TRIPASS XR تري باس

 Figure 49-3 Recommendations for screening and diagnosis of gestational diabetes. FBG, fasting blood glucose;

GDM, gestational diabetes mellitus; OGTT, oral glucose tolerance test. (Adapted with permission from Screening

and diagnosis of gestational diabetes mellitus. Committee Opinion No. 504. American College of Obstetricians and

Gynecologists. Obstet Gynecol. 2011;118: 751–753.)

Other oral hypoglycemics, such as the sulfonylureas, have inferior data and

increase risk of adverse effects.

74

J.B. is a good candidate for insulin therapy because she is greater than 30 weeks’

gestation and has a fasting blood sugar level less than 110 mg/dL. Doses should be

increased or decreased to achieve glycemic control.

RISK OF DEVELOPING DIABETES MELLITUS

CASE 49-4, QUESTION 4: Why is J.B. at risk for developing diabetes mellitus after delivery?

Glucose tolerance normalizes after delivery for most women. Women with GDM,

however, have a 15% to 50% chance of developing nongestational diabetes within 5

to 16 years.

72 The highest risk is in women who are obese or were diagnosed before

24 weeks’ gestation or who had marked hyperglycemia during or soon after

pregnancy. The risk of developing GDM in a future pregnancy is estimated to be 50%

66,78

J.B. should try to minimize the potential for development of insulin resistance by

exercising and maintaining a normal weight. She should also have her glucose

checked with a 2-hour OGTT at her postpartum appointment 6 weeks after delivery

and then at least every 1 to 3 years with screening of either fasting blood sugar or

HgbA1c. In addition, J.B. should be instructed about the importance of using an

effective birth control method to prevent unplanned pregnancies. She also needs to

schedule regular appointments with her primary-care clinician.

p. 982

p. 983

HYPERTENSION AND PREECLAMPSIA

Chronic Hypertension

CLINICAL PRESENTATION

CASE 49-5

QUESTION 1: T.D., a 37-year-old G1, P0, obese black woman was diagnosed with stage 1 hypertension

several months before her pregnancy (BP, 135–145 mm Hg systolic and 90 to 95 mm Hg diastolic). She had no

cardiovascular risk factors (i.e., smoking, diabetes mellitus, dyslipidemias) and was prescribed a trial of lifestyle

modification (i.e., weight loss and exercise). When she initiated prenatal care at 16 weeks’ gestation, her BP

ranged from 130 to 135 mm Hg systolic pressure and 82 to 85 mm Hg diastolic pressure. Her BP today at 28

weeks is 142/90 mm Hg. Her serum chemistry values are creatinine (SCr), 0.6 mg/dL, and UA, 4 mg/dL. A

random urinalysis did not demonstrate proteinuria. Ultrasound confirms an adequately growing fetus at 28

weeks’ gestation. What type of hypertension does T.D. have? What is the likelihood T.D. has preeclampsia?

Hypertensive disease occurs in 5% to 8% of all pregnancies and is a major cause

of maternal and perinatal morbidity and mortality.

80 From 15% to 24% of maternal

deaths in developed countries are attributed to hypertensive disorders in

pregnancy.

81,82 Hypertension in pregnancy is defined as a systolic BP of at least 140

mm Hg or a diastolic BP of at least 90 mm Hg on two separate occasions at least 6

hours apart.

Women with pregnancy-associated hypertension can be grouped into the following

categories: chronic hypertension, preeclampsia–eclampsia, preeclampsia

superimposed on chronic hypertension, and gestational hypertension.

80 After

delivery, gestational hypertension is ultimately delineated as either (a) transient

hypertension of pregnancy if preeclampsia is absent during delivery and BP

normalizes by 12 weeks postpartum or (b) chronic hypertension if BP remains

elevated.

80

Chronic hypertension is defined as hypertension diagnosed before conception or

before the 20th week of gestation, or hypertension persisting beyond 12 weeks

postpartum.

80 Hypertension noted after the 20th week of gestation might be difficult to

classify, particularly if a woman has had inadequate prenatal care without

appropriate BP monitoring.

