Anesthetic Management of the Pregnant Patient: Part 2

Transport Across the Placental Barrier

Placental exchange is a dynamic circulatory process throughout pregnancy. The determinants of drug transfer are influenced by the structural components that comprise the placental lining and the drug's individual pharmacologic profile (Table 1).² The outer uterine lining is composed of fatty, fibrous connective tissue called the perimetrium, which is made of an outer syncytiotrophoblast and an inner cytotrophoblast layer. The fundamental unit of the placental lining is made of fetal vascular projections called the chorionic villi. The outer syncytiotrophoblast layer of villi is in direct contact with maternal circulation and serves as the rate-limiting step for placental drug transfer.² In addition to the lipophilic outer membrane, the inner uterine endometrial lining is composed of tight junctions that provide a selective barrier, comparable with that of the blood-brain barrier. The endometrial lining undergoes constant remodeling throughout gestation, with dramatic changes in thickness, surface area, and concentration of transporter proteins. The original thickness of the placental lining decreases nearly 10 times by the third trimester.¹ With further progression of the pregnancy, the inner cytotrophoblast layer fades, which facilitates rapid drug diffusion to the fetus.² The aforementioned 2 layers control the exchange of gases, nutrients, hormones, and immune cells via various mechanisms of entry including passive diffusion, facilitated transport, active transport, and receptor-mediated endocytosis.

Table 1. Factors Affecting Drug Delivery Across the Placenta

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Most drugs cross the placenta by passive or facilitated diffusion. As an example, midazolam and acetaminophen commonly undergo passive diffusion, which occurs either transcellularly or through water channels within the placental membrane.² Drugs such as glucocorticoids and some antimicrobials (eg, cephalosporins) are structurally similar to endogenous compounds and rely on facilitated diffusion affected by the number of carrier proteins present and the extent of the concentration gradient. Another mode of drug transfer includes active transport. Unlike passive and facilitated transport, active transport relies on energy in the form of adenosine triphosphate to move drugs such as norepinephrine and dopamine against an unfavorable concentration gradient. Active transporters are found on both sides of the placental membrane and allow bidirectional drug delivery (ie, from mother to fetus and vice versa). Receptor-mediated endocytosis is much less understood. This mode of transport is believed to take a longer amount of time, as it requires membrane envelopment and release to the other side of the cell.

A multitude of other factors can influence the dynamics of drug transport across the placental barrier. For instance, infection to the placental lining may alter a drug's transfer via diffusion. Infection increases the membrane thickness and decreases the rate of diffusion. Meanwhile, maternal metabolic factors, such as hepatic function, can be highly variable so that there are decreased levels of circulating pseudocholinesterases and albumin during pregnancy. Changes to maternal serum pH can also alter the degree of drug ionization and thus affect drug transfer. In preeclampsia, the level of circulating albumin that usually comprises nearly 50% of plasma protein concentration can be reduced and allow for greater amounts of unbound drug to be transferred to the fetus.

Throughout gestation, fetal biotransformation of drugs is not as well developed in comparison with the mother. Pharmacokinetically, the maternal rate of drug clearance is generally faster than that of the fetus, yet it can vary dramatically depending on the stage of fetal development and various maternal conditions. Although cytochrome P450 isozymes are known to be present in the fetus, there has been minimal research into the extent and activity of these hepatic enzymes.³

In general, medications that cannot easily cross the blood-brain barrier have difficulty crossing the placental barrier. Thorough understanding of medications and the degree to which the drug may cross the placenta is critical to fetal safety, particularly in the first trimester. Most sedative and anesthetic medications can cross the placenta with relative ease, the noted exception being agents that are hydrophilic, highly ionized, or large in molecular size.² Uterine tight junctions, being similar to that of the blood-brain barrier, effectively prevent the crossing of large molecules, such as with heparin.⁴ Hydrophilic and ionized neuromuscular blocking agents generally neither cross the placenta nor the blood-brain barrier. Although the blood-brain and placental barriers have obviously different roles within the overall system of the human body, similarities exist at the structural level that may serve to further guide the understanding and management of the parturient undergoing sedation or general anesthesia.

