Chronic Hypertension and Hypertensive Emergencies

Chronic hypertension is defined as elevated blood pressure that is present before the onset of pregnancy or that begins before the 20th week of gestation. It affects up to 7% of pregnancies and represents a significant source of maternal and fetal mortality and morbidity (see Table 179-1).^13,14 The emergency physician may be required to provide therapy for hypertensive emergencies in patients with chronic hypertension and to differentiate between the various hypertensive disorders of pregnancy (Table 179-3).^13–15

In the treatment of chronic hypertension in pregnancy, the physician should try to balance the goal of reducing maternal blood pressure with the requirements to maintain cardiac output and to minimize adverse effects for both mother and fetus.13,14,16,17 Precipitous and marked decreases in blood pressure may significantly diminish uteroplacental blood flow. Treatment of patients with mild to moderate disease does not have an appreciable effect on perinatal outcomes, nor does it reduce the incidence of superimposed preeclampsia. In addition, these patients are likely to have a decrease in blood pressure without pharmacologic agents because of normal physiologic changes that occur in pregnancy, and they are often successfully managed without medications.^13,14,17 On the contrary, patients with more severe hypertension, patients with evidence of end-organ damage, and patients taking more than one pregestational antihypertensive medication probably need maintenance medical therapy (see Table 179-1).^13,17 Lifestyle modification is a potential mode of therapy, but it is unclear whether strict dietary and weight restrictions are appropriate in the gravid patient.¹⁸

Decisions about maintenance therapy are most appropriately made by the patient’s primary care practitioner in conjunction with her obstetrician. However, the emergency physician may be called on to make treatment decisions for patients with severely elevated blood pressure and for patients with superimposed eclampsia. Methyldopa remains the preferred maintenance agent, but nearly all of the major classes of antihypertensive agents are acceptable in the pregnant patient, with the exception of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers. Diuretics are considered second-line agents because of concerns about plasma volume constriction (see Table 179-1).^13,14,15,17 Hydralazine and labetalol are the agents most commonly used for hypertensive emergencies associated with eclampsia and are also appropriate for such emergencies in the patient with chronic hypertension. Sodium nitroprusside can cause fetal cyanide toxicity after several hours of infusion and is considered a second-line agent (Table 179-4).^13,17

Patients with chronic hypertension are more likely to have preeclampsia, a situation that results in increased morbidity and mortality compared with either process in isolation. Coexistence of the two disorders should be suspected in the following situations: (1) new onset of proteinuria after 20 weeks of gestation in a patient with known hypertension and (2) pregnant patients with hypertension and proteinuria before 20 weeks of gestation who have thrombocytopenia, increased transaminase levels, or an acute increase in proteinuria or blood pressure (see Table 179-3).¹⁸

Pulmonary Hypertension

The cardiovascular changes associated with pregnancy and delivery are poorly tolerated in patients with pulmonary hypertension. Data for pregnancy in women with pulmonary hypertension are generally limited to case series, but maternal mortality rates have classically been reported to range from 30 to 56%, depending on the underlying cause (primary pulmonary hypertension, secondary vascular pulmonary hypertension, or Eisenmenger’s syndrome). Recent case series suggest that a lower mortality rate is possible in the setting of aggressive monitoring and care, including use of prostacyclin analogues and phosphodiesterase inhibitors.19,20 Unfortunately, however, a recent literature review shows that mortality remains unacceptably high (17-33%).²¹

The primary goals in treatment of the pregnant patient with pulmonary hypertension are to ensure high right ventricular filling pressures by maintenance of adequate volume status and to obtain early consultation with obstetrics and cardiology services. Pregnancy is not recommended in women with pulmonary hypertension, and those with early gestations should be referred for elective pregnancy termination.

Acute Coronary Syndromes

Coronary artery disease is rare in pregnant women; a population-based study noted a diagnosis of acute myocardial infarction (AMI) in up to 6.2 per 100,000 deliveries.²² Prior mortality rates were reported to be approximately 20%, but more recent studies reveal rates ranging from 5 to 11%.^22–24 Normal physiologic changes of pregnancy, such as increased cardiac output and reduced oxygen-carrying capacity secondary to physiologic anemia, have the potential to exceed the threshold for angina if a fixed coronary artery stenosis is present. Certain conditions are also associated with an increased risk of pregnancy-related AMI, including advanced maternal age, thrombophilia, hypertensive disorders, anemia, diabetes mellitus, and tobacco use.^22,23 A review found that comorbid conditions such as tobacco use and diabetes are relatively common in gravid patients with AMI.²⁴ AMI can occur anytime during the gestational period but peaks during the last trimester and peripartum period.^22,23 Because increases in cardiac output peak during labor and delivery, maternal mortality from AMI is higher in the intrapartum period than during the antepartum or postpartum period.^23,24

There are a number of potential causes of AMI in pregnant women. Despite their relatively young age, a review found that only 13% of gravidas with AMI have normal coronary arteries.²⁴ Other pathophysiologic mechanisms besides atherosclerosis that cause AMI in the pregnant patient include coronary artery dissection, vasospasm, and coronary artery thrombosis in otherwise normal vessels. The relative significance of these lesions varies according to the gestational period. Atherosclerotic disease causes the majority of AMIs in the antepartum period, whereas coronary artery dissection is the most common causative lesion during the intrapartum and postpartum stages.²⁴ Pulmonary embolus, reflux esophagitis, biliary colic, and aortic dissection are all more common than myocardial ischemia during pregnancy and need to be considered in the differential diagnosis. Unfortunately, some women continue to use illicit drugs during their pregnancy, and it is important to consider cocaine use in the pregnant patient presenting with chest pain.

