Pregnancy, breast-feeding and drugs used in dentistry

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Pregnancy, breast-feeding and drugs used in dentistry Mark Donaldson, BSP, PharmD, FASHP, FACHE; Jason H. Goodchild, DMD

edication use during pregnancy is common; two of every three women take prescription medications during pregnancy.1 Despite advances in the study of birth defects related to exposures during pregnancy (teratology), medication use during pregnancy still causes anxiety and misunderstanding among both members of the public and health care professionals. This may result in a woman’s unknowingly taking a medication that may harm the fetus or cause a birth defect or in her discontinuing the use of medications necessary for treating conditions such as diabetes, asthma or influenza. For the health care professional, the challenge is to know which drugs may be safe for the pregnant patient and which medications to avoid. Although drug use is an uncommon cause of birth defects, approximately 120,000 children (3 to 5 percent of live births) are born with birth defects each year in the United States.2 Because of the obvious ethical and moral limitations of designing double-masked, prospective studies to ascertain the risk of medications’ causing birth defects or malformations, investigators typically have used cohort studies to examine fetal risk after maternal use

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AB STRACT Background and Overview. Despite advances in the study of birth defects related to drug exposures during pregnancy, medication use during pregnancy still causes anxiety and misunderstanding among both members of the public and health care professionals. This may result in a woman’s unknowingly taking a medication that may harm the fetus or cause a birth defect or discontinuing medications necessary for treating chronic conditions. Using medications while breast-feeding also represents a challenge for patients and prescribers. Many mothers are told they must stop breast-feeding or “pump and discard” their breast milk if they are taking certain medications; however, in many cases, this advice— based on what may be limited education on the part of the health care provider about breast-feeding and medication use—may be incorrect. The authors review the current evidence regarding drugs that may be safe for pregnant or breast-feeding patients and medications that such patients should avoid. Conclusions. When considering prescribing in pregnancy, the dentist must weigh the risk to the fetus versus the benefit to the mother, and the appropriate conclusion should reflect current evidence. In some cases medication dosing should be avoided or altered; however, there are times when it is unnecessary to stop the use of medications. Breast-feeding also represents a clinical challenge, the risks and benefits of which need to be understood by both the patient and practitioner before any medication is administered. Practice Implications. Dentists should be familiar with the risks and benefits for pregnant or breast-feeding patients posed by five types of medications: analgesics and anti-inflammatories, antibiotics, local anesthetics, sedatives and emergency medications. Key Words. Pregnancy; pregnancy complications; risk assessment; medications; lactation; fetotoxicity; teratology. JADA 2012;143(8):858-871.

Dr. Donaldson is the director of pharmacy services, Kalispell Regional Medical Center, Kalispell, Mont.; a clinical professor, Skaggs School of Pharmacy, University of Montana, Missoula; and a clinical assistant professor, School of Dentistry, Oregon Health & Sciences University, Portland. Address reprints to Dr. Donaldson at 310 Sunnyview Lane, Kalispell, Mont. 59901, [email protected]. Dr. Goodchild is a clinical associate professor, Department of Oral Medicine, School of Dental Medicine, University of Pennsylvania, Philadelphia; and a private practitioner in Havertown, Pa.

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of medication.3-5 The majority of birth defects have an unknown cause. To our knowledge and according to our research, no current statistics exist describing the risk of birth defects caused by maternal use of medication; however, authors of a 1973 article estimated that 2 to 3 percent of birth defects were thought to be caused by medications used during pregnancy.6 Medication use during breast-feeding also represents a challenge for patients and prescribers. Many new mothers are told they must discontinue breast-feeding or must “pump and discard” their breast milk if they are taking certain medications; however, in many cases, this advice— based on what may be limited education on the part of the health care provider about breastfeeding and medication use—may be incorrect. Pregnant patients can receive most dental treatment safely.7 The dental practitioner prescribes a relatively small group of medications, which somewhat simplifies the issue of medication use in patients who are either pregnant, trying to conceive or breast-feeding. Primarily, dentists should be familiar with the risks and benefits of five types of medications: analgesics and anti-inflammatories, antibiotics, local anesthetics, sedatives and emergency medications. Our purpose in this article is to provide, by using data collected by the U.S. Food and Drug Administration (FDA)8 and other sources, an organized reference for information about the use of prescription medication in the dental patient who is pregnant or breast-feeding. Health care professionals who are prepared with evidencebased information about the safety of medication use during pregnancy and breast-feeding can advise their patients regarding optimal medication therapy, thereby helping to ensure healthy outcomes for both mother and baby. We based this literature review on searches of knowledgebased resources without any restrictions on dates of publication: MEDLINE, PubMed, Embase, and the Cochrane Database of Systematic Reviews. The search terms were “pregnant” and “dentistry”; “lactation” and “dentistry”; “risk management”; “teratology”; and “fetotoxicity.” In addition, we also evaluated journals, Web sites, textbooks, studies, reports, conference proceedings, consensus statements and abstracts published in English. Our intention was to be as comprehensive as possible, but we focused specifically on the last 50 years because much of the newer information continues to reference older, original studies. THE PREGNANT DENTAL PATIENT

The pregnant dental patient represents two significant challenges to the dental professional.

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First, although most dental procedures are elective and 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. Second, not all women of childbearing age know that they may be pregnant, and when selecting and prescribing a medication for any woman of childbearing age, the clinician always should consider the possibility of her conceiving while she still is receiving the medication. The rate of unintended pregnancy fell nearly 20 percent between the early 1980s and the mid1990s,9 but it has remained relatively unchanged since.10 The initial decline probably was a result of better public education, higher prevalence of contraceptive use and use of more effective contraceptive methods; nevertheless, authors of one study estimated that 48 percent of women aged 15 to 44 years have had at least one unplanned pregnancy sometime in their lives.9 Therefore, the clinician must consider the potential adverse effects on a fetus whenever prescribing medication for women of childbearing age. In addition to routinely updating every patient’s medical and pharmacological history, one simple interview technique involving three questions for all female patients may aid greatly in risk mitigation: Are you pregnant? Do you know if you are pregnant? Are you trying to get pregnant? Teratogenic drugs are medications that may be associated with the development of structural abnormalities in a developing fetus (such as cleft lip, cleft palate and phycomelia). The greatest teratogenic risk to the fetus is from three to eight weeks after conception (five to 10 weeks’ gestation, with week one beginning on the first day of the last menstrual period).11 Placental transport of maternal substrates to the fetus and of substances from the fetus to the mother is established at about the fifth week of embryonic life.12 Therefore, abruptly ceasing intake of a drug at week 10 because of concerns about teratogenicity usually does not reduce the risk of malformation substantially. Beyond teratogenesis, fetotoxicity can occur at any time between the late first trimester and birth and may cause a variety of effects. An example is the use of nonsteroidal anti-inflammatory drugs (NSAIDs), which may be associated with fetal renal dysABBREVIATION KEY. AAP: American Academy of Pediatrics. CDC: Centers for Disease Control and Prevention. FDA: Food and Drug Administration. G6PD: Glucose-6-phosphate dehydrogenase. NSAIDs: Nonsteroidal anti-inflammatory drugs. OTC: Over the counter. PR: Pregnancy risk. JADA 143(8)

