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Drug Therapy in Pregnancy
Key Concepts
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Chemically induced birth defects are responsible for approximately 1% to 3% of anomalous births.
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Gestational age is crucial in determination of the impact of any given exposure, especially during organogenesis (days 21–56 of fetal life), when major body organs are formed.
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Human data on teratogenicity and fetal toxicity of medications are often limited, and causal associations are difficult to determine, especially with newer medications.
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In general, the health of the fetus is directly related to the health of the mother, and drugs should be given when the maternal benefits outweigh the risks to the fetus.
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Certain medications should be avoided during pregnancy because they are known teratogens or cause potential toxic effects in the newborn; these include anticonvulsants, warfarin derivatives, NSAIDs, sulfonamides, fluoroquinolones, and ACE inhibitors. If there are no alternatives to these agents, it is recommended to use the lowest dose for the shortest duration possible.
Foundations
More than 90% of women take at least one prescription or over-the-counter medication during pregnancy, and overall medication use during pregnancy has increased in the last 3 decades. One study revealed that only 22% of reproductive-aged women have pregnancy testing done when administered or prescribed potentially harmful or teratogenic medications in the emergency department (ED). Unfortunately, the majority of research on the use of medications during pregnancy is insufficient to determine reliable and accurate risks to the mother and fetus, especially for newer agents. Only a few medications have been tested specifically for safety and efficacy during pregnancy. Prescribing medications during pregnancy must account for the physiologic changes associated with pregnancy as well as the benefits and risks to the mother and developing fetus.
The fetal age at exposure to a medication is crucial in determining its impact on the pregnancy. The fetus is most vulnerable to toxic insults during the time of organogenesis (days 21–56 of fetal life). Exposure during this period may result in major anatomic defects. Exposure after the period of organogenesis may affect the growth and development of the fetus. Functional development of the central nervous system (CNS) is affected when it is exposed to a CNS teratogen during the 10th to 17th weeks of pregnancy.
Major birth defects affect 3% to 5% of all live births. Most are of unknown cause, but 1% to 3% of these are thought to be due to pharmaceutical or environmental agents. A teratogen is any chemical, pharmacologic, environmental, or mechanical agent that can cause disruptive development of the conceptus. Included in this definition are functional impairment, growth restriction, and congenital malformations.
The process of establishing teratogenicity is tedious and often flawed. Animal research, although valuable in determining risk initially, is not always applicable to humans, and controlled prospective human studies are generally not performed for ethical reasons. As a result, much of our current knowledge on teratogenicity has been derived from less rigorous studies, which are inherently weak in establishing a causal relationship between a specific exposure and malformations. The genetic background of the fetus, timing and duration of the exposure, environmental factors, multiple exposures, nutritional deficits, maternal illness, and illicit drug use all contribute to the outcome of pregnancy. Large population studies are needed to understand the connection between the outcome of a pregnancy and in utero exposures. Finally, as in the case of diethylstilbestrol, teratogenicity may not be apparent for years after birth.
Classification of Teratogenic Risk
The FDA issued a final rule for drug labeling called the Pregnancy and Lactation Labeling Rule (PLLR) in June 2015. The PLLR changed the content and format of prescription drug labeling to help health care providers better assess the benefits and risks in counseling pregnant and nursing women who are taking medications. The rule requires the removal of letter categories (A, B, C, D, and X) and mandates labeling that includes a summary of data on the risks of a drug used during pregnancy, lactation, and the impacts on male and female reproduction. It requires the provision of current data supporting that summary, and any relevant information to help health care providers make informed decisions and counsel patients. The PLLR also mandates the label be updated when new information becomes available. Drugs already approved before this rule are being phased in. Currently, a number of clinical teratology resources that assign risk are available online, such as Clinical Pharmacology, TERIS, and Micromedex Reprotox (Shepard’s Catalog of Teratogenic Agents ).
Drug Transfer Across the Placenta
Drug transfer across the placenta usually occurs by simple passive diffusion or protein transport. A thin layer of trophoblastic cells is all that separates maternal from fetal circulation. The degree to which a drug gains access to fetal circulation depends on molecular size, ionic state, lipid solubility, and extent of protein binding. Drugs with a molecular mass of less than 5 kilodaltons (kDa) readily diffuse. Anionic substances diffuse through the lipid layer more readily than ionized forms. A free drug diffuses more readily than a protein-bound drug. Because fetal pH is slightly more alkalotic than maternal pH, weak organic acids may become ion-trapped in the fetal circulation, increasing fetal exposure.
