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SELECTING DRUGS FOR THE PREGNANT DENTAL PATIENT
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SELECTING DRUGS FOR THE PREGNANT DENTAL PATIENT PAUL A. MOORE, D.M.D., PH.D.
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When treating pregnant patients, dental practitioners should avoid prescribing some drugs routinely used for local anesthesia, sedation, analgesia or infection. Dental practitioners need to determine that the potential benefits of the drug required for the mother’s dental care outweigh the risks to her fetus. This article briefly reviews the relative risks of therapeutic agents commonly used in dental care to help practitioners select the safest drugs for use by pregnant patients.
The selection of dental therapeutic agents for local anesthesia, se-
dation, postoperative pain control and treatment of infections is usually straightforward. For healthy young adults, dental practitioners might routinely select lidocaine hydrochloride with epinephrine, diazepam, codeine with acetaminophen and penicillin V-potassium. The use of alternative agents may be necessary for patients who have a history of drug allergy or who are medically compromised, extremely young or old, taking concomitant medications or pregnant. In the case of a pregnant patient, the dental practitioner must determine that the potential benefits of the dental therapy required for her care outweigh the risks to the fetus. Although most elective dental procedures can be postponed until after the pregnancy is over, dental treatment for a pregnant woman who has oral pain, advanced disease or infection should not be delayed. It is understood that none of the drugs used to treat pain and infection are totally without risk. The consequences of not treating an active infection during pregnancy, however, outweigh the possible risks presented by most of the drugs required for dental care. This article reviews the concerns associated with drug therapy for pregnant patients and provides a guide for selecting local anesthetics, peripherally acting analgesics, centrally acting opioids analgesics, antibiotics and sedatives/anxiolytics for use during pregnancy (Table).
PREGNANCY-RELATED PHYSIOLOGICAL CHANGES
Physiological changes that occur during pregnancy include weight gain, positional hypotension when placed in a supine position, frequent need to urinate, restricted respiratory function, potential for hypoglycemia and increased cardiac output sometimes associated with tachycardia and heart murmurs. Syncope and morning sickness also are common features of pregnancy. Changes in oral physiology seen during pregnancy include gingival inflammation and hypertrophy, as well as generalized tooth mobility.1,2 Higher anxiety levels associated with pregnancy may intensify the stress of a dental appointment. Dental care during pregnancy should accommodate these changes with short appointments, avoidance of prolonged supine positioning, oral hygiene and dietary instructions, and judicious use of radiographs.2 JADA, Vol. 129, September 1998 Copyright ©1998-2001 American Dental Association. All rights reserved.
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CLINICAL PRACTICE A goal of any drug therapy prescribed during pregnancy is to avoid adverse drug reactions in either the mother or the fetus. Hypersensitivity, allergies or toxic reactions that occur in a woman may compromise her health and limit her ability to support a pregnancy. Adverse drug effects that are specific to the health of the fetus include congenital defects, miscarriage, complications during delivery, low birth weight and postnatal drug dependence. These effects are usually specific to the timing of the drug administration—during the first, second or third trimester—the dosage and the duration of therapy. Dental therapies, which usually use drugs with short metabolic half-lives administered for limited periods, are, therefore, less likely to cause complications during pregnancy. The U.S. Food and Drug Administration, or FDA, has established five categories for classifying drugs according to the risks they pose to pregnant women and their fetuses.3 The five categories provide a guide to the relative safety of drugs prescribed to pregnant women. Category A includes drugs that have been studied in humans and have evidence supporting their safe use. Category B drugs show no evidence of risk in humans. Category C includes drugs for which teratogenic risk cannot be ruled out. Category D includes drugs that have demonstrated risks in humans, and category X includes agents that have been shown to be harmful to the mother or fetus. Drugs in categories A and B generally are considered appropriate for use during pregnancy. Category C drugs should be used with caution, and drugs in categories D and X should be avoided or are contraindicated. Less than 20 percent 1282
of all drugs classified by the FDA fall into categories A or B.4 Product information sheets provided with prescription and nonprescription drugs, as well as drug information found in Physicians’ Desk Reference, generally include these FDA use-in-pregnancy ratings.5 Of the thousands of drugs marketed, only a few drugs are known for certain to be teratogenic in humans.6,7 Thalidomide, developed in the 1950s as a tranquilizer and antiemetic, is the most well-known and prototypic human teratogen. Thalidomide’s teratogenesis is unusual because, when the drug is taken during the first three months of pregnancy, it induces a very high incidence of birth defects, including a unique anomaly called phocomelia that is charac-
Dental therapies, which usually use drugs with short metabolic half-lives administered for limited periods, are less likely to cause complications during pregnancy. terized by shortened arms and legs. Warfarin, retinoids, anticonvulsants and heavy metals also are known to produce significant physical birth defects. Fetal alcohol syndrome is associated with varying degrees of mental retardation in infants and is thought to be responsible for as much as 8 percent of the cases of mental retardation in the United States.7 Our knowledge of the risks associated with drug therapy during pregnancy is most clear when the frequency
of birth defects is high and the outcome is easily identified. Adverse effects of drug therapy during pregnancy that are subtle and delayed, such as minor changes in behavior and intelligence, are nearly impossible to determine.7,8 Many factors may contribute to uncertainty when determining the risks of drug therapy. Animal data, which are usually collected from studies that use extraordinarily high and prolonged exposures to drugs, are known to vary markedly by species. For some congenital defects, such as cleft lip with or without cleft palate, there are many possible causes, which complicates the assessment of added risk for any specific drug.9 The teratogenic potential for some drugs may be dependent on a genetic predisposition involved in fetal development.10 For many drugs that are new or infrequently prescribed, accurate assessment of human risk is impossible. Additionally, when multiple birth defects are reported, it is often difficult to determine whether the drug or the underlying disease requiring drug therapy is the etiologic factor. RISKS ASSOCIATED WITH SPECIFIC DRUG CLASSES
Local anesthetics. Most local anesthetics have not been shown to be teratogenic in humans and are considered relatively safe for use during pregnancy. The recommendation for caution (category C) when prescribing mepivacaine hydrochloride and bupivacaine hydrochloride relates primarily to limited data collected in animal teratogenicity studies. As such, adverse drug effects to humans cannot be ruled out for these agents. Because all local anesthetics can cross the placenta
JADA, Vol. 129, September 1998 Copyright ©1998-2001 American Dental Association. All rights reserved.