The diagnosis of acute coronary syndrome is similar to that in nonpregnant patients with certain exceptions. Electrocardiographic changes sometimes occur in normal pregnancies and delivery. These include T wave flattening and T wave inversion (mainly in lead III) and nonspecific ST changes during pregnancy as well as ST depression during labor induction for cesarean section.²⁴ As a result, additional evaluation may be necessary. Echocardiography is useful in correlation of suspicious electrocardiographic findings with wall motion abnormalities. The enzymatic diagnosis of myocardial infarction is unchanged except during and immediately after delivery, when troponin is preferred to creatine kinase, which rises above baseline during this time. Angiography is appropriate in high-risk patients with acute coronary syndrome but is generally avoided in low-risk and stable gravidas.²⁴ There have been reported cases of dissection resulting from percutaneous intervention during pregnancy.²⁴ Radionuclide studies carry a lower radiation risk than does angiography but are also generally avoided in stable and low-risk patients.

Treatment of AMI during pregnancy is similar in most respects to treatment of the nonpregnant patient. Survival of the mother is the primary concern, and therapy to improve maternal outcome should not be withheld. Standard treatment includes antiplatelet agents, nitroglycerin, beta-blockers, and antithrombotic agents. However, there are potential adverse effects of such therapy on the mother and fetus (see Table 179-1), and emergent consultation with a cardiologist is recommended. Regarding antiplatelet agents, aspirin remains the first-line agent. There is limited experience with clopidogrel and eptifibatide, but both have been used successfully and are considered safe from a teratogenic standpoint. Heparin has long been considered the antithrombotic agent of choice in pregnant patients, but newer low-molecular-weight agents, specifically dalteparin and enoxaparin, appear to be efficacious and safe and are deemed appropriate for use.²⁵ Heparin is preferable for patients in the late third trimester because there is a more predictable response to protamine sulfate should labor begin.

Experience with thrombolytic therapy in pregnancy is extremely limited; most experience has occurred in the setting of stroke, prosthetic valve thrombosis, and massive pulmonary embolism.26,27 The majority of pregnant patients receiving tissue plasminogen activator have had favorable maternal and fetal outcomes, but most were being treated for indications other than AMI.²⁶ Reported adverse effects have included maternal hemorrhage, maternal death, placental abruption, preterm delivery, fetal death, and fetal intracranial hemorrhage, although the causal relationship in many of these cases is unclear because neither tissue plasminogen activator nor streptokinase crosses the placenta. Because thrombolytic therapy precludes major surgery and epidural anesthesia in the hours to days immediately after administration, the emergency physician must carefully consider whether to use these agents in pregnant women who are close to term, especially if the need for cesarean delivery is anticipated. In addition, the use of thrombolytics in coronary artery dissection is not advised. Because of the lack of data and potential risks of fibrinolytics in gravidas, emergent percutaneous intervention is the treatment of choice for definitive management of AMI.^24,28

In the setting of peripartum AMI, labor should be conducted with continuous monitoring of both the mother’s hemodynamic status and fetal well-being. There are benefits and risks of both vaginal and operative delivery. Cesarean section avoids prolonged exertion by the mother but subjects the patient to general anesthesia if use of antithrombotic agents precludes epidural catheter placement. In addition, surgical delivery places the patient at risk for typical postoperative complications, such as infection, hemorrhage, and thromboembolism. Therefore, assisted vaginal delivery is preferred unless there is an obstetric reason for cesarean section.²⁴ Resolution of angina may occur during the postpartum period as physiologic demands lessen, but its occurrence during pregnancy merits a complete cardiac evaluation for acute coronary syndrome.

Valvular Heart Disease

Maternal valvular heart disease can be congenital or acquired and is one of the leading causes of nonobstetric death. Acquired valvular disease is mainly the result of rheumatic fever and endocarditis. In the United States, most cases of significant congenital heart disease are identified and corrected surgically before puberty. The ability of patients to tolerate pregnancy without significant adverse effects depends on the type and severity of the lesion. Mild to moderate lesions (New York Heart Association classes I and II) are often associated with good outcomes. On the other hand, mitral stenosis (beyond class I), advanced aortic stenosis, aortic and mitral lesions associated with moderate to severe ventricular dysfunction or pulmonary hypertension, and mechanical prosthetic valves requiring anticoagulation can result in significant maternal mortality and require directed therapy (see Table 179-1).²⁹

Anemia

By far the most common medical complication of pregnancy is anemia. The physiologic adaptations to pregnancy include expansion of plasma volume in excess of the increase in red blood cell (RBC) mass. This results in the dilutional, physiologic anemia of pregnancy, with nadir hemoglobin occurring near the beginning of the third trimester. Any type of anemia can complicate pregnancy, but the three types most commonly involved are iron deficiency, folate deficiency, and sickle cell hemoglobinopathy.

Epilepsy

Epilepsy is the most common neurologic complication of pregnancy but remains relatively rare, affecting less than 1% of all gestations. Epilepsy refers to a broad spectrum of seizure disorders that range from relatively benign and infrequent seizures to a disabling condition with daily, poorly controlled generalized convulsions; therefore, care is individualized. Management of epilepsy during pregnancy entails balancing the risk of increased frequency and duration of seizures to both the mother and the fetus against the teratogenic risks of antiepileptic medications (AEMs).

The effect of pregnancy on epilepsy is variable. Most (50-76%) epileptic patients experience no change in their seizure frequency, whereas approximately 15% experience more frequent seizures.54–56 A decrease in plasma drug concentrations is expected with certain AEMs, such as phenytoin, lamotrigine, oxcarbazepine, and levetiracetam.⁵⁴ This results from a number of potential pregnancy-related physiologic changes, including increased plasma volume, decreased protein binding, and increased renal clearance. In addition, some patients engage in voluntary noncompliance with medications to avoid teratogenic effects on the fetus.

