Because pregnant women become sick, and women with chronic medical problems become pregnant, care provided to pregnant women involves the administration of medications. In a prospective, longitudinal study of 9139 nulliparous pregnant women recruited in 2010 to 2013 at eight geographically diverse centers in the United States, 73.4% reported the use of at least one medication during pregnancy, excluding vitamins, supplements, and vaccines; 55.1% took medication in the first trimester. These results are very similar to another cross-sectional, multinational, web-based study which surveyed 9459 pregnant women in 2011 to 2012 and found 81.2% of respondents reported use of at least one prescribed or over-the-counter medication during pregnancy. The percentage was even higher for participants in Canada and the United States; 84.8% reported any medication use during pregnancy, with 75.6% taking drugs for a short-term illness and 64.2% reporting use of over-the-counter medications.
Once pregnant women are admitted to the hospital for birth, the number of drugs they are prescribed explodes. Parturients admitted for uncomplicated, term vaginal deliveries typically are prescribed multiple medications, including vitamins, oxytocics and other uterotonics, prophylactic and therapeutic antibiotics, analgesics including acetaminophen (paracetamol) prior to birth, opioids during labor, nonsteroidal antiinflammatory drugs (NSAIDs) postpartum, local anesthetics, antiemetics, antacids, histamine 2 -receptor antagonists, anticoagulants, sedatives, antihistamines, stool softeners, antiflatulents, bowel stimulants, and topical perineal anesthetics.
Drugs may be prescribed to the pregnant patient to treat a maternal condition with incidental fetal transfer or to treat a fetal problem (e.g., supraventricular tachycardia) with maternal exposure. Historically, most publications addressing drug use during pregnancy have focused on fetal safety. While remaining cognizant of fetal safety, it is also important to consider maternal efficacy and safety. Because pregnant women are physiologically and pharmacologically different than nonpregnant women, it cannot be assumed that dosing strategies developed for nonpregnant, healthy adults will achieve comparable results when used during pregnancy.
The anesthesia provider administers numerous medications during the peripartum period and at other times during gestation, and postpartum if surgery or intensive care is required. Because optimal pain management requires an understanding of the pharmacologic environment, which may be influenced by pregnancy as well as drugs prescribed by other healthcare providers, it is important that all individuals who care for obstetric patients appreciate the profound effects of pregnancy on drug disposition and efficacy.
This chapter focuses on the changes in pharmacokinetics (PK) during pregnancy that affect drug disposition, using familiar medications for illustration. The unique pharmacodynamic (PD) change in pain thresholds that occurs during pregnancy will be discussed. Basic principles of teratology and fetal drug exposure, changes in the Pregnancy and Lactation Labeling Rule of the US Food and Drug Administration (FDA), and drug transfer during lactation will also be discussed.
PHARMACOKINETIC CHANGES DURINGPREGNANCY
The changes during pregnancy that affect drug absorption, distribution, metabolism, and elimination can be divided into two broad categories: (1) normal obstetric physiology and (2) changes in hepatic metabolism. Although studies investigating the profound physiologic changes that occur during pregnancy were initially published in the earlier half of the 20th century, the first PK study describing the failure of a standard drug dose to achieve therapeutic concentrations during pregnancy was not published until 1977. Since then, especially since the turn of the millennium with expansion of FDA and US National Institutes of Health support, the understanding of pregnancy as a special pharmacologic condition has advanced significantly. Although these pharmacologic changes are often described in the context of pregnant versus nonpregnant states, the pregnant state is not uniform; individual changes in maternal physiology and hepatic metabolism evolve with different trajectories across gestational ages. As a result, pregnant women in the third trimester handle drugs differently than in the second or first trimesters.
Hormonal Changes During Pregnancy
Reproductive hormones play important roles from ovulation and implantation, through gestation, and ultimately lactation. Although our understanding is evolving and incomplete, the same hormones that modulate obstetric physiology also play critical roles in changing the PK environment during pregnancy. After ovulation and implantation, the corpus luteum continues to be the primary source of increased estrogen and progesterone production. Circulating human chorionic gonadotropin (hCG) from the nascent trophoblast quickly replaces pituitary gonadotropins in support of ovarian steroidogenesis. Between gestation weeks 7 and 10, the site of hormonal production shifts from the corpus luteum to the placental syncytiotrophoblast (the luteal-placental shift). Plasma progesterone concentration increases from 1 to 2 ng/mL just before ovulation to a midluteal concentration of 10 to 35 ng/mL. After implantation, the corpus luteum maintains production of progesterone until the placenta ramps up its synthetic machine and concentrations progressively rise to a peak of 100 to 200 ng/mL at term, a 10- to 20-fold increase compared with periovulation.
Concentrations of the three maternal estrogens, estradiol (E2), estrone (E1), and estriol (E3), also progressively and dramatically increase during pregnancy. Estradiol, the most potent of the three, increases approximately 500-fold, from a mean mid-follicular concentration of 50 pg/mL to approximately 25,000 pg/mL at term. During the same time period, estriol increases 1000-fold.
Plasma cortisol concentration also progressively increases during pregnancy from a prepregnancy low of 0 to 25 µg/dL, to 7 to 19 µg/dL in the first trimester, 10 to 42 µg/dL in the second trimester, and 12 to 50 µg/dL in the third trimester. During pregnancy, the usual negative feedback relationship between corticotrophin-releasing hormone (CRH) and cortisol is attenuated. Low cortisol concentrations typically trigger increases in hypothalamic CRH, which causes the anterior pituitary gland to secrete adrenocorticotrophic hormone (ACTH), which then stimulates the adrenal cortex to produce cortisol; as cortisol concentration rises, CRH and ACTH concentrations decrease. Paradoxically, during pregnancy, concentrations of CRH, ACTH, and cortisol are elevated above nonpregnant baseline values; the latter two increase approximately fourfold. The source of the increased stimulation is the pregnancy itself; CRH is produced by the placental syncytiotrophoblast, fetal membranes, and the decidua. Among multiple modulators, glucocorticoids increase placental CRH with a positive feedback relationship. Because the syncytiotrophoblast directly faces maternal vessels, placental CRH secreted into maternal vessels is responsible for most of the circulating maternal CRH. Maternal CRH progressively increases during gestation, until about 35 weeks, when it rapidly rises until labor onset, reaching concentrations 1000 to 10,000 times greater than nonpregnancy levels. Desensitization of the pituitary gland to these extremely high CRH levels prevents pathologic elevations of ACTH and cortisol. Placental CRH is thought to play a crucial role in regulation of both fetal maturation and the timing of delivery. After delivery of the placenta, maternal hypothalamic CRH secretion, which had been suppressed by circulating cortisol concentrations, returns to normal function within 12 weeks.
Impact of Obstetric Physiology on Pharmacokinetics
Increases in Blood Volume and Total Body Water
Blood volume increases substantially during pregnancy, starting from 6 to 8 weeks’ gestation (see Chapter 2 ). Extracellular fluid and total body water also increase proportionally to patient weight. In women in the third trimester of singleton pregnancy weighing 70 to 80 kg, the extracellular fluid space is approximately 0.255 L/kg compared with approximately 0.156 L/kg in nonpregnant women of similar weight. The expansion of plasma volume and total body water increases the volume of distribution (Vd) of hydrophilic medications and reduces the concentration-to-dose ratio (C/D) of their initial doses . Vd is the theoretical volume that would be necessary to contain the administered dose at the measured plasma concentration:
Vd = dose/concentration.
Relevant drug examples.
Enoxaparin has a Vd that is essentially plasma volume. The maximum antifactor Xa activity after a 40-mg subcutaneous (SC) dose of enoxaparin is significantly lower in the first and third trimesters (mean 0.46 and 0.40 IU/mL, respectively) compared with 6 to 8 weeks postpartum (0.57 IU/mL).
Ampicillin is hydrophilic and only 15% to 25% protein-bound; it readily distributes to approximately total body water. The maximum plasma ampicillin concentration (C max ) following a 500-mg oral dose was 41% lower during pregnancy compared with values attained when the same dose was given to the same women postpartum (mean 2.2 versus 3.7 µg/mL).
Furosemide (frusemide) PK was studied in hypertensive women at term following an oral dose of 40 mg. Its apparent volume of distribution (Vd/F) was almost six times greater and C max was 73% lower compared with values obtained from historic, nonpregnant subjects. Given that furosemide is approximately 96% protein-bound to albumin in nonpregnant individuals, it was concluded that these findings were the result of both an increased free drug fraction due to lower albumin concentration and the marked increase of approximately 8 L in total body water that occurs in term pregnancy.
Because body fat has an extensive capacity to absorb lipophilic drugs, the Vd for these drugs greatly exceeds the actual volume of body fat. Although pregnant women gain body fat, the impact on Vd of lipophilic medications is insignificant because this change only minimally increases the already large Vd.
Decreased Protein Binding
Plasma protein concentrations decrease during pregnancy. Albumin , the most abundant of the plasma proteins, binds acidic and neutral compounds. Its concentration decreases from 4.2 g/dL in nonpregnancy to 3.6 g/dL by the midtrimester of pregnancy. Another plasma protein, alpha-1 acid glycoprotein (AGP) , binds basic and some neutral drugs. Although earlier studies reported that AGP concentrations do not change during pregnancy, more recent evidence has demonstrated a concentration reduction of almost 50% during the third trimester of pregnancy. Lower plasma protein concentrations result in a greater free fraction of protein-bound drugs, resulting in greater drug effect, movement into other spaces, and availability for metabolism and/or clearance. Monitoring of free drug is often recommended during pregnancy for highly protein-bound medications that have a narrow therapeutic range (little difference between the minimal therapeutic and toxic concentrations) such as digoxin , phenytoin , and free T4 (thyroxine) .
Relevant drug examples.
Bupivacaine was shown to have a free fraction that was 52% higher in term laboring women than in nonpregnant women (median 8.2% versus 5.4%).
Lidocaine (lignocaine) was shown to have a free fraction that was higher in term pregnant women than in nonpregnant women (mean 47.7% versus 32.0%).
Midazolam was shown to have a free fraction that was 21% greater after oral administration at 28 to 32 weeks’ gestation than after administration to the same women at 6 to 10 weeks postpartum (mean 0.71% versus 0.61%).
Digoxin was shown to have a free fraction that was 5.8% greater after administration at 28 to 32 weeks’ gestation than after administration to the same women at 6 to 10 weeks postpartum (mean 67% versus 63%).
Increase in Cardiac Output
Cardiac output increases, with increases in both stroke volume and heart rate, and systemic vascular resistance decreases during pregnancy (see Chapter 2 ). These changes directly affect other processes that impact PK during pregnancy. Of primary importance, glomerular filtration rate (GFR) increases in parallel with cardiac output, which contributes to the enhanced renal clearance of some drugs.
Changes in Regional Blood Flow
The increased cardiac output during pregnancy is differentially distributed within the body. The placenta functions as a low-pressure, arteriovenous shunt and consumes 20% to 25% of cardiac output at term. Renal blood flow increases to 30% to 40% above the prepregnancy baseline during the first and second trimesters, and then decreases to 10% above baseline in the third trimester. Skin blood flow increases to dissipate heat generated by fetal metabolism ; blood flow to the developing breasts also increases. Arterial blood flow to the liver is unchanged but represents a lower percentage of cardiac output; however, beginning at 28 weeks’ gestation, portal venous blood flow increases from 150% to 160% of nonpregnant levels. The enhanced portal blood flow increases first-pass hepatic clearance of drugs with a high extraction ratio. Because of these hemodynamic changes, less cardiac output is available for skeletal muscle and other vascular beds, resulting in unpredictable and/or delayed absorption of medications administered intramuscularly.
Renal Clearance
Renal elimination comprises three components: (1) renal perfusion, (2) glomerular filtration, and (3) reabsorption and secretion within the nephric tubules. All three processes change with pregnancy (see Chapter 2 ). Stimulated by relaxin and nitric oxide, the increase in renal perfusion is detectable as early as 6 weeks’ gestation, and by 16 weeks’ gestation it is 75% greater than the prepregnancy baseline. After this peak, it decreases during the late second to the early third trimester from 10% to 40% above baseline. Although inulin clearance is the most accurate reflection of GFR, because of convenience, creatinine clearance (CrCl) , which includes a component of tubular secretion, has been used more commonly as an estimate of GFR during pregnancy. CrCl begins to increase by the late luteal phase (20% greater than week 1 of the menstrual cycle), and is 45% above the follicular phase baseline by 9 weeks’ gestation. It peaks at approximately 50% above baseline in the late second to early third trimester before slightly decreasing closer to term. CrCl begins to decrease during the second postpartum week, with a return to normal values by 6 to 8 weeks after delivery.
Renal Transporters and Renal Secretion andReabsorption
Glomerular filtration of many drugs is supplemented by the net effects of tubular reabsorption and secretion. Straddling membrane surfaces, drug transporters control movement of drugs and other compounds into and out of cells. In the kidney, specific transporters are found on tubular cell membranes facing either the afferent blood vessels or urine where they facilitate movement of compounds either from the blood across the tubular cell and into urine (secretion) or from the urine back into the blood (reabsorption) ( Fig. 16.1A ). Pregnancy increases the activity of some of these transporters, which in general, increases renal clearance of their substrates.
Amoxicillin Excretion and Changes in Selected Renal Transporters in the Nonpregnant (A) and Pregnant (B) Patient. Transcription of OAT1 and OAT3, which move drug from afferent renal vessels into tubular cells, increases during pregnancy, and PEPT1, which removes drug from the urine is downregulated. This results in a net increase in renal secretion of amoxicillin during pregnancy compared to postpartum. OAT1 , Organic anion transporter 1; OAT3 , organic anion transporter 3; PEPT1 , peptide transporter 1; P-gp , P-glycoprotein. Illustration by Naveen Nathan, MD, NorthShore University HealthSystem, University of Chicago Pritzker School of Medicine, Evanston, IL.
Relevant drug examples.
Amoxicillin is primarily excreted unchanged through a combination of renal filtration plus the net effect of two opposing movements within the tubules: secretion into urine via the organic anion transporter 1 (OAT1) and OAT3 and reabsorption out of the urine by the peptide transporter 1 (PEPT1) . Because of changes in both GFR and secretion, renal clearance of amoxicillin is increased by 50% in the second and third trimesters compared with the nonpregnant baseline. Net amoxicillin secretion increases during pregnancy because of upregulation of OAT1 and OAT3 (secretion) and progesterone-induced downregulation of PEPT1 (reabsorption) ( Fig. 16.1B ). Because of lower amoxicillin C max secondary to the increase in its Vd, coupled with potential subtherapeutic concentrations at the end of the dosing interval from increased renal clearance, pregnant women may require larger and more frequent ampicillin dosing.
Metformin is eliminated unchanged by the kidneys with the assistance of another transporter, organic cation transporter 2 (OCT2) . Renal clearance of metformin is increased by 49% in the second trimester and by 29% in the third trimester compared with postpartum. Renal secretion of metformin is also increased by 45% and 38%, in mid- and late-pregnancy, respectively, compared with postpartum.
Digoxin is a well-known probe substrate (probe drugs have a metabolic pathway that is uniquely catalyzed by one enzyme ) for a third transporter, P-glycoprotein (P-gp) , whose activity is also enhanced during pregnancy. With its long list of substrates, the efflux transporter, P-gp, plays a protective role, controlling drug movement out of cells in many tissues, including the intestines, liver, kidney, blood-brain barrier, and, importantly, the placenta. Located on the apical, urine-facing surface of renal tubular cells, P-gp moves digoxin into the urine against its concentration gradient. During the third trimester, the renal clearance of unbound digoxin was 52% higher and unbound digoxin renal secretion was 107% higher compared with postpartum. The authors of this PK study hypothesized that this increase in digoxin secretion resulted from upregulation of either one or both transporters, P-gp and/or organic anion transporter polypeptide , another digoxin transporter located on the basolateral surface of the tubules, which moves digoxin from blood into the renal cell.
Magnesium and lithium are cations whose renal clearances are enhanced during pregnancy. In a PK study of magnesium therapy, magnesium clearance was lower (3.98 versus 5.88 L/h) and the steady-state concentration of magnesium was higher (7.2 versus 5.1 mg/dL) in women with preeclampsia than in women without preeclampsia who were receiving magnesium for fetal neuroprotection. Women with greater maternal weight had lower serum magnesium concentrations immediately after the magnesium loading dose.
Lithium clearance closely parallels CrCl. In pregnant women receiving lithium, its concentration rapidly falls during the first trimester, remains relatively stable during the second trimester—albeit significantly lower than nonpregnant values—and then either remains low or variably normalizes during the third trimester. Because of its narrow therapeutic window, frequent monitoring of lithium concentrations with appropriate dose adjustment is recommended, especially during the first and third trimesters. Split dosing regimens (twice or three times daily) provide more consistent concentrations throughout the dosing interval. Lithium concentrations can vary in obstetric conditions that change either maternal hydration or renal clearance (e.g., nausea and vomiting, gastroenteritis, preeclampsia). Although multiple authors and societies have recommended decreasing or stopping lithium administration during labor, some investigators have shown that lithium concentrations during labor do not significantly change, and that neonatal complications are not associated with lithium concentrations at birth.
