Pharmacokinetic Changes During Pregnancy

The myriad physiologic changes of pregnancy influence drug absorption, distribution, and elimination. Changes in gastrointestinal function can alter oral drug absorption. Renal elimination is generally increased because of an increase in glomerular filtration rate. Hepatic metabolism may be increased, unchanged, or decreased, and the increase in total body water may alter drug distribution and peak concentrations. Protein binding is usually decreased; however, the free drug concentration may be unchanged because of increased drug clearance.

Transfer of Drugs Across the Placenta

The amount of drug that crosses the placenta depends on maternal cardiac output, fetal cardiac output, placental binding, and placental metabolism, as well as factors that influence passive diffusion across the placenta. Maternal plasma levels of a drug depend on the site of administration (e.g., oral, intravascular, or epidural space), the total dose, the dosing interval, and other drugs that may be coadministered (e.g., epinephrine). The amount of drug to which the fetus is exposed also depends on fetal metabolism (fetal blood carrying drugs away from the placenta passes first through the fetal liver), fetal protein binding (about half of maternal protein binding), and the distribution of fetal cardiac output (fetal distress results in redistribution of blood flow to the vital organs).

In general, good studies of human placental drug transfer and fetal exposure are limited. Interspecies differences in placental anatomy and function make animal model comparisons with humans risky. Ethical concerns have limited studies in pregnant women. Most studies of the placental transfer of anesthetic agents administered to the mother intrapartum report single measurements of drug concentration in the maternal and umbilical vein serum at the time of delivery (the fetal:maternal or F/M ratio). The measured fetal concentration does not reflect the effects of drug passage through the fetal liver, or the possibility of altered pharmacokinetics and pharmacodynamics in the fetus compared with the mother.

Teratogenicity

Possible adverse effects on the fetus of in utero drug exposure include structural malformations, intrauterine fetal death, altered fetal growth, neurobehavioral teratogenicity, acute neonatal intoxication, or neonatal abstinence syndromes. A major determinant of the effect of a drug on the fetus is the gestational age of the fetus. Traditionally, teratogenic effects of drugs have been defined as structural malformations. However, functional and behavioral effects are also likely to occur, and are much harder to identify because the effects of fetal drug exposure may be delayed and only apparent later in life. The mechanisms by which drugs cause teratogenicity are poorly understood, and may be direct or indirect (direct effect on the mother indirectly effects the fetus). There is interspecies variation in the ability of a drug to cause a specific congenital defect (e.g., thalidomide is not teratogenic in nonprimates).

The period of classic teratogenesis corresponds with the critical period of organogenesis and begins approximately 31 days after the first day of the last menstrual period until about 71 days after the last period. Exposure to teratogens before 31 days results in an all-or-none effect (survival without a defect or loss of pregnancy). Fetal development, particularly the central nervous system, continues into the second and third trimesters, and indeed after birth. Therefore fetal drug exposure at this time is not risk free.

Information on the teratogenic potential of many drugs comes from large-survey studies. These studies are often flawed because of reporting bias. They often do not control for other variables, including environmental exposures, exposure to multiple drugs (including alcohol, tobacco, nonprescription and illicit drugs), and the influence of the disease itself. Case reports of an association between in utero drug exposure and fetal anomalies are more likely to be published than if no anomaly occurred.

Food and Drug Administration Risk Classification

The US Food and Drug Administration (FDA) previously required labeling of drugs using the Pregnancy Category System ( Table 39.1 ). The FDA recognized that this system was often not helpful to the prescribing physician and pregnant patient. Starting in 2015, the FDA mandated a new drug labeling system (Pregnancy and Lactation Labeling Rule, or “Final Rule”), which requires three new subsections in the pregnancy and lactation sections of the package insert: risk summary, clinical considerations, and data sections ( Table 39.2 ).

