What Antibiotics Can a Pregnant Woman Take

Abstract

During pregnancy, untreated sexually transmitted or urinary tract infections are associated with significant morbidity, including low birth weight, preterm birth, and spontaneous abortion. Approximately one in four women will be prescribed an antibiotic during pregnancy, accounting for nearly 80% of prescription medications in pregnant women. Antibiotic exposures during pregnancy have been associated with both short-term (e.g., congenital abnormalities) and long-term effects (e.g., changes in gut microbiome, asthma, atopic dermatitis) in the newborn. However, it is estimated that only 10% of medications have sufficient data related to safe and effective use in pregnancy. Antibiotics such as beta-lactams, vancomycin, nitrofurantoin, metronidazole, clindamycin, and fosfomycin are generally considered safe and effective in pregnancy. Fluoroquinolones and tetracyclines are generally avoided in pregnancy. Physiologic changes in pregnancy lead to an increase in glomerular filtration rate, increase in total body volume, and enhanced cardiac output. These changes may lead to pharmacokinetic alterations in antibiotics that require dose adjustment or careful monitoring and assessment.

Reports suggest that antibiotics account for nearly 80% of all prescription medications during pregnancy and that approximately 20–25% of women will receive an antibiotic during pregnancy.1-3 The most common infections encountered during pregnancy include urinary tract infections (UTIs), including pyelonephritis; sexually transmitted infections (STIs); and upper respiratory tract infections (URTIs).1 Although use of any medication during pregnancy is a risk-versus-benefit decision, untreated infections such as UTIs or STIs are associated with significant fetal risk including spontaneous abortion, prematurity, and low birth weight.4, 5 Safety and efficacy information are not usually available from randomized controlled trials, as these studies are often not feasible in pregnant women and are potentially unethical. Thus, pregnancy is often a standard criterion for exclusion from clinical trials. It is estimated that only 10% of medications marketed since 1980 have sufficient data regarding infantile risk in pregnancy.6

Antibiotic exposure in pregnancy may have untoward short-term and long-term effects on infant weight. A recent study showed that after adjusting for a number of factors, prenatal exposure of the infant to antimicrobials (via self-reporting by the mother) resulted in a lower birth weight of approximately 138 g.7 Antimicrobial exposure during pregnancy has recently been linked to childhood obesity, although specific antimicrobial class exposure was not documented in the study.8 Prenatal antibiotic use and the risk of neurologic disease, including cerebral palsy and epilepsy, and atopic disease, including atopic dermatitis and asthma, have been studied independently. Several studies demonstrate an association while others do not.9-11 One study demonstrated an association with prenatal antibiotic use and the development of asthma by age 3 in children at risk for asthma (odds ratio [OR] 3.1, 95% confidence interval [CI] 1.4–6.8).9 There is even less information known about medication use by trimester and associated risk. Prenatal antibiotic risk associated with asthma and wheezing was significant when antibiotics were used by the mother in the second to third trimesters but not during the first.9, 12 Conversely, a 2015 Cochrane review of prophylactic antibiotic use in the second and third trimesters, which included seven randomized controlled trials, did not demonstrate an increased risk of congenital abnormality. However, the authors concluded there was insufficient evidence to fully evaluate possible fetal harm.13

As a method to establish teratogenic potential of medications, the United States Food and Drug Administration (FDA) established a pregnancy risk categorization system in 1979.14 This mandate required newly marketed agents to include pregnancy risk categories of A, B, C, D, and X supplemented by general statements for risk interpretation (Table 1). In December 2014, the FDA approved and unveiled a new format and content for product labeling, effective June 2015, that abolishes the original FDA Pregnancy Category system for all prescription medications approved since June 2001.15 Three narrative sections required in the product labeling, including "Pregnancy," "Lactation" and "Female and Male Reproductive Potential," replace previous sections (Figure 1). Specifically, the pregnancy section is divided into "Risk Summary," "Clinical Consideration," "Data" (human and animal), and "Pregnancy Exposure Registry" (if applicable). Labels will describe detailed information and are required to be revised when outdated.

Table 1. Food and Drug Administration Pregnancy Category Ratings with Required Package Labeling Statements Prior to June 2015 14

Pregnancy Category Rating	Level of Evidence	Accompanying Text Labeling Requirement
A	No risk in human studies; Adequate and well-controlled human studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters)	None
B	No risk in other studies; Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women	Nevertheless, because the studies in humans cannot rule out the possibility of harm, [name of drug] should be used during pregnancy only if clearly needed
C	Risk not ruled out; Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks	[Name of drug] should be given to a pregnant woman only if clearly needed
D	Positive evidence of risk; There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks	If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus
X	Contraindicated in pregnancy; Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits	[Name of drug] is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus

In addition to maternal and fetal safety, there are physiologic changes during pregnancy that may lead to pharmacokinetic changes and impact antibiotic therapy.16 Increases in total body water, blood volume (40–50%), and plasma volume (40–50%) contribute to increases in volume of distribution of various antibiotics.16, 17 Renal blood flow increases by 50%, possibly due to vasodilation of afferent and efferent arterioles as a result of increased progesterone.16 Serum creatinine decreases, while glomerular filtration rate (GFR) increases elimination of renally excreted antibiotics. The patient's GFR will approach postpartum values at approximately 3 weeks prior to delivery.18 Alterations in gastrointestinal motility may lead to changes in absorption, oral bioavailability, and delayed onset of action of certain antibiotics.17 There are known changes in hepatic enzymes during pregnancy that clinicians may use to adjust doses, but current data are controversial as to whether these changes lead to clinically significant changes in drug metabolism and subsequent serum concentrations.17, 18 Finally, decreases in albumin and alterations in maternal plasma pH are expected to lead to decreased protein binding and increased concentrations of unbound drug.16, 17

This concise review provides updated information as of June 2015 on antibiotics in pregnancy, including drug-specific risk evaluation (Table 2) and clinical utility based on published evidence.

