initially the predominant forms of hCG, with the beta core fragment emerging as the predominant form in the fifth week after conception. Additionally, intact and free beta subunit have the most day-to-day variability and are transiently undetectable even 10 days after detection of pregnancy.^{[8 ]}Optimally, tests used for early pregnancy detection should be able to recognize all forms of intact hCG, including the free beta subunit and the beta core fragment.

Currently, 4 main hCG assays are used: (1) radioimmunoassay, (2) immunoradiometric assay, (3) enzyme-linked immunosorbent assay (ELISA), and (4) fluoroimmunoassay. These assays are highly specific for hCG with antibodies directed against 2 or more isotopes on the intact hCG molecule. Time of detection is related to the sensitivity of the assay being used. Most current pregnancy tests have sensitivity to approximately 25 mIU/mL. Urine devices must be formulated to detect hyperglycosylated hCG, which is the key molecule in early pregnancy.

Characteristics of each hCG assay are listed as follows:

• Radioimmunoassay
  • Sensitivity – 5 mIU/mL
  • Time to complete – 4 hours
  • Postconception age when first positive – 10-18 days
  • Gestational age when first positive – 3-4 weeks
• Immunoradiometric assay (more sensitive)
  • Sensitivity – 150 mIU/mL
  • Time to complete – 30 minutes
  • Postconception age when first positive – 18-22 days
  • Gestational age when first positive – 4 weeks
• Immunoradiometric assay (less sensitive)
  • Sensitivity – 1500 mIU/mL
  • Time to complete – 2 minutes
  • Postconception age when first positive – 25-28 days
  • Gestational age when first positive – 5 weeks
• Enzyme-linked immunosorbent assay (more sensitive)
  • Sensitivity – 25 mIU/mL
  • Time to complete – 80 minutes
  • Postconception age when first positive – 14-17 days
  • Gestational age when first positive – 3.5 weeks
• Enzyme-linked immunosorbent assay (less sensitive)
  • Sensitivity – Less than 50 mIU/mL
  • Time to complete – 5-15 minutes
  • Postconception age when first positive – 18-22 days
  • Gestational age when first positive – 4 weeks
• Fluoroimmunoassay
  • Sensitivity – 1 mIU/mL
  • Time to complete – 2-3 hours
  • Postconception age when first positive – 14-17 days
  • Gestational age when first positive – 3.5 weeks

Dimeric hCG and both the alpha and beta subunits are produced in the pituitary gland of nonpregnant females and are released in association with LH. Although levels are much higher in postmenopausal women (110 pg/mL vs 10 pg/mL), they are still below the sensitivity of the most sensitive clinical assays (approximately 1 mIU/mL) used in pregnancy monitoring.

Serial hCG monitoring

hCG is detectable in the serum of approximately 5% of patients 8 days after conception and in more than 98% of patients by day 11. At 4 weeks’ gestation (18-22 d postconception), the dimer and beta subunit hCG doubling times are approximately 2.2 days (standard deviation ± 0.8 d) and fall to 3.5 days (standard deviation ± 1.2 d) by 9 weeks’ gestation. levels peak at 10-12 weeks’ gestation and then begin to decline rapidly until another, more gradual rise begins at 22 weeks’ gestation, which continues until term.

The initial rate of rise, measured by serial quantitative hCG testing, is important in the monitoring of early complicated pregnancies that have yet to be documented as viable and/or intrauterine. Failure to achieve the projected rate of rise may suggest an ectopic pregnancy or spontaneous abortion. hCG doubling times are subject to fluctuations of intact hCG during early pregnancy, so interpretation of these values must take into account the assays used and the clinical picture.

