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622 SECTION 11: Obstetrics and Gynecology TABLE 98-8 Antiemetics Antiemetic Brand Name U.S. Food and Drug Administration Category PO PR IV Promethazine Phenergan ® C 12.5–25 milligrams every 4 h 12.5–25 milligrams every 4 h IV extravasation causes tissue injury; 12.5–25 milligrams IM or IV every 4 h Prochlorperazine Compazine® — 5–10 milligrams every 3-4 h 25 milligrams every 12 h 10 milligrams over 2 min Maximum of 40 milligrams every 24 h Chlorpromazine Thorazine® C 10–25 milligrams every 4–6 h 100 milligrams every 6–8 h 25 milligrams in 500 mL NS at 250 mL/h Ondansetron* Zofran® B 4–8 milligrams every 8 h — 8 milligrams IV over 5 min Metoclopramide Reglan® B 10 milligrams orally every 6–8 h — 10 milligrams over 1–2 min every 6–8 h Maintenance Therapy for Nausea and Vomiting Doxylamine with pyridoxine Diclegis/Diclectin® A 2 tablets every evening — — Vitamin B6 — — 25 milligrams every 8 h — — Ginger — — 500–1000 milligrams daily — — Diphenhydramine Benadryl® B 25–50 milligrams every 6 h — — Abbreviation: NS = normal saline. *Evidence is insufficient to support or refute the teratogenicity of ondansetron. For that reason, many attempt symptom control with other agents first. Source: Adapted with permission from Pearlman M, Tintinalli JE (eds): Emergency Care of the Woman. New York: McGraw-Hill, Inc.; 1998. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Comorbid Disorders in Pregnancy Lori J. Whelan INTRODUCTION This chapter reviews the most common comorbid conditions encoun tered in pregnant women in the ED environment: diabetes and hypoglycemia; thyroid disorders; cardiac disorders and dysrhythmias; thromboembolism; asthma; urinary tract infections; headache; seizures; substance abuse; and intimate partner violence. Drug risk during preg nancy, lactation, and fetal effects of radiation are summarized based on currently available data. Resuscitation is covered in Chapter 25, “Resuscitation in Pregnancy. ”  DIABETES IN PREGNANCY The growing prevalence of gestational diabetes mellitus reflects the increase in obesity, sedentary lifestyles, and type 2 diabetes in the general population. Due to this increased prevalence and proposed new diagnostic criteria, it is estimated that any type of diabetes affects between 8% and 17% of pregnancies, 1 with 86% categorized as gestational diabetes mellitus.2,3 Because many women do not receive screening for dia betes before pregnancy, it can be challenging to distinguish gestational from preexisting diabetes. Pregnant diabetics are at increased risk for several pregnancy complications, including pregnancy-induced hypertension, preeclampsia, preterm labor, spontaneous abortion, pyelonephritis, and diabetic ketoacidosis (DKA). The goal of treatment during pregnancy is to prevent spontaneous abortions, hyperglycemia-induced congenital abnormalities, and ketoacidosis and hypoglycemia. CHAPTER The American College of Obstetricians and Gynecologists recommends the following goals for maintaining euglycemia in pregnant diabetic patients: a fasting blood glucose concentration of ≤95 milligrams/dL (5.27 mmol/L) and a 2-hour postprandial glucose concentration ≤120 milligrams/dL (6.66 mmol/L). A significant portion of gestational diabetics can be managed with diet alone if they can maintain glycemic goals with frequent glucose monitoring. When pharmacologic treatment is indicated, insulin is the preferred treatment for diabetes in pregnancy.

ostprandial glucose concentration ≤120 milligrams/dL (6.66 mmol/L). A significant portion of gestational diabetics can be managed with diet alone if they can maintain glycemic goals with frequent glucose monitoring. When pharmacologic treatment is indicated, insulin is the preferred treatment for diabetes in pregnancy. Among patients with preexisting type 1 and type 2 diabetes, the need for insulin increases throughout the course of pregnancy. In general, during the first trimester, the initial insulin requirement is 0.7 unit/kg/d. By late pregnancy, patients generally require 1 unit/kg/d. For basal insulin coverage, intermediate-acting neutral protamine Hagedorn (NPH) insulin has historically been considered first-line therapy and has been widely studied in this patient population. There is also recent literature supporting the use of long-acting insulin analogues, particularly insulin detemir (Levemir ® ), as an alternative. Insulin detemir is approved by the U.S. Food and Drug Administration for use in pregnancy and is category B. Compared to NPH insulin, it improves fasting plasma glucose and decreases hypoglycemic events. There is a strong evidence base to recommend insulin detemir in pregnancy, but the lack of definitive fetal benefit means that there is no pressing need to switch a woman whose diabetes is well controlled by NPH insulin to insulin detemir. Insulin glargine (Lantus ® ) was previously a pregnancy category C medication and was generally not initiated during pregnancy due to concerns of potential mitogenic activity. However, in 2015, the U.S. Food and Drug Administration started phasing out pregnancy class categories, and insulin glargine is now labeled “No human pregnancy data, ” requiring evaluation and use on an individual basis. Recent studies have shown it to be as safe as insulin detemir, and it seems reasonable to initiate and continue insulin glargine if it is successful in maintaining excellent glycemic control in a woman who is now pregnant. 5-7 For postprandial glycemic control, rapid-acting insulin analogues, such as insulin lispro and insulin aspart, do not cross the placenta and have been safely used in pregnancy. The American College of Obstetricians and Gynecologists recommends that these be used preferentially over regular insulin because both have a more rapid onset of action, enabling the patient to administer her insulin right at the time of a meal rather than 10 to 15 minutes before an anticipated meal. 3 This should provide less hypoglycemia from timing issues and better glycemic control. In women who decline insulin therapy, are unable to safely administer insulin, or cannot afford insulin, metformin is a reasonable alternative Tintinalli_Sec11_p0607-0668.indd 622 8/2/19 4:20 PM

5 minutes before an anticipated meal. 3 This should provide less hypoglycemia from timing issues and better glycemic control. In women who decline insulin therapy, are unable to safely administer insulin, or cannot afford insulin, metformin is a reasonable alternative Tintinalli_Sec11_p0607-0668.indd 622 8/2/19 4:20 PM CHAPTER 99: Comorbid Disorders in Pregnancy 623 TRANSIENT HYPERTHYROIDISM OF HYPEREMESIS GRAVIDARUM Women in the first trimester with weight loss, tachycardia, and vomiting consistent with hyperemesis gravidarum may also demonstrate labora tory evidence of hyperthyroidism or biochemical or transient hyperthyroidism. The most likely cause is thyrotropin receptor stimulation from high human chorionic gonadotropin serum concentrations. Women with transient hyperthyroidism have no previous history of thyroid disease, no palpable goiter, and except for tachycardia, no other symp toms or signs of hyperthyroidism. Test results for thyroid antibodies are negative. With transient hyperthyroidism of hyperemesis gravidarum, thyroid-stimulating hormone may be suppressed and free thyroxine elevated, but triiodothyronine is lower than in true hyperthyroidism. With true hyperthyroidism, both free thyroxine and triiodothyronine are usually elevated, and thyroid antibody tests will usually be positive. Only symptomatic treatment is suggested for transient hyperthyroidism, but hospitalization may be required for management of dehydration. Antithyroid medication is not recommended, although beta-blockers may be considered. HYPERTHYROIDISM True hyperthyroidism in pregnancy increases the risk of preeclampsia, low birth weight, maternal congestive heart failure, and possibly con genital malformations. Symptoms of hyperthyroidism can mimic symptoms of normal pregnancy and may consist of nervousness, palpitations, heat intolerance, and inability to gain weight despite a good appetite. Methimazole and propylthiouracil are equally efficacious in the treat ment of pregnant women. However, both medications have potential adverse effects. Methimazole is associated with congenital abnormalities during first-trimester organogenesis and has been linked to esophageal and choanal atresia and aplasia cutis. Propylthiouracil can cause hepatotoxicity. Recent studies revealed that children exposed to propylthiouracil also developed birth defects. 17 Therefore, current recommendations are to confirm potential pregnancies as soon as possible in patients currently on methimazole and propylthiouracil and evaluate the risk of withholding any antithyroid medication during the first trimester against the risk of thyroid storm. For patients requiring therapy, several expert committees recommend the use of propylthiouracil through 16 weeks of pregnancy, 18 followed by transitioning to methimazole for the second and third trimesters. Agranulocytosis, liver failure, and aplastic anemia are rare but serious complications in patients treated with antithyroid drugs. If such conditions develop, immediately discontinue the medication and obtain obstetrical consultation.  CARDIAC DISORDERS DYSRHYTHMIAS Pregnancy can precipitate cardiac arrhythmias not previously present in seemingly well individuals. The risk of arrhythmias rises during labor and delivery. Factors that promote arrhythmias in pregnancy include the direct cardiac electrophysiologic effects of hormones, changes in hemodynamics or autonomic tone, hypokalemia, and underlying heart disease. Reduction of uterine blood flow during prolonged tachyar rhythmic episodes may adversely affect the fetus. The incidence of arrhythmias in pregnancy is rising due to increasing maternal age and pregnancies in women successfully treated for congenital heart disease.