Levetiracetam , an anticonvulsant, is not appreciably protein-bound and is eliminated primarily by renal excretion with approximately 30% of the dose metabolized by nonhepatic enzymatic hydrolysis. Large studies have shown that levetiracetam clearance is either the same in all three trimesters at approximately 43% above baseline, or that it peaks in the second trimester and decreases slightly during the third trimester, at 1.22 and 1.15 times the baseline clearance, respectively. In 2023, physiologically based PK modeling predicted that the steady-state area under the concentration-time curve (AUC) for levetiracetam decreased to 83%, 62%, and 67% of baseline values in the first, second, and third trimesters, respectively, and the recommended dose of levetiracetam should be 1.2, 1.6, and 1.5 times the baseline dose to maintain therapeutic concentrations in the first, second, and third trimesters, respectively. Some authors have recommended therapeutic dose monitoring starting in the first trimester with appropriate dose escalation to prevent seizures from subtherapeutic concentrations. Although C/D ratios do not return to prepregnancy baselines until 4 weeks postpartum, they begin increasing within 3 to 5 days after delivery.
Hepatic Metabolism
Metabolic enzymes evolved to control concentrations of endogenous compounds and to detoxify dangerous environmental chemicals (xenobiotics). Hepatic metabolism is subdivided primarily into the Phase I and Phase II enzymes . Phase I enzymes catalyze chemical modifications of compounds, for example, oxidation or hydrolysis. The most important Phase I enzymes are the 12 cytochrome P450 (CYP) families, of which families 1, 2, and 3 are involved in drug metabolism. Phase II enzymes facilitate simple biotransformation by adding readily available compounds (glucuronic acid, glutathione, amino acids, methyl, acetyl, and sulfate groups) to make molecules more hydrophilic and able to be renally excreted. Both Phase I and Phase II enzymes are affected by pregnancy, which can result in changes in drug concentrations, and consequently efficacy and/or toxicity ( Table 16.1 ).
Table 16.1
Changes in Drug-Metabolizing Enzymes During Pregnancy
| Enzyme | Increases | Decreases | No Known Change |
|---|---|---|---|
| CYP1A2 | ✓ | ||
| CYP2A6 | ✓ | ||
| CYP2B6 | ✓? | ||
| CYP2C9 | ✓ | ||
| CYP2C19 | ✓ | ||
| CYP2D6 | ✓ | ||
| CYP2E1 | ✓ | ||
| CYP3A4/5 | ✓ | ||
| UGT1A1 | ✓ | ||
| UGT1A4 | ✓ | ||
| UGT1A9 | ✓? | ||
| UGT2B7 | ✓? | ||
| NAT-2 | ✓? | ||
| SULT | ✓? |
CYP , Cytochrome P450; NAT-2 : N -acetyltransferase-2; SULT : sulfotransferases; UGT , uridine 5′-diphosphate glucuronosyltransferase.
? Data are inconclusive or inconsistent.
Phase I Drug-Metabolizing Enzymes and Pregnancy
CYP3A4/5.
The CYP3A subfamily (CYP3A4, CYP3A5, and fetal/neonatal CYP3A7) is the most abundant of the cytochrome enzymes in humans and contributes to the metabolism of many endogenous compounds and 30% to 50% of drugs used today. Induction of CYP3A4 by enzyme-inducing drugs (EIDs) , such as rifampin and carbamazepine , occurs through stimulation of the xenobiotic sensing system, a mechanism that ramps up the metabolism when exposed to potentially toxic environmental chemicals. EIDs bind to the nuclear receptors pregnane X receptor (PXR) and/or constitutive androstane receptor (CAR), both of which evolved from a primitive estrogen receptor. This complex then binds to the hormone-responsive element within DNA and upregulates transcription of the target gene(s) and subsequent production of their proteins, including CYP3A4/5. Although numerous compounds can stimulate PXR/CAR, studies using cultured hepatocytes have suggested that the primary stimulus for induction of CYP3A4 during pregnancy is increased cortisol.
For many, drugs metabolized by CYP3A, CYP3A4 and CYP3A5 work together, with increased clearance in individuals who have both CYP3A4 and a functional CYP3A5 phenotype. However, there are marked ethnic differences in the distribution of the major inactive CYP3A5*3 allele, which is present in 92% to 94% of Europeans, 71% to 75% of East Asians, 55% to 65% of South Asians, 60% to 66% of people with Hispanic ethnicity, but only 29% to 35% of people of African descent. As a result, 65% to 71% of African Americans with functional CYP3A5 metabolize CYP3A4/5 drugs faster than other racial and ethnic groups. The impact of enhanced CYP3A5 metabolism is exemplified by tacrolimus ; dosing guidelines recommend increased dosing for African American transplant recipients. The impact of enhanced CYP3A5 metabolism on drugs used in obstetrics has not been well studied; however, investigators have reported that concentrations of the antimalarial drug lumefantrine are lower in pregnant women with the CYP3A5*1/*1 genotype, placing them at increased risk for treatment failure. Similarly, in a study of nifedipine for tocolysis, high CYP3A5 expressors had lower average plasma nifedipine concentration and greater nifedipine clearance than those with inactive CYP3A5.
Reflecting the importance CYP3A plays in the metabolism of many drugs used in obstetric care, numerous studies in pregnant women have confirmed enhanced clearance and reduced maximum concentrations of these medications. CYP3A activity has been shown to be induced by the end of the first trimester and it remains consistently elevated throughout pregnancy; however, it is not known how early it begins to increase in the first trimester or how quickly it normalizes postpartum.
Relevant drug examples.
Midazolam hydroxylation is a probe for CYP3A4/5 activity. After an oral dose of 2-mg midazolam, the apparent oral clearance of midazolam in the third trimester was 108% greater than postpartum.
Dextromethorphan (a cough suppressant) N- demethylation is another probe for CYP3A activity. In a “cocktail” of two probe drugs, dextromethorphan and caffeine , Tracy et al. showed that CYP3A activity had already increased by the early second trimester and remained elevated throughout pregnancy, at 35% to 38% above postpartum values.
Cholesterol is another probe for CYP3A activity. The metabolic ratio of 4β-hydroxycholesterol to cholesterol (4βOHC/C) was 26% greater in the third trimester of pregnancy compared with postpartum or nonpregnant controls as a result of increased CYP3A enzyme activity. The 4βOHC/C metabolic ratios were similar in the late first trimester, and in the second and third trimesters, all approximately 50% greater than the ratios in nonpregnant women.
Cortisol conversion to hydroxycortisol by CYP3A is enhanced during pregnancy as evidenced by the finding that the ratio of urinary 6-hydroxycortisol to 17-hydroxycorticosteroid (6-OHF/17-OHCS) was 4.9 times greater 1 week before delivery compared with 3 months after delivery.
Betamethasone clearance by CYP3A4/5 increased 1.2- to 1.6-fold during the second and third trimesters of pregnancy compared with nonpregnancy.
Nifedipine PK during pregnancy has been explored in two studies. Compared with historic, nonpregnant controls, nifedipine clearance was fourfold greater during the third trimester. A similar fourfold increase in nifedipine clearance was observed in pregnant women treated for preterm labor as well as additional enhanced clearance in women with one or two active CYP3A5*1 alleles.
Fentanyl is metabolized by CYP3A4 to its primary inactive metabolite norfentanyl. Table 16.2 lists the drug-metabolizing enzymes involved with each of the opioid medications. The mean urinary metabolic ratio of norfentanyl/fentanyl (NF/F) in 420 pregnant women was approximately threefold larger than the ratio in nonpregnant individuals (44.6 versus 14.8, respectively) ; these authors also noted the wide range of values for NF/F in both groups, especially among the samples from pregnant subjects. In a PK study of intranasal fentanyl for labor analgesia, the median plasma fentanyl concentration 15 minutes after the first 50-µg dose was 0.21 ng/mL, which was approximately one-third less than the concentrations observed in nonpregnant subjects receiving fentanyl for dental surgery. An analgesic concentration of fentanyl (0.5 mg/mL) was reached in only 10 of 15 pregnant subjects.
Table 16.2
Drug-Metabolizing Enzymes Involved in Opioid Metabolism
| Opioid | Active Drug | CYP3A | CYP2D6 | CYP2B6 | CYP2C19 | Other CYPs | UGTs | Other Enzymes |
|---|---|---|---|---|---|---|---|---|
| Alfentanil | ✓ | |||||||
| Buprenorphine | ✓ | CYP2C8 | UGT2B7, UGT1A1, UGT1A3 | |||||
| Butorphanol | Probably hepatic; enzymes not identified | |||||||
| Codeine | Morphine and Morphine-6-glucuronide | ✓ | ✓ | UGT2B7, UGT2B4 | ||||
| Fentanyl | ✓ | |||||||
| Hydrocodone | Hydromorphone and Dihydrocodone | ✓ | ✓ (minor) | |||||
| Hydromorphone | UGT2B7 | SULT1A3 | ||||||
| Meperidine (Pethidine) | ✓ | ✓ | ✓ | |||||
| Methadone | ✓ | ✓ | ✓ | (minor: 2C8, 2D6, 2C9) | UGT2B4, UGT2B7 | |||
| Morphine | ✓ (minor) | (minor:2C8) | UGT2B7 | SULTs (minor: UGT1A1, UGT1A3, UGT1A8, UGT1A9, UGT1A10, UGT2B4, UGT2B15, UGT2B17) | ||||
| Nalbuphine | Probably hepatic; enzymes not identified | |||||||
| Oxycodone | ✓ | ✓ | UGT2B4, UGT2B7 | |||||
| Oxymorphone | ✓ | ✓ | UGT2B7 | |||||
| Remifentanil | Hydrolysis by nonspecific blood and tissue esterases | |||||||
| Sufentanil | ✓ | |||||||
| R,R -Tramadol/ S,S -Tramadol | O -Desmethyltramadol (M1) | ✓ | ✓ | ✓ | UGT2B7, UGT1A8 |
CYP , Cytochrome P450; NAT-2 , N -acetyltransferase-2; SULT , sulfotransferase; UGT , uridine 5′-diphosphate glucuronosyltransferase.
Oxycodone is metabolized approximately 45% by CYP3A4 to the inactive metabolite noroxycodone, and 19% by CYP2D6 to the active metabolite, oxymorphone. Both the parent drug and its two metabolites also undergo glucuronidation by uridine 5′-diphosphate glucuronosyltransferase (UGT) 2B7 and UGT2B4 prior to renal excretion. In a PK study of pregnant women receiving intravenous oxycodone for analgesia during the first stage of labor, the Vd was smaller, clearance was greater, and the elimination half-life of oxycodone was shorter (2.6 versus 3.8 hours) compared with nonpregnant volunteers.
Tacrolimus is primarily metabolized by CYP3A4/5. Clearance of tacrolimus was shown to be 39% greater in the third trimester compared with postpartum.
Lumefantrine , an antimalarial drug, is extensively metabolized by CYP3A4. In pregnant women, day 7 mean lumefantrine concentrations were significantly lower than in nonpregnant women (geometric mean ratio 1.40), increasing the risk for subtherapeutic concentrations and treatment failure.
Protease inhibitors are primarily metabolized by CYP3A4. Because maintaining therapeutic concentrations is critical in the treatment of human immunodeficiency virus (HIV) disease, antiretroviral therapies have been better studied than any other class of drugs during pregnancy. Compared with postpartum values, the AUC of darunavir during the second and third trimesters is 38% to 39% smaller with once daily dosing and 26% smaller with twice daily dosing. The AUC of indinavir was decreased by 68% at 30 to 32 weeks’ gestation compared with values from the same women postpartum. The geometric mean ratio of third trimester and postpartum lopinavir AUC (when administered as lopinavir/ritonavir) was 0.72, and 82% of the pregnant women did not meet target lopinavir AUC. Because atazanavir AUC and trough concentration ( C min ) are reduced by 6% to 47% during pregnancy, even when coadministered with the pharmacoenhancer, ritonavir, some experts have recommended that the higher dose (atazanavir 400 mg/ritonavir 100 mg once daily) be used during pregnancy.
Carbamazepine , an anticonvulsant, is converted to its 10,11-epoxide metabolite primarily by CYP3A4 with a minor contribution by CYP2C8. Carbamazepine is a well-known EID, stimulating its own metabolism through upregulation of transcription of CYP3A4 via the xenobiotic sensors, PXR and CAR. However, compared with nonpregnant baselines, no significant change in carbamazepine clearance was reported to occur during pregnancy.
Methadone is N -demethylated mainly by CYP2B6 and CYP3A4, although there is some stereo-specificity among the minor enzymes involved in metabolism of its S- and R -enantiomers. Methadone clearance increases during pregnancy, presumably because of increased CYP3A4 activity, necessitating dose escalation to maintain therapeutic plasma concentrations.
Buprenorphine is metabolized by either (1) N -dealkylation to norbuprenorphine by CYP3A4 with some contribution by CYP2C8, followed by glucuronidation by UGT1A1 and UGT1A3, or (2) direct glucuronidation by UGT1A1, UGT1A3, and UGT2B7. Metabolism via both pathways is increased during pregnancy. Because plasma concentrations decreased below the theoretical level required to prevent withdrawal symptoms with the standard 12-hourly dosing in 50% to 80% of pregnant women, changing to a three to four times daily dosing schedule may be helpful to sustain therapeutic buprenorphine concentrations and improve adherence.
Ketamine is converted to norketamine by both CYP3A4 and CYP2B6, with some studies supporting CYP2B6 as the dominant enzyme and others showing a primary role for CYP3A4. Although there are no published PK studies of ketamine during pregnancy, given the involvement of CYP3A4, ketamine metabolism is most likely enhanced. Additional support for this hypothesis comes from PK studies of ketamine in women taking combined estrogen and progestin contraceptives, which showed that ketamine clearance was increased by 20% compared with men.
CYP2D6.
After CYP3A, CYP2D6 is the next most important CYP enzyme, contributing to the metabolism of about 20% of medications. CYP2D6 has pharmacogenetic variants that are associated with estimated 1000-fold differences in activity: phenotypic extensive metabolizers (EMs) have two normally active alleles, poor metabolizers (PMs) have two loss-of-function alleles, intermediate metabolizers (IMs) have one active and one loss-of-function allele, and ultrarapid metabolizers (UMs) have multiple copies of an otherwise normally active allele. Allelic distribution varies by ethnicity; CYP2D6 PMs are most prevalent among the White population (7% to 10%), followed by African (1.9% to 7.3%), Hispanic ethnicity (2.2% to 6.6%), and Asian (0% to 1.2%). In contrast, UMs are more common in Arabian, East African, and Mediterranean populations (8.7% to 29%), but relatively infrequent among people of European descent (0.8% to 1.3%).
Typically, CYP2D6 activity is not induced by PXR/CAR and the xenobiotic sensing system; the usual EIDs, rifampin and carbamazepine , do not change CYP2D6 activity. However, during pregnancy, studies examining CYP2D6 substrates have shown enhanced metabolism. The exact mechanism by which this occurs is not known. Unlike CYP3A activity during pregnancy, which stays consistently elevated from the first trimester through delivery, CYP2D6 activity progressively increases by 25% in the late first/early second trimester to 48% in the late third trimester. However, the increased activity is observed only in the EMs and UMs, with less change seen in the IMs, and no change in the PMs. CYP2D6 activity is enhanced to such a degree during pregnancy that clonidine , which is primarily renally cleared, appears to switch to CYP2D6 metabolism as its primary elimination mechanism during pregnancy.
Relevant drug examples.
Oral metoprolol was shown to have an apparent clearance 2 to 13 times greater in the third trimester compared with postpartum, and plasma concentrations during the third trimester were 12% to 55% of those after delivery. In another study, the apparent clearance after oral administration in CYP2D6 EMs was 1.8-fold higher in mid-pregnancy and threefold higher in late pregnancy compared with postpartum. Metoprolol clearance in the CYP2D6 IMs progressively increased during pregnancy but was consistently lower than in the EMs.
Dextromethorphan is O -demethylated by CYP2D6 to dextrorphan. By comparing dextromethorphan/dextrorphan metabolic ratios, CYP2D6 activity was shown to be 26% greater at 14 to 18 weeks’, 35% greater at 24 to 28 weeks’, and 48% greater at 36 to 40 weeks’ gestation compared with postpartum. When stratified by CYP2D6 phenotype, metabolism of dextromethorphan during pregnancy was increased in CYP2D6 EMs and IMs but decreased in PMs, compared with postpartum.
Clonidine was shown to have apparent oral clearance that was twofold greater in the second and third trimesters compared with historic, nonpregnant controls (440 versus 245 mL/min) without significant change in renal clearance.
Paroxetine concentrations in women taking the drug during pregnancy were found to progressively decrease in CYP2D6 EMs, while concentrations in IMs and PMs did not change or increased, respectively.
CYP1A2.
The CYP1 family of enzymes comprises three enzymes: CYP1A1, CYP1A2, and CYP1B1. CYP1A2 is found only in the liver and the other two only in extrahepatic tissues. CYP1A2 contributes to the metabolism of approximately 10% of medications, including caffeine , theophylline , tricyclic antidepressants , acetaminophen (minor), and estrogens . Among the compounds that inhibit CYP1A2, estradiol downregulates its transcription and decreases its activity. Caffeine metabolism is remarkably complex, but more than 95% is by CYP1A2. Using caffeine metabolism as a probe for CYP1A2, compared with postpartum, CYP1A2 activity was shown to progressively decrease during pregnancy with reductions of 32.8% at 14 to 18 weeks’, 48.1% at 24 to 28 weeks’, and 65.2% at 36 to 40 weeks’ gestation.
