Analgesics in Pregnancy and Lactation: Safe Medication Practices

Since the thalidomide tragedy more than 50 years ago, prescribing medications for pregnant and lactating women has been a concern for healthcare providers, mothers, and the public.¹ This ongoing apprehension is due to a lack of quality information about the effectiveness and safety of medicine use during pregnancy and lactation for most commercialized medications in the United States.^2,3 Animal studies cannot always predict teratogenic risks in humans, and pregnant and lactating women are generally excluded from clinical trials that generate most effectiveness and safety data.⁴ In addition, very few drug information systems assessing medication use at a population level capture data for all women of childbearing ages, limiting the amount of information collected through post-market surveillance.

Numerous studies have found that the use of prescription drugs during pregnancy is not only common but has been increasing over time.^5-9 Some investigators have demonstrated that two out of every three women take prescription medications during pregnancy.¹⁰ Taking medications while breastfeeding represents another challenge for patients and prescribers, and while the actual incidence of medication use among lactating women is not known, it is widely accepted that breastfeeding women take significantly more medications per month than pregnant women.¹¹ A recent Dutch study confirmed this trend in a study population of 292 pregnancies, in which 66% of the pregnancies recorded medication use, followed by 84.2% medication use while breastfeeding.¹²

Within the context of the opioid epidemic and renewed concerns for appropriately addressing patients' pain, along with the publication of recent guidelines and updated safety concerns for certain pain medications such as acetaminophen, the safe analgesic prescribing for pregnant or breastfeeding women may be less clear.^13-19 The purpose of this article is to provide an organized source of information about analgesic use for the pregnant or breastfeeding dental patient. With data regarding commonly used medications and pregnancy categories established by the US Food and Drug Administration (FDA), oral healthcare providers (OHCPs) that are prepared with evidence-based information about the safety of medication use during pregnancy and breastfeeding can advise their patients regarding optimal medication therapy, helping to ensure healthy outcomes for both mother and child.

The Pregnant Dental Patient

Pregnant dental patients represent two considerable challenges for OHCPs. First, not all women of childbearing age know that they may be pregnant, and when medications are being prescribed, the possibility of the patient conceiving while taking the medication should be a consideration and guide appropriate medication selection. Second, while most elective dental procedures can be postponed until after the pregnancy is over, dental treatment for a pregnant woman who has oral pain, infection, or advanced disease should not be delayed.

Unintended pregnancy rates fell nearly 20% between the early 1980s and the mid-1990s, but they have remained relatively unchanged since.^20,21 While that decline may have been the result of better public education, higher contraceptive prevalence, and the use of more effective birth control methods, a more recent publication found that just over one-third of women of reproductive age surveyed in 2016 (36.4%) had experienced at least one unplanned birth sometime in their lives.²⁰ Therefore, whenever prescribing for women of childbearing age, OHCPs must consider the potential adverse effects on the fetus. In addition to routinely updating every patient's pharmacological and medical history, a simple interview technique for all female patients that asks three questions may greatly aid in this risk mitigation: "Are you pregnant?" "Do you know if you are pregnant?" "Are you trying to get pregnant?"

Teratogenicity refers to medications that may be associated with structural abnormalities in the developing fetus (eg, cleft palate, cleft lip, phocomelia, etc). The time of greatest fetal teratogenic risk is from 3 to 8 weeks after conception (5 to 10 weeks' gestation, when week 1 begins at the first day of the last menstrual period).²² At about the fifth week of embryotic life, placental transport of maternal substrates to the fetus and of substances from the fetus to the mother is established.²³ For this reason, abruptly stopping a drug because of concerns about teratogenicity at week 10 does not usually reduce teratogenic risk substantially. Besides teratogenicity, fetotoxicity can occur anytime between the late first trimester and birth and can cause a variety of effects. One example is the use of the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen, which is associated with the development of fetal renal dysfunction in the second and third trimesters and premature closure of the ductus arteriosus in the third trimester.^24,25 These types of structural abnormalities are also easier to detect and more obvious than the effects of drugs on cognitive function and interference with brain development.

Any chemical substance or medication administered to the mother can cross the placenta to some extent unless it is altered or destroyed during passage, or its low lipid solubility and molecular size limit transplacental transfer.²⁶ Chemicals of low molecular weight freely diffuse across the placenta, propelled primarily by the concentration gradient and passive diffusion. Almost every substance used for therapeutic purposes can and does pass from the mother to the fetus²³; the notion of a "placental barrier" is a misnomer. Whether the rate and extent of transfer are sufficient to cause significant concentrations within the fetus resulting in either teratogenicity or fetotoxicity is of paramount importance.