In one study, 200 women who received a diagnosis of ectopic pregnancy by serial hCG were evaluated. Of no surprise, the rise in hCG values in women with ectopic pregnancies was slower than those with viable pregnancies and the decline of hCG values in women with ectopic pregnancies was slower than for those with completed spontaneous abortion. However, 20.8% of women with ectopic pregnancies presented with a rise in hCG values similar to the minimal rise for women with a viable gestation, and 8% of women presented with a fall in hCG values similar to women with a completed spontaneous abortion.^{[9 ]}Several over studies such as this one demonstrate that a single pattern of hCG does not exist for abnormal early pregnancy, so caution must be taken in interpreting serial hCG values in the evaluation of early pregnancy.

On the other hand, an abnormally high level or accelerated rise can prompt investigation into the possibility of molar pregnancy, multiple gestations, or chromosomal abnormalities.

False positive hCG results

As with most tests, hCG test results can be either falsely negative or positive. The prevalence of false-positive serum hCG results is low, with estimates ranging from 0.01-2%. False-positive serum hCG results are usually due to interference by non-hCG substances or the detection of pituitary hCG. Some examples of non-hCG substances that can cause false-positive results include human LH, antianimal immunoglobulin antibodies, rheumatoid factor, heterophile antibodies, and binding proteins. Most false-positive results are characterized by serum levels that are generally less than 1000 mIU/mL and usually less than 150 mIU/mL. The median serum concentration for patients with false-positive results reported to the Food and Drug Administration (FDA) from 1985-2001 is 75 mIU/mL. Also, note that only 2 (0.74%) of 271 separate hCG determinations in undiluted sera in both the FDA database and the literature were greater than 1000 mIU/mL.

Several methods are available to help detect false-positive serum hCG results. The first step is to check urine hCG levels. The free beta-hCG subunit is further degraded in the kidney to a beta subunit core fragment that has less than half the molecular weight of the free beta subunit. Some of the substances that can cause serum false-positive results have much higher molecular weights that are not easily filtered through the renal glomeruli; therefore, they do not produce a positive urine hCG result. Other steps to verify or disprove a positive serum hCG result include retesting the same specimen, testing a new specimen, taking serial measurements to look for a rise, performing serial dilutions to look for linearity, and testing using a different method.

The five potential sources of positive hCG results outside of pregnancy are described below:^{[10 ]}

• Phantom hCG
  • Caused by heterophilic antibodies that bind the capture and labeled antibodies together without hCG being present
  • Antibody production results from exposure to animals used to produce antibodies used in assay
  • Rule out with sensitive urine assay, as these antibodies do not cross into urine
• Pituitary hCG
  • Stimulated by gonadotropin-releasing hormone; suppressed by gonadotropin-releasing hormone agonist and estrogen/progestin therapy
  • Can be detected in postmenopausal women due to increased GnRH secretion (Snyder et al propose that postmenopausal women should have a higher cutoff for a negative hCG of 14 IU/L^{[11 ]})
  • Diagnosed by administering oral contraceptive pills, which should suppress hCG levels
• Exogenous administration of hCG
  • Used by some centers to aid in weight loss by intramuscular or oral administration
  • Repeat hCG assays should be negative if exogenous administration is discontinued for at least 24 hours
• Trophoblastic neoplasm – Consists of pregnancy, gestational trophoblastic neoplasia (GTN), and placental site trophoblastic tumors (PSTTs)
  • Gestational trophoblastic neoplasia
    • Quiescent – Constant, low levels of hCG without evidence of primary or metastatic malignancy; premalignant state; resistant to chemotherapy and surgery; follow with frequent hCG levels and if found to be rising, consider active gestational trophoblastic neoplasia
    • Active – Invasive cytotrophoblasts produce hyperglycosylated hCG found only in early pregnancy and invasive gestational trophoblastic neoplasia; thus, hyperglycosylated hCG or invasive trophoblastic antigen can be measured to rule in active disease
  • Placental site trophoblastic tumors – Diagnosed with low-level hCG in combination with intramyometrial lesions on imaging
• Nontrophoblastic neoplasm – Can be secreted by different cancers, (eg, testicular, bladder, uterine, lung, liver, pancreas, stomach)

False-negative hCG results
False-negative hCG test results usually involve urine and are due to the qualitative nature of the test. Reasons for a negative test result may include an hCG concentration below the sensitivity threshold of the specific test being used, a miscalculation in the onset of the missed menses, or delayed menses from early pregnancy loss. Delayed ovulation or delayed implantation are other reasons for low hCG concentrations at the time of testing, which yields a false-negative result.

