Hypertensive disorders of pregnancy

Hypertensive disorders of pregnancy include:

Pregnancy-Induced Hypertension
Essential Chronic Hypertension
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Preeclampsia
Eclampsia
Other causes

Renal artery stenosis

Coarctation of the aorta

Pheochromocytoma

Cushing’s syndrome

Primary aldosteronism (Conn’s syndrome)

Related conditions: Pregnancy-Induced Hypertension – PIH; Gestational hypertension without proteinuria; Preeclampsia – Toxemia; Gestational hypertension with proteinuria

1. Description of the problem

What every physician needs to know

Hypertension in pregnancy is defined as a systolic blood pressure (SBP) greater than or equal to 140 mm Hg or a diastolic blood pressure (DBP) greater than or equal to 90 mm Hg or an increase of at least 30 mm Hg in the SBP and an increase of at least 15 mm Hg in the DBP.

Gestational hypertension occurs without proteinuria and usually manifests as diastolic hypertension that resolves 1 to 2 months after delivery. Recurrent gestational hypertension is frequent with subsequent pregnancies, as is the development of chronic hypertension.

Essential hypertension is the presence of underlying prepartum hypertension, whether diagnosed or undiagnosed, and may be unmasked at any time during the pregnancy.

Preeclampsia is a multisystem disease that usually occurs most commonly after the 20th week of pregnancy but can also present up to 1 week after delivery with no prior evidence of intrapartum preeclampsia. Patients with chronic preexisting hypertension may develop superimposed preeclampsia with the onset of proteinuria after the 20th gestational week.

Eclampsia is defined as severe preeclampsia with generalized tonic-clonic seizures.

Clinical features

Mild preeclampsia is defined as SBP greater than or equal to 140 mm Hg or DBP greater than or equal to 90 mm Hg and proteinuria greater than or equal to 0.3 g in 24 hours without evidence of end-organ damage.

Preeclampsia is classified as severe if at least one of the following is present:

Resting SBP greater than or equal to 160 mm Hg or DBP greater than or equal to 110 mm Hg on two readings at least 6 hours apart.
Proteinuria greater than or equal to 5 g in 24 hours or greater than 3+ on two random samples collected at least 4 hours apart.
Oliguria with urine output less than 30 ml per hour for 3 consecutive hours or less than 500 mLs in 24 hours.
Evidence of end-organ damage: pulmonary edema, impaired liver function, left ventricular hypertrophy, right upper quadrant pain, headache or other cerebral symptoms, visual changes/retinopathy, and thrombocytopenia.

Eclampsia usually presents with generalized tonic-clonic seizures but may also present less commonly with intracranial hemorrhage or stroke. Posterior reversible leukoencephalopathy syndrome (PRES) may also be seen with eclampsia (Figure 1).

PRES on MRI scan showing vasogenic edema in the parieto-occipital regions of the brain.

Key management points

For all types of hypertensive disorders of pregnancy, avoid aggressive antihypertensive treatment to normalize BP. Gradual reductions in BP rather than abrupt precipitous drops in the BP that may induce ischemia, particularly of the fetal utero-placental vascular circulation.

Initial treatment guidelines for severe preeclampsia:

Intravenous magnesium administration for the prevention of seizures
BP control
Maternal and fetal monitoring

2. Emergency Management

Magnesium sulfate for seizure prevention and treatment

Magnesium therapy is initiated if evidence of severe preeclampsia or signs of impending seizure are present, such as visual blurring, scotomata or hyperreflexia. Magnesium can be administered either intramuscularly or intravenously. Most commonly, an intravenous loading dose of 4-6 grams in 200-250 mL of normal saline is given over 10-15 minutes, followed by an infusion of 1-2 grams per hour. Magnesium therapy is continued for 24 hours postpartum because of the risk of postpartum seizures in a small number of patients.

Hospitalization and antihypertensive therapy for severe acute hypertension

Hospitalization and immediate antihypertensive therapy is required for severe acute hypertension to avoid or halt the progression of further end-organ damage. The immediate goal is to gradually decrease the DBP to just below 100 mm Hg or to lower the mean arterial pressure (MAP) in increments of 10-15%. ICU admission may be required for severe preeclampsia because of the need for intravenous BP therapy, and monitoring and treatment of end-organ damage.

Monitoring of magnesium serum levels

A magnesium serum level should be checked 2-4 hours after the initial loading dose with optimal values at 2-3.5 mmol/L (4-7 mEq/L). Toxic magnesium levels in excess of the therapeutic range are suggested if there is evidence of maternal respiratory depression, severe hyporeflexia of the patellar reflexes and a change in the level of consciousness. One gram of calcium chloride (10 mL of a 10% solution) is the antidote for acute magnesium toxicity.

Urine output needs to be monitored closely since magnesium is renally excreted. The infusion rate should be lowered or withheld if the urine output significantly decreases or the serum creatinine level increases.

