Drug Therapy in Pregnancy

Daniel W. Robinson

Sara Krusenoski

PRINCIPLES

Risk Classification System

The U.S. Food and Drug Administration (FDA) changed medication labeling requirements regarding sections and content in 2014.¹ This change was implemented to provide more information about pregnancy and lactation risks and to mitigate decisions to use one agent over another based solely on drug category. The previous medication labeling included three sections, “Pregnancy,” “Labor and Delivery,” and “Nursing Mothers,” and provided letter categories to describe the risks and evidence related to each medication and its use during pregnancy and lactation. The letter categories are no longer used and will be removed from the labeling of current FDA-approved medications. The new labeling sections are “Pregnancy,” “Lactation,” and “Females and Males of Reproductive Potential.” The third section is new and provides information about patients with reproductive potential who may want to get pregnant. Given that there are no longer letter categories, each section will instead have a summary of the literature available at the time of FDA approval.¹

Teratogenicity

Teratogenicity occurs during organogenesis when a medication adversely affects the development of an organ, leaving it dysfunctional or malformed.² Factors influencing teratogenicity include the timing, dose, and duration of fetal exposure to offending agents; higher doses and longer durations increase the risk for teratogenicity.³ The route of administration also affects the teratogenicity of certain agents.³ Table 2.1 lists known teratogens.

Drug Transfer Across the Placenta

There are specific characteristics of a medication that make it more or less likely to cross the placenta and, therefore, determine the degree of fetal exposure. Drugs with a lower molecular weight will more readily cross the placenta.⁴ Lipophilic drugs readily cross the placenta, resulting in direct fetal exposure. Only drugs in their ionized state can cross the placenta. Drugs that are highly protein bound do not cross the placenta.⁴ There are different mechanisms for drug transport across the placenta: simple diffusion, facilitated diffusion, active transport, and pinocytosis. Simple diffusion is the most common. Both facilitated diffusion and active transport mechanisms can become saturated, leading to a maximum amount of drug transported across the cell, which is not the case for simple diffusion.⁴ Drug characteristics are important when assessing the
most appropriate therapy for a given patient. Table 2.2 lists commonly used drugs in pregnancy with associated relative risks and benefits.

TABLE 2.1 Known Teratogens

Anidulafungin

Carbamazepine

Caspofungin

Fluconazole

Itraconazole

Micafungin

Phenobarbital

Phenytoin

Posaconazole

Pseudoephedrine

Sulfamethoxazole-Trimethoprim

Succimer

Tetracycline

Valproic acid

Drug Transfer During Lactation

Many of the same principles of drug transfer during pregnancy apply to medications moving into breast milk. Drugs that are ionized, lipophilic, and have a small molecular weight will readily cross into breast milk.⁴ Drugs that are highly protein bound will not readily cross the cell membrane. Drugs with a large volume of distribution will have a lower concentration and, therefore, lower amounts diffuse into breast milk.⁴ Table 2.3 lists commonly used drugs during lactation with associated relative risks and benefits.

Drug Therapy During Pregnancy and Lactation

The available medication safety data come primarily from pregnancy registries and case reports. The clinician must consider the risks and benefits to the mother and fetus when prescribing medications during pregnancy and lactation as well as consider any alternative therapies. In general, optimizing the treatment of the mother is best for the fetus and takes precedence.

There are specific pharmacokinetic and pharmacodynamic changes in pregnancy that affect how the medication is absorbed, reaches its site of action, and is eliminated from the body. These changes need to be considered when determining medication dosing for pregnant patients. In general, increased cardiac output and renal blood flow increases the amount of drug that is eliminated. During pregnancy, there is a decrease in albumin concentrations, which increases the availability of free concentrations of medications that are highly protein bound.⁴^,⁵ If the drug can be monitored by drug level assays, it is useful to check levels more frequently in order to ensure therapeutic concentrations of these medications.⁵

