Hypertension Complicating Pregnancy
Hypertension in pregnancy requires treatment that balances optimal outcomes for both mother and fetus.
Hypertension during pregnancy is the second leading cause of maternal death, accounting for 15% of pregnancy-associated mortality in the United States. Approximately 8% of pregnancies are complicated by hypertension. Maternal complications of untreated hypertension during pregnancy include hepatic failure, acute renal failure, cerebral hemorrhage, abruptio placentae, and disseminated intravascular coagulation.Neonatal manifestations include prematurity, intrauterine growth retardation, spontaneous abortion, and stillbirth. Maternal mortality is less than 1%, whereas fetal mortality is approximately 9%. With the development of superimposed preeclampsia, mortality approaches 16% — 41%.
Pharmacological treatment of moderate to severe hypertension in pregnancy is necessary and has been proven to decrease both maternal and fetal complications. In mild hypertension, however, pharmacological treatment is controversial. There is also controversy regarding when to initiate pharmacotherapy,which agents to choose,and whether to maintain therapy during the first trimester in patients already on effective regimens. The National High Blood Pressure Education Program (NHBPEP) Working Group on High Blood Pressure in Pregnancy has combined reviews of clinical trials in women with hypertension of pregnancy and consensus documents from clinicians to summarize recommendations for diagnosing and treating hypertension in pregnancy. Classification of the hypertensive subtypes during pregnancy are listed in TABLE 1.
TABLE 1: Classification of Hypertension in Pregnancy
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Chronic Hypertension
Chronic hypertension is defined as hypertension present or diagnosed prior to the 20th week of gestation. This includes patients with hypertension prior to pregnancy. Patients are diagnosed using an absolute level of blood pressure (140/90 mmHg or greater) or by an increase in blood pressure from preconception or first trimester levels (systolic blood pressure increase >25 mmHg and/or diastolic blood pressure increase >15 mmHg). Most women with mild chronic hypertension of pregnancy (systolic blood pressure of 140 — 179 mmHg or diastolic blood pressure of 90 — 109 mmHg) are considered at low risk for cardiovascular complications within the short time frame of pregnancy. According to the Working Group, these women are candidates for nonphar-macologic therapy.There is a normal physiologic decrease in diastolic blood pressure that occurs in the first trimester, thus averting the need for pharmacologic intervention in the mildly hypertensive woman. Also, clinical trials have failed to show improved maternal or neonatal outcomes in mildly to moderately hypertensive women. Failure to improve outcomes is generally attributed to problems in study design.
For hypertensive patients who have been treated for several years, or have evidence of target organ damage, or are on a regimen of multiple antihypertensive agents, medication dosage sizes may be reduced on the basis of blood pressure readings. These medications should be maintained, however, if they are needed to control blood pressure. Systolic blood pressures >160 mmHg, diastolic blood pressures >110 mmHg, left ventricular hypertrophy, and renal insufficiency all warrant reinitiation of pharmacologic treatment during pregnancy.
Methyldopa is generally recommended as first-line therapy because it does not compromise uteroplacental blood flow and fetal hemodynamics (TABLE 2). Methyldopa is an antihypertensive agent that stimulates the central inhibitory alpha-adrenergic receptors. Oral doses are 500 — 750 mg per day to a maximum of 2 — 3 g/day in divided doses; IV doses are 250 — 500 mg at six-hour intervals to a maximum of 1 g every six hours. Blood pressure control occurs within 3 — 6 hours. Approximately 50% of an oral dose is absorbed, and the elimination half-life is 7 — 16 hours. Fifty percent of the dose is metabolized via hepatic mechanisms. Hemolytic anemia, hepatitis, and myocarditis are rare but potentially fatal adverse effects of methyldopa. The most common adverse effects include lightheadedness, dizziness, headache, and postural hypotension, which occur in 15% of patients and are the most common causes for treatment discontinuation. Dose-dependent sedation, sleep disturbances, nasal congestion, and dry mouth are other common adverse effects. Drug-induced depression is also common and must be monitored, especially in pregnant patients, since depression can have adverse effects on the fetus as well.