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TABLE 1

during the pregnancy depending on the disU.S. Food and Drug Administration pregnancy risk ease activity and the factor definitions.* gestation.17 For example, a woman CATEGORY DEFINITION with a flare-up of a A The results of controlled studies in women fail to demonstrate a risk to the fetus severe inflammatory in the first trimester (and there is no evidence of risk in later trimesters), and the possibility of fetal harm appears remote bowel disease may be B Either the results of animal reproduction studies have not demonstrated a fetal a candidate for biorisk but there are no controlled studies in pregnant women logical therapy in the OR first trimester (as the results of animal reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in several biological women in the first trimester and there is no evidence of risk in later trimesters agents have been C Either the results of studies in animals have revealed adverse effects (teratogenic, shown not to cross embryocidal or other) on the fetus and there are no controlled studies in women the placenta until OR results of studies in women and animals are not available; drug should be given well into the second only if the potential benefit justifies the potential risk to the fetus trimester18); however, D There is positive evidence of human fetal risk, but the benefits of use in pregnant in the third trimester, women may be acceptable despite the risk (for example, if the drug is needed in it may be reasonable a life-threatening situation or for a serious disease for which safer drugs cannot to try high-dose be used or are ineffective) steroids first because X Results of studies in animals or humans have demonstrated fetal abnormalities or evidence of fetal risk based on human experience, or both, and the risk of the use they may be considof the drug in pregnant women clearly outweighs any possible benefit; use of the ered safer.19 drug is contraindicated in women who are or may become pregnant To determine the * Sources: U.S. Food and Drug Administration. risks associated with the use of drugs in function in the second and third trimester and pregnancy, the FDA traditionally has classified premature closure of the ductus arteriosus in the drugs on the basis of the level of risk they pose third trimester.13,14 Potential effects of drugs on to the fetus8,20,21 (Table 18,20,21). Accordingly, drugs cognitive function by interference with brain in categories A and B are considered safe for development are less obvious and harder to use, whereas drugs in category C may be used detect than are structural anomalies or only if the benefits outweigh the risks. Use of malformations. drugs in category D should be avoided except in Any drug or chemical substance administered certain exceptional circumstances, and use of to the mother can cross the placenta to some category X drugs in pregnant women is strictly extent unless it is destroyed or altered during prohibited. passage, or unless its molecular size and low In May 2008, the FDA proposed major revilipid solubility limit transplacental transfer.15 sions to prescription drug labeling to inform preSubstances of low molecular weight (< 600 dalscribers more completely about the use of meditons) diffuse freely across the placenta, driven cines during pregnancy and breast-feeding.21 The primarily by the concentration gradient.16 Some proposed changes to medication labeling would examples of these medications include acetagive health care providers better information for minophen, aspirin and most glucocorticoids. It making prescribing decisions and for counseling is important to note that almost every subwomen who are pregnant, breast-feeding or of stance used for therapeutic purposes can and childbearing age. The FDA proposed that both the does pass from the mother to the fetus; in other pregnancy and lactation subsections of provider words, the concept of a “placental barrier” is a labeling include a risk summary, listing clinical misnomer. Of greater importance is whether the considerations to support patient care decisions rate and extent of transfer are sufficient to and counseling and containing a data section that result in significant concentrations within includes more detailed information. The proposed the fetus to cause either teratogenicity or regulations would eliminate the pregnancy catfetotoxicity. egories A, B, C, D and X owing to limitations in The aim when prescribing medication to a their ability to convey risk and benefit accurately pregnant patient is to balance the risks of the and consistently. Information about the use of drug’s potential adverse effects (usually on the medicines during labor and delivery would befetus) with the benefit (usually to the mother) of come a part of the pregnancy subsection. Oppotreating the disease. This balance may change nents of this proposal suggest that without stan8,20,21

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dardized labeling requirements, the private sector could conduct narrative discussions about risk and develop a wide array of schema and rules to support decisions about pregnancy risk for patient medication use that are not clinically relevant. Such discussions could lead to differing interpretations of risk assessment and could compromise patient safety. As of June 2012, the Final Rule is in the writing and clearance process and has yet to be approved officially. Box 1 highlights key clinical considerations for clinicians prescribing medications for pregnant patients. THE BREAST-FEEDING DENTAL PATIENT

In 2010, the Centers for Disease Control and Prevention (CDC) released data regarding the incidence of breast-feeding among U.S. children born between 2000 and 2008.22 The survey found that breast-feeding percentages in the early postpartum period, at six months after delivery and at 12 months after delivery were 81.9, 60.6 and 34.1 percent, respectively. These relatively high percentages may be due in part to the American Academy of Pediatrics’12 (p xvii) (AAP’s) position paper on this subject, which emphasized breastfeeding as the best nutritional mode for infants for the first six months of life. The high rates of breast-feeding, together with growing concern about health needs on the part of parents, may lead to more patients’ questioning physicians, pharmacists and dentists about the safety and potential toxicity of drugs and chemicals that may be excreted in breast milk. To date, many of the studies involving milk secretion and synthesis have been carried out in animals.23 The challenge in studying human lactation by using histologic techniques and the administration of radioactive isotopes is obvious. Unfortunately, there are considerable differences in the composition of milk in different species, and some of these differences in composition would bring about changes in drug elimination. Of great importance in this regard are the differences in the pH of human milk (usually > 7.0) and the pH of cow’s milk (usually > 6.8), in which drug excretion has been studied more extensively in the bovine model.12 In general, the factors that increase the transfer of medications into breast milk are low molecular weight, low protein binding (which leads to an increased amount of free drug), high lipid solubility and existing as a weak base.24 Many reviews include tables of the concentration of drugs in breast milk and, often, of the milk-to-plasma ratio.25-27 The values from which the data in these tables are derived consist of a