Pregnancy Risk Classification

In 1979, the US Food and Drug Administration (FDA) instituted labeling requirements for prescription drugs and biological products that included an assigned pregnancy letter category based on fetal risk (Table 2). However, that labeling system was updated in 2015 to provide more meaningful information to health care providers and patients. The current FDA labeling system no longer includes the pregnancy letter category but rather narratives organized by sections and subsections (Table 3). This new labeling scheme is mandatory for all newly FDA-approved drugs and is being phased in for existing drugs. Although similar governmental oversight exists in other countries such as the United Kingdom and Australia, there is notable variability in the recommendations across countries. For instance, in Japan, propofol is contraindicated for use in the pregnant patient, whereas in the United States, it is widely accepted.⁵

Table 2. Outdated FDA Pregnancy Risk Letter System

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Table 3. Current FDA Pregnancy Risk Narrative System

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Interestingly, the animal studies used by the FDA to determine medication teratogenicity and assignment of pregnancy category featured drug dosages, concentrations, and dosing intervals considerably higher than normally administered to humans. Exposure to such high drug concentrations is usually not encountered in the clinical setting. Accordingly, any medication, given significant long-term exposure and dosage, can affect fetal development if conditions also coincide with a vulnerable developmental stage during gestation, as outlined in Part 1. Studies of pregnant patients undergoing nonobstetric surgery with general anesthesia using standard anesthetic drug doses have failed to demonstrate an increased risk of fetal malformations.⁶ As with the use of any anesthetic agent, the risks and benefits must be weighed in light of the patient's medical condition. The benefits of administering a medication to the pregnant patient must outweigh the potential adverse effects to the mother or the fetus as a general rule.

Benzodiazepines

Benzodiazepines historically were assigned an FDA Pregnancy Category D, as some early studies suggested use as a possible risk factor for the development of cleft palate and cardiac defects. More recent studies have failed to implicate therapeutic doses of benzodiazepines as being teratogenic.⁷ Traditionally, it has been recommended to avoid the use of benzodiazepines in the first trimester, although meta-analysis has not demonstrated a clear link to its supposed teratogenicity.⁸ In a UK study involving subjects from a primary care database spanning from 1990 to 2010, women who had taken a prescription benzodiazepine in their first trimester for the treatment of depression were compared with those who had not, and the authors found nearly the same reported rate of congenital defects, concluding that benzodiazepine exposure in the first trimester did not impose a risk.⁹

Although the degree varies, all benzodiazepines are lipid soluble and cross the placenta at a greater rate in the latter stages of pregnancy. Benzodiazepine use is not recommended in the third trimester near anticipated delivery, as it has shown associations with hypotonia or “floppy infant syndrome,” lethargy, hypothermia, respiratory depression, and feeding difficulties after delivery. Globally, there has been an increased use of prescription benzodiazepines for the treatment of anxiety, depression, and, in the later stages of pregnancy, insomnia. Up to 70% of women experience symptoms of depression at some stage of their pregnancy. Gastroesophageal reflux disease is a contributing factor for sleeping difficulties during the third trimester, as the supine position increases discomfort. Women also experience more anxiety in the third trimester and seek prescription benzodiazepines. There is no clear consensus delineating the trimesters in which benzodiazepine exposure could cause fetal harm, and practitioners must take into consideration the aforementioned risks when weighing benzodiazepine use.

Recent studies have explored the possible benefits of preoperative anxiolysis with a benzodiazepine in the highly anxious patient to decrease the stress response and the upregulation of catecholamines, which could compromise uteroplacental perfusion in high-risk pregnancy. Severe anxiety and stress during pregnancy can also increase the risk of spontaneous abortions and preterm delivery, although a direct causal relationship has not been established. As there is no mechanism for autoregulation of uteroplacental hemodynamics, a patient facing uncontrollable anxiety and resultant elevated hemodynamics beyond baseline may warrant the use of benzodiazepines. For dental providers, foreknowledge of a pregnant patient routinely taking prescription benzodiazepines is important in assessing benefit for providing preoperative anxiolysis versus fetal risk.

