2nd ed. Silver Spring, MD: American Society for Parenteral and

Enteral Nutrition; 2005. (8)

Key Websites

American Society for Parenteral and Enteral Nutrition. http://

www.nutritioncare.org and http://www.nutritioncare.org/

library.asps to access content for:  ASPEN Board of Directors and the Clinical Guidelines Task

Force. Guidelines for the use of parenteral and enteral nutrition

in adult and pediatric patients [published correction appears in

JPEN J Parenter Enteral Nutr. 2002;26:144]. JPEN J Parenter Enteral

Nutr. 2002;26(Suppl 1):1SA. (1)  McClave SA et al. Guidelines for the Provision and Assessment

of Nutrition Support Therapy in the Adult Critically Ill Patient:

Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J

Parenter Enteral Nutr. 2009;33:277. (4)

Heyland DK et al. Canadian Critical Care Nutrition Clinical

Guidelines. Summary of topics and recommendations. Critical Care Nutrition. http://www.criticalcarenutrition.com/

index.php?option=com content&review=article&id=18&

Itemid=10. Accessed November 28, 2010. (19)

Institute for Safe Medication Practices (ISMP). Oral dosage

forms that should not be crushed. http://www.ismp.org/

Tools/DoNotCrush.pdf. Accessed January 17, 2011. (81)

fast before this test. The diagnosis of GDM is important to

the mother and the fetus because of the increased risks of fetal

hyperinsulinemia and macrosomia.

1124 Section 10 Women’s Health

140–179 mg/dL

Schedule 3-hour oral glucose

tolerance test (OGTT)

within 1 week

≥180 mg/dL

Schedule fasting blood

sugar (FBS) next day

≤139 mg/dL

Routine prenatal care

FBS

Draw venous plasma sample

If two or more values are met or

exceeded, treat as GDM with diet

and exercise, possibly may need

medication intervention (insulin

versus glyburide)

If one value is elevated,

likely glucose intolerance: Manage with diet

and exercise

Treat as GDM.

Start on diet and

exercise, may likely

need medication

therapy (insulin versus

glyburide)

≥95 mg/dL

Do not perform 3-hour

OGTT

<95 mg/dL

Proceed with 3-hour

OGTT

Diagnostic

Screening

100-g 3-hour OGTT (based on Carpenter and Coustan)

Draw venous plasma sample, patient must be fasting for this test

 FBS 1 hour 2 hour 3 hour

≥95 mg/dL ≥180 mg/dL ≥155 mg/dL ≥140 mg/dL

50-g Oral Glucose Challenge Test

Draw venous plasma sample

Patient does not need to be fasting

FIGURE 49-4 Recommendations for

screening and diagnosis of gestational

diabetes. A1C, hemoglobin A1C; 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.)

GESTATIONAL DIABETES MELLITUS TREATMENT

CASE 49-4, QUESTION 2: J.B. is screened with a 50-g

1-hour glucose challenge resulting at 161 mg/dL. Because

her screening test was elevated, a diagnostic 3-hour oral

glucose tolerance test (OGTT) was given to her the next

day, which required her to be fasting. The results of the

3-hour OGTT showed a fasting plasma glucose of 96 mg/dL,

a 1-hour glucose of 183 mg/dL, 2-hour glucose of 140 mg/

dL, and 3-hour glucose of 126 mg/dL. These results confirm

that J.B. has GDM. How should she be managed?

J.B. requires extensive education about a gestational diabetes

diet, use of a glucometer, the signs and symptoms of hyperglycemia and hypoglycemia, and treatment of low blood glucose.

She should start to monitor her blood glucose four times daily, at

fasting and 1 hour after the end of each meal. She should return to

the clinic in 1 week for an assessment of her blood sugars to evaluate the need for medication therapy (insulin versus glyburide

treatment).

Most women with GDM can control their glucose with

dietary modifications and regular exercise; however, management with medications (insulin versus oral hypoglycemics)

should be initiated if dietary management fails to maintain fasting plasma blood glucose concentrations at 90 mg/dL or less or to

achieve a 1-hour postprandial plasma concentration of less than

130 mg/dL.

