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Use of Drugs in Pulmonary Medicine in Pregnant Women

Fabre, Ernesto MD, PhD; Tajada, Mauricio MD, PhD; Agüero, Rafael González de MD, PhD

Clinical Pulmonary Medicine: January 2002 - Volume 9 - Issue 1 - p 20-32
Colleagues In Respiratory Medicine
Free

Lung diseases that are frequently seen in young people, such as bronchial asthma, pneumonia, and tuberculosis, occur with comparable prevalence in pregnant women. Their treatments do not greatly differ from those used in the nonpregnant state. However, pharmacokinetics of these drugs undergo changes due to the physiologic variations induced by pregnancy that we must consider. On the other hand, some drugs used for lung disease have a teratogenic potential and thus carry a risk for the fetus. In this article, we review the drugs most commonly used for the treatment of respiratory diseases in pregnancy and lactation and discuss the current data of their possible effects on the fetus and neonate. Asthma is the most common potentially serious medical disease complicating pregnancy and should be treated as aggressively in pregnant women as in nonpregnant women, because the perceived risk to the fetus caused by pharmacologic therapy is much less than the risk of uncontrolled asthma and the resulting hypoxia. Antepartum pneumonia and tuberculosis require prompt evaluation and empiric antimicrobial therapy. The clinician must choose antimicrobial agents considering efficacy as well as safety for both mother and fetus. Among the agents for antithrombotic therapy, heparin is the anticoagulant of choice during pregnancy. Data on the use of low molecular weight heparins are encouraging, but clinical experience with these agents is still limited. Oral anticoagulant therapy should be avoided because of its teratogenic potential and increased risk of fetal complications, and the use of thrombolytic agents must be limited to life-threatening situations.

From the Department of Obstetrics and Gynecology, Hospital Clínico Universitario “Lozano Blesa”, Avda. San Juan Bosco, 15 50009, Zaragoza, Spain.

Address correspondence to: Ernesto Fabre González, MD, PhD, Professor of Obstetrics and Gynecology Chief of Maternal and Fetal Medicine Department, Hospital Clínico Universitario “Lozano Blesa” Avda. San Juan Bosco 15 50009, Zaragoza Spain. Address e-mail to: efabreg@sego.es

Many pregnant women require drug therapy because of pregnancy-induced conditions, chronic conditions diagnosed before pregnancy, or acute conditions. Physicians are often reluctant to prescribe drugs to pregnant and lactating women, because this type of treatment is often considered elective rather than life-saving. Despite opinions and advisories disseminated by various organizations, scientists, and manufacturers, no one database provides definitive guidelines on the exact risks associated with drug use during pregnancy and lactation.

Drugs given before the 20th day after fertilization may have an all-or-nothing effect, killing the embryo or not affecting it at all. Teratogenesis is not likely during this stage. The period of organogenesis (between the third and eighth week) is critical for teratogenesis. During the first trimester of pregnancy, when the embryo in undergoing rapid cellular growth and differentiation, drug administration may cause physical deformities. This process is dependent on fetal genetic make-up, time and duration of exposure, and concentration of the drug or metabolites. The mechanisms responsible for these occurrences are not well understood, but the consequences can be immediate (e.g., thalidomide, which causes limb abnormalities) or delayed until much later in life (e.g., vaginal dysplasia and adenocarcinoma developed during adolescence in female offspring who had been exposed in utero to diethylstilbestrol, a synthetic estrogen). Drugs given after organogenesis (in the second and third trimesters) are unlikely to be teratogenic, although they may alter the growth and function of normally formed fetal organs and tissues (e.g., oligohydramnios and persistent ductus arteriosus circulation from noncorticosteroidal antiinflammatory agents given in the last trimester) (1).

Several principles should guide the selection of therapy during pregnancy. Because fetal safety is a major concern, effective drugs that have been in use for long periods and considered safe on the basis of either large cohort studies or meta-analyses of several studies, are preferable to newer alternatives. Newer drugs may be more specific or have fewer adverse effects in adults, but their safety for fetuses is less likely to be known. To minimize the fetal risk, the drug must be given only for specific indications, at the minimum effective dose, and the shortest duration necessary.

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FDA CLASSIFICATION OF TERATOGENICITY

To aid the clinician in the decision to prescribe medication during pregnancy, the Food and Drug Administration (FDA) has categorized drugs used during pregnancy based on the degree to which available information suggests risk to the fetus balanced against the drug’s potential benefit to the mother (Table 1). The categories are based on studies that involve limited numbers of patients, or on positive findings in animal studies, usually involving extremely high doses of medications. Drugs in FDA categories A and B pose either no risk or minimal risk, respectively. Category C drugs are those in which risk to humans can not be ruled out. The D rating is generally reserved for drugs with no safer alternatives. Class X drugs are contraindicated during pregnancy because of proven teratogenicity. Most of the therapeutic agents used for respiratory disorders are classified within categories B and C, and are assumed to be relatively safe during pregnancy.

