Prescribing guidelines for ENT medications during pregnancy.

Abstract

Profound physiologic changes occur during pregnancy, and they can alter the pharmacodynamics of an administered drug. Almost 85% of women take at least one prescription medication during a pregnancy. Nearly every drug administered to a mother crosses the placenta, and fetal drug levels can reach 50 to 100% of maternal serum concentrations. Because many otolaryngologic conditions are associated with pregnancy, it is essential that otolaryngologists who care for gravid patients know which drugs are safe and avoid unnecessary, prescriptions so that the best care can be delivered to the pregnant patient without harming her unborn child. In this article, we discuss the relative safety and efficacy of various types of drugs frequently prescribed for pregnant women by otolaryngologists.

Introduction

Nearly 85% of women will take at least one prescription medication during the course of a pregnancy. (1) According to a large survey conducted by the National Institutes of Health (NIH), the average pregnant woman takes three or four different drugs, excluding vitamins and mineral supplements. (2) Moreover, 40% of women in the NIH survey took medication during the critical first-trimester period of fetal development.

Many otolaryngologic conditions are associated with pregnancy. Therefore, when caring for gravid patients, otolaryngologists must be aware of maternal and fetal side effects of the medications commonly prescribed in otolaryngology.

Maternal-fetal physiology

Profound physiologic changes occur during pregnancy, and they can alter the pharmacodynamics of an administered drug. Most notable are the changes in maternal blood volume, serum albumin levels, renal excretion, and hepatic metabolism.

During pregnancy, maternal blood volume (i.e., distribution volume) increases by approximately 50% and thus lowers the serum concentrations of drugs. The gravid state results in a gradual decrease in maternal serum albumin, which leads to less protein-drug binding and more free circulating drug, which is the only fraction of a drug that can cross the placenta.

There is a gradual increase in renal function during pregnancy, which results in an augmented clearance rate of those agents that are eliminated primarily by the kidney (e.g., ampicillin and gentamicin). (3,4) The changes in hepatic elimination patterns during pregnancy are less consistent. Whether there is an increase or decrease in hepatic metabolism appears to vary from one class of drug to another. (5) Finally, the fetal liver and the placenta have been shown to demonstrate drug metabolism, although they contribute only marginally to the total elimination capacity of drugs by the maternal system.

Teratogenicity

Nearly every drug administered to the mother crosses the placenta, and fetal drug levels can reach 50 to 100% of maternal serum concentrations. (6) When considering the teratogenicity of compounds, the two most important factors are total fetal exposure to a drug and the gestational age of the fetus at first exposure. Teratogenic drug exposure around the time of conception and/or implantation (i.e., the first 2 weeks) is likely to result in spontaneous abortion. Teratogen exposure during weeks 3 through 10 can result in impaired organogenesis. If the exposure occurs during the early embryo stage (5 weeks), cardiac and central nervous system defects are more likely. Nearer the end of the embryo stage (10 weeks), defects in the palate and ears are more common. After the 10th week, physiologic defects and growth delay are the most common adverse effects, especially when exposure takes place over a sustained period rather than as a single or short-term insult.

FDA risk categories

In response to the thalidomide-induced birth defects that occurred in the early 1960s, the United States government generally prohibited women of child-bearing age from enrolling in most research studies. Although many of these restrictions were eased by most federal research agencies in the 1990s, the NIH and many hospital review boards continue to bar most pregnant women from research protocols. (6) Most drug safety data that apply to pregnancy are based on pregnancy registries, which are maintained by researchers or drug manufacturers, and on research on pregnant animals. Although experiments with animals have provided considerable information regarding the teratogenic effects of drugs, it is not always possible to extrapolate experimental findings from animals to humans.

