Respiratory System

The physiology of breathing in pregnancy is altered by both anatomic and hormonal changes. Anatomic changes include an increase in chest diameter and circumference, as well as a rise in the level of the diaphragm. The result is a reduction in total lung capacity by 5% and functional residual capacity by 20%. In contrast, vital capacity does not change.⁴ The respiratory rate also remains constant, but because of a progesterone-mediated increase in both tidal volume and minute ventilation, PaCO₂ decreases to an average of 30 mm Hg. The sensation of dyspnea is increased during pregnancy.

Hematologic and Immunologic Systems

Blood volume increases during pregnancy by an average of 40% to 50% secondary to both plasma volume expansion and increased erythrocyte mass. Plasma volume increases approximately 50%, with a plateau reached at 30 weeks of gestation. Erythrocyte mass increases 20% to 30% over prepregnancy levels and peaks near term, with greater increases associated with iron supplementation. Asymmetric expansion of the plasma and erythrocyte mass results in a relative anemia, referred to as the physiologic anemia of pregnancy. Plasma expansion begins earlier than erythropoiesis but then stabilizes, with the nadir in hemoglobin concentration occurring between weeks 16 and 28.⁵ Hemoglobin levels normally do not drop below 10.5 g/dL during the nadir period and should measure 11 g/dL or higher during the remaining pregnancy.

Procoagulation factors are increased during pregnancy, whereas inhibitors of coagulation are reduced or unchanged. These changes in the coagulation cascade may serve to protect the mother against peripartum hemorrhage, but when combined with venous stasis and vessel wall injury, they predispose a patient to thromboembolic disease.⁶

Pregnancy has been described as a state of immunodeficiency but is more accurately described as a period of modified immune response.⁷ The peripheral white blood cell count is elevated during pregnancy; it ranges from 5110/mm³ to 12,200/mm³ during gestation and rises even higher during labor. Additionally, changes in both chemotaxis and adherence of neutrophils occur during pregnancy, as well as a shift by the immune system away from the cell-mediated immune response toward antibody-mediated immunity. This altered immune focus allows tolerance of the maternal immune system to paternal antigens but increases susceptibility to pathogens and variation in the activity of autoimmune diseases.⁸

Cardiovascular System

Changes in diaphragm position and rib cage dimension cause the heart to be displaced to the left and upward and rotated on its long axis. On radiographic studies these changes are manifested as an increase in heart silhouette in the absence of actual cardiomegaly. Likewise, this change in position is responsible for apparent left axis deviation on an electrocardiogram.

Cardiac output consistently and dramatically increases during pregnancy, with a 37% to 53% increase over prepregnancy values.⁹ This change is driven by increases in both heart rate and stroke volume. The heart rate increases 15 to 20 beats/min over pregravid rates, and stroke volume increases by 20% to 30%. In the later stages of pregnancy, decreased venous return as a result of compression of the inferior vena cava leads to decreased cardiac output. The highest levels of cardiac output occur in the right and left lateral positions; the lowest levels occur in the supine, sitting, and standing positions. Supine hypotension with symptoms such as dizziness, nausea, and syncope develop in a small number of pregnant patients (5% to 10%).⁶ Despite the increase in cardiac output, the pregnancy-associated reduction in systemic vascular resistance causes an overall reduction in maternal blood pressure. Blood pressure, like cardiac output, is dependent on position, highest when sitting and lowest in the lateral recumbent position.

Dermatologic System

Striae gravidarum (“stretch marks”) occur in 50% to 90% of pregnancies during the late second or third trimester. Mechanical stretching of the skin along with hormonal changes affecting the dermis are implicated. Hormonal stimulation of melanocyte activity is responsible for the hyperpigmentation seen in as many as 90% of pregnancies.