At least 1 case report in the literature is notable when considering false-negative urine hCG test results. A 37-year-old woman presented to an emergency department in hypovolemic shock 13 weeks after her last menstrual period. She had a dilation and curettage for an intrauterine pregnancy 8 weeks before presentation. Two different samples yielded negative qualitative urine pregnancy test results. The third urine hCG test result was weakly positive, and, at that time, her serum hCG level was 22,430 mIU/mL. She was diagnosed with an interstitial ectopic pregnancy and underwent surgery, during which approximately 2000 mL of free blood was found in her peritoneal cavity. Interstitial pregnancies make up less than 3% of tubal pregnancies, but they can be present in conjunction with negative urine pregnancy test results.

Progesterone

Measuring serum progesterone may be a useful adjunct for evaluating abnormal early pregnancy. Serum progesterone is a reflection of progesterone production by the corpus luteum, which is stimulated by a viable pregnancy. Measurement of serum progesterone is inexpensive and can reliably predict pregnancy prognosis. Currently, radioimmunoassays and fluoroimmunoassays are available that can be completed in 3-4 hours. A dipstick ELISA that can determine a serum progesterone level of less than 15 ng/mL is also on the market. ELISA is helpful as a screening tool for at-risk populations because progesterone levels of greater than 15 ng/mL make ectopic pregnancy unlikely.^{[12 ]}

Viable intrauterine pregnancy can be diagnosed with 97.5% sensitivity if the serum progesterone levels are greater than 25 ng/mL (>79.5 nmol/L). Conversely, finding serum progesterone levels of less than 5 ng/mL (<15.9 nmol/L) can aid in the diagnosis of a nonviable pregnancy with 100% sensitivity. Finding serum progesterone levels of less than 5 ng/mL allows diagnostic evaluation of the uterus in a stable patient, even if an ectopic pregnancy cannot be distinguished from a spontaneous intrauterine abortion beforehand. In the event that the serum progesterone level is 5-25 ng/mL, further testing using US, additional hormonal assays, or serial examinations is warranted to establish the viability of the pregnancy. Algorithms using serum progesterone are available for the evaluation and management of patients with abnormal early pregnancy.

Early pregnancy factor

The early pregnancy factor (EPF) assay may be useful in the future. EPF is a poorly defined immunosuppressive protein that has been isolated in maternal serum shortly after conception and is the earliest available marker to indicate fertilization. It is detectable in the serum 36-48 hours after fertilization, peaks early in the first trimester, and is almost undetectable at term. EPF also appears within 48 hours of successful in vitro fertilization embryo transfers. EPF cannot be detected 24 hours after delivery or at the termination of an ectopic or intrauterine pregnancy. EPF is also undetectable in many ectopic pregnancies and spontaneous abortions, indicating that an inability to identify EPF during pregnancy heralds a poor prognosis.

EPF has limited clinical applications at this time because the molecule is difficult to isolate. Detection of EPF currently relies on a complex and unwieldy assay termed the rosette inhibition test. EPF may play a more prominent role in the future as the diagnosis of conception prior to implantation elucidates new strategies for contraception, highly accurate dating, and advanced genetic studies.

Home pregnancy tests

At least 25 different home pregnancy tests are currently marketed in the United States. These tests now use the modern immunometric assay. Most of these tests claim “99% accuracy” or some other similar statements on the packaging or product insert. Most of the tests also now advertise that they can be used “as early as the day of the missed menstrual period.” Several home pregnancy tests actually instruct that they may be used 3-4 days before the time of the missed period.