nomic tone, hypokalemia, and underlying heart disease. Reduction of uterine blood flow during prolonged tachyar rhythmic episodes may adversely affect the fetus. The incidence of arrhythmias in pregnancy is rising due to increasing maternal age and pregnancies in women successfully treated for congenital heart disease. Just as in a nonpregnant patient, treat any hemodynamically unstable arrhythmia in pregnancy with direct-current cardioversion (50 to 200 J). 20 Treat hemodynamically stable arrhythmias medically. The chronic use of beta-blockers in pregnancy can influence fetal and new born size, but only atenolol is singled out as being a U.S. Food and Drug Administration class D drug in this regard (some evidence for harm to the fetus). Other beta-blockers are U.S. Food and Drug Administration class B (sotalol) or C. Digoxin, verapamil, diltiazem, and adenosine have their usual efficacy without adverse fetal effects. choice. Glyburide treatment is not recommended as a first choice because it does not have equivalent outcomes to insulin.3 Recent studies in gestational diabetes have not shown metformin or glyburide to have any harmful fetal effects, but these agents are still not approved by the U.S. Food and Drug Administration for use in gesta tional diabetes, and long-term safety studies are still needed. HYPOGLYCEMIA Women with type 1 diabetes have three to five times more hypoglycemic episodes than the period prior to pregnancy. 8 Risk factors for severe hypoglycemia during pregnancy include a history of severe hypoglycemia in the year preceding pregnancy, impaired hypoglycemia awareness, long duration of diabetes, low hemoglobin A 1c in early pregnancy, fluctuating plasma glucose levels, and excessive use of insulin injections between meals. 8 Hypoglycemia generally presents as sweating, tremors, blurred or double vision, weakness, hunger, confusion, paresthesias, anxiety, palpitations, nausea, headache, or stupor. Moderate and infre quent hypoglycemic episodes are generally well tolerated by the fetus. Pregnant diabetic women should be educated about the symptoms and treatment of hypoglycemia. Treat mild hypoglycemia (i.e., a glucose level of <70 milligrams/dL [3.89 mmol/L] in patients who are able to follow commands) by giving juice, glucose, or food by mouth. Provide standard treatment for more severe hypoglycemia, with IV glucose or PO glucose or glucagon 1 to 2 milligrams SC, IM, or IV (see Chapter 223, “Type 1 Diabetes Mellitus, ” and Chapter 224, “Type 2 Diabetes Mellitus”). DIABETIC KETOACIDOSIS IN PREGNANCY DKA is a serious medical and obstetrical emergency previously con sidered typical of type 1 diabetes but now reported also in type 2 and gestational diabetes patients. 10,11 The incidence of DKA in pregnancy decreases with early diagnosis of insulin-dependent diabetes, improved prenatal counseling, and care with an identifiable primary care provider. 12 DKA still most commonly affects women in the second or third trimester or pregnant women with new-onset type 1 diabetes. A pregnant diabetic who is ill appearing, has persistent nausea and vomiting, and/or has a blood glucose level ≥ 180 milligrams/dL [9.99 mmol/L] should be screened for DKA with serum or urine ketones and a serum chemistry panel. Diabetic pregnant women at more than 20 weeks of gestation are more prone to develop more severe and rapidly progressive episodes of DKA (usually over hours) and at lower glycemic levels (<300 mg/dL [<16.65 mmol/L]). 11 Management guidelines for pregnant women with DKA are the same as for nonpregnant patients11 (see Chapter 225, “Diabetic Ketoacidosis”).

20 weeks of gestation are more prone to develop more severe and rapidly progressive episodes of DKA (usually over hours) and at lower glycemic levels (<300 mg/dL [<16.65 mmol/L]). 11 Management guidelines for pregnant women with DKA are the same as for nonpregnant patients11 (see Chapter 225, “Diabetic Ketoacidosis”). In addition to the usual care, obtain fetal heart tones, administer oxygen, and for third-trimester patients, place patient in the left lateral decubitus position to displace the uterus and improve uterine blood flow. Most fetal heart rate abnormalities subside after correction of maternal hypovolemia and acidosis. Consult with the patient’s physician, and admit the patient to the hospital. Women who use continuous SC insulin infusions (the insulin pump) can develop DKA whether they are pregnant or not. DKA can develop very quickly and unexpectedly, especially in patients who have recently started using the pump. 14,15 Use of continuous insulin pumps during pregnancy is equivalent, but not superior, to scheduled injections. Management of DKA in a pregnant woman with an insulin pump is the same as in the nonpregnant patient. DKA is not an indication for delivery. Although fetal heart rate monitoring in maternal DKA may initially demonstrate a nonreassuring pattern, patterns usually improve as maternal ketoacidosis is corrected, and mother will tolerate delivery or cesarean section better once acidosis resolves.  THYROID DISORDERS Please refer to Chapter 229, “Hyperthyroidism and Thyroid Storm, ” for treatment of thyroid storm in pregnancy. Tintinalli_Sec11_p0607-0668.indd 623 8/2/19 4:20 PM

ally improve as maternal ketoacidosis is corrected, and mother will tolerate delivery or cesarean section better once acidosis resolves.  THYROID DISORDERS Please refer to Chapter 229, “Hyperthyroidism and Thyroid Storm, ” for treatment of thyroid storm in pregnancy. Tintinalli_Sec11_p0607-0668.indd 623 8/2/19 4:20 PM 624 SECTION 11: Obstetrics and Gynecology  CARDIAC DYSRHYTHMIA TREATMENT Paroxysmal supraventricular tachycardia is the most common non sinus tachycardia in women of childbearing age. The treatment of supraventricular tachycardia in pregnant women is the same as for nonpregnant women.19 If vagal maneuvers are ineffective, give adenosine at usual doses. Case reports show both efficacy and a lack of any direct adverse or teratogenic side effects to the fetus. 21 Additionally, acute treatment with beta-blockers, verapamil, and diltiazem is safe in pregnancy when used in standard dosage. The goal of management of atrial fibrillation in pregnancy is rate control or conversion to sinus rhythm. Use diltiazem, beta-blockers, and/or digoxin, all of which are safe in pregnancy and with unchanged dosages. 21 Procainamide has not been associated with teratogenicity. Anticoagulation with unfractionated or low-molecular-weight heparin is safe in pregnancy and should be used if the patient meets criteria for anticoagulation described for nonpregnant patients. Ventricular arrhythmias may occur during pregnancy, particularly in patients with congenital heart disease, cardiomyopathy, or valvular disease. In hemodynamically stable patients with sustained ventricular tachycardia, both IV procainamide and lidocaine can be used for acute management. Procainamide has the same risks in pregnancy of hypo tension and QT prolongation requiring ECG monitoring. Although there are reports that lidocaine may be associated with an increase in myometrial tone, decrease in placental blood flow, and fetal bradycar dia, the use of the drug has not been linked to an increased incidence of birth defects. 22 Amiodarone is categorized as class D because its main metabolite (desethylamiodarone) and iodine cross the placenta. Chronic fetal exposure to amiodarone and its subsequent iodine overload is associated with neurotoxicity, fetal/neonatal hypothyroidism, and less frequently, goiter. Therefore, the use of amiodarone in pregnancy is limited to maternal/fetal tachyarrhythmias that are resistant to other drugs or are life threatening because short-term use has not been linked to any harmful effects. 21,23 The presence of an artificial pacemaker or implantable cardiac defi brillator does not affect the course of pregnancy.24 CHEST PAIN AND HEART FAILURE The differential diagnosis of chest pain is similar in pregnant and non pregnant women. However, aortic dissection and cardiomyopathy are actually more common in pregnancy. Advancing maternal age has made acute coronary syndrome in pregnancy more prevalent. Acute coronary syndrome is estimated to occur at least three times more often in pregnancy when compared to nonpregnant women of the same age group. 25 Acute coronary syndrome in pregnancy is especially challeng ing because it is not only seen in patients over 35 with coronary artery disease risk factors but also presents in younger, healthy women with no risk factors. Acute coronary syndrome in younger pregnant women is more likely caused by spontaneous coronary artery dissection, coro nary vasospasm, or coronary embolus, which are all extremely rare in the younger, nonpregnant patient. Spontaneous coronary artery dissection is the most common cause of pregnancy-related acute myocardial infarction, being the documented cause in >40% of cases.