CASE 49-4, QUESTION 3: J.B. returns to clinic at 30 weeks’

gestation with glucometer and logbook for a blood glucose

assessment. She has been compliant with her diabetic diet

and blood sugar monitoring for the past 4 weeks. She has

been able to control her blood sugars with diet and moderate walking after meals. However, she has noticed that

her fasting blood glucose has risen in the past week to an

average of 98 mg/dL and her dinner postprandial values are

averaging 139 mg/dL. How should J.B. be managed at this

time?

Treatment of GDM with insulin therapy is implemented similarly to the treatment for pregestational diabetes. An optimal

insulin regimen for GDM has not been determined. Similar dosing with a weight-based, split-mixed multidose regimen is used.

The insulin regimen must be tailored specifically to the needs of

the woman to successfully achieve target blood glucose levels.

More recently in the past 10 years, the role of oral hypoglycemic agents for the treatment of GDM has increased.

Traditionally, oral hypoglycemics have not been used during

1125Obstetric Drug Therapy Chapter 49

pregnancy because early animal studies implicated some agents

as teratogens. The studies failed to show whether the primary

teratogen was the drug itself or the effect of hyperglycemia and

altered maternal metabolism.84 Glyburide, a second-generation

sulfonylurea, has been used in several studies as an alternative

treatment modality in women with GDM who have relatively

mild hyperglycemia.85 A gestational age of more than 30 weeks,

fasting blood glucose level of less than 110 mg/dL, and 1-hour

postprandial values of less than 140 mg/dL are parameters that

have been shown in one study to predict glyburide success in

women with GDM who have failed diet therapy.86 In a randomized trial, glyburide therapy was compared with an intensive

insulin protocol in women between 11 and 33 weeks of gestation

with GDM who failed to achieve target blood glucose goals with

diet alone.85 Equivalent glycemic control was achieved with treatment of glyburide or insulin therapy. In addition, both groups had

similar pregnancy outcomes, including rates for cesarean delivery, pre-eclampsia, macrosomia, and neonatal hypoglycemia.85

Although the analysis of the cord serum of the infant did not

detect any glyburide in this randomly selected small sample, the

drug has been shown to cross the placenta.85

More recently, the Metformin in Gestational Diabetes trial

examined whether metformin treatment could provide equivalent outcomes to insulin treatment. Women with GDM at 20 to

33 weeks’ gestation were randomly assigned to open-label treatment with metformin (titrated up to 2,500 mg with the option to

add supplemental insulin if glycemic control was not achieved)

or to insulin treatment alone.87 The two groups achieved similar primary outcomes (composite score of neonatal morbidities),

but 46% of the group allocated to metformin required supplemental insulin therapy. Those requiring supplemental insulin

were more obese and had higher elevations of glycemic values

at presentation. The results indicate that metformin can be used

during pregnancy for GDM, but will less likely be successful as

monotherapy in women with higher glucose levels.87 Metformin

is usually reserved for patients with high insulin requirements

(>300 units daily) in the second and third trimesters.43 More

randomized trials are needed to further determine and to better

understand the role of oral hypoglycemic agents in pregnancy.

J.B. is a good candidate for glyburide therapy because she is

greater than 30 weeks’ gestation and has a fasting blood sugar

level less than 110 mg/dL. Glyburide 2.5 mg PO daily 30 minutes

before dinner should be started. Doses should be increased or

decreased to achieve glycemic control. If maximal dosages of

glyburide are reached and glycemic control is not achieved, J.B.

should be transitioned to SC insulin therapy.

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.74 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% to 70%.82

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.

HYPERTENSION AND

PRE-ECLAMPSIA

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 to 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 uric acid (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 pre-eclampsia?