Table 1

Table 1

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AAP CLASSIFICATION OF BREASTFEEDING

During lactation the issue of teratogenicity is no longer relevant; however, drugs excreted through breast milk may induce neonatal sedation, hyperactivity, jaundice, hematologic disorders, or respiratory distress. The American Academy of Pediatrics (AAP) makes recommendations about the use of medications and their potential risks while breastfeeding, usually indicating that the drug is compatible, not recommended, or that no data are available (2).

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UPPER RESPIRATORY MEDICATIONS

Antihistamines

Specific H1-receptor antagonists (antihistamines) are first-line therapy for treating allergic rhinitis. First-generation antihistamines (brompheniramine, clemastine, chlorpheniramine, diphenhydramine, and triprolidine) are still widely used in over-the-counter (OTC) and prescription products because of their efficacy and perceived low cost. Second-generation antihistamines offer equal, and in some cases better, efficacy with a much safer side-effect profile (loratidine).

These drugs are all in category B or C (Table 2). No association between the use of the antihistamines and congenital abnormalities has been found. Only brompheniramine is not recommended for maternal use because of an increase in the incidence of congenital abnormalities in one study (3). After maternal treatment during pregnancy with the phenothiazines, infants exhibited jaundice and extrapyramidal symptoms. Promethazine taken close to term may inhibit platelet aggregation in the newborn (4). The illicit use of a combination of an antihistamine (tripelennamine) and an opioid (pentazocine), is known as “Ts and Blues.” In human pregnancy, it has been associated with prematurity, growth retardation, and a neonatal withdrawal syndrome (3). No reports linking the second-generation antihistamines with congenital anomalies or other adverse fetal outcomes have been located. Terfenadine is not associated with an increased incidence of major malformations or rates of prematurity or developmental delays (5).

Table 2

Table 2

In general, it is recommended to avoid antihistamine therapy to the mother during the natural nursing, because 1) most antihistamines are excreted by the breast milk in small quantities (brompheniramine, clemastine, clorpheniramine, difenhydramine, loratidine, and triprolidine); 2) newborns, especially premature infants, may exhibit severe reactions when exposed to these drugs (irritability, tachycardia, refusal to feed, and convulsions); 3) the phenothiazines can cause drowsiness and lethargy in the infant; and 4) the drugs, for their anticholinergic action, can diminish the production of the milk. The AAP considers dexbrompheniramine and triprolidine to be compatible with breastfeeding (2).

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Decongestants

Decongestants are sympathomimetics that cause vasoconstriction in small blood vessels and decrease nasal secretions through α-adrenoreceptor stimulation. Most are relatively selective for the α-adrenoreceptor although some act at the β-adrenoreceptor (e.g., ephedrine, pseudoephedrine). Sympathomimetic amines are teratogenic in some animal species, but human teratogenicity has not been suspected (3). The potential for excessive use of OTC α-adrenergic agonists, such as nasal sprays, led to concern about adverse effects on uterine perfusion. Most α-adrenergic agonists have the potential to induce maternal hypertension and reduce uterine blood flow at doses comparable to those used to produce therapeutic effects. Uterine vessels are normally maximally dilated and they have only α-adrenergic receptors. Use of predominantly α-adrenergic stimulants could cause constriction of these vessels and reduce uterine blood flow, thereby producing fetal hypoxia. Pseudoephedrine does not result in an increase in blood pressure until more than four times its therapeutic dose. Ephedrine, administered in the third trimester, does not significantly alter blood pressure or blood flow velocities in the uterine or fetal circulation (4). Oxymetazoline, a selective α2-adrenergic agonist with a long-acting vasoconstrictor, does not affect maternal blood pressure or heart rate, and therefore is safe for the third trimester of normal pregnancy. Although pseudoephedrine is the preferred decongestant during pregnancy (6), a case-controlled study has associated first trimester use of oral pseudoephedrine with infant gastroschisis (7). Therefore, oral decongestants should probably be avoided during the first trimester, if possible. Pseudoephedrine is excreted into breast milk. The drug is compatible with breastfeeding (2) (Table 3).

Table 3

Table 3

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Intranasal Corticosteroids

The same compounds that are effective as inhaled corticosteroids for the treatment of asthma are used intranasally for the treatment of allergic rhinitis (4) (see Inhaled Corticosteroids).