PHARMACOLOGIC THERAPY

Opioid Analgesics

Pregnancy

Women may be taking opioids when they become pregnant or are prescribed opioids during pregnancy for a variety of indications including the use of methadone for opioid dependence. Opioids are known to cross the placenta, thereby exposing the fetus.⁶ There is conflicting evidence on whether opioids cause adverse effects as data are limited by several different opioids assessed within

the same study.⁶ However, some opioids have demonstrated adverse effects on the infant including fetal growth abnormalities and birth defects.⁶^,⁷ Tramadol and oxycodone use is associated with preterm birth,⁷^,⁸^,⁹ whereas the use of codeine, hydrocodone with acetaminophen, and oxycodone with acetaminophen has no increased risk of preterm birth.⁷^,⁸ There is evidence that prescribing narcotics for longer durations during pregnancy can lead to neonatal abstinence syndrome and fetal addiction.⁷^,⁹^,¹⁰^,¹¹^,¹²^,¹³

TABLE 2.1: Common medications in pregnancy. ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; DPP-4, dipeptidyl peptidase 4; GLP-1, glucagon-like peptide-1; LMWH, low-molecular-weight heparin; NSAIDs, nonsteroidal anti-inflammatory drugs; PPI, proton pump inhibitor; SGLT-2 inhibitors sodium-glucose cotransporter-2 inhibitors; SMZ/TMP, sulfamethoxazole/trimethoprim; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; UFH, unfractionated heparin.

Benefit > Risk	Benefit = Risk	Benefit < Risk	Lack of Data
ANALGESICS
Acetaminophen	Aspirin NSAIDs Opioids
ANTIBIOTICS
Aminoglycosides Azithromycin Beta-lactams Clindamycin Fosfomycin Vancomycin	Clarithromycin Daptomycin Linezolid Metronidazole Nitrofurantoin Streptomycin	Fluoroquinolones SMZ/TMP Tetracyclines Chloramphenicol^a
ANTICOAGULATION
LMWH UFH		Warfarin^b	Apixaban Dabigatran Edoxaban Rivaroxaban
ANTIFUNGALS
Amphotericin Nystatin	Fluconazole Itraconazole Posaconazole Micafungin
ANTIVIRAL
Acyclovir Antiretrovirals Oseltamivir Valacyclovir	Foscarnet Ganciclovir Valganciclovir
ANTITUBERCULOSIS
Ethambutol Isoniazid Pyrazinamide Rifampin		Streptomycin
CARDIOVASCULAR
Adenosine Digoxin Labetalol Lidocaine Methyldopa Nifedipine	Beta blockers Calcium channel blockers Hydralazine Ibutilide Flecainide Quinidine Procainamide	Amiodarone ACEi ARB
DECONGESTANTS
Brompheniramine Chlorpheniramine Dextromethorphan Guaifenesin Oxymetazoline	Pseudoephedrine Phenylephrine
DIABETIC MEDICATIONS
Insulin Metformin	Sulfonylureas DPP-4	SGLT-2 inhibitors GLP-1
GASTROINTESTINAL
Doxylamine Metoclopramide Promethazine Pyridoxine	H2 receptor antagonists Ondansetron PPI
NEUROLOGIC AGENTS
Mirtazapine	Aripiprazole Bupropion Chlorpromazine Clozapine Haloperidol Lacosamide Lamotrigine Levetiracetam Lurasidone Olanzepine Quetiapine Risperidone SSRI Topiramate TCA Triptans	Carbamazepine Ergot derivatives Phenobarbital Phenytoin Valproate
PULMONARY AGENTS
Montelukast	Anticholinergics Cromolyn Inhaled beta-agonists Inhaled corticosteroids Terbutaline Zileuton
RAPID SEQUENCE INTUBATION
	Etomidate Ketamine Rocuronium Succinylcholine
STEROIDS
Topical	Inhaled Systemic
THROMBOLYTICS
	Alteplase Tenecteplase
THYROID
Levothyroxine	Prophylthiouracil	Methimazole
ANTIDOTES
Activated charcoal	Acetylcysteine	Succimer	Fomepizole
Pyridoxine	Deferoxamine Digibind Dimercaprol Flumazenil Methylene blue Naloxone Physostigmine Pralidoxime Sodium nitrite Sodium thiosulfate
VASOPRESSOR THERAPY
	Dopamine Epinephrine Norepinephrine Phenylephrine Vasopressin
^aMay change based on relative time to delivery; ^bexcept in mechanical heart valves.

