Re-evaluating Therapeutic Drugs for Pregnant Dental Patients

Maintaining oral health and treating dental diseases are fundamental components of overall health. Current understanding of maternal and fetal health supports this concept. The recently published guidelines for providing dental care during pregnancy, Oral Health During Pregnancy and Early Childhood: Evidence-Based Guidelines for Health Professionals, states: “Prevention, diagnosis, and treatment of oral diseases, including needed dental radiographs and use of local anesthesia, are highly beneficial and can be undertaken during pregnancy with no additional fetal or maternal risk when compared to the risk of not providing care. Good oral health and control of oral disease protects a woman’s health and quality of life; and has the potential to reduce the transmission of pathogenic bacteria from mothers to their children.”¹ Clearly, the health benefits of providing needed dental care during pregnancy far outweigh the potential risks.

For the young healthy adult dental patient, the selection of dental therapeutic agents for local anesthesia, sedation, postoperative pain control, and treatment of infections is usually straightforward. A dental practitioner might routinely select lidocaine with epinephrine, triazolam, ibuprofen, or acetaminophen with hydrocodone and penicillin V.^2,3 Alternative agents may be necessary to safely treat patients who have a history of drug allergy, as well as those who are medically compromised, at age extremes, or taking concomitant medications. For a pregnant patient, a dentist must consider the additional risks drug therapy may have for the mother and fetus.

Drug therapy during pregnancy should aim to avoid adverse drug reactions to either the mother or the fetus. Hypersensitivity, allergy, or toxicity reactions by the mother may compromise her health and limit her ability to support a pregnancy. Adverse drug effects specific to the health of the fetus may include congenital defects, miscarriage, delivery complications, low birth weight, and postnatal drug dependence. These effects are usually specific to the timing of drug administration during pregnancy (ie, first, second, or third trimester), the dose given, and the duration of therapy. Compared to many medical therapies, dental treatment generally involves use of drugs with short elimination half-lives, which are administered for limited periods of time and are, therefore, less likely to cause complications.

Physiologic changes during pregnancy include weight gain, positional hypotension when placed supine, a frequent need to urinate, restricted respiratory function, and a potential for hypoglycemia. Morning sickness is also common. Pregnancy may intensify the stress and anxiety of a dental appointment. Dental care during pregnancy should make accommodations for these changes through short appointments, avoidance of prolonged supine positioning, clear oral hygiene instructions, and judicious use of radiographs.^1,4,5

A decrease in blood pressure and cardiac output may occur while the pregnant patient is in a supine position, particularly during the second and third trimesters.⁵ This has been attributed to decreased venous return to the heart as a result of compression of the inferior vena cava by the gravid uterus, resulting in a reduction of cardiac output.^6,7 This condition is known as supine hypotensive syndrome and is characterized by lightheadedness, hypotension, tachycardia, and syncope. The treatment is to place the patient in a 5º to 15º left lateral position to reduce the uterine pressure on the vena cava and administer 100% oxygen. If the hypotension is still not relieved, a full left lateral position is indicated.⁸

Pregnant women are at increased risk of pregnancy gingivitis, tooth mobility, dental caries, and erosion. Pregnancy gingivitis, the most common oral manifestation in pregnant women, is caused by elevated estrogen and progesterone levels, leading to increased capillary permeability during pregnancy.⁹ Pregnant patients experience gum irritation, weakening of tooth enamel, and dental caries due to the increased acidic exposure from morning sickness and gastroesophageal reflux disease (GERD). Preventative care through periodontal treatment and proper oral hygiene can help prevent such occurrences.

Although most elective dental procedures can be postponed, treatment of a pregnant patient presenting with oral pain, advanced disease, or infection should not be delayed. Effective oral hygiene instructions should be provided to the pregnant patient, describing the importance of plaque control in prevention of periodontal disease. If emergency treatment is indicated, it should be performed at any time to eliminate any physical stress to the patient or fetus. Although none of the drugs used to treat pain and infection are totally without risk, the consequences of not treating an active infection during pregnancy far outweigh the potential risks of most of the drugs required for dental care.

Pregnancy Risk Categories

The Food and Drug Administration (FDA) established 5 categories for classifying potential pregnancy risks associated with drug therapy.¹⁰ These categories, defined in Table 1, provide a guide for the relative safety of drugs prescribed to pregnant patients. Category A includes drugs that have been adequately studied in humans and have evidence supporting their safe use. Drugs in Category B have no evidence of risk in animal studies or human therapeutic use. Category C includes drugs where teratogenicity risk has been demonstrated in animals and cannot be ruled out in humans. Category D includes drugs that have demonstrated risks in humans, but their therapeutic benefit may outweigh the risks, while Category X includes agents that have been shown to be harmful to the mother or fetus with an unfavorable benefit-versus-risk profile.