Specific Drugs

Aspirin use during pregnancy may be associated with an increased risk of gastroschisis. Pregnant women should not use aspirin (>150 mg/day) regularly. Ibuprofen and naproxen during the first trimester do not appear to be teratogenic. Prostaglandin inhibitors have been associated with narrowing of the ductus arteriosus in utero. This effect increases with gestational age, although it appears reversible when the medication is stopped. Aspirin and other prostaglandin inhibitors may decrease amniotic fluid volume secondary to decreased fetal urine output, and they may prolong pregnancy and labor. An increased incidence of neonatal intracranial hemorrhage has been found in premature infants whose mothers ingested aspirin near birth. For these reasons, full-dose aspirin and nonsteroidal antiinflammatory drug (NSAID) therapy should be avoided in the third trimester. If a mild analgesic is indicated during pregnancy, acetaminophen is the drug of choice.

Fourteen percent of pregnant women fill an opioid prescription during their pregnancy. Chronic in utero exposure to opioids can lead to neonatal abstinence syndrome, and maternal opioid use should be minimized if possible. Neonatal abstinence syndrome presents at 24–72 hours of life. Infants have variable features and presentations, including central nervous system hyperirritability (i.e., excessive crying, tremors, increased muscle tone); autonomic nervous system dysfunction (i.e., nasal stuffiness, yawning, sweating); and gastrointestinal disturbances. There is no evidence that opioid agonist or agonist–antagonist exposure during pregnancy is teratogenic. Opioid analgesics should be reserved for patients with moderate to severe pain who have failed nonpharmacologic interventions and nonopioid multimodal analgesic medications.

Bupivacaine and lidocaine were not associated with risk of teratogenicity in the Collaborative Perinatal Project. The incidence of fetal anomalies was increased twofold in women who were exposed to mepivacaine; however, this group included a very small number of women, and so it is difficult to draw any conclusions from the data.

Several surveillance studies have found an association between maternal steroid use and orofacial clefts, while others have not. A limited trial of epidural steroid therapy is probably associated with minimal fetal risk after the first trimester of pregnancy.

Antidepressant medications are frequently used in the treatment of chronic pain. There is no evidence that tricyclic antidepressant drugs are teratogenic. First trimester exposure to most selective serotonin reuptake inhibitors (SSRIs) appears to have similar rates of congenital malformations than the general population. Paroxetine is the only SSRI that is associated with increased risk of major congenital heart anomalies. There is limited data, but studies with duloxetine suggest it may increase rates of spontaneous abortion in the first trimester. Exposure to SSRIs in the third trimester before delivery may lead to a neonatal withdrawal syndrome and transient QT interval prolongation. The long-term clinical consequences of these changes are not known. The noradrenergic and specific serotonergic antidepressant, venlafaxine and the serotonin-noradrenalin reuptake inhibitors, mirtazapine, appear to confer no risk of malformation or neonatal withdrawal syndrome, but these are newer drugs with fewer studies. Data on the teratogenicity of bupropion in pregnant women are limited, but suggest an increased risk of cardiac malformations.

Anticonvulsants have been implicated in fetal growth restriction and congenital malformation. The Medical Birth Registry of Norway compared 2600 children exposed to antiepileptics with 771,412 unexposed children. Carbamazepine, lamotrigine, oxcarbazepine, gabapentin, and pregabalin had low malformation rates, similar to the general population. Topiramate increased fetal growth restriction and microcephaly, and valproic acid increased risk for hypospadias and septal heart defects. Children of women with epilepsy who take anticonvulsants carry a higher risk of developmental delay and cognitive impairment than those who do not require therapy during pregnancy. Human studies demonstrate that phenytoin and valproic acid confer the highest potential for neurodevelopmental disorders, whereas lamotrigine and carbamazepine are least likely to lead to these adverse outcomes.

Ergotamine is contraindicated in pregnancy, as it may be teratogenic, and it also causes uterine contractions. There is no evidence that beta-blockers are teratogenic; however, they may be associated with intrauterine growth retardation.