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BOX 1

Clinical considerations regarding medication use in patients who are pregnant. Use medication only if the expected benefits (usually to the mother) are greater than the potential risks (usually to the fetus) Try to avoid prescribing medication during the patient’s first trimester of pregnancy Prescribe drugs that have been used extensively by pregnant women, not new drugs that may yet be untested in pregnant patients Prescribe the minimum dose required to obtain the desired effect Recognize that the absence of data does not imply safety

single measurement of the drug concentration, and important information—such as the maternal dose, the frequency of dose, the time from drug administration to sampling, the frequency of nursing and the length of lactation—is not provided. The clinical significance of these concentration tables is limited, because the mere knowledge that the drug is present in the milk does not equate to advice for the prescriber. With little information about the amount of the medication that the infant actually absorbs from the milk, we, therefore, have no way of determining the possible pharmacological effects on the infant. In fact, we found that much of the information in these tables was gathered decades ago, when analytic methodology was not as sensitive as it is today.26-30 For most drugs, the infant is exposed to a much higher concentration during pregnancy than during lactation. Therefore, if a drug is considered acceptable for use during pregnancy, it usually is reasonable to continue its use during breast-feeding.31 However, there are exceptions, and the most important factors to consider are the concentration of the drug in the infant’s blood and the effects that this might have. Small drug molecules enter breast milk more easily than do large molecules (for example, heparin, a large molecule, is not excreted in breast milk). The half-life of some drugs in the neonatal circulation also may be longer than that in the mother, because an infant’s liver metabolism is immature. This may lead to accumulation of the drug in the infant; this phenomenon particularly applies to morphine, lamotrigine, phenobarbital, some benzodiazepines and aspirin.12,32-34 The pump-and-discard strategy can be effective for women taking some medications with a short half-life.35-37 This is best demonstrated with the JADA 143(8)

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BOX 2

Clinical considerations regarding medication use in patients who are breast-feeding. Advise the patient to minimize the breast-fed child’s exposure to drugs the mother is receiving, such as by timing feedings or pumping and discarding milk Recognize potential drug effects in the child and make recommendations to the patient about monitoring or responding to these effects Consider adjusting dosage during lactation Understand the effects of the drug on milk production and explain these effects to the patient clearly Ascertain whether the drug is present in human milk (and if so, how much) Realize the effects of the drug on the breast-fed child and explain these effects to the patient clearly

enterally administered sedative triazolam. The lactating mother who is to receive triazolam is counseled to pump and save a surplus supply of her breast milk before the dental appointment. She receives triazolam before the dental appointment to help ameliorate her anxiety, and for the eight to 10 hours after the dental appointment (that is, four half-lives of the drug), she will pump and discard the milk, feeding her baby with the milk she had pumped and saved from the previous day. After the four half-lives have passed, she then can return to her regular breast-feeding schedule. It takes approximately four half-lives for more than 90 percent of most medications to be eliminated from the body.38 Box 2 summarizes and highlights key clinical considerations regarding medications and breast-feeding. DRUGS COMMONLY USED IN DENTISTRY

As previously mentioned, drugs should be prescribed in pregnancy only if the expected benefit to the mother is thought to be greater than the risk to the fetus, and use of all drugs should be avoided if possible during the first trimester. Clinicians should prescribe drugs that have been used extensively in pregnant patients and that appear to be usually safe rather than prescribe new or untried drugs, and they should prescribe the smallest effective dose for the shortest clinically effective length of time. Although only a few drugs have been shown conclusively to be teratogenic in humans, in early pregnancy, no drug is safe beyond all doubt. Medications that commonly are used in dentistry typically fall into five drug classes: analgesics and anti-inflammatories, antibiotics, local anesthetics, sedatives and emergency medica862 JADA 143(8)

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tions. There may be some additional miscellaneous medications such as antiseptics (such as chlorhexidine), fluoride supplements or drugs to treat xerostomia (such as pilocarpine); however, it is unlikely that drugs in these last three categories absolutely would need to be used in a pregnant or breast-feeding patient, and it is likely that their use could be delayed without harm to the patient. Chlorhexidine and fluoride supplements have been shown in pregnant and postpartum mothers to reduce caries risk and bacterial transmission between mother and child. Although these studies have focused primarily on factors other than teratogenesis, their investigators have not reported any harm to the child.39,40 Theoretically, prenatal fluoride supplementation could impart caries protection to the unborn child; however, it has been shown that it provides no additional benefit.41 In light of insufficient supporting evidence obviating fetal toxicity, prenatal fluoride supplementation cannot be recommended. In addition, the American Academy of Pediatric Dentistry42,43 does not support the use of prenatal fluoride supplementation as a benefit that outweighs potential risk. Fluoride has a FDA pregnancy risk factor rating of C. Within the emergency medications section, we will consider the seven drugs that make up the minimum emergency kit,44 including the two reversal agents, naloxone and flumazenil. Table 2 summarizes key clinical considerations for the medications typically used in dentistry; however, the absence of a drug from the list should not imply its safety in pregnant or breast-feeding patients. Analgesics and anti-inflammatories. Many analgesics are available over the counter (OTC)—that is, without a prescription—and can be purchased at many retail outlets besides pharmacies. As a result of this easy access, the wideranging effects of analgesics often are forgotten by patients and prescribers alike and not put into the context of being potentially dangerous during pregnancy or breast-feeding. A review of human studies by Burdan and Bełzek45 focusing on the ingestion of ibuprofen during pregnancy found that this drug caused embryonic implantation disturbances, inhibition of parturition and contraction of the ductus arteriosis leading to maternal pulmonary hypertension. Gastroschisis is a congenital malformation, often related to ibuprofen use, in which fetal organs develop outside the abdominal wall.46 Other drug-related cases of gastroschisis have been linked to maternal use of other NSAIDs, including aspirin and the decongestants pseudoephedrine and phenylpropanolamine.46 The glucocorticoids, such

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TABLE 2

Key medication considerations during pregnancy and breast-feeding. FDA PR* CATEGORY

SAFE DURING PREGNANCY?

SAFE DURING BREAST-FEEDING?

Analgesics and Anti-inflammatories† Acetaminophen Aspirin Codeine Glucocorticoids (dexamethasone, prednisone) Hydrocodone Ibuprofen§ Oxycodone

B C/D C C C C/D B

Yes Avoid Use with caution Avoid‡ Use with caution Avoid use in third trimester Use with caution

Yes Avoid Yes Yes Use with caution Yes Use with caution

Antibiotics¶# Amoxicillin Azithromycin Cephalexin Chlorhexidine (topical) Clarithromycin Clindamycin Clotrimazole (topical) Doxycycline Erythromycin Fluconazole Metronidazole

B B B B C B B D B C/D B

Yes Yes Yes Yes Use with caution Yes Yes Avoid Yes Yes (single-dose regimens) Yes

Nystatin Penicillin Terconazole (topical) Tetracycline

C B B D

Yes Yes Yes Avoid

Yes Yes Yes Yes Use with caution Yes Yes Avoid Use with caution Yes Avoid; may give breast milk an unpleasant taste Yes Yes Yes Avoid