Drugs in categories A and B are generally considered appropriate for use during pregnancy, while Category C drugs should be used with caution; drugs in categories D and X should be avoided or are contraindicated. Fewer than 20% of all drugs classified by the FDA are in categories A or B.^11,12 Information provided within the manufacturers’ package inserts included with prescription and nonprescription drugs include these FDA use-in-pregnancy ratings. The FDA is currently revising the labeling requirements for use of prescription drugs during pregnancy to provide a more complete description of specific risk; source of information (animal or human); the likelihood of specific developmental abnormalities and their seriousness, reversibility, and correctability; and the importance of dose, duration of exposure, and gestational timing of exposure.¹³

Teratogenicity

Of the thousands of drugs marketed, only a few are known with certainty to be teratogenic (induce birth anomalies) in humans. Thalidomide, which was developed in the 1950s as a tranquilizer and antiemetic, is the best-known human teratogen. Thalidomide’s teratogenesis is unusual because, when taken in the first 3 months of gestation, there is a high incidence of birth defects, including a unique anomaly called phocomelia, which is characterized by shortened arms and legs. Warfarin, retinoids, valproic acid, and heavy metals are also known to produce significant physical birth defects. Knowledge of the risks associated with drug use 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.^14,15

Many factors may contribute to uncertainty when determining the risk of drug therapy. Animal data, which are usually collected from studies that use extraordinarily high and prolonged exposures, are known to have marked species variability. Some congenital defects, such as cleft lip—with or without cleft palate—have high background rates, which complicate the assessment of added risk for any specific drug.¹⁶ The teratogenic potential for some drugs may depend on a genetic predisposition involved in fetal development.¹⁴ Additionally, when multiple birth defects are reported, it is often difficult to determine whether the etiologic factor was the drug or the underlying disease requiring drug therapy.

Accurate human risk assessment is impossible to obtain for many newly marketed or infrequently prescribed drugs. Fortunately, the therapeutic agents used in dental practice are used quite frequently, and evidence is available to evaluate their potential risk (Table 2). In recent years, new agents have come to the market and some changes have occurred to the previous risk classifications. This updated drug listing provides a summary of the current understanding of risk during pregnancy.

Selection of Dental Therapeutic Agents

Local Anesthetics

Most local anesthetics have not been shown to be teratogenic in humans and are considered relatively safe for use in dentistry. The recommendation for caution (Category C) for mepivacaine and bupivacaine relates primarily to limited data collected in animal teratogenicity studies. As such, possible birth defects in humans cannot be ruled out for these agents. In animal studies, fetal bradycardia can result from high concentrations of lidocaine, bupivacaine, or mepivacaine injected in the vicinity of the umbilical artery.¹⁷ Because all local anesthetics can cross the placenta and cause fetal depression, limiting the anesthetic dose to the minimum required for effective pain control is advisable.

Lidocaine, the local anesthetic agent most commonly used, has a maximum recommended dose of 4.3 mg\kg without a vasoconstrictor and 7mg\kg with a vasoconstrictor.¹⁸ Diluted blood volume and decreased protein binding during pregnancy may lower the maximum safe dosage. Intravascular injection combined with decreased protein binding could conceivably increase local anesthetic toxicity. However, the maximum recommended local anesthetic doses used in dentistry are very conservative and unlikely to reach significant fetal blood levels.^1,5 A limited dose of bupivacaine may be a valuable alternative to postoperative non-steroidal anti-inflammatory drugs (NSAIDs) and opioid analgesics for postoperative pain management in pregnant patients.

The most convincing evidence of local anesthetic safety is the Collaborative Perinatal Project (CPP). It was conducted from 1960 to 1994 at 12 university hospitals throughout the United States, examining prenatal exposure to various drugs and environmental factors. The study tracked 55,000 children, creating a large database. No evidence of teratogenicity or other adverse outcomes was noted from the appropriate use of benzocaine, procaine, tetracaine, or lidocaine in pregnancy.¹⁹

Prilocaine and benzocaine are recognized as inducers of methemoglobinemia. In methemoglobinemia, hemoglobin iron atoms are oxidized to a ferric state and will not carry oxygen to the same degree as normal. If severe, maternal anoxia would be potentially lethal to the fetus as well as the mother. A large dose of these two local anesthetics in a susceptible patient could theoretically cause a crisis. In patients who have no other toxic exposure or genetic defect, the dose of prilocaine to induce methemoglobinemia usually exceeds the maximum recommended dose for significant oxidation of hemoglobin iron.²⁰ Although there have been no published reports in the literature of any added hazard to mother or fetus compared to other anesthetics, limiting the dose of benzocaine and prilocaine to avoid a potential methemoglobinemia would be prudent.