Drug Transfer During Lactation
Generally, drugs that are ingested or injected by the mother diffuse passively into milk and then back into the maternal circulation for excretion. The amount of drug diffusing into milk depends on many factors. Lipid-soluble and nonionic substances diffuse more readily, and highly protein-bound substances diffuse less readily. Whether a substance is concentrated in maternal milk or not, the neonate generally is able to detoxify it with no adverse effects, and only a few drugs pose a serious danger to a breast-feeding infant. The interruption of breast-feeding should not be advocated except in rare situations of known drug toxicity to the infant and in all cases of maternal critical illness.
Drug Therapy During Pregnancy
In general, the health of the fetus is directly related to the health of the mother. Physicians should not withhold lifesaving medications from pregnant patients because of a reported risk to the fetus and should resuscitate pregnant patients according to advanced life support guidelines. Physicians may also prescribe any agent when the maternal benefits outweigh the risks to the fetus. Included in this category are therapeutic medications for asthma, arrhythmias, status epilepticus, life-threatening overdoses, and human immunodeficiency virus (HIV) infection. When prescribing drugs to pregnant and lactating women, the benefits of treatment must be weighed against the inherent risks of treatment or disease. The drug with the lowest known toxicity should be chosen, and used at the lowest effective dose.
Pharmacologic Therapy
Analgesic Agents
Over-the-counter analgesics are used commonly during pregnancy, with acetaminophen being used by at least two-thirds of pregnant women. Studies are emerging that call for a reassessment of the safety of these medications. Several studies report increasing use and adverse pregnancy outcomes with opioids, such as neonatal abstinence syndrome and birth defects ( Table 175.1 ).
TABLE 175.1
Analgesic Medications
Adapted data from: Lopes LM, Carrilho MC, Francisco RPV, Lopes MAB, Krebs VLJ, Zugaib M. Fetal ductus arteriosus constriction and closure: analysis of the causes and perinatal outcome related to 45 consecutive cases. J Matern Fetal Neonatal Med . 2016;29(4):638–645; ACOG Practice Bulletin No. 196: Thromboembolism in pregnancy. Obstet Gynecol . 2018;132(1):e1-e17; Shenai N, Shulman J, Gopalan P, Cheng E, Cerimele JM. Fetal outcomes in intentional over-the-counter medication overdoses in pregnancy. Psychosomatics . 2018;59(4):400-404; Mullins N, Galvin SL, Ramage M, et al. Buprenorphine and naloxone versus buprenorphine for opioid use disorder in pregnancy: a cohort study. J Addict Med . 2019;14(3):185-192; Acar S, Keskin-Arslan E, Erol-Coskun H, Kaya-Temiz T, Kaplan YC. Pregnancy outcomes following quinolone and fluoroquinolone exposure during pregnancy: A systematic review and meta-analysis. Reprod Toxicol . 2019;85:65-74; Mallah N, Tohidinik HR, Etminan M, Figueiras A, Takkouche B. Prenatal exposure to macrolides and risk of congenital malformations: a meta-analysis. Drug Saf . 2019:43(3):1-11; Sheehy O, Santos F, Ferreira E, Berard A. The use of metronidazole during pregnancy: a review of evidence. Curr Drug Saf . 2015;10(2):170-179; Committee Opinion No. 717: Sulfonamides, nitrofurantoin, and risk of birth defects. Obstet Gynecol . 2017;130(3):e150-e152; Alsaad AM, Kaplan YC, Koren G. Exposure to fluconazole and risk of congenital malformations in the offspring: a systematic review and meta-analysis. Reprod Toxicol . 2015;52:78-82; Floridia M, Dalzero S, Giacomet V, et al. Pregnancy and neonatal outcomes in women with HIV-1 exposed to integrase inhibitors, protease inhibitors and non-nucleoside reverse transcriptase inhibitors: an observational study. Infection . 2020;48(2):249-258.