Hypertensive disease occurs in 5% to 8% of all pregnancies and is a major cause of maternal and perinatal morbidity and mortality.88 From 15% to 24% of maternal deaths in

developed countries are attributed to hypertensive disorders in

pregnancy.89,90 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, pre-eclampsia superimposed on chronic

hypertension, and gestational hypertension.88 After delivery,gestational hypertension is ultimately delineated as either (a) transient

hypertension of pregnancy if pre-eclampsia is absent during delivery and BP normalizes by 12 weeks post partum or (b) chronic

hypertension if BP remains elevated.88

Chronic hypertension is defined as hypertension diagnosed

before conception or before the 20th week of gestation, or hypertension persisting beyond 12 weeks post partum.88 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, similarly 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.91 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 pre-eclampsia during the second half of pregnancy in women with late prenatal

care or inadequate BP monitoring. It is also difficult to diagnose

pre-eclampsia 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 pre-eclampsia. Without coexisting proteinuria

(≥0.3 g/24 hours or ≥1+ in a random urine sample) or evidence

1126 Section 10 Women’s Health

of renal dysfunction, a diagnosis of pre-eclampsia would be a

reach.88 T.D. has no proteinuria, and a normal SCr and serum

uric acid. T.D has chronic hypertension, but it is unlikely that

T.D. has pre-eclampsia at this time.

RISK FACTORS FOR PRE-ECLAMPSIA

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

for developing pre-eclampsia?

Pre-eclampsia is a pregnancy-specific condition usually occurring after 20 weeks’ gestation and consisting of hypertension

with proteinuria.88 Pre-eclampsia 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 pre-eclampsia. Pre-eclampsia is a consequence of progressive

placental and maternal endothelial cell dysfunction, increased

platelet aggregation, and loss of arterial vasoregulation. A variant

of pre-eclampsia is HELLP syndrome, which consists of hemolysis (H), elevated liver enzymes (EL), and low platelet count (LP).

HELLP can be also be life threatening and may not always present

with proteinuria and increases in BP.92

When women with pre-eclampsia exhibit seizures, the term

eclampsia is used. Women with pre-eclampsia may unpredictably

progress rapidly from mild to severe pre-eclampsia and to eclampsia within days or even hours. Eclampsia is a potentially preventable complication of pre-eclampsia. About 20% of women

who experience eclampsia have a diastolic BP less than 90 mm

Hg or no proteinuria.93

The term gestational hypertension is used when BP is increased

during pregnancy or is increased in the first 24 hours post partum

in a woman without signs or symptoms of pre-eclampsia and

without pre-existing hypertension.88 Women with gestational

hypertension are at high risk of recurrence during subsequent

pregnancies.

Pre-eclampsia occurs most commonly during the first pregnancy (two-thirds of cases). Obesity and increasing maternal

age are risk factors.94 Chronic diseases that increase the risk for

pre-eclampsia include diabetes mellitus or insulin resistance and

renal disease. Pregnancy-associated risk factors include multifetal gestations, urinary tract infection, certain fetal chromosomal

anomalies, and hydatiform moles. A family history of a sister

or mother with pre-eclampsia significantly increases the risk of

developing pre-eclampsia. Women with previous pre-eclampsia

are at high risk for recurrence in subsequent pregnancies, particularly if it developed before 30 weeks’ gestation.94,95 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 pre-eclampsia.95

MONITORING

CASE 49-5, QUESTION 3: What subjective and objective

data should be monitored in T.D. for the development of

pre-eclampsia?

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.88 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 pre-eclampsia, such as nondependent

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

disturbances. The latter two are signs of severe pre-eclampsia

and may indicate impending eclampsia. Upper abdominal pain

also can be a sign of severe pre-eclampsia, indicating hepatic subcapsular hemorrhage.94 Because T.D. has chronic hypertension,

worsening of hypertension alone may not be a reliable sign of

superimposed pre-eclampsia. Proteinuria is the best indicator of

superimposed pre-eclampsia in a pregnant woman with chronic

hypertension and no renal disease.93

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.88 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.94 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.88 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.97,98 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 pre-eclampsia is unchanged.99 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.99

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.88,93,97 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 pre-eclampsia are similar to those of the general

obstetric population.93 Although chronic hypertension is a major

risk factor for pre-eclampsia, treating T.D.’s uncomplicated mild

chronic hypertension is unlikely to prevent the development of

pre-eclampsia.