Genitourinary System

Changes in the urinary system during normal pregnancy include increases in kidney size, glomerular filtration rate, and renal blood flow. Additionally, dilation of the ureters, renal pelvis, and renal calices occurs as a result of mechanical compression by the expanding uterus and ovarian structures, as well as progesterone-mediated smooth muscle relaxation. The right ureter is more commonly affected than the left one, probably secondary to anatomic susceptibility. The glomerular filtration rate increases 50% over nongravid values by the end of the first trimester and is maintained throughout pregnancy. This increase and the subsequent increase in filtration fraction leads to decreases in both creatinine and blood urea nitrogen levels. The dependent edema accumulated during the day is mobilized at night, which results in increased nocturia during pregnancy. An increased incidence of glycosuria is common during pregnancy and may be unrelated to blood glucose levels or kidney dysfunction, but hematuria or proteinuria before labor should be considered pathologic.

The weight of the uterus increases from 70 to 1100 g, and intrauterine volume increases from 10 to 5000 mL. The gradual change in color of the vaginal walls to dark blue or black (Chadwick sign) is secondary to venous congestion.

Gastrointestinal System

Changes in the gastrointestinal system during pregnancy include an overall decrease in gastric tone and motility. There is also a decrease in lower esophageal sphincter tone caused by altered hormone levels. This muscle relaxation, coupled with compression of the stomach by the expanding uterus, leads to an increase in gastroesophageal reflux disease. Paradoxically, a concurrent decrease in peptic ulcer disease takes place.

Liver anatomy and function are essentially unchanged. However, serum alkaline phosphatase levels are elevated during the third trimester secondary to placental production of the isoenzyme. Gallbladder emptying is slower and less efficient during pregnancy. In addition to stasis, changes in the chemical composition of bile lead to increased formation of cholesterol crystals. The result is an increase in symptomatic cholelithiasis.

Musculoskeletal System

To counterbalance the expanding uterus and prevent an anterior shift in the center of gravity, the degree of lordosis of the lumbar spine increases throughout pregnancy, which often results in low back pain. Increased laxity of the ligament of the pubic symphysis and sacroiliac joints can also cause pain. Increasing tenderness of the breasts is common in pregnancy.

Endocrine System

Enlargement of the breasts and nipples is normal, and discharge of colostrum from the nipples during the later stages of pregnancy is not uncommon. Despite histologic changes, women remain euthyroid during pregnancy, and the slight increase in thyroid size that does occur is not clinically detectable. A palpable increase in the thyroid during pregnancy is pathologic and must be further evaluated. The results of laboratory tests commonly used to evaluate thyroid function should be within normal limits. Significant hypothyroidism during pregnancy is associated with fetal neurologic defects such as mental retardation and lower IQ scores.^10,11

The pituitary gland increases 136% in comparison with its prepregnancy size. This increase in size makes the gland more susceptible to infarction with hemorrhage (Sheehan syndrome) but does not impair the optic chiasm.

Some level of glucose intolerance is associated with pregnancy. Normal pregnancy is marked by hyperglycemia after eating, followed by hypoglycemia when fasting. Postprandial hyperglycemia ensures adequate delivery of nutrients to the fetus.

Diabetes

Diabetes occurs in approximately 3% to 5% of all gestations.¹² Three types of diabetes affect pregnancy: type 1, type 2, and gestational diabetes. Gestational diabetes accounts for 90% of cases. Fetal risks during pregnancy in women with diabetes include congenital malformation, intrauterine growth retardation, macrosomia, fetal hypoglycemia, fetal respiratory distress syndrome, neonatal hypocalcemia, hyperbilirubinemia, polycythemia, intrauterine demise, and neonatal jaundice.¹³ These risks are greatest for women with type 1 diabetes, although type 2 and gestational diabetes are also associated with a significant increase in fetal mortality.

With tight glucose control, the perinatal mortality rate of diabetic pregnancies can approach that of uncomplicated pregnancies. However, maintaining normal blood sugar levels is extremely difficult because of the changing degree of insulin resistance throughout pregnancy.

Patients who are unable to achieve glucose control with diet and exercise require insulin therapy. The side effects of oral hypoglycemic agents in pregnant patients have not been studied extensively. Some agents may be associated with an increased rate of congenital malformation, and frequently they do not provide adequate glucose control.