ely caused by spontaneous coronary artery dissection, coro nary vasospasm, or coronary embolus, which are all extremely rare in the younger, nonpregnant patient. Spontaneous coronary artery dissection is the most common cause of pregnancy-related acute myocardial infarction, being the documented cause in >40% of cases. 26 The occurrence of spontaneous coronary artery dissection is thought to be due to progesterone and other hormone-related vessel wall changes and shear forces secondary to increased blood volume. It is most frequent in the third trimester or postpartum period. Spontaneous coronary artery dissection is fre quently found in multiple vessels and is associated with an increased incidence of cardiogenic shock, life-threatening arrhythmias, and a high maternal and fetal mortality. 27 Coronary vasospasm is more prevalent in patients with migraine headaches, suggesting an overall “vasospastic” propensity coupled with an overall increase in reactivity of the vessels in pregnancy. Coronary emboli are simply due to the fact that pregnancy itself is a hypercoagulable state, and reports indicate that close to 10% occur in otherwise normal coronary arteries. Treatment of acute coronary syndrome in pregnancy is complicated given the multiple etiologies discussed earlier. Additionally, many drugs in current acute coronary syndrome guidelines are not recommended in pregnancy (angiotensin inhibitors and statins) or have limited to no human safety data (beta-blockers, nitroglycerin, and novel anticoagu lants). Resuscitate and stabilize as you would for any nonpregnant patient and obtain emergent cardiology consultation. Although they may worsen a dissection, aspirin and heparin are reasonable choices because you will be unaware of a dissection until imaging is obtained. Use of thrombolytics during pregnancy can cause maternal hemorrhage, placental abruption, uterine bleeding, and postpartum hemorrhage. As of this writing, thrombolytic therapy is not recommended due to lack of reversibility and the risk of worsening a possible coronary dissection. Thrombolytic therapy could be considered for patients with life-threatening acute coronary syndrome when there is no access to percutaneous coronary intervention. 28 Therefore, immediate transfer to a hospital with catheterization laboratory capabilities is advised. 29 Debate continues regarding whether medical management or stent placement is the best treatment option for spontaneous coronary artery dissection given recent data showing iatrogenic dissections and propagation of dissection during stent placement and successful medical management in stable patients. Overall outcomes are significantly worse for acute coronary syndrome in pregnancy, and many who survive will eventually require emergent coronary artery bypass graft, so prompt and accurate diagnosis and referral are imperative. Peripartum cardiomyopathy is a dilated cardiomyopathy resulting in left ventricular dysfunction that usually develops in the third trimester or the first few months after delivery. Diagnosis is made when there is no apparent cause or preexisting history of cardiac disease. Risk factors include multiparity, maternal age >40 years old, and gestational hyper tension. Peripartum cardiomyopathy needs to be considered in any postpartum patient with dyspnea, especially a younger patient, because is it easily misdiagnosed as an upper respiratory infection or pneumonia. Diagnose and treat congestive heart failure and pulmonary edema with standard modalities 30 (see Chapter 53, “ Acute Heart Failure”). Sympathetic crashing acute pulmonary edema is an extreme form of flash pulmonary edema, preceded by long-standing hypertension and ventricular dysfunction, and can accompany preeclampsia or eclampsia.

reat congestive heart failure and pulmonary edema with standard modalities 30 (see Chapter 53, “ Acute Heart Failure”). Sympathetic crashing acute pulmonary edema is an extreme form of flash pulmonary edema, preceded by long-standing hypertension and ventricular dysfunction, and can accompany preeclampsia or eclampsia. Sympathetic catecholamine release causes worsening of ventricular stiffening, and the physiologic plasma increase associated with pregnancy may make it easier for sympathetic crashing acute pulmonary edema to present in pregnancy even without preceding hypertension. Initial treatment is the same for the nonpregnant patient: high-dose IV nitro glycerin (500 to 1000 micrograms) until stabilization and ventilatory support with bilevel positive airway pressure, high-flow nasal cannula, or intubation, as needed.  VENOUS THROMBOEMBOLISM Venous thromboembolism includes deep venous thrombosis (DVT) and pulmonary embolism and is the leading cause of maternal morbidity and mortality in industrialized nations as well as developing countries. 32 The risk of venous thromboembolism increases fivefold during pregnancy and is increased by even more in the first 3 months after delivery. 33,34 Pregnancy-related hypercoagulability, which is necessary to prevent maternal hemorrhage, is due to increased levels of clotting factors, increased platelet and fibrin activation, and decreased fibrinolytic activity. Pregnancy increases venous pooling and uterine compression of the inferior vena cava and iliac veins. Clots develop in the deep venous system of the legs and pelvis. Up to 20% of DVTs may be complicated by pulmonary embolism, so early DVT diagnosis is important. DEEP VENOUS THROMBOSIS  CLINICAL PRESENTATION The clinical assessment of DVT is difficult because many of the typical clinical signs and symptoms are seen in normal pregnancy, including leg edema, shortness of breath, and tachycardia. Proximal extension of the DVT into the pelvic veins can result in abdominal or back pain, which is also very common in a normal pregnancy. DVT in pregnant women is more often left-sided (85% vs. 55% nonpregnant) and is more com monly found in proximal iliofemoral veins (72% vs. 9% nonpregnant). Tintinalli_Sec11_p0607-0668.indd 624 8/2/19 4:20 PM

VT into the pelvic veins can result in abdominal or back pain, which is also very common in a normal pregnancy. DVT in pregnant women is more often left-sided (85% vs. 55% nonpregnant) and is more com monly found in proximal iliofemoral veins (72% vs. 9% nonpregnant). Tintinalli_Sec11_p0607-0668.indd 624 8/2/19 4:20 PM CHAPTER 99: Comorbid Disorders in Pregnancy 625 Up to 10% of pregnancy-related DVTs may be found in the pelvic veins, which is uncommon in nonpregnant patients. 37 However, any patient with unilateral calf pain and swelling, swelling of the entire leg, or groin or back pain needs to be evaluated for DVT. Additional risk factors include a previous history or family history of DVT, obesity, maternal age >35 years, smoking, sickle cell disease, diabetes, hypertension, immobility, in vitro fertilization (greater for twins than for single gestation), and preeclampsia.  WELLS’ SCORE The Wells’ score for DVT (see Table 56-6), the most validated clinical decision rule in the diagnosis of DVT, has not been validated in pregnant women. 38,39 Chan’s LEFt clinical prediction tool is the only pregnancyspecific, validated prediction tool available. Three variables—symptoms in the left leg (L), calf circumference difference >2 cm (edema [E]), and first trimester (Ft) presentation—are predictive of positive imaging for DVT in pregnant women. 40 However, the LEFt rule does not help after the first trimester and has not yet been applied prospectively in clinical trials. Therefore, it should not be used in isolation to rule out DVT.  D-DIMER D-dimer levels normally increase throughout pregnancy, and there is no agreed-upon cutoff for a venous thromboembolism–associated D-dimer increase in pregnant women. The high negative predictive value of a normal D-dimer in pregnancy has many wanting to forgo imaging; however, thromboembolism has been reported with normal D-dimer levels. 41 As of this writing, the American College of Obstetricians and Gynecologists, the Society of Obstetricians and Gynaecologists of Canada, the Royal College of Obstetricians and Gynaecologists, and the American Thoracic Society/Society of Thoracic Radiology recommend against the use of D-dimer alone to rule out pulmonary embolism in pregnant women.  COMPRESSION DUPLEX ULTRASOUND Compression duplex US with color flow Doppler is the first-line imag ing technique given the safety profile, and sensitivity and specificity for detecting proximal DVT are 96% and 99%, respectively. Compression US is less sensitive in detecting DVT below the knee just as in nonpregnant patients; therefore, repeat imaging is recom mended. There is a large prospective study under way to evaluate the use of whole-leg US to catch distal DVTs, which have a 10% to 20% risk of propagation in the nonpregnant patient. 42,43 There is continued debate on whether to treat distal (below the knee) DVT or to repeat US to rule out progression; however, it is recommended to treat any DVT found in pregnancy. 35 Emergency physicians have become proficient at performing their own DVT US exams at the bedside and have published considerable literature showing the utility of a limited 2-point exam (and D-dimer) to rule out DVT. 44,45 However, there have been no studies of limited US on pregnant patients. Iliac or pelvic vein thrombosis is more difficult to diagnose if isolated and not associated with clot in the femoral vein. Magnetic resonance venography is an MRI that uses a special technique to specifically look at blood vessels. Magnetic resonance venography has been shown to be sensitive and specific for the detection of pelvic vein thrombosis without the need for gadolinium contrast.