CLINICAL PRACTICE TABLE
DENTAL THERAPEUTICS FOR PREGNANT PATIENTS. DRUG
Generic Name
PRC*
POSSIBLE NEGATIVE PREGNANCY OUTCOME
Brand Name Examples (Manufacturer) Local Anesthetics
Bupivacaine hydrochloride
Marcaine (Eastman Kodak), Sensorcaine (Astra USA, Inc., Pharmaceuticals)
C
Etidocaine hydrochloride
Duranest (Astra USA, Inc., Pharmaceuticals)
B
Lidocaine hydrochloride
Xylocaine (Astra USA, Inc., Pharmaceuticals)
B
Mepivacaine hydrochloride
Carbocaine (Eastman Kodak), Polocaine (Astra USA, Inc., Pharmaceuticals)
C
Prilocaine hydrochloride
Citanest (Astra USA, Inc., Pharmaceuticals)
B
Acetaminophen
Tylenol (McNeil Consumer Products)
Aspirin
Bayer (Sterling Drug Inc.), Bufferin (BristolMyers Company), Ecotrin (SmithKline Beecham Consumer)
C (3D)†
Ibuprofen
Advil (Whitehall Laboratories), Motrin (McNeil Consumer Products Co.)
B (3D)
Delayed labor and prolonged pregnancy in mother
Naproxen
Aleve (Procter & Gamble), Anaprox (Roche Laboratories)
B (3D)
Delayed labor and prolonged pregnancy in mother
Codeine with acetaminophen
Tylenol with codeine (McNeil Laboratories)
C (3D)
Multiple birth defects, neonatal respiratory depression, neonatal opioid withdrawal
Hydrocodone bitartrate and acetaminophen
Vicodin (Knoll Laboratories)
C (3D)
Neonatal respiratory depression, neonatal opioid withdrawal
Hydrocodone bitartrate and ibuprofen
Vicoprofen (Knoll Laboratories)
C (3D)
Neonatal respiratory depression, neonatal opioid withdrawal
Oxycodone with acetaminophen
Percocet (Dupont Pharmaceuticals), Tylox (McNeil Laboratories)
C (3D)
Neonatal respiratory depression, neonatal opioid withdrawal
Fetal bradycardia
Fetal bradycardia
Peripherally Acting Analgesics B Postpartum hemorrhage and delivery complications in mother and fetus
Centrally Acting Opioid Anesthetics
Antibiotics Amoxicillin
Amoxil (SmithKline Beecham), Polymox (Bristol-Myers Squibb)
B
Cephalexin
Keflex (Dista)
B
Chloramphenicol
Chlormycetin (Parke-Davis)
X
Clindamycin hydrochloride
Cleocin (Pharmacia & Upjohn)
B
Doxycycline hyclate
Doryx (Parke-Davis), Vibramycin (Pfizer Laboratories)
D
Erythromycin base
E-Mycin (Knoll Laboratories), ERYC (Parke-Davis)
Erythromycin estolate
Ilosone (Lilly),
Erythromycin ethylsuccinate
E.E.S. (Abbott Laboratories)
Gentamicin
Garamycin (Shering Co.)
Metronidazole
Flagyl (Searle & Co.)
B
Penicillin V-potassium
Pen-Vee K (Wyeth-Ayerst)
B
Maternal toxicity and gray syndrome and possible death in infant
Tooth discoloration, inhibition of bone development in infant
B B‡
Increased risk of maternal cholestatic hepatitis
B C (3D)
Potential ototoxicity in fetus
Sedatives/Anxiolytics Benzodiazepines (for Valium (Roche Laboratories), Xanax (Pharmacia & Upjohn) example, diazepam and alprazolam) Nitrous oxide
D
Possible oral clefts in fetus with prolonged exposure
Not Classified
Spontaneous abortions and delayed fertility in mother
* PRC: Pregnancy risk category. Category A: drugs that have been studied in humans and have evidence supporting their safe use. Category B: drugs that show no evidence of risk in humans. Category C: drugs for which teratogenic risk cannot be ruled out. Category D: drugs that have demonstrated risks in humans. Category X includes agents that have been shown to be harmful to the mother or fetus. † A category in parentheses (for example, 3D) refers to risk for use during the third trimester of pregnancy. ‡ Use of erythromycin base rather than the estolate salt is recommended.
JADA, Vol. 129, September 1998 Copyright ©1998-2001 American Dental Association. All rights reserved.
