Pharmacogenetics

Genetic differences are responsible for some of the variation in drug response among individuals. Pregnancy does not obviously modify these pharmacogenetic differences, although some obstetric conditions such as preeclampsia are related to complex genetic factors. There are, however, some examples in which underlying genetic differences do affect obstetric management.¹

The metabolism of codeine to morphine is greatly affected by polymorphisms of the cytochrome P450 (CYP) isoenzyme CYP2D6. It has been recognized only recently that mothers who are ultrarapid metabolizers may produce and transfer sufficient morphine through breast milk to cause neonatal central nervous system (CNS) depression and even death.²

Two of the possible changes at the β₂-adrenergic receptor are an arginine-to-glycine substitution at codon 16 (Arg16Gly) and a glutamine-to-glutamate substitution at codon 27 (Glu27Gln). When β₂-receptor agonists were used for tocolysis, Arg16 homozygotes had longer gestation and better neonatal outcome.³ In the management of hypotension during spinal anesthesia for cesarean delivery, Gly16 homozygotes and Glu27 homozygotes required less ephedrine.⁴

The µ-opioid receptor gene may have an adenine-to-guanine substitution at nucleotide position 118 (A118G). There have been many studies of the effects of this polymorphism on opioid dose requirements and response, although the studies in obstetric patients have had conflicting results. For example, laboring women who were AA homozygous had an increased intrathecal fentanyl requirement for analgesia.⁵ In contrast, AA homozygous women receiving intrathecal morphine for postcesarean analgesia reported less pain and required less patient-controlled morphine but had a higher incidence of nausea and vomiting.⁶ Wong⁷ summarized the conflicting evidence and noted that the true effect of this polymorphism is probably small. Many other genetic factors influence opioid disposition and response, and even more factors influence pain perception. Indeed, a meta-analysis found that A118G polymorphism only explained 7% of the variability in opioid requirements.⁸ Thus, at present there are no indications for pharmacogenetic testing in routine obstetric practice.⁹

Pharmacokinetic Changes

The major physiologic changes during pregnancy would be expected to alter drug disposition.^10,11 However, the magnitude and time course of these changes vary throughout pregnancy and among individuals. The results of many older studies are unreliable because the studies were often of low quality. Thus, making generalizations about the effects of pregnancy on drug disposition can be difficult, and individualized dosing is important.

Pharmacodynamic Changes

Changes in the concentrations of various hormones may alter the response to other substances. In particular, progesterone and endorphins may enhance sedation and anti-nociception, respectively. A pharmacodynamic difference specifically refers to a change in response to a given effect-site concentration, but it is difficult during pregnancy to carry out the high-fidelity studies necessary for accurate pharmacokinetic-pharmacodynamic modeling. Thus, the demonstrations of pharmacodynamic changes in pregnancy have been limited to specific experimental designs where there are large differences in effect.

General Teratology

Teratology is the study of abnormal development or birth defects. Teratogens are substances that act to irreversibly alter growth, structure, or function of the developing embryo.⁵⁹ Ideally, preclinical studies would identify teratogens, but drug teratogenicity unfortunately can be markedly species-specific. For example, thalidomide produces phocomelia in primates but not in rodents.

In the United States, major malformations affect 2% to 3% of neonates.⁶⁰ A major malformation is defined as one that is incompatible with survival (e.g., anencephaly), one that requires major surgery for correction (e.g., cleft palate, congenital heart disease), or one that causes mental retardation. If all minor malformations (e.g., ear tags, extra digits) are included, the incidence of congenital anomalies may be as high as 7% to 10%. Exogenous causes of birth defects (e.g., radiation, infections, maternal metabolic disorders, drugs, environmental chemicals) account for almost 10% of all major birth defects and therefore affect only 0.2% to 0.3% of all births. Drug exposure explains only 2% to 3% of birth defects, and the majority of birth defects are of unknown etiology.

To avoid unnecessary and potentially teratogenic exposures, nonpharmacologic techniques should be used when possible and drugs should be used only when necessary. The risk-to-benefit ratio should justify the use of a drug given to a pregnant woman, and the minimum effective dose should be employed. Long-term effects of fetal drug exposure may not become apparent for many years. Therefore, physicians and patients should exercise caution in the use of any drug during pregnancy. On the other hand, the physician should ask the following question: what would be the appropriate treatment in the nonpregnant patient with the same condition? In most cases, the answer is the same as that for women who are pregnant.⁶¹

Sensitive serum pregnancy tests can diagnose pregnancy as early as 1 week after conception. Before drug therapy is started, a sensitive test should be used if there is any question about drug safety during a potential pregnancy.

It is also important to remember that the male partner may be taking teratogenic drugs and the drug may be present in semen at low concentrations. Although the magnitude of fetal risk is unclear, men are advised to avoid drugs such as thalidomide, ribavirin, and isotretinoin if their partners could become pregnant.

The maternal and fetal genotype and phenotype can affect individual susceptibility to an agent. For example, fetuses with low levels of the enzyme epoxide hydrolase are more likely to manifest fetal hydantoin syndrome than those with normal levels of this enzyme.⁶²

Drug teratogenicity is affected by the timing of exposure. Teratogen exposure in the first 2 weeks after conception is generally thought to be an all-or-nothing phenomenon (i.e., having either no effect or resulting in spontaneous fetal loss). Among women with a 28-day menstrual cycle, the classic period of susceptibility to teratogenic agents is during the period of organogenesis, which occurs primarily at to 8 weeks after conception (31 to 71 days, or 4 to 10 weeks, after the first day of the last menstrual period) (Figure 14-3). During organogenesis, each organ system has different critical periods of sensitivity and there may be striking differences in effect. When administered between 35 and 37 days’ gestation, thalidomide produces ear malformations; when administered between 41 and 44 days’ gestation, it produces amelia or phocomelia. After this period, embryonic development is characterized primarily by increasing organ size; thus, the principal effect of exposure consists of growth restriction and/or effects on the nervous system and gonadal tissue. For example, diethylstilbestrol exposure during the second trimester results in uterine anomalies that do not become apparent until after puberty. Fetal alcohol syndrome may occur with chronic exposure to alcohol during pregnancy.

The drug dosing regimen can influence teratogenicity. In most cases, administration of a low dose has no effect whereas malformations may occur at intermediate doses and death may occur at higher doses. Fetal death may allow organ-specific teratogenic activity to go unnoticed. Small doses administered over several days may have an effect different from that observed with the same total dose administered at one time. Sequential drug administration may induce the production of an enzyme that metabolizes the drug and thus results in less exposure. Constant exposure may destroy cells that would have catabolized the drug if it had been administered in periodic doses. Combinations of agents may produce different degrees of malformation and growth restriction from those that occur with drugs administered individually. For example, fetuses whose mothers receive combination anticonvulsant therapy are at the highest risk for malformations, including neural tube defects and facial dysmorphic features.

U.S. Food and Drug Administration Categories

In 1979, the U.S. Food and Drug Administration (FDA) introduced a drug classification system to discourage nonessential use of medications during pregnancy (Box 14-1).

Unfortunately, maternal anxiety related to medication use can lead to unnecessary pregnancy terminations. Several characteristics of the FDA drug classifica­tion system contribute to public perception—and misperception—of the dangers of using medication during pregnancy. Although only 20 to 30 commonly used drugs are known teratogens, 7% of all the medications that are listed in the Physicians’ Desk Reference are classified as Category X.^63,64 All new medications are classified as Category C, leading to an exaggerated impression of the danger of many medications. In addition, the manufacturer’s prescribing information for many drugs may state that the drug is not approved for use in pregnancy despite a long history of uncomplicated unlicensed or “off-label” use.⁶⁵

The FDA categories imply a progressive fetal risk from Category A to X; however, the drugs in different categories may pose similar risks but may be listed in different categories on the basis of risk-to-benefit considerations. In addition, the categories create the impression that drugs within a category present similar risks whereas the category definition permits inclusion (in the same category) of drugs that vary in type, degree, and extent of risk.