Local Anesthetics Articaine Bupivacaine Lidocaine (with or without epinephrine) Mepivacaine (with or without levonordefrin) Prilocaine Benzocaine (topical) Dyclonine (topical) Lidocaine (topical) Tetracaine (topical)

C C B C B C C B C

Use with caution Use with caution Yes Use with caution Yes Use with caution Yes Yes Use with caution

Use with caution Yes Yes Yes Yes Use with caution Yes Yes Use with caution

D/X C C

Avoid Use with caution Use with caution

Avoid Use with caution Yes

Emergency Medications Albuterol

C

Yes

Diphenhydramine Epinephrine Flumazenil Naloxone Nitroglycerin

B C C C C

Steroid and β2-agonist inhalers are safe Yes Use with caution Use with caution Use with caution Use with caution

AGENT

Sedatives Benzodiazepines Zaleplon Zolpidem

Avoid Yes Use with caution Use with caution Use with caution

* FDA PR: U.S. Food and Drug Administration Pregnancy Risk. See Table 1 for FDA PR category definitions. † In the case of combination products (such as oxycodone with acetaminophen), the safety with respect to either pregnancy or breast-feeding is dependent on the highest-risk moiety. In the example of oxycodone with acetaminophen, the combination of these two drugs should be used with caution, because the oxycodone moiety carries a higher risk than the acetaminophen moiety. ‡ Oral steroids should not be withheld from patients with acute severe asthma. § Ibuprofen is representative of all nonsteroidal anti-inflammatory drugs. In breast-feeding patients, avoid cyclooxygenase selective inhibitors such as celecoxib, as few data regarding their safe use in this population are available, and avoid doses of aspirin higher than 100 milligrams because of risk of platelet dysfunction and Reye syndrome. ¶ Antibiotic use during pregnancy: The patient should receive the full adult dose and for the usual length of treatment. Serious infections should be treated aggressively. Penicillins and cephalosporins are considered safe. Use higher-dose regimens (such as cephalexin 500 mg three times per day rather than 250 mg three times per day), as they are cleared from the system more quickly because of the increase in glomerular filtration rate in pregnancy. # Antibiotic use during breast-feeding: These agents may cause altered bowel flora and, thus, diarrhea in the baby. If the infant develops a fever, the clinician should take into account maternal antibiotic treatment.

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as prednisone and dexamethasone, have been associated with oral clefts when administered during the first trimester of pregnancy.47,48 For these reasons, the abovementioned medications all are listed as pregnancy risk factor C or D by the FDA. The AAP,49 however, did report that use of these medications may be safe during breastfeeding—with the exception of aspirin, of which daily doses of more than 100 milligrams should be avoided because of the associated risk of platelet dysfunction and Reye syndrome. On the basis of the results of three large-scale epidemiologic studies, the safest analgesic in a pregnant patient is considered to be acetaminophen (also known as paracetamol).46,50,51 The AAP49 also considers acetaminophen to be compatible with breast-feeding. Although low concentrations of acetaminophen are excreted into breast milk and can be detected in the urine of nursing infants, adverse reactions generally have not been observed; however, Matheson and colleagues52 reported that one breast-fed infant developed a rash as a result of acetaminophen exposure. Narcotics such as codeine, hydrocodone and oxycodone generally are not recommended as first-line drugs to treat dental pain, as they lack anti-inflammatory activity.53,54 If a practitioner chooses to prescribe one of these agents regardless, codeine is considered the safest in regard to breast-feeding according to the AAP,49 whereas hydrocodone and oxycodone carry a higher risk of causing sedation and respiratory depression in the infant than does codeine23; symptoms of opioid withdrawal also may occur after the cessation of breast-feeding.55,56 Of these three drugs, oxycodone may be the safest; it is listed as pregnancy risk factor B, and codeine and hydrocodone are listed as pregnancy risk factor C. However, the clinician must exercise caution if prescribing these drugs for prolonged periods or in high doses. In most cases, the risk to the infant is minimal, thus making it unnecessary for a mother receiving an opioid analgesic to discard breast milk.23 Antibiotics. Some antibiotics can cross the placental membrane and be deposited in the embryo’s bones and teeth at sites of active calcification. All of the tetracyclines demonstrate this class effect: as little as 1 gram per day of tetracycline hydrochloride administered during the third trimester of pregnancy can produce yellow staining of both primary and secondary teeth.57 Doxycycline also has been implicated in tooth staining.58 Each of these medications is listed as pregnancy risk factor D by the FDA. All tetracyclines, including doxycycline, are 864 JADA 143(8)

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excreted in breast milk and, therefore, breastfeeding is not recommended by the manufacturer.59 The AAP49 considers all of these agents to be compatible with breast-feeding, however. Doxycycline is less bound to the calcium in breast milk, which may lead to greater absorption compared with other tetracyclines. Only minimal amounts of doxycycline are excreted in human milk, and the relative amount of tooth staining has been reported to be lower when compared with other tetracycline analogs. On the basis of information from the results of animal studies, the progenitor manufacturer of clarithromycin has stated that this antibiotic should not be used in pregnant women except in clinical circumstances in which no alternative therapy is appropriate. Clarithromycin is listed as pregnancy risk factor C by the FDA and although it is not known if clarithromycin is excreted in human breast milk, the manufacturer recommends that caution be exercised when administering clarithromycin to breastfeeding women.60 Other macrolides such as erythromycin and azithromycin are considered compatible with breast-feeding.61,62 The FDA lists all of the other antibiotics commonly used in dentistry—amoxicillin, azithromycin, cephalexin, clindamycin, erythromycin, metronidazole and penicillin—as pregnancy risk factor B. The AAP49 considers all of these agents to be compatible with breastfeeding with the exception of metronidazole, which is considered to be an in vitro mutagen (meaning that the clinician should suggest that the patient discontinue breast-feeding for 12 to 24 hours to allow excretion after receiving the single-dose therapy). Erythromycin also should be used with caution, as this drug is concentrated in human milk, and there are documented cases of pyloric stenosis being induced in the breast-fed newborn.63,64 Although antifungal agents are not prescribed commonly by dentists, the appearance of oral thrush may at times necessitate the use of these drugs. In the case of oral thrush, oral nystatin (FDA pregnancy risk factor C) is the safest agent to use both in pregnant patients and in patients who are breast-feeding, because absorption after oral use is poor, greatly reducing the risk to the fetus or the breast-fed newborn.65 The other common indication for antifungals is for the female dental patient who develops a vaginal yeast infection secondary to one of the previously listed antibiotic treatments. Vaginal candidiasis (moniliasis or thrush) is a common and frequently distressing infection for many women, and it is even more common in preg-