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Antitussives

Codeine in prolonged or high doses taken at term may lead to respiratory depression in the neonate and neonatal withdrawal syndromes to the same degree as other narcotic analgesics. Codeine is excreted into human breast milk in small amounts, and is usually compatible with breastfeeding (2). Dextromethorphan is the methyl ether of the d-isomer form of levorphanol, an opiate analgesic. It is generally considered safe for use during pregnancy. Safe use of benzonatate during both pregnancy and lactation has been established (Table 3).

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Expectorants

No teratogenic effects have been associated with the use of guaifenesin in pregnant women (3). Use of iodines, potassium iodide (category D), and iodinated glycerol (category X), in pregnant women is contraindicated. The human fetal thyroid begins to concentrate iodines in the 12th to 14th week of gestation. The prolonged administration of iodides to pregnant women can result in large fetal goiters, tracheal obstruction, congenital hypothyroidism, and fetal death (8). The AAP, although recognizing that the maternal use of iodides during lactation may affect the infant’s thyroid activity by producing elevated iodine levels in breast milk, considers the agents to be compatible with breastfeeding (2) (Table 3).

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ASTHMA MEDICATIONS

Management of asthma during pregnancy differs little from therapy of nonpregnant patients. The pregnant patient should be treated as aggressively as the nonpregnant patient. The goals of treatment are to maintain normal pulmonary function, control symptoms, avoid exacerbations, and, ultimately, the delivery of a healthy neonate. The perceived risk to the fetus caused by pharmacologic therapy is much less than the risk of uncontrolled asthma and the resulting hypoxia. Because asthma varies in severity, specific treatment must be tailored and varied with respect to an individual patient’s needs and circumstances (9). Inhalation therapy generally is preferred to systemic treatments. Inhaled medications are delivered directly to the airway, thus minimizing systemic side effects. However, when inhaled medications are insufficient to adequately treat the patient, there should be no hesitation in the initiation of oral or parenteral therapy.

Asthma medications are thus categorized into two general classes: long-term control medications taken daily on a long-term basis to achieve and maintain control of persistent asthma, and quick-relief medications taken to provide prompt reversal of acute airflow obstruction and relief of accompanying bronchoconstriction (10). Long-term control drugs include antiinflammatory medications, such as inhaled (and oral) glucocorticosteroids; inhaled nonsteroidal agents, such as cromolyn and nedocromil; leukotriene-receptor antagonists; and bronchodilatadors, such as long-acting β2-agonists and methylxanthines. Relievers are represented by the inhaled short-action β2-agonist and anticholinergics.

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Antiinflammatory Agents

Corticosteroids.

Corticosteroids are the most potent and effective antiinflammatory medication currently available. Corticosteroids can be administered parenterally (e.g., methylprednisolone, hydrocortisone), orally (e.g., prednisone, prednisolone, methylprednisolone), or as aerosols (beclomethasone, budenoside, flunisolide, fluticasone, and triamcinolone). The inhalation form is used in the long-term control of asthma. Systemic corticosteroids are often used to gain prompt control of the disease when initiating long-term therapy.

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Inhaled Corticosteroids.

Inhaled corticosteroids are the most effective long-term therapy for mild, moderate, or severe persistent asthma. Inhalation provides local steroid activity with minimal systemic effects (11). Although systemic absorption of inhaled corticosteroids can occur, the low plasma levels achieved by inhalation make it unlikely that fetal effects will be seen. Adverse local effects of inhaled corticosteroids include dysphonia and oral candidiasis. Systemic effects are all dose-related and occur mainly with doses exceeding 2000 μg/day.

The largest human experience of inhaled corticosteroids is with beclomethasone and it is therefore the inhaled steroid of choice in pregnancy (12). Although some risk of teratogenicity with beclomethasone has been shown in animal models (cleft palate in rats), its use in pregnant women has not been associated with teratogenicity. Beclomethasone appeared to have no effect on the pregnancy’s outcome and does not to increase the risk to the fetus (13–14). The incidence of premature deliveries and low birth weight infants is slightly increased in pregnant women treated with beclomethasone, although this is most likely due to the effects of asthma itself rather than the corticosteroid (15). The newer and more potent inhaled corticosteroids, such as triamcinolone, fluticasone and flunisolide, have not been studied in humans although animal studies indicate an increased likelihood of teratogenicity associated with triamcinolone (12). There are no published reports of triamcinolone acetonide therapy for asthma during pregnancy, except a retrospective cohort study (16). The data suggest that triamcinolone acetonide appears to be at least as efficacious for the treatment of asthma during pregnancy as beclomethasone. Experience with budesonide and fluticasone in pregnancy is more limited (Table 4).