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CLINICAL PRACTICE and cause fetal depression, limiting the dose to the minimum required for effective pain control is obviously advisable. Epinephrine, a naturally occurring hormone, is generally considered to have no teratogenic effects when administered with dental anesthetics.1,11 Because epinephrine is known to stimulate cardiovascular function, its administration demands careful technique and proper dosing. Peripherally acting analgesics. The peripherally acting class of analgesics includes a number of commonly used agents that should be avoided. When acetaminophen is administered in therapeutic doses, it generally is considered to be the best choice for managing oral-facial pain during pregnancy.7,11,12 Aspirin should be avoided—particularly late in pregnancy—because it is associated with delivery complications and postpartum hemorrhage in the mother.13 Chronic use of aspirin early in the pregnancy has been associated with anemia in pregnant women. Aspirin and the newer nonsteroidal anti-inflammatory drugs, or NSAIDs, such as ibuprofen and naproxen, have the common mechanism of inhibiting prostaglandin synthesis. By blocking synthesis of the prostaglandins involved in induction of labor, NSAIDs may prolong pregnancy. Additionally, prostaglandin inhibitors may cause constriction of the ductus arteriosus in the fetus, resulting in pulmonary hypertension in the infant. Therefore, aspirin and any of the other NSAIDs should be avoided, particularly during the third trimester of pregnancy.13 The synthetic prostaglandin analog misoprostol (Cytotec, G.D. 1284
Searle & Co.) has recently been marketed to prevent gastric ulcers induced by chronic NSAID therapy. NSAIDs decrease prostaglandin levels in the gastric mucosa to below the amount needed to maintain the mucous layer, which protects the stomach from acid degradation. Misoprostol restores the gastric prostaglandin levels, thereby preventing this common adverse reaction to chronic NSAID therapy.14 Misoprostol, however, is very effective in inducing labor
The peripherally acting class of analgesics includes a number of commonly used agents that should be avoided. and is known to have significant abortifacient properties.15 The use of misoprostol to prevent gastric ulcers during NSAID therapy is rarely necessary in acute dental therapy, and it never should be administered to pregnant women or women with childbearing potential. Centrally acting opioid analgesics. Opioid analgesics should be used cautiously and only when indicated. The use of codeine and propoxyphene during pregnancy has been evaluated as part of the Collaborative Perinatal Project.16 This prospective study monitored 41,337 pregnancies for possible drug-related birth defects and toxicities. The results suggested that codeine and propoxyphene are associated with multiple congenital defects, including heart defects and cleft lip or palate. Because other opioids, such as oxycodone and hydrocodone, are administered in-
frequently during pregnancy, little is known about their risks to fetuses. As discussed in the introduction to this article, the medical disorders that necessitated the use of these opioids also may have induced heart defects and cleft lip or palate. Neonatal respiratory depression and opioid withdrawal also have been reported with opioid use.10 The prolonged or high-dose use of opioids late in pregnancy significantly increases the risk of the fetus developing heart defects or cleft lip or palate. Antibiotics. The penicillin and cephalosporin antibiotics most commonly used in dentistry—penicillin V-potassium, amoxicillin and cephalexin—are generally thought to be safe to prescribe during pregnancy. Clindamycin, metronidazole and erythromycin also are believed to have minimal risk. Erythromycin estolate may be more likely to induce hepatic toxicity in a pregnant patient and, therefore, is not recommended.17 The greatest concern regarding antibiotic use is with agents that have limited indications in dentistry. Aminoglycosides, such as gentamicin, may induce ototoxicity in the fetus when administered late in pregnancy. Tetracyclines, including doxycycline hyclate, have been implicated for causing tooth discoloration and inhibition of bone development in infants. Chloramphenicol is contraindicated in pregnancy because of maternal toxicity and fetal circulatory failure, called gray syndrome.10,13,16 Sedatives/anxiolytics. Administration of any of the central nervous system depressants commonly used for sedation is problematic. Because sedative agents inhibit neuronal function
JADA, Vol. 129, September 1998 Copyright ©1998-2001 American Dental Association. All rights reserved.
CLINICAL PRACTICE and generally cross placental barriers, their use during pregnancy is generally viewed with apprehension. Of the antianxiety drugs that are commonly prescribed, the benzodiazepine diazepam has been assessed most frequently. Investigations of both animals and humans have noted an association between diazepam exposure during pregnancy and oral clefts.18,19 Yet, confirmation of these reports has not always been possible.20,21 A single exposure to a clinically acceptable dose of any benzodiazepine as compared with chronic therapy throughout a pregnancy would have minimal risk for teratogenicity.22,23 Overall, the evidence cautions against prolonged use of all benzodiazepines during pregnancy. Prolonged high-dose exposure to nitrous oxide in rats has produced skeletal and behavioral teratogenic effects.8,24,25 Additionally, occupational exposure to nitrous oxide has been observed in spontaneous abortions and reduced fertility in humans.26,27 Nitrous oxide blocks the vitamin B12-dependent enzyme methionine synthase, thereby depleting tetrahydrofolate, which is necessary for deoxyribonucleic acid synthesis. Thus, prolonged exposure to ambient concentrations of nitrous oxide could conceivably inhibit cell division.28 Short exposure during general anesthesia to agents, such as nitrous oxide, is not thought to be teratogenic.29 Nevertheless, because nitrous oxide may inhibit cell replication, minimizing prolonged use when possible is prudent. CONCLUSION
Drug and chemical exposure during pregnancy is believed to account for only about 1 percent of congenital malformations.6
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Delivery complications and birth defects are more commonly caused by the mother’s poor nutrition, smoking, alcohol consumption, disease, genetic predisposition and age.10,30 Maintaining a healthy lifestyle, including optimal oral health, is essential for women who are currently pregnant or who are planning to become pregnant. For example, recent evidence has implicated periodontal infections as a possible factor associated with the delivery of low-birth-weight babies.31 Dental practitioners should provide essential care for pregnant patients, particularly when acute infections are present. In this article, the current knowledge about safe drug therapy during pregnancy has been reviewed and recommendations specific to dental therapy have been provided. When dental treatment is needed to maintain a pregnant Dr. Moore is a prowoman’s oral fessor of pharmacology, Department of health, selecting Dental Public Health, the safest 614 Salk Hall, University of agents, limiting Pittsburgh, School of the duration of Dental Medicine, the drug regiPittsburgh, Pa. 15261. Address mens and minireprint requests to mizing dosages Dr. Moore.