Use of potentially teratogenic drugs in pregnancy is surprisingly commonplace. Over 63% of pregnant patients in Canada filled a prescription for at least one drug, with almost 8% filling a prescription for a Category D or X medication.⁶⁶

When counseling patients or responding to queries from physicians, we prefer to avoid referring to the Physicians’ Desk Reference. Rather, we use specific descriptions in teratogen databases to provide the best information available. Many resources are freely available online, in addition to the commercially available databases (Table 14-1).

The Teratology Society has suggested abandonment of the FDA classification scheme.⁶³ In 1997, the FDA held a public meeting to discuss labeling of drugs. There was consensus that the current classification scheme is probably oversimplified and confusing, does not address the range of clinical situations or the range of possible effects, and should be replaced with narrative labeling. Subsequently, a concept paper was presented that outlined a new model for labeling and included sections such as “clinical management statement,” “summary risk assessment,” and “discussion of data” for both pregnant and breast-feeding women.⁶⁷ This proposal has not yet been implemented. The FDA Office of Women’s Health has created a pregnancy registry website, which lists a variety of registries that women who have used specific medications during pregnancy can consult (see Table 14-1). In 2008, the FDA stated they will eliminate the A, B, C, D, X classification system.⁶⁸ As of 2013, the new system has yet to be implemented despite completion of the 90-day comment period some time earlier.⁶⁹

Analgesics

There is no known teratogenic risk associated with the use of acetaminophen (paracetamol),⁷⁰ which is the preferred mild analgesic or antipyretic during pregnancy.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have not been associated with an increased risk for birth defects overall, but the occasional review has suggested an association with specific defects.⁷¹ For example, aspirin is not associated with an overall increase in rates of congenital malformations, but one review suggested a higher risk for gastroschisis.⁷² Aspirin is not usually the first choice of NSAID, but low-dose aspirin may still have a role in some situations, such as preventing fetal loss associated with antiphospholipid antibody syndrome.⁷³ Studies of the use of NSAIDs and aspirin in the first trimester have reported increased risk for pregnancy loss (adjusted odds ratio [OR], 1.8 to 8.1).⁷¹ In the second trimester, their use has been associated with fetal cryptorchidism. In the third trimester, NSAIDs and aspirin are usually avoided because of significant fetal risks, such as renal injury, oligohydramnios, and intrauterine constriction of the ductus arteriosus, an effect that increases with advancing gestational age.⁷⁴ Renal injury, necrotizing enterocolitis, and intracranial hemorrhage are other potential complications.

Opioids such as propoxyphene and codeine have no known teratogenic risk,⁷⁵ but they have well-known potential for addiction. Excessive antepartum use can also lead to neonatal opioid-withdrawal symptoms.⁷⁶ Surprisingly, a recent case-control study found that maternal opioid treatment (mostly codeine and hydrocodone) between 1 month before pregnancy and the first trimester was associated with an increased OR of 1.8 to 2.7 for various cardiac birth defects, spina bifida, and gastroschisis.⁷⁷

Tramadol has analgesic effects from weak opioid activity and inhibition of serotonin and norepinephrine uptake. Despite availability in some countries for more than 30 years, few data are available regarding potential adverse effects in pregnancy. Tramadol exposure in early pregnancy was associated with a higher number of spontaneous abortions, and it should be avoided in the first trimester.⁷⁸ Chronic tramadol use in later pregnancy may result in neonatal withdrawal syndrome.

Sedatives

Human epidemiologic studies of the possible teratogenic effects of various tranquilizers are inconsistent. One report of nearly 400 patients found a 12% incidence of birth defects in the offspring of meprobamate users.⁷⁹ Another study of similar size did not identify any higher risk for malformations.⁸⁰ These latter two articles found similar results for chlordiazepoxide.^79,80 A recent study evaluating meprobamate used in high doses to attempt suicide did not show any teratogenic or fetotoxic effects.⁸¹ A sample of 35 pregnant women who self-poisoned with chlordiazepoxide showed no association with congenital abnormalities but did show dose-related fetal growth restriction.⁸²

Some studies have suggested that first-trimester exposure to diazepam increases the risk for cleft lip with or without cleft palate, neural tube defects, intestinal atresia, and limb defects.⁸³ Other reports have not suggested an increase in rate of congenital abnormalities after fetal exposure to benzodiazepines. In a case-control study of 611 infants with cleft lip or cleft palate and 2498 controls with other birth defects, after adjustment of the data for potential confounders, no association between diazepam and cleft palate was found (OR, 0.8 for cleft lip with or without cleft palate, with 95% confidence interval [CI] of 0.4 to 1.7, and OR, 0.8 for cleft palate alone, with 95% CI of 0.2 to 2.5).⁸⁴ Reanalysis of the Hungarian Case-Control Surveillance of Congenital Abnormality data also showed a weak relationship between exposure to diazepam in early pregnancy and neural tube defects, limb deficiency defects, and possibly intestinal atresia or stenosis.⁸³ One study found no difference in the incidence of congenital anomalies between 460 women exposed to benzodiazepines during pregnancy and 424 control women without such exposure (i.e., 3.1% versus 2.6%, respectively).⁸⁴ Perinatal use of diazepam has been associated with hypotonia, hypothermia, and respiratory depression.⁸⁵ Overall, it appears that the teratogenic risk of benzodiazepines is small at most,^86,87 but there may be a small risk for preterm birth and low birth weight.⁸⁸ Benzodiazepines should only be used in the first trimester if the perceived benefit offsets the possible teratogenic risks and later neonatal effects of continued use. Some benzodiazepines such as temazepam are classified as FDA Category X.

Anticonvulsants

Epilepsy is the most common serious neurologic problem during pregnancy.⁸⁹ It has been estimated that 3 to 5 births per thousand will be to women with epilepsy.⁹⁰ All anticonvulsants cross the placenta. The fetal congenital anomaly rate in pregnant women with epilepsy who ingest anticonvulsant drugs is 4% to 8%, compared with a background incidence in the general popula­tion of 2% to 3%.^91,92 A twofold higher risk for minor malformations also exists in this population.⁹² Cleft lip, with or without cleft palate, and congenital heart disease are especially common. Administration of valproic acid or carbamazepine entails a 1% risk for neural tube defects and other malformations; thus, alpha-fetoprotein screening and targeted ultrasonography are appropriate for patients taking these agents. In addition, the offspring of epileptic women have a 2% to 3% incidence of epilepsy, which is five times that of the general population.

Holmes et al.⁹³ attempted to refute the unproven theory that women with epilepsy have a genetic propensity to have children with a higher risk for birth defects that is separate from the greater risk associated with the use of anticonvulsants. These investigators studied children of women who had a history of seizures but took no medications during the pregnancy. There was no difference in physical features or cognitive function between these children and a group of matched controls. In a second study, Holmes et al.⁹⁴ screened 128,049 pregnant women at delivery to identify the following three groups of infants: (1) those exposed to anticonvulsant drugs, (2) those unexposed to anticonvulsant drugs but with a maternal history of seizures, and (3) those unexposed to anticonvulsant drugs with no maternal history of seizures (control group). The frequency of anticonvulsant embryopathy was higher in the 223 infants exposed to one anticonvulsant drug than in the 508 control infants (20.6% versus 8.5%, respectively; OR, 2.8; 95% CI, 1.1 to 9.7). The frequency was also higher in 93 infants exposed to two or more anticonvulsant drugs than in the controls (28.0% versus 8.5%; OR, 4.2; 95% CI, 1.1 to 5.1). The 98 infants whose mothers had a history of epilepsy but took no anticonvulsant drugs during pregnancy did not have a higher frequency of abnormalities than the control infants. The investigators concluded that “a distinctive pattern of physical abnormalities in infants of mothers with epilepsy is associated with the use of anticonvulsant drugs during pregnancy, rather than with epilepsy itself.” A more recent meta-analysis also did not support the view that epilepsy per se represents a teratogenic risk.⁹⁵

Possible causes of these congenital malformations include genetic differences in drug metabolism, the specific drugs themselves, and deficiency states (e.g., decreased folate levels) induced by the drugs. No congenital malformations appear to be unique to any one anticonvulsant. The characteristics of these syndromes are so similar that the broad term fetal anticonvulsant syndrome, consisting primarily of orofacial, cardiovascular, and digital malformations, has been applied to almost every anticonvulsant drug.⁹⁶