| Drug | Breast-Feeding | Clinical Risk Summary |
|---|---|---|
| Acetaminophen | Compatible, excreted in breast milk | CP, NHT; studies suggest increased risk of neurodevelopmental problems such as attention-deficit/hyperactivity-hyperkinetic disorder, cryptorchidism, childhood asthma/wheezing |
| Ibuprofen | Compatible, excreted in breast milk | CP, increased risk of spontaneous abortion at time of conception, association with structural cardiac defects and gastroschisis; risk in third trimester of premature closure of ductus arteriosus and subsequent primary pulmonary hypertension; potential increased risk of asthma with use in pregnancy |
| Aspirin | Potential toxicity, excreted in breast milk | CP; increased risk of spontaneous abortion at time of conception, avoid chronic or high doses in pregnancy; high doses may increase perinatal mortality, teratogenic effects; increased risk of gastroschisis in first trimester; increased risk of IUGR and fetal and maternal hemorrhage in third trimester; risk in third trimester of premature closure of ductus arteriosus and subsequent primary pulmonary hypertension; near-term use may prolong gestation, labor |
| Codeine | Potential toxicity Use with caution Excreted in breast milk, metabolized to morphine |
LHS; congenital malformation data in humans are inconsistent; avoid prolonged use or high doses near term; may develop respiratory depression and/or withdrawal symptoms, neonatal abstinence syndrome |
| Oxycodone | Potential toxicity Use with caution Potential for SAR |
LHS; use during organogenesis associated with low absolute risk of congenital birth defects; may result in preterm birth, poor fetal outcomes, NOWS |
| Morphine | Potential toxicity Usually compatible for short-term use Use with caution |
CP; use during organogenesis associated with low risk of CBD; may result in preterm birth and poor fetal outcomes; prolonged maternal use during pregnancy may result in NOWS |
CBD, Congenital birth defects; CP, crosses placenta; IUGR, intrauterine growth restriction; LHS, limited human studies; NHT, no human teratogenicity; NOWS, neonatal opioid withdrawal syndrome; SAR, serious adverse reactions.
Acetaminophen
Acetaminophen (paracetamol) is the most widely used analgesic during pregnancy. It has not been associated with congenital malformations and does not appear to increase the risk of adverse outcomes. There is weak evidence suggesting a link between maternal acetaminophen use in pregnancy with a higher risk of multiple neurodevelopmental problems including hyperkinetic disorders and attention-deficit hyperactivity disorder–like behaviors in children. Still, it is considered by most clinicians to be the safest analgesic and antipyretic medication currently available during pregnancy and lactation.
Nonsteroidal Antiinflammatory Drugs
Prostaglandin synthesis inhibitors, such as nonsteroidal antiinflammatory drugs (NSAIDs), taken in the first trimester may lead to increased risk of spontaneous abortions, although most of the studies showing this association are limited by not controlling for the conditions for which the medication was taken. The mechanism for this association is inhibition of prostaglandin production by NSAIDs, which is essential for embryonic implantation. Some epidemiologic and animal studies show an increase in ventricular septal defects and gastroschisis with NSAID use during pregnancy. When used in the third trimester, NSAIDs inhibit labor and may be used as tocolytic agents for premature labor. NSAID use in the latter part of pregnancy has been linked to a number of negative effects on the neonate, most notably premature closure of the ductus arteriosus, leading to neonatal pulmonary hypertension, and death. Use in the latter part of pregnancy is therefore discouraged. NSAIDs in general appear to be safe during lactation.
Aspirin
Studies show a proposed increased risk of spontaneous abortion with aspirin use around the time of conception. Chronic or high doses of aspirin during pregnancy should be avoided and may affect maternal and newborn hemostasis and bleeding abnormalities, leading to increased perinatal morbidity and mortality. Aspirin use has been associated with premature closure of the ductus arteriosus causing primary pulmonary hypertension in the newborn, and neonatal death. Low doses of aspirin (60 to 100 mg/day) may be beneficial in pregnancies complicated by systemic lupus erythematosus with antiphospholipid antibodies and those at risk for gestational hypertension and preeclampsia, as well as fetuses with intrauterine growth restriction (IUGR). Aspirin is excreted into breast milk and its use is discouraged during breast-feeding due to risk of Reye syndrome.