CYP2A6.
CYP2A6 is involved with the metabolism of approximately 3% of commonly used medications. It is the primary enzyme responsible for the oxidation of nicotine and cotinine . CYP2A6 is highly polymorphic with approximately 40 allelic variations that differ in their level of activity. Estrogen induces activity of CYP2A6 through the estrogen receptor (ERα), which acts as a transcription factor when bound to a promoter element associated with the CYP2A6 gene. Nicotine C-oxidation via CYP2A6 was shown to be higher in early and late pregnancy (1.07-fold and 1.11-fold, respectively) compared with postpartum, as determined by analyzing urine samples from pregnant smokers. In addition, nicotine N -glucuronidation by UGT2B10 was increased during early and late pregnancy (1.33-fold and 1.67-fold, respectively) compared with postpartum.
CYP2B6.
The status of CYP2B6 activity during pregnancy is unclear. Although estradiol induces transcription of CYP2B6 RNA in cultured hepatocytes, studies of medications metabolized by CYP2B6 during pregnancy are either less definitive or show no significant changes. Assessing specific CYP2B6 activity is often problematic because CYP2B6 contributes to the metabolism of approximately 25% to 30% of the drugs metabolized by CYP3A4, and few drugs are uniquely metabolized by CYP2B6.
Relevant drug examples.
Efavirenz , an antiretroviral medication, is a probe drug for CYP2B6. Its PK parameters were either not significantly different during pregnancy compared with postpartum or insufficiently different to warrant a dosing adjustment.
Bupropion , a smoking cessation drug, is metabolized by CYP2B6 to hydroxybupropion. The metabolic ratio of hydroxybupropion to bupropion (OHBUP/BUP) has been used as a CYP2B6 probe. Compared with postpartum, no significant changes were observed in the OHBUP/BUP ratio or OHBUP concentrations in mid- or late pregnancy. These findings were confirmed in a subsequent study; steady-state plasma concentrations and clearances of the bupropion enantiomers and metabolites were not different during pregnancy and the distant postpartum period.
Methadone C/D ratios, conversely, decrease and clearance increases during pregnancy ; however, it is not known whether these changes occur because of the increased activity of CYP3A4 or CYP2B6, because both metabolize methadone.
CYP2C9.
Estradiol increases CYP2C9 activity in cultured hepatocytes by unknown mechanisms that do not involve increased mRNA transcription. This observation has been confirmed by PK studies during pregnancy with drugs metabolized by CYP2C9.
Relevant drug examples.
Indomethacin ’s apparent oral clearance in the second trimester was greater (14.5 versus 6.5 to 9.8 L/h) and the mean plasma concentration after a 25-mg oral dose was 37% lower compared with historic controls.
Glyburide clearance in pregnant women with type 2 diabetes mellitus was twofold higher during the third trimester compared with nonpregnant women. Using modeling simulations, the authors of this study predicted that, compared with the usual twice daily dose of 1.25 to 10 mg, glyburide would have to be increased during pregnancy to as much as 23.75 mg twice daily for optimal glucose control.
CYP2C19.
Similar to CYP2D6, CYP2C19 has common phenotypes with dramatically different activity: poor (two loss-of-function or no-function alleles), intermediate (one loss-of-function and one normal-function or gain-of-function allele), extensive (two normal-function alleles), rapid (one normal-function and one gain-of-function allele), and UMs (two gain-of-function alleles). Hepatocyte studies confirm downregulation of CYP2C19 expression by estrogens.
Relevant drug examples.
Proguanil conversion to the active antimalarial drug cycloguanil is decreased by approximately 60% during the third trimester of pregnancy in CYP2C19 EMs. This conversion was also decreased in women taking estrogen-containing contraceptives. Pregnancy did not affect the metabolic activity of CYP2C19 PMs. These authors recommended an increase in proguanil dosing during pregnancy.
Esomeprazole ( S -omeprazole) is primarily metabolized by CYP2C19 to a desmethyl metabolite and a 5-hydroxy metabolite, while a smaller amount is metabolized by CYP3A4 to 3-hydroxyomeprazole. After a single dose, esomeprazole clearance was 42.2% lower in pregnant versus nonpregnant patients.
CYP2E1.
CYP2E1 is an unusual CYP enzyme; it is not activated by nuclear receptors but rather induced by human placental lactogen (hPL) through the phosphoinositol 3-kinase pathway. Because of the enzyme’s preference for small molecules, CYP2E1 is not involved in the metabolism of many drugs. During pregnancy, hPL increases 10-fold.
Relevant drug examples.
Ethanol is a substrate for CYP2E1 (ethanol oxidation) as well as both an inducer and inhibitor.
Acetaminophen metabolism by CYP2E1 is responsible for hepatotoxicity.
Halothane , isoflurane , sevoflurane , enflurane , and desflurane are metabolized predominantly by CYP2E1. However, with the exception of sevoflurane, of which 5% to 8% is metabolized, metabolism of the newer halogenated anesthetic agents is minimal. Less than 2% of isoflurane can be recovered in the urine as metabolites and an even smaller amount of desflurane (<0.02%) is metabolized. The impact of increased CYP2E1 activity during pregnancy on sevoflurane metabolism has not been studied.
Caffeine is primarily (70% to 80%) metabolized via 3- N demethylation to paraxanthine by CYP1A2. Only 7% to 8% is converted to theobromine by CYP1A2 and CYP2E1 (1-N demethylation) and another 7% to 8% is metabolized to theophylline by CYP2C8/9, CYP3A4, and possibly CYP2E1 and CYP1A2 (7-N demethylation). Of the remainder, approximately 15% is C-8 hydroxylated by CYP1A2, CYP3A4, CYP2C8/9, and CYP2E1. However, in a PK study in pregnant women, the dominant metabolite was theobromine rather than paraxanthine, reflecting suppression of CYP1A2 and induction of CYP2E1 during pregnancy. CYP2E1 activity and theobromine concentration were shown to be increased in pregnant women by consumption of charbroiled meat (a known inducer of CYP2E1 activity) and by acetaminophen use (twofold and fivefold increases, respectively).
Phase II Drug-Metabolizing Enzymes and Pregnancy
Uridine 5′-diphosphate glucuronosyltransferases.
Mammalian UGTs are divided into two families: UGT1 and UGT2. In humans, the UGT1A gene cluster is located on chromosome 2q37 and contains nine functional isoforms: UGT1A1, and UGT1A3 through UGT10, plus four defunct pseudogenes. UGT2A (three isoforms) and UGT2B (seven isoforms) subfamilies are located on chromosome 4q13. UGT enzymes are primarily produced within the liver and gastrointestinal tract, but they also play significant roles in the kidney and can be found in the pancreas, trachea, lung, heart, bone marrow, spleen, thymus, adrenal gland, thyroid, ovary, uterus, cervix, placenta, breast, testis, prostate, adipose, skeletal muscle, brain, nasal mucosa, and bladder. Expression of UGTs and their activities vary significantly among individuals and is influenced by multiple transcription factors, many of which are either enzyme- or family-specific (e.g., inducing UGT1A but not UGT2B). Each enzyme also has numerous pharmacogenetic variants with variable degrees of function. Some drugs are uniquely conjugated by one of the UGT enzymes; many compounds are substrates of multiple UGTs.
UGT1A1.
UGT1A1 metabolizes labetalol and bilirubin as well as several of the antiretroviral integrase inhibitors, bictegravir , dolutegravir , and raltegravir . It contributes to the metabolism of acetaminophen , many NSAIDs , and statins , as well as morphine and buprenorphine . In hepatocyte studies, progesterone is one of several factors that increase transcription of UGT1A1. During pregnancy, UGT1A1 activity progressively increases across gestational age.
Relevant drug examples.
Oral labetalol , taken by pregnant women for chronic hypertension, was shown to have apparent clearance that was 1.4-fold greater in the late first trimester and 1.6-fold greater at term compared with postpartum. In an earlier study, the elimination half-life of labetalol in the third trimester was shorter than in nonpregnant controls (1.7 versus 6 to 8 hours). Authors of both studies advised that the dosing interval for labetalol may need to be shortened during pregnancy to maintain hypertensive control.
UGT1A4.
Of all the metabolic enzyme processes studied during pregnancy, none changes as dramatically as UGT1A4 glucuronidation. UGT1A4 is either the primary or contributing enzyme for approximately two dozen medications, including lamotrigine , valproic acid , midazolam , multiple antipsychotics , cyclobenzaprine , amitriptyline , phenytoin , and ethinyl estradiol . Using hepatocyte cultures, estrogen has been shown to upregulate UGT1A4 transcription.
Relevant drug examples.
Lamotrigine , an anticonvulsant and mood-stabilizing drug, is primarily metabolized by UGT1A4. When lamotrigine was administered to women taking oral contraceptives, its clearance did not change in women taking progestin-only pills, while it increased, and breakthrough seizures occurred, in women taking combination estrogen and progestin contraceptives. Subsequent investigations have shown that enhanced lamotrigine clearance begins from as early as 5 weeks’ gestation and progressively increases until it peaks in the third trimester at 248% to 330% above baseline. However, not all pregnant women exhibit the same marked increase in glucuronidation. In a PK study of women receiving lamotrigine who were pregnant or planning pregnancy, Polepally et al. identified two subpopulations: in 77% of 64 pregnancies, third trimester oral lamotrigine clearance increased 219% above baseline, where as in 23%, it rose by only 21%. Factors that differentiate these populations have not been identified. Many authors recommend monthly drug monitoring with serial dose increases to maintain stable therapeutic lamotrigine concentrations during pregnancy. Because clearance of lamotrigine falls rapidly after delivery and returns to nonpregnant levels by 3 weeks postpartum, dose tapering should begin within the first week after delivery to prevent possible lamotrigine toxicity.
Dexmedetomidine is hepatically metabolized to inactive metabolites by two pathways: (1) direct glucuronidation by UGT1A4 and UGT2B10 and (2) hydroxylation of a smaller fraction by CYP2A6. Although induction mechanisms for UGT2B10 are currently unknown, UGT1A4 and CYP2A6 are both upregulated by estrogen. No studies exploring the maternal PK of dexmedetomidine have been performed.
UGT2B7.
UGT2B7 contributes to the glucuronidation of approximately 35% of commonly used medications. Important substrates include (1) the opioid drugs morphine , codeine , buprenorphine , and naloxone ; (2) other drugs, including zidovudine , efavirenz , haloperidol , ethanol , lorazepam , NSAIDs , and chloramphenicol ; (3) the endogenous compounds bile acids , fatty acids , and retinoic acids ; and (4) multiple steroid hormones, including estrogens , catecholestrogens , androgens , glucocorticoids , and mineralocorticoids . UGT2B7 is widely distributed throughout the body: in the liver, small intestine, kidney, breast, lung, placenta, adipose, skin, pancreas, bladder, uterus, brain, and adrenal. Regulation of UGT2B7 transcription involves a system unrelated to the xenobiotic nuclear receptors that induce some of the CYP and UGT1A genes. Instead, UGT2B7 is regulated by the transcription factors, hepatocyte nuclear factor 1α (HNF1α) and HNF4α with contributions from caudal-related homeobox transcription factor 2 (CDX-2). Classic hormonal changes during pregnancy do not appear to influence this regulatory system.
Relevant drug examples.
Zidovudine is metabolized (60% to 70%) to its inactive metabolite 5′-glucuronyl zidovudine exclusively by UGT2B7, making it an ideal probe for UGT2B7 activity. In multiple PK studies performed in pregnant women, zidovudine total body clearance, maximum concentration, and elimination half-life were not significantly different from the same parameters in nonpregnant adults.
Morphine is metabolized predominantly by UGT2B7. In nonpregnant adults, approximately 60% is glucuronidated to inactive morphine-3-glucuronide (M3G), while 5% to 10% is glucuronidated to the active metabolite, morphine-6-glucuronide (M6G). A third pathway, catalyzed primarily by CYP3A4 and CYP2C8, is N -demethylation to normorphine. UGT2B7 is the dominant enzyme facilitating both glucuronidation pathways ; however, in vitro studies have shown that other UGTs can participate, including UGT2B4, UGT2B15, UGT2B17, UGT1A1, UGT1A3, UGT1A9, and UGT1A10 in the formation of M3G, and UGT2B4, UGT1A1, UGT1A3, and UGT1A8 to produce M6G. In a PK study of morphine used for labor analgesia, its elimination half-life was approximately 49% shorter, plasma clearance was 70% greater, and the metabolic ratio of M3G/morphine at 10 minutes was 88% greater in pregnant women compared with nonpregnant subjects. Given that UGT2B7 has been shown not to change during pregnancy, one potential explanation for the increased metabolism is that minor UGT enzymes, which are known to increase their activity during pregnancy, assume greater responsibility for morphine metabolism.
UGT1A6.
In addition to metabolizing the endogenous hormone serotonin , UGT1A6 conjugates acetaminophen and aspirin . Although UGT1A6 may weakly respond to PXR/CAR induction, its primary transcription control appears to be exerted through the aryl hydrocarbon receptor (AhR), which influences transcription similar to PXR/CAR.
UGT1A9.
UGT1A9 conjugates a variety of compounds, including ethanol , nicotine , NSAIDs , propranalol , hydroxywarfarin , furosemide , acetaminophen , and cannabinol . Transcriptional regulation of UGT1A9 appears to involvesimilar mechanisms as UGT2B7: HNF1α and HNF4α with CDX-2.
Relevant drug examples.
Propofol and its hydroxy metabolite (created by CYP2C9 and CYP2B6) are exclusively conjugated by UGT1A9. In a study of women who received propofol anesthesia for first-trimester termination of pregnancy, specific UGT1A9 pharmacogenetic variants shortened the duration of effective analgesia and sedation. Propofol clearance was shown to be 30% faster in women having cesarean delivery compared with women undergoing laparoscopic sterilization. In the latter study, the authors did not analyze metabolites, so it is unknown which pathway (UGT1A9 and/or CYP2C9/2B6) drove the increase in propofol clearance.
Furosemide elimination in nonpregnant individuals is 40% to 70% by unchanged drug excretion in urine and 20% to 30% by metabolism within the kidney and liver by UGT1A9 and UGT1A1. In hypertensive women at term, the median apparent oral clearance was two- to threefold higher (25.3 L/h) compared with historical data from nonpregnant individuals (8.3 to 15.7 L/h) after administration of 40 mg. Of interest, glucuronidation played a more dominant role in furosemide elimination in pregnant patients, contributing to 90% of total clearance (22.7 L/h), compared with 60% (3.7 to 10.6 L/h) in the nonpregnant controls. It is unknown whether UGT1A9 contributes to the increase in glucuronidation or if it is solely by UGT1A1.
Acetaminophen (paracetamol) is metabolized through three different pathways. In nonpregnant adults, approximately 47% to 62% is converted to an inactive glucuronide (by UGT1A6 and UGT1A9 with minor contribution from UGT1A1 and UGT2B15), and 30% to 44% is sulfate conjugated. Eight to 10% is oxidized to the reactive metabolite, N -acetyl- p -benzoquinone-imine (NAPQI), primarily by CYP2E1, with minor contribution from CYP3A4, CYP1A2, CYP2D6, and CYP2A6. NAPQI is rapidly conjugated by hepatic glutathione, thereby preventing hepatic toxicity at therapeutic dosing. Less than 5% is excreted in the urine as unchanged drug.
When acetaminophen was given intravenously to women after cesarean delivery (2-g loading dose followed by 1 g 6-hourly maintenance doses), total clearance was almost twice as high (21.1 versus 11.7 L/h) compared with a subset of the same patients who received a 2-g loading dose 10 to 15 weeks postpartum. Further analysis revealed that the increase in clearance was due to enhanced glucuronidation (11.6 versus 4.76 L/h), increased oxidation (4.95 versus 2.77 L/h), and increased urinary excretion of unchanged drug (1.15 versus 0.75 L/h). In contrast, sulfate conjugation was unchanged. Increased acetaminophen clearance during pregnancy has been confirmed in other studies. Although increasing the acetaminophen dose may counter the impact of this increased clearance, caution was advised because a higher dose would also increase production of NAPQI and the risk of hepatoxicity. Increased acetaminophen clearance also occurs in women taking oral combination hormonal contraceptives. Compared with controls, plasma acetaminophen clearance was approximately 64% higher (470 versus 287 mL/min) and the elimination half-life was lower (1.67 versus 2.40 hours). Hormonal contraception also increased glucuronidation without change in sulfation. It is not known which of the reproductive hormones is responsible for the induction of glucuronidation and which of the UGT enzymes is/are induced.
UGT2B15.
UGT2B15 is widely expressed throughout the body, including in reproductive organs, and is involved in the metabolism of endogenous steroids and a number of drugs, including acetaminophen , oxazepam , and lorazepam . Control of its transcription is complex but studies have identified the presence of an estrogen receptor binding site with estradiol upregulation.
Relevant drug examples.
Lorazepam is administered as a racemic mixture of which only the S- enantiomer is biologically active. Both enantiomers are metabolized by the same enzymes (predominantly UGT2B15, plus UGT2B4 and UGT2B7) as well as stereo-specific enzymes ( R -lorazepam is also metabolized by UGT1A7 and UGT1A10). In a PK study of oral lorazepam (2 mg) in laboring women, the apparent Vd was increased (mean 178.8 L) compared with historic controls (93 to 116 L), owing to decreased protein binding and increased total body water. Apparent clearance after oral lorazepam administration was approximately twofold higher (mean 2.61 mL/min kg) compared with historic controls (0.84 to 1.8 mL/min kg) and the mean elimination half-life was lower (10 hours) compared with 16 hours in historic controls.