are the fundamental principles of safe therapy. ■ A patient pamphlet entitled “Pregnancy and Oral Health” provides advice on nutrition, oral hygiene, gingivitis, drug use, radiographs and dental care during pregnancy. It can be obtained through the ADA Salable Products Catalog by calling 1-800-947-4746. Specific drug therapy information can be obtained from the ADA Council on Scientific Affairs by calling 1-312-440-2878; ADA members can call the toll-free number on the back of their membership cards and ask for Extension 2878. A national information service for drug safety during pregnancy that provides practitioners with local referrals is available through the Organization of Teratology Information Services by calling 1-801-328-2229 or visiting its Web site at “http://orpheus.ucsd.edu/otis/”. 1. Miller MC. The pregnant dental patient. J Calif Dent Assoc 1995;23(8):63-70. 2. Tarsitano BF, Rollings RE. The pregnant dental patient: evaluation and management. Gen Dent 1993;41(3):226-31. 3. United States Food and Drug Administration. Labeling and prescription drug advertising: content and format for labeling for human prescription drugs. Fed Regist 1979;44(124):37434-67. 4. Teratology Society Public Affairs Committee. FDA classification of drugs for teratogenic risk. Teratology 1994;49(6):446-7. 5. Physicians’ Desk Reference. 52nd ed. Montvale, N.J.: Medical Economics Company; 1998. 6. Rang HP. Pharmacology. 3rd ed. New York: Churchill Livingstone; 1995. 7. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation: A reference guide to fetal and neonatal risk. 3rd ed. Baltimore: Williams & Wilkins; 1990. 8. Mullenix PJ, Moore PA, Tassinari MS. Behavioral toxicity of nitrous oxide in rats following prenatal exposure. Toxicol Ind Health 1986;2(3):273-87. 9. Hayes DP. Teratogenesis: a review of the basic principles with a discussion of selected agents. Part 1. Drug Intell Clin Pharm 1981;15:444-58. 10. Stern L. Drug use in pregnancy. Sydney, Boston: ADIS Health Science Press; 1984. 11. Folbs PI, Dukes MNG. Drug safety in
JADA, Vol. 129, September 1998 Copyright ©1998-2001 American Dental Association. All rights reserved.
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CLINICAL PRACTICE pregnancy. Amsterdam: Elsevier; 1990. 12. Balligan FJ, Hale TM. Analgesic and antibiotic administration during pregnancy. Gen Dent 1993; 41(3):220-5. 13. Hayes DP. Teratogenesis: a review of the basic principles with a discussion of selected agents. Part 2. Drug Intell Clin Pharm 1981;15:542-65. 14. Champion GD, Feng PH, Azuma T, et al. NSAID-induced gastrointestinal damage: epidemiology, risk and prevention with an evaluation of the role of misoprostol—an AsianPacific perspective and consensus. Drugs 1997;53(1):6-19. 15. Kadanali S, Kucukozkan T, Zor N, Kumtepe Y. Comparison of labor induction with misoprostol vs. oxytocin/prostaglandin E2 in term pregnancy. Int J Gynaecol Obstet 1996;55(2):99-104. 16. Heinonen OP, Slone D, Shapiro S. Birth defects and drugs in pregnancy. Littleton, Mass.: Publishing Sciences Group; 1977. 17. McCormack WM, George H, Donner A, et al. Hepatotoxicity of erythromycin estolate during pregnancy. Antimicrob Agents Chemother 1977;12:630-5. 18. Saxen I. Associations between oral clefts
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and drugs taken during pregnancy. Int J Epidemiol 1975;4(1):37-44. 19. Safra JM, Oakley GP. Association between cleft lip with or without cleft palate and neonatal exposure to diazepam. Lancet 1975;2:478-80. 20. Rosenberg L, Mitchell AA, Parsells JL, Pashayan H, Lonik C, Shipiro S. Lack of relation of oral clefts to diazepam use during pregnancy. N Engl J Med 1983;309:1282-5. 21. Schlumpf M, Ramseier H, Abriel H, Youmbi M, Baumann JB, Lichtenstein W. Diazepam effects on the fetus. Neurotoxicology 1989;10:501-16. 22. Schardein JL. Psychotropic drugs. In: Chemically induced birth defects. New York: Dekker; 1993. 23. Koren G, Pastuszak A, Ito S. Drugs in pregnancy. N Engl J Med 1998;338(16):1128-37. 24. Mazze RI, Wilson AI, Rice SA, Baden JM. Reproduction and fetal development in rats exposed to nitrous oxide. Teratology 1984;30:259-65. 25. Tassinari MS, Mullenix PJ, Moore PA. The effects of nitrous oxide after exposure during middle and late gestation. Toxicol Ind Health 1986;2:261-71.
26. Rowland AS, Baird DD, Weinberg CR, Shore DL, Shy CM, Wilcox AJ. Reduced fertility among women employed as dental assistants exposed to high levels of nitrous oxide. N Engl J Med 1992;327:993-7. 27. Cohen EN, Gift HC, Brown BW, et al. Occupational disease in dentistry and chronic exposure to trace anesthetic gases. JADA 1980;101(1):21-31. 28. Finnell RH, Greer KA, Barber RC, Piedrahita JA. Neural tube and craniofacial defects with special emphasis on folate pathway genes. Crit Rev Oral Biol Med 1998;9(1):38-53. 29. Mazze RI, Kallen B. Reproductive outcome after anesthesia and operation during pregnancy: a registry study of 5405 cases. Am J Obstet Gynecol 1989;161:1178-85. 30. Hayes DP. Teratogenesis: a review of the basic principles with a discussion of selected agents. Part 3. Drug Intell Clin Pharm 1981;15:639-50. 31. Offenbacher S, Katz V, Fertik G, et al. Periodontal infection as a possible risk factor for preterm low birth weight. J Periodontol 1996;67(10):1103-13.
JADA, Vol. 129, September 1998 Copyright ©1998-2001 American Dental Association. All rights reserved.