METHYLDOPA

CASE 49-5, QUESTION 5: When T.D. returns to the clinic

2 weeks later at 30 weeks’ gestation, her BP ranged from

1127Obstetric Drug Therapy Chapter 49

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.100

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.43

Dizziness and sedation, accompanied by a loss of energy, are

among the most common adverse effects reported by pregnant

women.100 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.100 Patients should be monitored for methyldopainduced liver damage.93 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 49-5.101–106

T.D. should be started on methyldopa 500 mg PO three 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.97

Mild Pre-Eclampsia

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 pre-eclampsia in

T.D.? Does she have mild or severe pre-eclampsia?

ETIOLOGY AND PATHOGENESIS

The causes of pre-eclampsia 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.107 Incomplete physiologic

placental vascular bed changes and endothelial cell dysfunction

are integral to the pathogenesis of pre-eclampsia (see Placental

Physiology section).

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

TABLE 49-5

Drugs for Treatment of Chronic Hypertension in Pregnancy and Lactation

Drug Dose Comments

Methyldopa 750–1,000 mg/d start twice a day,

increase up to 2–3 g/d, divided

in three to four doses if needed99

Longest safety record in pregnancy. Considered a first-line drug.91 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 breast-feeding.

Labetalol 200–400 mg/d start, increase to up

to 2,400 mg/d, divided in two or

sometimes three doses

Combined α- and β-receptor antagonist properties. Considered a first-line drug.91

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.101

Other β-blockers Various Atenolol in particular associated with decreased placental weight and IUGR.102,103 IUGR

thought to be related to β-blocker–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.104,105 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,

long-acting

30 mg/d start, increase to up to

120 mg/d, once daily

Limited pregnancy data on nifedipine or other calcium-channel blockers such as

verapamil, diltiazem, and amlodipine. Concentrations of nifedipine in breast milk are

low and considered compatible with breast-feeding.101,106

Diuretics Various Not first-line agents, although probably safe.88 Concern regarding potential interference

with normal blood volume expansion in pregnancy. Avoid if pre-eclampsia 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.43 Increased risk major birth

defects with first-trimester ACEI exposure.79 Minimal amounts of captopril and

enalapril in breast milk and both considered compatible with breast-feeding.101

Minimal amounts of benazepril in breast milk.

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

1128 Section 10 Women’s Health

arteries are responsible for creating a fixed low-resistance arteriolar circuit, which increases blood supply to the growing fetus.

In pre-eclampsia, these physiologic changes do not occur completely, resulting in decreased perfusion and, consequently, placental ischemia.107,108

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.108

In normal pregnancy, prostacyclin is increased eight to ten

times, creating an increased ratio of prostacyclin to thromboxane A2.

107 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

pre-eclampsia, 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.107 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.107 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 pressors such as

angiotensin II.88

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.107,108 Endothelial damage eventually leads to disruption of the vascular lining, which causes leaking capillary membranes, allowing fluid to

leak into the interstitium.108 In severe pre-eclampsia, 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.108

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 pre-eclampsia includes the elevated serum UA

concentration, which is a sensitive marker for pre-eclampsia, and

elevated SCr.94 T.D. denies headaches, visual disturbances, and

abdominal pain, which are symptoms of severe pre-eclampsia.

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 pre-eclampsia; however, a 24-

hour urine collection should be obtained to measure protein

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

pre-eclampsia.

TREATMENT OF PRE-ECLAMPSIA

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 pre-eclampsia were noted. How should T.D.’s mild

pre-eclampsia be managed?

The delivery of the fetus is the only cure for pre-eclampsia 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 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 pre-eclampsia. If T.D.’s fetus is severely growth restricted

or if subsequent fetal biophysical testing is abnormal, premature delivery would be indicated.88 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 pre-eclampsia, such as T.D.88 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.88

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.

For an illustration showing the lateral

decubitus position, go to http://thepoint.

lww.com/AT10e.

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 pre-eclampsia (e.g.,

headaches, visual disturbances, epigastric or right upper quadrant

pain). Fetal surveillance is indicated.88 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 Pre-Eclampsia

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 U/L

1129Obstetric Drug Therapy Chapter 49

ALT, 16 U/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 pre-eclampsia support this diagnosis in

T.D., and what complications may occur?