Other Phase II enzymes.
In an early study, N -acetyltransferase-2 (NAT-2) activity was shown to be significantly decreased during pregnancy using caffeine metabolism (a secondary pathway). However, subsequent studies have reported different results. Also using caffeine, the activity of NAT-2 in pregnant women (all fast acetylators), decreased by only 13% and only during early pregnancy; NAT-2 activity returned to nonpregnant levels during mid- and late pregnancy. The absence of significant change in NAT-2 activity between pregnant and nonpregnant individuals was confirmed using hydralazine. Although there was a clear difference between fast and slow acetylators, and the study did not explore the first trimester, the authors demonstrated that hydralazine PK during the second and third trimesters of pregnancy was reasonably comparable with that of nonpregnant subjects in prior studies. Although activity of SULT2A1, one of the most important of the sulfotransferase (SULT) enzymes, is upregulated by estradiol in cultured hepatocytes, sulfation of acetaminophen during pregnancy does not appear to change. Very little is known about the activity of other Phase II enzymes during pregnancy.
Medications Metabolized by Enzymes Affected VariablyDuring Pregnancy
Meperidine ( pethidine ) transformation to its active metabolite, normeperidine (norpethidine), is catalyzed by CYP2B6, CYP3A4, and CYP2C19. In vitro hepatocyte studies have shown that CYP2B6, CYP3A4, and CYP2C19 account for 57%, 28%, and 15%, respectively, of the total intrinsic clearance of meperidine. In a PK study of meperidine administered to pregnant women in labor, no differences were observed in metabolism or clearance of meperidine, compared with nonpregnant controls in the early follicular phase (low estradiol/no progesterone). One possible explanation for these findings is that the decrease in CYP2C19 activity counters the increase in CYP3A4 activity. Based on current knowledge, CYP2B6 does not change, resulting in no significant net change in meperidine metabolism.
Sertraline is metabolized to its desmethyl metabolite by CYP2C19 and CYP3A4, with minor contributions by CYP2C9, CYP2B6, and CYP2D6. Studies have shown that the CYP2C19 phenotype impacts sertraline metabolism and dosing requirements in nonpregnant patients; lacking one of the primary enzymes that metabolize sertraline, CYP2C19 PMs have higher sertraline C/D ratios and often require lower starting doses. In a PK study of sertraline across pregnancy and postpartum, the mean pregnant and postpartum C/D ratios in women with functional CYP2C19 activity (EMs/UMs/rapid metabolizers) were not significantly different because the increase in CYP3A4 metabolism was countered by the decrease in CYP2C19 activity. However, a significant difference was observed in CYP2C19 PMs/IMs; with primarily CYP3A4 to metabolize sertraline, their mean C/D ratios during pregnancy were approximately 50% lower than postpartum, potentially placing them at risk of inadequate therapy during pregnancy.
PHARMACODYNAMIC CHANGES DURING PREGNANCY: IMPACT ON ANESTHETIC AND ANALGESIC DRUGS
Distinct from PK, which focuses on the processes that affect drug concentration, PD relates to the interaction of the drug with its environment, its receptor or enzyme binding site, and ultimately its impact on downstream biochemical and physiologic effects. Although the complex physiologic changes that occur during pregnancy affect the PD environment of many of the medications we use, this discussion will focus on the perception of pain in the pregnant woman and its impact on drugs used for anesthesia and analgesia.
Endogenous opioids, acting through their respective receptors, modulate pain and influence other functions by inhibiting voltage-gated calcium channels and/or by opening potassium channels, both of which inhibit neuronal excitability. Opioid receptors are located within the brain, spinal cord, peripheral neurons, gastrointestinal tract, heart, immune cells, and other tissues, including extensively within the placenta. Early research dating back to the 1980s has identified both kappa- (most prevalent) and mu-opioid receptors within the placenta, as well as all three endogenous opioid families: β-endorphin , enkephalins (both methionine and leucine), and dynorphins , with dynorphin 1 to 8 being the major form in the human chorionic villi. One of the endogenous opioids, β-endorphin, is derived from proopiomelanocortin (POMC), a protein that is cleaved into four different peptides: ACTH, α-melanocyte-stimulating hormone, β-lipotropin, and β-endorphin. Theplacenta synthesizes significant amounts of CRH, which induces placental production of POMC and β-endorphin. Although placental opioids are known to increase nitric oxide locally, stimulate release of hCG and hPL, and suppress interleukin-8 (IL-8) production (which could otherwise initiate preterm labor), the full extent of the role of placental opioids remains elusive.
Beyond the placenta, endogenous opioids contribute to the support of pregnancy through the regulation of several neuroendocrine systems which optimize fetal growth, protect the fetus from maternal stress, inhibit preterm labor throughout gestation, and facilitate parturition and subsequent lactation. Endogenous opioids inhibit posterior pituitary secretion of oxytocin, thus expanding oxytocin storage during pregnancy until just before labor onset. They inhibit dopamine secretion into the hypothalamic-hypophyseal portal blood system, thereby promoting prolactin surges both in early pregnancy and during lactation. Endogenous opioids also contribute to attenuation of the hypothalamic-pituitary-adrenal axis response to psychologic and physical stressors during pregnancy, including increasing the threshold for perception of pain.
The physiologic changes that occur during human pregnancy and parturition create opioid-mediated maternal analgesia that operates through the spinal cord dynorphin/kappa-opioid system. Evidence to support the role of endogenous opioids in pregnancy-induced analgesia can be found in experiments with other mammals. Maternal pain thresholds were evaluated across pregnancy and postpartum in pregnant rats by measuring the intensity of an electric shock that elicited reflexive jumping. Pain thresholds gradually rose during the second half of gestation and then rapidly increased 1 to 2 days before parturition. This increased pain threshold was abolished by exposure to the opioid antagonist naltrexone. Administration of estradiol and progesterone in concentrations that simulate pregnancy to nonpregnant, ovariectomized rats produced elevated pain thresholds similar to that observed during actual pregnancy. These changes were blocked by naltrexone. Administration of estrogen and progesterone separately or sequentially failed to produce the increased pain thresholds. In response to mild thermal stimulation, pregnant pigs exhibited increased pain thresholds so profound that just before labor the majority of the sows failed to respond at all. Administration of naloxone to half of the sows during labor reversed this tolerance.
Similar results have been reported in human pregnancies, although the findings have not been as consistent as those in animals. Compared with nonpregnant controls, heat pain thresholds progressively increased in both the forearm and T10 dermatome in pregnant women when tested during the early and late third trimester and early labor. The contact heat-evoked potentials were significantly lower at 40 weeks’ compared with 32 weeks’ gestation, supporting a general inhibitory mechanism during pregnancy that increases at term. Other investigators reported that heat pain tolerance was higher before delivery and 1 to 2 days postdelivery in pregnant women than in nonpregnant conrols. In contrast, a subsequent study by the same authors observed no change in pain evaluations (conditioned pain modulation, mechanical temporal stimulation and temperature pain scores) in the first, second, and third trimesters compared with 6 to 12 weeks postpartum.
This reduced capacity to feel pain is one mechanism that underlies the changes in dosing requirement observed in pregnant women for both anesthetic and analgesic medications; minimal alveolar concentration (MAC) values for volatile anesthetic agents during pregnancy are reduced. MAC values for isoflurane , halothane , and methoxyflurane in anesthetized pregnant ewes were reduced by 25% to 40% compared with nonpregnant ewes. Similarly, MAC values for halothane in pregnant rats were decreased by 19% during midgestation and by 16% at term, and returned to control values by 5 days postpartum.
The MAC values for volatile anesthetic agents during pregnancy were first evaluated in women undergoing early pregnancy termination (8 to 12 weeks). Using transcutaneous electrical stimulation to elicit pain, isoflurane MAC was decreased by 28% compared with nonpregnant controls. In a subsequent study in a similar population, MAC for enflurane was decreased by 30% and halothane by 27% compared with MAC values in nonpregnant women undergoing laparoscopy. The authors then evaluated MAC for isoflurane at 28 to 126 hours after delivery in women undergoing tubal ligation. The 30% reduction in MAC persisted for 24 to 36 hours after delivery and then gradually returned to normal values by 72 hours after delivery. Other investigators performed a similar study with isoflurane in women undergoing postpartum tubal ligation and confirmed the findings ; MAC for isoflurane was reduced by 28% within the first 12 hours after delivery and returned to normal values by 25 hours.
Some authors have hypothesized that increased progesterone is responsible for the observed changes in the MAC values for volatile anesthetic agents. The addition of progesterone reduced the MAC for halothane in rabbits, and lower concentrations of sevoflurane were needed to maintain a constant bispectral index in women during the luteal phase of the menstrual cycle when ovarian progesterone is elevated compared with the follicular phase when progesterone concentrations are negligible. However, studies in human pregnancy and postpartum have inconsistently correlated changes in MAC to progesterone concentrations.
Local anesthetics employed for nerve blocks have faster onset and longer duration during pregnancy. The time to onset of a conduction block of the vagus nerve with bupivacaine was faster in both an in vitro sheath nerve preparation and live animal studies in pregnant compared with nonpregnant rabbits. Lidocaine blockade of the sciatic nerve was achieved at the same time in pregnant versus nonpregnant rats, but it lasted 48% longer in the pregnant rats and the lidocaine concentration at return of deep pain sensation was 43% lower in the pregnant animals. The same phenomenon was observed in humans; median nerve block at the wrist with lidocaine inhibited sensory nerve action potentials to a greater extent in pregnant woman compared with nonpregnant subjects.
Dosing for neuraxial anesthesia during pregnancy is also affected by anatomic factors; pregnant women have increased epidural blood volume, especially in the supine position, which decreases the capacity of the epidural space and volume of lumbar cerebral spinal fluid (see Chapter 2 ). By itself, this increases the spread of local anesthetic within the subarachnoid space. In a study of motor block with intrathecal plain bupivacaine in pregnant and nonpregnant women undergoing cesarean delivery or elective gynecologic surgery, the ED 50 (median effective dose) was 3.96 mg for pregnant women versus 4.51 mg for nonpregnant women. In a similar study, the ED 50 for motor block with intrathecal bupivacaine was 3.4 mg for pregnant women versus 5.2 mg for nonpregnant women.
GENERAL PRINCIPLES OF TERATOLOGY AND DRUG USE DURING PREGNANCY
Safe use of drugs during pregnancy includes consideration of not only maternal safety but also potential fetal impact. Afetal effect of particular concern is teratogenesis. A broad definition of a teratogen is a substance that has an adverse effect on the developing fetus by altering the growth, structure, or function of the developing embryo. The principles of teratology as outlined by Wilson are shown in Box 16.1 . Potential fetal risks from intrauterine exposure to anesthetic drugs are summarized in Table 16.3 . Structural and behavioral teratology of anesthetic agents are discussed in Chapter 10 , Chapter 18 . Data for nonanesthetic drugs are shown in Appendix 16.1 (online only).
Box 16.1
Principles of Teratology
-
1.
A teratogen produces a specific abnormality or constellation of abnormalities.
Example: Fetal warfarin syndrome consists of facial and skeletal anomalies.
-
2.
There is a dose-effect relationship with progressively higher doses leading to more severe findings.
Example: More frequent malformations are associated with doses of warfarin > 5 mg/d.
-
3.
A teratogen must reach the fetus in a sufficient amount to cause this effect.
Example: Drugs that do not cross the placenta (e.g., heparin) cannot be teratogenic; drugs that have very limited fetal exposure because of either placental export or fetal metabolism are unlikely to be teratogenic.
-
4.
Teratogen exposure must happen at a stage in fetal development to cause that effect.
Example: Development of most organs and structures (organogenesis) occurs very early during pregnancy (beginning at approximately 2 weeks’ gestation) and is largely complete by approximately 12 weeks’ gestation. Neurodevelopment occurs throughout gestation and neonatal life ( Fig. 16.2 ). Exposure to a specific drug at less than 4 weeks’ gestation may cause miscarriage, at 2–8 weeks’ gestation may cause major congenital heart defects, and at greater than 12 weeks’ gestation may have no adverse structural impact at all. A drug that is teratogenic and causes neural tube development anomalies may have no effect when introduced in the second trimester because the neural tube is formed by this time. In contrast, drugs that could potentially impact neurodevelopment such as psychoactive agents have risk of teratogenicity throughout gestation.
Fig. 16.2 Embryo-fetal development according to gestational age determined by the first day of the last menses. Times are approximate.
Illustration by Naveen Nathan, MD, NorthShore University HealthSystem, University of Chicago Pritzker School of Medicine, Evanston, IL.
-
5.
Susceptibility to teratogenesis depends on the genotype of both mother and fetus.
Example: Severity of fetal hydantoin syndrome depends on genotype-related alterations in activity of epoxide hydrolase.
Table 16.3
Potential Fetal Risks From Intrauterine Exposure to Anesthetic Drugs
| Drug | Class | Comments/Potential Risks |
|---|---|---|
| General Anesthetic Drugs | ||
| Desflurane | Inhalational halogenated anesthetic | No reports of potential teratogenicity from exposure early in human pregnancy. Not teratogenic in animals. Can cause neonatal depression, which may last up to 24 h. Dose-related relaxation of gravid uterine muscle reversible with oxytocin. |
| Isoflurane | Inhalational halogenated anesthetic | No reports of potential teratogenicity from exposure early in human pregnancy. Not teratogenic in animals. Can cause neonatal depression, which may last up to 24 h. Dose-related relaxation of gravid uterine muscle reversible with oxytocin. |
| Sevoflurane | Inhalational halogenated anesthetic | No reports of potential teratogenicity from exposure early in human pregnancy. Teratogenic in mice (cleft palate). Can cause neonatal depression, which may last up to 24 h. Dose-related relaxation of gravid uterine muscle reversible with oxytocin. |
| Ketamine | General anesthetic, nonbarbiturate, phencyclidine derivative (NMDA receptor antagonist) | For isolated use for anesthesia indications, excluding chronic use for treatment of depression: no reports of malformations from exposure in humans or animals; however, no first trimester reports. Rapidly crosses the placenta. Maternal (hypertension) and neonatal (neonatal depression, increased skeletal muscle tone) adverse effects were observed with higher doses (1.5–2.2 mg/kg) in earlier studies and are less common with lower doses (0.2–0.5 mg/kg). Neonatal depression lower or absent with induction to delivery time < 10 min. |
| Nitrous oxide (N 2 O) | General anesthetic, sedative, analgesic, inorganic gas | Animal studies have suggested that exposure increases risks of dose-related fetal loss, growth restriction, skeletal malformations, major anomalies, and lower male-to-female sex ratios of surviving fetuses. However, with few exceptions, these studies were performed with exposures much higher and much longer than typical surgical exposures. 1970s and early 1980s studies of personnel in dental offices using N 2 O sedation and hospital ORs prior to universal installation of anesthetic gas scavenging implicated occupational exposure in increased risk of spontaneous abortion with a dose-response association with duration of exposure versus unexposed subjects. In 1985, combined data showed RR 1.3 (95% CI, 1.2 to 1.4) for spontaneous abortion in pregnant physicians and nurses working in ORs. Although the OR environment contains other anesthetic agents, studies were performed in N 2 O-only environments. Exposure is shorter for individual operations. In The Collaborative Perinatal Project, 76 of 50,282 monitored pregnancies were exposed to N 2 O during first trimester surgery and there was no evidence of association with observed defects. The concomitant use of N 2 O and ketamine (both NMDA receptor antagonists) without addition of a GABA agonist (e.g., halothane, isoflurane, propofol, benzodiazepines) was shown in animals to potentiate neurotoxicity of N 2 O, especially in immature brains. When children aged 5–13 y born to mothers exposed to waste anesthetic gases during pregnancy were compared with unexposed controls, developmental milestones were similar, but exposed children had significantly lower gross motor ability and evidence of inattention/hyperactivity, and level of exposure negatively correlated with fine motor ability and IQ performance; it was concluded that occupational exposure to waste anesthetic gases during pregnancy might be a risk factor for minor neurologic deficits in the offspring. N 2 O used for labor analgesia does not affect uterine activity, and does not adversely affect neonatal neurobehavior at 15 min, 2 h, or 24 h of age compared with unexposed neonates. |
| Propofol | General anesthetic and hypnotic | Most reports have shown no difference in Apgar scores or time to sustained spontaneous respiration in infants exposed to propofol versus other general anesthetics, and no correlation has been found between Apgar scores and umbilical blood concentration of propofol. However, one study reported lower Apgar scores in infants exposed to propofol compared with infants born by spontaneous vaginal delivery. |
| Local Anesthetic Drugs | ||
| 2-Chloroprocaine | Amino-ester local anesthetic | Rapid hydrolysis by esterases minimizes fetal exposure. No detectable parent drug in umbilical vein after perineal infiltration for episiotomy. |
| Bupivacaine | Amino-amide local anesthetic | Lowest fetal/maternal total concentration ratio among amide-type agents owing to extensive binding to maternal alpha-1-acid glycoprotein. As a weak base, it may accumulate in the fetus in the setting of fetal acidosis. |
| Lidocaine (lignocaine) | Amino-amide local anesthetic | Crosses the placenta but no reported harm from exposure in the first 4 mo of pregnancy. Most studies during delivery have suggested no adverse fetal effects. One report of infant hypotonia and tonic seizures 1 h after birth and toxic levels of lidocaine following maternal perineal nerve block. |
| Ropivacaine | Amino-amide local anesthetic | Increased free drug concentrations compared with bupivacaine owing to lower lipid solubility and protein binding; however, adverse fetal effects not reported. As a weak base, it may accumulate in the fetus in the setting of fetal acidosis. |
CI , Confidence interval; FDA , US Food and Drug Administration; GABA , gamma-amino-butyric acid; IQ , intelligence quotient; NMDA , N -methyl- d -aspartate; OR , operating room; RR , risk ratio.