The accuracy claims are derived from an FDA guideline that refers to the test’s ability to identify approximately 100 nonpregnant urine samples supplemented with intact hCG from a similar number of urine samples not supplemented with hCG. The broad 99%-accuracy statement is made for tests with sensitivities for hCG concentrations ranging from 25 mIU/mL (fairly sensitive) to tests with sensitivities of 100 mIU/mL (less sensitive). The 99%-accuracy statement in reference to the FDA guideline is misleading in that it has no bearing on the ability of the home pregnancy test to detect early pregnancy.

Home pregnancy tests are most commonly used in the week after the missed menstrual period (fourth completed gestational week). Urine hCG values are extremely variable at this time and can range from 12 mIU/mL to greater than 2500 mIU/mL. This variability continues into the fifth week, when values have been shown to range from 13 mIU/mL to greater than 6000 mIU/mL. Both weeks have a percentage of urine hCG values that is below the sensitivities of detection for common home pregnancy tests (range 25-100 mIU/mL).

Several studies have tested different home pregnancy tests for sensitivity and accuracy claims.

• One study tested 18 different home pregnancy tests at 5 different hCG concentrations (0, 12.5, 25, 50, and 100 mIU/mL). No difference in sensitivity was detected between tests that had longer reading times (usually approximately 5 min) compared with those with shorter reading times (1 min). Clearly positive results were only found in 44% of the brands when tested at the highest hCG concentration (100 mIU/mL). The sensitivity was improved to 83% of brands tested at 100 mIU/mL when a faintly discernible line was also considered a positive result. Test sensitivity was also increased when reading times were extended to 10 minutes. Overall, 100% accuracy was only achieved in all 18 brands tested when the highest hCG concentration (100 mIU/ml) was used, an extended reading time was used, and faintly discernible results were included as positive.
• Another study evaluated 7 home pregnancy tests and found that despite the claims, the detection of pregnancy on the day of missed period varied from 16-95%, and some devices were faulty (defined as devices failing to yield a band in the control window).
• Other studies have found that home pregnancy tests with digital reading may offer significant benefits over traditional nondigital tests.

The limitations of these tests must be understood so that pregnancy detection is not significantly delayed. Early pregnancy detection allows for the commencement of prenatal care, potential medication changes, lifestyle changes to promote a healthy pregnancy (appropriate diet; avoidance of alcohol, tobacco, and certain medications), or early pregnancy termination if desired.

Serum hCG values in infertility

Serum hCG values for the diagnosis of early pregnancy in patients undergoing in-vitro fertilization–embryo transfer (IVF-ET) have been studied.^{[13 ]} Serum hCG levels 14 days after embryo transfer correlate with pregnancy outcome. In a study of 111 patients with positive quantitative hCG levels 14 days after embryo transfer, the following pregnancy outcomes were observed:

• Levels <300 mIU/mL, ongoing pregnancy rate was 9%
• Levels 300-600 mIU/mL, ongoing pregnancy rate was 50%
• Levels >600 mIU/mL, multiple pregnancy rate was 100%

Therefore, in this particular population, quantitative assay results can be used to guide counseling and further evaluation.

Ultrasonography

With the advent of transvaginal ultrasonography (TVUS), the diagnosis of pregnancy can be made even earlier than is possible with transabdominal ultrasonography (TAUS). US has long been used in uncomplicated pregnancies for dating and as a screening examination for fetal anomalies. US is not typically used to diagnose pregnancy unless the patient presents with vaginal bleeding or abdominal pain early in gestation or is a high-risk obstetric patient. TVUS is the most accurate means of confirming intrauterine pregnancy and gestational age during the early first trimester.

TVUS has several advantages over TAUS during early pregnancy. TVUS can help detect signs of intrauterine pregnancy approximately 1 week earlier than TAUS. Patients are not required to have a full bladder and are not required to endure uncomfortable pressure on the abdominal wall from the external probe. TVUS is also better for patients who are obese or those who guard during TAUS. One disadvantage is that some patients are anxious about the transvaginal probe and may object to its insertion.