There is no evidence demonstrating the deposition of inhaled corticosteroids in breast milk. Based on pharmacokinetic data, beclomethasone can be excreted in milk; nevertheless, the therapeutic doses employed are not expected to result in significantly high concentrations (17). Inhaled glucocorticoids can generally be continued during lactation.

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Systemic Corticosteroids.

Systemic corticosteroids are used short-term (3–10 days) to gain prompt control of inadequately controlled persistent asthma when initiating long-term therapy and for long-term prevention of symptoms in severe persistent asthma (10). There are many biologically active glucocorticoids, but the most commonly used are the short-acting agents, prednisone, prednisolone, and methylprednisolone, and the longer-acting dexamethasone and betamethasone. Following maternal administration, small amounts of prednisone and prednisolone have been detected (8–10-fold lower quantity than seen in the mother’s blood) in cord blood. The fluorinated preparations, dexamethasone and betamethasone, are less efficiently metabolized by the placenta than other glucocorticoid preparations. Therefore, these medicines reach the fetus at much higher concentrations than prednisone and prednisolone. For this reason, dexamethasone and betamethasone may be preferable for the treatment of fetal disorders, whereas prednisone and prednisolone may be more advantageous for treating maternal disease.

Systemic corticosteroids (FDA pregnancy category C) are teratogenic in rodent species, with increases in cleft palate, internal hydrocephaly, and skeletal defects. The question of whether systemic use of corticosteroids during the first trimester of pregnancy increases the risk of congenital malformations in people has still not been resolved and has resulted in inconsistent recommendations regarding their use during early pregnancy. Case-control study shows a relationship between exposure to corticosteroids during the first trimester of pregnancy (18) or periconceptional period (1 month before to 3 months after conception) (19), and an increased risk of cleft lip (with or without cleft palate) in the newborn infants. Increased risks were not observed for the other anomaly groups studied. These data in conjunction with other epidemiologic data suggest a possible causal association between cleft lip and palate and corticosteroid use (20). Thus, we believe that the use of systemic corticosteroids during the first trimester of pregnancy should be restricted to the following situations, for life-threatening situations, for those diseases without any other safe therapeutic alternative, or for those cases with replacement therapy (Table 4).

Although the chronic maternal administration of systemic corticosteroids has been associated with decreased birth weight, intrauterine growth retardation, and accentuation of several pregnancy-induced maternal complications (e.g., gestational diabetes and maternal adrenal insufficiency), such use is justified in women with severe asthma to avoid potentially fatal attacks (9). For patients who have been treated with corticosteroids during pregnancy and who have prolonged labor and delivery or require a cesarean section, we suggest using stress doses of corticosteroids (100 mg hydrocortisone sodium succinate, administered intravenously every 8 hours) in the peripartum period. Furthermore, neonates born to these mothers should be monitored for evidence of adrenal insufficiency.

Corticosteroids are excreted into breast milk in small amounts. Prednisone and prednisolone are considered safe in breastfeeding mothers because only a small percentage (<10%) of active drug is secreted into breast milk and does not pose a clinically significant risk to a nursing infant (3). For long-term or high-dose therapy (more than 20 mg/d), we suggest waiting 4 hours following medication ingestion before resuming nursing. The AAP has classified prednisolone and prednisone as usually compatible with breastfeeding (2).

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Cromolyn and Nedocromil.

Cromolyn sodium and nedocromil sodium are two structurally different antiinflammatory medications for the treatment of chronic asthma that have similar properties. They have no bronchodilating activity and are useful only in prophylaxis. They may be used as preventive treatment prior to unavoidable exposure to known allergens (10). The safety of cromolyn and nedocromil during pregnancy has not been established unequivocally, but no damaging effects on the fetus have been reported (21). Studies in animals have shown that cromolyn causes a reduction in the number of successful pregnancies and a decrease in the weight of the animal fetus only when given by injection in very large amounts. Cromolyn is a category B drug, and because more is known about this drug than nedocromil, cromolyn is preferred during pregnancy. Less than 10% of an inhaled dose of cromolyn is believed to be absorbed systematically. No information was located on the transfer of cromolyn or nedocromil across the placenta or its excretion into breast milk (4).

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Leukotriene Modifiers.

Leukotrine modifiers include montelukast and zafirlukast, selective competitive inhibitors of LTD4 and LTE4 receptors, and zileuton, a 5-lipoxygenase inhibitor. Safety issues with the use of leukotriene modifiers in pregnancy and breastfeeding remain to be fully addressed (22).

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Bronchodilators

β2-Agonists (β-Adrenergic Agonist).