Opiate Analgesics
In general, short-term, episodic use of opiates such as oxycodone, hydrocodone, morphine, and fentanyl appear to be safe in pregnancy. Their use near term, however, may result in respiratory depression of the neonate. Prescribing of narcotics for long periods may be associated with preterm birth, low birth weight, reduced infant head circumference, congenital malformations, sudden infant death, and neonatal abstinence syndrome. Neonatal abstinence syndrome is characterized by CNS hyperirritability, autonomic nervous system dysfunction, and higher infant mortality. The short-term use of opiates during lactation appears to be safe, but nursing infants should be closely monitored for respiratory depression.
Rapid Sequence Intubation Agents
Data regarding the use of these agents during pregnancy are limited and have primarily been obtained from animal studies and retrospective human data. None of the agents has been consistently associated with congenital malformations or had adverse effects on the fetus ( Table 175.2 ).
TABLE 175.2
Rapid Sequence Intubation Medications
| Drug | Breast-Feeding | Clinical Risk Summary |
|---|---|---|
| Fentanyl | Compatible; may cause sedation or respiratory depression | CP; associated congenital birth defects; may cause neonatal respiratory depression, transient neonatal muscular rigidity, NOWS |
| Etomidate | Probably compatible | CP; animal studies show no teratogenicity; transient decrease in newborn cortisol levels of unknown clinical significance; LHS not harmful when used as induction agent |
| Propofol | Probably compatible, but not recommended | CP; animal studies show no malformations, LHS with no data on use in first and second trimesters; use at term appears to be safe, but high doses may be associated with neonatal CNS, respiratory depression |
| Thiopental | Probably compatible; use with caution | CP; LHS; animal studies show no congenital defects, even with high doses; may cause respiratory depression |
| Ketamine | Probably compatible; plasma levels undetectable after 12 hr | CP; used frequently in obstetrics, not associated with fetal developmental malformations; dose-dependent oxytocic effect; in high doses (>2 mg/kg), associated with uterine tetany; may increase maternal blood pressure and heart rate; may increase neonatal muscle tone or cause apnea and depression of the newborn, SAR usually dose-related |
| Midazolam | Use with caution Avoid with other CNS depressants |
CP; animal studies show no congenital effects, even with high doses; LHS, human observational studies show no malformations, no data on use in first and second trimesters; use near term has resulted in adverse neonatal neurobehavior and neonatal respiratory depression |
| Succinylcholine | Probably compatible because of rapid hydrolysis | Not embryotoxic or teratogenic in animals; may result in neonatal apnea and partial or complete newborn paralysis in neonates with pseudocholinesterase deficiency |
| Rocuronium | Probably compatible; LHS | CP; LHS; animal data suggest low risk; newborn neuromuscular blockade is potential complication but probably rare, may have prolonged blockade when used with magnesium |
| Vecuronium | Probably compatible | CP; LHS; use late in gestation appear to carry little if any risk to the newborn; use lower doses if administering magnesium sulfate |
CNS, Central nervous system; CP, crosses placenta; LHS, limited human studies; NHT, no human teratogenicity; NOWS, neonatal opioid withdrawal syndrome; SAR, serious adverse reactions.
Anticoagulants
Low-molecular-weight-heparin (LMWH) is preferred over unfractionated heparin and warfarin when indicated in pregnancy for therapeutic and prophylactic anticoagulation. Warfarin has the highest teratogenicity of the anticoagulants. The heparins, as a class, do not cross the placenta. All three anticoagulants are considered compatible with breast-feeding ( Table 175.3 ). Oral DTI (dabigatran) and anti-Xa inhibiitors (apixaban, rivaroxaban, edoxaban) have been extensively studied in pregnancy and therefore should be avoided.
TABLE 175.3
Anticoagulant Medications
Additional data adapted from: ACOG Practice Bulletin No. 203. Chronic hypertension in pregnancy. Obstet Gynecol . 2019;133(1):e26-e50; ACOG Committee Opinion No. 767. Emergent therapy for acute-onset, severe hypertension during pregnancy and the postpartum period. Obstet Gynecol . 2019;133(2):e174-e180.