Among women taking phenytoin, there is a 2% to 5% risk for major congenital anomalies, primarily midline heart defects, orofacial clefts, and urogenital defects.⁹¹ Fetal hydantoin syndrome is a constellation of minor anomalies, such as craniofacial abnormalities (short nose, flat nasal bridge, wide lips, hypertelorism, ptosis, epicanthal folds, low-set ears, and low hairline) and limb anomalies (distal digital hypoplasia, absent nails, and altered palmar crease). In addition, neonatal growth and performance delays have been documented. The risk for fetal hydantoin syndrome for the child of a woman taking phenytoin is approximately 10%.⁹⁴ Phenytoin may act as a competitive inhibitor of the placental transport of vitamin K. This results in a decrease in fetal coagulation factors II, VII, IX, and X. In addition, phenytoin may induce fetal hepatic metabolism of the coagulation factors. The resulting reduction in fetal coagulation factors is associated with a higher risk for hemorrhagic disease of the newborn.⁹⁷ To help prevent this coagulopathy, some physicians advocate oral vitamin K supplementation (10 mg daily) for pregnant epileptic patients during the last month of pregnancy in addition to the parenteral administration of vitamin K to the neonate at birth.⁹⁸ Several anticonvulsant medications have metabolites that typically are eliminated by the enzyme epoxide hydrolase. In one study, 19 women taking phenytoin underwent amniocentesis. All 4 of the women with low enzyme activity in amniocytes had affected fetuses. The 15 fetuses with normal amniocyte epoxide hydrolase activity did not have the characteristics of fetal hydantoin syndrome.⁶²

Carbamazepine is used to treat all types of seizure disorders, with the exception of petit mal epilepsy. It is most commonly used in the treatment of psychomotor (temporal lobe) epilepsy and grand mal epilepsy. In a prospective study involving 72 women with epilepsy who were taking carbamazepine, the incidence of congenital anomalies was higher in the 35 fetuses exposed only to this drug. There was an 11% incidence of craniofacial defects, a 26% incidence of fingernail hypoplasia, and a 20% incidence of developmental delay.⁹⁹ This constellation of fetal effects, named fetal carbamazepine syndrome, closely resembles the malformations seen in cases of fetal hydantoin syndrome. In addition, maternal carbamazepine exposure has been specifically associated with spina bifida. An analysis of all available data involving cohorts of pregnant women ingesting carbamazepine supports the conclusion that fetal exposure to this drug carries a 0.5% to 1% risk for spina bifida.¹⁰⁰ Although it is generally agreed that the use of carbamazepine in pregnancy is associated with a risk for neural tube defects and other anomalies, the exact magnitude of the risk from use of carbamazepine alone is unclear.^101–104

Phenobarbital is used in the treatment of partial and generalized tonic-clonic seizures and status epilepticus.¹⁰⁵ Fetal exposure to phenobarbital has been associated with major malformations, such as congenital heart defects and orofacial clefting. Fetal phenobarbital syndrome is characterized by minor dysmorphic features similar to those seen with fetal hydantoin syndrome.⁹¹ Fetal exposure to phenobarbital has also been associated with decreased intellectual and cognitive development in neonates and children. Maternal phenobarbital use during pregnancy can result in hemorrhagic disease of the newborn and neonatal withdrawal symptoms after delivery. The withdrawal symptoms consist mostly of irritability, begin at about 7 days of life, and usually last for 2 to 6 weeks.¹⁰⁵

Valproic acid is used to treat absence and generalized tonic-clonic seizures. Infants exposed to valproic acid have a 1% to 2% risk for spina bifida. The neural tube defect tends to be lumbosacral. Fetal valproic acid exposure has also been associated with cardiac defects, orofacial clefting, and genitourinary anomalies. Fetal valproate syndrome has been described; it is characterized by dysmorphic features, including epicanthal folds, shallow orbits, hypertelorism, low-set ears, flat nasal bridge, upturned nasal tip, microcephaly, thin vermillion borders, downturned mouth, thin overlapping fingers and toes, and hyperconvex fingernails.⁹¹ Jentink et al.¹⁰⁶ found a markedly increased risk for spina bifida (OR, 12.7) craniosynostosis, cleft palate, atrial septal defect, and hypospadias. They concluded that valproic acid monotherapy should be avoided during pregnancy. A report of the Quality Standards Subcommittee and Therapeutics and Technology Subcommittee of the American Academy of Neurology and the American Epilepsy Society concluded that valproic acid and polytherapy should be avoided if possible during the first trimester to decrease the risk for major congenital malformations.¹⁰⁷ They also concluded that, if possible, avoidance of valproic acid and polytherapy throughout pregnancy should be considered, and avoidance of phenytoin and phenobarbital throughout pregnancy may be considered, to prevent poor cognitive outcomes.¹⁰⁷ Other reviews have also confirmed that valproic acid and carbamazepine are associated with neural tube defects and that valproic acid is associated with hypospadias, thus lending further support to limiting its use in women of reproductive age.

There are insufficient data to establish risks for birth defects with the newer anticonvulsants.^108,109 Felbamate was approved by the FDA for monotherapy, but later its use was severely restricted because of its association with aplastic anemia and hepatic failure. Gabapentin was initially released in the United States as an adjunctive treatment for partial seizures and secondarily generated tonic-clonic seizures. This agent inhibits dopamine release in the CNS. Lamotrigine appears to have efficacy comparable to that of carbamazepine in the monotherapy for partial epilepsy. An inhibitor of dihydrofolate reductase, lamotrigine decreases embryonic folate levels in experimental animals. This finding raises the concern that human use of lamotrigine may result in developmental toxicity. The manufacturer has established a registry to evaluate this possibility. A preliminary report from this registry has described a 6% rate of congenital malformations in fetuses exposed to this drug; this rate does not represent a clear increase in the baseline rate of malformations. However, there have not been sufficient numbers of fetal exposures to support any definitive conclusions.^110–112

Many patients who present to prenatal clinics are already taking these newer anticonvulsants. Patients should be counseled that even though little information is available, no clear evidence of their teratogenicity exists. Some investigators have suggested avoiding the newer anticonvulsants until evidence of their safety is accumulated.¹⁰⁵ Even in the two decades since newer agents such as lamotrigine were introduced, definitive evaluation of their teratogenic potential has not been published.

Some women may be taking anticonvulsant drugs without having been reevaluated recently for their need to continue drug therapy. If a patient with idiopathic epilepsy has been seizure-free for 2 years and has normal EEG findings, the neurologist may try to withdraw the drug before pregnancy.¹¹³

If a patient first presents for care during pregnancy, most authorities agree that the benefits of anticonvulsant therapy during pregnancy outweigh the risks of discontinuing the drug. The blood level of the drug should be monitored to minimize the dose needed to ensure a therapeutic level of drug.