Epinephrine and Vasoconstrictors

An inadvertent intravascular injection of a 1.8-mL cartridge of local anesthetic formulation containing 1:100,000 epinephrine can deliver 18 μg of epinephrine. Clinically significant intravascular doses of α-adrenergic agents are to be avoided in order to maintain appropriate placental perfusion and fetal viability.^20,21 Normally used dental dosages of local anesthetics with vasoconstrictors, without inadvertent intravascular injection, do not expose the fetus or uterus to significant levels of epinephrine. When administering a dental anesthetic containing epinephrine, it is imperative that it be injected slowly, using repeated aspiration. Vasoconstrictors decrease the toxicity of local anesthetics by decreasing absorption. There are no significant contraindications for the use of epinephrine in the recommended dosages, provided intravascular injection does not occur.^1,5

Epinephrine improves local anesthesia, reducing peak blood levels of local anesthetics and prolonging neural blockade. Epinephrine in the blood has dose-related effects on uterine blood flow and contractility, causing both a decrease in blood flow and uterine activity. Epinephrine can also cause constriction of the umbilical artery, but it has been demonstrated to be of possible significance only when there is fetal compromise.²⁰ In general, there does not appear to be any significant contraindication for the careful use of lidocaine with epinephrine in pregnant patients.¹

Levonordefrin, another vasoconstrictor used in local anesthetic solutions, has pharmacologic activity similar to epinephrine. In equal concentrations, levonordefrin is less potent than epinephrine in raising blood pressure or as a vasoconstrictor. However, in dental cartridges, the concentration of levonordefrin (1:20,000) is five times the normally employed concentration of epinephrine (1:100,000). This higher concentration of levonordefrin is a more potent vasoconstrictor, and, therefore, carries a higher risk to the fetus. Thus, levonordefrin is a poor choice for the pregnant patient.⁵

Peripheral Analgesics

Aspirin and NSAIDs have the common mechanism of inhibiting prostaglandin synthesis. Prostaglandin E2 is one of the hormones involved in the induction of labor. By blocking the production of prostaglandins, NSAIDs may prolong labor. In addition, prostaglandin inhibitors raise concerns about premature fetal ductus arteriosus constricture, resulting in pulmonary hypertension in the fetus. These concerns were derived from studies on patients taking large doses of aspirin and extrapolated to apply to other NSAIDs.²² There may be a slightly increased risk of congenital anomalies, including cardiac defects, when NSAIDs—such as ibuprofen, naproxen, or celecoxib—are taken early in pregnancy as well.²³

Newborns of mothers who have ingested 5 g to 10 g of aspirin 5 days before delivery are associated with bleeding tendencies, specifically intracranial hemorrhage. No bleeding tendencies were found if aspirin was taken no fewer than 6 days prior to delivery.²⁴ Aspirin and other NSAIDs should be avoided, especially during the third trimester of pregnancy. The alternative to aspirin and other NSAIDs is acetaminophen, which causes less gastric irritation and does not cause bleeding tendencies. The dosage of acetaminophen should be closely monitored to preclude potential hepatic toxicity.²⁵

Centrally Acting Analgesics

The opioid analgesics should be used cautiously and only when indicated. The use of codeine during pregnancy has been evaluated as part of the large Collaborative Perinatal Project. This prospective study monitored pregnancies for possible drug-related birth defects and toxicities. The results suggest that codeine is associated with multiple congenital defects, including heart defects and cleft lip/palate.^26-27 Because other opioids, such as oxycodone and hydrocodone, are administered infrequently during pregnancy, little is known about their potential fetal risks. The medical disorders that necessitated the use of these opioids may also have induced these defects. Neonatal respiratory depression as well as opioid withdrawal has also been reported with opioid use.²⁸ The prolonged or high-dose use of opioids significantly increases these risks when used late in pregnancy.

Antibiotics

The penicillin and cephalosporin antibiotics most commonly used in dentistry (penicillin V, amoxicillin, and cephalexin) are generally considered safe for use during pregnancy. Clindamycin, metronidazole, and erythromycin are also believed to have minimal risk. The estolate salt of erythromycin may be more likely to induce hepatic toxicity in a pregnant mother and is, therefore, not recommended.²⁹ The greatest concerns regarding antibiotic use are with agents that have limited indications in dentistry. Aminoglycosides, such as gentamicin, may induce ototoxicity when administered late in pregnancy. Tetracyclines, including doxycycline, have been implicated in causing tooth discoloration and impaired bone metabolism.