Diabetic ketoacidosis occurs in as many as 10% of patients with type 1 diabetes. Treatment during pregnancy is the same as for nongravid patients but should include assessment of fetal status and supportive measures such as oxygen and use of the left lateral decubitus position to maximize fetal blood flow.

Urinary Tract Infections

The incidence of acute cystitis or acute pyelonephritis is approximately 1% during pregnancy. Asymptomatic bacteriuria is a related condition in which urine culture is positive in an asymptomatic patient. The incidence of asymptomatic bacteriuria is similar in both gravid and nongravid populations, with 2% to 10% of the population being affected.^14,15 However, gravid patients have a much higher rate of progression to symptomatic infection, and as many as 40% of cases eventually progress to acute pyelonephritis. Chronic cystitis and chronic and acute pyelonephritis are associated with negative outcomes, and patients should receive antibiotic therapy. Patients with recurrent asymptomatic bacteriuria or urinary tract infection may require daily suppressive therapy or postcoital prophylaxis.

Treatment of asymptomatic bacteriuria and acute cystitis can be accomplished with 3 to 7 days of oral therapy consisting of amoxicillin, a cephalosporin, or nitrofurantoin. Unless sensitivities are known, nitrofurantoin is the preferred agent because of higher levels of resistance to the other agents. Acute pyelonephritis during pregnancy increases the risk for preterm labor and should be managed aggressively. Patients require admission and intravenous antibiotic therapy until clinical improvement is demonstrated.

Asthma

Approximately 4% of pregnancies are complicated by asthma,^16,17 roughly mirroring its incidence in women of childbearing age. The course of asthma during pregnancy is not uniformly predictable. One third of patients will have improvement in their symptoms during pregnancy, one third will experience stable disease, and another third will have worsening of their symptoms.¹⁸ Though somewhat controversial, patients with asthma have been reported to have increased rates of preeclampsia, cesarean delivery, and preterm rupture of membranes. Fetal risks include increased mortality, prematurity, intrauterine growth retardation, and low birth weight.

Monitoring and treatment of asthma in pregnant patients are much the same as for nonpregnant patients. Commonly used measures include the peak expiratory flow rate and forced expiratory flow in 1 second. Beta-agonists are the initial medication of choice both for acute exacerbation and for maintenance. Inhaled corticosteroids are safe and effective, but intravenous corticosteroids may be required during acute exacerbations.

Seizure Disorders

Epilepsy is associated with an increased incidence of obstetric and fetal complications. However, more than 90% of pregnant women with epilepsy have a normal pregnancy with a good outcome.¹⁹ Seizure disorders affect approximately 1% of the general population and affect a similar percentage of gestations. As many as one third of women with epilepsy experience an increase in seizure activity during pregnancy. Patients with a higher pregravid incidence of seizures are at greater risk for increased seizure frequency during pregnancy. Increased seizure activity may result from decreased compliance with medical therapy, altered pharmacologic distribution, increased elimination of medications, or a combination of factors.

Status epilepticus during pregnancy is a grave danger for both the mother and fetus and should be treated aggressively with early intubation, pharmacologic therapy, and evaluation for eclampsia. Benzodiazepines, phenytoin, and fosphenytoin are all effective in the treatment of status epilepticus. New seizure activity during pregnancy merits investigation to determine its cause; eclampsia should be suspected in the third trimester.

Migraine

Migraine symptoms are reduced or resolved in 60% to 80% of women during pregnancy.²⁰ Acceptable pharmacologic agents to treat symptoms include acetaminophen, narcotics, and antiemetics such as prochlorperazine, promethazine, and metoclopramide. Caffeine is sometimes effective and may be used in moderation. Propranolol is generally considered safe for migraine prophylaxis but may carry a risk for intrauterine growth retardation.

Other commonly used agents should be avoided. Ergotamines may cause birth defects secondary to vascular alteration. Triptans may cause vasospasm resulting in an increased incidence of preterm birth and intrauterine growth retardation. As is the case in other conditions, nonsteroidal antiinflammatory drugs (NSAIDs) should be avoided.