D
J
A
✷
IO N
A
T
T
CON I
N U
IN G
ED
U
ARTICLE 3
SELECTING DRUGS FOR THE PREGNANT DENTAL PATIENT PAUL A. MOORE, D.M.D., PH.D.
A
B
S
T
R
A
C
T
When treating pregnant patients, dental practitioners should avoid prescribing some drugs routinely used for local anesthesia, sedation, analgesia or infection. Dental practitioners need to determine that the potential benefits of the drug required for the mother’s dental care outweigh the risks to her fetus. This article briefly reviews the relative risks of therapeutic agents commonly used in dental care to help practitioners select the safest drugs for use by pregnant patients.
The selection of dental therapeutic agents for local anesthesia, se-
dation, postoperative pain control and treatment of infections is usually straightforward. For healthy young adults, dental practitioners might routinely select lidocaine hydrochloride with epinephrine, diazepam, codeine with acetaminophen and penicillin V-potassium. The use of alternative agents may be necessary for patients who have a history of drug allergy or who are medically compromised, extremely young or old, taking concomitant medications or pregnant. In the case of a pregnant patient, the dental practitioner must determine that the potential benefits of the dental therapy required for her care outweigh the risks to the fetus. Although most elective dental procedures can be postponed until after the pregnancy is over, dental treatment for a pregnant woman who has oral pain, advanced disease or infection should not be delayed. It is understood that none of the drugs used to treat pain and infection are totally without risk. The consequences of not treating an active infection during pregnancy, however, outweigh the possible risks presented by most of the drugs required for dental care. This article reviews the concerns associated with drug therapy for pregnant patients and provides a guide for selecting local anesthetics, peripherally acting analgesics, centrally acting opioids analgesics, antibiotics and sedatives/anxiolytics for use during pregnancy (Table).
PREGNANCY-RELATED PHYSIOLOGICAL CHANGES
Physiological changes that occur during pregnancy include weight gain, positional hypotension when placed in a supine position, frequent need to urinate, restricted respiratory function, potential for hypoglycemia and increased cardiac output sometimes associated with tachycardia and heart murmurs. Syncope and morning sickness also are common features of pregnancy. Changes in oral physiology seen during pregnancy include gingival inflammation and hypertrophy, as well as generalized tooth mobility.1,2 Higher anxiety levels associated with pregnancy may intensify the stress of a dental appointment. Dental care during pregnancy should accommodate these changes with short appointments, avoidance of prolonged supine positioning, oral hygiene and dietary instructions, and judicious use of radiographs.2 JADA, Vol. 129, September 1998 Copyright ©1998-2001 American Dental Association. All rights reserved.
✷
1281
C
CLINICAL PRACTICE A goal of any drug therapy prescribed during pregnancy is to avoid adverse drug reactions in either the mother or the fetus. Hypersensitivity, allergies or toxic reactions that occur in a woman may compromise her health and limit her ability to support a pregnancy. Adverse drug effects that are specific to the health of the fetus include congenital defects, miscarriage, complications during delivery, low birth weight and postnatal drug dependence. These effects are usually specific to the timing of the drug administration—during the first, second or third trimester—the dosage and the duration of therapy. Dental therapies, which usually use drugs with short metabolic half-lives administered for limited periods, are, therefore, less likely to cause complications during pregnancy. The U.S. Food and Drug Administration, or FDA, has established five categories for classifying drugs according to the risks they pose to pregnant women and their fetuses.3 The five categories provide a guide to the relative safety of drugs prescribed to pregnant women. Category A includes drugs that have been studied in humans and have evidence supporting their safe use. Category B drugs show no evidence of risk in humans. Category C includes drugs for which teratogenic risk cannot be ruled out. Category D includes drugs that have demonstrated risks in humans, and category X includes agents that have been shown to be harmful to the mother or fetus. Drugs in categories A and B generally are considered appropriate for use during pregnancy. Category C drugs should be used with caution, and drugs in categories D and X should be avoided or are contraindicated. Less than 20 percent 1282
of all drugs classified by the FDA fall into categories A or B.4 Product information sheets provided with prescription and nonprescription drugs, as well as drug information found in Physicians’ Desk Reference, generally include these FDA use-in-pregnancy ratings.5 Of the thousands of drugs marketed, only a few drugs are known for certain to be teratogenic in humans.6,7 Thalidomide, developed in the 1950s as a tranquilizer and antiemetic, is the most well-known and prototypic human teratogen. Thalidomide’s teratogenesis is unusual because, when the drug is taken during the first three months of pregnancy, it induces a very high incidence of birth defects, including a unique anomaly called phocomelia that is charac-
Dental therapies, which usually use drugs with short metabolic half-lives administered for limited periods, are less likely to cause complications during pregnancy. terized by shortened arms and legs. Warfarin, retinoids, anticonvulsants and heavy metals also are known to produce significant physical birth defects. Fetal alcohol syndrome is associated with varying degrees of mental retardation in infants and is thought to be responsible for as much as 8 percent of the cases of mental retardation in the United States.7 Our knowledge of the risks associated with drug therapy during pregnancy is most clear when the frequency
of birth defects is high and the outcome is easily identified. Adverse effects of drug therapy during pregnancy that are subtle and delayed, such as minor changes in behavior and intelligence, are nearly impossible to determine.7,8 Many factors may contribute to uncertainty when determining the risks of drug therapy. Animal data, which are usually collected from studies that use extraordinarily high and prolonged exposures to drugs, are known to vary markedly by species. For some congenital defects, such as cleft lip with or without cleft palate, there are many possible causes, which complicates the assessment of added risk for any specific drug.9 The teratogenic potential for some drugs may be dependent on a genetic predisposition involved in fetal development.10 For many drugs that are new or infrequently prescribed, accurate assessment of human risk is impossible. Additionally, when multiple birth defects are reported, it is often difficult to determine whether the drug or the underlying disease requiring drug therapy is the etiologic factor. RISKS ASSOCIATED WITH SPECIFIC DRUG CLASSES
Local anesthetics. Most local anesthetics have not been shown to be teratogenic in humans and are considered relatively safe for use during pregnancy. The recommendation for caution (category C) when prescribing mepivacaine hydrochloride and bupivacaine hydrochloride relates primarily to limited data collected in animal teratogenicity studies. As such, adverse drug effects to humans cannot be ruled out for these agents. Because all local anesthetics can cross the placenta
JADA, Vol. 129, September 1998 Copyright ©1998-2001 American Dental Association. All rights reserved.