In 1979, the federal Food and Drug Administration (FDA) introduced regulations that were intended to improve labeling for the use of medications during pregnancy. The FDA created five risk categories that address potential adverse fetal effects, including congenital abnormalities (table 1). The FDA recognizes that the utility of this classification scheme is limited, and it has charged a Pregnancy Labeling Task Force with developing a narrative format that will better assist clinicians in prescribing drugs to pregnant women and in counseling them about fetal risks. All classifications noted in this manuscript are derived from the prescribing information sheets for each particular medication. (7) More up-to-date information can be obtained through the online REPRORISK[R] system from Micromedex (www.micromedex.com/products/reprorisk/), which contains four databases with information on reproductive risk. Additional prescribing guidelines and patient counseling services can be obtained on two other Web sites (www.motherisk.org and www.otispregnancy.org).

Antimicrobials

Bacterial infections of the head and neck are common during pregnancy, and they often require treatment with antimicrobials. Virtually all antimicrobial agents readily cross the placenta. Thus, there exists the potential for adverse effects on the fetus. Unfortunately, there are few scientific data regarding the use and safety of various antibiotics during pregnancy.

Nevertheless, many of these agents have been used in pregnant women for many years without apparent adverse effects and can, therefore, be prescribed with a great degree of comfort when indicated. These include the penicillins (including those combined with clavulanic acid and sulbactam), the cephalosporins, clindamycin, and certain macrolides (e.g., azithromycin and erythromycin), all of which the FDA classifies as category B agents (table 2). Another macrolide, clarithromycin, has been associated with adverse outcomes in animal experiments, and it is listed as a category C drug by its manufacturer.

Other antibiotics that are specifically known to have caused abnormalities in human and/or animal studies, and therefore should be avoided in pregnant patients, include the following agents, which are listed in either category C or D: the aminoglycosides, the quinolones, the sulfonamides, the tetracycline derivatives, chloramphenicol, and vancomycin.

Antivirals

During pregnancy, elevated cortisol levels place the patient in a relatively immunosuppressed state that can allow for the reactivation of latent viral infections. Antiherpetic formulations (e.g., acyclovir, famciclovir, and valacyclovir) have exhibited no teratogenic effects in animal or human pregnancies, and they are listed in category B.

Analgesics

Both acetaminophen and aspirin are believed to be safe for use during the first two trimesters. However, the use of aspirin (category C) closer to term may result in excessive bleeding in both the mother and fetus. (8) Acetaminophen, which lacks antiplatelet activity, is a category B drug and has become the antipyretic and analgesic of choice during pregnancy. Of course, ingestion of large doses of acetaminophen or the protracted use of this drug may result in renal and hepatic toxicity in the adult and, at least theoretically, could cause the same complications in the fetus.

Ibuprofen and naproxen, two common nonsteroidal anti-inflammatory drugs, have not been associated with an increased risk of congenital malformations, although ibuprofen has been reported to be associated with decreased amniotic fluid volume. (9) Moreover, because they are both prostaglandin synthetase inhibitors, ibuprofen and naproxen could, in theory, cause premature closure of the ductus arteriosus. Therefore, they should be avoided after 34 weeks of gestation. They are both listed in category B. The newer cyclo-oxygenase-2 inhibitors (e.g., celecoxib and rofecoxib) fall into category C and should be avoided.

Narcotic analgesics (category C) should be reserved for those patients whose pain is refractory to more conservative approaches. Codeine, hydrocodone, oxycodone, and morphine may be used, but they carry the potential to cause dependence and withdrawal symptoms in the fetus and newborn if they are abused or even used regularly. (8) Fetal respiratory depression is another potential complication of narcotics if they are used around the time of delivery.

Corticosteroids

Corticosteroids cross the placenta, and animal studies have suggested that these compounds are teratogenic when they are administered systemically, especially during the first two trimesters. Therefore, all glucocorticoid formulations are listed in category C. Nonetheless, corticosteroids are often prescribed during premature labor to stimulate fetal lung maturation. (10) To date, no evidence of any apparent adverse fetal effects has been noted. Most experts agree that corticosteroids can be taken safely during the third trimester when medically indicated for conditions such as Bell's palsy, laryngeal edema, or sudden sensorineural hearing loss.