Although gravid patients with epilepsy may be at increased risk for cesarean section, postpartum hemorrhage, and other adverse outcomes (see Table 179-1),⁵⁷ the primary complication in these pregnancies is congenital malformations.⁵⁶ Of primary concern is the risk for NTDs, facial clefts, and cardiac anomalies with the older generation agents: valproate, carbamazepine, and phenytoin. There is a twofold or threefold increase in the incidence of serious congenital malformations in offspring of epileptic mothers taking these agents. The risk is greatest with valproate and is also increased with AEM polypharmacy.^55,56,58,59 Of all the older agents, carbamazepine appears to be the safest for use as monotherapy.^55,56,58 Controversy exists as to whether infants of epileptic patients not taking AEMs have an increased incidence of congenital malformations compared with the general population. Studies comparing these infants with infants born to mothers without epilepsy noted a similar incidence of malformations.⁵⁸ Data are limited, but preliminary results suggest that the rate of congenital malformations with the newer agents lamotrigine and levetiracetam is similar to that in the general population, and these agents are being used with increased frequency in gravid patients.^59–62

Care should be provided by specialists in high-risk obstetrics and neurology disciplines. However, emergency physicians may be forced to confront this problem in several clinical scenarios: the pregnant patient with a first-time seizure or status epilepticus and the patient with epilepsy who is found to be pregnant.

Multiple Sclerosis

Multiple sclerosis (MS) affects approximately 400,000 Americans and is twice as common in women as in men. The peak age at onset is 20 to 35 years, which overlaps peak childbearing years. The disease is characterized by intermittent episodes of central nervous system demyelination with consequent neurologic impairment that follows a relapsing-remitting course. Progressive neurologic deficits and permanent disability develop in certain patients.

The impact of pregnancy on the course of MS has been closely studied in various cohorts of women, and a pattern has emerged. As in other autoimmune diseases, the frequency and severity of exacerbations of MS improve because of the immunosuppressant effects of pregnancy. This effect is most pronounced in the third trimester. During the 3 months after delivery, the rate of relapse increases and then returns to the pre-pregnancy baseline.⁶⁵ The risk of postpartum relapse is increased in those women with relapses during the pre-pregnancy year and during pregnancy. Relapses are also more likely in MS patients with higher disability at the time of pregnancy onset. On the other hand, it does not seem that postpartum relapses are related to the duration of disease or the total number of relapses before conception.⁶⁵ In addition, pregnancy does not appear to have any significant long-term adverse effects on disease progression.⁶⁵ In fact, pregnancies occurring after onset of MS may confer a protective effect in regard to disease course.⁶⁶

MS patients with disease exacerbation are often treated with immunomodulators such as intravenous immune globulin (IVIG), corticosteroids, and interferon beta. Although concerns exist about the use of interferon during pregnancy, small studies in gravid patients have shown that use of IVIG during pregnancy and the postpartum period is safe and may decrease the relapse rate.67–69 Likewise, the use of intermittent steroids in the postpartum period may decrease the likelihood of disease relapse.⁷⁰

Maternal relapse rate is unaffected by epidural anesthesia,⁶⁵ and decisions about anesthesia should be based solely on obstetric considerations. Labor may be complicated by fatigue and uncoordinated voluntary motor activity in pushing, and MS patients may be more likely to require assisted vaginal delivery.⁷¹ These pregnancies may also be at increased risk for preterm delivery and small-for-gestational-age infants.⁷² In general, however, pregnancies in the setting of MS have outcomes similar to those in unaffected patients.⁷¹

Spinal Cord Injuries

Because spinal cord injury (SCI) occurs mainly in young people and usually does not impair fertility, there is a relatively large population of paraplegic and quadriplegic patients who become pregnant. Although many of these pregnancies are uneventful, these patients are at risk for certain complications.

The increased coagulability of pregnancy combined with chronic immobilization results in an increased incidence of thromboembolic disease.⁷³ The incidence of urinary tract infection is also markedly increased as a result of neurogenic changes and the need for catheterization.⁷³ Infections are even more likely during pregnancy⁷⁴ and may progress to pyelonephritis, with the subsequent increased risk of fetal loss, prematurity, and maternal sepsis.

A unique problem in the patient with SCI is the detection of the onset of labor, which may be painless and precipitous. Patients with spinal cord lesions below T10 to T12 have an intact uterine nerve supply and will experience labor pains; however, with lesions above T10, labor may be imperceptible or experienced as only mild abdominal discomfort.⁷³ In addition, up to 85% of patients with high lesions (above T5 to T6) experience potentially life-threatening autonomic dysreflexia.⁷⁵ This is manifested as severe paroxysmal hypertension, headache, tachycardia, diaphoresis, piloerection, mydriasis, and nasal congestion. Because the response is not specific to labor and may be precipitated by distention of bowel or bladder, other causes may need to be pursued as well. Pregnant patients with SCI who have these symptoms should be assessed for cervical dilation and have uterine contractions monitored. Emergency department treatment is directed at restoration of normal blood pressure with standard agents. Definitive therapy is with regional anesthesia. Both spinal anesthesia and epidural anesthesia obliterate and prevent this response and should be used as soon as possible during labor for all women with SCI.⁷⁵ Because of the difficulty in detecting labor, pregnant patients with SCI are sometimes admitted for observation near term.

Myasthenia Gravis

Myasthenia gravis is a rare disorder in which autoimmune destruction of the postsynaptic cholinergic receptor results in profound muscle fatigability. Treatment with cholinesterase inhibitors can supply additional acetylcholine to achieve virtually normal muscle contractility but should be titrated to avoid precipitation of a cholinergic crisis. Adjustments in medication dosing are frequently required to preserve this balance.