CLINICAL PRACTICE TABLE
DENTAL THERAPEUTICS FOR PREGNANT PATIENTS. DRUG
Generic Name
PRC*
POSSIBLE NEGATIVE PREGNANCY OUTCOME
Brand Name Examples (Manufacturer) Local Anesthetics
Bupivacaine hydrochloride
Marcaine (Eastman Kodak), Sensorcaine (Astra USA, Inc., Pharmaceuticals)
C
Etidocaine hydrochloride
Duranest (Astra USA, Inc., Pharmaceuticals)
B
Lidocaine hydrochloride
Xylocaine (Astra USA, Inc., Pharmaceuticals)
B
Mepivacaine hydrochloride
Carbocaine (Eastman Kodak), Polocaine (Astra USA, Inc., Pharmaceuticals)
C
Prilocaine hydrochloride
Citanest (Astra USA, Inc., Pharmaceuticals)
B
Acetaminophen
Tylenol (McNeil Consumer Products)
Aspirin
Bayer (Sterling Drug Inc.), Bufferin (BristolMyers Company), Ecotrin (SmithKline Beecham Consumer)
C (3D)†
Ibuprofen
Advil (Whitehall Laboratories), Motrin (McNeil Consumer Products Co.)
B (3D)
Delayed labor and prolonged pregnancy in mother
Naproxen
Aleve (Procter & Gamble), Anaprox (Roche Laboratories)
B (3D)
Delayed labor and prolonged pregnancy in mother
Codeine with acetaminophen
Tylenol with codeine (McNeil Laboratories)
C (3D)
Multiple birth defects, neonatal respiratory depression, neonatal opioid withdrawal
Hydrocodone bitartrate and acetaminophen
Vicodin (Knoll Laboratories)
C (3D)
Neonatal respiratory depression, neonatal opioid withdrawal
Hydrocodone bitartrate and ibuprofen
Vicoprofen (Knoll Laboratories)
C (3D)
Neonatal respiratory depression, neonatal opioid withdrawal
Oxycodone with acetaminophen
Percocet (Dupont Pharmaceuticals), Tylox (McNeil Laboratories)
C (3D)
Neonatal respiratory depression, neonatal opioid withdrawal
Fetal bradycardia
Fetal bradycardia
Peripherally Acting Analgesics B Postpartum hemorrhage and delivery complications in mother and fetus
Centrally Acting Opioid Anesthetics
Antibiotics Amoxicillin
Amoxil (SmithKline Beecham), Polymox (Bristol-Myers Squibb)
B
Cephalexin
Keflex (Dista)
B
Chloramphenicol
Chlormycetin (Parke-Davis)
X
Clindamycin hydrochloride
Cleocin (Pharmacia & Upjohn)
B
Doxycycline hyclate
Doryx (Parke-Davis), Vibramycin (Pfizer Laboratories)
D
Erythromycin base
E-Mycin (Knoll Laboratories), ERYC (Parke-Davis)
Erythromycin estolate
Ilosone (Lilly),
Erythromycin ethylsuccinate
E.E.S. (Abbott Laboratories)
Gentamicin
Garamycin (Shering Co.)
Metronidazole
Flagyl (Searle & Co.)
B
Penicillin V-potassium
Pen-Vee K (Wyeth-Ayerst)
B
Maternal toxicity and gray syndrome and possible death in infant
Tooth discoloration, inhibition of bone development in infant
B B‡
Increased risk of maternal cholestatic hepatitis
B C (3D)
Potential ototoxicity in fetus
Sedatives/Anxiolytics Benzodiazepines (for Valium (Roche Laboratories), Xanax (Pharmacia & Upjohn) example, diazepam and alprazolam) Nitrous oxide
D
Possible oral clefts in fetus with prolonged exposure
Not Classified
Spontaneous abortions and delayed fertility in mother
* PRC: Pregnancy risk category. Category A: drugs that have been studied in humans and have evidence supporting their safe use. Category B: drugs that show no evidence of risk in humans. Category C: drugs for which teratogenic risk cannot be ruled out. Category D: drugs that have demonstrated risks in humans. Category X includes agents that have been shown to be harmful to the mother or fetus. † A category in parentheses (for example, 3D) refers to risk for use during the third trimester of pregnancy. ‡ Use of erythromycin base rather than the estolate salt is recommended.