Acute antihypertensive therapy

The goal is to prevent maternal complications such as stroke, intracranial hemorrhage, and acute heart failure. Avoid aggressive therapy inducing “relative” hypotension and ischemia. Bolus intravenous antihypertensive therapy is required for severe acute hypertension. Patients with severe BP elevations may require ICU admission for intravenous infusions of antihypertensive medications.

3. Diagnosis

Severe preeclampsia

A diagnosis of severe preeclampsia is based most commonly on clinical critieria that include a SBP greater than or equal to 160 mm Hg or DBP greater than or equal to 110 mm Hg, oliguria, and evidence of end-organ damage after 20 weeks gestation and laboratory evidence of proteinuria. SBPs greater than or equal to 200 mm Hg should prompt the clinician to consider other underlying hypertensive disorders, such as preeclampsia superimposed on chronic hypertension.

The only single reliable laboratory test that determines a diagnosis of preeclampsia is proteinuria with the following results:

greater than or equal to 5 grams in a 24-hour collection.
greater than 3+ by 2 random urine samples.
Urine protein-to-creatinie ratio greater than or equal to 0.2.

Other than proteinuria, there is no single reliable laboratory test that determines the diagnosis. Suggestive, but nondiagnostic, abnormal laboratory tests include the following

Elevated uric acid levels.
Mild elevation of alanine aminotransferase (ALT) levels up to 60 U/L.
Mild elevations of bilirubin and fibrinogen serum levels.
Mild elevated creatinine levels depending on duration and intensity of the oliguria.
Variable thrombocytopenia.
Increased blood urea nitrogen (BUN), hemoglobin, and hemocrit values suggesting hemoconcentration.
Rarely consumptive coagulopathy (DIC) may manifest with elevated prothrombin (PT) and partial thromboplastin times (PTT).

Preeclampsia must be distinguished by clinical criteria from other forms of hypertension in pregnancy, including essential hypertension and pregnancy-induced hypertension. Preeclampsia should also be differentiated by other forms of systemic nonpregnancy related hypertensive conditions, including coarctation of the aorta, renal artery stenosis, pheochromocytoma, primary aldosteronism and Cushing’s syndrome.

Eclampsia

Clinical generalized tonic-clonic seizures.
May see evidence of PRES on CT or MRI brain scanning or cerebral angiography.

4. Specific Treatment

For mild to moderate preeclampsia or mild hypertension associated with pregnancy-related hypertensive disorders

Oral methyldopa, 250 mg orally 2 to 3 times daily to a maximum daily dose of 4 grams
Oral labetalol, 100 mg orally twice daily to a maximum of 400 mg twice daily

For severe preeclampsia or other forms of severe pregnancy-related hypertensive disorders

Intravenous bolus therapy of either hydralazine and/or labetalolol
Continuous intravenous infusions of labetalol, nicardipine, nitroglycerine, or nitroprusside

Intravenous bolus therapy

Hydralazine: caution should be exercised because this medication can cause precipitous drops in the BP because of the hypovolemic state of preeclampsia. Give patient boluses of 2.5 to 10 mg every 15 to 20 minutes.

Labetalol: 20 mg initial bolus and repeat boluses of 40 mg and then 80 mg boluses. Subsequent boluses should be titrated every 10 to 15 minutes up to a maximum of 300 mg.

Continuous intravenous infusions

Labetalol infusion at 1 mg/kg.
Nicardipine infusion at 5 to 10 mg/hr.
Nitroprusside (nipride) infusion at 0.2 micrograms/kg/min increasing every 5 minutes to a maximum of 4 micrograms/kg/min. Limit to only a few hours of therapy because of the theoretical concerns for fetal cyanide toxicity.
Nitroglycerin infusion at 5 micrograms/min and doubled every 5 minutes to a maximum of 100 micrograms/min.

Expeditious delivery of the fetus

Should be considered if gestational age is 32 weeks or more.
Should be performed if there is signficant evidence of severe end-organ disease despite appropriate antihypertensive and support therapy.
Requires steroid therapy for fetal lung maturation prior to delivery.

Supportive measures in preeclampsia include careful monitoring of both the mother and the fetus to prevent untoward complications. The risk of developing further end-organ damage in patients with severe preeclampsia mandates that these patients are closely followed. The risks of developing eclamptic seizures, pulmonary edema, or renal and/or hepatic alterations, including hepatic capsular rupture, are not insignificant.

Early delivery of the fetus is warranted once the mother is stabilized and fetal lung maturity has been ascertained. There are occasions when early delivery needs to be initiated if worsening of the preclampsia is continuing to compromising maternal well-being despite adequate medical therapy.

5. Disease monitoring, follow-up and disposition

Continued postpartum followup for BP monitoring should occur in all patients because of the risk of continued chronic hypertension, with careful monitoring of patients who presented with hypertension during a prior pregnancy because of the risk of recurrence.