The effect of pregnancy and the postpartum state on myasthenia gravis is unpredictable in the individual patient, but overall approximately 25 to 40% of patients experience exacerbation of disease, with the remainder having improvement or no change in disease severity.76–78 Several important pregnancy complications are associated with myasthenia gravis. Because of weight gain, anemia, and other physiologic adjustments of pregnancy that may result in fatigue, the distinction between normal pregnancy symptoms and myasthenia may be difficult. Most deliveries are accomplished vaginally without complication in adequately treated patients; assisted and surgical delivery in these women is indicated mainly for obstetric reasons rather than for specific myasthenia-related care.^76,77,79

Up to 30% of neonates born to mothers with myasthenia gravis have a transient neonatal myasthenic syndrome through placental transport of acetylcholine receptor antibodies.⁷⁷ The risk of neonatal myasthenia gravis is decreased in those infants born to mothers who have undergone thymectomy.^77,80 Onset of neonatal myasthenia is typically within the first hours of life but may be delayed by a period of days. Manifestations include poor feeding and suck, diminished reflexes, hypotonia, and respiratory failure. As in adults, the symptoms respond to cholinesterase inhibitors, but treatment should be done in an intensive care unit setting. The duration of the syndrome depends on its severity; severely affected infants sometimes require therapy for several months.⁷⁷

Fortunately, myasthenic crises during pregnancy are rare.77,78 When exacerbations do occur, treatment is no different from treatment of nonpregnant patients (see Table 179-1). Assessment of pulse oximetry, forced vital capacity, and arterial blood gas parameters will guide respiratory therapy. For patients presenting with weakness, an edrophonium (Tensilon) challenge test to distinguish myasthenic from cholinergic crisis is appropriate after initiation of appropriate ventilatory support. Standard medical treatment is continued during labor and delivery to maximize motor strength. Epidural anesthesia is also recommended to reduce pain and fatigue. Sedatives and other agents that increase fatigue are best avoided during this time. The physician should be aware that 30% of patients experience an exacerbation during the postpartum period as the protective immunosuppressant effect of pregnancy dissipates.⁷⁷ In addition, puerperal infections place the patient at risk for disease exacerbation and warrant aggressive therapy.⁷⁷

Diabetes

Three types of diabetes are involved in pregnancy: type 1, or insulin-dependent diabetes mellitus (IDDM); type 2, or non–insulin-dependent diabetes mellitus (NIDDM); and gestational diabetes mellitus (GDM). Although NIDDM is sometimes considered a more benign form of disease, the risk of malformations is the same for both NIDDM and IDDM.⁸⁹ Maternal and fetal complications relate to inadequate glycemic control as well as to the presence of vascular complications or severe renal insufficiency more than to the type of diabetes. All pregnant patients with diabetes are considered “brittle” and require regular follow-up by appropriate specialists. In addition, all patients, including those with GDM, should perform routine self-monitoring of glucose concentration.

Gestational Diabetes

GDM is defined as glucose intolerance that begins (or is first detected) during pregnancy. As the incidences of both NIDDM and IDDM have increased, so has that of gestational disease.¹⁰³ It is important to detect and to address glycemic disorders because maternal glucose intolerance increases the likelihood of adverse perinatal outcomes, such as fetal macrosomia and maternal hypertensive disorders, even at glycemic levels that are considered below the threshold for diagnosis of diabetes.^104–107 GDM is also a risk factor for the subsequent development of nongestational diabetes; an increased risk is seen with obesity, higher HbA_1c values in pregnancy, advanced age at time of GDM diagnosis, lower beta cell function, and need for insulin dosing in late pregnancy.^108–111 It is recommended that all postpartum patients with GDM be educated about diet and exercise and undergo routine postnatal screening at repeated intervals long term.^108,109,112

The exact protocol to follow for the diagnosis of GDM and preexisting, undiagnosed diabetes mellitus is controversial. It is recommended that pregnant patients undergo screening at the beginning of prenatal care in an effort to identify those patients who are at risk for GDM and pregestational diabetes mellitus to minimize adverse pregnancy outcome and progression of diabetic complications.¹⁰⁵ However, it remains unclear whether universal laboratory testing at the first prenatal visit (as opposed to clinical screening) is cost-effective or if this type of screening should be applied only to those populations with a high prevalence of diabetes.¹⁰⁵ The International Association of the Diabetes and Pregnancy Study Groups recommends laboratory screening of all women (if prevalence of disease is high in the population being tested) or only high-risk women at the first prenatal visit with subsequent testing at 24 to 28 weeks’ gestation for all women unless they have already been diagnosed with a glycemic disorder.¹⁰⁵ The American Diabetes Association advocates selective laboratory assessment as soon as possible in gestation for patients at high risk for GDM. This group includes patients older than 25 years; certain high-risk ethnic groups; and patients with obesity, known first-degree relatives with diabetes, personal history of diabetes or glucose intolerance, and personal history of poor pregnancy outcome.¹⁰⁹ Average-risk women and those high-risk women not diagnosed with GDM early in pregnancy then undergo laboratory screening at 24 to 28 weeks’ gestation.¹¹¹ On the other hand, the American College of Obstetricians and Gynecologists recommends universal laboratory screening.¹⁰⁸

The majority of patients with GDM achieve metabolic control with dietary therapy. Traditionally, insulin administration is indicated if dietary control is unsuccessful108,109 (see Table 179-1). Standard practice has been to avoid oral medications because of concerns for placental transfer. However, glyburide has minimal transfer, and studies comparing insulin with glyburide in GDM found that glyburide provided similar glycemic control without an increase in adverse pregnancy outcomes.^110,113,114 A summary from the Fifth International Workshop-Conference on GDM noted that glyburide may be considered in patients with GDM as long as care is taken to prevent maternal hypoglycemia.¹¹⁵ Similarly, initial investigations of metformin in the setting of GDM have not noted any increase in perinatal complications, although some patients taking these agents have required supplemental insulin.^101,116 At this time, however, further study is recommended before its widespread use.¹¹⁵ There are limited data for other oral medications.