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nancy.66 The Cochrane Pregnancy and Childbirth Group Trials Register has reviewed the Cochrane Central Register of Controlled Trials and concluded that topical treatments with either terconazole or clotrimazole not only are preferred in pregnant women, given the decreased systemic absorption, but also appear to be more effective than oral therapies such as nystatin for treating symptomatic vaginal candidiasis during pregnancy.67 Patients may selfmedicate, because many of these preparations are available OTC. However, the Cochrane Review on this topic suggests that pregnant women may require a longer treatment than the shorter courses more commonly used in women who are not pregnant; longer courses (seven days) cured more than 90 percent of women, whereas standard (four-day) courses cured only about one-half the affected women.67 Newer oral agents such as fluconazole provide for equally efficacious, short-course treatment (from a single 150-mg dose up to a once-daily, three-day course) and may be preferred for compliance reasons. Fluconazole is listed as pregnancy risk factor C by the FDA for the single-dose vaginal candidiasis regimen and risk factor D for all other indications. Regardless, the investigators in a 2008 trial in Denmark who examined the maternal use of fluconazole and risk of congenital malformations found no overall increased risk of congenital malformations after fetal exposure to short-course treatment with fluconazole in early pregnancy.68 Fluconazole is considered safe in regard to breast-feeding, according to the AAP.49 Local anesthetics. All local anesthetics used in dentistry can cross the placental barrier, primarily through passive diffusion. In general, there are no contraindications to the careful use of lidocaine with epinephrine or prilocaine in pregnant patients (both drugs are listed by the FDA as pregnancy risk factor B), and both are considered compatible with breast-feeding according to the AAP.49 Even in doses exceeding the maximum allowed in humans, both lidocaine and prilocaine showed no evidence of fetal harm.69-73 Authors of articles have listed fetal bradycardia as a possible complication for bupivacaine and mepivacaine; in addition, bupivacaine has shown to be embryocidal in rabbits at five times the maximum recommended daily dose and can cause decreased survival in newborn rats at nine times the maximum recommended daily dose.69,70 Owing to the chance of increased free-drug concentrations in pregnant women, Suresh and Radfar72 recommended avoiding the

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use of long-acting local anesthetics such as bupivacaine in these women to minimize the risk of fetal exposure and toxicity. Unlike lidocaine and prilocaine, the last three commonly used local anesthetics—articaine, bupivacaine and mepivacaine—all are listed by the FDA as pregnancy risk factor C. Only articaine is not considered compatible with breastfeeding according to the AAP.49 Topical anesthetics commonly used in dentistry include benzocaine, dyclonine, lidocaine and tetracaine. Of these, lidocaine preparations are listed by the FDA as pregnancy risk factor B; the remainder are listed by the FDA as pregnancy risk factor C. Local and topical anesthetics have been associated with a rare, but serious potential health concern for both mother and fetus: a condition called methemoglobinemia. It is caused by the conversion of the iron molecule in hemoglobin from the ferrous to the ferric state, which results in an inability of the hemoglobin molecule to transport oxygen. Risk factors for developing acquired methemoglobinemia include the use of oxidative drugs, patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency and use of local anesthetics.74-78 Practitioners should use benzocaine and tetracaine preparations (for example, both sprays and gels) with caution in pregnant patients, as these medications have been implicated in acquired methemoglobinemia and possible hypoxemia in both mother and fetus.72,74 For the same reasons, the clinician should be cautious in using the injectable local anesthetic prilocaine. The use of benzocaine, tetracaine and prilocaine should be avoided altogether in patients who have a history of either congenital or acquired methemoglobinemia. In a review of case reports published in 2000 or later, Guay79 found that benzocaine (in 79 percent of cases) and prilocaine (in 12 percent of cases) were the local anesthetics most commonly associated with acute methemoglobinemia episodes. Twelve episodes of methemoglobinemia were associated with the use of lidocaine; however, seven of these cases involved the use of another concomitantly administered oxidative drug (such as nitrates, trimethoprimsulfamethoxazole, dapsone, phenazopyridine or phenacetin). Because of the unpredictability of recognizing which patients may develop methemoglobinemia after even a single exposure to benzocaine, it was Guay’s opinion that benzocaine topical anesthetic should not be used. To prevent methemoglobinemia, Guay79 also recommended that the use of prilocaine be avoided in pregnant women, patients receiving other oxidaJADA 143(8)

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tive drugs and patients with G6PD deficiency. Moore and Braatvedt80 reported a rare case of acquired methemoglobinemia during pregnancy in which the mother experienced high levels of methemoglobin; fortunately, the fetus showed no signs of distress or growth retardation. The use of lidocaine with epinephrine to achieve profound anesthesia in pregnant or breast-feeding patients is not contraindicated.69,71,72,75 Vasoconstrictors commonly are added to local anesthetics to retard systemic absorption, increase efficacy and prolong duration. In general, the concern for pregnant women involves epinephrine’s α-adrenergic effects, which may decrease uterine blood flow, and its β-adrenergic activity, which may decrease uterine activity and prolong labor.72,81 Vasoconstrictor concentrations in commonly used preparations include 1:100,000 (0.01 mg per milliliter) or 1:200,000 (0.005 mg/mL) epinephrine or 1:20,000 (0.05 mg/mL) levonordefrin. If careful technique is used to prevent intravascular injection, a cumulative dose of as much as 0.1 mg can be used safely in healthy pregnant patients (the equivalent of five carpules of dental local anesthetic containing 1:100,000 epinephrine concentration, or 10 carpules containing a 1:200,000 epinephrine concentration).82 No studies currently exist describing the use of epinephrine during human lactation; however, because of its short half-life, it is unlikely that epinephrine distributes into breast milk and, therefore, it is not contraindicated for use during lactation.82-84 Neves and colleagues85 studied the effects of lidocaine with and without epinephrine in 31 pregnant women with rheumatic heart disease. Their results showed no interferences in maternal blood pressure and heart rate, fetal heart rate, maternal uterine contractions, fetal body movement and nonstress test with the use of 1.8 mL of 2 percent lidocaine with 1:100,000 epinephrine. The authors noted a higher frequency of arrhythmias (defined as > 10 extrasystoles per hour) in patients who received the vasoconstrictor versus patients who did not, 42 percent versus 14 percent, respectively, suggesting an increased adrenergic response in pregnant women. Levonordefrin is the other vasoconstrictor available in dental local anesthetic carpules. It is supplied as 1:20,000, a dose commonly considered equally as potent and efficacious as 1:100,000 epinephrine (epinephrine is five times as potent as levonordefrin).86 Because of levonordefrin’s disproportionate effects on the α-adrenergic system (75 percent α-adrenergic 866