Antidepressants

A summation of 14 studies assessing the effect of fetal exposure to tricyclic antidepressants evaluated 414 cases of first-trimester exposure¹¹⁴; when the study data were pooled or viewed individually, no significant association between fetal exposure to tricyclic antidepressants and congenital malformations was found.¹¹⁴ In a surveillance study of Michigan Medicaid recipients,¹¹⁵ 467 neonates had been exposed to amitriptyline and 75 neonates had been exposed to imipramine during the first trimester; there was no association between tricyclic antidepressant use and congenital anomalies. However, a large review of data from the Swedish Medical Birth Register reported that use of tricyclic antidepressants was associated with a greater risk for congenital malformations compared with other antidepressants.¹¹⁶ Results of the latter study are making their way into reviews that state a concern about tricyclic antidepressants.¹¹⁷ Overall, tricyclic antidepressants have been replaced by selective serotonin reuptake inhibitors (SSRIs) as first-line therapy for depression (see Chapter 51).¹¹⁸

The SSRIs include sertraline, paroxetine, fluoxetine, and citalopram. No higher risk for major malformations or developmental (language and behavior) abnormalities was identified with their use in earlier studies.^119–121 In a multicenter evaluation of birth defects, use of SSRIs was not associated with a higher risk for cardiac defects.¹²² However, in analyses of the individual medications, sertraline was associated with an increased risk for septal defects (OR, 2.0; 95% CI, 1.2 to 4.0), and paroxetine was associated with a higher risk for right ventricular outflow tract obstruction (OR, 3.3; 95% CI, 1.3 to 8.8). Sertraline was also associated with an increased risk for omphalocele, but this association was based on only three subjects. Another study found significantly higher risks for craniosynostosis, omphalocele, and anencephaly in association with exposure to SSRIs as a group; this study also found an association between paroxetine and right ventricular outflow tract lesions.¹²³ The association of septal heart defects with sertraline^124,125 and citalopram has been seen in other studies.¹²⁴

A cohort study compared postnatal outcome for infants exposed to fluoxetine in late gestation (up to the time of delivery) with that for infants whose exposure was limited to the first trimester.¹²⁶ Infants exposed in the third trimester had a greater incidence of perinatal complications, including preterm delivery, admission to the special care nursery, poor neonatal adaptation, lower mean birth weight, and shorter body length.¹²⁶ A subsequent study suggested an association between the maternal use of SSRIs in late pregnancy and a higher risk for persistent pulmonary hypertension of the newborn (PPNH).¹²⁷ The association between SSRIs and PPHN has been confirmed in other studies, which showed an increase from the background rate of 1.2/1000 neonates to about 3/1000, and appears to be a class effect.¹²⁸

The American College of Obstetricians and Gynecologists (ACOG) has recommended that use of paroxetine in pregnant women (and in women planning pregnancy) be avoided, if possible.¹²⁹ In addition, it was suggested that fetal echocardiography should be considered in women who have used paroxetine during early pregnancy. Further, the ACOG has stated that treatment with all SSRIs should be individualized.¹²⁹ A report from the American Psychiatric Association and the ACOG concluded that although antidepressant use in pregnancy is well studied, available research has not yet adequately controlled for other factors such as maternal illness and behaviors that can adversely affect pregnancy.¹³⁰

Lithium

In the International Registry of Lithium Babies, 25 of 217 (11.5%) infants exposed to lithium during the first trimester of pregnancy were malformed.¹³¹ Eighteen infants had cardiovascular anomalies, and six had the rare Ebstein anomaly, which occurs only once in 20,000 nonexposed pregnancies. Subsequent studies have suggested that ascertainment bias may have flawed the findings; the reported risk for anomalies after lithium exposure is much less than that reported by the registry.

In a cohort study linking the Swedish Birth Registry with the records of women with bipolar disorder, 59 infants were identified whose mothers had been treated with lithium early in pregnancy.¹³² Four (6.8%) of the 59 infants exposed to lithium had congenital heart disease, compared with 2 (0.9%) of 228 infants not exposed to lithium (relative risk [RR], 7.7; 95% CI, 1.5 to 41.2). None of the infants had Ebstein anomaly. In a prospective cohort study of 148 women treated with lithium during the first trimester and 148 controls not exposed to any known teratogen, there was no significant difference between groups in the incidence of major congenital anomalies or cardiac malformations,¹³² although one lithium-exposed infant did have Ebstein anomaly. The investigators concluded that lithium is not a major human teratogen, but they recommended that women exposed to lithium be offered ultrasonography and fetal echocardiography.¹³³ If the data are pooled, these two cohort studies do not suggest a statistically significant increase in risk for congenital malformations or cardiac malformations in women exposed to lithium during pregnancy. Although the risk for congenital malformations associated with intrauterine lithium exposure is likely to be lower than previously reported, an absence of risk cannot be assumed from the available data. Recent reviews of available data have come to the same conclusion that the risk for anomalies is small, but it is prudent to perform fetal echocardiography after first-trimester exposure.¹³⁴

Two published cases associated polyhydramnios with maternal lithium treatment.^135,136 Nephrogenic diabetes insipidus has been reported in adults taking lithium; thus, the presumed mechanism of polyhydramnios is fetal diabetes insipidus. Polyhydramnios may signal fetal lithium toxicity.

Pregnancy accelerates the excretion of lithium, so serum lithium levels should be monitored in pregnant women.¹³⁷ Perinatal effects of lithium include hypotonia, lethargy, and poor feeding in the infant. In addition, complications (e.g., goiter, hypothyroidism) similar to those seen in adults taking lithium have been noted in neonates.

Some authorities recommend discontinuation of lithium and substitution with another medication during pregnancy. However, the discontinuation of lithium is associated with a 70% chance of relapse of the affective disorder in 1 year, as opposed to a 20% risk for relapse with continuation of lithium therapy.¹³¹

Cardiovascular Drugs

There are no reports of teratogenicity related to the use of inotropic agents such as dopamine, dobutamine, or digoxin. Physicians should monitor the maternal digoxin level to ensure a therapeutic level of drug during pregnancy.

Methyldopa and labetalol are often used to treat mild chronic hypertension during pregnancy. There is no evidence of teratogenicity or other adverse fetal effects with either of these drugs. In one randomized double-blind trial of 152 women with hypertension, there were no malformations in either the labetalol group or the placebo group, although the exposure to labetalol occurred in the second and third trimesters.¹³⁸

In a large analysis of published trials involving beta-adrenergic receptor antagonist therapy, there was little or no information on teratogenicity for the multiple agents studied, including atenolol, labetalol, metoprolol, oxprenolol, pindolol, and propranolol.¹³⁹ Maternal administration of propranolol may result in modest fetal growth restriction.¹⁴⁰ It seems prudent to use ultrasonography to assess intrauterine fetal growth in women receiving propranolol. Maternal administration of propranolol within 2 hours of delivery may result in neonatal bradycardia.⁷⁵ Atenolol was associated with lower birth weight and a trend toward more frequent preterm delivery than with other antihypertensive drugs and with no therapy. These effects were more pronounced when the drug was administered earlier in pregnancy and for a long duration.¹⁴¹ In one study, treatment of hypertension (mostly with atenolol) reduced the risk for severe hypertension and preterm labor.¹⁴¹ In a randomized clinical trial, the same group observed that atenolol prevented preeclampsia but resulted in the birth of infants who weighed 440 g less than infants in the placebo group.¹⁴²

The angiotensin-converting enzyme (ACE) inhibitors initially did not appear to be teratogenic when administered during the first trimester.¹⁴³ However, a 2007 study suggested an increase in the incidence of congenital anomalies, particularly cardiac and CNS defects, after first-trimester exposure to ACE inhibitors.¹⁴⁴ Some authorities contend that this study had major limitations.¹⁴⁵ A very large epidemiologic database study of 465,754 mother-infant pairs showed no difference in abnormality rate between women who used ACE inhibitors during the first trimester, those who used other antihypertensive agents, and those who had hypertension but used no medications.¹⁴⁶ The authors postulated that any increased risk for birth defects may be due to the hypertension. A different set of investigators made the same conclusion.¹⁴⁷ Later in pregnancy, ACE inhibitors can cause fetal renal failure and oligohydramnios, which may result in fetal limb contractures, craniofacial deformities, and pulmonary hypoplasia¹⁴⁸; therefore, use of ACE inhibitors should be avoided if possible during this period.

Amiodarone is structurally similar to thyroxine and contains 37% iodine by weight. In a review of 64 reported pregnancies in which amiodarone was administered to the mothers, there was no clear increase in the incidence of malformations. However, 11 (17%) infants had evidence of hypothyroidism, and two (3%) neonates had goiter.^149,150 The use of amiodarone in pregnancy was associated with mild abnormalities of neurodevelopment in some of the hypothyroid infants, although this was also observed in some euthyroid infants.¹⁵⁰ This agent is most often used during pregnancy to treat fetal arrhythmias, and first-trimester exposure is rare.