Sedative Agents

The use of any of the central nervous system depressants commonly used for sedation therapy is problematic. Because sedative agents are neuronal function inhibitors and generally cross-placental barriers, their use during pregnancy is viewed with apprehension. Of the anti-anxiety drugs commonly prescribed, the benzodiazepine diazepam (Valium) has been most frequently assessed. Both animal and human investigations have noted an association between diazepam exposure during pregnancy and oral clefts.^30,31 Yet, confirmation of these reports has not always been possible. A single-dose exposure with clinically acceptable doses, as compared with chronic therapy throughout a pregnancy, would suggest minimal risk for teratogenicity following benzodiazepine sedation/anesthesia. Overall, the evidence cautions against the prolonged use of benzodiazapines, particularly during pregnancy.

Nitrous Oxide and Anesthesia

Prolonged high-dose exposure to nitrous oxide in rats has demonstrated skeletal and behavioral teratogenic effects.^32,33 In addition, spontaneous abortions and reduced fertility have been implicated with occupational exposure to nitrous oxide.³⁴ Nitrous oxide can inactivate vitamin B12 and thereby inhibit the vitamin B12-dependent enzyme methionine synthetase. This inhibition is known to deplete tetrahydrofolate levels that are necessary for DNA synthesis.

Prolonged exposure to ambient concentrations of nitrous oxide could conceivably inhibit cell division. Short exposure during general anesthesia with such agents as nitrous oxide, halothane, and thiopental are not thought to be teratogenic.¹ However, because prolonged exposure to nitrous oxide has been demonstrated to inhibit cell replication, minimizing long appointments using N2O—particularly during the first trimester—would seem indicated.

Substance Use

Pregnancy complications and birth defects caused by alcohol, tobacco, or illicit drug use are completely preventable. Practitioners should advise women to stop the use of all these substances immediately upon planning to become pregnant or are pregnant.

Alcohol consumption during pregnancy is a significant health concern. No amount of alcohol consumption has been proven safe or can be considered safe during pregnancy. The US Surgeon General recommends complete abstinence from alcohol for all women who are pregnant or are planning a pregnancy.³⁵ Many women are unaware that any alcohol consumption during pregnancy can result in harm to the fetus. According to the Centers for Disease Control and Prevention, 1 in 12 pregnant women drink, and approximately 1 in 30 pregnant women report binge drinking (5 or more alcoholic drinks on one occasion).³⁶

Alcohol consumption during pregnancy increases the risks of premature birth, stillbirth, and miscarriage.^37,38 Neonatal effects include mental retardation, skeletal abnormalities, organ malformations, low birth weight, learning problems, and fetal alcohol syndrome.

Tobacco use during pregnancy is also associated with adverse birth outcomes, including ectopic pregnancy, spontaneous abortion, placental abruption, placental previa (a low-lying placenta that covers the uterus), preterm delivery, stillbirth, and low birth weight. The detrimental effects of smoking extend to the lives of the infants born to women who use tobacco during pregnancy, and include cleft lip or palate, prematurity, low birth weight, neonatal mortality, and sudden infant death syndrome (SIDS).³⁹ Almost one-quarter of all SIDS deaths may be attributed to prenatal maternal smoking, and fetal mortality rates are 35% higher among pregnant women who smoke compared to those who do not.⁴⁰

In the United States, approximately 4% of pregnant women use illicit drugs, including marijuana, heroin, cocaine, and amphetamines.⁴¹ Illicit drug use by pregnant women can cause serious problems in the developing fetus and newborn. The growth of the fetus is greatly impacted, premature births are more common, and the transmission of sexually transmitted diseases and hepatitis can occur.

Conclusion

Maintaining a healthy lifestyle, including optimal oral health, is essential for women who are currently pregnant or planning to become pregnant. Dental practitioners should provide all necessary care for pregnant patients, particularly when managing an acute infection.

Drug and chemical exposure during pregnancy is believed to account for about 1% of congenital malformations.⁴² However, delivery complications and birth defects associated with pregnancy are more commonly due to poor nutrition, smoking and alcohol consumption, diseases, genetic predisposition, and maternal age.¹⁵

When dental treatment is necessary to maintain oral health, selecting the safest agents, limiting the duration of the drug regimens, and minimizing dosages are the fundamental principles for safe therapy.

References

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About the Authors

Jonathan Mendia, DMD
Resident, Dental Anesthesiology
Department of Dental Anesthesiology
University of Pittsburgh School of Dental Medicine
Pittsburgh, Pennsylvania

Michael A. Cuddy, DMD
Associate Professor, Dental Anesthesiology
University of Pittsburgh School of Dental Medicine
Pittsburgh, Pennsylvania

Paul A. Moore, DMD, PhD, MPH
Professor, Public Health and Pharmacology
Chair, Department of Dental Anesthesiology
University of Pittsburgh School of Dental Medicine
Pittsburgh, Pennsylvania