Specific Highly Teratogenic Drugs
Some drugs are so highly teratogenic that two simultaneous forms of reliable contraception are recommended or required during treatment of either partner, sometimes to be continued for months or years after stopping the drug. Examples include: (1) thalidomide (and analogs), which is still used to treat erythema nodosum leprosum and multiple myeloma (fetal effect: severe malformations of the limbs [phocomelia], axial skeleton, head, face, eyes, ears, tongue, teeth, gastrointestinal tract, central nervous system, cardiovascular system, and respiratory systems) ; (2) the antiviral ribavirin , which is used for hepatitis C and viral hemorrhagic fevers (fetal effect: severe malformations and embryolethality at doses below recommended human doses reported in animal data) ; (3) isotretinoin , which is used for cystic acne (fetal effect: profound, extensive abnormalities of the central nervous, craniofacial and cardiovascular systems) ; and (4) acitretin , another retinoid that is used for severe psoriasis and is sequestered in fat tissue for at least 3 years. In Europe, use of valproate requires a pregnancy prevention program (fetal effect: cardiovascular, craniofacial, genitourinary, and musculoskeletal malformations plus cognitive developmental delay).
Drug Labeling for Pregnancy and Lactation
In 2014, the FDA published the Pregnancy and Lactation Labeling Rule (PLLR) . This rule supplanted the previously used letter (ABCDX) categories, which were oversimplified and of limited utility in risk-benefit decision making. The PLLR was implemented on June 30, 2015, and applies to all prescription drugs approved on or after June 30, 2001. The label must be updated whenever new information is available and thus should serve as a reliable source of up-to-date information in a standardized format. The PLLR requires narrative descriptions of available data in three categories under the “Use in Specific Populations” section: (1) Pregnancy, (2) Lactation, and (3) Females and Males of Reproductive Potential ( Box 16.2 ).
Box 16.2
Food and Drug Administration Pregnancy and Lactation Labeling Rule
Modified from Food and Drug Administration. Content and format of labeling for human prescription drug and biological products: requirements for pregnancy and lactation labeling. Fed Regist . 2014;79:72064–72103.
Pregnancy Section
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Pregnancy Exposure Registry: This section is only required if a scientifically acceptable registry exists that includes the labeled drug. It lists contact information to enroll in the registry or obtain additional information.
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Risk Summary : This section describes the risk of adverse developmental outcomes based on all relevant human, animal, and pharmacologic data. Adverse developmental outcomes include structural abnormalities, embryo-fetal and/or infant mortality, functional impairment, and alterations to growth. Information on the background risk of major birth defects and miscarriage should be included for systemically absorbed medications.
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Clinical Considerations : This section provides information to aid healthcare providers in prescribing and provision of risk-benefit counseling. Where information is available, this section includes five subheadings: (1) disease-associated maternal and/or embryo/fetal risk, (2) dose adjustments during pregnancy and the postpartum period, (3) maternal adverse reactions, (4) fetal/neonatal adverse reactions, and (5) labor or delivery.
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Data: This section describes the data that provided the scientific basis for the information presented in the “Risk Summary” and “Clinical Considerations” sections.
Lactation Section
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Risk Summary : This section summarizes information on the presence of a drug and/or its active metabolite(s) in human milk, the effect of the drug/metabolite(s) on the breastfed child, and the effect of the drug/metabolite(s) on milk production.
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Clinical Considerations : This section includes information on methods to minimize exposure of the breastfed child and available interventions for monitoring and mitigating adverse drug reactions in the breastfed child.
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Data : This section describes the data that provided the scientific basis for the information presented in the “Risk Summary” and “Clinical Considerations” sections.
Females and Males of Reproductive Potential Section
Pregnancy Testing, Contraception, and Infertility : These sections address whether pregnancy testing or contraception is recommended or required before, during, or after drug therapy and available data regarding adverse effects on fertility.
The PLLR guidelines are designed to overcome several limitations of the former letter-based categories, but many prescribers remain unfamiliar with the updated labeling guidelines. A 2018 survey of members of the American Academy of Allergy, Asthma, and Immunology found that less than half of respondents were aware of the updated labeling guidelines and 95% of respondents continued to use the former letter categories to make decisions. Fifty-six percent of respondents indicated that the PLLR narrative format was unhelpful compared with the letter-based categories. The utility of the PLLR narrative is inherently confined by the amount of pregnancy and lactation data available for a particular drug. An analysis of new drugs approved between 2010 and 2019 found that only 10.7% and 2.8% had available human data for pregnancy and lactation, respectively. Nearly half of medications evaluated had no animal or human lactation data. It will be imperative to continue to evaluate awareness and perceived utility of the PLLR system as the number of medications that are PLLR-compliant and the amount of available human data increase.
Drug Use During Lactation
Studies estimate that 66% to 84% of breastfeeding women use medication(s) during lactation. Nursing parents are understandably concerned about the transfer of drugs and chemicals to breast milk. Accurate advice is important to prevent unnecessary cessation of breastfeeding or discontinuation of appropriate drug treatment. Unfortunately, nearly half of all medications have no data on use during lactation, and less than 5% have available human data. The most comprehensive up-to-date information for individual agents can be found in the Drugs and Lactation Database (LactMed) of the National Library of Medicine’s Toxicology Data Network (TOXNET) . Potential infant risks from anesthetic drugs in lactating mothers are summarized in Table 16.4 . Data for nonanesthetic drugs are shown in Appendix 16.2 (online only).
Table 16.4
Potential Infant Risks From Anesthetic Drugs in Lactating Mothers
| Drug | Class | Neonatal Exposure M/P, RID (%) | Lactation Recommendation | Comments/Potential Risks |
|---|---|---|---|---|
| General Anesthetic Drugs | ||||
| Because a combination of anesthetic agents is normally used, the interval postprocedure for which the lactating mother should abstain (pump and dump) before resuming breastfeeding should be based on the most problematic medication. Breastfeeding immediately prior to anesthesia may decrease anesthetic requirements . | ||||
| Desflurane | Inhalational halogenated anesthetic | n/a | Compatible with breastfeeding | No published data on desflurane during lactation. Probably excreted into breast milk; however, because plasma half-life is very short and oral absorption is poor, minimal infant exposure is expected. Breast milk concentrations should be lower than with other halogenated agents because of low blood and tissue solubility and rapid washout. No waiting period or discarding of milk is required. |
| Isoflurane | Inhalational halogenated anesthetic | n/a | Compatible with breastfeeding | No published data on isoflurane during lactation. Probably excreted into breast milk; however, because plasma half-life is short and oral absorption is poor, minimal infant exposure is expected. No waiting period or discarding of milk is required. |
| Sevoflurane | Inhalational halogenated anesthetic | n/a | Compatible with breastfeeding | No published data on sevoflurane during lactation. Sevoflurane is probably excreted into breast milk; however, because the plasma half-life is short and the drug is poorly orally absorbed, the infant exposure is expected to be minimal. No waiting period or discarding of milk is required. |
| Nitrous oxide | General anesthetic, sedative, analgesia, inorganic gas | n/a | Compatible with breastfeeding | No data. Because the plasma half-life of nitrous oxide is less than 3 min, extensive passage into milk is not expected and the infant is not expected to absorb it. |
| Ketamine | General anesthetic nonbarbiturate, phencyclidine derivative |
|
|
Excreted with active metabolite, norketamine, into milk in very low concentrations. Oral bioavailability is low for both, so expected to pose little risk to breastfed infants. Elimination half-life approximately 2.17 h. Some authors have recommended an 11-h postdose abstention period (pump and dump), after whichthe drug should be undetectable in maternal plasma. Monitor infant for sedation and poor feeding. |
| Propofol | General anesthetic and hypnotic | RID: 0.2% | Compatible with breastfeeding | Amounts of propofol in breast milk are small and not expected to be absorbed by the infant. Discarding milk or deferring breastfeeding based on propofol exposure is not required. A green discoloration of breast milk following propofol use has been reported by some authors. |
| Local Anesthetic Drugs | ||||
| Bupivacaine | Amino-amide local anesthetic |
|
Compatible with breastfeeding | Among breastfed infants of mothers who received bupivacaine during delivery, 2/42 had transient tachypnea of unknown origin but none required readmission. |
| 2-Chloroprocaine | Amino-ester local anesthetic | n/a | Probably compatible; however, because of the absence of data, an alternative drug may be preferred | There are no published data on the use of 2-chloroprocaine during breastfeeding. Based on known low excretion of other local anesthetics into breastmilk and the extremely short half-life of 2-chloroprocaine, it is unlikely to adversely affect the breastfedinfant. |
| Lidocaine | Amino-amide local anesthetic | M/P: 1.07 | Compatible with breastfeeding | No adverse effects reported |
| Ropivacaine | Amino-amide local anesthetic | M/P: 0.23–0.25 | Compatible with breastfeeding | No adverse effects reported |
M/P , Ratio of drug concentration in milk/drug concentration in maternal plasma; n/a , not available; RID , relative infant dose (%) = infant dose (mg/kg/d)/maternal dose (mg/kg/d) × 100.
Infant exposure to maternal medication can be minimized simply by breastfeeding just prior to drug administration. For medications that were also taken during pregnancy, it is important to note that medication exposure through breast milk will almost always be much lower than fetal exposure in utero . Thus, it is generally appropriate to continue medications that were used during pregnancy while breastfeeding. Few medications are truly contraindicated during lactation. These include antineoplastics , ergot alkaloids , some anticonvulsants , gold , iodine , radiopharmaceuticals , and recreational drugs .
Maternal drugs may also affect lactation, and some are used therapeutically for this purpose. Galactagogues are medications or herbal therapies intended to increase milk production. However, the quality and quantity of available data on galactagogue efficacy are low. A systematic review and metaanalysis of two commonly used off-label galactagogues, domperidone and metoclopramide , found a significant increase in milk supply among mothers of preterm infants with low supply with domperidone but not metoclopramide. Domperidone is not approved for the purpose of increasing milk production in the United States because of safety concerns, including arrhythmias, cardiac arrest, and sudden death. The effect of herbal compounds such as fenugreek on milk production in well-controlled trials is mixed, though a network metaanalysis of multiple studies found a significant effect of fenugreek compared with controls.
Drugs that increase the secretion of prolactin could theoretically stimulate milk production, though a direct relationship between prolactin levels and milk volume has not been established. Drugs associated with increased prolactin levels include dopamine antagonists such as phenothiazines and haloperidol , and antipsychotics such as sulpiride and risperidone . Drugs that may decrease milk production include first-generation anticholinergics , high-dose estrogen , and dopamine agonists such as bromocriptine and cabergoline .
Transfer of Drugs to Breast Milk
Transfer of drugs between plasma and breast milk largely occurs via passive diffusion and is bidirectional. During colostrum production in the first 3 to 4 days postpartum, the mammary epithelium allows passage of large molecules and cells. Although this suggests a higher potential for drug transfer in early breastfeeding, minimal milk intake during this early period is likely to limit infant exposure. Over the first week postpartum, mammary epithelial cells establish tight junctions that limit transfer of large molecules. Most drugs move between blood and breast milk via passive diffusion down the concentration gradient formed by the nonionized, unbound drug on either side of the semipermeable lipid barrier. Large molecules such as monoclonal antibodies and heparins typically cannot diffuse into breast milk, although inflammatory conditions such as mastitis can disrupt the epithelial barrier and allow for increased paracellular drug transfer into breast milk.
Additional properties beyond molecular weight that affect the concentration in breast milk include lipid solubility, protein binding, and degree of ionization. Highly lipid-soluble drugs pass more readily into breast milk. Fat is the most variable macronutrient in breast milk, and higher concentrations will favor higher concentrations of lipid-soluble drugs. Fat content is higher in hindmilk compared with foremilk, during the day compared with early morning and at night, and earlier in the postpartum period.
Ionization status also affects drug concentrations in breast milk. Breast milk is more acidic than plasma, which allows ionized weak bases to concentrate in breast milk while ionized weak acids concentrate in plasma. For example, breast milk concentrations of codeine , a weak base, are 1.5 times higher than plasma concentrations. Other weak bases that may disproportionately concentrate in breast milk include amphetamines and benzodiazepines . The degree to which this phenomenon occurs is influenced by breast milk pH, which can vary from 6.7 to 7.4.
Protein binding also affects the transfer of drugs into breast milk. Protein concentrations are significantly higher in plasma than breast milk (75 versus 8 to 9 g/L), and the majority of proteins in breast milk have low affinity for drug binding. Consequently, highly protein-bound drugs tend to be retained in the plasma. Drugs that are more than 85% protein bound do not typically result in infant exposure. Exceptions have been noted for drugs that were also administered during pregnancy or during delivery as well as for those given at high doses in the first week postpartum.
Alhough most drugs move by passive diffusion, a small number undergo active transport. The sodium iodide transporter and the breast cancer resistance protein actively transport substrates into breast milk. This leads to an increased concentration of transporter substrates in breast milk, including iodide, acyclovir, cimetidine, methotrexate, and nitrofurantoin .
Approximations of infant exposure are often quantified as the relative infant dose (RID) :
The infant dose for the RID can be determined from the maternal plasma concentration (C maternal ), the ratio between milk and plasma concentrations (M/P), and the volume of milk ingested (V milk ), which is estimated to be 150 mL/kg/day if the specific value is unknown.
A World Health Organization Working Group proposed that drugs with an RID > 10% of the lowest maternal or infant weight-adjusted dose may not be safe in breastfeeding and drugs with an RID > 25% should be avoided. Others have proposed a more conservative 5% threshold. Importantly, the RID does not account for infant age, pharmacogenomic factors, active metabolites, or variable toxicity among drugs.
Infant age modifies risk owing to both changes in volume of milk consumption and maturation of infant metabolic and excretory pathways. These differences can result in prolonged drug half-lives in neonates. Among reported adverse events in breastfed infants, approximately two-thirds occurred in the first month postpartum and three-quarters within the first 2months.
Maternal and infant pharmacogenomics can also affect toxicity. For example, the prodrug, codeine , and its active metabolite, morphine , are generally found at clinically insignificant concentrations in breast milk, and a large, population-based cohort study found no association between adverse infant outcomes and maternal codeine use. However, a report of infant death secondary to maternal codeine use highlights the potential impact of pharmacogenomic variants. The mother in this case was determined to be a CYP2D6 UM, resulting in much more rapid conversion of codeine to morphine. While this case represents an extremely rare event, it underscores the potential for pharmacogenomic variants to significantly modify infant exposures in breastfeeding.
KEY POINTS
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Approximately two-thirds of pregnant women in North America report the use of over-the-counter medications.
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Much of the care provided to pregnant patients involves the use of medications.
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Drugs administered to the pregnant patient may be prescribed to treat a maternal condition with incidental fetal transfer, or they may be prescribed to treat a fetal problem with maternal exposure.
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Because of the physiologic, pharmacokinetic, and pharmacodynamic changes that occur during gestation, pregnancy is considered the fifth special pharmacologic population (in addition to people with hepatic disease, people with renal disease, children, and geriatric adults).
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Dosing strategies developed for healthy nonpregnant adults may not achieve comparable results when prescribed for pregnant patients.
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Concentrations of reproductive hormones as well as cortisol dramatically increase during pregnancy.
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The expansion of plasma volume and total body water increases the volume of distribution of hydrophilic medications and reduces the concentration-to-dose ratio of their initial doses.
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The plasma proteins albumin and alpha-1 acid glycoprotein have lower concentrations during pregnancy; this results in protein-bound drugs having a greater free fraction for (1) drug effect, (2) movement of drug into nonplasma spaces (tissue concentrations are increased), and (3) drug availability for metabolism and/or clearance. Monitoring of free drug is often recommended during pregnancy for drugs that are highly protein-bound and have a narrow therapeutic range.
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Increased cardiac output during pregnancy leads to increased glomerular filtration, which, coupled with changes in activity of renal drug transporters, increases the renal clearance of many drugs.
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The activities of drug-metabolizing enzymes are variably affected during pregnancy; activities may increase or decrease, and a few do not change, compared with the nonpregnant state.
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An increase in endogenous opioids promotes maintenance of the pregnant state and enhances fetal health via multiple pathways.
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Endogenous opioids increase pain threshold during pregnancy; this contributes to a reduction in the MAC values of volatile anesthetic agents and faster onset and longer duration of local anesthetics employed for nerve blocks in pregnant patients.
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Teratogens are substances that adversely affect the developing fetus by altering its growth, structure, or function.
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A teratogen produces a specific abnormality or constellation of abnormalities with a dose-effect relationship.