Respiratory Drugs

Maternal asthma is relatively common in pregnancy, affecting 4% to 8% of pregnant women. It is important to maintain appropriate treatment because asthma can increase the risk for adverse fetal and maternal outcomes.¹⁵¹

Inhaled β₂-adrenergic receptor agonists, cromolyn sodium, and corticosteroids have not been associated with congenital malformations. Currently, albuterol is the preferred short-acting β₂-receptor agonist, and salmeterol is the preferred long-acting β₂-receptor agonist. Budesonide is the recommended inhaled corticosteroid because it has a long history of safe usage, but there is no evidence against the other options, which include beclomethasone, ciclesonide, fluticasone, flunisolide, mometasone, and triamcinolone.

Severe persistent asthma may require systemic oral corticosteroid therapy, and this has been associated with low birth weight and a three- to five-fold increase in the relative risk for cleft lip and palate.^152,153 However, other studies have found no adverse effects and, given the risks from severe asthma, oral corticosteroids should be used if required.

The 5-lipoxygenase inhibitors and leukotriene receptor antagonists are newer agents with no evidence of teratogenicity.¹⁵⁴ Women using montelukast enrolled in several teratogen information services around the world showed no increased risk for birth defects in 160 live births.¹⁵⁵

Methylxanthines such as theophylline and aminophylline have no adverse fetal effects, but the protein binding and metabolism of theophylline are both reduced during pregnancy, making it necessary to monitor drug concentrations and adjust maintenance doses.

Anticoagulants

Warfarin use in early pregnancy can result in an embryopathy similar to the X-linked chondrodysplasia punctata. The embryopathy can occur with fetal exposure between 6 and 12 weeks’ gestation. Because deficiency of arylsulfatase E is responsible for the chondrodysplasia, the embryopathy may result from inhibition of arylsulfatase E by warfarin. The period between 6 and 9 weeks’ gestation is especially critical. Fetal warfarin syndrome consists of nasal hypoplasia, depressed nasal bridge (often with a deep groove between the alae and nasal tip), stippled epiphyses, nail hypoplasia, mental retardation, and growth restriction. Second- and third-trimester exposures can result in other adverse fetal effects, including microcephaly, blindness, deafness, and growth restriction. Three prospective studies of women exposed only in the second and third trimesters found that the incidence of malformations must be exceedingly low because there was no evidence of fetal or neonatal CNS or eye abnormalities.¹⁵⁶ Some evidence suggests that a lower dose (< 5 mg/day) has less teratogenic potential.¹⁵⁷

Heparin is a large, water-soluble molecule that does not cross the placenta. Maternal administration does not have an adverse effect on the fetus, and heparin is the drug of choice for most pregnant women who require anticoagulation daily. Daily administration of 20,000 units of standard unfractionated heparin for more than 20 weeks may be associated with maternal bone demineralization.¹⁵⁸ Unfractionated heparin should be used for prolonged periods only when it is clearly necessary.

Low-molecular-weight heparin (LMWH) has some advantages over standard unfractionated heparin.¹⁵⁹ LMWH does not cross the placenta and has a longer half-life than standard unfractionated heparin, which typically allows once-daily dosing in nonpregnant patients. In addition, LMWH has a more predictable dose-response relationship in nonpregnant patients, which obviates monitoring. However, pregnancy is associated with a higher volume of distribution and accelerated clearance of LMWH. Use of LMWH thromboprophylaxis during pregnancy requires adjustments in the dose of LMWH to accommodate for the changes in the pharmacokinetics of this drug that occur during pregnancy. For example, pregnant women may require twice-daily doses.¹⁶⁰

Full anticoagulation is necessary in pregnant women with cardiac valve prostheses. In a systematic review of anticoagulation in pregnant women with mechanical heart valves, Chan et al.¹⁶¹ evaluated outcomes with the following three anticoagulation regimens: (1) oral anticoagulants (most commonly warfarin) given throughout pregnancy, (2) heparin administered during the first trimester and then warfarin for the duration of pregnancy, and (3) heparin administered throughout pregnancy. The data demonstrated progressively higher rates of maternal death with regimens 1, 2, and 3 (1.8%, 4.2%, and 15.0%, respectively). The use of warfarin throughout pregnancy was associated with warfarin embryopathy in 6.4% of live-born infants. The substitution of heparin at or before 6 weeks’ gestation eliminated that risk.¹⁶¹

For women with prosthetic heart valves, the American College of Chest Physicians (ACCP) has recommended use of one of the following three regimens: (1) adjusted-dose LMWH twice-daily throughout pregnancy, with doses adjusted to achieve the manufacturer’s peak anti–factor Xa LMWH levels 4 hours after subcutaneous injection; (2) adjusted-dose unfractionated heparin administered subcutaneously every 12 hours throughout pregnancy, with doses adjusted to keep the mid-interval activated partial thromboplastin time at least twice control or to attain an anti–factor Xa heparin level of 0.35 to 0.70 units/mL; or (3) unfractionated heparin or LMWH as just described until the 13th week of pregnancy, with substitution by vitamin K antagonists until close to delivery, when unfractionated heparin or LMWH is resumed.¹⁶⁰ In women at very high risk for thromboembolism in whom there is concern about the efficacy and safety of unfractionated heparin or LMWH, it is suggested to administer vitamin K antagonists throughout pregnancy with replacement by unfractionated heparin or LMWH close to delivery.¹⁶⁰ In high-risk women with prosthetic heart valves, it is suggested to add low-dose aspirin 75 to 100 mg/day.¹⁶⁰

Antiemetics

Most women in early pregnancy have nausea, with or without vomiting (see Chapter 2 and Chapter 16).¹⁶² Complementary therapies such as acupressure and ginger may be effective, but approximately 10% of women will require drug therapy. Although many different drugs can be effective, vitamin B₆ should be the drug of choice.¹⁶³ A combination of vitamin B₆ with the antihistamine doxylamine was previously available as Bendectin, but this was withdrawn by the manufacturer in 1983 because of allegations of teratogenicity that were later found to be false. Other formulations are now available, and there is no evidence of teratogenicity with them or other antihistamines. Trimethobenzamide is structurally related to antihistamines such as diphenhydramine, but it has only weak antihistamine activity. The mechanism of action is unclear, but it probably acts at the chemoreceptor trigger zone. It has few side effects but also variable efficacy. Nausea and vomiting can also be treated with phenothiazines, but they may cause sedation.

The prokinetic agent and dopamine antagonist metoclopramide is not sedating, but it has a “black box” warning because chronic usage has been associated with rare cases of tardive dyskinesia. There are no specific safety concerns during pregnancy. A multicenter study did not observe an increased incidence of anomalies,¹⁶⁴ and a large trial of 3458 women exposed to metoclopramide in the first trimester found no association with increased risk for birth defects, low birth weight, preterm delivery, or perinatal death.¹⁶⁵

The 5-hydroxytryptamine receptor antagonists are widely used and very effective antiemetics with few side effects, so they are also increasingly being used in pregnancy. Ondansetron was similar in efficacy to promethazine for the treatment of hyperemesis gravidarum but less sedating.¹⁶⁶ There is no evidence that it has a teratogenic effect.¹⁶⁷

Corticosteroids such as dexamethasone are now commonly used for postoperative and chemotherapy-induced nausea and vomiting. Methylprednisolone has been used for refractory nausea and vomiting during pregnancy. However, a meta-analysis concluded that the use of glucocorticoids before 10 weeks’ gestation was associated with a threefold to fivefold increased risk for cleft lip with or without cleft palate¹⁵²; and thus, they should not be used during this period.

Antihistamines

Some pregnant patients may be treated with antihistamines for allergies or upper respiratory tract infections. These drugs provide symptomatic therapy with no influence on the course of the disease. If considered necessary, combinations of drugs should be avoided if possible. Topical nasal sprays result in less fetal exposure than systemic medication. One study suggested an association between pseudoephedrine and defects attributable to vascular disruption, including gastroschisis, small intestinal atresia, and hemifacial microsomia.¹⁶⁸ Physicians should discourage the use of nonprescription drugs for trivial indications because the long-term fetal effects of the chronic maternal use of these drugs are unknown.