Opioids

Opioids were considered an FDA Pregnancy Category C medication, with the exception of oxycodone being Category B. For chronic and high-dose opioid users among pregnant women, opioids readily cross the placenta and can be problematic. When administered in appropriate therapeutic doses to treat acute and chronic pain, there have been no links to increased risks to the fetus. The possibility of opioid “imprinting” occurring to the fetus when fentanyl crosses into the fetal circulation and amniotic fluid has been suggested.¹⁰ In a study of pregnant women between 6 and 16 weeks of gestation scheduled to undergo fetal termination, fentanyl was found in fetal serum 10 to 15 minutes after a 1.5-μg/kg bolus.¹¹ Although fentanyl does readily cross the placenta, its ability to prime a newborn for opioid dependency in utero needs further research.

The National Birth Defects Prevention Study (NBDPS), one of the largest studies conducted on birth defects, looked at several different factors including early exposure to opioids during months 1 to 4 of pregnancy and found that among study participants who reported a birth defect, 2.6% had used an opioid. Maternal use of codeine, oxycodone, and hydrocodone was implicated among the opioids that may contribute to congenital heart defects, neural tube defects, and clubfoot. Although a growing body of research suggests a link between opioid use and birth defects, causal agents, trimester timing, and duration of exposure are all variables that require further evaluation if a true link is to be established. From the literature gathered, a one-time exposure to an opioid in the first trimester is unlikely to contribute to poor birth outcomes or congenital birth defects.

In a study documenting pregnant women from 1995 to 2009, 68% to 72% of pregnant women sought out prescription opioids for lower back and pelvic pain toward the late stages of their pregnancy.¹² As the percentage of pregnant women who use opioids at some point in their pregnancy increases, it is important for providers to be aware of a patient's experience with pain tolerance and related opioid-use history. The American College of Obstetricians and Gynecologists recommends the following for pregnant patients regarding opioid use and abuse prevention¹³:

• Before prescribing opioids, health care providers should ensure that opioids are appropriately indicated, discuss the risks and benefits of opioid use and review treatment goals, and take a thorough history of substance use and review the prescription drug-monitoring program data to determine whether patients have received prior opioid prescriptions.

• Breast-feeding should be encouraged in women who are stable on their opioid agonists, who are not using illicit drugs, and who have no other contraindications, such as human immunodeficiency virus (HIV) infection. Women should be counseled about the need to suspend breast-feeding in the event of a relapse.

• Access to adequate postpartum psychosocial support services, including substance use disorder treatment and relapse prevention programs, should be made available.

Nonsteroidal Anti-inflammatory Drugs

For postoperative pain control, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) can influence various aspects of fertility, pregnancy, and fetal development. Chronic use of NSAIDs for pain management in patients suffering from infertility and for those late in the third trimester of pregnancy are at highest risk for adverse maternal-fetal effects.¹⁴ NSAIDs are inhibitors of PGE2, a prostaglandin involved in promoting female fertility that is present in the early stages of implantation and has notable levels of production throughout the female reproductive tract.¹⁵ NSAIDs inhibit PGE2 production, and in dental patients of childbearing age or planning pregnancy with a known history of miscarriages or infertility, the use of alternative pain control options (eg, acetaminophen) is advisable for managing dental-related pain.¹⁶