Women with chronic hypertension, similar to T.D., commonly have a normal BP

during the first half of pregnancy because of the physiologic decline of BP during the

second trimester.

83 BP usually returns to the prepregnancy level by the third trimester.

T.D.’s diastolic pressure decreased from the prepregnancy levels of 90 to 95 mm Hg

to 86 to 90 mm Hg during the second trimester. It is normal for T.D.’s BP to increase

during the third trimester. These changes in BP make it difficult to differentiate

chronic hypertension from preeclampsia during the second half of pregnancy in

women with late prenatal care or inadequate BP monitoring. It is also difficult to

diagnose preeclampsia superimposed on existing hypertension using BP

measurements alone. A sharp increase in T.D.’s pressure of more than 30 mm Hg

systolic or more than 15 mm Hg diastolic could be consistent with preeclampsia.

Without coexisting proteinuria (≥0.3 g/24 hours or ≥1+ in a random urine sample) or

evidence of renal dysfunction, a diagnosis of preeclampsia would be a reach.

83 T.D.

has no proteinuria, and a normal SCr and serum UA. T.D has chronic hypertension,

but it is unlikely that T.D. has preeclampsia at this time.

RISK FACTORS FOR PREECLAMPSIA

CASE 49-5, QUESTION 2: What risk factors does T.D. have for developing preeclampsia?

Preeclampsia is a pregnancy-specific condition usually occurring after 20 weeks’

gestation and consisting of hypertension with proteinuria.

83 Preeclampsia can affect

multiple organ systems (e.g., kidney, liver, hematologic, CNS). The signs and

symptoms are often unpredictable and can be mistaken for other disorders. Because

edema is so common in normal pregnancy and is not specific, it is no longer used as a

criterion for the diagnosis of preeclampsia. Preeclampsia is a consequence of

progressive placental and maternal endothelial cell dysfunction, increased platelet

aggregation, and loss of arterial vasoregulation. A variant of preeclampsia is

Hemolysis, elevate Liver enzymes, Low Platelet count (HELLP) syndrome, which

consists of hemolysis (H), elevated liver (EL) enzymes, and low platelet (LP) count.

HELLP can also be life–threatening and may not always present with proteinuria and

increases in BP.

84

When women with preeclampsia exhibit seizures, the term eclampsia is used.

Women with preeclampsia may unpredictably progress rapidly from mild-to-severe

preeclampsia and to eclampsia within days or even hours. Eclampsia is a potentially

preventable complication of preeclampsia. About 20% of women who experience

eclampsia have a diastolic BP less than 90 mm Hg or no proteinuria.

85

The term gestational hypertension is used when BP is increased during pregnancy

or is increased in the first 24 hours postpartum in a woman without signs or

symptoms of preeclampsia and without preexisting hypertension.

80 Women with

gestational hypertension are at high risk of recurrence during subsequent pregnancies.

Preeclampsia occurs most commonly during the first pregnancy (two-thirds of

cases). Obesity and increasing maternal age are risk factors.

86 Chronic diseases that

increase the risk for preeclampsia include diabetes mellitus or insulin resistance and

renal disease. Pregnancy-associated risk factors include multifetal gestations, urinary

tract infection, certain fetal chromosomal anomalies, and hydatidiform moles. A

family history of a sister or mother with preeclampsia significantly increases the risk

of developing preeclampsia. Women with previous preeclampsia are at high risk for

recurrence in subsequent pregnancies, particularly if it developed before 30 weeks’

gestation.

86,87

In addition to her age and obesity, chronic hypertension is the most

significant aspect of T.D.’s medical history, which confers a 25% risk of developing

superimposed preeclampsia.

87

Monitoring

CASE 49-5, QUESTION 3: What subjective and objective data should be monitored in T.D. for the

development of preeclampsia?

T.D. should have her BP monitored frequently. If protein is detected in a random

urinalysis, then a 24-hour urine collection for protein and creatinine can be repeated

to determine accurately the degree of proteinuria and severity of disease.