TABLE 2: Current Drug Therapy Recommedations
| Place in Therapy | Drug | Dose | Route | Mechanism | Adverse Effects |
| TREATMENT OF CHRONIC HYPERTENSION | |||||
| FIRST LINE | Methyldopa
(Aldomet) |
500-750 mg/day Max: 2-3 g/day in divided doses; 250-500 mg at 6 h intervals |
Oral
IV |
Central alpha-2 agonist | Sedation, lethargy, depression, postural hypotension |
| SECOND LINE | Labetalol | 100-200 mg/day 2 mg/kg, IV 0.5-2 mg/min |
Oral IV Bolus IV Infusion |
Alpha/beta-adrenergic blocker | Hypotension, bradycardia, N/V |
| ALTERNATIVE | Atenolol
(Tenormin) |
50-100 mg QD | Oral | Beta-adrenergic blocker | Associated with fetal growth retardation when used long term throughout pregnancy |
| ALTERNATIVE | Thiazide | 12.5-50 mg QD-BID Max: 100 mg BID |
Oral | Diuretic | Hypokalemia, hyperuricemia, SLE |
| TREATMENT OF ACUTE, SEVERE HYPERTENSION | |||||
| FIRST LINE | Hydralazine
(Apresoline) |
5 mg bolus every 1-2 minutes as needed; after 20 min repeat as necessary | IV | Vasodilator | Lupus syndrome, tachycardia, peripheral neuropathy |
| SECOND LINE | Labetalol | 20 mg bolus 40 mg bolus 1 mg/kg |
IV Bolus IV Infusion PRN |
Alpha/beta-adrenergic blocker | Hypotension, bradycardia, N/V |
| ALTERNATIVE | Nifedipine
(Adalat) |
30-60 mg SR QD, maintenance:30-90 mg SR QD |
Oral | Calcium channel blocker, dihydropyridine | Perpheral edema, headache-dizziness, tachycardia |
| ALTERNATIVE | Sodium nitroprusside
(Nitropress) |
2-4 mcg/kg/min | IV Infusion | Vasodilator | Headache, hypostension, tachycardia |
| PREVENTION OF ECLAMPSIA | |||||
| FIRST LINE | Magnesium sulfate | 10g IM loading dose; then 5 g IM every 4 h | IM | Anticonvulsant | Magnesium toxicity, hypotension, abnormal eye movements |
| SECOND LINE |
Phenytoin | 1,000 mg loading dose IV infusion over 1 h; then 500 mg oral dose 10 h later | IV and PO | Anticonvulsant | Nystagmus-ataxia, lethargy, blood, dyscrasias, cardiotoxicity |
| Abbreviations: N/V — nausea and vomiting; CI–continuous infusion; SLE — systemic lupus erythematosus; IV — intravenous; IM — intramuscular; PO — oral; SR — sustained release; Max — maximum; PRN — as needed; QD — daily | |||||
If methyldopa cannot be tolerated, labetalol is recommended. A selective alpha-blocking and nonselective beta-adrenergic blocking agent with weak intrinsic sympathomimetic activity, labetalol has no membrane-stabilizing activity and moderate lipid solubility. The usual initial doses in hypertension are 100 mg orally twice a day, increasing gradually to maintenance doses of 200 — 400 mg twice a day. Intravenous bolus dosing consists of 20 mg infused over two minutes, with repeated doses of 40 mg or 80 mg given in 10-minute intervals. Alternatively, labetalol may be administered via continuous intravenous infusion at the rate of 2 mg per minute, with the effective dose usually within 50 — 200 mg. Oral labetalol is rapidly absorbed, producing hypotensive effects in one hour. It is metabolized in the liver, with 50% — 60% of the dose excreted in the urine and the remainder excreted in the bile. The half-life is 5 — 8 hours. Common adverse effects include hypotension, dizziness, and nausea. Aggravation of airway obstruction has been reported in asthmatic patients. Positive tests for antinuclear antibodies and a lupus-like illness have occurred. Severe hepatic injury is reported rarely. Hepatic necrosis and death have been reported but are also rare. During beta-blocker therapy, monitoring parameters include fetal and neonatal heart rate, serum blood glucose, respiratory rate, liver function tests, and fetal growth rate. Labetalol therapy should be discontinued in patients who develop laboratory or clinical signs of liver injury.
Labetalol has both alpha- and beta-blocking properties. It has been shown to be as effective as methyldopa for acute blood pressure control. Labetolol has a more rapid onset of action and a smoother control of blood pressure versus hydralazine. It has also been effectively used to treat hypertensive emergencies and to attenuate intubation-induced hypertensive responses in patients with preeclampsia. Beta-blockers have been shown to be no different in efficacy, with fewer adverse effects from methyldopa. Yet NHBPEP guidelines suggest that beta-blockers be reserved for use in the latter stages of pregnancy.