Thromboembolic Disease

Thromboembolic disease is a major source of maternal morbidity and mortality during pregnancy. The incidence of venous thromboembolism increases by a factor of 5 during pregnancy, and pulmonary embolism is a leading cause of maternal mortality in the United States.²¹ Factors believed to contribute to the increased incidence of venous thromboembolism include alteration of normal clotting factor levels, increased stasis, and vessel damage. These factors may be aggravated by advanced maternal age and inherited or acquired thrombophilias.

Ultrasonography safely and reliably detects lower extremity deep vein thrombosis. If pelvic or iliac thrombosis is suspected, venography may be required for diagnosis, but magnetic resonance imaging is increasingly being used. Ventilation-perfusion scans are useful in assessing for pulmonary embolism; however, spiral computed tomography, available at most institutions, is associated with lower fetal radiation exposure than ventilation-perfusion scans are. Both heparin and low-molecular-weight heparin are commonly used for the treatment of acute thromboembolism. Warfarin is contraindicated in pregnant patients because of its association with fetal malformation and fetal demise.

Hypertension

Pregnant women with elevated blood pressure may have preexisting hypertension, gestational hypertension, preeclampsia, or eclampsia.²²

No consensus regarding initiation of antihypertensive therapy during pregnancy has currently been established. Most authorities prescribe treatment for patients with a blood pressure of 160/105 or higher; others argue that a lower threshold of 150/100 should be the criteria for treatment. In one review of pregnant patients experiencing stroke secondary to preeclampsia, systolic blood pressures recorded before the event were 159 to 198 mm Hg, and diastolic blood pressures were 81 to 113 mm Hg²³; arterial hemorrhage was the cause of stroke in 93% of patients who underwent intracranial imaging. Of note, evidence is not sufficient to recommend bed rest as an effective or practical treatment of hypertension during pregnancy.²⁴

Alcohol and Other Recreational Drugs

Alcohol use is reported in 10% to 15% of pregnancies; no safe level of intake has been determined. Alcohol abuse is associated with fetal alcohol syndrome. Common features of this syndrome include low IQ, microcephaly, short palpebral fissures, smooth filtrum, thin upper lip, and ventricular septal defects.

Cigarette smoking increases the risk for spontaneous abortion, prematurity, small-for-gestational-age births, placental abruption, placenta previa, and premature rupture of membranes. The adverse effects of smoking are dose related and reduced by cessation of smoking, even after a pregnancy is diagnosed.

Opiates, cocaine, and methamphetamine are all associated with obstetric complications. Cocaine use during pregnancy is believed to cause increased rates of placental abruption, preterm labor, and small-for-gestational-age infants. However, these studies are limited in that many of the mothers using cocaine have polysubstance abuse.

EPs should be aware of the reporting requirements of drug abuse in the states in which they practice.

Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome

Treatment of human immunodeficiency virus (HIV) infection during pregnancy with antivirals can reduce the incidence of perinatal transmission from mother to infant by 70%. The combination of antiviral therapy and elective cesarean delivery may reduce perinatal HIV transmission by as much as 85%. In the United States, where safe breast milk replacement is readily available, breastfeeding is discouraged because of the risk for transmission from mother to child. Referral to infectious disease and high-risk obstetric services is mandatory for pregnant women found to be HIV positive.

Analgesic Agents

No evidence has implicated acetaminophen as a teratogen, and thus it is the preferred agent when a mild analgesic or antipyretic is indicated. The use of NSAIDs such as ibuprofen and naproxen is generally discouraged during pregnancy, although the risk appears to be mostly in the third trimester. Indomethacin has been reported to be associated with oligohydramnios, pulmonary hypertension, and constriction of the ductus arteriosus.

Despite the lack of conclusive human data indicating that aspirin is a teratogen, its other ill effects limit its use during pregnancy. Aspirin has been linked to delayed onset of labor, protracted labor, and increased risk for prolonged pregnancy. It inhibits prostaglandin synthesis, which leads to premature closure of the ductus arteriosus, as well as increases the incidence of hemorrhage because of a decrease in platelet aggregation.