Prednisone is regarded as the oral steroid of choice, while dexamethasone is a commonly used intravenous formulation. Hilsinger et al reported that two-thirds of pregnant women with Bell's palsy received steroids during their third trimester, and in no case were there any fetal side effects. (11) In that study, the authors recommended using up to 60 mg of prednisone for 5 days and then tapering the dosage over the following 5 days.

Decongestants

Upper respiratory infections, sinusitis, rhinitis, and nasal congestion are relatively common during pregnancy. Decongestants may be administered either topically or systemically to provide symptomatic relief. According to their manufacturers, systemic decongestants carry a theoretical risk for decreasing uterine blood flow, but no data to confirm this have been published. Nonetheless, the use of systemic vasoconstrictors should be avoided in the gravid patient with suspected placental insufficiency and in the presence of pregnancy-related hypertension.

Although pseudoephedrine is in category C, it has been recommended as the oral decongestant of choice in a position statement released in 2000 by the American College of Obstetrics and Gynecology and the American College of Allergy, Asthma, and Immunology. (12) Epidemiologic studies of more than 1,000 first-trimester human pregnancies exposed to pseudoephedrine indicate that it is not associated with congenital anomalies. (13) Topical sympathomimetic sprays (e.g., oxymetazoline and phenylephrine) may also be used for relief of nasal congestion, but they carry a risk of causing rebound rhinitis medicamentosa.

Antihistamines and allergy medications

Allergic rhinitis may develop or worsen during pregnancy. The treatment of pregnancy-associated allergic rhinitis begins with environmental control. Chlorpheniramine (category B) is generally the antihistamine of choice for use during pregnancy (table 3). (14) If sedation becomes an issue, cetirizine and loratadine (both category B) are approved for use in pregnant women, but ideally only after the first trimester. (14) Fexofenadine and azelastine are in category C and should be avoided.

Leukotriene inhibitors (e.g., montelukast and zafirlukast) are in category B. Manufacturers of leukotriene inhibitors maintain active registries to monitor the pregnancy outcomes of women who are exposed to these relatively new medications.

Patients with chronic allergic symptoms can safely us intranasal cromolyn (category B) and topical intranasal steroid preparations, which, although they are in category C, should not reach plasma levels high enough to affect the growing fetus. Of the topical intranasal steroids, mometasone is essentially free of systemic absorption (0.1% bioavailability) and is quantitatively the safest of these preparations during pregnancy. (15) Finally, patients who are undergoing immunotherapy for allergy hyposensitization can be continued on these injections during pregnancy. (16) However, allergy testing during pregnancy should not be undertaken because of the potential risk of an anaphylactic response. (17)

Gastrointestinal agents

Gastroesophageal reflux occurs with a much higher frequency during pregnancy, and it is most prevalent during the third trimester. (18) The [H.sub.2] receptor antagonists cimetidine, famotidine, and ranitidine are all category B agents and are preferred over nizatidine, which is listed in category C (table 4).

The proton-pump inhibitors esomeprazole, lansoprazole, pantoprazole, and rabeprazole are all in category B. Omeprazole is the only member of this class that carries a category C listing.

Antivertigo and antinausea agents

Isolated episodes of vertigo and exacerbations of preexisting Meniere's disease are common during pregnancy. Conservative management with antiemetics and vestibular suppressants is the treatment of choice during pregnancy. Dimenhydrinate and meclizine are category B drugs and are especially safe when administered in the smaller doses required to control vertigo and the accompanying nausea. Both ondansetron and metaclopramide (category B) are safe and effective antinausea medications, and they should be used instead of prochlorperazine (category C) and diazepam (category D). Diazepam carries an increased risk of congenital malformations when used during the first trimester.

Table 1. FDA labeling categories for medication use
during pregnancy

Category   Risk

A          Controlled human studies have failed to
           demonstrate a risk to the fetus.