Hyperthyroidism

The most common cause of hyperthyroidism is Graves’ disease, in which autoimmune thyroid-stimulating immunoglobulin results in increased production and release of thyroid hormone. Because the symptoms of hyperthyroidism resemble the physiologic changes expected during pregnancy in many respects, the diagnosis may not be immediately evident. Patients with Graves’ disease have disease-specific findings including a diffusely enlarged, soft, mildly tender thyroid gland, exophthalmos, and dermopathy. Other symptoms, such as dyspnea, heat intolerance, hyperemesis, tachycardia, palpitations, systolic flow murmurs, increased appetite, and fatigue, are common to both conditions, making clinical diagnosis difficult. In cases of suspected hyperthyroidism, thyroid function studies and antibody assays are indicated and will confirm the presence of disease.

There are several obstetric concerns for both the mother and the fetus in the setting of untreated clinical hyperthyroidism (see Table 179-1).¹¹⁷ Thyroid storm is the most serious manifestation of the disease. It may be precipitated by stressors such as infection and delivery, and it is manifested with fever, dysrhythmias, myocardial dysfunction, mental status changes, and circulatory collapse. In addition to the more general complications stemming from thyroid hormone excess, Graves’ disease places the fetus at risk for autoimmune-mediated thyroid dysfunction through placental transfer of maternal thyroid-stimulating immunoglobulins. Up to 17% of neonates of mothers with Graves’ disease and positive thyroid-stimulating immunoglobulin values have transient hyperthyroidism lasting 3 to 12 weeks. The condition gradually clears as maternal antibodies are metabolized.¹¹⁸ Manifestations are potentially severe and include irritability, tachycardia, goiter, cardiomegaly, congestive heart failure, premature craniosynostosis, low birth weight, and failure to thrive.¹¹⁹ These infants also have an increased mortality rate, so routine thyroid assessment is indicated in all infants born to mothers with autoimmune thyroid disease.¹²⁰

The mainstay of treatment of hyperthyroidism (see Table 179-1) consists of antithyroid drugs. Propylthiouracil is preferred to methimazole because of an increased potential for adverse congenital drug effects from methimazole.^120,121 However, both medications cross the placenta and can stimulate the fetal thyroid, so maternal thyroid function should be assessed periodically during pregnancy with the goal of keeping free thyroxine in the high-normal range.¹²⁰ Most patients respond to pharmacologic manipulation, although thyroidectomy may be considered in severe cases in which patients cannot tolerate antithyroid medication or in the setting of medication failure.¹²⁰ Use of iodine-131 radionuclide to ablate the maternal thyroid is contraindicated because it will also destroy the fetal thyroid gland.

Additional therapy with beta-blockade to mitigate the hemodynamic effects of sympathetic stimulation may be required in certain cases pending adequate disease control with antithyroid medications. In the nonpregnant patient, iodides may be used to transiently block the release of stored T₄ from the thyroid gland and to inhibit organification of iodide. However, the fetal thyroid is extremely sensitive to iodide, which may result in neonatal goiter and hypothyroidism. Therefore, iodide is considered class D in pregnancy, and its use should be reserved for severe cases with duration of therapy limited to a period of days. As with other autoimmune conditions, transient improvement of Graves’ disease during pregnancy is common, with rebound and clinical deterioration occurring in a majority of patients after delivery.¹²²

Hypothyroidism

The most common cause of hypothyroidism is Hashimoto’s thyroiditis. Overt hypothyroidism is often associated with infertility, so most cases seen during pregnancy are less severe or subclinical forms or occur in patients already undergoing levothyroxine therapy for known disease. Undiagnosed subclinical hypothyroidism may be manifested during pregnancy as physiologic adjustments result in a greater requirement for thyroid hormone production. In addition, iodine deficiency may be exacerbated by pregnancy because renal losses of iodine increase as the glomerular filtration rate increases and as the fetus diverts iodine for its own thyroid hormone synthesis. When signs and symptoms do occur, they are identical to those in the nonpregnant state. Myxedema coma is extremely rare but should be considered along with other causes of coma in a pregnant patient.

As with hyperthyroidism, there is an increased incidence of adverse maternal and fetal effects in women with clinical hypothyroidism (see Table 179-1).^117,126 The majority of patients who are already undergoing treatment for hypothyroidism will require an increased dosage of levothyroxine during pregnancy, and close monitoring of thyroid function is recommended as soon as possible after conception.^120,127,128 Treatment of newly diagnosed patients consists of prompt initiation of thyroid hormone replacement with the goal being to achieve a normal TSH level.^117,120

Approximately 3 to 5% of women of childbearing age have subclinical hypothyroidism,¹²⁹ as defined by an elevated TSH level and a normal T₄ level.¹³⁰ It has been noted that clinical and subclinical hypothyroidism result in adverse perinatal outcomes and adverse neurologic outcomes for affected infants.^120,130 One study also found an increased risk of placental abruption and preterm delivery in subclinical hypothyroidism, and the authors suggested that premature birth may have a direct impact on cognitive outcome in affected infants.¹³¹ Conversely, another more recent analysis found no increase in adverse outcomes in subclinical hypothyroidism.¹³²

The issue of whether to provide routine prenatal screening for hypothyroidism remains controversial. At present, both the American College of Obstetricians and Gynecologists and the Endocrine Society note that there is insufficient evidence to confirm that diagnosis and treatment of subclinical disease significantly improve perinatal neurologic outcomes.120,130 These organizations state that screening should include symptomatic patients and those at risk for disease (prior thyroid diagnoses or other endocrine or autoimmune problems).^120,130 On the other hand, other sources recommend assessment of TSH levels in all women before conception or as soon as possible after becoming pregnant because targeted screening may miss up to one third of affected women.^133,134

Congenital hypothyroidism, associated with severe mental retardation, occurs in approximately 4 in 10,000 births in the United States.¹³⁵ It is most often the result of sporadic fetal thyroid dysgenesis or ectopy rather than maternal thyroid dysfunction.¹³⁶ Diagnosis is often difficult because clinical signs and symptoms may be masked by maternal thyroid hormone. Congenital hypothyroidism is successfully treated with hormone replacement begun in the first days of life, and screening for congenital hypothyroidism is routinely performed in most developed countries.