d and not associated with clot in the femoral vein. Magnetic resonance venography is an MRI that uses a special technique to specifically look at blood vessels. Magnetic resonance venography has been shown to be sensitive and specific for the detection of pelvic vein thrombosis without the need for gadolinium contrast. 46-48 MRI or magnetic resonance venography without contrast should be the preferred method to evaluate pelvic vein thrombosis with the addition of contrast only if absolutely necessary. PULMONARY EMBOLISM Pregnant women with symptoms suggestive of pulmonary embolism who are positive for DVT by compression US should receive anticoagulation without waiting for further confirmatory diagnostic studies. In hemodynamically stable patients, consider no further imaging to spare the mother and fetus from additional radiation exposure. In unstable patients, further imaging may be required to eliminate other causes of hypotension and evaluate the need for aggressive treatment. Bedside or formal echocardiography can detect acute right ventricular dysfunction, which suggests a large clot burden that may benefit from more aggres sive therapy than standard anticoagulation alone. 49,50 Patients with symptoms suggestive of pulmonary embolism with a normal compression US of the extremities require further diagnostic testing. The current acceptable options are CT pulmonary angiography and pulmonary ventilation-perfusion scanning. CT pulmonary angiog raphy has somewhat higher maternal breast radiation, and ventilationperfusion scans have higher fetal radiation exposure. However, as of this writing, the fetal and maternal radiation dose with either modality is felt to be within acceptable limits. 51 Typically, in most institutions, a consensus is obtained between emergency physicians, obstetricians, and radiologists for imaging decisions. Table 99-1 lists advantages and disadvantages of different imaging modalities. CT pulmonary angiography is frequently recommended as the firstline diagnostic test of choice. 32,52 However, there are also published algorithms that suggest proceeding to ventilation-perfusion first, if chest radiograph is normal in pregnancy, as there is a lower incidence of artifact or concomitant chronic disease, which typically impedes accuracy in older patients. 35,53 However, if the ventilation-perfusion scan is non diagnostic, then the patient will need CT pulmonary angiography, and any perceived benefit of less harmful radiation exposure is lost. Time to completion of imaging should also factor in the imaging decisions as there should be as little delay as possible in making the correct diagnosis and initiation of treatment. TABLE 99-1 Imaging Modalities for Diagnosis of Pulmonary Embolism in Pregnancy Radiation Limitations Disadvantages Advantages Lactation Chest radiograph Minimal Nonspecific and nonsensitive Results determine next imaging study, requiring more time to diagnosis May identify another cause of pulmonary symptoms No change CTPA High maternal breast radiation; lower fetal radiation than V. /Q. scan Contrast allergy and renal insufficiency Hyperdynamic state in pregnancy can affect interpretation High sensitivity and specificity; needed if abnormal chest radiograph No need to discard breast milk V. /Q.

cause of pulmonary symptoms No change CTPA High maternal breast radiation; lower fetal radiation than V. /Q. scan Contrast allergy and renal insufficiency Hyperdynamic state in pregnancy can affect interpretation High sensitivity and specificity; needed if abnormal chest radiograph No need to discard breast milk V. /Q. scan Low breast radiation but higher fetal radiation than CTPA Not useful if abnormal chest radiograph, asthma, COPD, or underlying pulmonary disease If negative or inconclusive and suspicion for PE remains, will need a CTPA; limited availability and time for isotope preparation, which delays diagnosis Negative perfusion study effectively rules out PE Discard breast milk for 12 h MRI/MRV No radiation and no evidence of uncontrasted MRI having adverse fetal effects Gadolinium during any time of pregnancy associated with an increased risk of negative fetal outcomes Limited availability Can detect pelvic and iliac thrombosis No need to discard breast milk if uncontrasted MRI Abbreviations: COPD = chronic obstructive pulmonary disease; CTPA = chest CT pulmonary angiography; MRV = magnetic resonance venography; PE = pulmonary embolism; V . /Q . scan = ventilation-perfusion scan. Tintinalli_Sec11_p0607-0668.indd 625 8/2/19 4:20 PM

thrombosis No need to discard breast milk if uncontrasted MRI Abbreviations: COPD = chronic obstructive pulmonary disease; CTPA = chest CT pulmonary angiography; MRV = magnetic resonance venography; PE = pulmonary embolism; V . /Q . scan = ventilation-perfusion scan. Tintinalli_Sec11_p0607-0668.indd 625 8/2/19 4:20 PM 626 SECTION 11: Obstetrics and Gynecology TREATMENT OF DEEP VENOUS THROMBOSIS AND PULMONARY EMBOLISM Treatment of venous thromboembolism in pregnancy currently includes unfractionated heparin or low-molecular-weight heparin because neither crosses the placental barrier. 54 Most published guidelines recommend low-molecular-weight heparin as the first-line treatment of pregnant women with acute venous thromboembolism. 35 Low-molecular-weight heparin is highly efficacious, has a low risk of bleeding complications, and has negligible risk of heparin-induced thrombocytopenia, and most patients do not need daily drug activity monitoring. Unfractionated heparin may be used for patients at extremes of body weight or patients with recurrent venous thromboembolism while on therapeutic anticoagulation, since the activated PTT or anti–factor Xa levels will be monitored and doses can be adjusted to ensure therapeutic effect. Unfractionated heparin can be given IV through a continuous infusion or SC twice-daily injections. Protamine sulfate may be used safely in pregnancy for patients who require rapid reversal of heparin anticoagulation. Fondaparinux, a synthetic, selective anti–factor Xa inhibitor, is rec ommended in the United States for the prevention and treatment of venous thromboembolism in heparin-allergic or heparin-intolerant pregnant patients. Do not use warfarin in pregnancy because it crosses the placenta and is associated with embryopathy in the first trimester; in the second and third trimesters, it may lead to CNS and ophthalmologic abnormalities. Warfarin should only be considered for women with mechanical heart valves who demonstrate a very high risk of venous thromboembolism despite treatment with unfractionated heparin or low-molecular-weight heparin. An inferior vena cava filter is indicated when anticoagulation is con traindicated, when an acute embolic event occurs despite anticoagulation, or when acute venous thromboembolism occurs with impending delivery of the fetus. TREATMENT OF LIFE-THREATENING PULMONARY EMBOLISM Massive or high-risk pulmonary embolism is defined as sustained hypotension (systolic blood pressure of <90 mm Hg for more than 15 minutes) with the patient showing symptoms of shock. Thrombolytic therapy is a key treatment option for patients in extremis from pul monary embolism, with treatment options ranging from systemic and catheter-guided thrombolysis to surgical or catheter-guided embolec tomy. Although data are limited, thrombolytics have been used suc cessfully and data regarding maternal-fetal outcomes are limited to case reports. 56,57 As of this writing, there is no formal consensus on whether systemic versus catheter-guided treatment is preferred. Catheter-guided thrombolysis and embolectomy require precious time for prepara tion. Recombinant tissue plasminogen activator (10-milligram bolus, 90-milligram infusion over 2 hours) does not cross the placenta, and reported rates of maternal bleeding complications are between 1% and 6% with no maternal deaths, and rates of fetal loss are between 2% and 5%. 56-59 Streptokinase (250,000-unit bolus, 100,000 units/h infusion for 24 hours) is also used, but with higher rates of subchorionic hemorrhage and allergic complications and longer infusion duration than tissue plasminogen activator. Catheter-directed thrombolysis allows for earlier reperfusion and likely improved long-term pulmonary function com pared with systemic therapy.