Short-acting inhaled β2-agonists, such as albuterol (salbuterol), are efficient drugs for treating acute asthma symptoms due to bronchospasm. Inhaled (salmeterol and formoterol) and oral (albuterol) long-acting β2-agonists, may be considered as an adjunct to antiinflammatory therapy for providing long-term control of symptoms, especially nocturnal symptoms and to prevent exercise-induced bronchospasm; this class of medication is not used for exacerbations (10).

There is no evidence of a teratogenic risk with the commonly used inhaled β2-agonist albuterol, terbutaline, and fenoterol. Adverse reactions observed in the fetus and mother following the use of β2-agonists are secondary to the cardiovascular and metabolic effects. These drugs may cause tremor, increased anxiety, inhibition of uterine contractions, fetal and maternal tachycardia, maternal hypotension, transient fetal and maternal hyperglycemia followed by an increase in serum insulin, and neonatal hypoglycemia, but these effects are minimal and less common when β2-agonists are administered via inhalation. Women with asthma who used inhaled bronchodilators during pregnancy, showed no significant increases in the incidence of perinatal mortality, congenital malformations, preterm births, low-birth weight infants, Apgar scores, labor/delivery complications, or postpartum bleeding (23). Most of the β2-agonists are classified in category C, with terbutaline in category B (Table 5). In humans, intravenous terbutaline and albuterol are effective in arresting premature labor. Delayed labor does not occur with bronchodilators administered by metered-dose inhaler or wet nebulization (21).

Table 4

Table 4

Table 5

Table 5

Safety of metaproterenol and isoetharine during pregnancy has not been determined. Epinephrine is an α- and β-adrenergic agonist with a short duration of action. It is used in hospitals subcutaneously for status asthmaticus. Epinephrine is teratogenic in some animal species, but human teratogenicity has not been suspected. The drug also has profound effects on the cardiovascular system. Epinephrine’s α-adrenergic properties might lead to a decrease in uterine blood flow, and for that reason should be used rarely and cautiously during pregnancy. Subcutaneous terbutaline is the sympathomimetic drug of choice for acute asthmatic attacks during pregnancy. Salmeterol is a long-acting β2 selective adrenergic agonist bronchodilator, different from the other adrenergic bronchodilators because it does not act quickly enough to relieve an asthma attack that has already started. The safety for use of salmeterol during human pregnancy has not been established.

Terbutaline is excreted into breast milk and the infant ingests approximately 0.7% of the maternal dose. The AAP considers terbutaline to be compatible with breastfeeding (2). No information was located on the albuterol, epinephrine, isoetharine, isoproterenol or metaproterenol excretion into breast milk.

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Methylxanthines.

Theophylline is a methylxanthine that acts as a weak bronchodilator. It can be used as a sustained-release oral preparation that provide a longer duration of action to relieve the symptoms of nocturnal asthma. It may be given intravenously in its salt form, aminophylline, for status asthmaticus. Theophylline has a narrow therapeutic window and individual differences in the doses required are high. Serum levels of theophylline, due to liver metabolism, may be markedly affected by a number of variables, including age, diet, pregnancy, disease states, and drug interactions. The toxic effects include gastrointestinal disturbances, cardiac arrhythmias, headache, and seizures; these appear to be associated with elevated serum theophylline levels (>20 μg/mL). Serum theophylline levels should be monitored periodically and the level maintained between 5 and 12 μg/mL during pregnancy (9).

In animal experiments, theophylline has been shown to cause cardiovascular and bone defects in the fetus, but available human data suggest that there is little risk of teratogenic effects from theophylline therapy during pregnancy (3). The theophylline may aggravate the nausea and reflux suffered by some pregnant women. A transient toxicity including vomiting, tachycardia, and jitteriness was reported in newborns having theophylline levels higher than 10 μg/mL. Because fetal cord levels so closely approximate maternal levels, it is possible that therapeutic maternal levels could potentially cause toxicity in the neonate. Apnea has been associated with theophylline withdrawal in a newborn (4).

Theophylline is excreted into breast milk. Although less than 1% of maternal theophylline is transferred to the infant, differences in the metabolism of this drug, compared to adults, may produce toxic effects in the newborn. Except for the precaution that theophylline and aminophylline may cause irritability in the nursing infant, the AAP considers the drugs to be compatible with breastfeeding (2).

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Anticholinergics.