80 Periodic

ultrasounds should be obtained to assess fetal growth because IUGR is common in

pregnant women with chronic hypertension. T.D. should be taught to recognize and

immediately report all signs and symptoms of preeclampsia, such as nondependent

edema (i.e., swelling of face or hands), headaches, and visual disturbances. The

latter two are signs of severe preeclampsia and may indicate impending eclampsia.

Upper abdominal pain also can be a sign of severe preeclampsia, indicating hepatic

subcapsular hemorrhage.

86 Because T.D. has chronic hypertension, worsening of

hypertension alone may not be a reliable sign of superimposed

p. 983

p. 984

preeclampsia. Proteinuria is the best indicator of superimposed preeclampsia in a

pregnant woman with chronic hypertension and no renal disease.

85

Antihypertensive Drug Therapy

CASE 49-5, QUESTION 4: Should T.D.’s chronic hypertension be treated with antihypertensive drugs to

prevent preeclampsia?

The goal of antihypertensive therapy for women with chronic hypertension during

pregnancy is to minimize the risks to the mother of an elevated BP without

compromising placental perfusion.

84 The value of treating pregnant women with

chronic antihypertension drugs remains an area of ongoing debate. A sustained

diastolic BP of more than 100 mm Hg may cause maternal vascular damage,

especially if the diastolic pressure is more than 105 to 110 mm Hg.

86 Morbidity is

unlikely with a diastolic BP of less than 100 mm Hg. Therefore, many clinicians

recommend treatment with antihypertensive drugs to lower diastolic pressures of

more than 100 to 110 mm Hg.

80 Treatment of a diastolic BP of less than 100 mm Hg

should be reserved for women with chronic hypertension and target organ damage

(e.g., left-ventricular hypertrophy) or underlying renal disease because

antihypertensive drugs can decrease placental blood flow, which might increase fetal

growth restriction.

88,89 Treatment of mild-to-moderate hypertension is associated with

a decrease in the risk of developing severe hypertension by approximately 50%, but

the overall risk of developing preeclampsia is unchanged.

90 Furthermore, there is no

evidence of a reduction in the risk of stillbirth, fetal growth restriction, or preterm

birth if women with chronic hypertension with systolic BP of 140 to 169 mm Hg or

diastolic BP of 90 to 109 mm Hg are given antihypertensive therapy.

90 Moreover,

women treated with antihypertensive therapy were more likely to experience adverse

drug effects compared with those who received placebo or were untreated.

Antihypertensive therapy, however, is required to reduce the risk of cardiovascular

morbidity such as heart or renal failure and acute risk of stroke in pregnant women

with severe hypertension (diastolic >110 mm Hg).

T.D. has normal renal function and her BP is less than 100 mm Hg; she does not

need antihypertensive drug treatment at this time. If T.D. had been on drug therapy

before conception, some experts would have her continue during the pregnancy.

80,85,88

In such cases, however, the doses of the antihypertensive agents often need to be

lowered or discontinued altogether to prevent hypotension because the maternal BP

naturally decreases during the second trimester. Perinatal outcomes in women with

untreated chronic hypertension who do not progress to preeclampsia are similar to

those of the general obstetric population.

85 Although chronic hypertension is a major

risk factor for preeclampsia, treating T.D.’s uncomplicated mild chronic

hypertension is unlikely to prevent the development of preeclampsia.

Methyldopa

CASE 49-5, QUESTION 5: When T.D. returns to the clinic 2 weeks later at 30 weeks’ gestation, her BP

ranged from 160 to 165 mm Hg systolic pressure and 85 to 92 mm Hg diastolic pressure. Which medication

should T.D. be started on?

Methyldopa, a centrally acting α-agonist that decreases sympathetic outflow to

decrease BP, is the most commonly used antihypertensive agent for chronic treatment

of hypertension in pregnancy in the United States. The usual starting dose of 750 to

1,000 mg/day, to be administered in three to four daily divided doses, can be

increased to 2 or 3 g/day if needed. Higher doses may be needed to control BP in

pregnancy.