Another controversy involves the use of diuretic agents during pregnancy. Theoretically, diuretics may decrease plasma volume, resulting in decreased uteroplacental perfusion. Regardless, diuretics have been shown to be effective in controlling blood pressure for patients with hypertension of pregnancy in randomized controlled trials. A meta-analysis of nine randomized trials involving >7,000 subjects receiving diuretics revealed a reduced tendency among treated women to develop edema, hypertension, or both, and confirmed no increased incidence of adverse effects to the mother or fetus.
One option in treating chronic hypertension in pregnancy is to maintain an already effective regimen, provided the regimen does not contain an angiotensin converting enzyme (ACE) inhibitor or angiotensin II receptor blockers (ARBs). ACE inhibitors have been associated with fetal growth retardation, oligohydramnios, neonatal renal failure, and possibly, abnormal fetal morphology when administered to patients in the second and third trimesters. The effects of ARBs are thought to be similar to those of ACE inhibitors; thus, ARBs are also not recommended during pregnancy. There is much controversy on the use of atenolol during pregnancy since atenolol may decrease fetal birth weight.
Preeclampsia
Preeclampsia is defined as a pregnancy-specific syndrome of reduced organ perfusion related to vasospasm and activation of the coagulation cascade. In this syndrome, elevated blood pressure is only one sign that typically occurs after 20 weeks gestation.Classic symptoms of preeclampsia include increased blood pressure with proteinuria. Even if proteinuria is absent, any or all of the following suggest the development of preeclampsia: headache, blurred vision, abdominal pain, low platelet counts, or abnormal liver enzymes. The major maternal abnormalities occur in kidneys, liver, brain and coagulation systems. Consequently, the ensuing multi-organ failure impairs uteroplacental blood flow and may cause fetal growth retardation or intrauterine death.
Preeclampsia is associated with maternal adverse effects. The maternal disease is characterized by activation of the coagulation system, vasospasm, and changes in neurohormonal mechanisms related to blood pressure control. These pathophysiologic changes are ischemic, affecting the placenta, kidney, liver, and brain. The main difference between preeclampsia and chronic or gestational hypertension is that preeclampsia is a life-threatening systemic syndrome, even when blood pressure is only mildly elevated.Lowering blood pressure is only one aspect of managing preeclampsia, however. Maternal and fetal monitoring is essential to assess worsening preeclampsia or impending fetal demise, which may necessitate premature delivery.
Low-dose aspirin, calcium supplementation,and fish oil supplementationhave all been unsuccessful in preventing preeclampsia/eclampsia. Vitamin C and vitamin E supplementation, however, were associated with a decrease in preeclampsia,but further studies are needed.
The drugs most widely used to lower blood pressure acutely in pregnancy include nifedipine, labetalol, and hydralazine.Ketanserin, a specific serotonin S2 receptor antagonist, is not currently marketed in the U.S., but is considered to be an effective alternative to hydralazine, though there is no clear consensus on this issue. Blood pressure >170 per 110 mmHg should be lowered to protect the mother against risk of stroke or eclampsia (convulsions in a person with preeclampsia). In addition to the above antihypertensives, magnesium sulfate is used to prevent and treat convulsions. It may lower blood pressure, but is generally inadequate to treat severe hypertension in pregnancy.
Chronic Hypertension with Preeclampsia
When preeclampsia is superimposed on chronic hypertension, the prognosis is much worse for both mother and fetus.A sudden increase in proteinuria in a pregnant woman with preexisting hypertension prior to 20 weeks gestation is the main clinical diagnostic criterion. Others include a sudden increase in proteinuria or a sudden increase in blood pressure in a woman whose hypertension has been otherwise well controlled. Hospitalization for the duration of pregnancy is indicated upon onset of severe gestational hypertension or preeclampsia. This permits intensive maternal and fetal surveillance to determine platelet count, serum liver enzyme levels, renal function, and urinary protein excretion. At gestational week 33 — 34 the fetus may benefit from corticosteroid administration. Delivery is the only curative treatment for preeclampsia.
Gestational Hypertension
Gestational hypertension is diagnosed when women have blood pressure elevations for the first time after mid-pregnancy without proteinuria. Gestational hypertension can be an early manifestation of preeclampsia. It may also be an early sign of unrecognized chronic hypertension. Patients with gestational hypertension must be monitored closely for signs and symptoms of worsening. The point at which to initiate pharmacotherapy for patients with gestational hypertension is not clear at this time and is currently left to clinical judgment. Pharmacotherapy along with counseling, restricted activity, diet, and home blood pressure monitoring are the mainstays of the treatment of hypertension of pregnancy. Effective blood pressure control must be achieved with minimal adverse effects while maintaining normal uterine perfusion. Minimal long-term adverse effects on the fetus remain the long-term goal of treatment.
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