Vaginal probes are typically of higher frequency (5-8 MHz) than abdominal probes (3-5 MHz). The higher frequency allows for better resolution of the image but less penetration of the signal. Also, practice is necessary for familiarization with the orientation on the US monitor when performing TVUS.

The earliest structure identified is the (GS). The GS can be seen on TVUS images by 4-5 weeks’ gestation and grows at a rate of 1 mm/d in early gestation. By 5.5-6 weeks’ gestation, a double-decidual sign can be seen, which is the GS surrounded by the thickened decidua. The presence of an early GS can be confused with a small collection of fluid or blood or the pseudo GS of an ectopic pregnancy. Because of this, the diagnosis of intrauterine pregnancy should not be made on the basis of visualization of the GS alone.

The yolk sac can be recognized by 4-5 weeks’ gestation and is seen until approximately 10 weeks’ gestation. The yolk sac is a small sphere with a hypoechoic center and is located within the GS (see Media file 2).

Pregnancy diagnosis. The arrow is pointing to the yolk sac as seen within the gestational sac (GS). The yolk sac is usually identified before the GS is larger than 10 mm. Likewise, if the yolk sac is larger than 7 mm without signs of a developing fetal pole, the chance of an abnormal pregnancy is increased.

Observing a GS that is larger 10 mm without a yolk sac is rare, and if this is observed, it most likely represents an abnormal pregnancy (see Media file 3).

Pregnancy diagnosis. This is a gestational sac (GS) that measures approximately 2 X 3 cm, without evidence of a yolk sac. When the GS is larger than 10 mm and no yolk sac is identified, an abnormal pregnancy is likely. This particular situation is referred to as a blighted ovum or an anembryonic pregnancy.

Likewise, a yolk sac larger than 7 mm without evidence of a developing fetal pole suggests a nonviable pregnancy. The diagnosis of intrauterine pregnancy can be made once the yolk sac is present, which also excludes ectopic pregnancy, except in the rare instance of heterotopic pregnancy. A heterotopic pregnancy, an intrauterine pregnancy, and an ectopic pregnancy during the same gestation was once thought to be extremely rare but has now been shown to be present in as many as 1 in 3000 pregnancies.The fetal or embryonic pole is first seen on TVUS images at approximately 5-6 weeks’ gestation. It should always be seen by TVUS when the GS is larger than 18 mm or by TAUS when the GS is larger than 2.5 cm. The fetal pole is a linear hyperechoic structure that grows at approximately 1 mm/d.

Cardiac motion can sometimes be identified in a 2- to 3-mm embryo but is almost always present when the embryo grows to 5 mm or longer. At 5-6 weeks’ gestation, the fetal heart rate ranges from 100-115 beats per minute. The heart rate will steadily increase to a mean of 140 beats per minute by 9 weeks’ gestational age.

Ultrasonography and Human Chorionic Gonadotropin

Ultrasonography becomes even more useful for the diagnosis of early pregnancy and for identifying abnormal pregnancies when it is used in conjunction with assessing quantitative hCG levels. The identification of gestational structures by ultrasonography correlates with specific levels of hCG, termed discriminatory levels. A discriminatory level is the level of hCG at which the structure in question should always be identified.

The GS has been identified by TVUS with hCG levels as low as 300 mIU/mL, and most experienced TVUS operators should visualize the GS when levels are approximately 1000 mIU/mL. The discriminatory level for the GS is approximately 3600 mIU/mL, and if it is not seen at this point, other pathology must be excluded. Many use a more conservative discriminatory level for the GS, at 2000 mIU/mL by TVUS and 3600 mIU/ml by TAUS, and will begin to rule out pathology if the GS is not seen. The adnexa should be scanned for an ectopic pregnancy, and sonograms and hCG levels should be followed until a diagnosis is made. Furthermore, one study showed that all viable intrauterine pregnancies had a GS identified by TAUS for hCG levels of greater than 6500 mIU/mL.