91

Methyldopa, classified as category B for fetal risk, has the longest and best safety

record of all antihypertensive agents during pregnancy. Despite its common use, few

adverse effects have been reported in neonates exposed to methyldopa in utero. In

addition, no congenital anomalies are associated with methyldopa.

38

Dizziness and sedation, accompanied by a loss of energy, are among the most

common adverse effects reported by pregnant women.

91 Generally, these adverse

effects occur early in therapy and tend to subside, but may recur with an increased

dosage. Problems with postural hypotension usually do not occur in pregnant

women.

91 Patients should be monitored for methyldopa-induced liver damage.

87 Other

drugs used to treat hypertension in pregnancy include labetalol and calcium-channel

blockers. A review of drug therapies for the treatment of chronic hypertension in

pregnancy is listed in Table 49-4.

92–97

T.D. should be started on methyldopa 500 mg PO 3 times daily. If T.D. cannot

tolerate the side effects, she can be switched to labetalol 200 mg PO twice daily. The

only antihypertensive drugs absolutely contraindicated during pregnancy are ACEI

and angiotensin II receptor blockers because of the association with fetal and

newborn morbidity and mortality.

88

Mild Preeclampsia

CASE 49-5, QUESTION 6: T.D. returns to her obstetrician 1 week later at 31 weeks’ gestation complaining

of mild hand and leg edema. She has 1+ proteinuria by dipstick, and her BP is 155/102 mm Hg. An ultrasound

demonstrates fetal growth restriction. Laboratory results are as follows:

SCr, 0.9 mg/dL

Serum UA, 6.0 mg/dL

Aspartate aminotransferase (AST), 25 units/L

Alanine aminotransferase (ALT), 16 units/L

Platelets, 230,000/μL

She is currently on labetalol 200 mg PO twice daily and has been compliant with her medications. What signs

and laboratory evidence are consistent with preeclampsia in T.D.? Does she have mild or severe preeclampsia?

ETIOLOGY AND PATHOGENESIS

The causes of preeclampsia currently remain unknown. Although the pathogenesis

begins early in pregnancy, the disease is not clinically evident until the latter half of

the pregnancy and persists until the fetus is delivered.

98

Incomplete physiologic

placental vascular bed changes and endothelial cell dysfunction are integral to the

pathogenesis of preeclampsia.

Placental Ischemia

Early in a normal pregnancy, the trophoblastic migration and invasion of the uterine

spiral arteries result in physiologic changes within the placental vascular bed that

facilitate maximal intervillous blood flow. The physiologic changes within these

spiral arteries are responsible for creating a fixed low-resistance arteriolar circuit,

which increases blood supply to the growing fetus. In preeclampsia, these

physiologic changes do not occur completely, resulting in decreased perfusion and,

consequently, placental ischemia.

98,99

Endothelial Damage

An intact vascular endothelium assists in preserving the integrity of vasculature,

mediating immune and inflammatory responses, preventing intravascular coagulation,

and modulating the contractility of the underlying smooth muscle cells.

99

In normal pregnancy, prostacyclin is increased 8 to 10 times, creating an increased

ratio of prostacyclin to thromboxane A2

.

98 The biologic dominance of prostacyclin

along with nitric oxide plays an important role in maintaining vasodilation throughout

pregnancy. Prostacyclin may be responsible for vascular refractoriness to angiotensin

II in normal pregnancy. In preeclampsia, the ratio of prostacyclin to thromboxane A2

is reversed. Thromboxane A2

is biologically dominant during preeclampsia, leading

to increased vascular sensitivity to angiotensin II and norepinephrine.

98 The

increased release of thromboxane A2

is believed to be caused by endothelial cell

dysfunction. The end result is vasospasm, which further increases endothelial cell

dysfunction and increases BP.

98 Reduced activity of nitric oxide synthase and

decreased nitric oxide-dependent or nitric oxide-independent endothelium-derived

relaxing factor are believed to increase the vasoconstrictive potential of pressures

such as angiotensin II.