Ipratropium bromide is a quaternary compound that is absorbed negligibly; because systemic absorption is minimal, the drug has virtually no side effects. There is no evidence of teratogenic effects after oral administration or inhalation of ipratropium in animals. Although there is less experience with this drug, it appears to be safe for use during pregnancy, as it is poorly absorbed when administered by the inhaled route and has not been identified as imparting an increased risk of fetal malformations. It is not known whether ipratropium is excreted in breast milk. Although lipid-insoluble quaternary ammonium compounds pass into the breast milk, it is unlikely that ipratropium would reach the infant in amounts that could produce effects, especially when it is taken by inhalation by the mother (4).

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INFECTIOUS PULMONARY DISEASES

Antibiotics

Pneumonia is an infrequent but nevertheless serious complication of pregnancy. It is the most frequent cause of nonobstetric infection and the third most frequent cause of indirect obstetric death (24). The mainstay of drug therapy for bacterial pneumonia is antibiotic treatment. The selection of antibiotics in the absence of an etiologic diagnosis is based on multiple variables, including severity of the illness, the patient’s age, antimicrobial intolerance or side effects, clinical features, comorbidities, concomitant medications, exposures, and epidemiologic setting. The antimicrobial agents preferred for most patients nonpregnant are a macrolide, doxycycline, or a fluoroquinolone. Alternative options include, amoxicillin-clavulanate and some second-generation cephalosporins (25). In pregnancy, second-generation cephalosporins will cover most cases of uncomplicated community acquired pneumonia, with erythromycin added if atypical agents are suspected. For severe illness in a critical care setting, additional coverage can be obtained through the use of a third-generation cephalosporin (or beta-lactam/beta-lactamase inhibitor combination), in addition to an aminoglycoside and erythromycin (24) or azithromycin (Table 6).

Table 6

Table 6

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Penicillins.

The penicillins are among the most effective and least toxic antimicrobial agents available. These are among the most widely used antibiotics and are safe to use during pregnancy in nonallergic patients. There are no fetal adverse effects known (category B).

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Cephalosporins.

The first- and second-generation cephalosporins are safe to use during pregnancy (category B). Third-generation agents have yet to be extensively used during pregnancy and should be reserved for use only when safer alternatives do not exit. Cephalosporins with a methylthiotetrazole side chain have been implicated in the inhibition of the synthesis of vitamin K dependent clotting factors, which may result in clinical bleeding.

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Macrolides.

Erythromycin has been very widely used in pregnancy, and there is no evidence of toxicity to the fetus. Placental transfer is more limited than with other antibiotics; fetal plasma concentrations are 5% to 20% of maternal concentrations. Erythromycin base and azithromycin (a semisynthetic macrolide chemically related to erythromycin) are considered safe, have no known teratogenic effects, and may be used for patients allergic to penicillin (category B). Erythromycin estolate is specifically contraindicated during pregnancy as it is associated with an increased risk of intrahepatic cholestasis, a condition to which pregnant women are particularly susceptible. Clarithromycin is a category C drug in pregnancy, and its safety has not been established.

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Aminoglysides.

Use of aminoglycosides during pregnancy should be limited to the treatment of serious gram-negative infections. Streptomycin and kanamycin have caused congenital deafness in children born to treated mothers. Although this has not been reported with other aminoglycosides, gentamicin and tobramycin, they should be avoided, if possible, particularly in the first trimester when the risk of ototoxicity is greatest. Gentamicin is the most extensively drug studied of the group and therefore, is the preferred during pregnancy.

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Tetracyclines.

Tetracyclines are contraindicated in pregnancy (category D). Tetracyclines have been associated with maternal hepatotoxicity, with acute fatty liver when given intravenously in high doses to patients with renal disease. Tetracyclines readily cross the placenta. These agents are complexed by calcium and deposited in fetal teeth and long bones, producing permanent staining and hypoplasia of the deciduous teeth and stunting of long bone growth. Calcification of the deciduous teeth begins in the 12th week, but the adverse effects of the tetracyclines are most prominent in the last trimester. As far as we know, there is no evidence for human teratogenic potential of doxycycline use during pregnancy. Thus, if doxycycline treatment is necessary during pregnancy, there would appear to be no contraindication (26).

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Cotrimoxazole.

Cotrimoxazole, and sulfamethoxazole or trimethoprim alone, have been used in pregnancy for many years. There is no significant evidence that they are teratogenic, and they must be regarded as safe. Trimethoprim works as a folate antagonist and is teratogenic in rats. There is no good evidence of serious neonatal free hyperbilirubinemia due to maternal sulfonamide treatment. Nonetheless, sulfonamides should be avoided if premature delivery is anticipated because of the theoretical risk of interfering with neonatal bilirubin binding. In the G6PD-deficient women, sulfa drug are avoided, as they are associated with hemolytic anemias.

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Others.