The usefulness of TVUS evaluation when the hCG is less than 1000 mIU/mL has been debated. One study showed that valuable information can still be garnered in women presenting for emergent TVUS with an hCG level of less than 1000 mIU/mL. In this study, approximately 13% of the abnormal intrauterine pregnancies and 39% of the ectopic pregnancies were identified by TVUS. Ultrasonography should not be delayed purely on the basis of hCG levels.^{[14 ]}

Other structures are also anticipated in correlation with specific hCG levels. The yolk sac (see Media file 2) is commonly observed with an hCG level of approximately 2500 mIU/mL, although it may not be identified until levels are much higher. The embryonic pole usually becomes evident at a level of approximately 5000 mIU/mL, and the fetal heartbeat can be seen in the vast majority of normal gestations when the hCG level reaches 10,000 mIU/mL.

Pregnancy diagnosis. The arrow is pointing to the yolk sac as seen within the gestational sac (GS). The yolk sac is usually identified before the GS is larger than 10 mm. Likewise, if the yolk sac is larger than 7 mm without signs of a developing fetal pole, the chance of an abnormal pregnancy is increased.

Conclusion

The diagnosis of pregnancy can be made by several methods. Normocyclic women who present with amenorrhea and typical history and physical examination findings have the classic presentation and can be diagnosed with a viable intrauterine pregnancy if they progress appropriately. Currently, most women are diagnosed with pregnancy after a missed menstrual cycle and a positive urine or serum hCG finding. The pregnancy is diagnosed as viable with serial examinations and normal pregnancy development, a normal result after dating ultrasonography, or a positive finding of fetal heart tones using Doppler studies.

Women who are considered high-risk or those who present with abdominal pain or vaginal bleeding in early gestation are more likely to be evaluated with ultrasonography and additional hormonal assays. A number of different combinations can aid in the diagnosis of a viable intrauterine pregnancy. The physician must ascertain what is most appropriate at the time of patient presentation.

For excellent patient education resources, visit eMedicine’s Pregnancy and Reproduction Center. Also, see eMedicine’s patient education articles Home Pregnancy Test, Ectopic Pregnancy, Birth Control Overview, and Birth Control FAQs.

Multimedia

Media file 1: Pregnancy diagnosis. Sonogram showing a complex mass in the adnexa (labeled EP). It was found to be an ectopic pregnancy at the time of surgery.

Media file 2: Pregnancy diagnosis. The arrow is pointing to the yolk sac as seen within the gestational sac (GS). The yolk sac is usually identified before the GS is larger than 10 mm. Likewise, if the yolk sac is larger than 7 mm without signs of a developing fetal pole, the chance of an abnormal pregnancy is increased.

Media file 3: Pregnancy diagnosis. This is a gestational sac (GS) that measures approximately 2 X 3 cm, without evidence of a yolk sac. When the GS is larger than 10 mm and no yolk sac is identified, an abnormal pregnancy is likely. This particular situation is referred to as a blighted ovum or an anembryonic pregnancy.

