The Healthy Pregnancy

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118 The Healthy Pregnancy

Epidemiology

Each year, 4.1 million live births in the United States result from approximately 6.5 million pregnancies.1,2 These women routinely go to the emergency department (ED) for general medical complaints, as well as for pregnancy-specific issues. In addition, more patients with complex medical problems are becoming pregnant because of advances in fertility treatments. Pregnancy can be an emotionally stressful condition that requires special attention from caregivers. Because diagnostic and management strategies are altered in pregnancy, a thorough understanding of the physiologic changes that accompany pregnancy is mandatory (Box 118.1).

Presenting Signs and Symptoms

Emergency physicians (EPs) should consider the possibility of pregnancy in every female patient of childbearing age regardless of the chief complaint or symptoms. One study documented pregnancy in 7% of ED respondents who indicated that their last menstrual period was on time and normal and that there was “no chance” that they were pregnant.3 Early signs of pregnancy include missed menses, vaginal bleeding, nausea, vomiting, breast tenderness, urinary frequency, fatigue, near-syncope, and abdominal pain or bloating. Some patients may not have these symptoms or may ignore them and later go to the ED with an obviously enlarged uterus or in labor.

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.

Common Medical Diseases and Pregnancy

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.

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.

Medication Use During Pregnancy

Medication use during pregnancy can be a source of apprehension for both patients and physicians because of the paucity of data on safety. Pharmaceutical companies have excluded pregnant patients from testing of new agents for decades, thus resulting in little knowledge about the teratogenicity of products in humans. Additionally, animal models may not be representative of human risk. EPs prescribing medication for pregnant or lactating women should use the resources available in both electronic and text format.

Fetal toxicity is affected by the dose, duration of exposure, and gestational age when the exposure occurs. During the 31-day period following the last menstrual period, teratogens have essentially a binary (all-or-nothing) effect—the conceptus is either aborted or survives without harm. The next stage of development is the crucial period of organogenesis and lasts from 31 to 71 days after the last menstrual period. The effect of exposure to a teratogen depends on the time during this period that the fetus was exposed. Early exposure may affect the cardiovascular or central nervous systems (or both), whereas later exposure may affect the musculoskeletal system, such as palate and ears.

The U.S. Food and Drug Administration classifies medications into five categories according to potential fetal risk based on animal and human studies (Table 118.1).25 Medications commonly used in the ED and generally considered safe are listed in Box 118.3; often-used medications considered unsafe for use during pregnancy are listed in Table 118.2.

Table 118.1 U.S. FDA Pharmaceutical Pregnancy Categories

PREGNANCY CATEGORY DESCRIPTION
A Adequate well-controlled studies in pregnant women have not shown an increased risk for fetal abnormalities.
B Animal studies have revealed no evidence of harm to the fetus; however, there are no adequate and well-controlled studies in pregnant women.orAnimal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus.
C Animal studies have shown an adverse effect, and there are no adequate well-controlled studies in pregnant women.orNo animal studies have been conducted, and no adequate well-controlled studies have been performed in pregnant women.
D Adequate well-controlled or observational studies in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy may outweigh the potential risks.
X Adequate well-controlled or observational studies in animals or pregnant women have demonstrated positive evidence of fetal abnormalities. Use of the product is contraindicated in women who are or may become pregnant.

FDA, Food and Drug Administration.

Modified from Meadows M. Pregnancy and the drug dilemma. FDA Consum 2001;35:16-20. Available at http://www.fda.gov/fdac/features/2001/301_preg.html.

Box 118.3 Medications Considered Safe During Pregnancy

Table 118.2 Common Emergency Department Pharmaceutical Agents Contraindicated in Pregnancy

AGENT CONTRAINDICATION
Analgesics
Aspirin Premature closure of the ductus arteriosus, increased incidence of hemorrhage
NSAIDs (ibuprofen, indomethacin, naproxen) Oligohydramnios, pulmonary hypertension, constriction of the ductus arteriosus
Antimicrobials
Tetracyclines Discolored teeth, inhibition of bone growth
Fluoroquinolones Arthropathy in immature animals
Aminoglycosides Ototoxicity, nephrotoxicity
Anticoagulants
Warfarin Nasal bone hypoplasia, bone stippling, ophthalmologic abnormalities, mental retardation
Antiepileptics
Phenytoin Fetal hydantoin syndrome (ossification abnormalities, cleft lip and palate, impaired growth, cardiac abnormalities)
Carbamazepine, valproic acid Dysmorphic syndrome, similar to fetal hydantoin syndrome
Antihypertensives
ACE inhibitors Renal malformation, oligohydramnios, craniofacial malformations, lung malformations
Angiotensin II receptor blockers Linked to malformations similar to those from ACE inhibitors
Other
Isotretinoin Craniofacial, cardiac, thymic, and CNS malformations

ACE, Angiotensin-converting enzyme; CNS, central nervous system; NSAIDs, nonsteroidal antiinflammatory drugs.

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.

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.

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.

References

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