The practice of prescribing medications during pregnancy is a balance between the benefit (usually to the mother) of treating the disease versus the risks of the potential adverse effects of the drug (usually to the fetus). This balance can change during pregnancy depending on the gestation and the disease activity.²⁷ For example, a woman with a severe inflammatory bowel disease flare may be a candidate for monoclonal antibody therapy in the first trimester since several biologics have been shown not to cross the placenta until well into the second trimester²⁸; however, in the third trimester it may be reasonable to try corticosteroids first. At term, the therapeutic intervention of delivery of the fetus can rapidly improve the maternal condition of the disease.

In December 2014, the FDA published its final Pregnancy and Lactation Labeling Rule (PLLR) on prescription drug labeling to better inform prescribers on the safe use of medicines during pregnancy and breastfeeding.²⁹ The PLLR removed the historical pregnancy letter categories-A, B, C, D, X, and N-where drugs in categories A and B were considered safe for use, drugs in category C could be used if the benefits outweighed the risks, drugs in category D were to be avoided with some exceptional circumstances, and those in category X were to be strictly avoided in pregnant women; if a drug has not yet been classified by the FDA into a specified pregnancy category, it is designated as "N." Labeling for over-the-counter (OTC) medicines did not change, so it is still important to know the FDA pregnancy risk factor definitions (Table 1).²⁹

These changes to prescription medication labeling give all healthcare providers better information for counseling women who are of childbearing age, pregnant, or breastfeeding, and for making more informed prescribing decisions.³⁰ The pregnancy section of the PLLR also includes a risk summary, clinical considerations, additional data, and information for a pregnancy exposure registry for the drug if one is available. The new labeling system will also reduce the "innocent until proven guilty" bias, where untested drugs with no known harmful side effects (category B) were perceived to be safer than tested drugs with known side effects (category C). Table 2 highlights key clinical considerations for medications and the pregnant dental patient.³⁰

The Breastfeeding Dental Patient

The Centers for Disease Control and Prevention's (CDC) most recent Breastfeeding Report Card, published in 2020, found that the incidence of breastfeeding among US children born in 2017 was 84.1%, with 58.3% breastfeeding at 6 months and 35.3% at 12 months.³¹ This relatively high percentage may be due in part to the American Academy of Pediatrics' (AAP) very first position paper on this subject, which emphasized breastfeeding as the best nutritional mode for infants for the first 6 months of life.³² The high rate of breastfeeding, together with growing concerns of parents about baby health needs, has led to increased questioning of pharmacists, physicians, and OHCPs about the safety and potential toxicity of medications that may be excreted in breast milk.

Most studies concerning breast milk synthesis and secretion are from animal trials, making the challenge of studying human lactation using histological techniques and the administration of radioactive iso­topes more difficult.³³ Unfortunately, there are consider­able dif­fer­ences in the compo­sition of breast milk from different animal species, and these differences may reflect differences in drug elimination. Interestingly, the pH of human milk (pH usually >7.0) is very different compared to the pH of cow's milk (pH <6.8), in which drug excretion has been extensively studied. The relationship between pH and medication absorption as well as elimination refers to the propensity for drugs to be in either the charged or neutral (uncharged) form at a particular pH, as only the uncharged form of molecules will readily pass across enteral membranes, typically by passive diffusion. The transmembrane distribution of a molecule is determined by its pKa and the pH gradient across the membrane. The pKa is the pH at which half the drug is in its ionized (charged) form.³⁴

Most references on this subject report the concentration of medications in breast milk, and often these studies give a milk-to-plasma ratio. Many of the values consist of a single measurement of the medication concentration, however, and important information such as the maternal dose, frequency of administration, time from drug administration to sampling, frequency of nursing, and length of lactation is not given. The significance of these data, then, may only be directional, meaning that the medication is present in breast milk, but offering no guidance for providers to safely proceed. Often the drug in the nursing infant's blood or urine is not coincidentally reported, so there is scant information on the amount of medication that is actually absorbed by the infant from the breast milk and, therefore, no way of determining the possible pharmacological effects. In fact, a critical examination of published data demonstrates that much of the information was gathered decades ago when analytic methodologies were not as sensitive as contemporary means.^35-40