80

p. 984

p. 985

Table 49-4

Drugs for Treatment of Chronic Hypertension in Pregnancy and Lactation

Drug Dose Comments

Methyldopa 750–1,000 mg/day start

twice a day, increase up to

2–3 g/day, divided in 3–4

doses if needed

99

Longest safety record in pregnancy. Considered a first-line

drug.

88 Dizziness, sedation, and lack of energy are common

symptoms, which tend to resolve. Can cause liver toxicity.

Low breast milk concentrations, so considered safe in breastfeeding

Labetalol 200–400 mg/day start,

increase to up to 2,400

mg/d, divided in 2 or

sometimes three doses

Combined α- and β-receptor antagonist properties.

Considered a first-line drug.

88

Increasingly preferred to

methyldopa owing to fewer side effects. Neonatal effects

could include bradycardia and hypotension. Low

concentration in breast milk and generally considered safe in

breast-feeding

92

Other β-blockers Various Atenolol in particular associated with decreased placental

weight and IUGR.

94,95

IUGR thought to be related to βblocker-induced increased vascular resistance in mother and

fetus. Atenolol, acebutolol, metoprolol, nadolol, and sotalol

can have high milk-to-plasma ratios and accumulate in breast

milk, creating potential risk for neonatal blockade.

96,97

Propanolol found in only small amounts in breast milk and

generally considered safe, but infants should be monitored for

hypotension, bradycardia, and blood glucose changes

Nifedipine, longacting

30 mg/day start, increase

to up to 120 mg/day, once

daily

Limited pregnancy data on nifedipine or other calciumchannel blockers such as verapamil, diltiazem, and

amlodipine. Concentrations of nifedipine in breast milk are

low and considered compatible with breast-feeding

107,108

Diuretics Various Not first-line agents, although probably safe.

88 Concern

regarding potential interference with normal blood volume

expansion in pregnancy. Avoid if preeclampsia or IUGR

already present. Concentration low in breast milk, but may

decrease milk production

ACEI or ARB Contraindicated Contraindicated in pregnancy in all trimesters. Fetal renal

failure when used after first trimester, resulting in

oligohydramnios, limb contractures, pulmonary hypoplasia,

skull hypoplasia, and irreversible neonatal renal failure.

38

Increased risk major birth defects with first-trimester ACEI

exposure.

75 Minimal amounts of captopril and enalapril in

breast milk and both considered compatible with breastfeeding.

229 Minimal amounts of benazepril in breast milk

ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; IUGR, intrauterine growth

restriction.

Endothelial cell dysfunction in pregnancy is thought to be caused by oxidative

stress. Intermittent hypoxic and reperfusion injury that occurs as a consequence of

decreased placental perfusion may increase oxidative stress.

98,99 Endothelial damage

eventually leads to disruption of the vascular lining, which causes leaking capillary

membranes, allowing fluid to leak into the interstitium.

99

In severe preeclampsia, this

results in hypovolemia, hemoconcentration, and consequently an increase in

hematocrit. The loss of plasma volume, vasospasm, and microthrombi decrease

perfusion of the kidney, CNS, liver, and other organs. The loss of intravascular

proteins in the urine secondary to renal damage, and through damaged epithelia,

decreases plasma oncotic pressure and leads to a rapid onset of nondependent

edema. The imbalance of endogenous procoagulants and anticoagulants produces

platelet consumption and results in thrombocytopenia and coagulation defects.

99

T.D.’s diastolic BP is now higher than it was before her pregnancy and has

increased by 12 mm Hg in the last 3 weeks. Although an increase in BP by itself is

not diagnostic of preeclampsia, the new finding of proteinuria confirms the diagnosis.

Other evidence for preeclampsia includes the elevated serum UA concentration,

which is a sensitive marker for preeclampsia, and elevated SCr.