Lactation

All opioids are excreted into breast milk to varying degrees.⁷ As a class, they may cause sedation, drowsiness, or respiratory depression in an infant receiving breast milk containing opioids. There are reports of infants withdrawing from opioids when maternal use is stopped. If use of opioids is unavoidable, side effects and signs of withdrawal should be closely monitored in the infant.⁷

Mothers prescribed codeine or oxycodone who are rapid metabolizers of the enzyme converting these drugs into active metabolites are at risk of exposing the infant to higher concentrations.⁷ Opioids should be limited to the smallest effective dose for the shortest duration of time while breastfeeding.⁷ There are no effects on lactation production or delivery.⁷

TABLE 2.3: Common medications and lactation. ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; DPP-4, dipeptidyl peptidase 4; GLP-1, glucagon-like peptide-1; LMWH, low-molecular-weight heparin; NSAIDs, nonsteroidal anti-inflammatory drugs; PPI, proton pump inhibitor; SMZ/TMP, sulfamethoxazole/trimethoprim; SGLT-2 inhibitors, sodium-glucose cotransporter-2 inhibitors; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; UFH, unfractionated heparin.^a May change based on relative time to delivery.

Compatible with Breastfeeding	Compatible with Known Adverse Effects	Incompatible	Lack of Data	Effect on Lactation
ANALGESICS
Acetaminophen Ibuprofen	Aspirin NSAIDs Opioids
ANTIBIOTICS
Aminoglycosides Beta-lactam Clindamycin Daptomycin Linezolid Macrolides Streptomycin Vancomycin	Chloramphenicol^a Fluoroquinolones Metronidazole Nitrofurantoin SMZ/TMP Tetracyclines		Fosfomycin
ANTICOAGULATION
LMWH UFH Warfarin			Apixaban Dabigatran Edoxaban Rivaroxaban
ANTIFUNGALS
Fluconazole			Amphotericin Itraconazole Posaconazole Micafungin
ANTIVIRAL
Acyclovir Antiretrovirals Oseltamivir Valacyclovir			Foscarnet Ganciclovir Valganciclovir
ANTITUBERCULOSIS
Ethambutol Isoniazid Pyrazinamide Rifampin Streptomycin
CARDIOVASCULAR
ACEi Adenosine ARB Beta blockers Calcium channel blockers Digoxin Flecainide Hydralazine Ibutilide Labetalol Lidocaine Methyldopa Nifedipine Procainamide Quinidine	Amiodarone
DECONGESTANTS
Brompheniramine Chlorpheniramine Guaifenesin Oxymetazoline Pseudoephedrine Phenylephrine	Dextromethorphan
DIABETIC MEDICATIONS
DPP-4 GLP-1 Insulin Metformin SGLT-2 inhibitors Sulfonylureas
GASTROINTESTINAL
Doxylamine H2 receptor antagonists Ondansetron PPI Promethazine Pyridoxine	Metoclopramide			Metoclopramide
NEUROLOGIC AGENTS
Carbamazepine Phenytoin Valproate	Aripiprazole Bupropion Chlorpromazine Clozapine Ergot derivatives Haloperidol Lamotrigine Levetiracetam Lurasidone Mirtazapine Olanzapine Phenobarbital Quetiapine Risperidone SSRI Topiramate TCA Triptans		Lacosemide	Aripiprazole SSRI
PULMONARY AGENTS
Anticholinergics Cromolyn Inhaled beta-agonists Inhaled corticosteroids Montelukast Terbutaline Zileuton
RAPID SEQUENCE INTUBATION
Ketamine			Etomidate Rocuronium Succinylcholine
STEROIDS
Inhaled Systemic Topical
THROMBOLYTICS
			Alteplase Tenecteplase
THYROID
Levothyroxine Methimazole Prophylthiouracil
ANTIDOTES
			Acetylcysteine Activated charcoal Deferoxamine Digibind Dimercaprol Fomepizole Flumazenil Methylene blue Naloxone Physostigmine Pralidoxime Pyridoxine Sodium nitrite Sodium thiosulfate Succimer
VASOPRESSOR THERAPY
			Dopamine Epinephrine Norepinephrine Phenylephrine Vasopressin	Dopamine Epinephrine Phenylephrine Norepinephrine