| Drug | Breast-Feeding | Clinical Risk Summary |
|---|---|---|
| Warfarin | Compatible; however, caution advised when breast-feeding premature infants due to increased risk for intraventricular hemorrhage | CP; known dose-dependent teratogen affecting 4%–5% of exposed fetuses; greatest risk at gestational wk 6–9; fetal warfarin syndrome associated with corpus callosum agenesis, hypoplasia of nasal bones, midline dysplasia, optic atrophy and blindness; also associated with fetal osteogenesis, CNS malformations, fetal intraventricular hemorrhage, stillbirths, spontaneous abortions, abnormal development of bones, stippled epiphyses; school-age children exposed in utero had increased incidence of mild neurologic dysfunction |
| Heparin (UFH) | Compatible | DNCP; associated with maternal osteopenia, immune-mediated thrombocytopenia, maternal hemorrhage at delivery, requiring careful monitoring; has reduced bioavailability, shorter half-life, lower peak plasma concentrations during pregnancy; risk of antepartum bleeding ≈1% |
| Low-molecular-weight heparin | Compatible | DNCP; lower risk of osteoporosis than UFH has reduced bioavailability, shorter half-life, lower peak plasma concentrations during pregnancy; lower rate of bleeding, HIT, lower allergic response versus heparin; recommended over UFH for VTE |
CP, Crosses placenta; DNCP, does not cross placenta; HIT, heparin-induced thrombocytopenia; UFH, unfractionated heparin; VTE, venous thromboembolism.
Thrombolytic Agents
Alteplase, reteplase, urokinase, and streptokinase have been used successfully in pregnant women in cases of life-threatening pulmonary embolus, myocardial infarction, ischemic stroke, thrombosis of cardiac valve prosthesis, and deep venous thrombosis. Complication rates when used for these indications were similar compared to nonpregnant patients, and none of the live-born children had permanent defects. Recombinant tissue plasminogen activator does not cross the placenta. Poor fetal outcomes have been associated with poor maternal prognosis. To date, no teratogenic effects have been reported in humans, but intrapartum maternal hemorrhage, fetal hemorrhage, spontaneous abortion, preterm delivery, and fetal death have been reported. Most thrombolytics are thought to be compatible with breast-feeding ( Table 175.4 ).
TABLE 175.4
Thrombolytic Medications
Additional data adapted from: ACOG Committee Opinion No. 767: Emergent therapy for acute-onset, severe hypertension during pregnancy and the postpartum period. Obstet Gynecol . 2019;133(2):e174-e180; ACOG Practice Bulletin No. 212. Pregnancy and heart disease. Obstet Gynecol . 2019;133(5):e320-e356. doi:doi: 10.1097/AOG.0000000000003243; ACOG Practice Bulletin No. 190. Gestational diabetes mellitus. Obstet Gynecol . 2018;131(2):e49-e64.
| Drug | Breast-Feeding | Clinical Risk Summary |
|---|---|---|
| Alteplase | Compatible Unknown if excreted in breast milk |
Embryocidal, not teratogenic, in animal studies; LHS; use if benefits to mother outweigh risks; has been used in human pregnancy with normal fetal outcomes, risk of hemorrhage at any time in gestation |
| Streptokinase | Use with caution; unknown safety | Use with caution; CP in minimal amounts; no fetal abnormalities reported; antistreptokinase antibodies cross the placenta |
| Reteplase | Probably compatible Use with caution Unknown if crosses into breast milk |
Unknown if CP; risk for bleeding during labor and delivery; abortifacient, but no teratogenicity in animals; LHS; several cases of use with normal infants |
| Tenecteplase | Hold breast-feeding Unknown safety | Unknown if CP; use with caution, safety unknown; risk of bleeding during labor and delivery; toxicity to mother in animal studies; LHS |
| Urokinase | Probably compatible Unknown if excreted in breast milk | Probably acceptable in pregnancy; not fetotoxic or teratogenic in animal studies; unknown if CP; placental hemorrhage and separation may occur; increased risk of bleeding during pregnancy; LHS |
CP, Crosses placenta; LHS, limited human studies.
Antidotes
There are limited human data on the risks of antidote use during pregnancy. Generally, antidotes should be used when there is a clear maternal indication and the potential benefits outweigh the possible risk ( Table 175.5 ). In general, overdoses of medication with higher rates of placental transfer have increased potential for fetal toxicity.