86 T.D. denies

headaches, visual disturbances, and abdominal pain, which are symptoms of severe

preeclampsia. The transaminases and platelet count are normal; therefore, she does

not have HELLP syndrome at this time. T.D.’s clinical presentation is consistent with

mild preeclampsia; however, a 24-hour urine collection should be obtained to

measure protein excretion, quantify the urine output, and further rule out severe

preeclampsia.

TREATMENT OF PREECLAMPSIA

General Principles

CASE 49-5, QUESTION 7: T.D. is admitted to the hospital. The 24-hour urine protein is 500 mg/24 hours.

Although fetal growth is restricted, all other fetal testing is reassuring. After 24 hours, her BP decreased to

140/95 mm Hg. Her platelet counts remained stable and greater than 200/μL, and transaminases were normal.

No other signs and symptoms of preeclampsia were noted. How should T.D.’s mild preeclampsia be managed?

The delivery of the fetus is the only cure for preeclampsia and would be the best

treatment option for T.D. if she were at more than 37 weeks’ gestation. T.D. has mild

disease, however, and is not close to term. Her delivery should be postponed

p. 985

p. 986

because premature delivery increases neonatal morbidity and mortality. T.D.’s

fetus is somewhat growth restricted, which is common in women with chronic

hypertension, with or without superimposed preeclampsia. If T.D.’s fetus is severely

growth restricted or if subsequent fetal biophysical testing is abnormal, premature

delivery would be indicated.

80 Because neither of these is evident in the present

circumstances, T.D. should continue her pregnancy under very close medical

supervision. It has been suggested that continued hospitalization is appropriate for

women with preterm onset of mild preeclampsia, such as T.D.

80 This would allow

for rapid intervention in case of rapid progression of disease or associated

complications. Probably, a role exists for outpatient monitoring of some select

women with very frequent maternal and fetal monitoring, and rehospitalization for

worsening disease.

80

T.D. is also a candidate for administration of glucocorticoids for fetal lung

maturation (see Case 49-7, Question 7). Bed rest in the lateral decubitus position is

usually suggested and may help reduce BP and promote diuresis by decreasing

vasoconstriction and improving renal and uteroplacental perfusion.

T.D. should have her BP measured regularly each day. Liver transaminases,

platelets, and creatinine should be measured periodically and whenever her clinical

status changes. She also should be assessed for symptoms of severe preeclampsia

(e.g., headaches, visual disturbances, epigastric or right upper-quadrant pain). Fetal

surveillance is indicated.

80 One approach is to perform a modified biophysical

profile, a test performed to ensure fetal well-being using ultrasonography measuring

fetal breathing, tone, movement, and amniotic fluid volume with an assessment in

fetal heart rate, twice a week and whenever maternal clinical status changes, and an

ultrasound for fetal growth every 3 to 4 weeks.

Severe Preeclampsia

CLINICAL PRESENTATION

CASE 49-5, QUESTION 8: T.D.’s BP for about 2 weeks ranged from 140 to 150 mm Hg systolic and 90 to

100 mm Hg diastolic with bed rest. Her proteinuria remained stable at 1+ to 2+ by dipstick. During the past 2

days T.D.’s BP started to increase again, and today her BP is 160/112 mm Hg and her urine dipstick is 3+. She

complains of headaches, dizziness, and visual disturbances and has significant edema in her face, hands, legs,

and ankles. T.D. is transferred to the Labor and Delivery Unit for delivery. Pertinent laboratory results are as

follows:

SCr, 1.3 mg/dL

UA, 6.7 mg/dL

AST, 30 units/L

ALT, 16 units/L

Total bilirubin, 1 mg/dL

Platelets, 95,000/μL

Hematocrit, 38%

Hemoglobin, 13 g/dL

Random urine protein, 4+

Estimated fetal weight by ultrasound is 1,700 g, which is between the 10th and 25th percentile for a

gestational age of 34 weeks. What signs, symptoms, and laboratory evidence of severe preeclampsia support

this diagnosis in T.D., and what complications may occur?

T.D. has developed severe preeclampsia.