Clindamycin is effective in the treatment of many aerobic and anaerobic infections. No teratogenic effects have been documented. There are no unusual adverse effects reported; however, pseudomembranous enterocolitis is a serious adverse effect. The use of metronidazole during pregnancy is controversial. Reports of mutagenesis and carcinogenesis in rodents limit its use to serious infections for which treatment alternatives do not exist, specially in the first trimester. However, there is ample evidence that metronidazole is not teratogenic in humans. The fluoroquinolones are not embryotoxic or teratogenic in animals. However, because of arthropathy in immature animals, they are contraindicated in pregnancy and breastfeeding (3).

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ANTITUBERCULOSIS DRUGS

In a pregnant women with tuberculosis it is essential to give effective therapy. The initial treatment regimen should consist of isoniazid and rifampin (27). Ethambutol should be included unless primary isoniazid resistance is unlikely. Isoniazid, rifampicin, and ethambutol all cross the placenta, but these drugs have not been demonstrated to have teratogenic effects. Isoniazid is the most effective and safest of the antituberculous drugs in pregnancy. Theoretically it can interfere with pyridoxine metabolism and it is reasonable to give small pyridoxine supplements. Rifampin is important in the clinical treatment of tuberculosis and if indicated it should be given. During the first trimester there may be more reason to use alternatives to rifampin, but the risk from the drug of teratogenesis is small if it exists at all. Ethambutol is not known to be associated with an increased incidence of fetal abnormalities. Aminosalicylic acid was widely used in treatment tuberculosis in pregnancy for many years. If there is any risk to the fetus is very small. However, its principal side effect is gastrointestinal intolerance, which, from a practical point of view, can make use of the drug difficult, particularly in the first trimester. Because the small concentrations of antituberculosis drugs in breast milk do not produce toxicity in the nursing newborn, breastfeeding should not be discouraged. (Table 7).

Table 7

Table 7

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FUNGAL INFECTIONS

Amphotericin B is the only antifungal agent possessing an FDA category B rating for use in pregnancy. Evidence indicates that amphotericin B can be safely employed without teratogenicity for treatment of coccidioidomycosis during pregnancy, with manageable toxicities as anemia, hypokalemia, and renal dysfunction for both mother and fetus. Transcervical, intrathecal, and intraventricular infusions of amphotericin B have also been safely administered during pregnancy. Use of amphotericin B requires close monitoring and prudent dosage adjustments throughout gestation and the postpartum period. Amphotericin B treatment for disseminated fungal infection during pregnancy generally produces favorable maternal and fetal outcomes. From our analysis of the literature, it appears advisable to administer amphotericin B in all cases of disseminated mycoses during pregnancy. However, when infection is limited to the lungs, the decision can be individually tailored as appropriate for disease severity versus risks and benefits of therapy. Severe cryptococcal pneumonia with multilobar disease, resting hypoxemia, or clinical instability warrants amphotericin B therapy at the time of diagnosis, regardless of gestational age (28).

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VIRAL INFECTIONS

Acyclovir (category C) is an antiviral agent that acts against herpes viruses including varicella-zoster. No fetal toxicity or teratogenicity in animals is known. There is little information about its use in early pregnancy. No established indications for use have been reported, but it seems reasonable to use it for life-threatening varicella pneumonia. The AAP considers acyclovir to be compatible with breastfeeding (2). Amantadine (category C) is embryotoxic and teratogenic in animals in high doses, and may be a human teratogen, although reports have not been located. Is excreted into breast milk in low concentrations; no reports of adverse effects in nursing infants have been located. Ribavirin (category X) is teratogenic and/or embryolethal in nearly all animal species tested. The use of ribavirin during pregnancy is contraindicated (3).

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ANTITHROMBOTIC THERAPY

Anticoagulant therapy is indicated during pregnancy for the prevention and treatment of deep vein thrombosis and pulmonary embolism. Several questions concerning anticoagulant therapy during pregnancy remain unanswered (29–30).

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Heparin

Extensive clinical experience and retrospective cohort studies have established heparin (unfractionated heparin) to be the safest anticoagulant to use during pregnancy. Heparin does not cross the placenta, and therefore is not teratogenic and does not cause an anticoagulant effect in the fetus (31). Because it is safe for the fetus, heparin is the anticoagulant of choice during pregnancy for situations in which its efficacy is established (32).