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versus 25 percent β-adrenergic effects), it sometimes is considered to possess less vasopressor activity and to incite less cardiac and central nervous system stimulation.87 This, however, has been shown not to be the case in the concentrations used in dentistry.88 Levonordefrin has no FDA pregnancy risk classification; therefore, its use cannot be recommended, although some authors have suggested it is safe for women to use during pregnancy and lactation.69,70,75 Sedatives. Benzodiazepines are the most commonly used drugs in the United States for the treatment of anxiety, phobias and tension.89 The effects of using benzodiazepines (such as alprazolam, diazepam, lorazepam, midazolam and triazolam) during pregnancy may lead to fetal abortion, malformations, intrauterine growth retardation, functional deficits, carcinogenesis and mutagenesis, with the greatest risks occurring between two and eight weeks after conception.80,81 When these drugs are used near term, fetal dependence and withdrawal have been known to occur.89,90 For all of these reasons, this class of medications is listed by the FDA as pregnancy risk factor D/X depending on the particular drug, dose and duration of use.72 Although it did not address triazolam in particular, the AAP did not consider most benzodiazepines to be compatible with breastfeeding.49 The pump-and-discard strategy for breast milk described above for short-acting benzodiazepines such as midazolam and triazolam has been successful for some patients.91 Infant exposure is reduced if breast-feeding is avoided during times when the mother receives sedative medications; however, because relatively small amounts of the drug are excreted into breast milk, some mothers may opt to continue nursing after weighing the benefits of breast-feeding against the potential risk to the infant. Zaleplon and zolpidem are nonbenzodiazepines that also produce their sedative and hypnotic effects via selective stimulation of the αsubunit of the gamma-amino-butyric acid-A macromolecular complex.92 If a pregnant or breast-feeding patient requires an oral sedative to help her relax throughout her dental appointment, either of these agents would be preferable to the benzodiazepines, because they are listed by the FDA as pregnancy risk factor C. Zaleplon has not been reviewed, but the AAP49 considers zolpidem to be safe in regard to breast-feeding. Emergency medications. β2-adrenergic receptor agonists. The most common β2adrenergic receptor agonist used to treat acute bronchospasm that may be experienced during

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an asthmatic attack or anaphylaxis is albuterol, administered via inhalation.44 Albuterol relaxes bronchial smooth muscles and inhibits chemical mediators released during hypersensitivity reactions. Unlike other β2-adrenergic receptor agonists, albuterol is an excellent choice because it is associated with fewer cardiovascular adverse effects than are other bronchodilators.44 Unfortunately, antiasthmatic drugs such as albuterol are listed by the FDA as category C medications, although they frequently are used by pregnant women who have asthma.93 Researchers have observed an increase in the risk of congenital malformation associated with the use of albuterol during pregnancy,94 although findings of previous studies also have demonstrated that pregnant women with untreated asthma are at substantially increased risk of experiencing many adverse pregnancy outcomes.95,96 In an emergency situation, the benefits to the mother exceed the risk to the fetus, and this medication needs to be administered. In addition, although no published data exist regarding the use of albuterol via inhaler during lactation, data regarding the related drug, terbutaline, indicate that little is expected to be excreted into breast milk and, therefore, the drug should be safe.97 Histamine blockers. Histamine blockers reverse the actions of histamine by occupying H1-receptor sites on the effector cell and are indicated for patients with mild or delayedonset allergic reactions. Diphenhydramine typically is administered as a 50-mg intramuscular injection followed by 25 to 50 mg orally every three to four hours for as long as three days after such a reaction.44 Diphenhydramine is safe for a pregnant patient, as it is listed by the FDA as a category B medication. Although the AAP has not published comments on the use of this medication during breast-feeding, occasional small doses of diphenhydramine would not be expected to cause any adverse effects in breastfed infants according to a study by Ito and colleagues.98 Epinephrine. Epinephrine is the single most important injectable drug in the emergency kit.44 Epinephrine is an endogenous catecholamine that stimulates both α- and βadrenergic receptors. It is the drug of choice for treating cardiovascular and respiratory manifestations of acute allergic reactions. When administered in resuscitative dosages, epinephrine causes bronchodilation and increased systemic vascular resistance, heart rate, arterial blood pressure, myocardial contractility, and myocardial and cerebral blood flow.99 For treat-

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ment of life-threatening signs and symptoms of an acute allergic reaction, the clinician must administer epinephrine immediately, injecting the drug subcutaneously (0.3 to 0.5 mg of a 1:1,000 epinephrine solution) or intramuscularly for a more serious emergency (0.4 to 0.6 mg of the same epinephrine solution). Epinephrine is available in ampules as well as in preloaded syringes or autoinjectors for immediate use.100 Epinephrine also is indicated for the treatment of acute asthmatic attacks that are unrelieved by β2-adrenergic receptor agonists such as albuterol.101 As with albuterol, in an emergency situation, the benefits of epinephrine use to the mother exceed the risk to the fetus, and this medication needs to be administered. In addition, no information is available on the use of epinephrine during breast-feeding. Because of its poor oral bioavailability and short half-life, any epinephrine in milk is unlikely to affect the infant and therefore should be safe.102 Epinephrine is listed by the FDA as pregnancy risk factor C. Antidotal drugs. If dentists administer opioids or benzodiazepines to induce moderate or deep sedation or general anesthesia, they must include antidotal drugs in the emergency kit.44 Naloxone is a specific opioid antagonist that reverses opioid-induced respiratory depression.103 Flumazenil is a specific benzodiazepine antagonist that reverses sedation and respiratory depression resulting from benzodiazepine administration.104 Although both of these medications are listed by the FDA as category C with respect to use in pregnancy, in an emergency situation, the benefits to the mother exceed the risk to the fetus and either of these medications should be administered if indicated. According to authors of studies involving nursing mothers, naloxone does not affect lactation hormone levels.105,106 If a mother requires naloxone, it is not a reason for her to discontinue breast-feeding.105,106 Flumazenil. Flumazenil has not been reviewed by the AAP; however, intravenous flumazenil has been given directly to neonates to reverse the sedative effects of diazepam administered to the mother immediately before delivery without any noted adverse effects.107,108 Administration to a lactating patient would carry an even lower risk given the short elimination half-life (mean, 54 minutes), and the poor oral bioavailability that will further mitigate transfer into breast milk. Nitroglycerin. Nitroglycerin for the dental office is available as sublingual tablets or translingual sprays.44 Nitroglycerin is the treatment JADA 143(8)