Tuberculosis

Acquisition and presentation of tuberculosis are unchanged during pregnancy. However, the effect of tuberculosis on pregnancy is unclear. Some studies reveal an increase in gestational complications137–139 (see Table 179-1), but these outcomes are likely to be significantly influenced by the site of disease and specifics of treatment. In addition, conclusions are limited by the fact that these studies are often small or performed retrospectively. Other small studies found no significant increase in gestational complications in 32 and 111 pregnant patients with properly treated tuberculosis.^140,141 Complications are more likely in patients with inadequate or delayed treatment, delayed diagnosis, and extrapulmonary (extranodal) tuberculosis.^137,138 Neonatal tuberculosis acquired by exposure to undiagnosed and untreated active disease places infants at significant risk for acquiring tuberculosis during the first year of life, with significant mortality. In addition, congenital tuberculosis is possible after the fetus becomes infected through the placenta or aspiration of infected amniotic fluid. The latter is rare if the mother has received appropriate therapy.

Current recommendations are to administer a tuberculin skin test early in pregnancy to all patients at high risk for disease and to obtain a chest radiograph if the purified protein derivative (PPD) skin test response is positive or if the patient’s signs and symptoms suggest tuberculosis. Universal screening should be considered in urban areas with a high prevalence of disease. Definitive treatment is indicated in all pregnant patients with confirmed tuberculosis as well as in those high-risk women with suspected disease (see Table 179-1).¹⁴² Isoniazid, ethambutol, and rifampin in their usual doses have not been shown to be teratogenic to human fetuses and are acceptable during pregnancy and breast-feeding.¹⁴³ On the other hand, streptomycin causes fetal ototoxicity, and little is known about the safety of other second-line agents during pregnancy. These less commonly used agents should be avoided except in the case of multidrug-resistant disease (MDR-TB). One retrospective study of 38 gravidas with MDR-TB found no significant increase in perinatal complications, and even patients with drug-resistant disease can be considered for continuation of pregnancy.¹⁴⁴

HIV Infection and AIDS

Human immunodeficiency virus (HIV) infection is one of the leading health problems in pregnancy. In 2008, 25% of reported cases of HIV infection and acquired immunodeficiency syndrome (AIDS) in the United States were in women, with a significant percentage being in women of childbearing age.¹⁴⁵ Estimates of the seroprevalence of HIV infection in pregnant women vary on a regional basis. In the United States, the overall prevalence and number of perinatally infected infants are low but also vary according to the population, with increased rates seen in the southern states and in the black and Hispanic populations.^145,146

The mechanism of vertical transmission is multifactorial. The majority of cases are thought to occur during delivery through exposure to maternal blood and secretions; other infants are likely to be infected in utero or through breast-feeding. Various factors influence the rate of transmission. The most important is maternal viral load, although infection can occur even with low maternal viral load.147–149 Other contributing factors for transmission include vaginal infections, injection drug use, premature delivery, low birth weight, and prolonged rupture of membranes.^{147,149–151} Vertical transmission of HIV in the United States and other developed countries has declined significantly since its peak in the early 1990s because of the implementation of a number of interventions, including routine voluntary testing, antiretroviral therapy (ART), use of elective cesarean section, and avoidance of breast-feeding.¹⁵² However, vertical transmission remains a concern in women without adequate prenatal care as well as a global concern. It is estimated that perinatal infection occurs in approximately 20% of deliveries if the mother is untreated, whereas the previously mentioned interventions reduce this rate to less than 1 or 2%.^{149,150,152–154} Because of this beneficial effect, it is recommended that all pregnant women undergo screening during their routine prenatal evaluation, with repeated screening in the third trimester for women engaging in high-risk behavior or those who have concurrent sexually transmitted diseases (STDs). Rapid HIV screening is recommended for women in labor whose HIV status is unknown.^147,155,156

Treatment of the pregnant patient with HIV infection includes appropriate ART as well as standard therapy for opportunistic infections (see Table 179-1).^147,157 There are limited data on specific therapy for opportunistic infections during pregnancy, but the practitioner should take into account the fact that medication clearance may be affected by various pregnancy-related changes, including increased renal clearance, dilutional anemia, and fetal metabolism of medications.¹⁵⁷ Periodic ultrasonographic assessments of fetal growth are indicated if required medications have an unknown safety profile in pregnancy.