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Teratogen exposure must occur at a specific stage of gestation to have an effect.
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Susceptibility to teratogenesis is affected by the genotype of both mother and fetus.
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The 2014 FDA Pregnancy and Lactation Labeling Rule supplanted the previous letter system and provides detailed information regarding pregnancy, lactation, and reproductive effects of drugs.
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Most drug transfer to breast milk occurs via passive diffusion and is bidirectional. Drug transport is affected by molecular size, lipid solubility, protein binding, and degree of ionization.
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The NICHD Drugs and Lactation Database (LactMed) ( https://www.ncbi.nlm.nih.gov/books/NBK501922/ ) provides the most comprehensive and up-to-date information for the use of specific medications during breastfeeding.
Appendix 16.1
Potential Fetal Risks From Intrauterine Exposure to Nonanesthetic Drugs
| Drug | Class | Comments/Potential Risks |
|---|---|---|
| Analgesics/Antipyretics | ||
| Acetaminophen/paracetamol/APAP | Nonopioid antipyretic analgesic | Risks of maternal and fetal hepatic toxicity with overdosage. The long-held position of the US FDA that APAP-containing products are of minimal risk when used as directed in pregnancy was challenged in 2021. Although the risks are very low and the data often inconsistent and sometimes confounded by the indication itself, long-term exposure has been associated with cryptorchidism, decreased IQ, ADHD, and other problems in neurodevelopment. In contrast, short-term use of APAP was usually beneficial, did not cause these harms, and often prevented additional harms associated with the febrile illness itself. In response, an ACOG position paper reiterated that they “…have always identified acetaminophen as one of the only safe pain relievers for pregnant individuals during pregnancy. This consensus statement, and studies that have been conducted in the past, show no clear evidence that proves a direct relationship between the prudent use of acetaminophen during any trimester and fetal developmental issues.” Their concluding recommendation: “…as always, any medication taken during pregnancy should be used only as needed, in moderation, and after the pregnant patient has consulted with their doctor.” |
| Ibuprofen, indomethacin, ketorolac, naproxen sodium, aspirin (analgesicdosing) | NSAID, nonspecific COX inhibitor | Risks of neonatal periventricular leukomalacia, intraventricular hemorrhage, necrotizing enterocolitis and oligohydramnios. Periconception exposure may prevent blastocyst implantation based on animal studies. One study in 3173 women exposed to NSAIDs in the first trimester found a small but significant increase in a variety of congenital defects; however, the authors cautioned that additional studies were needed because these associations had not been reported in other databases. Third-trimester exposure: fetal ductus arteriosus stenosis with premature ductal closure and persistent pulmonary hypertension. Recommendations: avoid use in third trimester, limit use in first trimester, balance risks and benefits of administration for less than or equal to 48 h in second trimester. |
| Celecoxib | NSAID, selective COX-2 inhibitor | Celecoxib is not mutagenic in animal testing. Because of prostaglandin synthesis inhibition, periimplantation exposure to female rats resulted in embryo losses and reduced fetal survival. In humans, a case-control study found an association with celecoxib use and increased risk for spontaneous early pregnancy loss. In a study comparing the tocolytic effects of celecoxib and indomethacin for preterm labor, partial premature constriction of the fetal ductus arteriosus occurred in the indomethacin group, but not in the celecoxib group. A transient decrease in amniotic fluid volume was observed in both groups but more so with indomethacin. Both drugs were equally effective in the maintenance of tocolysis; however, the safety of celecoxib was superior to that of indomethacin. |
| Antacids | ||
| Famotidine | H2-receptor antagonist | In animal studies with dosages up to 50-fold higher than human exposures, no evidence of fetotoxicity, teratogenicity, or changes in postnatal behavior was observed. In the two largest studies of H2-receptor antagonists in pregnancy (2398 and 1148 exposures), no increases in congenital malformations, spontaneous abortion, preterm birth, or small-for-gestational-age births were observed. |
| Omeprazole/esomeprazole, lansoprazole, pantoprazole, rabeprazole | Protein pump inhibitor | Although individual case reports have suggested associated malformations, large database studies and metaanalyses have reported no difference in the rate of malformations for early pregnancy exposure with any of the protein pump inhibitors, nor any increase in spontaneous abortions, preterm births, perinatal mortality, or small-for-gestational-age infants. |
| Antiarrhythmic Drugs | ||
| Amiodarone | Potassium channel blocker (plus beta-2-adrenergic receptor antagonist and sodium channel blocker) | Amiodarone use has been associated with fetal hypothyroidism, although it appears to be transient. ACOG recommends against use of amiodarone in pregnancy. Its use should be reserved for refractory cases only. |
| Digoxin | Cardiac glycoside | Digoxin is one of the most well-studied antiarrhythmics in pregnancy with well-documented fetal safety. |
| Diltiazem | Calcium channel blocker | Increased risk of fetal growth restriction. Skeletal, cardiac, tongue, and retinal abnormalities in animal models. At 4–6 times recommended human dose, embryo and fetal lethality in mice, rats, and rabbits. Use with caution in pregnancy. |
| Dofetilide | Potassium channel blocker | Do not use in pregnancy. Human data lacking. In pregnant rats, dofetilide caused fetal resorption and skeletal abnormalities if administered during organogenesis. In rats, dofetilide caused significant bradycardia at gestational days 11 and 13, even at the lower dose of 2.5 mg/kg. |
| Dronedarone | Multiple channel blocker | Do not use in pregnancy. Significant fetal adverse events including vascular and limb abnormalities and cleft palate. |
| Flecainide | Sodium channel blocker | Sodium channel blockers and beta-adrenergic receptor antagonists (i.e., flecainide, sotalol) exhibit transplacental passage and can be used to treat maternal or fetal arrhythmias. Current data do not suggest risk of fetal harm with therapy. |
| Procainamide | Sodium channel blocker | Minimal human and fetal data. |
| Sotalol | Beta-adrenergic receptor antagonist | No teratogenic potential. Small risk of fetal bradycardia and hypoglycemia. In rats and rabbits, at nine and seven times maximum recommended human dose, teratogenic effects were not observed. |
| Anticoagulants | ||
| Argatroban | Direct thrombin inhibitor | May be associated with risk of postpartum hemorrhage. No evidence of fetal toxicity in animal studies. Limited data in humans, but it does cross the placenta. |
| Aspirin | Nonspecific cyclooxygenase inhibitor (COX-1, COX-2) | Low-dose aspirin has a well-documented safety profile in pregnancy without evidence of adverse fetal effects. |
| Clopidogrel | Antiplatelet agent | Clopidogrel has not been associated with adverse fetal effects. It should be withheld 7 d prior to delivery to avoid complications related to regional anesthesia or postpartum hemorrhage. |
| Fondaparinux | Factor Xa inhibitor | Although there are limited data suggesting safety in pregnancy, there is evidence that fondaparinux crosses the placenta; therefore, its use is restricted to situations where heparin or LMWH are contraindicated. Of the newer oral anticoagulants, because fondaparinux has the most data available suggesting safety in pregnancy, it is the preferred alternative to heparin/LMWH. |
| Heparin, LMWHs (enoxaparin, dalteparin) | Factor Xa inhibitor | These agents do not cross the placenta and have no fetal effect. |
| Rivaroxaban | Factor Xa inhibitor | Rivaroxaban has had reports of both adverse fetal effects as well as increased risk of hemorrhage. Not a preferred agent in pregnancy. |
| Warfarin | Vitamin K antagonist | Warfarin readily crosses the placenta and is teratogenic, with first trimester use associated with warfarin embryopathy characterized by nasal hypoplasia and skeletal abnormalities. Warfarin exposure during the second and third trimesters is associated with possible seizures, developmental delay, and hypotonia attributable to intracranial microhemorrhages. When warfarin is needed in pregnancy it is recommended to defer initiation until the second trimester or use at a low dose of less than 5 mg/d. |
| Antiemetics | ||
| Doxylamine | Antihistamine, ethanolamine class | The combination of doxylamine and pyridoxine (vitamin B 6 ) has been shown to be safe and without an increased risk of associated malformations in numerous studies. |
| Dimenhydrinate | Ethanolamine-derivative sedating antihistamine | In general, antihistamines are considered safe in pregnancy. Dimenhydrinate should not be used during labor for its oxytocic effects, because of the risks of associated uterine hyperstimulation and fetal compromise. |
| Metoclopramide | Dopamine antagonist | No significant association between metoclopramide and any fetal malformation. Not associated with increased risk of spontaneous abortion. Maternal adverse effects: fatigue, dizziness, agitation. Coadminister with diphenhydramine to reduce metoclopramide-associated akinesia. |
| Ondansetron | Serotonin (5-HT3) antagonist | With controlling for potential confounding variables, no significant associations were seen with either oral or IV ondansetron and cardiac malformations or overall malformations. Although an earlier study with oral ondansetron could not exclude as association with oral clefts, the study with IV ondansetron showed no association with oral clefts. |
| Prochlorperazine | Piperazine phenothiazine | The Collaborative Perinatal Project monitored 50,282 pregnancies, of which 877 had first trimester exposure to prochlorperazine and 2023 recorded anytime use during pregnancy; there was no evidence to support a relationship to malformations, or change in perinatal mortality rate, birth weight, or IQ scores at 4 y. The Swedish Medical Birth Registry (n = 958,729 births) evaluated 224 pregnancies with first trimester exposure to prochlorperazine. There was no associated increased risk for malformations, preterm delivery, low birth weight, high birth weight, or intrauterine fetal demise. |
| Promethazine | Phenothiazine antihistamine | Not teratogenic in animal studies. In the Collaborative Perinatal Project (n = 50,282 pregnancies), 114 pregnancies had first-trimester exposure to promethazine and 746 had any use during pregnancy; neither group was associated with major or minor malformations. May impair platelet aggregation in the newborn when administered within 2 w of delivery. |
| Trimethobenzamide | Substituted benzamide | Both animal data and limited human pregnancy experience suggest that fetal risk associated with exposure is low. Following first trimester use of trimethobenzamide in 193 pregnant women, severe congenital defects were not increased. |
| Scopolamine | Anticholinergic | No teratogenicity in animal studies. No reported malformations when used in pregnancy. In the Collaborative Perinatal Project (n = 50,282 pregnancies), 309 pregnancies had first trimester exposure to scopolamine and 881 had any use during pregnancy; neither group was associated with major or minor malformations. Scopolamine should be avoided in women with severe preeclampsia because eclamptic seizures have been observed shortly after scopolamine administration. |
| Antihistamines | ||
| Cetirizine | Second-generation H1-receptor antagonist | No association identified between cetirizine and increased rates of birth defects, preterm delivery, or low birth weight. Because cetirizine is a P-glycoprotein substrate, limited transfer across the placenta is expected. |
| Diphenhydramine | First-generation H1-receptor antagonist | Not associated with spontaneous abortion or preterm birth. No association with birth defects across multiple studies. Other studies have identified associations with multiple defects, but no consistent pattern of defects was identified. |
| Fexofenadine | Second-generation H1-receptor antagonist | No association found between fexofenadine use in pregnancy and major birth defects, spontaneous abortion, preterm birth, small-for-gestational-age status, or stillbirth. P-glycoprotein substrate expected to have limited transfer across placenta. |
| Loratadine | First-generation H1-receptor antagonist | One study suggested a relationship between loratadine and hypospadias, but multiple subsequent studies did not replicate this finding. |
| Meclizine | First-generation H1-receptor antagonist | No association with birth defects across multiple studies after controlling for indication. |
| Antihypertensive Drugs | ||
| Benazepril, captopril, enalapril/enalaprilat, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril | ACE inhibitor | Exposure throughout pregnancy is strictly contraindicated. These drugs cross the placenta with significant adverse fetal effects. ACE inhibitors have been associated with congenital malformation, renal failure, oligohydramnios, neonatal hypotension, and death. |
| Azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan | ARB | Exposure throughout pregnancy is strictly contraindicated. These drugs cross the placenta with significant adverse fetal effects. ARBs have been associated with congenital malformations, renal failure, oligohydramnios, neonatal hypotension, and death. |
| Amlodipine | Calcium channel blocker | Calcium channel blockers are safe and effective for use in pregnancy without evidence of adverse fetal effects. |
| Atenolol | Beta-adrenergic receptor antagonist | Because atenolol has been associated with an increased risk for small-for-gestational-age, other beta-adrenergic receptor antagonists are preferred in pregnancy. Treatment starting in the early second trimester is associated with the greatest decrease in fetal and placental weights, whereas treatment restricted to the third trimester primarily affects only placental weight. Newborns exposed to atenolol near delivery should be observed for signs of beta-blockade. |
| Clonidine | Centrally acting alpha-2-adrenergic receptor agonist | Weigh the risks and benefits before use in pregnant patients, use only if clearly needed. Clonidine readily crosses the placenta, achieving equal concentrations when measured in maternal and umbilical serum with amniotic fluid concentrations up to four times those found in serum. No reports linking the use of clonidine with congenital defects have been published. |
| Labetalol | Alpha- and beta-adrenergic receptor antagonist | Although growth restriction is a possibility with this class of drugs, most studies have found no effect on fetal growth. |
| Metoprolol | Beta-adrenergic receptor antagonist | Metoprolol is well tolerated in pregnancy without adverse maternal or fetal effects. Although growth restriction is a possibility with this class of drugs, most studies have found no effect on fetal growth. |
| Nifedipine | Calcium channel blocker | Calcium channel blockers are safe and effective for use in pregnancy without evidence of adverse fetal effects. Nifedipine does not appear to be a major teratogen based on several studies. |
| Antiinfectives: Antibacterial Drugs | ||
| Azithromycin | Macrolide antibiotic | Generally considered to be safe in pregnancy. No association with adverse fetal effects in most, but not all, studies. |
| Carbapenems | Beta-lactam antibiotic | Limited pregnancy data available. Reserve for pregnant individuals with contraindications to penicillins and cephalosporins. |
| Cephalosporins | Beta-lactam antibiotic | Cephalosporins cross the placenta. No association with congenital abnormalities after first trimester use and no association with abnormalities in infant development in the first 18 mo of life. |
| Ciprofloxacin, ofloxacin | Fluoroquinolone antibiotic | Fluoroquinolones are generally contraindicated in pregnancy owing to arthropathies observed in animal models. Malformations have been reported after exposure to fluoroquinolones in human pregnancies but without a consistent pattern. Other human studies have not identified a relationship between ciprofloxacin use in pregnancy and either spontaneous abortion or major malformations. Malformations after exposure to ofloxacin specifically have been reported in some but not all human studies. |
| Clarithromycin | Macrolide antibiotic | Teratogenicity reported in multiple animal studies but to date no consistent association with malformations has been reported in human pregnancy data. One study reported a higher rate of spontaneous abortions compared with nonteratogenic antibiotics; however, the incidence was still within the expected baseline rate. |
| Dalbavancin | Lipoglycopeptide antibiotic | Human data not yet available. Increased embryo lethality and offspring death in animal studies. |
| Erythromycin | Macrolide antibiotic | Association with pyloric stenosis reported but not replicated in subsequent studies. Cardiovascular defects, mostly mild, have been reported. |
| Kanamycin, streptomycin | Aminoglycoside antibiotic | Cross the placenta. Associated with potential ototoxicity and hearing loss. Avoid except in the context of severe infections not responsive to other therapies. |
| Metronidazole | Nitroimidazole antibiotic | Crosses the placenta. Associated with spontaneous early pregnancy loss in some studies, though unclear if association is driven by metronidazole or underlying infection. Some studies report an association with congenital hydrocephaly. Other defects have been reported in a minority of studies without a consistent pattern. As a precaution it is generally recommended that metronidazole be avoided in the first trimester. |
| Monobactams | Beta-lactam antibiotic | Cross the placenta. No fetal adverse effects reported in small studies of aztreonam in pregnancy. Because of limited data, reserve for pregnant individuals with contraindications to penicillins. |
| Oritavancin | Lipoglycopeptide antibiotic | Human data not yet available. No evidence of toxicity in animal studies. |
| Penicillins | Beta-lactam antibiotic | Cross the placenta by passive diffusion. Generally considered safe for use in pregnancy. |
| Sulfamethoxazole-trimethoprim | Sulfonamide antibiotic | First-trimester use associated with increased risk of spontaneous abortion. Mixed data on association with congenital malformations, with some studies finding no association and others indicating a higher rate of cardiovascular and urinary tract defects. Theoretical concern for adverse effects resulting from trimethoprim folate antagonism. Sulfamethoxazole competes with bilirubin for albumin binding, increasing free bilirubin, which can cross the blood-brain barrier. Use prior to birth carries the theoretic risk of neonatal kernicterus. |
| Telavancin | Lipoglycopeptide antibiotic | Crosses the placenta. Human data not yet available. Animal data suggests potential for limb and skeletal malformations, though the strength of this association has been contested. |
| Tetracycline | Tetracycline antibiotic | Should not be used in pregnancy, especially after the fifth week. Binds to calcium in developing fetus, causing tooth discoloration and inhibition of bone growth. Inconsistent associations between tetracycline and other malformations including hypospadias, inguinal hernia, and limb hypoplasia. |