B          Either animal studies have not demonstrated
           a fetal risk but there have been
           no controlled human studies, or animal
           studies have shown an adverse effect
           that has not been confirmed in controlled
           human studies.

C          Either animal studies have revealed
           adverse effects and there have been no
           controlled human studies, or studies in
           women or animals are not available.
           Use only if the potential benefit outweighs
           the potential risk to the fetus.

D          There is positive evidence of human
           fetal risk. Use only in a life-threatening
           situation or for a serious disease for
           which safer drugs cannot be used or
           are ineffective.

X          They use of such a drug during pregnancy
           is contraindicated.

Table 2. FDA classification of selected
antimicrobials

Category   Drug

B          Azithromycin
           Cephalosporins
           Clindamycin
           Erthromycin
           Penicillins (including amoxicillin/
             clavulanic acid and ampicillin/
             sulbactam)

C/D        Aminoglycosides
           Chloramphenicol
           Clarithromycin
           Quinolones
           Sulfonamides
           Tetraycyclines derivatives
           Vancomycin

Table 3. FDA classification of selected
antihistamines

Category   Drug

B          Azatadine
           Cetirizine
           Chlorpheniramine
           Clemastine
           Dimenhydrinate
           Diphenhydramine
           Loratadine

C          Azelastine
           Brompheniramine
           Fexofenadine
           Hydroxyzine
           Promethazine

Table 4. FDA classification of selected
gastrointestinal agents

Category   Drugs

B          Cimetidine
           Esomeprazole
           Famotidine
           Lansoprazole
           Pantoprazole
           Rebeprazole
           Ranitidine

C          Nizadine
           Omeprazole

References

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(2.) Abrams RS. Will It Hurt the Baby? The Safe Use of Medications during Pregnancy and Breastfeeding. Reading, Mass.: Addison-Wesley Publishing, 1990:1-5.

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(10.) Gilstrap L, Little B. Antiasthma agents during pregnancy. In: Gilstrap L. Little B, eds. Drugs and Pregnancy. 2nd ed. New York: Chapman and Hall, 1998:103-20.

(11.) Hilsinger RL, Jr., Adour KK, Dory HE. Idiopathic facial paralysis, pregnancy, and the menstrual cycle. Ann Otol Rhinol Laryngol 1975; 84:433-42.

(12.) The use of newer asthma and allergy medications during pregnancy. The American College of Obstetricians and Gynecologists (ACOG) and The American College of Allergy, Asthma and Immunology (ACAAI). Ann Allergy Asthma Immunol 2000;84:475-80.

(13.) Aselton P, Jick H, Milunsky A, et al. First-trimester drug use and congenital disorders. Obstet Gynecol 1985;65:451-5.

(14.) Schatz M, Petitti D. Antihistamines and pregnancy. Ann Allergy Asthma Immunol 1997;78:157-9.

(15.) LaForce C. Use of nasal steroids in managing allergic rhinitis. J Allergy Clin Immunol 1999;103(Pt 2):S388-94.

(16.) Rabin R, Patterson R. Guidelines for using allergen immunotherapy. Journal of Respiratory Diseases 1981;2:64-72.

(17.) Schatz M, Zeiger R. Allergic disease during pregnancy: Current treatment options. Journal of Respiratory Diseases 1998;19:834-42.

(18.) Torsiglieri AJ, Jr., Tom LW, Keane WM, Atkins JP, Jr. Otolaryngologic manifestations of pregnancy. Otolaryngul Head Neck Surg 1990;102: 293-7.

From the Department of Otolaryngology-Head and Neck Surgery, Thomas Jefferson University, Philadelphia.

Reprint requests: Edmund A. Pribitkin, MD, Department of Otolaryngology-Head and Neck Surgery, Thomas Jefferson University, 925 Chestnut St., Sixth Floor, Philadelphia, PA 19107. Phone: [phone]; fax: [phone]; e-mail: [e-mail]

Originally presented at the annual meeting of the American Academy of Otolaryngology-Head and Neck Surgery; Sept. 9-12, 2001; Denver.