infusion for 24 hours) is also used, but with higher rates of subchorionic hemorrhage and allergic complications and longer infusion duration than tissue plasminogen activator. Catheter-directed thrombolysis allows for earlier reperfusion and likely improved long-term pulmonary function com pared with systemic therapy.  ACUTE ASTHMA Asthma is the most common medical disease in pregnancy and complicates between 3.7% and 8.4% of all pregnancies. 60,61 The clinical course may improve, remain unchanged, or worsen during pregnancy. Women with asthma have higher odds of preeclampsia, gestational diabetes, placental abruption, placenta previa, preterm delivery, low birth weight, maternal hemorrhage, pulmonary embolism, and intensive care unit admission. Symptoms of cough, wheezing, and dyspnea are the same as in non pregnant patients. Initial assessment should include history of asthma exacerbations and intubation, peak expiratory flow rate measurements or forced expiratory volume in 1 second, physical examination, assessment of oxygen saturation, and a fetal assessment (if >20 weeks’ gesta tion). Peak expiratory flow rate is not altered in pregnancy, with normal rates ranging between 380 and 550 L/min. Use peak expiratory flow rate as a guide to therapy. If the pregnancy has reached viability, apply continuous electronic fetal monitoring. Treat rapidly and aggressively to reduce readmission rates and improve fetal outcomes. 63 The principles of management are the same as in nonpregnant patients. Maintain oxygen saturation >95%, administer repetitive or continuous inhaled β2-agonist (albuterol/salbutamol); give inhaled ipratropium and systemic corticosteroids; give IV magnesium; monitor maternal response to therapy; and monitor the fetus for signs of distress. Terbutaline sulfate, 0.25 milligram every 20 minutes, administered SC, may be used if needed. Avoid epinephrine because concerns exist about epinephrine vasoconstriction of the uteroplacental circulation. Admission and discharge criteria are the same as in the nonasthmatic patient. For discharged women, prescribe oral prednisone, 40 to 60 milligrams per day (or equivalent), for 5 to 10 days, and a shortacting rescue beta-agonist. Anticipate maternal hyperglycemia when systemic corticosteroids are given. Inhaled corticosteroids reduce recurrence during pregnancy and decrease readmission rates following a hospitalization for asthma. Budesonide has been safely used in pregnancy. Emphasize close follow-up and development of formal asthma treat ment plans to minimize exacerbations as the pregnancy progresses.66  ASYMPTOMATIC BACTERIURIA, CYSTITIS, AND PYELONEPHRITIS Hormonal and mechanical changes of pregnancy increase the risk of urinary stasis and subsequent urinary tract infection. After mid-pregnancy, mild right-sided hydronephrosis is found in 75% of women, and mild left-sided hydronephrosis is found in 33%. Asymptomatic bacteriuria is diagnosed by urine culture, demonstrating the presence of bacteria in the urine in the absence of maternal symptoms of urinary tract infection. Reagent strips have limited sen sitivity, and use in screening depends on resources available, but in general, a positive leukocyte esterase or urinary nitrite should be treated and a negative specimen should be cultured. 67,68 Treatment reduces the incidence of pyelonephritis and low birth weight.69 Causative organisms of symptomatic cystitis and pyelonephritis are similar to those in the general population and include Escherichia coli (75%), Klebsiella pneumoniae, Proteus, and gram-positive organisms such as group B Streptococcus. Obtain a urinalysis and culture with drug sensitivities in pregnant women with urinary tract symptoms and also in those with hyperemesis.

ephritis are similar to those in the general population and include Escherichia coli (75%), Klebsiella pneumoniae, Proteus, and gram-positive organisms such as group B Streptococcus. Obtain a urinalysis and culture with drug sensitivities in pregnant women with urinary tract symptoms and also in those with hyperemesis. Urinary tract infections need prompt treatment because acute pyelonephritis can precipitate preterm labor, bacteremia, or septic shock. Recurrent infections can occur as a result of bacteriuria, glycosuria, and mechanical compression of the ureter in the third trimester. Reflux nephropathy increases the risk of sudden escalating hypertension and worsening renal function. 70 Urolithiasis is associated with recurrent urinary tract infections. First-line treatment for asymptomatic bacteriuria and simple cystitis is either amoxicillin, 500 milligrams PO two to three times daily for 3 to 7 days, or cephalexin, 500 milligrams two to four times daily for 3 to 7 days. Recent studies have raised concerns about possible nitrofurantoinlinked birth defects, and although it is still pregnancy class B, current American College of Obstetricians and Gynecologists guidelines recommend to avoid nitrofurantoin in the first trimester unless there are no other options available. 72,73 Trimethoprim-sulfamethoxazole is also not a good choice in preg nancy. Trimethoprim, a folate antagonist, can be used after the first trimester; sulfonamides can be taken during the first and second trimesters but not during the third trimester because sulfonamides can cause kernicterus in the infant. Do not use fluoroquinolones and tetracyclines during pregnancy. Fluoroquinolones are avoided because Tintinalli_Sec11_p0607-0668.indd 626 8/2/19 4:20 PM

rimester; sulfonamides can be taken during the first and second trimesters but not during the third trimester because sulfonamides can cause kernicterus in the infant. Do not use fluoroquinolones and tetracyclines during pregnancy. Fluoroquinolones are avoided because Tintinalli_Sec11_p0607-0668.indd 626 8/2/19 4:20 PM CHAPTER 99: Comorbid Disorders in Pregnancy 627 of observed fetal malformations in animal studies. Tetracyclines impair bone and tooth calcification. Pregnant women with pyelonephritis are generally hospitalized, aggressively hydrated, and treated with parenteral antibiotics. The antibiotic of choice is a second- or third-generation cephalosporin. Continue IV antibiotics until the patient is afebrile for at least 48 hours and costovertebral angle tenderness has resolved. The most common reason for treatment failure is antibiotic resistance. Patients discharged after hospitalization need to complete a 10-day course of therapy. Many providers choose to continue women with an episode of pyelonephritis on antibiotic suppression for the remainder of pregnancy.  HEADACHE AND STROKE SYNDROMES IN PREGNANCY In pregnant women, headaches can be a symptom of a variety of neurologic or systemic disorders. Table 99-2 lists the differential diagnosis of headaches in pregnancy (see Chapter 165, “Headache”). Warning symptoms and signs of a potentially life-threatening disease are important to elicit during the initial evaluation and are listed in Table 99-3. Obtain imaging studies if concerning signs or symptoms are encountered. CT scan of the brain can be safely performed with appropriate shielding of the fetus. CT scan is best to evaluate acute intracranial or subarachnoid hemorrhage, whereas MRI is superior for evaluation of cerebral infarct, tumor, infection, or cerebral vein thrombosis. INTRACEREBRAL HEMORRHAGE In pregnancy, the incidence of intracerebral hemorrhage ranges from 0.01% to 0.05%, but is the cause for 5% to 12% of all maternal deaths. The risk of cerebral hemorrhage extends from pregnancy through the 6-week postpartum period. 74 Risk factors include older maternal age, African-American race, and alcohol or cocaine use. The most common cause for spontaneous intracerebral hemorrhage is hypertension. If there is no history of hypertension, then consider other causes such as neoplasm, hemorrhagic disorder, and vascular malformation. Presenting symptoms vary with the location and extent of hemor rhage, so consider cerebral hemorrhage in a woman with an abrupt neurologic change. For diagnosis, obtain CT/MRI and consult the neurosurgeon. Treatment is blood pressure control and correction of coagulopathy. SUBARACHNOID HEMORRHAGE Subarachnoid hemorrhage during pregnancy is the third most common cause of nonobstetric maternal death, and more than half of cases occur postpartum. 74 Causes include hypertension, 75 aneurysm, vascular mal formation, tumors, and venous thrombosis. Independent risk factors for subarachnoid hemorrhage from all etiologies include advancing age; African-American race; Hispanic ethnicity; hypertensive disorders; coagulopathy; tobacco, drug, or alcohol abuse; intracranial venous thrombosis; sickle cell disease; and hypercoagulability. Suspect subarachnoid hemorrhage in a woman with severe headache, nausea, vomiting, decreased level of consciousness, or seizure. Diagnosis is by CT/MRI and/or lumbar puncture. In general, pregnant women should be treated the same as nonpregnant patients with bed rest, anal gesia, sedation, neurologic monitoring, and control of blood pressure. STROKE Pregnancy is associated with an increased risk of ischemic and hemorrhagic stroke, and stroke contributes to more than 12% of all maternal deaths, with the majority occurring in the third trimester or puerperium .