| Vancomycin | Glycopeptide antibiotic | Crosses the placenta. Generally considered to be safe in pregnancy. No associations identified with ototoxicity, nephrotoxicity, or adverse fetal outcomes. |
| Antiinfectives: Antiretroviral Medications | ||
| Abacavir | Nucleoside reverse transcriptase inhibitor | Crosses the placenta. Limited human data available, but a cohort study did not identify an increase in birth defects with abacavir use in pregnancy. |
| Atazanavir/ritonavir | Protease inhibitor | Some studies have found no association with fetal anomalies, while others report an increased incidence of malformations of the skin, cardiovascular system, and musculoskeletal system. Some studies have found an association with delayed language development at 12 but not 24 mo. Possible increased risk of neonatal jaundice. These side effects do not merit discontinuation, as risks of untreated HIV infection are greater. |
| Darunavir/ritonavir | Protease inhibitor | Crosses the placenta. No increased incidence of congenital malformations above baseline population risk reported with use in pregnancy. |
| Dolutegravir | Integrase strand transfer inhibitor | Crosses the placenta. Potential risk of neural tube defects. No increased risk of preterm birth, low birth weight, or small-for-gestational-age infants compared with nondolutegravir-based HIV regimens. |
| Doravirine | Nonnucleoside reverse transcriptase inhibitor | Crosses the placenta but no human data currently available to assess fetal safety profile. Animal data do not indicate increased risk. |
| Efavirenz | Nonnucleoside reverse transcriptase inhibitor | Association with central nervous system congenital anomalies reported in some but not all studies. One study found significantly worse outcomes at 24 mo with respect to developmental milestones, receptive language, locomotor, and fine motor development after exposure to efavirenz-based triple antiretroviral therapy. |
| Emtricitabine | Nucleoside reverse transcriptase inhibitor | Limited human data but no indication of increased incidence of adverse fetal outcomes. |
| Etravirine | Nonnucleoside reverse transcriptase inhibitor | Crosses the placenta. Limited human safety data available but no adverse effects reported. |
| Lamivudine | Nucleoside reverse transcriptase inhibitor | Crosses the placenta. Incidence of adverse events not elevated above baseline rates. |
| Lopinavir/ritonavir | Protease inhibitor | No increased incidence of congenital malformations above baseline population risk reported with use in pregnancy. |
| Nevirapine | Nonnucleoside reverse transcriptase inhibitor | Crosses the placenta. No adverse fetal effects reported. |
| Raltegravir | Integrase strand transfer inhibitor | Crosses the placenta. Most studies do not report an association with adverse effects though most available data are from exposure after the first trimester. Available data from infants exposed in the first trimester do not indicate an increase in anomalies above the baseline population incidence. |
| Rilpivirine | Nonnucleoside reverse transcriptase inhibitor | Limited human safety data available. Similar delivery outcomes, including incidence of birth defects, among women who switched to a rilpivirine-free regimen compared with those who continued rilpivirine treatment. |
| Tenofovir | Nucleoside reverse transcriptase inhibitor | Crosses the placenta. No difference in the incidences of small-for-gestational-age status, low birth weight, length, or head circumference at birth, though head circumference-for-age and length-for-age were slightly decreased at 1 y. No increased incidence of fetal malformations over baseline population risk. |
| Zanamivir | Neuraminidase inhibitor | Not associated with increased risk for major defects, preterm delivery, or low birth weight. |
| Zidovudine | Nucleoside reverse transcriptase inhibitor | Crosses the placenta. Association reported between zidovudine use and heart defects in some but not all studies. Small potential increase in male genital malformations. |
| Antiinfectives: Antiviral—HSV | ||
| Acyclovir | Nucleoside analog | No increased incidence of congenital malformations above baseline population risk reported with use in pregnancy. Treatment of HSV decreases the risk of adverse effects due to infection. |
| Valacyclovir | Nucleoside analog | Limited pregnancy-specific data available, but given that valacyclovir is a prodrug of acyclovir, it is presumed to have a similar safety profile. |
| Antiinfectives: Antiviral—Influenza | ||
| Oseltamivir | Neuraminidase inhibitor | Not associated with increased risk for preterm delivery, small-for-gestational-age status, low Apgar scores, or malformations. Some data suggest a decreased risk for small-for gestational-age status and low birth weight owing to decreased complications from influenza. |
| Peramivir | Neuraminidase inhibitor | No adverse events attributable to peramivir across a small number of reported cases. Additional human data are needed, but data for other neuraminidase inhibitors are reassuring. |
| Zanamivir | Neuraminidase inhibitor | Not associated with increased risk for major defects, preterm delivery, or low birth weight. |
| Antiinfectives: COVID-19 | ||
| Dexamethasone | Corticosteroid | Hydrocortisone or methylprednisolone preferred for treatment longer than 2 d, as repeated doses of dexamethasone have been associated with adverse neonatal outcomes. Use in the first trimester associated with a small absolute risk of oral clefts. |
| Hydrocortisone | Corticosteroid | Associated with decreased birth weight in some but not all studies. Asmall increase in the incidence of cleft lip with or without cleft palate has been reported. Cataracts in offspring have also been reported, though a causal relationship has not been definitively established. |
| Nirmatrelvir/ritonavir | Protease inhibitor | Human data are currently limited, but nirmatrelvir/ritonavir is not contraindicated in pregnancy. A case series of treated pregnant patients did not identify any increase in complications. Ritonavir has not been associated with an increase in the risk of major birth defects. |
| Remdesivir | Nucleoside analog | Comprehensive human data not yet available. Available data do not suggest serious safety signals but more systematic study, including a focus on first-trimester exposure, is needed. |
| Antiseizure Medications (Note: Polytherapy significantly increases the risk of congenital abnormalities and intrauterine fetal demise. ) | ||
| Carbamazepine | Sodium channel blocking, tricyclic antiseizure medication; active epoxide metabolite | Studies and pregnancy registries have reported dose-dependent neural tube, craniofacial, cardiac, renal, and hypospadias abnormalities plus other major and minor congenital malformations, with one study reporting a serious outcomes rate of 8.2% (fetal death 3.6% and congenital malformations 4.5%) in pregnancies exposed to carbamazepine. A 2016 Cochrane review reported that children exposed to carbamazepine monotherapy were at a higher risk of malformation than children born to women without epilepsy (n=1367 versus 2146, RR 2.01, 95% CI, 1.20 to 3.36) and women with untreated epilepsy (n = 3058 versus 1287, RR 1.50, 95% CI, 1.03 to 2.19). Although folate supplementation is recommended, it is not known if replacement reduces the risk of neural tube defects associated with carbamazepine. |
| Gabapentin | GABA analog, GABA receptor agonist | Limited reports of pregnancy exposure. Because gabapentin is often administered combined with other medications, assigning causality is difficult. Gabapentin readily crosses the placenta and achieves concentrations that exceed maternal plasma: mean umbilical cord/maternal plasma ratio at birth was 1.7 (range 1.3–2.1). Although some studies have reported an increased risk of congenital cardiovascular anomalies, hypospadias, and psychomotor developmental delay, the Cochrane 2016 review reported no increase in major congenital abnormalities with gabapentin monotherapy. |
| Lamotrigine | Sodium channel blocking antiseizure medication | Multiple pregnancy registries have not detected an increased risk for major congenital malformations with lamotrigine monotherapy and its use is not associated with increased risk of miscarriage, preterm labor, growth restriction, or fetal death. Although several studies have shown a small risk of orofacial clefts during first-trimester exposure (absolute risk between 0.1% and 0.4%), a larger, more recent systematic review showed the incidence of cleft defects to be no different compared with controls. Because lamotrigine inhibits dihydrofolate reductase, folate supplementation is recommended. |
| Levetiracetam | Presynaptic calcium channel inhibitor | Monotherapy is not associated with increase in congenital abnormalities, neurodevelopmental abnormalities, preterm delivery, or growth restriction. |
| Phenobarbital | Long-acting barbiturate | Two- to threefold greater risk for major congenital defects, including cardiac, midline clefts, renal, smaller head circumference, plus others with a dose-dependent increase in risk for daily doses > 80 mg. Phenobarbital has been associated with early hemorrhagic disease of the newborn and neonatal barbiturate withdrawal. Its association with cognitive impairment has been inconsistent. |
| Phenytoin | Sodium channel blocker | Two- to threefold greater risk for major congenital defects, including cleft lip/palate, club foot, and fetal hydantoin syndrome (spectrum of numerous craniofacial defects, hypoplasia and ossification of the distal phalanges, and other skeletal abnormalities) compared with offspring born to women without epilepsy and untreated women with epilepsy. Multiple case reports suggest that phenytoin is a transplacental carcinogen, in particular associated with neuroblastoma. Phenytoin may cause early hemorrhagic disease of the newborn. In a large metaanalysis, children exposed to phenytoin in utero did not show significant differences in cognitive development, autism, or psychomotor development compared with offspring of untreated women with epilepsy. Folate supplementation is recommended. |
| Oxcarbazepine | Prodrug, metabolized to its active 10-monohydroxy derivative; odium channel blocker | Although data are limited, no increase in risk of major congenital abnormalities has been observed with oxcarbazepine exposure or cognitive developmental problems. An increased risk of autism has been observed; however, the risk becomes nonsignificant when compared with offspring of untreated women with epilepsy. No increased risk of fetal death. |
| Topiramate | Sulfamate modified monosaccharide | Two- to threefold greater risk for major congenital defects, in particular cleft lip and palate, plus genitourinary abnormalities. A Cochrane review reported a higher risk of malformations (RR, 3.69; 95% CI, 1.36 to 10.07) compared with children born to women without epilepsy. Increased risk of spontaneous abortion and fetal death (OR, 23.58; 95% CrI, 1.18 to 549.60) compared with no treatment. Higher doses and third-trimester exposure are associated with fetal growth restriction. |
| Valproic acid, valproate sodium, divalproex sodium | Low-molecular-weight branched-chain fatty acid; antiseizure medication | Valproic acid and its related compounds are known human teratogens. Not recommended in pregnancy. If possible, stop prior to attempting pregnancy and transition to alternative therapy. Frequency of serious adverse outcomes (fetal death or congenital abnormalities) in valproate-exposed pregnancies 20.3%. Increased risk of fetal death and spontaneous abortion (OR, 1.83; 95% CrI, 1.04 to 3.45). Offspring exposed to valproate were at a higher risk for any malformation (cardiovascular, craniofacial, genitourinary, musculoskeletal) compared with children born to women without epilepsy (n = 467 versus 1936; RR 5.69; 95% CI, 3.33 to 9.73) and to women with untreated epilepsy (n = 1923 versus 1259; RR, 3.1; 95% CI, 2.16 to 4.54). Increased risk of cleft lip/palate (OR, 3.26; 95% CrI, 1.38 to 5.58). More importantly, more than any other antiseizure medication, valproate exposure is significantly associated with an increased risk of cognitive developmental delay compared with control women with epilepsy not exposed to antiseizure medications (OR, 7.40; 95% CrI, 3.00 to 18.46). Significantly greater odds of developing autism occur compared with offspring of women with epilepsy not taking antiseizure medications (OR, 17.29; 95% CrI, 2.40 to 217.60). |
| Hypoglycemic Drugs | ||
| Glyburide | Sulfonylurea | Glyburide crosses the placenta. It is not associated with congenital anomalies but has been associated with a higher rate of adverse perinatal outcomes compared with other options, including macrosomia and neonatal hypoglycemia. |
| Insulin | Peptide hormone | Insulin does not cross the placenta and has no direct fetal impact. |
| Metformin | Biguanide | Metformin crosses the placenta but has not been associated with an increased risk of congenital anomalies and appears to be safe with use in pregnancy, although long-term impact of metformin on childhood outcomes remains poorly studied. |
| Immunosuppressants | ||
| Azathioprine | Purine synthesis inhibitor | Not associated with adverse fetal effects. |
| Cyclosporine | Calcineurin inhibitor | Not associated with adverse fetal effects in humans. |
| Dexamethasone, betamethasone | Corticosteroid | Dexamethasone and betamethasone cross the placenta. Although a limited course is used to reduce prematurity-related morbidity, repeated doses or prolonged use may have adverse fetal effects. Use in pregnancy is supported for maternal benefit. |
| Methotrexate | Antimetabolite | Associated with fetal teratogenicity, contraindicated in pregnancy. |
| Mycophenolate | Guanosine synthesis inhibitor | Associated with fetal teratogenicity including increased risk of pregnancy loss and malformations; not recommended in pregnancy. |
| Prednisone, prednisolone | Corticosteroid | Prednisone and prednisolone exhibit some placental transfer (less than dexamethasone or betamethasone). Although earlier data suggested an increased risk of cleft palate with first-trimester exposure, more recent data do not support that, and the absolute risk remains small (approximately 1–2 per 1000). Prednisone should be used as clinically indicated for maternal benefit. |
| Tacrolimus | Calcineurin inhibitor | Not associated with increased risk of congenital anomalies. |
| Opioids | ||
| Buprenorphine | Nonselective, mixed agonist-antagonist opioid receptor modulator | Although dose-dependent skeletal abnormalities were seen in some animal studies, no congenital abnormalities have been reported in buprenorphine-exposed human pregnancies. In opioid-dependent patients, compared with methadone, no differences were seen in Apgar scores at 1 and 5 min, or in maternal or fetal adverse effects. Compared with methadone, the occurrence, severity, and duration of treatment for neonatal opioid withdrawal syndrome were less with buprenorphine. |
| Butorphanol | Synthetic opioid mixed agonist-antagonist | No reports examining the association between butorphanol and congenital abnormalities have been published. Transient sinusoidal fetal heart rate patterns were observed in 75% of laboring women after butorphanol; however, because no neonatal adverse effects were observed, the authors concluded that it was not indicative of fetal hypoxia. Prolonged used during pregnancy can result in neonatal opioid withdrawal syndrome. |
| Codeine | Opioid analgesic; prodrug converted to active metabolites morphine and codeine-6-glucuronide | First-trimester exposure to codeine has been associated with genitourinary abnormalities, umbilical and inguinal hernias, cleft lip and palate, musculoskeletal defects, and cardiovascular abnormalities. Second-trimester use in pregnancy was associated with hydrocephaly, pyloric stenosis, umbilical and inguinal hernias, and alimentary tract defects. Exposure during labor associated with increased neonatal respiratory depression. Chronic use associated with maternal addiction and neonatal opioid withdrawal syndrome. |
| Fentanyl | Synthetic opioid agonist | Rapid transplacental transfer without accumulation. Fentanyl IV may produce transient loss of FHR variability without causing fetal hypoxia or change in Apgar scores. Similarly, epidural fentanyl may reduce FHR variability transiently but does not influence Apgar scores or neonatal respiration. The addition of fentanyl to bupivacaine for neuraxial anesthesia had no effect on neonatal respiration or Apgar scores. Chronic fentanyl exposure throughout pregnancy, including the first trimester, may be associated with a modest increase in absolute risk for a variety of birth defects. Late third-trimester use has the potential to cause neonatal sedation, respiratory depression, and neonatal opioid withdrawal syndrome. |
| Hydrocodone | Semisynthetic opioid agonist | Insufficient data to inform a drug-associated risk for major birth defects or early pregnancy loss. The National Birth Defects Prevention Study (1997–2005) found evidence that opioid use, including hydrocodone, during organogenesis was associated with a low absolute risk of congenital birth defects, without a particular spectrum. Late third-trimester use has the potential to cause neonatal sedation, respiratory depression, and neonatal opioid withdrawal syndrome. |
| Hydromorphone | Semisynthetic opioid agonist | Insufficient data to inform a drug-associated risk for major birth defects or early pregnancy loss. The National Birth Defects Prevention Study (1997–2005) found evidence that opioid use, including hydromorphone, during organogenesis was associated with a low absolute risk of congenital birth defects, without a particular spectrum. Late third-trimester use has the potential to cause neonatal sedation, respiratory depression, and neonatal opioid withdrawal syndrome. |
| Meperidine (pethidine) | Synthetic opioid agonist | Insufficient data to inform a drug-associated risk for major birth defects or miscarriage. The National Birth Defects Prevention Study (1997–2005) found evidence that opioid use, including meperidine, during organogenesis was associated with a low absolute risk of congenital birth defects, without a particular spectrum. Not recommended by ACOG for use during labor because the long half-life of its active metabolite normeperidine in neonates (up to 72–85 h) and its inability to be reversed by naloxone has resulted in neonatal depression, sometimes fatal. Late third-trimester use has the potential to cause neonatal sedation, respiratory depression, and neonatal opioid withdrawal syndrome. |
| Methadone | Synthetic opioid agonist | The National Birth Defects Prevention Study (1997–2005) found evidence that opioid use, including methadone, during organogenesis was associated with a low absolute risk of congenital birth defects, without a particular spectrum. Maternal methadone use is associated with increased risk of preterm birth (<32 w), small-for-gestational-age infants with at least one-third weighing less than 2500 g, and admission to the neonatal intensive care unit. Neonatal withdrawal symptoms occurred in approximately 60%–90% of infants with in utero methadone exposure and with increased intensity if the daily maternal dosage exceeded 20 mg. However, more recent studies have not observed an escalating dose response. Additional problems reported in methadone-exposed infants include increased mortality, SIDS, jaundice, and thrombocytopenia. In the MOTHER study, findings in offspring up to 3 y of age suggest that prenatal opioid agonist exposure is not deleterious to normal physical and mental development. |