For most medications, infants are exposed to a much higher concentration during pregnancy than during lactation. Therefore, if a drug is considered acceptable during pregnancy, it is reasonable to continue it during breastfeeding; however, there are exceptions. The most important factors to consider are the concentration of drug in the infant's blood and the pharmacological effects this might have. Small molecules get into breast milk more easily than large molecules (eg, heparin is not excreted in breast milk). The half-life of certain drugs in the neonatal circulation may also be longer than in the mother, because infant liver metabolism is still immature. This may lead to drug accumulation in the infant and particularly applies to analgesics such as morphine and aspirin.^21-23,41

To limit the infant's drug exposure, the "pump and discard" strategy was believed to be effective for some analgesics with a short half-life. The most recent statement on breastfeeding by the American Society of Anesthesiologists, however, refutes this practice as being an outdated recommendation, stating, "because analgesic and anesthetic drugs appear in such low levels in breastmilk, it is not recommended that patients ‘pump and dump.'"⁴² Table 3 highlights key clinical considerations for medications and breastfeeding.

While the AAP has been the authority on the transfer of drugs and chemicals into human milk since the organization's first publication on this subject in 1983, revisions can no longer keep pace with the rapidly changing information available via the internet, published studies, and new drug approvals.^43-45 A more comprehensive and current database is available at LactMed.⁴⁶ LactMed includes up-to-date information on drug levels in infant serum and human breast milk, potential effects on lactation, possible adverse effects on breastfeeding infants, and recommendations for possible alternative medications to consider; common herbal products are also included.

Pain Management in Pregnant and Breastfeeding Dental Patients

Studies have reported that up to 55% of pregnant women experience oral health problems related to odontogenic pain.^47-49 Guidelines issued by the American Dental Association and American College of Obstetrics and Gynecologists emphasize the importance of dental treatment for optimizing maternal-fetal health across all trimesters, especially for emergent dental issues related to pain.^50-52 Appropriate management of odontogenic pain is essential to help ensure a healthy pregnancy for both mother and child and for successful breastfeeding.

As mentioned previously, medications 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 all drugs should be avoided if possible during the first trimester. Medications that have been extensively prescribed during pregnancy and appear to be safe should be prescribed in preference to new or untested drugs, and the smallest effective dose should be used for the shortest period of time. While only a few drugs have been shown conclusively to be teratogenic in humans, no drug is safe beyond all doubt in early pregnancy.

Many analgesics and anti-inflammatory medications are available OTC (without a prescription) and can be purchased at many retail outlets besides pharmacies. Given their widespread use, ease of availability, and long history of treating numerous common ailments, safety concerns in the pregnant or breastfeeding patient may not be fully appreciated. The most ubiquitous of all analgesics, acetaminophen, is still considered safe during both pregnancy and lactation; however,  recent experimental and epidemiological research has shown that prenatal exposure to it might alter fetal development, which could increase the risks of some neurodevelopmental, reproductive, and urogenital disorders.^19,46,53

Burdan and Belzek studied the ingestion of ibuprofen during pregnancy and found that it caused embryonic implantation disturbances, inhibition of parturition, and contraction of the ductus arteriosis leading to maternal pulmonary hypertension.⁵⁴ A congenital ibuprofen-related malformation known as gastroschisis, in which fetal organs develop outside the abdominal wall, is also possible. Other drug-related cases of gastroschisis have been linked to maternal use of other NSAIDs, including aspirin, and the decongestants pseudoephedrine and phenylpropanolamine.⁵⁵ In addition, a recent meta-analysis suggested that exposure to any NSAID during pregnancy, and not just ibuprofen, is associated with a significantly increased risk of miscarriage.⁵⁶ However, because of the extremely low levels seen in breast milk, its short half-life, and safe use in infants in doses much higher than those excreted in breast milk, ibuprofen is still the preferred choice as an analgesic or anti-inflammatory agent in nursing mothers.⁴⁶ Following low-dose aspirin in daily doses between 75 mg and 325 mg, no aspirin was detected in breast milk, and salicylate levels (a metabolite of aspirin) were low. Nursing mothers should avoid daily aspirin doses greater than 325 mg, however, because of the potential risk of platelet dysfunction and Reye's syndrome in the baby. Low-dose daily aspirin is considered compatible with breastfeeding.⁴⁶ While the etiology and pathophysiology of Reye's syndrome, which is characterized by the acute onset of encephalopathy, liver dysfunction, and fatty infiltration of the liver and other viscera, are not clear,the epidemiologic evidence for an association between aspirin use in children and Reye's syndrome was sufficiently compelling that in 1986 labeling of aspirin and aspirin-con­taining medications to indicate Reye's syndrome as a risk in children was man­dated. Since then, the use of aspirin in children has declined dramatically, and Reye's syndrome has almost disappeared.