patients with bed rest, anal gesia, sedation, neurologic monitoring, and control of blood pressure. STROKE Pregnancy is associated with an increased risk of ischemic and hemorrhagic stroke, and stroke contributes to more than 12% of all maternal deaths, with the majority occurring in the third trimester or puerperium . 76 Arterial occlusion is the most common cause of pregnancy-related stroke. 76 Risk factors include hypertension, heart disease, smoking, diabetes, lupus, sickle cell disease, African-American heritage, substance abuse, and cesarean delivery. Consider stroke in women with neurologic deterioration or new focal neurologic deficits. Once hemorrhage and eclampsia are excluded, consider thrombolytic therapy after consultation with neurology and obstetrics. To date, there are no randomized controlled trials of thrombolytics for stroke in pregnancy; however, recombinant tissue plasminogen activator (risk category C) does not cross the placenta, and there is no evidence of teratogenicity in animal studies. 77 There are more than 200 reports in the literature of pregnant women who have received thrombolytic therapy for various indications including myocardial infarction, pulmonary embolism, superior vena cava syndrome, and ischemic stroke. 76 Use of thrombolytics in pregnancy is not without its risks, although the overall maternal mortality and fetal loss are relatively low at 1% and 6%, respectively.76,78 CENTRAL VENOUS THROMBOSIS Central venous thrombosis usually presents in the second and third trimesters and may occur up to 4 weeks postpartum. Symptoms include severe headache, focal neurologic deficit, vomiting, or seizure, depend ing on which veins are occluded. Venous thrombosis increases venous pressure and cerebral blood volume, elevating dural sinus pressure and leading to rupture of small cortical veins. Treatment is low-molecularweight heparin, unless there is associated intracranial hemorrhage. Once the patient has been stabilized and hemorrhage from an aneurysm is excluded, the mainstay of treatment for the underlying thrombosis is still anticoagulation for the duration of the pregnancy. MIGRAINE HEADACHE Most patients see an improvement in migraine frequency as the preg nancy progresses; therefore, address red flag symptoms and consider other life-threatening causes of severe headache (central venous thrombosis) especially in the second or third trimester before diagnosing TABLE 99-2 Causes of Headaches in Pregnancy Life threatening •  Subarachnoid  hemorrhage •  Intraparenchymal  hemorrhage •  Central  venous thrombosis •  Ischemic  stroke •  CNS  tumor or infection •  Preeclampsia/eclampsia •  Meningitis Non–life threatening •  Tension  headache •  Migraine •  Sinus  headache •  Benign  intracranial hypertension (pseudotumor cerebri) TABLE 99-3 Warning Symptoms and Signs of Headaches •  New-onset  headaches in pregnancy •  Postpartum  headaches •  Visual  disturbance or visual field defect •  Headaches  with different characteristics from previous headaches •  Worst  headache of life, reaching maximum intensity in <1 min •  Focal  neurologic deficit or seizure •  Meningismus •  Fever •  Altered  consciousness or personality changes •  Papilledema  or other signs of increased intracranial pressure •  Retinal  hemorrhages •  Increased  blood pressure (may herald preeclampsia or eclampsia) Tintinalli_Sec11_p0607-0668.indd 627 8/2/19 4:20 PM

Focal  neurologic deficit or seizure •  Meningismus •  Fever •  Altered  consciousness or personality changes •  Papilledema  or other signs of increased intracranial pressure •  Retinal  hemorrhages •  Increased  blood pressure (may herald preeclampsia or eclampsia) Tintinalli_Sec11_p0607-0668.indd 627 8/2/19 4:20 PM 628 SECTION 11: Obstetrics and Gynecology migraine. Although the ergot alkaloids are contraindicated in preg nancy, acute migraine headaches can be successfully treated in preg nancy with the same first-line antiemetics that are used in nonpregnant patients. Metoclopramide (Reglan ® ) is class B, and prochlorperazine (Compazine® ), promethazine (Phenergan® ), and droperidol (Inapsine® ) are all class C. Avoid NSAIDs. Sumatriptans (class C) do not appear to increase fetal malformations, and if already prescribed by the obstetri cian or primary physician during pregnancy, sumatriptans can be con tinued as an outpatient.  GI DISORDERS IN PREGNANCY GASTROESOPHAGEAL REFLUX DISEASE Gastroesophageal reflux disease is extremely common in pregnancy and is characterized by epigastric pain or burning radiating into the chest and neck, pain with recumbency, and pain exacerbated by acidic foods. Symptoms increase in the second trimester and peak in the third tri mester due to loosening of the lower esophageal sphincter and delayed gastric emptying from pregnancy-related hormones. Always reinforce lifestyle modifications such as elevating the head of bed, not eating 3 hours before bed, eating small meals, and eliminating trigger foods. Over-the-counter antacids are safe and effective and should be first-line medical therapy. Treat mild, persisting symptoms with H 2 antagonists such as cimetidine or ranitidine. Moderate to severe symptoms can be treated with sucralfate and proton pump inhibitors. H 2 antagonists, proton pump inhibitors, and metoclopramide have been extensively studied for teratogenic effects, and no significant abnormal findings have been associated with their use in pregnancy. HEMORRHOIDS Hemorrhoids are common during pregnancy and are caused by a com bination of constipation due to slowed bowel transit from progesterone effects in the last trimester and elevated pressure in the veins below the level of the enlarged uterus. Most symptoms are mild and can be treated with prevention of constipation with increased fluids and high-fiber intake, sitz baths, and topical medications including witch hazel com presses, suppositories, corticosteroids, or topically applied anesthetics. Do not use agents containing epinephrine or phenylephrine. Proctofoam has specifically been studied and is safe. 83 Consider surgical or obstetric referral for prolapsed, bleeding, or incarcerated hemorrhoids or when conservative measures fail. There are no studies of the risks versus benefits of ED excision of a thrombosed clot in pregnancy. Risks include hemorrhage and recurrence. CHOLECYSTITIS During pregnancy, approximately 1 in 1000 women will develop chole cystitis. Pregnancy-related hormones affect gallbladder contractility and increase residual gallbladder volume and sludge, which in turn can lead to gallstone formation. Many women ultimately require cholecystec tomy during pregnancy for persistent symptoms. It is preferable to wait until the second trimester if the patient’s condition allows, as surgery during the first trimester carries a risk of spontaneous miscarriage, and cholecystectomy in the third trimester is technically difficult and can result in preterm labor. APPENDICITIS Appendicitis occurs about once in every 500 to 2000 pregnancies and is the most common extrauterine condition requiring abdominal opera tion in pregnancy.