Nonopioid Analgesics

Pregnancy

Nonopioid analgesics should be used for a specific indication for the shortest duration possible. Acetaminophen is known to cross the placenta; however, its effects on the fetus are minimal. Some studies find no increased risk of asthma, congenital malformations, or effects on intelligence quotient (IQ).⁷ Several case reports describe cardiac septal defects in newborns exposed during the third trimester; however, larger cohort studies have failed to replicate this association.⁷^,¹⁴ There is an association between acetaminophen use and adverse neurologic outcomes such as hyperactivity symptoms and use of more attention deficit hyperactivity disorder (ADHD) medications, especially with use of greater than 1-month duration.¹⁵^,¹⁶ There is a possible risk of cryptorchidism and childhood asthma with acetaminophen exposure early in pregnancy.¹⁵^,¹⁷^,¹⁸^,¹⁹^,²⁰ Aspirin is a nonsteroidal anti-inflammatory drug (NSAID) commonly prescribed, and the adverse effects tend to depend on the dose and duration of exposure to the fetus.⁷^,²¹ At low doses, aspirin is well tolerated by the fetus.⁷ At higher doses of aspirin exposure, the fetus may be at increased risk for intrauterine growth restriction (IUGR), neonatal hypoglycemia, metabolic acidosis, perinatal mortality, and hemostasis abnormalities, leading to hemorrhage in the third trimester; however, the data are conflicting.⁷ Other NSAIDs including ibuprofen, naproxen, and ketorolac have potential adverse effects to the fetus in the first and third trimesters.⁷^,²¹ Congenital malformations, including orofacial clefts and spontaneous abortions, are described among fetuses exposed to NSAIDs.⁷ Exposure to NSAIDs in the third trimester increases the risk of premature ductus arteriosus closure and subsequent development of pulmonary hypertension and death in the newborn.⁷ NSAIDs have tocolytic effects and may be used for preterm labor; however, this has to be weighed against the risk of periventricular hemorrhages, renal toxicity, oligohydramnios, and gastrointestinal (GI) bleeding.⁷^,¹¹^,²²

Lactation

Acetaminophen has no adverse effects in the newborn despite obtaining measureable concentrations in breast milk.⁷ NSAIDs are measurable in breast milk; however, they do not cause the same
adverse effects across the class. Ibuprofen has no increased risk of adverse effects in the infant and is regarded as the NSAID of choice in breastfeeding.⁷ Ketorolac and naproxen increase the risk of GI effects and bleeding in the infant but are not frequently seen clinically.⁷ Aspirin is excreted into breast milk and increases the risk of bleeding, metabolic acidosis in the infant, and a theoretical risk of Reye syndrome.⁷^,²³ No effect on lactation in breastfeeding women has been observed with either acetaminophen or NSAIDs.⁷

Antibiotics

Pregnancy

The risk of harm due to antibiotic use must be carefully weighed against the risk of harm due to the infection itself. Administering medications for the shortest duration possible while ensuring adequate disease eradication is recommended. Aminoglycosides cover both gram-negative and gram-positive pathogens as a synergistic agent. They are known to cross the placenta but are not teratogenic.⁷^,²⁴ With the exception of streptomycin, which has been linked to hearing loss, the aminoglycosides are not associated with adverse effects on the fetus if administered at appropriate doses.⁷^,²⁴ The penicillin class of antibiotics encompasses a variety of beta-lactams that are prescribed for a variety of infections and cover a wide range of gram-negative and gram-positive pathogens.²⁴ Penicillins do not cause significant adverse effects to the fetus despite crossing the placenta and having detectable concentrations in the fetus.⁷^,²⁴ Similarly, the cephalosporin class of beta-lactams is generally safe to administer during pregnancy with no significant adverse effects on the fetus.⁷^,²⁴ Therefore, penicillins and cephalosporins are the preferred antibiotic of choice when clinically indicated.²⁵^,²⁶