The most common maternal complications of heparin use include hemorrhage, heparin-induced thrombocytopenia (HIT), and heparin-associated osteopenia. Bleeding is an obvious risk with any anticoagulant, but the rate of serious bleeding in pregnant patients treated with heparin (2%) is comparable to the rate in nonpregnant patients. Subcutaneous heparin can cause persistent anticoagulation (24 hours) after cessation of use. This may be associated with an increased risk of major hemorrhage at the time of delivery and the need to withhold epidural analgesia. It is therefore prudent to check the partial thromboplastin time (PTT) close to the anticipated time of delivery and if necessary, reverse any excessive anticoagulation with protamine sulphate. Adequate anticoagulation should be confirmed by prolongation of the PTT above 1.5 times control values. Osteopenia induced by heparin has been reported in pregnancy, although it is usually associated with the administration of at least 20,000 IU per day for more than 6 months. The osteopenia appears to be reversible in most cases. Although the risk of symptomatic fractures is low (calculated at 2%), subclinical reduction in bone density (documented radiographically) occurs in up to one third of patients receiving heparin therapy. HIT occurs in an estimated 5% to 30% of patients treated with heparin (31). Heparin is not secreted in breast milk and can be administered safely to nursing mothers.

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Low Molecular Weight Heparins and Heparinoids

Low molecular weights heparins (LMWH) have a longer plasma half-life, exhibit a more predictable dose response, and are less likely to induce HIT than unfractionated heparin, and appear to reduce the risk of bleeding and osteoporosis (32). In pregnant women who develop HIT and require ongoing anticoagulant therapy, use of the heparinoid danaparoid is recommended because it is an effective antithrombotic agent and has much less crossreactivity with unfractionated heparin and, therefore, less potential to produce recurrent HIT than LMWH.

None of the currently available LMWH preparations are approved for use in pregnancy. Studies of several different LMWH preparations used in pregnant women have failed to demonstrate any placental transfer, and therefore use of these drugs is likely safe for the fetus. Animal studies have shown no teratogenic effects, even at massive doses. Reported case series and prospective cohort studies of the use of LMWH during pregnancy have failed to demonstrate any increased rate of fetal adverse effects (32). LMWH can be given safely to postpartum mothers who breast feed (33). Data on the use of LMWH during pregnancy are encouraging, but clinical experience with these agents is still limited

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Coumarin Derivatives

Coumarin compounds (derivatives of 4-hydroxycoumarin) should not be used during pregnancy because of their teratogenic potential and increased risk of fetal complications. Fetal coumarin exposure between 6 to 12 weeks of gestation results in an estimated 10% to 25% risk of a characteristic embryopathy (fetal warfarin syndrome) consisting of nasal hypoplasia, stippled epiphyses, and limb hypoplasia (3). Coumarin use at any time during pregnancy is associated with an increased risk of microcephaly, mental retardation, optic atrophy, fetal hemorrhage, and death. Because warfarin enters the fetal circulation, it causes an anticoagulant effect in the fetus as well as the mother. Oral anticoagulant therapy should be avoided in the weeks before delivery because of the risk of serious perinatal bleeding caused by the trauma of delivery to the anticoagulated fetus (32).

Warfarin is not secreted in significant amounts in breast milk and does not anticoagulate breastfed infants of mothers receiving full anticoagulant doses of this medication. Warfarin therefore, may be used safely in the postpartum period. Warfarin and dicumarol are classified by the AAP to be compatible with breastfeeding. Other oral anticoagulants should be avoided by the lactating women. (Table 8) Phenindione is contraindicated during breastfeeding because of the risk of hemorrhage in the infant (2).

Table 8

Table 8

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Thrombolytic Therapy

In addition to anticoagulation, thrombolytic therapy using lytic agents such as streptokinase, urokinase or recombinant tissue-type plasminogen activator have a role in the management of all patients with massive pulmonary embolism where there is evidence of right ventricular dysfunction and systemic hypotension. No controlled trials on the safety and efficacy of thrombolytics in pregnant patients have been done. The use of thrombolytic agents during pregnancy has been limited to life-threatening situations (with massive pulmonary embolism and severe hemodynamic instability) because of the risk of fetal loss and substantial maternal bleeding, especially at the time of delivery and immediately post partum (31). The risk of placental abruption and fetal death due to these drugs is currently unknown.

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SUMMARY

Few drugs have been properly studied during pregnancy. In this situation, we must use every resource available to decide rationally about the prescription of a drug for a pregnant woman. When there is a maternal pathology that can obtain benefit from pharmacologic therapy, it must be treated. Pulmonary illnesses are not an exception for this rule. However, we must consider at least two questions before the prescription of a drug: Does the pathology require pharmacologic treatment? And, if a positive response, which is the safest drug? Every pregnant women must receive information about the necessity of the treatment, the expected benefits, and the possible risks for her and her fetus and/or neonate.

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Keywords:

Respiratory; Drugs therapy; Pregnancy; Breastfeeding; Fetus

© 2002 Lippincott Williams & Wilkins, Inc.