The purpose of this article is to clarify clinically impactful features of the perioperative and postoperative pharmacologic management of pregnant and lactating patients in the maxillofacial or dental setting. Before prescribing any drug to a nursing mother or pregnant patient, the maxillofacial surgeon and other dental and medical providers should consider the available evidence, benefits, and risk for that particular drug. There are many complex factors to consider when prescribing in order to maintain the safety of the pregnant individual, fetus, and infant. This article aims to provide concise, memorable, and actionable information to use in your clinical practice.
The new FDA labeling system for the safety of medications in pregnant and lactating patients provides a nuanced array of data and risks
Available data related to the safe use of medications in pregnant and lactating patients are complex and incomplete.
Before prescribing any drug to a nursing mother or pregnant patient, the maxillofacial surgeon and other dental and medical providers should consider the available evidence, benefits, and risk for that particular drug.
In the United States, there are more than 6 million pregnancies every year. It is estimated that a pregnant woman receives 3 to 5 prescription drugs during pregnancy. The purpose of this article is to clarify clinically impactful features of the perioperative and postoperative pharmacologic management of pregnant and lactating patients in the maxillofacial or dental setting.
We hope to provide you with concise, memorable, and actionable information to use in your clinical practice. We will also discuss the relevant physiologic changes of the gravid and postpartum patient, and the recent changes to the federal safety labeling guidelines. We will focus on the pharmacologic strategies that will minimize the risk to the mother, fetus, and child. This is not intended to be a comprehensive resource; we will direct you to helpful and comprehensive resources for further reading and reference.
FDA categories: old and new
Patients, along with their medical and dental providers, rely on evidence-based safeguards and guidelines to make informed decisions about which medication choices are the safest ( Table 1 ). It is critical for the safety and wellbeing of the mother, fetus, and child to have a functional classification or labeling system that can guide pharmacologic management. In 1979, the US Food and Drug Administration (FDA) published Labeling for Prescription Drugs Used in Man Regulations which instituted a letter labeling system that categorized medications in an attempt to emphasize the risk a medication may have to a fetus (categories A, B, C, D, and X).
|FDA Pregnancy Risk Categories|
|Category A||Adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of a risk in later trimesters)|
|Category B||Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women|
|Category C||Animal reproduction studies have shown an adverse effect on the fetus, if there are no adequate and well-controlled studies in humans, and if the benefits from the use of the drug in pregnant women may be acceptable despite its potential risks|
|Category D||There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks|
|Category X||Studies in animals or humans have demonstrated fetal abnormalities or if there is positive evidence of fetal risk based on adverse reaction reports from investigational or marketing experience, or both, and the risk of the use of the drug in a pregnant woman clearly outweighs any possible benefit|
The letter system was established to create guidance for safely prescribing medication for pregnant patient. However, over time the letter categorization system presented significant shortcomings. The system can oversimplify decision-making for prescription medications for pregnant patients. To illustrate this issue, consider that 60% of all medications fall into the category C. Category C medications have data supporting adverse effects in animals, yet they also include medications with no data from animal studies. This results in drugs with evidence of potential risk and those without evidence of risk being grouped together in the same category. In addition, the reductionist A-B-C-D-X labels may be misinterpreted or misused and often the labeling lacked clarity of specific risks. Furthermore, the categories did not include meaningful evidence-based clinical information as it relates to exposure during pregnancy and lactation. The consequences to the mother and fetus of discontinuing a drug therapy needed during pregnancy were also not included. There is a potential bias toward choosing A and B medications, pressuring providers toward medicolegal defensive medicine and unnecessary obstetrician consultations causing delays in treatment. Importantly, the letter categories focus on the quality and quantity of data available, and not the severity or incidence of risk. ,
To respond to the need for updated risk categories, the FDA published a rule entitled Content and format of labeling for human prescription drug and biological products; requirements for pregnancy and lactation labeling; Final Rule. These new FDA labeling guidelines for prescribing to pregnant and lactating patients went into effect on June 30, 2015. Pregnancy Lactation Labeling Rule (PLLR) replaced the previous letter system eliminating the A, B, C, D, and X risk categories. Pertinent details of the PLLR will be discussed next.
Labels now have a section with information on the available pregnancy exposure registry, risk summary, clinical considerations, and data. The pregnancy exposure registry is a voluntary study where data are collected from pregnant patients who are taking certain medications or vaccines during pregnancy. These data may inform future guidelines on the use of the medication during pregnancy and lactation. Within the portion of the clinical consideration, subsections include disease-associated maternal and fetal risk, relevant dose adjustments during pregnancy and the postpartum period, maternal and fetal adverse reactions, and labor or delivery information (when this information is available).
The previous “Nursing mother” section will become the “Lactation” section including a “Risk summary,” “Clinical considerations,” and “Data.” The lactation label will include information such as the presence of the drug in breast milk, effects on milk production, any potential risk for the child, and a statement on the risk-versus-benefit analysis for its use. There will also be a new section addressing females’ and males’ reproductive prudential risk including pregnancy testing, contraception, and infertility.
The PLLR hopes to deliver concise, standardized summaries of the available evidence. This will provide the provider with up-to-date data. Though this system is more complex and potentially more time-consuming, it does provide an evidence-based tool for clinical decision-making.
New pregnancy-risk categories
These include subset categories.