References

1. Paspulati RM, Bhatt S, Nour SG. Sonographic evaluation of first-trimester bleeding. Radiol Clin North Am. Mar 2004;42(2):297-314. [Medline].
2. Dart RG. Role of pelvic ultrasonography in evaluation of symptomatic first-trimester pregnancy. Ann Emerg Med. Mar 1999;33(3):310-20. [Medline].
3. Seeber BE, Barnhart KT. Suspected ectopic pregnancy. Obstet Gynecol. February 2006;107(2):399-413. [Medline].
4. Female Sterilization: Risk of Ectopic Pregnancy After Tubal Sterilization Fact Sheet. Atlanta, GA: Centers for Disease Control and Prevention; 2008. [Full Text].
5. Speroff L, Fritz MA. Clinical Gynecologic Endocrinology and Infertility. 7^th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.
6. Berek JS, Adashi EY, Hillard PA. Novak’s Gynecology. 14th. Baltimore, MD: Lippincott Williams & Wilkins; 2006.
7. Paul M, Schaff E, Nichols M. The roles of clinical assessment, human chorionic gonadotropin assays, and ultrasonography in medical abortion practice. Am J Obstet Gynecol. Aug 2000;183(2 Suppl):S34-43. [Medline].
8. McChesney R, Wilcox AJ, O’Connor JF, et al. Intact HCG, free HCG beta subunit and HCG beta core fragment: longitudinal patterns in urine during early pregnancy. Hum Reprod. Apr 2005;20(4):928-35. [Medline].
9. Silva C, Sammel MD, Zhou L, et al. Human chorionic gonadotropin profile for women with ectopic pregnancy. Obstet Gynecol. Mar 2006;107(3):605-10. [Medline].
10. Olson TG, Barnes AA, King JK. Elevated hCG Outside of Pregnancy – Diagnostic Considerations and Laboratory Evaluation. Obstet Gynecol Survey. Oct 2007;62(10):669-74. [Medline].
11. Snyder JA, Haymond S, Parvin CA, et al. Diagnostic considerations in the measurement of human chorionic gonadotropin in aging women. Clin Chem. Oct 2005;51(10):1830-5. [Medline].
12. Davies S, Byrn F, Cole LA. Human chorionic gonadotropin testing for early pregnancy viability and complications. Clin Lab Med. Jun 2003;23(2):257-64, vii. [Medline].
13. Guth B, Hudelson J, Higbie J, et al. Predictive value of hCG level 14 days after embryo transfer. J Assist Reprod Genet. Jan 1995;12(1):13-4. [Medline].
14. Dart RG, Kaplan B, Cox C. Transvaginal ultrasound in patients with low beta-human chorionic gonadotropin values: how often is the study diagnostic?. Ann Emerg Med. Aug 1997;30(2):135-40. [Medline].
15. Ankum WM, Van der Veen F, Hamerlynck JV, et al. Suspected ectopic pregnancy. What to do when human chorionic gonadotropin levels are below the discriminatory zone. J Reprod Med. Jul 1995;40(7):525-8. [Medline].
16. Barnhart K, Esposito M, Coutifaris C. An update on the medical treatment of ectopic pregnancy. Obstet Gynecol Clin North Am. Sep 2000;27(3):653-67, viii. [Medline].
17. Barnhart KT, Sammel MD, Rinaudo PF, et al. Symptomatic patients with an early viable intrauterine pregnancy: HCG curves redefined. Obstet Gynecol. Jul 2004;104(1):50-5. [Medline].
18. Barnhart KT, Simhan H, Kamelle SA. Diagnostic accuracy of ultrasound above and below the beta-hCG discriminatory zone. Obstet Gynecol. Oct 1999;94(4):583-7. [Medline].
19. Braunstein GD. False-positive serum human chorionic gonadotropin results: causes, characteristics, and recognition. Am J Obstet Gynecol. Jul 2002;187(1):217-24. [Medline].
20. Bree RL, Edwards M, Bohm-Velez M, et al. Transvaginal sonography in the evaluation of normal early pregnancy: correlation with HCG level. AJR Am J Roentgenol. Jul 1989;153(1):75-9. [Medline].
21. Cole LA, Khanlian SA, Sutton JM, et al. Accuracy of home pregnancy tests at the time of missed menses. Am J Obstet Gynecol. Jan 2004;190(1):100-5. [Medline].
22. Cole LA, Sutton-Riley JM, Khanlian SA, et al. Sensitivity of over-the-counter pregnancy tests: comparison of utility and marketing messages. J Am Pharm Assoc (2003). Sep-Oct 2005;45(5):608-15. [Medline].
23. Goldstein SR, Snyder JR, Watson C, et al. Very early pregnancy detection with endovaginal ultrasound. Obstet Gynecol. Aug 1988;72(2):200-4. [Medline].
24. Kim SW, Ha YR, Chung SP, et al. Ruptured interstitial pregnancy presenting with negative beta-hCG and hypovolemic shock. Am J Emerg Med. Oct 2003;21(6):511. [Medline].
25. Klee GG. Interferences in hormone immunoassays. Clinics in Laboratory Medicine. Mar 2004;24, Number 1.
26. Moore KL, Persaud TVN. The Developing Human: Clinically Oriented Embryology. 5^th ed. Philadelphia, Pa: WB Saunders; 1993:14-69.
27. Nyberg DA, Laing FC, Filly RA. Threatened abortion: sonographic distinction of normal and abnormal gestation sacs. Radiology. Feb 1986;158(2):397-400. [Medline].
28. Nyberg DA, Mack LA, Harvey D, et al. Value of the yolk sac in evaluating early pregnancies. J Ultrasound Med. Mar 1988;7(3):129-35. [Medline].
29. Romero R, Kadar N, Copel JA, et al. The value of serial human chorionic gonadotropin testing as a diagnostic tool in ectopic pregnancy. Am J Obstet Gynecol. Aug 1986;155(2):392-4. [Medline].
30. Timor-Tritsch IE, Yeh MN, Peisner DB, et al. The use of transvaginal ultrasonography in the diagnosis of ectopic pregnancy. Am J Obstet Gynecol. Jul 1989;161(1):157-61. [Medline].
31. Tomlinson C, Marshall J, Ellis JE. Comparison of accuracy and certainty of results of six home pregnancy tests available over-the-counter. Curr Med Res Opin. Jun 2008;24(6):1645-9. [Medline].