rimester carries a risk of spontaneous miscarriage, and cholecystectomy in the third trimester is technically difficult and can result in preterm labor. APPENDICITIS Appendicitis occurs about once in every 500 to 2000 pregnancies and is the most common extrauterine condition requiring abdominal opera tion in pregnancy. The diagnosis is often missed or delayed because mild abdominal discomfort, nausea, and vomiting occur frequently in normal pregnancies. Additionally, the appendix shifts in location from the right lower quadrant to the right upper quadrant during the second and third trimesters. US has become the first diagnostic test of choice in children and many adults. However, in pregnant patients, adequate visualization of the appendix is difficult, especially later in pregnancy. Recent studies suggest using MRI as the initial imaging modality given the high rate of inconclusive US results. 85-87 Noncontrast MRI (without gadolinium) is recommended due to recent concerns of fetal effects from gadolinium exposure. If US or MRI is unavailable, CT should be performed with out delay. Focal appendiceal CT may be considered since it provides less radiation to the fetus than full abdominopelvic CT. However, focal abdominal imaging may limit discovery of an alternative diagnosis. An abdomen or pelvis CT confers about 30 mGy of radiation, and 50 mGy of radiation is generally accepted to be safe in pregnancy.  OVARIAN TORSION Torsion of the ovary is a true gynecologic emergency, and up to one fifth of ovarian torsion occurs during pregnancy. Torsion can occur in any trimester, although it is most common in the first trimester. 88 Infertility treatment is a risk factor. Ovarian torsion can recur in the same preg nancy, in particular in enlarged multicystic ovaries. 89 The corpus luteal cyst and enlarged ovaries stemming from the pregnancy hormones are thought to increase the risk. Tissue necrosis can occur rapidly, so timely diagnosis is essential to preserve ovarian function and the pregnancy. The diagnosis is often missed due to the vague clinical presentation of moderate unilateral lower abdominal pain, which may also be intermittent or constant. US may show an enlarged or edematous ovary with absent or decreased blood flow. However, the presence of ovarian blood flow does not exclude the diagnosis of torsion if symptoms are suggestive. 90 Therefore, consult an obstetrician/gynecologist as soon as the diagnosis is clinically suspected.  SEIZURE DISORDERS Seizure frequency can increase in pregnancy because of the increased volume of distribution and plasma clearance of antiepileptic drugs in pregnancy or because of poor medication compliance. Most of the antiepileptic drugs can cause a range of birth defects. Valproic acid, carbamazepine, and phenytoin are still listed under the old U.S. Food and Drug Administration classification as class D. Y et, discontinuing these drugs can increase morbidity and mortality for both the mother and fetus. Therefore, the risks and benefits of chronic treat ment should be discussed and managed by the primary physician. Medication doses may need to be increased in pregnancy. Therapeutic serum target levels remain unchanged. Monotherapy with levetiracetam or lamotrigine should be used whenever possible . 91 Acute treatment of seizures in the pregnant woman is similar to that in the nonpregnant patient (see Chapter 171, “Seizures and Status Epilepticus in Adults”). Even though lorazepam and diazepam are class D medications, they are so categorized based on long-term use. Use of benzodiazepines for an acute seizure outweighs any potential risk to the fetus. 92,93 If the seizure if self-limited, administer oxygen and position the patient in the left lateral decubitus position and provide supportive care.

nd diazepam are class D medications, they are so categorized based on long-term use. Use of benzodiazepines for an acute seizure outweighs any potential risk to the fetus. 92,93 If the seizure if self-limited, administer oxygen and position the patient in the left lateral decubitus position and provide supportive care. Fetal bradycardia lasting for up to 20 minutes may follow a single brief maternal seizure. Status epilepticus poses a real threat to both mother and the fetus, with a significant maternal and fetal mortality. Provide aggressive management, including intubation and ventilation, early in the management of pregnant women with status epilepticus (see Chapter 171).  HUMAN IMMUNODEFICIENCY VIRUS INFECTION Pregnancy does not appear to alter the natural course of human immu nodeficiency virus (HIV) disease, nor do uninfected babies born to HIV-positive women appear to be at increased risk for neonatal com plications when compared with appropriate control patients. With over 1 million women of childbearing age living with HIV in the United States, it is important to initiate antiretroviral therapy as soon as possible not only for the health of the mother but also because appropriate therapy can eliminate mother-to-child transmission. Tintinalli_Sec11_p0607-0668.indd 628 8/2/19 4:20 PM

over 1 million women of childbearing age living with HIV in the United States, it is important to initiate antiretroviral therapy as soon as possible not only for the health of the mother but also because appropriate therapy can eliminate mother-to-child transmission. Tintinalli_Sec11_p0607-0668.indd 628 8/2/19 4:20 PM CHAPTER 99: Comorbid Disorders in Pregnancy 629 In general, women who are already on a fully suppressive regimen when they become pregnant should continue their regimens. Key exceptions include medications with high risk for toxicity in pregnancy (didanosine, stavudine, and treatment-dose ritonavir).95 Another exception would be efavirenz, which is a highly recommended drug as part of a three-drug regimen, but it is not recommended until after the first 8 weeks of pregnancy. However, if an HIV-infected woman who is already taking efavirenz becomes pregnant, the regimen may be continued because changing it risks loss of virologic control. 94 Additionally, some common drug regimens, such as elvitegravir/cobicistat, are not as effective in pregnancy. These drugs should be replaced with antiretrovirals recommended in pregnancy. Recommended optimal initial regimens for most patients include three different drugs: two nucleoside reverse transcriptase inhibitors plus an integrase strand transfer inhibitor. 94 Other effective regimens include nonnucleoside reverse transcriptase inhibitors or boosted pro tease inhibitors with two nucleoside reverse transcriptase inhibitors. There are many current drug combinations that can be safely used in pregnancy and that have different side effect profiles, number of pills or doses per day, and price points. The treatment plan should be individualized to optimize compliance and efficacy while minimizing side effects and drug interactions. Prophylaxis for opportunistic infections is similar to that for nonpregnant patients. Patients with CD4+ T-cell counts of <200/mm 3 should be maintained on prophylaxis for Pneumocystis jirovecii pneumonia using trimethoprim-sulfamethoxazole. Although a small increased risk of birth defects may be associated with first-trimester exposure to tri methoprim, women in their first trimester with P . jirovecii pneumonia still should be treated with trimethoprim-sulfamethoxazole because of its considerable benefit. Additional folate supplementation (higher than usual doses in pregnancy) may be added, but it is unclear whether the higher doses of folate supplementation lower risk. Alternatively, aerosolized pentamidine may be used in the first trimester, as it is minimally systemically absorbed. Treatment of overt opportunistic infections in HIV-infected pregnant women is addressed in the same way as in nonpregnant women. Early intubation to reverse hypoxemia may be necessary to improve maternalfetal outcome in women with respiratory infections.  SUBSTANCE ABUSE DURING PREGNANCY Substance abuse in pregnancy results in approximately 225,000 infants yearly with prenatal exposure. 97 Refer pregnant women identified in the ED as substance abusers to a high-risk obstetrics clinic and offer them substance abuse counseling. COCAINE Cocaine use is associated with placental abruption, fetal death in utero, intrauterine growth restriction, preterm labor, premature rupture of membranes, spontaneous abortion, and cerebral infarcts in the fetus. Maternal complications of cocaine use include myocardial infarction, hypertension (which can result in aortic dissection), pulmonary edema, and cardiac dysrhythmias. Subarachnoid hemorrhage, ruptured aneu rysms, and strokes are reported in cocaine users and are most likely related to transient hypertension.

the fetus. Maternal complications of cocaine use include myocardial infarction, hypertension (which can result in aortic dissection), pulmonary edema, and cardiac dysrhythmias. Subarachnoid hemorrhage, ruptured aneu rysms, and strokes are reported in cocaine users and are most likely related to transient hypertension. Treatment of the pregnant woman with acute cocaine intoxication is handled in the same manner as in the nonpregnant patient (see Chapter 187, “Cocaine and Amphetamines”). OPIOIDS Although acute opioid withdrawal poses minimal maternal risk, there is significant risk to the fetus, including meconium, hypoxia, preterm labor, and fetal demise. 98 Illicit opioid use can cause intermittent fetal withdrawal when there is maternal lack of access to the drug. Therefore, it is standard to refer opioid-addicted pregnant patients for supervised methadone or buprenorphine therapy for the duration of the pregnancy. Even though methadone/buprenorphine will cause neonatal abstinence syndrome (opioid withdrawal) after birth, this is a treatable condition and carries less harm to the infant than acute opioid withdrawal in utero. Maternal detoxification from opioids should be done in a supervised inpatient setting, and only for select patients, as the relapse rate is very high. Mild maternal opioid withdrawal can be treated with clonidine, 0.1 to 0.2 milligram every 4 to 6 hours, until the signs of withdrawal resolve. Severe maternal opioid withdrawal may require administration of an opioid agonist and admission for fetal monitoring and induction of methadone therapy. 98,99 ALCOHOL Alcohol consumption during pregnancy is a risk factor for fetal alcohol syndrome, birth defects, and low birth weight. Binge drinking is particularly harmful to fetal neurodevelopment. In the United States, the prevalence of fetal alcohol syndrome has been estimated at 0.5 to 2.0 cases per 1000 births, but even with conser vative estimates, the prevalence may be close to 50 cases per 1000 births in certain communities in the United States. Pregnant women who present in coma due to acute alcohol intoxica tion or in alcohol withdrawal are managed in the same way as nonpregnant patients. Disulfiram (Antabuse® ) is a potential teratogen. Do not prescribe in pregnancy .101 There are no data on disulfiram, acamprosate, or naltrexone in pregnancy, and these agents are not recommended.  INTIMATE PARTNER VIOLENCE One in four women and one in nine men in the United States have experienced rape, physical violence, or stalking by an intimate partner in their lifetime. 102 Factors associated with intimate partner violence during pregnancy are late entry into prenatal care, unintended pregnancy, drug and alcohol use, depression, and housing problems. Violence increases the risk for preterm labor, placental abruption, fetal fractures, uterine rupture, chorioamnionitis, delivering a low-birth-weight infant, and homicide. The American College of Obstetricians and Gynecologists recommends routine screening for intimate partner violence during pregnancy. 103 See Chapter 294, “Intimate Partner Violence and Abuse, ” for more discussion. Pregnant women with injuries should be treated according to usual trauma protocols. Institute fetal monitoring for direct or indirect blunt abdominal trauma and major multiple trauma. Administer Rh immu noglobulin to Rh-negative women with blunt abdominal trauma (see Chapter 25, “Resuscitation in Pregnancy”).  MEDICATIONS IN PREGNANCY AND LACTATION The classic teratogenic period is 2 to 15 weeks of gestation. During this critical time, organs are forming, and teratogens may cause malforma tion. Administration of drugs early in the period of organogenesis affects the organs developing at that specific time, such as the heart or neural tube.