TABLE 175.5
Antidotes
Additional data adapted from: Lai T, Wu M, Liu J, et al. Acid-suppressive drug use during pregnancy and the risk of childhood asthma: A meta-analysis. Pediatrics . 2018;141(2):e20170889; McParlin C, O’Donnell A, Robson SC, et al. Treatments for hyperemesis gravidarum and nausea and vomiting in pregnancy: a systematic review. JAMA . 2016;316(13):1392-1401; Bonham CA, Patterson KC, Strek ME. Asthma outcomes and management during pregnancy. Chest . 2018;153(2):515-527; Chambers C. Over-the-counter medications: Risk and safety in pregnancy. Semin Perinatol . 2015;39(7):541-544.
| Drug | Breast-Feeding | Clinical Risk Summary |
|---|---|---|
| N -Acetylcysteine | Probably compatible unknown if excreted in milk so consider waiting 30 hr for elimination | CP; not teratogenic or embryotoxic in animal studies; LHS; no adverse fetal outcome when administered IV as antidote in acetaminophen overdose |
| Deferoxamine | Probably compatible Unknown if excreted in breast milk |
LHS; no adverse toxic or teratogenic effects seen; animal studies show toxicity and teratogenicity (delayed ossification, skeletal anomalies) |
| Digoxin immune fragment | Probably compatible Unknown if excreted in breast milk |
Unknown if CP; LHS; no adverse outcomes in fetus or newborn |
| Dimercaprol | Contraindicated Unknown if excreted in breast milk |
Animal studies show teratogenicity; safety in pregnancy unknown; chelates essential elements including zinc, copper, and iron that may alter fetal development but LHS |
| Flumazenil | Probably compatible Unknown if excreted in breast milk |
Unknown if CP, but may occur; animal studies show no teratogenicity or impaired fertility; LHS |
| Fomepizole | Hold breast-feeding | No animal or human studies; safety unknown |
| Hydroxocobalamin | Probably compatible, but monitoring of infant recommended | Animal studies showed no teratogenicity; LHS, safety unknown |
| Methylene blue | Probably compatible Unknown if excreted in breast milk |
Epidemiologic evidence of teratogenicity; diagnostic intraamniotic injection resulted in hemolytic anemia, hyperbilirubinemia, methemoglobinemia, jejunal-ileal atresias |
| Naloxone | Probably compatible Unknown if excreted in breast milk LHS |
CP; animal studies show no teratogenicity, no adverse fetal outcomes in human studies |
| Physostigmine | Probably compatible but safety unknown | Rarely used in pregnancy; no reports linking it with teratogenicity; safety unknown |
| Pralidoxime | Hold breast-feeding for 6 to 7 hr after dose | Rarely used in pregnancy; safety unknown; limited human case reports, with no adverse outcomes |
| Pyridoxine | Compatible | High doses appear to pose little risk to the fetus; no increased risk of malformations in first trimester in human trials |
| Succimer | Contraindicated Heavy metals may be excreted in breast milk, cause harm to newborn |
Teratogenic and fetotoxic in animals; avoidance in first trimester recommended for pregnant women unless severe symptoms; LHS |
CP, Crosses placenta; LHS, limited human studies.
N -Acetylcysteine
N -Acetylcysteine has been used successfully and without untoward effects in pregnant women who have overdosed on acetaminophen. No teratogenic effects have been reported, and pregnant patients who overdose on acetaminophen should be treated the same as nonpregnant patients. It is most likely safe during lactation because it has been used in neonates without untoward effects.
Deferoxamine
Deferoxamine has been associated with developmental effects on ossification in some animal species. Experience in humans is limited, but has been used in pregnancy without adverse effect on the fetus. The effects of deferoxamine on the nursing infant are not known, but are probably compatible.
Digoxin Immune Fragment
There are very few case reports of the use of digoxin immune fragment (Fab) during pregnancy, so effects on the fetus are inconclusive. In cases of life-threatening digitalis overdose with arrhythmias, the benefits of treatment of the mother outweigh the risk to the fetus. Digoxin fab is probably safe for use during lactation.
Dimercaprol
Dimercaprol, or British antilewisite, is teratogenic in mice and has been associated with increased mortality, growth restriction, cleft facial features, cerebral herniation, and abnormal digits, but experience in humans is limited. In general, with heavy metal poisonings, the maternal benefits of treatment will outweigh the potential risks to the fetus. Breast-feeding is contraindicated in patients poisoned by heavy metals.
Flumazenil
No teratogenic effects have been reported with flumazenil in animals, and there are limited human data. Its use in pregnancy and lactation depends on the potential maternal benefit compared with possible risks to the fetus and nursing infant. Because it has a short half-life, breast-feeding may resume after a few hours.