Pathophysiology

The exact pathogenesis of preeclampsia is unknown but is believed to be related to endothelial cell injury and dysfunction of different maternal organs systems as a result of toxic substances released from a poorly perfused placenta. Genetic and immunologic factors have also been implicated in the pathogenesis of preeclampsia.

Preeclampsia induces generalized vasospasm with specific predilection for the cerebral and renal vasculature. A decrease in renin and aldosterone secretion, decreased renal prostaglandin synthesis, and increased systemic blood pressures may play a role in the pathogenesus of preeclampsia.

Although sodium retention occurs in preeclamspia, plasma volume is diminished in these patients and care should be exercised in resuscitating these patients with aggressive fluids since cardiac output and filling pressures are normal to high in preeclamptic patients.

Epidemiology

Prexisting hypertension complicates about 3% of all pregnancies and about 6% of pregnant women are diagnosed with gestational hypertension. The incidence of preeclampsia in the United States is 5-8% and in 3-14% of all pregnancies worldwide. The highest frequency occurs in primigravidas and the second highest group is among older multiparous women who have higher morbidity and mortality rates associated with the preeclamptic state. Incidence is higher in those with preexisting hypertension or renal vascular disease.

Mild preeclampsia occurs in 75% of cases in the United States and is severe in the remaining 25%. Risk factors include:

Preeclampsia with prior pregnancy.
Multifetal pregnancy.
Chronic hypertension.
Pregestational diabetes mellitus.
Obesity.
Maternal age 35 years or older.
African-American race.
Antiphospholipid syndrome.
Vascular and connective tissue diseases.

Prognosis

There is an increased recurrence rate of preeclampsia of up to 65% in subsequent pregnancies, particularly in women who have had early onset and severe preeclampsia. The incidence is significantly lower (5-7%) in women who had only mild preeclampsia with their first pregnancy.

Studies have indicated that preeclampsia is predictive of future cardiovascular and cerebrovascular disease, including hypertension, ischemic heart disease, stroke and venous thromboembolism. These events occur more frequently in women who had early onset and severe preclampsia, gestational hypertension, or preclampsia with onset as a multipara.

What's the evidence?

“ACOG Committee on Practice Bulletins – Obstetrics. ACOG practice bulletin: diagnosis and management of preeclampsia and eclampsia. Number 33, January 2002”. Obstet Gynecol. vol. 99. 2001. pp. 159-67. (This document from the American Congress of Obstetricians and Gynecologists presents relevant clinical and scientific advances and guidelines for the diagnosis and management of preeclampsia and eclampsia as well as reviewing the complications associated with these unique syndromes.)

(The latest NICE clinical guidelines from the Royal College of Obstetricians and Gynaecologists for the complete management of all hypertensive disorders in pregnancy are presented in this paper, including detailed algorithms and pharmaceutical management.)

“Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy”. Am J Obstet Gynecol. vol. 183. 2000. pp. S1-22. (This report focuses on the classification, pathophysiologic features and management of the hypertensive disorders associated with pregnancy. Pharmacologic therapy includes a discussion of specific agents to be used for the treatment of these disorders.)

Redman, CW, Sargent, IL. “Latest advances in understanding preeclampsia”. Science. vol. 308. 2005. pp. 1592-4. (This paper presents some new and interesting findings in understanding the complex immunologic pathogenesis of preeclampsia and the role of circulating factors from the placenta that contribute to this clinical syndrome.)

Wagner, LK. “Diagnosis and management of preeclampsia”. Am Fam Physician. vol. 70. 2004. pp. 2317-24. (This paper is a review of the various diagnostic and treatment modalities in preeclampsia. Early access to prenatal care, early detection of this disorder, careful monitoring and appropriate treatment are crucial to prevent preeclampsia-related maternal and fetal deaths.)

Sibai, BM. “Chronic hypertension in pregnancy”. Obstet Gynecol. vol. 100. 2002. pp. 369-77. (This paper discusses pregnant women with underlying chronic hypertension who are at significant risk for maternal and fetal complications during the pregancy and after delivery as well. The author reviews the complications associated with hypertension and the specific intrapartum management of these women based on whether they are classified as "high risk" or "low risk.")

McDonald, SD, Malinowski, A, Zhou, Q. “Cardiovascular sequelae of preeclampsia/eclampsia: a systematic review and meta-analyses”. Am Heart J. vol. 156. 2008. pp. 918-30. (The purpose of this review was to determine if women with a history of preeclampsia/eclampsia are at increased risk of long-term cardiovascular complications. In reviewing 5 case-control studies and 10 cohort studies, the authors found that women with a history of preeclampsia/eclampsia have double the risk of early cardiac, cerebrovascular and peripheral arterial disease, and cardiovascular mortality.)

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