PREGNANCY AND LACTATION The classic teratogenic period is 2 to 15 weeks of gestation. During this critical time, organs are forming, and teratogens may cause malforma tion. Administration of drugs early in the period of organogenesis affects the organs developing at that specific time, such as the heart or neural tube. Teratogens given closer to the end of the classic teratogenic period will affect the ear and palate. Before week 2, exposure to a teratogen produces an all-or-none effect (i.e., the conceptus either does not survive or survives without anomalies). If the organism remains viable after exposure before week 2, organ-specific anomalies do not develop because repair or replacement permits normal development. A similar insult at a later stage of development may produce organ-specific defects. In 1979, the U.S. Food and Drug Administration established five letter risk categories (A, B, C, D, or X) to indicate the potential of a drug to cause birth defects if used in pregnancy ( Table 99-4). In 2015, the U.S. Food and Drug Administration replaced the former risk letter categories with the Pregnancy and Lactation Labeling Rule, which provides more information in a new format to assist providers in assessing benefit versus risk to aid in counseling of pregnant women who need medication Tintinalli_Sec11_p0607-0668.indd 629 8/2/19 4:20 PM

ug Administration replaced the former risk letter categories with the Pregnancy and Lactation Labeling Rule, which provides more information in a new format to assist providers in assessing benefit versus risk to aid in counseling of pregnant women who need medication Tintinalli_Sec11_p0607-0668.indd 629 8/2/19 4:20 PM 630 SECTION 11: Obstetrics and Gynecology TABLE 99-5 2015 U.S. Food and Drug Administration Pregnancy and Lactation Labeling Rule Required Information on Package Insert for Every Medication In Both Pregnancy and Lactation •  Risk summary: What are the known risks in context with background risk? •  Risk  statement based on human data •  Risk  statement based on animal data •  Risk  statement based on pharmacology •  Background  risk information in general population •  Background  risk information in disease population •  Clinical considerations: What medical/disease factors should be considered? •  Disease-associated  maternal and/or embryo/fetal risk •  Dose  adjustments during pregnancy and the postpartum period •  Maternal  adverse reactions •  Fetal/neonatal  adverse reactions •  Labor  or delivery •    Data: Human and animal data and pregnancy drug registries that support the summary •   Human data: Description includes study type, number, duration, exposure information, and limitations. •   Animal data: Description includes study type, species, animal doses and basis for the exposures, duration and timing, findings, presence of maternal toxicity, and limitations. In Reproductive Potential •  Contraception •  Infertility •  Pregnancy  testing TABLE 99-6 Drugs Used in Emergency Settings With Known Adverse Effects in Human Pregnancy Drug Effect Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers Renal failure, oligohydramnios Aminoglycosides Ototoxicity (gentamicin class D, Black Box Warning) Androgenic steroids Masculinize female fetus Anticonvulsants (carbamazepine, hydantoins, valproate) Dysmorphic syndrome, anomalies, neural tube defects Antithyroid agents Fetal goiter Aspirin (high doses) Bleeding, antepartum and postpartum Cytotoxic agents (e.g., methotrexate) Multiple anomalies Erythromycin estolate Maternal hepatotoxicity Fluoroquinolones Fetal cartilage abnormality Isotretinoin Hydrocephalus, deafness, anomalies Lithium Congenital heart disease (Ebstein’s anomaly) NSAIDs (prolonged use after 32 wk) Oligohydramnios, constriction of fetal ductus arteriosus Streptomycin Fetal cranial nerve VIII damage Sulfonamides Fetal hemolysis, neonatal kernicterus (near term) Tetracyclines Fetal teeth and bone abnormalities Trimethoprim, methotrexate Folate antagonist (first trimester) Thalidomide Phocomelia Warfarin Embryopathy—nasal hypoplasia, optic atrophy TABLE 99-7 World Health Organization General Cautions for Drugs and Breastfeeding104 Guideline Drugs Breastfeeding contraindicated Anticancer drugs, radioactive substances, amphetamines, ergotamines, statins, and nitrofurantoin (for <1 mo old and for those with glucose-6-phosphate dehydrogenase deficiency) Avoid unless absolutely necessary Chloramphenicol, tetracyclines, fluoroquinolones Monitor infant for drowsiness Selected psychiatric and anticonvulsant agents Monitor infant for jaundice Sulfonamides, dapsone, sulfadoxine/ pyrimethamine (Fansidar ® ), mefloquine May inhibit lactation; use alternative drug Estrogens, thiazides TABLE 99-4 U.S. Food and Drug Administration Pregnancy Drug Categories, 1979 Drug Category Risk During Pregnancy A Controlled studies show no fetal risk in any trimester, and so the pos sibility of fetal harm is remote. B Animal studies show no fetal risk, but there are no controlled human studies.

Estrogens, thiazides TABLE 99-4 U.S. Food and Drug Administration Pregnancy Drug Categories, 1979 Drug Category Risk During Pregnancy A Controlled studies show no fetal risk in any trimester, and so the pos sibility of fetal harm is remote. B Animal studies show no fetal risk, but there are no controlled human studies. Animal studies have shown an adverse effect that was not confirmed in controlled human studies in women in the first trimester (and there is no evidence of risk in later trimesters). C Animal studies have shown adverse fetal effects (teratogenic or embryocidal), and there are no controlled studies in humans. No human or animal studies are available. Drugs should be used only if the potential benefit justifies the potential fetal risk. D Evidence of human fetal risk exists, but the benefits of use in pregnant women may be acceptable despite the risk. X Studies in animals or humans have shown fetal risk, or there is evidence of fetal risk based on human experience. The risk of use in pregnancy clearly outweighs any possible benefit. Drugs are contraindicated for use in women who are or may become pregnant. (Table 99-5). All medications approved after 2015 will be required to use the new format in the package labeling, which gives detailed infor mation about the drug. Medications approved on or after 2001 will be phased in gradually but will eventually be required to provide all the same information. However, all prescription drugs were required to remove pregnancy letter categories as of June 2018. The new labeling still does not provide a definitive yes or no answer in most cases, and clinical interpretation will be required on a case-by-case basis. Some therapeutic agents with adverse effects during pregnancy are listed in Table 99-6. The National Library of Medicine provides a detailed reference list in the Developmental and Reproductive Toxicol ogy Database. Table 99-7 lists some general cautions for using drugs during lacta tion. When prescribing, check each drug individually. Because information can change, we recommend referring to the following sources for information about drug safety in lactation: • Drugs and Lactation Database (LactMed), U.S. National Library of Medicine—http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT (accessed April 2018) • World Health Organization, Breastfeeding and Maternal Medication, http://www.who.int/maternal_child_adolescent/documents/55732/ en/ (last updated 2003; accessed July 2018) • Thomas Hale, Medications and Mothers’ Milk , ISBN-13 (978- 0984774630), Hale Publishing, May 2013, 15th ed. Tintinalli_Sec11_p0607-0668.indd 630 8/2/19 4:20 PM