Optimal therapy to prevent vertical transmission includes three stages: antepartum administration of highly active antiretroviral therapy (HAART), intrapartum intravenous zidovudine dosing, and treatment of the infant with 4 to 6 weeks of zidovudine.147,158 The specific ART regimen to follow depends on a number of variables. In patients who are already taking ART with good disease control (viral load < 1000 copies/mL) at the time or pregnancy diagnosis, the current medication regimen should be continued with the exception of efavirenz, which should be discontinued.¹⁴⁷ Women who have never received ART are started on a standard multidrug HARRT regimen that avoids use of efavirenz in the first trimester. Delayed initiation of HAART until the second trimester may be considered in women if the only goal of therapy is to prevent mother-to-child transmission (maternal viral load < 1000 copies/mL).^147,158 In HIV-infected mothers without prenatal care, intrapartum ART followed by postexposure zidovudine treatment of the infant reduces the likelihood of infection but is less effective than the recommended three-stage regimen.¹⁴⁷ Elective cesarean section is recommended in mothers with a viral load greater than 1000 copies/mL.¹⁴⁷ It is reasonable to present cesarean delivery as an option for patients with lower viral loads, although the benefit for these lower risk mothers in uncertain,^147,159 and the risk of mother-to-child transmission by vaginal delivery is very low when mothers have received effective HAART.^148,160

Whereas breast-feeding is associated with mother-to-child transmission of HIV infection and is not recommended in urban areas with access to formula preparations, it remains the preferred mode of feeding in resource-poor areas where formula use is not possible. Studies have shown that continued infant prophylaxis with ART is effective in reducing mother-to-child transmission through breast-feeding, with the absolute risk of transmission being very low.161,162 Exclusive breast-feeding has also been shown to confer a mortality benefit and to reduce the risk of acquired infections,^163,164 and the World Health Organization now encourages exclusive breast-feeding in women when adequate and safe formula-feeding is not possible.¹⁶⁵ Ideally, breast-feeding mothers should be maintained with ART. If ART is not available, breast-feeding is preferable when replacement nutrition is not an option.¹⁶⁵

Even in the setting of ART, commonly used serologic tests to detect antibodies for HIV yield positive results in virtually all neonates born to HIV-positive mothers because of placental transfer of maternal antibodies. These antibodies may be present for up to 18 months and are not necessarily indicative of infection. The preferred means of diagnosis of perinatal HIV infection is by use of assays to detect viral RNA or DNA. Infants are considered noninfected if there have been two negative viral assays after 1 month of age, with one of the assays being done after 4 months of age, or with negative results of two antibody tests done on separate occasions after 6 months of age. In addition, there should be no clinical or other laboratory findings to suggest infection.¹⁶⁶ Clinical assessment for possible HIV infection is also warranted. Infants with AIDS typically present with recurrent bacterial infections, Pneumocystis pneumonia, encephalopathy, extrapulmonary tuberculosis, and generalized wasting. Recent analysis reveals that HAART therapy in infants and children is extremely effective in reducing HIV-related morbidity and mortality.¹⁶⁷

The effects of pregnancy in women with symptomatic HIV infection include an increased incidence of infant mortality, prematurity, stillbirth, and low birth weight and also gestational diabetes.164,168,169 Seropositive mothers who undergo cesarean delivery generally have an uncomplicated postoperative course, although some studies note a slightly increased risk of postpartum endometritis and other maternal infections, with the highest rate of infection seen in women who have low CD4⁺ cell counts.^170–172 It is also important to consider the effect of ART on pregnancy outcomes. It is recommended that efavirenz be avoided in the first trimester of pregnancy because of potential teratogenicity and fetal anomalies.^{147,173–175} Overall, however, most antiretroviral medications are considered safe in this regard. Several large studies have noted no increase in adverse outcomes in women taking ART, with the possible exception of preterm delivery, although this remains a matter of controversy.^176–178

The effect of pregnancy is unclear. An observational cohort study in which a majority of women were using HAART found that pregnancy had no impact on the rate of disease progression.¹⁷⁹ Additional studies are necessary for definitive conclusions to be drawn.

Syphilis

The incidence of primary and secondary syphilis among reproductive-age women in the United States increased during 2004 through 2008, with a current rate of 1.5 cases per 100,000 women.¹⁸⁰ Unfortunately, the incidence of congenital syphilis has shown a similar increase from 2005 to 2008, with a current rate of 8.2 per 100,000 live births.¹⁸¹ Of all the congenital syphilis cases for 2008, half were born to black mothers and an additional 30% to Hispanic mothers, highlighting the need for better screening in these high-risk populations.¹⁸¹

Syphilis causes numerous gestational complications (see Table 179-1), but its most significant sequela is congenital syphilis. This syndrome is characterized by clinical abnormalities such as hepatosplenomegaly, osteochondritis, jaundice, rash, lymphadenopathy, rhinitis, Hutchinson’s teeth, and anemia. Infant mortality for cases occurring in 2008 was 6.5%.¹⁸¹ Screening for all pregnant patients is indicated at the first prenatal visit and again in the early third trimester and at delivery for high-risk patients¹⁵⁶ because vertical transmission rates can be reduced significantly with appropriate penicillin therapy.^156,182 Either the Venereal Disease Research Laboratory (VDRL) or rapid plasma reagin (RPR) test can be used to detect nontreponemal antibody. Pregnancy may cause false-positive results for nontreponemal studies, so confirmation with specific treponemal tests is indicated for a positive VDRL or RPR study. Patients with latent syphilis and those whose titers fail to respond to therapy should undergo cerebrospinal fluid analysis to screen for tertiary syphilis. In addition, fetal ultrasonography before the 20th week of gestation is indicated to assess for abnormalities consistent with congenital syphilis.¹⁵⁶

Treatment is identical to that given to nonpregnant patients with use of benzathine penicillin G appropriate for the disease stage¹⁵⁶ (see Table 179-1). Penicillin-allergic patients are sometimes treated with macrolides.¹⁸² However, it is preferable that these patients undergo skin testing and desensitization if the skin test result is positive because alternative therapy is not reliably effective in preventing congenital syphilis.^156,183,184 Treatment failures are rare with appropriately administered penicillin but do occur. Failures leading to congenital syphilis are more likely in mothers with secondary syphilis, high VDRL or RPR levels, and an interval from treatment to delivery of less than 30 days.^{156,182,184,185}