T.D. has developed severe pre-eclampsia.92 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

pre-eclampsia 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.93,94 Severe pre-eclampsia 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).93

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.94 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.93,100 This drug induces a

baroreceptor-mediated tachycardia and increases cardiac output,

which increases uterine blood flow as the BP is lowered.94

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.94,109 Therefore, doses of hydralazine

should not be repeated more frequently than every 20 to 30

minutes to prevent drug accumulation.100 Nausea, vomiting,

tachycardia, flushing, headache, and tremors could occur. Some

of these hydralazine-induced adverse effects mimic symptoms

associated with severe pre-eclampsia and imminent eclampsia,

making it difficult for a clinician to differentiate between drugassociated and disease-related problems.100 Fetal hydralazine

serum concentrations are reportedly the same as or higher than

maternal serum concentrations, but drug-associated fetal abnormalities have not been reported.43

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.110

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.100,111 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.111 Labetalol also

does not appear to decrease uteroplacental blood flow even with

a decrease in maternal BP.100 Labetalol reduces cerebral perfusion

pressure, which occurs in up to 43% of women with severe preeclampsia, without negatively affecting cerebral blood flow.112

Decreased cerebral perfusion pressure may prevent progression

to eclampsia. However, it should be avoided in women with

asthma and decompensated heart failure.88,109 Labetalol has also

been associated with higher rates of neonatal bradycardia and

hypotension than hydralazine, but not higher rates of neonatal

intensive care admission.113,114

NIFEDIPINE

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

of severe hypertension during pregnancy because it can be given

orally.100 Nifedipine is effective in decreasing BP without reducing

uteroplacental blood flow or decreasing fetal heart rate. Shortacting 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.97 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.115

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.116,117 Nifedipine lowers BP to less than 160 mm Hg systolic and less than

100 mm Hg diastolic earlier than labetalol,116 but it increases

cardiac index117 (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.109

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.93 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.93,109

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 pre-eclampsia.109 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.

1130 Section 10 Women’s Health

Eclampsia

MAGNESIUM SULFATE PROPHYLAXIS

CASE 49-5, QUESTION 10: T.D. will undergo an induction

of labor for her severe pre-eclampsia. 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-methyld-aspartate.115 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.115

Although termination of the pregnancy is the definitive treatment for severe pre-eclampsia, the intrapartum and immediate postpartum periods are also the periods of greatest risk for

eclampsia.94 Although the incidence of eclampsia is extremely

low, maternal morbidity and mortality are high.118 In the United

States, it has been usual practice to treat all pre-eclamptic women

with magnesium sulfate during labor and for 12 to 24 hours postpartum.88,93 In the United Kingdom, however, it is common to

reserve magnesium sulfate therapy for severe pre-eclampsia.119

The evidence for magnesium sulfate prevention of the progression of disease in mildly pre-eclamptic 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 pre-eclamptic women by 58%

compared with placebo.119 An observational study of nearly 2,500

women with mild pre-eclampsia (BP of 140/90 mm Hg and 1+

protein) found an incidence of eclampsia of about 1% without

the use of seizure prophylaxis.120

In a prospective, randomized study, magnesium sulfate was

superior to phenytoin for the prevention of eclampsia in hypertensive pregnant women.118 In addition, magnesium sulfate was

more effective than nimodipine for seizure prophylaxis in severely

pre-eclamptic women.121

A regimen of magnesium sulfate 4 to 6 g IV as a loading

dose followed by a continuous infusion of 2 g/hour is the most

commonly used regimen in the United States.122 Lower dosages

(e.g., 1 g/hour) have been associated with treatment failures.123 IV

loading doses of 6 g followed by continuous infusions of 2 g/hour

maintain therapeutically effective magnesium serum concentrations between 4 and 8 mg/dL.123 Because magnesium is excreted

by the kidneys and will accumulate in cases of renal dysfunction,

the continuous infusion rate must be lowered with oliguria or

an elevated SCr.

Because of the potential for infusion errors and significant

patient morbidity and even mortality with accidental overdoses

of magnesium sulfate, the Institute of Medicine has identified

magnesium sulfate as a high-risk medication.124 All infusions of

magnesium sulfate must be given through a controlled pump

designed to protect against free flow. If such an infusion pump