Carbapenems provide broad gram-negative and gram-positive coverage within the beta-lactam class and have no associated adverse effects on the fetus.²¹ Due to changes in drug pharmacokinetics during pregnancy, imipenem-cilastatin administration can result in subtherapeutic concentrations and is therefore avoided or the dosing must be optimized.²⁴ Aztreonam use in pregnancy has no increased risk of adverse effects on the fetus.⁷

The fluoroquinolones, such as ciprofloxacin and levofloxacin, target a variety of gram-positive and gram-negative pathogens and are commonly used in place of penicillin.²⁴ There is evidence suggesting fluoroquinolones have an increased risk of congenital abnormalities including cardiac and neurologic effects when used in the first trimester.⁷^,²⁴ There is a potential risk of cartilage and bone abnormalities, but the evidence is controversial, much of which comes from animal data that cannot always be extrapolated to human data.⁷^,²⁴

Vancomycin is a glycopeptide that is used for serious gram-positive infections. It is known to cross the placenta but has no significant toxicity to the fetus.⁷ Similar to other agents, changes in pharmacokinetics may be apparent and more frequent monitoring is recommended.²⁴ Oral vancomycin is not readily absorbed and, therefore, the effects on the fetus are minimal.²¹^,²⁴ Linezolid and daptomycin are agents that can be utilized for serious gram-positive infections where vancomycin is not appropriate.²¹ Although neither has demonstrated teratogenicity, human data are limited with minimal effects observed on the fetus.⁷^,²⁴ Animal data have shown embryonic death, lower birth weight, and skeletal abnormalities.⁷^,¹¹

Azithromycin and clarithromycin are macrolide antibiotics known to cross the placenta.⁷ Azithromycin has no increased risk of adverse effects on the fetus, whereas clarithromycin has a risk of causing congenital abnormalities, but the data are controversial.⁷^,²⁴ Erythromycin is shown to cause pyloric stenosis, although the data are weak.⁷^,¹¹^,²⁵^,²⁶^,²⁷

Tetracycline and doxycycline cross the placenta and are associated with teratogenicity and congenital abnormalities such as genitourinary abnormalities, inguinal hernias, and limb abnormalities.⁷^,¹¹^,²⁴^,²⁵^,²⁶^,²⁷ When used past the first trimester, tetracyclines can cause permanent discoloration of the bones and teeth and are generally avoided.²⁴ Clindamycin crosses the placenta but has no adverse effects on the fetus.⁷^,²⁴

Metronidazole has mixed evidence on whether or not the fetus is adversely affected by its use in pregnancy.⁷ Animal studies have shown it to be a mutagenic and carcinogenic agent.⁷^,¹¹ Generally, when adverse effects are seen, they occur in the first trimester.⁷^,²⁴ Sulfamethoxazole and trimethoprim have demonstrated teratogenic effects and congenital abnormalities including neural tube defects and possible oral clefts.⁷^,²⁴ Because of its folate antagonism, it should be avoided in the first trimester and late in pregnancy.²⁴

Chloramphenicol is used in the treatment of several serious infections including rickettsial diseases. It is known to cross the placenta but does not appear to be teratogenic and there are no major adverse effects on the fetus when used early in pregnancy.⁷ The use of chloramphenicol close to delivery poses a serious risk for the newborn of “Gray Baby Syndrome,” characterized by cardiovascular instability, cyanosis, and abdominal distention caused by a newborn’s inability to metabolize and eliminate the drug leading to elevated chloramphenicol concentrations.²⁸ This syndrome can be fatal and therefore the use of chloramphenicol at or near the time of delivery poses a significant risk to the newborn.⁷

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