Sedating or first-generation antihistamines are available in over-the-counter medications and have not been reported to increase fetal risk.¹⁶⁹ Examples include chlorpheniramine, diphenhydramine, methapyrilene, thonzylamine, pyrilamine, tripelennamine, phenyl­toloxamine, and buclizine. Despite conflicting reports, a meta-analysis found no evidence to implicate brompheniramine as a teratogen.¹⁷⁰ In the Boston Collaborative Program,¹⁷¹ none of the sedating antihistamines was associated with malformations. Two combination products—triprolidine with pseudoephedrine (Actifed) and phenylpropanolamine with chlorpheniramine (Ornade)—were not associated with malformations. In a cohort of 1502 women, antihistamines were not associated with congenital malformations.¹⁷² Azatadine was not found to be teratogenic among 127 Michigan Medicaid recipients.¹¹⁵

Limited safety information is available for the nonsedating antihistamines. In a cohort study, 114 women exposed to astemizole were matched with 114 women exposed to known nonteratogens.¹⁷³ There were two major malformations in the astemizole group and two in the control group. In a study of 39 women exposed to cetirizine, the rate of malformations was no higher than in a control group.¹⁷⁴ This finding was replicated in a study performed through a teratogen information service.¹⁷⁵ There are no controlled human studies for loratadine or fexofenadine. Desloratadine is the major metabolite of loratadine; most data do not point to a risk for congenital abnormalities.¹⁶⁹

Several antihistamines have primary indications not directly related to upper respiratory complaints. Hydroxyzine is used for treatment of pruritus, meclizine for dizziness, diphenhydramine for sleep and pruritus, and doxylamine (a component of the former Bendectin) for treatment of nausea and vomiting of pregnancy. A meta-analysis of antihistamines used mostly for morning sickness in early pregnancy found a protective effect against malformations (OR, 0.76; 95% CI, 0.60 to 0.94).¹⁷⁶ This apparent benefit may have resulted from an association between maternal nausea and good fetal outcomes rather than from a direct effect of antihistamines.

Anti-infective Drugs

Sepsis is a leading cause of maternal mortality. When administering perioperative antibiotics, anesthesia providers should be aware of the considerations regarding their use during pregnancy.¹⁷⁷ Although penicillins and cephalosporins are considered first-line treatment because of their long safety record, therapy is ultimately guided by local microbiology policies and bacterial sensitivity.

Tetracyclines should not be administered after the fifth week of pregnancy. They bind to developing enamel and cause discoloration of the teeth. They affect deciduous teeth when administered between approximately 26 weeks’ gestation and 6 months of age in the infant, and they affect permanent teeth only if administered to children between approximately 6 months and 5 years of age. In addition, tetracyclines deposit in developing osseous sites and inhibit bone growth beginning in the second trimester.¹⁷⁷

Quinolones (e.g., ciprofloxacin, norfloxacin) should not be used in pregnancy or in children. They have a high affinity for bone tissue and cartilage and may cause arthropathies in children. However, no malformations or musculoskeletal problems were noted in 38 infants exposed during the first trimester.¹⁷⁷

Malaria is a significant cause of maternal and fetal death. Pregnant women should avoid traveling to malaria-endemic areas, but chloroquine or mefloquine can be used for malaria chemoprophylaxis. They are not associated with an increase in spontaneous abortions or congenital malformations. Doxycycline, primaquine, and atovaquone-proguanil are not to be used in pregnancy.

Treatment of herpes simplex and herpes zoster infections in the first trimester with acyclovir or valacyclovir has not been associated with an increased risk for birth defects.¹⁷⁸

Zidovudine has been studied because of its role in the treatment of acquired immunodeficiency syndrome (AIDS). In a prospective cohort study, children exposed to it during the perinatal period in the Pediatric AIDS Clinical Trials Group Protocol 076 (PACTG 076) were studied to a median age of 4.2 years; no adverse effects were observed.¹⁷⁹ Combination antiretroviral therapy has not been associated with major infant toxicity, even when the therapy was initiated in the first trimester of pregnancy.¹⁸⁰

The Antiretroviral Pregnancy Registry was established in 1989 to detect any major teratogenic effect of the antiretroviral drugs. Each year it enrolls approximately 15% of all HIV-positive women who give birth to live infants in the United States plus a small number from other countries. It depends on voluntary reporting of prenatal exposure; therefore, drug-associated adverse events may not necessarily reflect true rates. Results of retrospective and clinical studies are also reviewed. Through January 2013, no apparent increase in the frequency of birth defects after first-trimester exposure to antiretroviral drugs compared with population-based comparators was reported.¹⁸¹ A modest but statistically significant elevation of defect rates with didanosine and nelfinavir was reported, the clinical relevance of which is unclear.

It is generally appropriate to administer vaccinations during pregnancy because the risks of the disease may outweigh the risk of the vaccine. No evidence exists of risk to the fetus from vaccinating pregnant women with inactivated virus or bacterial vaccines or toxoids. However, live vaccines pose a theoretical risk to the fetus, so vaccination with live attenuated virus (e.g., varicella, measles-mumps-rubella [MMR]) or tuberculosis (e.g., bacillus Calmette Guérin [BCG]) is considered contraindicated.¹⁸² Influenza vaccination is recommended with the inactivated virus preparation.¹⁸³ Prevention and treatment of influenza with either zanamivir or oseltamivir is possible during pregnancy¹⁸⁴; no adverse fetal effects have been reported.¹⁸⁵

Caffeine

No evidence suggests that caffeine has teratogenic effects in humans. Early uncontrolled studies suggested that heavy ingestion of caffeine was associated with an increased incidence of spontaneous abortion, low birth weight, preterm delivery, and stillbirth. However, these studies did not control for the use of tobacco and alcohol. A contemporary meta-analysis showed no association with caffeine consumption and preterm birth.¹⁸⁶ In 2010, the ACOG published a committee opinion based on studies of caffeine use in pregnancy.¹⁸⁷ They concluded that (1) daily intake of less than 200 mg of caffeine was not associated with an increased risk for miscarriage, but contradictory data did not allow for a recommendation regarding daily intake above this level; (2) moderate caffeine intake does not appear to contribute to preterm birth; and (3) the association between caffeine intake and fetal growth restriction was equivocal. A subsequent review concluded with more certainty that moderate or even high amounts of caffeine-containing foods and beverages did not increase the risk for congenital malformations, miscarriage, or growth restriction.¹⁸⁸

Smoking Cessation Therapies

Smoking during pregnancy is clearly linked to multiple adverse fetal, neonatal, and childhood effects. Drug interventions to stop smoking include nicotine replacement therapy, antidepressants, bupropion (dopamine and norepinephrine reuptake inhibitor and nicotine antagonist), bromocriptine (dopamine agonist), varenicline (nicotine partial agonist), and cytisine (plant alkaloid). Bupropion and bromocriptine therapy were not associated with congenital malformations or other adverse outcomes.¹⁸⁹ Animal data show no increase in malformations with varenicline, but there are no human data.

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. Some examples are (1) thalidomide, which is still used for erythema nodosum leprosum and multiple myeloma; (2) the antiviral ribavirin, which is used for hepatitis C and viral hemorrhagic fevers; (3) isotretinoin, which is used for cystic acne; and (4) acitretin, which is used for severe psoriasis.

General Principles

Nursing mothers are understandably concerned about the transfer of drugs and chemicals to breast milk. Correct advice is important to prevent them from unnecessarily stopping breast-feeding or discontinuing appropriate drug treatment. Unfortunately, it can be difficult to decide which of the many, sometimes conflicting, sources of public information to trust. Pharmaceutical information leaflets from the manufacturers often discourage the use of drugs during breast-feeding simply as a general precaution. The most comprehensive up-to-date information is found in the Drugs and Lactation database (LactMed) of the National Library of Medicine’s Toxicology Data Network (TOXNET).¹⁹⁰ The American Academy of Pediatrics (AAP) has published policy statements on the benefits of breast-feeding¹⁹¹ and the use of drugs during lactation.¹⁹² The Centers for Disease Control and Prevention (CDC) provides online information regarding breast-feeding and various toxins and infectious diseases.¹⁹³

Only a few types of drugs such as cytotoxic and immunosuppressive drugs (e.g., cyclophosphamide, methotrexate) and radioactive compounds are strongly contraindicated during breast-feeding.⁵⁹ Mothers breast-feeding infants with glucose-6-phosphate-dehydrogenase (G6PD) deficiency should avoid drugs such as sulfonamides, including the combination of sulfamethoxazole and trimethoprim, nitrofurantoin, and primaquine.