The glucocorticoids such as prednisone and dexamethasone have been associated with oral clefts when administered during the first trimester of pregnancy.^57,58 For these reasons, the FDA has historically listed these medications as either pregnancy risk factor C or D depending on the trimester of exposure, drug, dose, and length of maternal exposure. Infants born of mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism. The AAP has historically reported that these medications are safe during breastfeeding because no information is available on the use of systemic dexamethasone during breastfeeding, and local injections would not be expected to cause any adverse effects in breastfed infants but might occasionally cause temporary loss of milk supply.^45,46 While an alternate corticosteroid may be preferred, especially while nursing a newborn or preterm infant (eg, methylprednisolone, prednisolone, or prednisone since no adverse reactions in breastfed infants have been reported in mothers taking these drugs), the lack of case reports on the safety of dexamethasone during breastfeeding does not imply that it would be any less safe.

Opioid-containing analgesics such as codeine, hydrocodone, and oxycodone are generally not recommended as first-line therapies to treat dental pain, as they lack anti-inflammatory activity.^59,60 Most opioid-containing analgesics were classified by the FDA under category C for use in pregnancy, indicating evidence of potential harm to the fetus from animal studies and the absence of well-controlled human studies. One exception, however, is oxycodone, which was classified as category B, indicating no evidence of harm to the fetus from animal studies and the absence of well-controlled human studies.⁶¹ (Table 4 lists key analgesic considerations during pregnancy and breastfeeding.)

Maternal use of oral opioid-containing analgesics during breastfeeding can cause infant drowsiness and severe central nervous system depression in the baby. Newborn infants are particularly sensitive to the effects of even small doses of narcotic analgesics, and once the mother's milk comes in, it is best to provide pain management with a non-narcotic analgesic.⁶² If the baby shows signs of increased drowsiness, difficulty breastfeeding, limpness, or breathing difficulties a physician should be contacted immediately. Excessive sedation in the mother correlates with excess sedation in the breastfed infant. A number of professional organizations and regulatory agencies prefer other agents over codeine or to avoid codeine completely during breastfeeding.^33,63-66 Other opioid alternatives have been studied less and may not be safer.^67,68 Although tramadol is unlikely to adversely affect nursing infants with usual maternal dosages, the FDA and the manufacturer also recommend against the use of tramadol during breastfeeding.⁶⁴

Conclusions

This article highlighted for OHCPs the common analgesics considered relatively safe to use in pregnant and breastfeeding patients and those that should be avoided. When considering prescribing during pregnancy, the OHCP must weigh the balance between benefit to the mother and risk to the fetus, and the appropriate conclusion should reflect current evidence. In some cases, certain analgesics should be avoided or altered; other times, stopping or avoiding the use of certain analgesics will be unnecessary. A trusting, open relationship between the OHCP and patient is vitally important to optimize the mother's treatment during her pregnancy. In particular, OHCPs should help pregnant or breastfeeding patients understand all of the risks and benefits before they take any prescribed medication. To accomplish this, OHCPs should draw on up-to-date sources for guidance and collaborative interprofessional relationships with physicians, obstetricians, and pharmacists.

About the Authors

Mark Donaldson, BSP, ACPR, PharmD
Associate Principal, Vizient Pharmacy Advisory Solutions, Irving, Texas; Clinical Professor, School of Pharmacy, University of Montana, Missoula, Montana; Clinical Assistant Professor, School of Dentistry, Oregon Health & Sciences University, Portland, Oregon; Adjunct Professor, Faculty of Dentistry, University of British Columbia, Vancouver, British Columbia; Fellow, American Society of Health-System Pharmacists; Fellow, American College of Healthcare Executives^®

Jason H. Goodchild, DMD
Vice President of Clinical Affairs, Premier Dental Products Co., Plymouth Meeting, Pennsylvania; Associate Clinical Professor, Department of Oral and Maxillofacial Surgery, Creighton University School of Dentistry, Omaha, Nebraska; Adjunct Assistant Professor, Division of Oral Diagnosis, Department of Diagnostic Sciences, Rutgers School of Dental Medicine, New Brunswick, New Jersey

Queries to the author regarding this course may be submitted to authorqueries@broadcastmed.com.

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