Fomepizole
Fomepizole use during pregnancy has not been studied in animals or humans. Its safety during pregnancy is not known. In cases of toxic alcohol poisoning, the benefits of treatment of the mother outweigh the possible risks to the fetus or nursing infant. Use of ethyl alcohol in these situations may be considered. Breast-feeding is not recommended during treatment.
Hydroxycobalamin
The effects of hydroxycobalamin on human pregnancy have not been studied, but benefits of its use in cyanide poisoning outweigh any risk to the fetus. Use is considered compatible with breast-feeding.
Methylene Blue
Historically, methylene blue was injected into the amniotic sac to identify twins and detect rupture of the membranes, but these practices were associated with hemolytic disease in the newborn, hyperbilirubinemia, and deep blue staining of the newborn. Methylene blue in pregnancy has also been associated with an increased incidence of intestinal obstruction and atresia in the newborn, primarily with intra-amniotic or intrauterine administration. Methylene blue has been used successfully in pregnant women with methemoglobinemia; however, the benefits of treatment should outweigh the risks of the therapy and must be considered. The effects of methylene blue on the nursing infant are expected to be minimal.
Naloxone
Naloxone readily crosses the placenta. Although it has not been associated with reproductive abnormalities, its use during pregnancy results in increased fetal wakefulness, increased fetal movement, and increased heart rate, effects attributable to the antagonism of fetal endorphins. In addition, its use in opiate-addicted mothers may precipitate withdrawal in mother and term fetus. The use of buprenorphine with naloxone in pregnant women with opioid use disorder has been found to be safe. It is compatible with breast-feeding.
Physostigmine
Experience during pregnancy is limited, and its effects on the developing fetus are unknown. Use of physostigmine at term has been associated with only mild decreases in Apgar scores at 1 and 5 minutes. Physostigmine is thought to be safe with breast-feeding.
Pralidoxime
Experience with pralidoxime in pregnancy is limited, and its effects on fetal development are not known. In cases of organophosphate poisoning, the benefits to the mother generally outweigh the possible risk to the fetus. Breast-feeding can be resumed after 6 to 7 hours after the last dose.
Pyridoxine
Pyridoxine, vitamin B 6 , has not been associated with any adverse developmental effects when given in high doses, and it is safe in lactation.
Dimercaptosuccinic Acid (Succimer)
Succimer has been linked to congenital defects in animal models, possibly because of its negative effects on zinc and copper metabolism. Experience with the use of succimer in human pregnancy is limited to case reports, and adverse effects are unknown. Breast-feeding is contraindicated in heavy metal poisoning.
Antiinfective Agents
Infections during pregnancy potentially affect outcomes as well as fetal development. In the first trimester, infections are a common cause of spontaneous abortion and, in the second or third trimester, they are the most common cause of low birth weight and preterm labor. Antimicrobial agents may also adversely affect the pregnancy. Aminoglycosides, for example, may be nephrotoxic and ototoxic to the mother and newborn, tetracyclines may result in dental staining of the developing fetus, and lincosamides may be skeletotoxic.
The penicillins, cephalosporins, and macrolide antibiotics are the drugs of choice for infections during pregnancy. Alternative classes of antibiotics are prescribed only if these have failed to control the infection or in cases of severe maternal intolerance to these drugs. The choice of antimicrobial therapy will depend on the gestational age of the pregnancy, severity of infection, and maternal tolerance for the drug used. Many drugs are secreted into breast milk. Potential problems for the neonate include direct effects on the neonate, changes in bowel flora, diarrhea, and potential interference with culture results ( Table 175.6 ).