The use of opiates is considered safe throughout pregnancy. However, opiate use shortly before delivery can result in respiratory and central nervous system depression in the newborn. Because long-term opiate use during pregnancy can cause newborn addiction and withdrawal, patients using opiates chronically should be monitored carefully by their physician during pregnancy.

Anticoagulants

Warfarin is a known human teratogen associated with nasal bone hypoplasia, bone stippling, ophthalmologic abnormalities, and mental retardation; therefore, it is contraindicated in pregnancy. Heparin and low-molecular-weight heparin are thought to be safe during pregnancy and can be used when anticoagulation is indicated.

Antiemetics

Multiple antiemetic agents are commonly prescribed during early pregnancy. Dopamine agonists such as the phenothiazines, promethazine, chlorpromazine, perphenazine, and metoclopramide are all well tolerated and appear to be safe in pregnancy. The serotonin 5-HT₃ receptor antagonist ondansetron also appears to be both safe and effective for nausea and vomiting during pregnancy, although fewer data are available about this agent. Vitamin B₆ has been reported to be an effective treatment of nausea and vomiting in several randomized, double-blind, placebo-controlled trials.

Antimicrobial Agents

All antibiotics have been shown to cross the placenta and enter the fetal circulation to some degree.^26,27 Penicillin and its derivative compounds, including nafcillin, dicloxacillin, amoxicillin, and ampicillin, have been used extensively in pregnant patients without any ill effects on fetal development being reported. Newer derivatives, such as piperacillin and ticarcillin, have not been used as extensively but are believed to be safe in pregnancy. Cephalosporins are prescribed routinely, although there is less experience with the use of cephalosporins than with penicillin and ticarcillin.

The macrolides (erythromycin, azithromycin, clarithromycin) are considered safe during pregnancy with the exception of erythromycin estolate, which is contraindicated because of the risk for maternal hepatotoxicity. Clindamycin and nitrofurantoin, both commonly used during pregnancy, are considered safe.

Metronidazole has not been shown to be a human teratogen. However, its use is somewhat controversial because of potential mutagenesis and carcinogenicity. Trimethoprim-sulfamethoxazole has two contraindications, one related to each of its constituents—trimethoprim should be avoided during the first trimester because it is a folate antagonist and its use may lead to an increased incidence of neural tube defects; use of sulfamethoxazole is discouraged near term because of competitive binding of albumin with bilirubin, which leads to concern for an increased risk for kernicterus. Although this concern exists for all sulfonamides, no cases of kernicterus resulting from prenatal use have been reported.²⁷

Tetracyclines are contraindicated during pregnancy as a result of calcium binding, which causes staining of deciduous teeth, poor development of tooth enamel, and inhibition of skeletal growth in the fetus. Fluoroquinolones have not been shown to increase the rate of fetal malformation in humans but are contraindicated because of the development of arthropathy in immature animals exposed to quinolones.^28,29

The aminoglycosides streptomycin and kanamycin are associated with ototoxicity and are potentially nephrotoxic. Gentamicin is potentially ototoxic and nephrotoxic; dosing must be adjusted for renal function, and it should be used with caution.

Antiviral Agents

Women with disseminated herpes infection or a first genital herpesvirus infection occurring during pregnancy should be treated with acyclovir. No cases of fetal abnormalities caused by acyclovir have been reported. A genital herpes outbreak at term necessitates cesarean delivery.

Antiepileptic Drugs

Management of epilepsy during pregnancy is difficult and requires a multidisciplinary approach. The risk for maternal death during pregnancy can be up to 10 times higher than that for patients without epilepsy.³⁰ In addition, rates of intrauterine fetal demise and malformation are also increased.³¹ Many commonly available anticonvulsive medications are known or suspected teratogens, which can make management decisions difficult for both caregivers and patients.