| Morphine | Opioid agonist | Morphine is not teratogenic in rats at 35 times the human dose. The National Birth Defects Prevention Study (1997–2005) found evidence that opioid use, including morphine, during organogenesis was associated with a low absolute risk of congenital birth defects, without a particular spectrum. Late third-trimester use, including during labor, has the potential to cause neonatal sedation, respiratory depression, and neonatal opioid withdrawal syndrome. |
| Oxycodone | Semisynthetic opioid agonist | The National Birth Defects Prevention Study (1997–2005) found evidence that opioid use, including oxycodone, during organogenesis was associated with a low absolute risk of congenital birth defects, without a particular spectrum. Late third-trimester use, including during labor, has the potential to cause neonatal sedation, respiratory depression, and neonatal opioid withdrawal syndrome. |
| Remifentanil | Synthetic opioid agonist | No studies have examined the potential teratogenicity of remifentanil in human pregnancies; however, remifentanil is not teratogenic in animals. The rapid metabolism of remifentanil is thought to reduce the risk of neonatal depression when used in labor. In the handful of case reports or small series reporting on remifentanil use during labor or delivery, no neonatal adverse effects were observed. In one study that randomized laboring people to either IV remifentanil or IM meperidine, maternal and neonatal outcomes were not different. |
| Tramadol | Synthetic opioid agonist, oral | The National Birth Defects Prevention Study (1997–2005) found evidence that opioid use, including tramadol, during organogenesis was associated with a low absolute risk of congenital birth defects, without a particular spectrum. Late third-trimester use, including during labor, has the potential to cause neonatal sedation, respiratory depression, and neonatal opioid withdrawal syndrome. Using the Swedish Medical Birth Registry, early pregnancy exposure to tramadol in 1751 pregnancies was associated with an increased risk for any malformation, cardiovascular defects, and pes equinovarus. However, hypospadias and polydactyly were not increased. |
| Psychotropic Medications | ||
| Amitriptyline | Tricyclic antidepressant | Although there have been occasional reports of congenital abnormalities (limb reductions and other bony defects ), most studies have reported relative safety with its use in pregnancy. Neonatal abstinence syndrome has not been reported with amitriptyline use in pregnancy. |
| Bupropion | Aminoketone antidepressant | Although a small increase in heart defects (left ventricular outflow tract obstruction) and an association with ADHD in offspring have been reported, confounding by cigarette smoking cannot be excluded. Bupropion is only weakly associated with neonatal abstinence syndrome. |
| Citalopram/escitalopram | SSRI | Congenital abnormalities, including cardiac malformations, were not associated with first-trimester exposure. Controlling for level of maternal depression and sociodemographic and lifestyle factors, SSRI use during pregnancy was not associated with increased risk of preterm birth or low birth weight. Compared with women with untreated depression, SSRI use was not associated with in increased risk of preeclampsia. Exposure to SSRIs close to delivery was associated with a 1.4–1.9-fold increased risk for postpartum hemorrhage. Late-pregnancy use is associated with neonatal abstinence syndrome and a small increased risk of persistent pulmonary hypertension of the newborn (adjusted OR, 1.28; 95% CI, 1.01 to 1.64). |
| Fluoxetine | SSRI | Larger studies have shown that congenital abnormalities, including cardiac malformations, were not associated with first-trimester exposure. Controlling for level of maternal depression and sociodemographic and lifestyle factors, SSRI use during pregnancy was not associated with increased risk of preterm birth or low birth weight. Compared with women with untreated depression, SSRI usewas not associated with an increased risk of preeclampsia. Late-pregnancy use is associated with neonatal abstinence syndrome and a small increased risk of persistent pulmonary hypertension of the newborn (adjusted OR, 1.28; 95% CI, 1.01 to 1.64). Exposure to fluoxetine did not affect early childhood IQ, language, or behavior, but IQ was negatively associated with duration of depression and language was negatively associated with number of depressive episodes after delivery. |
| Haloperidol | Butyrophenone-type antipsychotic | Limited human experience impairs assessment of fetal risk. Although there does not appear to be an increase in overall congenital abnormalities, infants born with limb reduction abnormalities after first-trimester haloperidol exposure have been reported. Neonatal withdrawal with tardive dyskinesia symptoms have also beenreported. |
| Lithium | Elemental salt; mood stabilizer | Human data suggest risk. A prospective observational study that compared 183 lithium-exposed pregnancies with 72 disease-matched (bipolar disease not on lithium) and 748 nondiseased, nonexposed pregnancies reported that the risk of spontaneous abortion in women on lithium (16.4%) was twice that in women with bipolar disease not on lithium (8.3%) and almost three times greater than in the controls (5.7%), but the rates of fetal demise and preterm labor were not different. Although earlier registry data reported an increased occurrence of cardiovascular abnormalities, including Ebstein’s anomaly, subsequent case-controlled studies concluded that the risk was much lower than previously reported, especially in women with closely monitored therapy (no cases of Ebstein’s anomaly among 207 lithium-exposed pregnancies). In a cohort study of 1,325,563 Medicaid enrollees delivered between 2000 and 2010, cardiac malformations were present in 16/663 (2.41%) lithium-exposed infants, 1.15% of the nonexposed infants, and 1.39% of lamotrigine-exposed infants born to mothers with similar disease. The adjusted RR for cardiac disease was dose dependent: RR 1.11 (95% CI, 0.46 to 2.64) for a daily dose of less than or equal to 600 mg, 1.60 (95% CI, 0.67 to 3.80) for 601–900 mg, and 3.22 (95% CI, 1.47 to 7.02) for greater than or equal to 900 mg. The prevalence of right ventricular outflow tract obstruction defects, including Ebstein’s anomaly, was 0.60% among lithium-exposed infants versus 0.18% among unexposed infants, but the adjusted risk ratio was not significant, 2.66; 95% CI, 1.00 to 7.06. Pregnancies with first-trimester exposure should undergo a comprehensive second-trimester (18–20 w) ultrasonographic anatomic survey with fetal echocardiography. Third-trimester exposure prior to delivery has been associated with reversible toxicity in the newborn, which may include cyanosis, hypotonia, bradycardia, diabetes insipidus, and others. |
| Mirtazapine | Tetracyclic antidepressant | Limited data on pregnancy exposure suggests that the risk of congenital abnormalities is low. In the largest study, no significant differences were seen in the rates of major malformations between the 357 mirtazapine, 357 SSRI, and control pregnancies. Rates of preterm delivery and birth weights were also similar. |
| Paroxetine | SSRI | Although individual studies have shown conflicting results, a large 2016 metaanalysis reported that, compared with nonexposure, first-trimester paroxetine use was associated with an increased risk of any major congenital malformations (pooled OR, 1.23; 95% CI, 1.10 to 1.38; 15 studies) and major cardiac malformations (pooled OR, 1.28; 95% CI, 1.11 to 1.47; 18 studies). In a study of multiple SSRIs and the SNRI, venlafaxine, only paroxetine and venlafaxine were associated with an increased risk of spontaneous abortion, (paroxetine: OR, 1.75; 95% CI, 1.31 to 2.34) and (venlafaxine: OR, 2.11; 95% CI, 1.34 to 3.30). Late-pregnancy use of paroxetine is associated with neonatal abstinence syndrome, thought to be greater than with other SSRIs. Because of the increased risks associated with paroxetine exposure during pregnancy, ACOG considers it a second-line treatment option. |
| Phenelzine | Monoamine oxidase inhibitor | Safe use in pregnancy is not established owing to limited published exposure data. In mice studies with doses exceeding recommended human doses, a reduced number of viable offspring was observed. |
| Quetiapine | Atypical antipsychotic | Although no structural malformations have been associated with quetiapine use, the number of exposures is too low to fully assess the embryo-fetal risk. In the only large review, quetiapine use in 433 pregnancies was not associated with an increased rate of malformations. |
| Risperidone | Atypical antipsychotic | Although no structural malformations attributable to risperidone have been reported, the number of exposures is too limited to fully assess fetal risk. In one study of 713 pregnancies exposed to risperidone, the rates of structural abnormalities and spontaneous abortion were consistent with background rates. In three other studies, risperidone was associated with a small increase risk of overall malformations (5.1%, 5.3%, and RR, 1.26; 95% CI, 1.02 to 1.56 ) and cardiac malformations (RR, 1.26; 95% CI, 0.88 to 1.81 ). Limited extrapyramidal effects were observed in neonates after third-trimester exposure. |
| Sertraline | SSRI | Larger studies have shown that congenital abnormalities, including cardiac malformations, were not associated with first-trimester exposure. Controlling for level of maternal depression and sociodemographic and lifestyle factors, SSRI use during pregnancy was not associated with increased risk of preterm birth or low birth weight. Compared with women with untreated depression, SSRI use was not associated with an increased risk of preeclampsia. Late-pregnancy use is associated with neonatal abstinence syndrome and a small increased risk of persistent pulmonary hypertension of the newborn (adjusted OR, 1.28; 95% CI, 1.01 to 1.64). |
| Respiratory Drugs | ||
| Albuterol (salbutamol) | SABA | First-line SABA in pregnancy. Studies do not suggest an association with preterm birth, low birth weight, or decreased Apgar scores. Multiple studies have found no increase in birth defects, while a subset of studies identified associations with cleft lip or palate, cardiac anomalies, gastroschisis, esophageal atresia, and omphalocele. A causal relationship is difficult to determine owing to confounding effects of uncontrolled asthma. |
| Benralizumab | Anti-IL-5 monoclonal antibody | IgG molecule predicted to cross the placenta with increased transport in later trimesters. Human data not yet available. |
| Budesonide | Inhaled corticosteroid | No increase in the incidence of fetal malformations. No adverse effects with respect to gestational age, birth weight, or length. |
| Cromolyn sodium | Mast cell stabilizer | Most data indicate no increase in major birth defects. One study noted a potential increased risk for musculoskeletal malformations, but no specific pattern was reported. No increased risk for preterm delivery or low birth weight in most studies. |
| Formoterol | LABA | No difference in incidence of low birth weight, preterm birth, or SGA compared with salmeterol. Cardiac malformations and preterm birth have been reported in some studies but may be confounded by asthma severity. |
| Fluticasone | Inhaled corticosteroid | No increased risk of major congenital malformations, low birth weight, preterm birth, or SGA status compared with other inhaled corticosteroids. |
| Ipratropium bromide | Anticholinergic | Safety data are limited, but may be appropriate for short-term management of acute exacerbations. |
| Mepolizumab | Anti-IL-5 monoclonal antibody | IgG molecule predicted to cross the placenta with increased transport in later trimesters. Human data not yet available. |
| Montelukast | Leukotriene receptor antagonist | No association with major malformations, low Apgar scores, or reduced length or head circumference. Mixed associations with preterm birth, which may be confounded by asthma severity. |
| Omalizumab | Anti-IgE monoclonal antibody | IgG molecule predicted to cross the placenta. No increased risk of major congenital anomalies compared with disease-matched cohorts. Higher incidence of preterm birth, though additional studies are needed to rule out confounding by other cohort factors. |
| Prednisone | Corticosteroid | Associations reported between oral corticosteroids and preterm delivery and lower birth weight. Some studies report an association between first-trimester prednisone use and cleft lip with or without cleft palate, though this finding is not replicated in more recent studies. |
| Reslizumab | Anti-IL-5 monoclonal antibody | IgG molecule predicted to cross the placenta with increased transport in later trimesters. Human data not yet available. |
| Salmeterol | LABA | No association with preterm birth or fetal growth restriction. Minimal maternal plasma concentrations after use suggest limited fetal exposure. Some congenital malformations reported in women using a LABA during pregnancy, but incidence did not exceed baseline rate of congenital malformations and could not be causally linked to LABAuse. |
| Terbutaline | LABA | Crosses the placenta. Umbilical vein concentration up to 50% of maternal concentration. Not contraindicated in pregnancy, though moredata are available for salmeterol and formoterol. |
| Theophylline | Methylxanthine | No reported association with adverse fetal outcomes but not preferred in pregnancy owing to narrow therapeutic index and pharmacokinetic changes in pregnancy. |
| Sedatives | ||
| Note: 12/16/2016 FDA Drug Safety Communication: FDA review resulted in new warnings about using general anesthetics and sedation drugs in young children and pregnant women: “The U.S. Food and Drug Administration (FDA) is warning that repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures in children younger than 3 years or in pregnant women during their third trimester may affect the development of children’s brains. Consistent with animal studies, recent human studies suggest that a single, relatively short exposure to general anesthetic and sedation drugs in infants or toddlers is unlikely to have negative effects on behavior or learning…. Health care professionals should balance the benefits ofappropriate anesthesia in young children and pregnant women against the potential risks, especially for procedures that may last longer than 3 hours or if multiple procedures are required in children under 3 years…. This list includes anesthetic and sedation drugs that block N-methyl-D-aspartate (NMDA) receptors and/or potentiate gamma-aminobutyric acid (GABA)activity.” | ||
| Alprazolam | Benzodiazepine | No congenital anomalies or increased pregnancy loss have been associated with early pregnancy exposure to alprazolam ; however, in some reports large numbers of patients were lost to follow-up and often the results were confounded by frequent concomitant drug and alcohol use. Neonatal withdrawal has been reported after chronic alprazolam use throughout pregnancy. |
| Dexmedetomidine | Alpha-2-adrenergic receptor agonist | Available published data over several decades of dexmedetomidine use during pregnancy have not identified a risk of major birth defects or early pregnancy loss; however, the reported exposures occurred after the first trimester. Most of the available data are based on use at the time of cesarean delivery, and these studies have not identified an adverse effect on maternal outcomes or Apgar scores. In pregnant rats, concomitantly administered dexmedetomidine during anesthesia, attenuated neuronal injury induced by maternal propofol anesthesia in the fetal brains, providing neurocognitive protection in the offspring. |
| Diazepam | Benzodiazepine | Studies with diazepam use in early pregnancy have shown increased risks of congenital malformations, including oral clefts, inguinal hernia, cardiac defects, and pyloric stenosis. Use of benzodiazepines late in pregnancy may result in neonatal abstinence syndrome or floppy infant syndrome. Benzodiazepines are not recommended for use in labor or delivery owing to risks of residual pharmacologic effects in theneonate. |
| Clonazepam | Benzodiazepine | Clonazepam at increased dosages was not teratogenic in mice and rats but did produce a similar pattern of malformations in rabbits, including cleft palate, other facial changes, and limb defects. Although the numbers are limited, no associated increase in fetal abnormalities has been observed with human early pregnancy exposure. Chronic clonazepam exposure throughout pregnancy has not been associated with cognitive or psychomotor developmental delays. Toxicity in the newborn (apnea, cyanosis, lethargy, and hypotonia) has been reported with chronic third-trimester exposure. |
| Midazolam | Benzodiazepine, short acting | There are no reports of midazolam or its adverse effects in the first or second trimester. Studies comparing midazolam with thiopental (thiopentone) for induction of anesthesia have shown increased risks of neonatal depression after cesarean delivery in the infants exposed to midazolam; more infants required tracheal intubation or oxygen by facemask. However, they did not meet the criteria for “floppy infant syndrome,” like diazepam. |
| Others | ||
| Cannabis | Cannabinoid receptor agonist | Cannabis use in pregnancy is associated with adverse perinatal outcomes including SGA and preterm birth. Intrauterine exposure may potentially impact neurodevelopmental outcomes in childhood. |
| Caffeine | Methylxanthine, dietary supplement | Recommended at less than 200 mg/d. Increased risk of neonatal cardiac arrhythmias at greater than 200 mg/d. |
| Magnesium | Elemental therapy | Maternal adverse effects: hot flushes, maternal and fetal hypotonia, respiratory depression, cardiac depression. Increased perinatal mortality with infusion rates in excess of 2 g/h. Contraindicated in myasthenia gravis, hypocalcemia, moderate to severe renal failure, cardiac ischemia, heart block, or myocarditis. |
| Sumatriptan | Triptan | No evidence for increased risks for either spontaneous early pregnancy loss or congenital anomalies; may be associated with worse child emotionality and activity outcomes at 3 y of age. Of the available triptans, sumatriptan has had the greatest exposure in pregnancy. |
| Butalbital | Barbiturate | Avoid use in pregnancy. Habituation risk; increased risk of overuse headache; no significant additional analgesia in combination products; first-trimester use associated with cardiac malformations. |
ACE , Angiotensin-converting enzyme; ACOG , American College of Obstetricians and Gynecologists; ADHD , attention deficit/hyperactivity disorder; AED , antiepileptic drug; ARB , angiotensin receptor blocker; CI , confidence interval; COVID-19 , coronavirus disease 2019; COX , cyclooxygenase; COX-1 , cyclooxygenase-1; COX-2 , cyclooxygenase-2; CrI , credible interval; FDA , Food and Drug Administration; FHR , fetal heart rate; GABA , gamma-aminobutyric acid; HIV ,human immunodeficiency virus; HSV , herpes simplex virus; IgE , immunoglobulin E; IgG , immunoglobulin G; IL-5 , interleukin-5; IQ ,intelligence quotient; LABA , long-acting beta-2-adrenergic receptor agonist; LMWH , low-molecular-weight heparin; NSAID , nonsteroidal antiinflammatory drug; OR , odds ratio; RR , relative risk; SABA , short-acting beta-2-adrenergic receptor agonist; SGA , small-for-gestational-age; SIDS , sudden infant death syndrome; SNRI , serotonin-norepinephrine reuptake inhibitor; SSRI , selective serotonin reuptake inhibitor.
References
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