Hepatitis

Systemic Lupus Erythematosus

SLE primarily affects women of reproductive age, and fertility is usually unaffected. The disease course during pregnancy varies, but studies indicate that acute flares occur in less than one third of patients in clinical remission at the time of conception.199–201 Disease activity tends to involve the skin and musculoskeletal system, although renal involvement is not uncommon, especially in those patients with active lupus nephritis.^202–204 The gestational effects of SLE also depend on the underlying severity of disease. Patients with active disease, especially lupus nephritis, have a higher incidence of disease flares and pregnancy complications,^{199,201,203–205} and it is best for women to achieve good disease control before pregnancy. Many patients have acceptable outcomes, but lupus pregnancies are associated with an increased maternal mortality as well as an increased rate of other complications, including preeclampsia, preterm delivery, thrombocytopenia, anemia, intrauterine growth retardation, fetal loss, and need for cesarean section.^{199,205–207} Other comorbid conditions that adversely affect pregnancy, such as diabetes and thrombophilia, are also seen more commonly in SLE patients.²⁰⁷ The risk of preeclampsia is especially increased in patients with active lupus nephritis.^201,203 As with other renal disease, increasing proteinuria warrants a careful evaluation to distinguish between lupus glomerulonephritis and preeclampsia. The presence of abnormal urine sediment, increasing titers of anti-DNA antibody, and decreasing levels of C3 and C4 suggest lupus nephritis.

Numerous other organ systems in addition to the kidneys are involved in SLE, and differentiation from pregnancy-related changes may be difficult. Mild thrombocytopenia occurs in normal pregnancies and is also common in patients with SLE, although the severity and clinical significance vary from patient to patient. Anemia is a frequent complication of lupus and magnifies the normal dilutional anemia of pregnancy. Various musculoskeletal and cutaneous symptoms associated with pregnancy, such as arthralgias and facial and palmar erythema, can also resemble active SLE. In addition, preexisting lupus rashes become more erythematous because of the increased cutaneous blood flow during pregnancy. Neurologic disease in SLE may be manifested as psychosis, seizures, chorea, or peripheral neuropathy. The incidence of these complications is low during pregnancy, although the occurrence of seizures in late pregnancy in patients with coexistent hypertension and renal insufficiency may pose a diagnostic dilemma between the neurologic effects of SLE and eclampsia.

Other Rheumatologic Diseases

RA is characterized by chronic, destructive, symmetrical joint inflammation. Less common manifestations include the development of subcutaneous nodules, neuropathy, pleuropericarditis, and vasculitis. Systemic symptoms, including weight loss, lymphadenopathy, and fatigue, are common. Because the median age at onset is later with RA, this disorder is seen less frequently than SLE in the pregnant population.²⁰⁸ Disease improvement has classically been estimated to occur in approximately two thirds of patients with RA. However, a prospective study noted disease improvement in about half of pregnant patients, with almost 40% of patients experiencing a subsequent exacerbation after delivery.²⁰⁹

Patients with RA tend to have good pregnancy outcomes in the setting of well-controlled disease. Those women with active disease are more likely to have small-for-gestational-age infants,²¹⁰ possibly as a result of underlying vasculopathy and associated effects on the placenta.²¹⁰

Treatment

The rheumatologic diseases are similar with respect to the therapeutic approach. Corticosteroids form the basis of treatment for most disease complications and exacerbations. These drugs may result in a minimally increased risk of cleft deformities (data are inconclusive) but have not been found to have any other significant teratogenic effects and are considered relatively safe to use for disease control in pregnant patients.211,212 Steroid use during pregnancy does have a dose-related effect on intrauterine growth retardation and predisposes the patient to GDM and hypertension, so close monitoring is advised.

Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) are also a mainstay of therapy in many patients with rheumatic diseases and may be used in pregnancy. There are potential adverse effects of aspirin and NSAIDs on gestation, including miscarriage when they are taken early in pregnancy, premature closure of the fetal ductus arteriosus, increased maternal hemorrhage, and prolongation of gestation and labor when they are taken later in pregnancy. There are also conflicting data about an increased risk for gastroschisis, cleft defects, and cardiac defects with NSAID use.213–217 If a true association exists, the risk for these anomalies remains extremely small in absolute terms. Use of these agents after 32 weeks of gestation should be avoided to minimize the risks of maternal and fetal hemorrhage and premature ductus closure.

Acute flares often require institution of cytotoxic drugs. Cyclophosphamide and methotrexate are contraindicated during the first trimester and should be used only in extreme circumstances because of their teratogenicity and abortifacient properties. Azathioprine has a much more favorable safety profile, and it is the cytotoxic agent of choice during pregnancy. Although the drug and its metabolites cross the placenta, it does not appear to have any major teratogenic effects.218,219 There is an association between azathioprine use and preterm delivery and low birth weight, but it is likely that these adverse outcomes are also related to the underlying disease.^219,220 Cyclosporine also seems to lack teratogenicity and is an acceptable alternative to azathioprine.²²¹

The antimalarial agents chloroquine and hydroxychloroquine are also useful in the treatment of SLE and RA and have been found to be safe during pregnancy. Gravis patients using antimalarials have a decrease in lupus activity, and as a result, these agents may allow a decrease in corticosteroid dosage.222,223 In addition, patients who have been maintained with hydroxychloroquine before conception experience an increased rate of disease flares when the agent is discontinued.²²²

There are limited numbers of pregnant patients using the newer anti–tumor necrosis factor medications, such as infliximab and etanercept. A review of the Food and Drug Association database noted an increase in congenital malformations with anti–tumor necrosis factor agents.²²⁴ However, other data suggest that these agents have an acceptable risk profile and that they may be continued in pregnancy.^225,226 Because the safety of these medications remains uncertain, their use should be reserved for patients with severe disease who are not adequately treated by other more established medications.²²⁵