84 Her systolic and diastolic BP are

greater than 160 and 112 mm Hg, respectively. She has greater than 3+ protein in a

random urine sample, and her SCr is elevated. She complains of headaches and

visual disturbances. T.D. is also thrombocytopenic as her platelet count is

95,000/μL. Although her liver transaminases are currently normal, she may be

developing HELLP syndrome, a variant of severe preeclampsia associated with a

high incidence of maternal and perinatal morbidity and mortality. Therefore, her

laboratory values should continue to be monitored even as delivery is being planned.

COMPLICATIONS

T.D. is at risk for cerebral hemorrhage, cerebral edema, encephalopathy,

coagulopathies, pulmonary edema, liver failure, renal failure, and eclamptic

seizures.

85,86 Severe preeclampsia is dangerous not only to T.D. but also to her fetus

because uteroplacental perfusion is compromised. T.D. requires drug treatments to

both lower her BP and prevent eclampsia, as well as delivery.

ACUTE TREATMENT OF SEVERE HYPERTENSION

CASE 49-5, QUESTION 9: How should T.D.’s severe hypertension be treated?

The goal of antihypertensive therapy in T.D. is to prevent cerebral complications

(e.g., encephalopathy, hemorrhage).

85 Although it is important to reduce the maternal

BP, it must be accomplished gradually while the fetus is in utero because a sudden

large drop in maternal BP could result in the reduction of uteroplacental perfusion.

86

Because of the potential for fetal bradycardia during or after acute treatment of

maternal hypertension, continuous fetal heart rate monitoring should be considered.

Hydralazine

Hydralazine, a direct arterial smooth muscle dilator, has in the past been the drug of

choice for the acute treatment of severe hypertension in pregnancy.

85,91 This drug

induces a baroreceptor-mediated tachycardia and increases cardiac output, which

increases uterine blood flow because the BP is lowered.

86

The onset of antihypertensive effect for hydralazine ranges from 10 to 20 minutes,

and duration of action ranges from 3 to 6 hours after an IV dose.

86,100 Therefore, doses

of hydralazine should not be repeated more frequently than every 20 to 30 minutes to

prevent drug accumulation.

91 Nausea, vomiting, tachycardia, flushing, headache, and

tremors could occur. Some of these hydralazine-induced adverse effects mimic

symptoms associated with severe preeclampsia and imminent eclampsia, making it

difficult for a clinician to differentiate between drug-associated and disease-related

problems.

91 Fetal hydralazine serum concentrations are reportedly the same as or

higher than maternal serum concentrations, but drug-associated fetal abnormalities

have not been reported.

38

Labetalol

Labetalol is also a commonly used drug to treat severe hypertension during

pregnancy. It should be administered IV in increasing doses of 20, 40, and 80 mg

every 10 minutes to a cumulative dose of 300 mg or until the diastolic pressure is

less than 100 mm Hg.

101 The onset of action is within 5 minutes, and its effect peaks

in 10 to 20 minutes with a duration of action ranging from 45 minutes to 6 hours.

IV labetalol is as effective as IV hydralazine in lowering BP in patients with

hypertension during pregnancy, but has fewer reported adverse effects.

91–102

In a

meta-analysis of β-blocker trials for the treatment of hypertension in pregnancy,

labetalol was associated with less maternal hypotension, fewer cesarean deliveries,

and no increase in perinatal mortality.

102 Labetalol

p. 986

p. 987

also does not appear to decrease uteroplacental blood flow even with a decrease

in maternal BP.

91 Labetalol reduces cerebral perfusion pressure, which occurs in up

to 43% of women with severe preeclampsia, without negatively affecting cerebral

blood flow.

103 Decreased cerebral perfusion pressure may prevent progression to

eclampsia. However, it should be avoided in women with asthma and

decompensated heart failure.

104,105 Labetalol has also been associated with higher

rates of neonatal bradycardia and hypotension than hydralazine, but not higher rates

of neonatal intensive care admission.

106,107

Nifedipine

Nifedipine has been used in doses of 10 mg for acute treatment of severe

hypertension during pregnancy because it can be given orally.