Pregnancy (including labor and delivery)
Pregnancy exposure registry
Females and Males of Reproductive Potential
The FDA online Drug Safety-related Labeling Changes can be accessed ( www.accessdata.fda.gov/scripts/cder/safetylabelingchanges/ )
Pharmacology in lactating patients
It is the position of the American Academy of Pediatrics (AAP) that “breastfeeding and human milk is the normative standard for infant nutrition ( Table 2 ).” In addition, the World Health Organization subscribes to the same ideal. There are well-documented medical and neurodevelopmental advantages to breastfeeding infants for the first 6 months of life, followed by continued breastfeeding as foods are introduced. They go on to support continued breastfeeding for 1 year or longer. During that period, a lactating individual may require medication. Therefore, as a clinician, it is critical to understand the implications that medications may have on the mother and child. Ideally, a clinician’s therapeutic choices should limit the negative effects that medications may have on the mother, child, and milk production. Generally, there are a limited number of medications that are contraindicated, and a suitable replacement can typically be found. Adherence to medications may also improve if the mother is fully informed of the risks, benefits, and alternatives for her and her child when she takes them. This portion of the text will review common medications found in the dental setting and also how these medications may impact the individual who is lactating and the infant receiving the milk.
|Table||Medication||Use During Pregnancy||Use During Breastfeeding||Previous Letter Classification||Hale Lactation Risk Category||Comments|
|Local Anesthetics||Lidocaine||Yes||Yes||B||L2||No evidence of harm|
|Mepivacaine||Yes||Yes||C||L3||Risk of methemoglobinemia|
|Prilocaine||Yes||Yes||B||Unknown||Risk of methemoglobinemia|
|Bupivacaine||No, may cause hypotension||Yes||C||L2||—|
|Benzocaine||(Avoid)||Avoid||C||Unknown||Risk of methemoglobinemia|
|Epinephrine||C||L1||Reports of fetal malformations with intravenous doses no significant documented risk when used in association with a local anesthetic|
|Amoxicillin and clavulanate potassium (Augmentin)||Yes||Yes||B||L1||—|
|Clindamycin||Yes||Yes||B||L2||Use in the first trimester only if clearly needed|
|Azithromycin||(Yes)||Yes, caution (risk-benefit analysis)||B||L2||Avoid in the first trimester|
|Erythromycin||Yes||Yes, caution (risk-benefit analysis)||B||L2
L3 early postnatal (pylorus- stenosis!)
|Avoid in the first trimester|
|Metronidazole (Flagyl)||(Yes)||Yes, caution (risk-benefit analysis)||B||L2||Fetal carcinogen in nonhuman mammals; no proven risk in humans; contraindicated for use in the first trimester as per manufacturer|
|Ibuprofen||Avoid in the third trimester; may close PDA||Yes||B||L1||Associated with ductus arteriosus constriction when used during the first trimester|
|Aspirin||No, associated with IUGR||Yes||C/D||L3||—|
|COX-2 inhibitor||Avoid in the third trimester; may close PDA||Yes||C||L2||—|
|Acetaminophen||Yes||Yes||B||L1||Associated with pulmonary hypertension when used in the third trimester|
|Opioids (oxycodone, hydrocodone, codeine)||Yes||Yes, caution (risk-benefit analysis), monitor baby||B/C||L3||Frequent use may be associated with a fetal abnormality. First trimester use: low risk of neural tube defects. Third trimester use: risk of fetal dependence and newborn respiratory depression|
|Fentanyl||Yes||Yes||B||L2||Breastfeeding can be resumed when the mother recovers from anesthesia.|
|Diazepam (Valium)||No||No||D||L3; L4 if used chronically||Associated with fetal craniofacial and thoracic abnormalities in the first/second trimester|
|Triazolam||No||No||X||L3||No known association with fetal abnormalities|
|Midazolam||No, risk for fetal craniofacial anomalies||(No)||D||L3||Use near birth associated with adverse neonatal neurobehavior|
|Barbiturates||No, risk for fetal craniofacial anomalies||D||L3||—-|
|Nitrous Oxide||Controversial, avoid in the first trimester||Yes, after recovery from anesthesia||Not assigned||L3||It is generally considered safe in pregnant and nursing patients as long as there is <50% of N 2 O with supplemental oxygen coadministration. Theoretically, these patients may benefit from prophylactic folic acid, methionine, and vitamin B12. However, it should be avoided in the first trimester.|
|Steroids||Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects|
|Dexamethasone||Avoid in the first trimester||Avoid||NA||L3||Low risk of oral clefts during the first trimester|
|Triamcinolone||Avoid in the first trimester||Yes, lack of evidence, alternative preferred||C||L3||Pregnancy: First-trimester risk of oral clefts; continued use may restrict fetal growth;
Lactation: As a nasal spray or local injections, such as for tendinitis, it would not be expected to cause any adverse effects.
|Prednisone||Avoid in the first trimester||Yes||NA||L2||Low risk of oral clefts during the first trimester
No adverse effect has been reported in breastfed infants with maternal use of any corticosteroid during breastfeeding. With high maternal doses, the use of prednisolone instead of prednisone and avoiding breastfeeding for 4 h after a dose.
|Muscle relaxant||Cyclobenzaprine||Yes||Yes, caution (risk-benefit analysis), monitor baby||B||L3||May continue breastfeeding. Monitor the infant for drowsiness, adequate weight gain, and developmental milestones, particularly in neonates and preterm infants.|