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BOX 3

infarction. If the patient has never Pregnancy, breast-feeding and drugs used received a diagnosis in dentistry: key considerations for clinicians of angina pectoris and develops symptoms of and proposed areas for future research. a possible acute KEY CONSIDERATIONS FOR CLINICIANS myocardial infarction, dThe benefit of continuing medication in pregnancy often outweighs the potential risks such as chest pain or dPrepregnancy assessment and counseling should be offered to all women of childbearing chest pressure, the age who are receiving medication clinician should condClinicians should seek the latest information on specific drugs to allow the pregnant sider administering or breast-feeding dental patient to make an informed choice 0.4 mg of sublingual dThe benefit of continuing medication during breast-feeding often outweighs the potential risks nitroglycerin if the PROPOSED AREAS FOR FUTURE RESEARCH patient’s systolic dLarge-scale observational studies of the use of common medications during pregnancy blood pressure is dStudies that take into account the potential for active disease to affect the fetus adversely acceptable (> 90-100 and the need for clinicians to interpret the benefits and risks regarding the role mm of mercury) after of medication accordingly first calling 911 dStudies regarding the effect of prepregnancy counseling on medication use compliance (emergency assistduring pregnancy ance) and adminisLarge-scale observational studies regarding the effect of paternal medication on fetal d teratogenesis rate tering aspirin. As with the other emerBOX 4 gency medications previously discussed, the benefits to the mother exceed the risk to the Online resources regarding fetus and this medication needs to be adminisdrug safety in pregnancy. tered. No information is available on the use of nitroglycerin during breast-feeding, but because Breastfeeding Online of its short half-life, any nitroglycerin in milk is www.breastfeedingonline.com/meds.shtml unlikely to affect the infant and therefore National Library of Medicine Drugs and Lactation should be considered safe.109,110 Database (LactMed) http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT Future directions and resources. Box 3 Organization of Teratology Information Specialists highlights the main messages and proposed www.otispregnancy.org areas for future research on these topics; Box 4 SafeFetus.com offers references to consult when investigating www.safefetus.com whether a drug is safe in pregnancy. Texas Tech University Health Sciences Center Infant Risk Center www.infantrisk.com U.S. Food and Drug Administration www.fda.gov

of choice for the patient with angina who may experience acute chest pain. It acts primarily by relaxing vascular smooth muscle, dilating systemic venous and arterial vascular beds, which leads to a reduction in venous return and systemic vascular resistance. These actions of reestablishing the balance between oxygen supply and oxygen demand in the coronary circulation result in the elimination of the chest pain. If the patient does not bring his or her own nitroglycerin to the dental office, the clinician should administer one tablet or metered spray (0.4 mg). This dosage may be repeated twice at five-minute intervals for a total of three doses. Relief should occur within one to two minutes; if the discomfort is not relieved, the dentist must consider a diagnosis of evolving myocardial 868

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CONCLUSIONS

This review highlights common dental drugs to avoid and drugs that are considered relatively safe to use in pregnant and breast-feeding patients. When considering prescribing in pregnancy, the dentist must weigh the balance between risk to the fetus and benefit to the mother, and the appropriate conclusion should reflect current evidence. In some cases, medication dosing should be avoided or altered; however, there are times when it is unnecessary to stop or avoid the use of medications. A trusting, open relationship between the dentist and patient is of vital importance to optimize the mother’s treatment during her pregnancy. In particular, dentists should help pregnant or breast-feeding patients understand all of the risks and benefits before they use any prescribed medication, as it is possible to manage the care of these patients and their conditions safely. ■

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Disclosure. Drs. Donaldson and Goodchild did not report any disclosures. 1. Andrade SE, Gurwitz JH, Davis RL, et al. Prescription drug use in pregnancy. Am J Obstet Gynecol 2004;191(2):398-407. 2. Centers for Disease Control and Prevention, National Center on Birth Defects and Developmental Disabilities, National Birth Defects Prevention Network. Important Information About Preventing Birth Defects. www.nbdpn.org/docs/Pamplet_BDprevention.pdf. Accessed June 8, 2012. 3. Chambers CD, Braddock SR, Briggs GG, et al. Postmarketing surveillance for human teratogenicity: a model approach. Teratology 2001;64(5):252-261. 4. Irl C, Hasford J. Assessing the safety of drugs in pregnancy: the role of prospective cohort studies. Drug Saf 2000;22(3):169-177. 5. Martínez-Frías ML. Postmarketing analysis of medicines: methodology and value of the Spanish case-control study and surveillance system in preventing birth defects. Drug Saf 2007;30(4):307-316. 6. Wilson JG. Present status of drugs as teratogens in man. Teratology 1973;7(1):3-15. 7. Michalowicz BS, DiAngelis AJ, Novak MJ, et al. Examining the safety of dental treatment in pregnant women. JADA 2008;139(6): 685-695. 8. U.S. Food and Drug Administration. Drug safety and availability. www.fda.gov/Drugs/DrugSafety/default.htm. Accessed June 26, 2012. 9. Henshaw SK. Unintended pregnancy in the United States. Fam Plann Perspect 1998;30(1):24-29, 46. 10. Finer LB, Henshaw SK. Disparities in rates of unintended pregnancy in the United States, 1994 and 2001. Perspect Sex Reprod Health 2006;38(2):90-96. 11. Simpson JL. Genetics in Obstetrics and Gynecology. New York City: Grune & Stratton; 1982:203-210. 12. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk. 9th ed. Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins; 2011: xvii, 406-408, 497. 13. Boubred F, Vendemmia M, Garcia-Meric P, Buffat C, Millet V, Simeoni U. Effects of maternally administered drugs on the fetal and neonatal kidney. Drug Saf 2006;29(5):397-419. 14. Adverse Drug Reactions Advisory Committee. Premature closure of the fetal ductus arteriosus after maternal use of non-steroidal anti-inflammatory drugs. Med J Aust 1998;169(5):270-271. 15. Illsley NP, Hall S, Penfold P, Stacey TE. Diffusional permeability of the human placenta. Contrib Gynecol Obstet 1985;13:92-97. 16. Kraemer K. Placental transfer of drugs. Neonatal Netw 1997; 16(2):65-67. 17. Jankowitz J. Drugs in pregnancy. In: Gibbs RS, Danforth DN, eds. Danforth’s Obstetrics and Gynecology. 10th ed. Philadelphia: Lippincott Williams & Wilkins; 2008:122-123. 18. Kane SV, Acquah LA. Placental transport of immunoglobulins: a clinical review for gastroenterologists who prescribe therapeutic monoclonal antibodies to women during conception and pregnancy. Am J Gastroenterol 2009;104(1):228-233. 19. Van Assche G, Lewis JD, Lichtenstein GR, et al. The London position statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn’s and Colitis Organisation: safety. Am J Gastroenterol 2011;106(9):1594-1602. 20. U.S. Food and Drug Administration. Labeling requirements for over-the-counter drugs. 21 CFR Part 201.80. http://www.accessdata. fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=201.80&utm_ campaign=Google2&utm_source=fdaSearch&utm_medium= website&utm_term=1979 prgnancy categories&utm_content=3. Accessed June 26, 2012. 21. U.S. Food and Drug Administration. Content and format of labeling for human prescription drug and biological products; requirements for pregnancy and lactation labeling (proposed rule). Fed Regist 2008;73(104): 30831-30868. 21 CFR Part 201. www.gpo.gov/ fdsys/pkg/FR-2008-05-29/html/E8-11806.htm. Accessed June 8, 2012. 22. Centers for Disease Control and Prevention. Breastfeeding Among U.S. Children Born 2000-2008, CDC National Immunization Survey. www.cdc.gov/breastfeeding/data/NIS_data/index.htm. Accessed June 8, 2012. 23. Hendrickson RG, McKeown NJ. Is maternal opioid use hazardous to breast-fed infants? (published online ahead of print Dec. 13, 2001). Clin Toxicol (Phila) 2012;50(1):1-14. doi:10.3109/ 15563650.2011.635147. 24. American Academy of Pediatrics. AAP issues policy statement on the transfer of drugs and other chemicals into human milk. Am