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CLINICAL PRACTICE and cause fetal depression, limiting the dose to the minimum required for effective pain control is obviously advisable. Epinephrine, a naturally occurring hormone, is generally considered to have no teratogenic effects when administered with dental anesthetics.1,11 Because epinephrine is known to stimulate cardiovascular function, its administration demands careful technique and proper dosing. Peripherally acting analgesics. The peripherally acting class of analgesics includes a number of commonly used agents that should be avoided. When acetaminophen is administered in therapeutic doses, it generally is considered to be the best choice for managing oral-facial pain during pregnancy.7,11,12 Aspirin should be avoided—particularly late in pregnancy—because it is associated with delivery complications and postpartum hemorrhage in the mother.13 Chronic use of aspirin early in the pregnancy has been associated with anemia in pregnant women. Aspirin and the newer nonsteroidal anti-inflammatory drugs, or NSAIDs, such as ibuprofen and naproxen, have the common mechanism of inhibiting prostaglandin synthesis. By blocking synthesis of the prostaglandins involved in induction of labor, NSAIDs may prolong pregnancy. Additionally, prostaglandin inhibitors may cause constriction of the ductus arteriosus in the fetus, resulting in pulmonary hypertension in the infant. Therefore, aspirin and any of the other NSAIDs should be avoided, particularly during the third trimester of pregnancy.13 The synthetic prostaglandin analog misoprostol (Cytotec, G.D. 1284
Searle & Co.) has recently been marketed to prevent gastric ulcers induced by chronic NSAID therapy. NSAIDs decrease prostaglandin levels in the gastric mucosa to below the amount needed to maintain the mucous layer, which protects the stomach from acid degradation. Misoprostol restores the gastric prostaglandin levels, thereby preventing this common adverse reaction to chronic NSAID therapy.14 Misoprostol, however, is very effective in inducing labor
The peripherally acting class of analgesics includes a number of commonly used agents that should be avoided. and is known to have significant abortifacient properties.15 The use of misoprostol to prevent gastric ulcers during NSAID therapy is rarely necessary in acute dental therapy, and it never should be administered to pregnant women or women with childbearing potential. Centrally acting opioid analgesics. Opioid analgesics should be used cautiously and only when indicated. The use of codeine and propoxyphene during pregnancy has been evaluated as part of the Collaborative Perinatal Project.16 This prospective study monitored 41,337 pregnancies for possible drug-related birth defects and toxicities. The results suggested that codeine and propoxyphene are associated with multiple congenital defects, including heart defects and cleft lip or palate. Because other opioids, such as oxycodone and hydrocodone, are administered in-
frequently during pregnancy, little is known about their risks to fetuses. As discussed in the introduction to this article, the medical disorders that necessitated the use of these opioids also may have induced heart defects and cleft lip or palate. Neonatal respiratory depression and opioid withdrawal also have been reported with opioid use.10 The prolonged or high-dose use of opioids late in pregnancy significantly increases the risk of the fetus developing heart defects or cleft lip or palate. Antibiotics. The penicillin and cephalosporin antibiotics most commonly used in dentistry—penicillin V-potassium, amoxicillin and cephalexin—are generally thought to be safe to prescribe during pregnancy. Clindamycin, metronidazole and erythromycin also are believed to have minimal risk. Erythromycin estolate may be more likely to induce hepatic toxicity in a pregnant patient and, therefore, is not recommended.17 The greatest concern regarding antibiotic use is with agents that have limited indications in dentistry. Aminoglycosides, such as gentamicin, may induce ototoxicity in the fetus when administered late in pregnancy. Tetracyclines, including doxycycline hyclate, have been implicated for causing tooth discoloration and inhibition of bone development in infants. Chloramphenicol is contraindicated in pregnancy because of maternal toxicity and fetal circulatory failure, called gray syndrome.10,13,16 Sedatives/anxiolytics. Administration of any of the central nervous system depressants commonly used for sedation is problematic. Because sedative agents inhibit neuronal function
JADA, Vol. 129, September 1998 Copyright ©1998-2001 American Dental Association. All rights reserved.
CLINICAL PRACTICE and generally cross placental barriers, their use during pregnancy is generally viewed with apprehension. Of the antianxiety drugs that are commonly prescribed, the benzodiazepine diazepam has been assessed most frequently. Investigations of both animals and humans have noted an association between diazepam exposure during pregnancy and oral clefts.18,19 Yet, confirmation of these reports has not always been possible.20,21 A single exposure to a clinically acceptable dose of any benzodiazepine as compared with chronic therapy throughout a pregnancy would have minimal risk for teratogenicity.22,23 Overall, the evidence cautions against prolonged use of all benzodiazepines during pregnancy. Prolonged high-dose exposure to nitrous oxide in rats has produced skeletal and behavioral teratogenic effects.8,24,25 Additionally, occupational exposure to nitrous oxide has been observed in spontaneous abortions and reduced fertility in humans.26,27 Nitrous oxide blocks the vitamin B12-dependent enzyme methionine synthase, thereby depleting tetrahydrofolate, which is necessary for deoxyribonucleic acid synthesis. Thus, prolonged exposure to ambient concentrations of nitrous oxide could conceivably inhibit cell division.28 Short exposure during general anesthesia to agents, such as nitrous oxide, is not thought to be teratogenic.29 Nevertheless, because nitrous oxide may inhibit cell replication, minimizing prolonged use when possible is prudent. CONCLUSION
Drug and chemical exposure during pregnancy is believed to account for only about 1 percent of congenital malformations.6
D
o you have comments or questions about this article? JADA now offers an online resource called Ask the Author, which can put you in touch with the author of one featured article per issue. Check out Ask the Author in the ADA Publishing Co. portion of ADA ONLINE at “http://www.ada.org”.
Delivery complications and birth defects are more commonly caused by the mother’s poor nutrition, smoking, alcohol consumption, disease, genetic predisposition and age.10,30 Maintaining a healthy lifestyle, including optimal oral health, is essential for women who are currently pregnant or who are planning to become pregnant. For example, recent evidence has implicated periodontal infections as a possible factor associated with the delivery of low-birth-weight babies.31 Dental practitioners should provide essential care for pregnant patients, particularly when acute infections are present. In this article, the current knowledge about safe drug therapy during pregnancy has been reviewed and recommendations specific to dental therapy have been provided. When dental treatment is needed to maintain a pregnant Dr. Moore is a prowoman’s oral fessor of pharmacology, Department of health, selecting Dental Public Health, the safest 614 Salk Hall, University of agents, limiting Pittsburgh, School of the duration of Dental Medicine, the drug regiPittsburgh, Pa. 15261. Address mens and minireprint requests to mizing dosages Dr. Moore.