Phenytoin, carbamazepine, valproate, and lamotrigine are associated with an increased incidence of congenital abnormalities. A recent review of data from 25 epilepsy centers recorded the following rates of serious adverse outcomes: valproate, 20.3%; phenytoin, 10.7%; carbamazepine, 8.2%; and lamotrigine, 1.0%.³² Newer antiepileptic drugs, including levetiracetam, felbamate, gabapentin, oxcarbazepine, tiagabine, and topiramate, seem to be safe for use in pregnancy, although fewer data are available for these agents.³³

Despite these risks, most physicians agree that patients with a well-established diagnosis of epilepsy should continue taking their medications during pregnancy. Women taking antiepileptic drugs during pregnancy should receive folic acid supplementation and undergo frequent monitoring. Seizures occurring during pregnancy or labor may be treated with benzodiazepines on an as-needed basis. Early studies demonstrated a risk for teratogenesis (mostly cleft abnormalities), but these findings have not been reproduced in more recent studies. Lorazepam does not cross the placenta at as fast a rate as other benzodiazepines do and, except during the first trimester, is considered safe. Sedation of the fetus around delivery is a minor concern and should not be considered a contraindication if needed for maternal seizures.

Antihypertensive Medications

Several agents for the treatment of hypertension during pregnancy have favorable safety profiles. Commonly used medications include α-methyldopa and hydralazine. Hydralazine has been used extensively in pregnancy and is available in both intravenous and oral formulations.^34–36 Beta-blockers are believed to be safe in pregnancy, although some association with lower placental and fetal weight has been reported with atenolol.³⁷ Labetalol is the preferred agent because it does not carry this risk. The combined alpha- and beta-blocking characteristics of labetalol may act to preserve uteroplacental blood flow.

Although fewer data are available on calcium channel blockers, they also appear to be safe and effective for use during pregnancy. Short-acting sublingual formulations of nifedipine should be avoided because they may cause maternal hypotension and fetal distress. Diuretics are safe but are not often used during pregnancy because preeclampsia may arise from a fluid-depleted state.

Two classes of antihypertensive agents, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, are contraindicated during pregnancy. Angiotensin-converting enzyme inhibitors have been associated with fetal renal malformation, oligohydramnios, craniofacial malformations, and lung malformations. Angiotensin II receptor blockers are associated with a similar set of malformations, probably caused by a similar mechanism.

Antihyperglycemic Agents

Insulin is the primary medication for the treatment of diabetes during pregnancy and has been proven to be safe and effective. A regimen that includes multiple daily doses of both short- and long-acting insulin is often required. Data regarding the use of oral hypoglycemic agents in pregnancy are still limited. Glyburide and metformin have been used and appear to be safe, but there is little indication for initiating these agents in the ED setting. Patients are at increased risk for hypoglycemic episodes associated with oral hypoglycemic use and thus should be monitored closely.

Immunizations

Indications for vaccines composed of toxoid or inactivated virus are similar to those for nongravid females. In general, the protection gained by vaccination during pregnancy usually outweighs the risks.³⁸ Live virus or attenuated vaccines (measles, mumps, poliomyelitis, rubella, yellow fever, and varicella) may cause infection or malformation (or both) in the fetus and are therefore contraindicated. Patients planning to became pregnant should ideally have their vaccines updated several months before conceiving.

Influenza is indicated for all women who will be pregnant during the flu season (October to March) and for all women at high risk for pulmonary complications.³⁹ Tetanus–diphtheria toxoid vaccine should be administered as usual for tetanus-prone wounds.

Over-The-Counter Medications

Most over-the-counter cold medications contain a combination of compounds. Little information is available regarding the effects of these agents alone and even less when they are used in combination. Decongestants act via vasoconstriction, and this mechanism also serves, at least theoretically, to decrease placental blood flow; their use during pregnancy should be avoided. Antihistamines such as diphenhydramine have been used during pregnancy and are considered safe. However, it should be noted that over-the-counter cold remedies are effective for relief of symptoms only and do not modify the course of disease; rest, hydration, and time are still the best treatment of the common cold.