91 Nifedipine is

effective in decreasing BP without reducing uteroplacental blood flow or decreasing

fetal heart rate. Short-acting nifedipine capsules are no longer recommended for the

treatment of acute hypertensive urgency, however, because of the risk of stroke or

myocardial infarction, and it was never FDA-approved for this indication.

Immediate-release nifedipine continues to be used to treat hypertension in pregnancy,

however, because this unique patient population may not be at high risk for ischemic

events secondary to atherosclerotic disease.

88 Calcium gluconate or calcium chloride

should be available for IV administration in the event of sudden hypotension. Caution

should be used when giving nifedipine to women concomitantly treated with

magnesium sulfate because these drugs have synergistic effects, causing hypotension

and neuromuscular blockade.

106

Several studies comparing immediate-release oral nifedipine with IV labetalol in

hypertensive emergencies of pregnancy have found them to be equally effective in

lowering BP.

107,108 Nifedipine lowers BP to less than 160 mm Hg systolic and less

than 100 mm Hg diastolic earlier than labetalol,

107 but it increases cardiac index

108

(see Chapter 21, Hypertensive Crises). The use of sustained-release nifedipine

capsules as an alternative is associated with a delay in BP control to 45 to 90

minutes, which is probably not acceptable.

100

Hydralazine 5 mg IV for 1 to 2 minutes should be administered to T.D. and

repeated in doses of 5 to 10 mg every 20 to 30 minutes to a cumulative dose of 20

mg.

85 T.D. should have repeated measurements of her BP at 15-minute intervals.

Because intervillous blood flow depends on maternal perfusion pressure, the goal is

to decrease the diastolic pressure to not less than 90 mm Hg.

85,100 Lowering the

maternal BP excessively may decrease uteroplacental perfusion and compromise the

fetus. A hypotensive overshoot can be observed with hydralazine, particularly in the

setting of volume depletion, which is typical of preeclampsia.

100

If one or two doses

of hydralazine are not effective in lowering T.D.’s diastolic to less than 100 mm Hg,

labetalol 20 mg IV every 10 to 15 minutes can be given.

Eclampsia

MAGNESIUM SULFATE PROPHYLAXIS

CASE 49-5, QUESTION 10: T.D. will undergo an induction of labor for her severe preeclampsia. Which

medication should be given to T.D. to prevent seizures?

The precise mechanism of anticonvulsant action of magnesium for the prevention

and treatment of eclamptic seizures is unknown. The anticonvulsant activity may be

partly mediated through blockade of an excitatory amino acid receptor, N-methyl-Daspartate.

106 Seizures are thought to be caused by decreased cerebral blood flow

because of vasospasm. Magnesium sulfate is a potent cerebral vasodilator and

increases the synthesis of prostacyclin, an endothelial vasodilator. It also causes a

dose-dependent decrease in systemic vascular resistance, which may explain its

transient hypotensive effect. Magnesium may also protect against oxidative injury to

endothelial cells.

106

Although termination of the pregnancy is the definitive treatment for severe

preeclampsia, the intrapartum and immediate postpartum periods are also the periods

of greatest risk for eclampsia.

84 Although the incidence of eclampsia is extremely

low, maternal morbidity and mortality are high.

109

In the United States, it has been

usual practice to treat all preeclamptic women with magnesium sulfate during labor

and for 12 to 24 hours postpartum.

80,85

In the United Kingdom, however, it is common

to reserve magnesium sulfate therapy for severe preeclampsia.

110 The evidence for

magnesium sulfate prevention of the progression of disease in mildly preeclamptic

women had been largely anecdotal in the past. In a large international study of more

than 10,000 women, published in 2002, magnesium sulfate clearly decreased the risk

of eclampsia in preeclamptic women by 58% compared with placebo.

110 An

observational study of nearly 2,500 women with mild preeclampsia (BP of 140/90

mm Hg and 1+ protein) found an incidence of eclampsia of about 1% without the use

of seizure prophylaxis.

111