Prenatal NSAID exposure has been reported to have adverse outcomes in the first trimester and then again after 30 weeks. If NSAIDs are absolutely necessary, the lowest effective dose at the shortest duration possible should be used. Among patients late into the second trimester administered NSAIDs for up to 7 days, fetotoxic effects were observed such as significant ductus arteriosus constriction, which may severely compromise fetal circulation. In a study of full-term parturient rats, the administration of ibuprofen, naproxen, and diclofenac delivered in amounts equivalent to those used in humans led to a dose-dependent constriction of the fetal ductus arteriosus.¹⁷ Severe ductus arteriosus constriction can induce heightened pressures in the right ventricle and cause irreversible pulmonary vascular changes and portopulmonary hypertension.¹⁷ In oligohydramnios, in which too little amniotic fluid is present, NSAIDs have the potential to induce fetal renal damage. NSAIDs should be avoided in the third trimester, as the maternal body has a higher level of responsiveness to prostaglandin inhibitors from 31 weeks to term. If NSAIDs are the only mode of pain control available, it is recommended for use at the lowest effective dose possible as a last resort.¹⁸ Naproxen use was found to be associated with orofacial congenital anomalies.¹⁹ As an alternative to NSAIDs, acetaminophen may be used at all trimesters, as no direct birth defects have been reported.

Local Anesthetics

The amide local anesthetic lidocaine combined with epinephrine (ie, 2% lidocaine with 1:100 000 epinephrine) likely represents the most commonly used agents during dental treatment in the United States. Pregnancy itself is a factor that heightens the risk of systemic local anesthetic toxicity in addition to other factors such as age and body weight.²⁰ Lidocaine was historically designated as a FDA Category B drug, whereas epinephrine was Category C. Deleterious and harmful effects have been observed with epinephrine administered during organogenesis; however, the animal studies in question used doses substantially higher (eg, ≥7 times) than maximum recommended intramuscular and subcutaneous doses for humans. Epinephrine at that concentration would not occur during common dental procedures.

A more likely local anesthetic consideration that may risk systemic toxicity in the parturient is accidental intravascular injection. When intravascular injection of local anesthetic with epinephrine occurs, the resultant symptoms typically include transient hypertension, tachycardia, dizziness, and, in extreme cases, cardiac dysrhythmias. Uterine muscles contain both α- and β-adrenergic receptors, which balance uterine contraction and relaxation during pregnancy. Epinephrine actually causes inhibition of contractions during the later stages of pregnancy. However, higher systemic concentrations of epinephrine that might accompany an overdose or intravascular injection tend to favor α1 adrenoreceptor activity. Although much more complex and not well studied in humans, a large increase in vascular tone may produce a decrease in uteroplacental blood flow and disrupt fetal circulation, possibly creating an anoxic environment.²¹ Performing syringe aspiration and employing the smallest effective doses needed to achieve profound local anesthesia are critical safety measures when using local anesthetics.

Although no human studies exist on the toxicity of bupivacaine in the fetus or pregnant patients, a small animal study on the effects of bupivacaine demonstrated that lower doses produced systemic toxicity effects (ie, convulsions).²² The relative decrease in albumin that occurs with pregnancy presumably resulted in an increase in free or unbound bupivacaine that likely contributed to the study's outcome. That same animal study also found that the rate of cardiovascular collapse was similar for nonpregnant (control) and pregnant (experimental) groups.

Muscle Relaxants and Reversal Agents

Inhalation Anesthetics

Volatile anesthetics such as sevoflurane are not considered teratogenic agents and were designated FDA Pregnancy Category B.¹⁹ A major consideration when using volatile anesthetics is uterine smooth muscle relaxation and maternal hypotension attributed to a dose-dependent decrease in systemic vascular resistance and cardiac output. Risks to fetal perfusion directly correlate with anesthetic gas concentration. As uterine perfusion is directly tied to maternal blood pressure, sympathomimetics such as ephedrine may be required to maintain adequate blood pressure (ie, within 20% of baseline) while maintaining a balanced level of anesthesia. Although pregnancy is associated with decreased minimum alveolar concentration requirements, excessive stimulation coupled with inadequate anesthetic depth could induce uterine vasoconstriction due to stress response.

Intravenous Induction and/or Maintenance Agents

Antiemetic Agents