TABLE 175.6
Antiinfective Medications
Additional data adapted from refs. (24-37)
| Drug | Breast-Feeding | Clinical Risk Summary |
|---|---|---|
| Aminoglycosides | Probably compatible Excreted in breast milk Oral absorption poor |
No definable structural risk of any aminoglycoside when exposed in utero; streptomycin—low incidence of ototoxicity with careful dosing |
|
Compatible | CP; NHT (most studies); conflicting studies on risk of congenital defects in first trimester |
|
Compatible | CP; immune hemolytic reactions observed, especially with cefotetan |
|
Compatible | CP; immune hemolytic reactions observed |
|
Compatible | CP; LHS |
| Chloramphenicol | Potential toxicity (LHS) Excreted in breast milk |
CP; may cause grey baby syndrome; idiosyncratic bone marrow suppression |
| Clindamycin | Compatible Excreted in breast milk |
CP; no reports of fetal toxicity or malformations |
| Fluoroquinolones | Compatible Excreted in breast milk |
Ciprofloxacin, ofloxacin, and levofloxacin CP; few reports of arthrotoxicity; risk of major malformations low; caution use during first trimester, risk of cardiac defects |
| Linezolid | Potential toxicity (LHS) Excreted in breast milk |
No studies in pregnancy Use with caution |
| Macrolides | Compatible Excreted in low concentrations in breast milk |
Estolate salt—may induce hepatotoxicity in pregnant patients; no risk of congenital heart malformations or pyloric stenosis, but use of erythromycin in infancy associated with pyloric stenosis |
| Metronidazole | Compatible Excreted in breast milk—but AAP recommends cessation of breast-feeding during use |
CP; in vitro mutagen; NHT |
| Nitrofurantoin | Compatible | Caution advised with G6PD deficiency—may cause hemolytic anemia; limit use in later pregnancy |
| Penicillins | Compatible Small amount excreted in breast milk |
CP; long-standing safety data |
| Sulfonamides | Compatible Excreted in breast milk Caution in newborns, infants with known G6PD deficiency |
CP; adverse effects rare; most reports fail to demonstrate congenital malformations; concern for jaundice, hemolytic anemia, kernicterus; trimethoprim is folate antagonist—use with caution |
| Tetracyclines | Compatible Excreted in breast milk |
CP; doxycycline poses little teratogenic risk; adverse effects on fetal bone development; discoloration of adult teeth; oxytetracycline shows neural tube defects, cleft palate, cardiac defects |
| Vancomycin | Compatible IV form found in breast milk, but, no oral absorption |
No toxicity or teratogenicity found |
| Clotrimazole | Compatible | Systemic absorption from skin minimal; vaginal and topical formulations preferred over oral lozenge; NHT; avoid vaginal use during first trimester; some reports suggest increased risk of spontaneous abortions |
| Fluconazole | Compatible | High dose in first trimester associated with malformations; If necessary vaginal formulation preferred. |
| Ketoconazole | Compatible Excreted in breast milk |
NHT, but teratogenicity seen in animal studies |
| Nystatin | Compatible Not excreted in breast milk |
Poor systemic absorption from vaginal formulation (preferred route); often first-line therapy in pregnancy |
| Terbinafine | Potential toxicity Excreted in breast milk |
LHS; Likely compatible |
| Isoniazid | Compatible Excreted in breast milk |
CP; benefits of treatment outweigh risks; NHT |
| Ethambutol | Compatible Excreted in breast milk |
CP; benefits of treatment outweigh risks; no adverse effects seen |
| Rifampin | Compatible Excreted in breast milk |
CP; benefits of treatment outweigh risk; hemorrhagic disease of newborn |
| Acyclovir | Compatible Excreted in breast milk |
CP—found in higher concentrations than in maternal blood; systemic use should be avoided unless benefits outweigh the risks; NHT |
| Valacyclovir | Compatible Excreted in breast milk |
CP; LHS |
| Famciclovir | Potential toxicity | Unknown if crosses placenta or enters breast milk; LHS |
| Amantadine | Potential toxicity (LHS) Excreted in breast milk |
CP; teratogenicity in animals; associated with cardiac malformations. |
| Oseltamivir | Compatible Excreted in breast milk but in low concentration |
Benefits of treatment during gestation likely greatly outweigh risks; no congenital malformations identified |
AAP, American Academy of Pediatrics; CP, crosses placenta; G6PD, Glucose-6-phosphate dehydrogenase; LHS, limited human studies; LS, limited studies; NHT, no human teratogenicity.
Antibiotics
Aminoglycosides
Aminoglycosides do not appear to have any structural teratogenic effects in humans. Kanamycin and streptomycin have been reported to cause ototoxicity in the mother and her offspring. There are no reports definitively linking in utero exposure to gentamicin, streptomycin, tobramycin, and neomycin with ototoxicity or nephrotoxicity. Aminoglycosides are probably compatible with breast-feeding.
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