Maternal drugs may also affect lactation, and some are used therapeutically for this purpose. Drugs that increase the secretion of prolactin can stimulate milk production; these include dopamine antagonists such as phenothiazines, haloperidol, metoclopramide, and domperidone, as well as sulpiride, risperidone, and methyldopa. Drugs that decrease the production of milk include diuretics, estrogen, and dopamine agonists such as bromocriptine, cabergoline, lisuride, and quinagolide. Bromocriptine is no longer approved for postpartum lactation suppression because of its association with puerperal seizures, stroke, and myocardial infarction. Women who smoke also have lower milk production.

Drug transfer to breast milk occurs by passive diffusion, but transporter systems are also present.¹⁹⁴ The rate of passive transfer into breast milk depends on the lipid solubility, molecular weight, degree of ionization, and protein binding of the drug. Nonionized molecules of small molecular weight (e.g., ethanol) are readily transferred into breast milk. Drugs that have more than 85% maternal protein binding are often not detectable in the infant.¹⁹⁵

The amount of a drug in breast milk is a variable fraction of the maternal blood concentration, which is proportional to the maternal dose. Quoted maternal milk-to-plasma ratios can vary because drug transfer is a time-dependent process. Even when calculated under steady-state conditions, there can be large individual variation. Absolute infant dose (µg/kg/day) can be calculated as the product of the average concentration in milk and the estimated daily volume of milk intake, and relative infant dose can be estimated by dividing absolute infant dose by the maternal dose.¹⁹⁶ It has been suggested that a relative infant dose less than 10% is generally safe,¹⁹⁶ but this will also depend on the oral bioavailability of the drug in the infant and the relative toxicity of individual agents. However, physicians and patients should be aware of the following disclaimers. First, in the case of toxic drugs, any exposure may be inappropriate. Second, the infant may be allergic to a drug consumed by the mother. Third, there may be unknown, long-term effects of even small doses of drugs. Fourth, individual variability in drug disposition may lead to unexpectedly high maternal blood and breast milk concentrations. Finally, infants have immature enzyme systems and metabolic pathways and some drugs are eliminated more slowly. The benefits of breast-feeding are well known, and the risk of drug exposure must be weighed against these benefits.

Lactation is not fully established during the first several days postpartum. The neonate receives only a small volume of colostrum, and little drug is excreted through milk at this time. Thus, only very small amounts of drugs administered after vaginal or cesarean delivery would reach the neonate and significant effects should be unlikely. However, neonatal metabolism and elimination are also poorly developed, and several days of maternal opioid analgesia with drugs such as meperidine (pethidine) and codeine may result in neonatal accumulation and side effects.

When a mother requires a daily dose of a drug during lactation, the minimum effective dose should be used. Some mothers requiring long-term therapy would already have been taking drugs during pregnancy, and the fetus would have been exposed to concentrations much greater than those achieved in the infant through breast-feeding. Thus, if a drug has been acceptable during pregnancy, it is often reasonable to continue it during breast-feeding unless there are drug-specific factors to the contrary.¹⁹⁷ For example, poor neonatal elimination of lamotrigine may eventually lead to drug accumulation in the infant and adverse effects. In general, medications should be taken after breast-feeding, and long-acting preparations should be avoided. If the infant nurses less frequently overnight, ingestion of a drug dose at night after nursing will decrease the infant’s exposure.

Anesthetic Drugs

There are generally no concerns regarding anesthetic drugs and perioperative medicines in the breast milk of women who require an anesthetic.^198,199 However, the prolonged use of postoperative medications such as analgesics will obviously increase the infant dose, the potential effects of which are discussed next.

Analgesics

No harmful effects of acetaminophen or NSAIDs have been noted except for aspirin.⁷¹ Some NSAIDs specifically recommended as compatible with breast-feeding are ibuprofen, flurbiprofen, naproxen, and celecoxib. Other NSAIDs may be discouraged simply because of limited information, although there are some concerns about diflunisal and carisoprodol based on animal data.¹⁹² Surprisingly, the FDA has singled out ketorolac with a “black box” warning that it is “contraindicated in nursing mothers because of the potential adverse effects of prostaglandin-inhibiting drugs on neonates”; the basis for this decision is unclear. Theoretically, NSAIDs with antiplatelet effects should be avoided by mothers who are breast-feeding neonates with platelet dysfunction. With aspirin, there is limited transfer of salicylic acid into breast milk because it exists mostly in the ionized form. After single oral doses, peak milk levels occur at approximately 3 hours with milk-to-plasma concentration ratios between 0.03 and 0.05.²⁰⁰ However, maternal ingestion of high doses (e.g., more than 16 tablets per day) may result in maternal and breast milk concentrations sufficiently high to affect platelet aggregation in the infant. Reduced neonatal clearance of salicylic acid may lead to drug accumulation and toxic effects, even when repeated exposures are small.²⁰¹ Because of these concerns, the World Health Organization (WHO) Working Group on Human Lactation has classified salicylates as unsafe for use by nursing women.²⁰² Low doses of aspirin prescribed as anti-platelet therapy may be acceptable.¹⁹²

It was thought previously that opioids used by nursing mothers were highly unlikely to have adverse effects on breast-fed infants. Normal maternal doses of codeine, morphine, tramadol, and meperidine do not have obvious adverse effects on most nursing infants.^78,192 The dose detectable in breast milk is 1% to 2% of the mother’s dose and is unlikely to have significant pharmacologic activity. However, in one patient who took propoxyphene in a suicide attempt, the breast milk concentration of propoxyphene was half that of the maternal serum level.²⁰³ Theoretically, a breast-feeding infant could receive up to 1 mg of propoxyphene per day if the mother were to consume the maximum dose.

Neonates are particularly vulnerable because their drug metabolism and elimination are poorly developed. Neonates of mothers receiving meperidine by intravenous patient-controlled analgesia after cesarean delivery had significant neurobehavioral depression by the third day.²⁰⁴ The cumulative maternal meperidine dose at 48 hours postpartum was 14 mg/kg. No neonatal depression was seen in a morphine group in whom the cumulative maternal dose at 48 hours was 2.1 mg/kg. Both opioids and their major metabolites accumulated in colostrum. In a subsequent study,²⁰⁵ the cumulative opioid doses at 48 hours were lower (meperidine 4.7 mg/kg and morphine 0.54 mg/kg), but infants in the morphine group were still more alert and oriented. With lower maternal morphine doses, concentrations in colostrum may even be undetectable.²⁰⁶

Recently, it has been recognized that infants of breast-feeding mothers taking codeine may have CNS depression. In 2006, the full-term 13-day-old infant of a mother taking a modest dose of codeine for episiotomy pain died of an apparent morphine overdose. It was discovered that the mother was heterozygous for a CYP2D6*2A allele with CYP2D6*2×2 gene duplication, making her an ultra-rapid metabolizer of codeine. This condition resulted in a breast milk morphine concentration of 87 ng/mL, compared with the expected typical range of 1.9 to 20.5 ng/mL.²⁰⁷ This case prompted the FDA to release a Public Health Advisory advising caution in the use of codeine-containing medications by breast-feeding women.²⁰⁸ The FDA recommended that the lowest effective dose for the shortest necessary duration should be used and that women should be taught how to recognize signs of high morphine levels in their infants. The number of ultra-rapid metabolizers is estimated to vary between 1 and 28 per 100 people.²⁰⁸ In addition, genetic variability in UGT2B7 may increase the formation of active morphine-6-glucuronide. It is estimated that 1.4% of Western European women would have both the CYP2D6 and UGT2B7 variants promoting neonatal depression.²⁰⁹

Ultra-rapid metabolism has been reported as a problem for breast-feeding only with codeine, although the FDA suggested that “it has the potential to affect other opioids.”²⁰⁸ Maternal oxycodone for postpartum analgesia has been associated with neonatal depression.²¹⁰ However, polymorphisms have less effect on the metabolism and analgesic effects of oxycodone, hydrocodone, and tramadol than codeine.²¹¹