Keywords

conception, parturition, pregnancy, gestation, pregnancy signs, pregnancy symptoms, Hegar sign, Chadwick sign, ectopic pregnancy, abnormal pregnancy, spontaneous abortion, positive pregnancy test, negative pregnancy test, pregnancy test, home pregnancy test, false-positive hCG, false-negative hCG

Contributor Information and Disclosures

Author

Andrea D Shields, MD, Director, Antenatal Counseling and Diagnostic Center, Department of Maternal-Fetal Medicine, Wilford Hall Medical Center; Associate Faculty, Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences
Andrea D Shields, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Obstetricians and Gynecologists, American Institute of Ultrasound in Medicine, American Medical Association, Association of Women Surgeons, and Society for Maternal-Fetal Medicine
Disclosure: Nothing to disclose.

Medical Editor

Bruce A Meyer, MD, MBA, Vice President for Medical Affairs, Associate Dean for Health System Affairs and Director of the Faculty Practice Plan, Professor, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical School
Bruce A Meyer, MD, MBA is a member of the following medical societies: American College of Obstetricians and Gynecologists, American College of Physician Executives, American Institute of Ultrasound in Medicine, Association of Professors of Gynecology and Obstetrics, Massachusetts Medical Society, Medical Group Management Association, and Society for Maternal-Fetal Medicine
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

CME Editor

Frederick B Gaupp, MD, Consulting Staff, Department of Family Practice, Hancock Medical Center
Frederick B Gaupp, MD is a member of the following medical societies: American Academy of Family Physicians
Disclosure: Nothing to disclose.

Chief Editor

David Chelmow, MD, Professor of Obstetrics and Gynecology, Tufts University School of Medicine; Program Director, Tufts University Affiliated Hospitals OB/GYN Residency Program; Chair, Tufts University Health Sciences Campus Institutional Review Board; Vice Chair for Research and Education, Dept of OB/GYN, Tufts Medical Center
David Chelmow, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists, American Medical Association, Association of Professors of Gynecology and Obstetrics, Massachusetts Medical Society, Phi Beta Kappa, Sigma Xi, Society for Gynecologic Investigation, and Society for Medical Decision Making
Disclosure: Nothing to disclose.