are the fundamental principles of safe therapy. ■ A patient pamphlet entitled “Pregnancy and Oral Health” provides advice on nutrition, oral hygiene, gingivitis, drug use, radiographs and dental care during pregnancy. It can be obtained through the ADA Salable Products Catalog by calling 1-800-947-4746. Specific drug therapy information can be obtained from the ADA Council on Scientific Affairs by calling 1-312-440-2878; ADA members can call the toll-free number on the back of their membership cards and ask for Extension 2878. A national information service for drug safety during pregnancy that provides practitioners with local referrals is available through the Organization of Teratology Information Services by calling 1-801-328-2229 or visiting its Web site at “http://orpheus.ucsd.edu/otis/”. 1. Miller MC. The pregnant dental patient. J Calif Dent Assoc 1995;23(8):63-70. 2. Tarsitano BF, Rollings RE. The pregnant dental patient: evaluation and management. Gen Dent 1993;41(3):226-31. 3. United States Food and Drug Administration. Labeling and prescription drug advertising: content and format for labeling for human prescription drugs. Fed Regist 1979;44(124):37434-67. 4. Teratology Society Public Affairs Committee. FDA classification of drugs for teratogenic risk. Teratology 1994;49(6):446-7. 5. Physicians’ Desk Reference. 52nd ed. Montvale, N.J.: Medical Economics Company; 1998. 6. Rang HP. Pharmacology. 3rd ed. New York: Churchill Livingstone; 1995. 7. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation: A reference guide to fetal and neonatal risk. 3rd ed. Baltimore: Williams & Wilkins; 1990. 8. Mullenix PJ, Moore PA, Tassinari MS. Behavioral toxicity of nitrous oxide in rats following prenatal exposure. Toxicol Ind Health 1986;2(3):273-87. 9. Hayes DP. Teratogenesis: a review of the basic principles with a discussion of selected agents. Part 1. Drug Intell Clin Pharm 1981;15:444-58. 10. Stern L. Drug use in pregnancy. Sydney, Boston: ADIS Health Science Press; 1984. 11. Folbs PI, Dukes MNG. Drug safety in
JADA, Vol. 129, September 1998 Copyright ©1998-2001 American Dental Association. All rights reserved.
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CLINICAL PRACTICE pregnancy. Amsterdam: Elsevier; 1990. 12. Balligan FJ, Hale TM. Analgesic and antibiotic administration during pregnancy. Gen Dent 1993; 41(3):220-5. 13. Hayes DP. Teratogenesis: a review of the basic principles with a discussion of selected agents. Part 2. Drug Intell Clin Pharm 1981;15:542-65. 14. Champion GD, Feng PH, Azuma T, et al. NSAID-induced gastrointestinal damage: epidemiology, risk and prevention with an evaluation of the role of misoprostol—an AsianPacific perspective and consensus. Drugs 1997;53(1):6-19. 15. Kadanali S, Kucukozkan T, Zor N, Kumtepe Y. Comparison of labor induction with misoprostol vs. oxytocin/prostaglandin E2 in term pregnancy. Int J Gynaecol Obstet 1996;55(2):99-104. 16. Heinonen OP, Slone D, Shapiro S. Birth defects and drugs in pregnancy. Littleton, Mass.: Publishing Sciences Group; 1977. 17. McCormack WM, George H, Donner A, et al. Hepatotoxicity of erythromycin estolate during pregnancy. Antimicrob Agents Chemother 1977;12:630-5. 18. Saxen I. Associations between oral clefts
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and drugs taken during pregnancy. Int J Epidemiol 1975;4(1):37-44. 19. Safra JM, Oakley GP. Association between cleft lip with or without cleft palate and neonatal exposure to diazepam. Lancet 1975;2:478-80. 20. Rosenberg L, Mitchell AA, Parsells JL, Pashayan H, Lonik C, Shipiro S. Lack of relation of oral clefts to diazepam use during pregnancy. N Engl J Med 1983;309:1282-5. 21. Schlumpf M, Ramseier H, Abriel H, Youmbi M, Baumann JB, Lichtenstein W. Diazepam effects on the fetus. Neurotoxicology 1989;10:501-16. 22. Schardein JL. Psychotropic drugs. In: Chemically induced birth defects. New York: Dekker; 1993. 23. Koren G, Pastuszak A, Ito S. Drugs in pregnancy. N Engl J Med 1998;338(16):1128-37. 24. Mazze RI, Wilson AI, Rice SA, Baden JM. Reproduction and fetal development in rats exposed to nitrous oxide. Teratology 1984;30:259-65. 25. Tassinari MS, Mullenix PJ, Moore PA. The effects of nitrous oxide after exposure during middle and late gestation. Toxicol Ind Health 1986;2:261-71.
26. Rowland AS, Baird DD, Weinberg CR, Shore DL, Shy CM, Wilcox AJ. Reduced fertility among women employed as dental assistants exposed to high levels of nitrous oxide. N Engl J Med 1992;327:993-7. 27. Cohen EN, Gift HC, Brown BW, et al. Occupational disease in dentistry and chronic exposure to trace anesthetic gases. JADA 1980;101(1):21-31. 28. Finnell RH, Greer KA, Barber RC, Piedrahita JA. Neural tube and craniofacial defects with special emphasis on folate pathway genes. Crit Rev Oral Biol Med 1998;9(1):38-53. 29. Mazze RI, Kallen B. Reproductive outcome after anesthesia and operation during pregnancy: a registry study of 5405 cases. Am J Obstet Gynecol 1989;161:1178-85. 30. Hayes DP. Teratogenesis: a review of the basic principles with a discussion of selected agents. Part 3. Drug Intell Clin Pharm 1981;15:639-50. 31. Offenbacher S, Katz V, Fertik G, et al. Periodontal infection as a possible risk factor for preterm low birth weight. J Periodontol 1996;67(10):1103-13.
JADA, Vol. 129, September 1998 Copyright ©1998-2001 American Dental Association. All rights reserved.