Sedatives

Long-acting drugs such as diazepam are metabolized slowly in the infant, and accumulation can lead to sedation and poor feeding. Perinatal use of diazepam has been associated with hypotonia, hypothermia, and respiratory depression.⁸⁵ If a sedative must be used in a lactating woman, a relatively short-acting agent with inactive metabolites, such as oxazepam, lorazepam, alprazolam, or midazolam, is recommended.²¹² The infant should be monitored for sedation during maternal drug use and for withdrawal symptoms after the medication is stopped or after discontinuation of breast-feeding.²¹³

Anticonvulsants

Carbamazepine and valproic acid have low excretion into breast milk and are considered the safest choices.²¹⁴ Studies have detected only small amounts of phenytoin, phenobarbital, and diazepam in breast milk.^215,216 However, infants eliminate phenobarbital and diazepam slowly, so these agents may accumulate. Women taking a barbiturate or a benzodiazepine should observe their infants for evidence of sedation and withdrawal.^92,192 There are conflicting recommendations for the newer anticonvulsants. Lamotrigine concentrations in breast-fed infants can be very high, and some recommend that the drug should be avoided.²¹⁴ However, other authors note that the mother has usually been taking this drug throughout pregnancy already and that there is no evidence to recommend stopping the drug.²¹⁷

Cruikshank et al.²¹⁸ measured breast milk magnesium concentrations in 10 preeclamptic women who were receiving magnesium sulfate 1 g/h intravenously for 24 hours after delivery. The mean breast milk magnesium concentration was 6.4 ± 0.4 mg/dL, compared with 4.8 ± 0.5 mg/dL in controls. Breast milk calcium concentrations were not affected by magnesium sulfate therapy.

Antidepressants and Lithium

Psychotropic agents may be of concern because many of these medications have long half-lives and the effect of even small doses on the developing nervous system is not known. Nevertheless, the many medications available to treat depression or postpartum depression appear to have little if any immediate effect on the infant.²¹⁹ Many antidepressants have low milk-to-plasma ratios. There are few reports of neonatal problems with the use of SSRIs and related drugs.²²⁰ Fluoxetine and its metabolite have relatively long elimination half-lives, so other drugs such as sertraline and paroxetine are preferred.²²¹

Breast milk concentrations of lithium are one third to one half of maternal serum concentrations,^222,223 and infant serum concentrations during breast-feeding are much lower than fetal serum concentrations that occur when mothers take lithium during pregnancy. Neonatal clearance of lithium is reduced, and it may be useful to monitor neonatal lithium concentrations.

Cardiovascular Drugs

Amiodarone concentrations in the infant are unpredictable but may be sufficiently high to cause cardiac effects. Iodine released during its metabolism may cause thyroid dysfunction. Amiodarone has a very long half-life and is still excreted in breast milk weeks after stopping the drug.

Beta-adrenergic receptor antagonists with low protein binding have relatively higher transfer to breast milk, and those excreted renally are more likely to accumulate in neonates. Thus, atenolol with 10% protein binding and 85% renal excretion would not be the best choice. Breast milk concentrations of atenolol are approximately three times maternal plasma concentrations.²²⁴ Even though the total infant dose is only 1% of the maternal therapeutic dose, and the infant plasma concentration would not normally cause side effects in the infant, atenolol has been associated with neonatal cyanosis and bradycardia.

Other common drugs such as ACE inhibitors and antihypertensives are considered safe. However, diuretics may reduce milk production. Maternal protein binding of digoxin limits infant drug exposure; after a maternal dose of 0.25 mg, a peak breast milk concentration of 0.6 to 1.0 ng/mL occurs and the milk-to-plasma concentration ratio at the 4-hour peak is between 0.8 and 0.9 ng/mL. In 24 hours an infant might receive approximately 1% of the maternal digoxin dose,²²⁵ and no adverse effects have been reported in nursing infants of mothers taking this drug. Breast milk clonidine concentrations are almost twice maternal serum concentrations. However, this exposure does not seem to have any adverse effects on the infant.²²⁶

There are no safety data for statins, but they are not recommended during breast-feeding because of concerns that they may disrupt infant lipid metabolism.

Respiratory Drugs and Corticosteroids

Salbutamol, terbutaline, and salmeterol inhalers are considered compatible with breast-feeding. Maximum milk concentrations of theophylline are achieved between 1 and 3 hours after an oral dose. It has been calculated that the nursing infant receives less than 1% of the maternal dose. Such exposure appears to have no adverse effects.

Inhaled and oral corticosteroids are also considered safe. Katz and Duncan²²⁷ obtained breast milk 2 hours after an oral dose of 10 mg of prednisone in one nursing mother. They detected breast milk concentrations of prednisone and prednisolone that would be unlikely to result in any deleterious effect on the infant. McKenzie et al.²²⁸ administered 5 mg of radioactive prednisolone to seven patients and found that 0.14% (a negligible quantity) of the radioactive label was secreted in the milk in the subsequent 60 hours. Thus, breast-feeding is not contraindicated in mothers taking corticosteroids. Even at a maternal dosage of 80 mg/day, the nursing infant would ingest a dose equivalent to less than 10% of its endogenous cortisol production.²²⁹

Anticoagulants

Most mothers who require anticoagulation may continue to nurse their infants with no problems. Warfarin is 98% protein bound. Orme et al.²³⁰ reported no warfarin in breast milk or infant plasma in seven women taking warfarin 5 to 12 mg/day. Similarly, de Swiet and Lewis²³¹ found that warfarin appears in breast milk in insignificant quantities. Heparin does not cross significantly into breast milk and is not active when administered orally.

Antihistamines

No harmful effects have been noted with maternal use of antihistamines.²³² These drugs do not appear to affect the milk supply. Little antihistamine is excreted into breast milk, further confirming safety of use during lactation.¹⁶⁹

In theory, histamine type 2 (H₂)-receptor antagonists might suppress gastric acidity or cause CNS stimulation in the infant, but these effects have not been confirmed in published studies. Famotidine, nizatidine, and roxatidine are less concentrated in breast milk and may be preferable to cimetidine.²³³

Anti-infective Drugs

Penicillin and its derivatives are safe in nursing mothers. With the usual therapeutic doses of ampicillin, the milk-to-plasma concentration ratio is 0.2 or less and no adverse effects are noted in nursing infants.²³⁴ Theoretically, infant diarrhea or candidiasis might occur with prolonged therapy. Cephalosporins appear in trace amounts in breast milk and are also safe.

Sulfonamides displace bilirubin from binding sites on albumin, so these drugs are best avoided during the first 5 days of life or in mothers of preterm infants with hyperbilirubinemia. Sulfonamides appear in breast milk in small amounts. Sulfasalazine has been associated with diarrhea and bloody diarrhea in an infant.¹⁹² Sulfonamides should be avoided in infants with G6PD deficiency.

Tetracyclines are normally avoided during breast-feeding because of the potential for tooth staining and delayed bone growth. The breast milk concentration of tetracycline is about half the maternal plasma concentration, but tetracycline has a high affinity for both calcium and protein, and the amount of free tetracycline available for systemic absorption is very small. Thus, some references consider a short course of tetracyclines to be compatible with breast-feeding. Similarly, quinolones are usually avoided in pregnancy, but there is disagreement over their safety during breast-feeding.

Maternal administration of acyclovir does not contraindicate breast-feeding. If a mother takes 1 g/day, the infant probably receives less than 1 mg/day, a very low dose.²³⁵

Most vaccines, except for yellow-fever and smallpox, can be administered during breast-feeding.¹⁹²

Caffeine

Moderate maternal intake of caffeine does not adversely affect the breast-fed infant. One study noted that breast milk contains only 1% of the total maternal dose of caffeine.²³⁶ If a mother drinks excessive amounts of coffee, caffeine might accumulate in the infant and the infant might show signs of caffeine stimulation (e.g., irritability, poor sleeping pattern). Nursing mothers should limit their intake to a moderate level of caffeinated beverages (e.g., 2 to 3 cups per day).¹⁹²