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patient. Quintessence Int 2006;37(6):455-468. 83. Porter RS, ed. The Merck Manual Home Health Handbook for Patients and Caregivers: Drug Use During Pregnancy. www. merckmanuals.com/home/womens_health_issues/drug_use_during_ pregnancy/drug_use_during_pregnancy.html#v810071. Accessed June 8, 2012. 84. Hale TW. Medications and Mother’s Milk: A Manual of Lactational Pharmacology. 14th ed. Amarillo, Texas: Hale Publishing; 2010:359-360. 85. Neves IL, Avila WS, Neves RS, et al. Maternal-fetal monitoring during dental procedure in patients with heart valve disease. Arq Bras Cardiol 2009;93(5):463-472. 86. Robertson VJ, Taylor SE, Gage TW. Quantitative and qualitative analysis of the pressor effects of levonordefrin. J Cardiovasc Pharmacol 1984;6(5):929-935. 87. Lawaty I, Drum M, Reader A, Nusstein J. A prospective, randomized, double-blind comparison of 2 percent mepivacaine with 1:20,000 levonordefrin versus 2 percent lidocaine with 1:100,000 epinephrine for maxillary infiltrations. Anesth Prog 2010;57(4):139-144. 88. Guglielmo A, Reader A, Nist R, Beck M, Weaver J. Anesthetic efficacy and heart rate effects of the supplemental intraosseous injection of 2 percent mepivacaine with 1:20,000 levonordefrin. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;87(3):284-293. 89. Iqbal MM, Sobhan T, Ryals T. Effects of commonly used benzodiazepines on the fetus, the neonate, and the nursing infant. Psychiatr Serv 2002;53(1):39-49. 90. Jauniaux E, Jurkovic D, Lees C, Campbell S, Gulbis B. In-vivo study of diazepam transfer across the first trimester human placenta. Hum Reprod 1996;11(4):889-892. 91. Howie WO, McMullen PC. Breastfeeding problems following anesthetic administration. J Perinat Educ 2006;15(3):50-57. 92. Donaldson M, Chanpong B, Gizzarelli G. Oral sedation: a primer on anxiolysis for the adult patient. Anesth Prog 2007;54(3): 118-129. 93. Wen SW, Yang T, Krewski D, et al. Patterns of pregnancy exposure to prescription FDA C, D and X drugs in a Canadian population (published online ahead of print Feb. 21, 2008). J Perinatol 2008; 28(5):324-329. doi:10.1038/jp.2008.6. 94. Källén B, Otterblad Olausson P. Use of anti-asthmatic drugs during pregnancy, part 3: congenital malformations in the infants (published online ahead of print Feb. 6, 2007). Eur J Clin Pharmacol 2007;63(4):383-388. doi:10.1007/s00228-006-0259-z. 95. Wen SW, Demissie KW, Liu S. Adverse outcomes in pregnancies of asthmatic women: results from a Canadian population. Ann Epidemiol 2001;11(1):7-12. 96. Demissie K, Breckenridge MB, Rhoads GG. Infant and maternal outcomes in the pregnancies of asthmatic women. Am J Respir Crit Care Med 1998;158(4):1091-1095. 97. Lindberg C, Boreus LO, de Chateau P, Lindstrom B, Lonnerholm G, Nyberg L. Transfer of terbutaline into breast milk. Eur J Resp Dis 1984;134:87-91. 98. Ito S, Blajchman A, Stephenson M, Eliopoulos C, Koren G. Prospective follow-up of adverse reactions in breast-fed infants exposed to maternal medication. Am J Obstet Gynecol 1993;168(5): 1393-1399. 99. Joint Task Force on Practice Parameters; American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. The diagnosis and management of anaphylaxis: an updated practice parameter (published correction appears in J Allergy Clin Immunol 2008;122[1]:68). J Allergy Clin Immunol 2005; 115(3 suppl 2):S483-S523. 100. Brown AF. Anaphylaxis gets the adrenaline going. Emerg Med J 2004;21(2):128-129. 101. McFadden ER Jr. Acute severe asthma. Am J Respir Crit Care Med 2003;168(7):740-759. 102. Radzyminski S. The effect of ultra low dose epidural analgesia on newborn breastfeeding behaviors. J Obstet Gynecol Neonatal Nurs 2003;32(3):322-331. 103. Longnecker DE, Grazis PA, Eggers GW Jr. Naloxone for antagonism of morphine-induced respiratory depression. Anesth Analg 1973;52(3):447-453. 104. Klotz U, Kanto J. Pharmacokinetics and clinical use of flumazenil (Ro 15-1788). Clin Pharmacokinet 1988;14(1):1-12. 105. Johnson MR, Andrews MA, Seckl JR, Lightman, SL. Effect of naloxone on neurohypophyseal peptide responses to breast feeding and breast stimulation in man. Clin Endocrinol 1990;33(1):81-86. 106. Cholst IN, Wardlaw SL, Newman CB, Frantz AG. Prolactin

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response to breast stimulation in lactating women is not mediated by endogenous opioids. Am J Obstet Gynecol 1984;150(5 Pt 1):558-561. 107. Richard P, Autret E, Bardol J, et al. The use of flumazenil in a neonate. J Toxicol Clin Toxicol 1991;29(1):137-140. 108. Dixon JC, Speidel BD, Dixon JJ. Neonatal flumazenil therapy reverses maternal diazepam. Acta Paediatr 1998;87(2):225-226.

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109. Sheikh AU, Harper MA. Myocardial infarction during pregnancy: management and outcome of two pregnancies. Am J Obstet Gynecol 1993;169(2 part 1):279-283. 110. Maekawa K, Ohnishi H, Hirase T, Yamada T, Matsuo T. Acute myocardial infarction during pregnancy caused by coronary artery spasm. J Intern Med 1994;235(5):489-492.

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