Table 2. Antibiotic Pregnancy Ratings 19, 26

Antibiotic	FDA Pregnancy Category Ratingb b Pregnancy rating categories were current as of summer of 2015. New guidelines will require a change in pregnancy warning language.	Notes
Aminoglycosides	D	Streptomycin linked to hearing loss in newborns and should be avoided, unless specific benefit established. Short-term use of others in class acceptable with monitoring, if benefits outweigh the risks
Beta-lactams and mono-bactams
Penicillins
Including amino-penicillins; extended-spectrum penicillins; and beta-lactam/beta-lactamase inhibitor combinations	B	Generally safe to use
Cephalosporins (all generations) and cephamycinsa a Ceftolozane-tazobactam and ceftazidime-avibactam were recently approved at the time of this manuscript, but also carry a Pregnancy Category B rating.	B	Generally safe to use; use ceftriaxone with caution at term due to risk of kernicterus
Carbapenems
Doripenem, ertapenem, and meropenem	B C	Use with caution only when penicillins or cephalosporins not an option
Imipenem-cilastatin
Aztreonam	B	Use only if severe allergy to beta-lactams
Fluoroquinolones	C	Avoid in pregnancy unless benefits outweigh risks
Glycopeptides and lipoglycopeptides
Vancomycin	B	Appears to be safe and effective
Lipoglycopeptides
Telavancin, dalbavancin, oritavancin	C	Avoid in pregnancy unless benefits outweigh risks
Macrolides and ketolides
Macrolides
Azithromycin, erythromycin	B C	Generally safe to use azithromycin; use erythromycin and clarithromycin with caution and only if benefits outweigh risks
Clarithromycin
Telithromycin	C	May use if benefits outweigh risks
Oxazolidinones
Linezolid, tedizolid	C	May use if benefits outweigh risks
Tetracyclines
Tetracycline, minocycline, doxycycline	D	Should be avoided
Miscellaneous Antibiotics
Clindamycin	B	Appears to be safe and effective; review STI guidelines regarding oral vs vaginal routes
Daptomycin	B	May use if benefits outweigh risks
Fidaxomicin	B	Limited use, however limited systemic exposure decreases potential risk to fetus
Fosfomycin	B	Appears to be safe and effective
Metronidazole	B	Topical metronidazole should be avoided
Nitrofurantoin	B	Appears to be safe and effective
Polymyxins
Polymyxin B, polymyxin E	C	Should be used with caution. Careful monitoring of adverse events
Folate antagonists
Sulfamethoxazole, trimethoprim	C	Avoid trimethoprim and sulfamethoxazole in first trimester due to major congenital malformations. Sulfamethoxazole should be avoided after 32 wks' gestation due to risk of kernicterus
Tigecycline	D	Avoid in pregnancy unless benefits outweigh risks
Antimycobacterial agents
Isoniazid (INH)	C B C C B	Hepatic enzymes should be monitored closely during pregnancy while on tuberculosis therapy. Pyridoxine (B6) should be given with INH during pregnancy
Ethambutol
Pyrazinamide
Rifampin, rifabutin, rifapentine
Bedaquiline

• ^a Ceftolozane-tazobactam and ceftazidime-avibactam were recently approved at the time of this manuscript, but also carry a Pregnancy Category B rating.
• ^b Pregnancy rating categories were current as of summer of 2015. New guidelines will require a change in pregnancy warning language.

Aminoglycosides

Amikacin, gentamicin, streptomycin, and tobramycin are the most commonly prescribed aminoglycosides. During pregnancy, the serum half-life of aminoglycosides is shorter and clearance is increased. Due to this and a larger volume of distribution in pregnant women, aminoglycosides may have a lower serum peak concentration compared to nonpregnant women.19 Aminoglycosides cross the placenta and may result in toxicities, especially if administered in the first trimester of pregnancy.19 Case reports of irreversible bilateral congenital deafness with maternal use of streptomycin in the first trimester have been described, leading to a boxed warning and FDA Pregnancy Category of D for the class in the United States.1 Other aminoglycosides have not commonly been associated with similar hearing loss; however, if hearing abnormalities did occur, symptoms were mild without clinical significance.5, 6 Animal studies with gentamicin in rats and rabbits did not result in fetal toxicity.1 Traditional or extended interval dosing of aminoglycosides in pregnancy are both supported in the literature.20 Despite toxicity reports, short courses of aminoglycosides may be used in pregnant women with careful monitoring if the likely benefit outweighs the potential risk. Possible risks should be explained to the patient, especially in the first trimester. Due to the risks specifically associated with streptomycin use, this agent should be avoided.

Beta-Lactams and Related Antibiotics

Penicillins

Penicillins and their newer derivatives are the most widely prescribed antimicrobial class during pregnancy.1, 2 Intravenous penicillin from the time of rupture of the placental membranes until delivery remains first-line prophylaxis if the patient is colonized with Group B Streptococcus, while ampicillin is recommended as a suitable alternative.21 Penicillins generally cross the placenta in high concentrations. Penicillins with increased protein binding such as the anti-staphylococcal penicillins (except methicillin) produce lower fetal tissue concentrations compared with penicillins such as penicillin G or ampicillin that have low protein binding.22 Due to increased plasma volume and creatinine clearance in pregnant women, serum penicillin concentrations may be decreased by as much as 50%, which may require increased doses and/or frequency.23

Penicillins have a long track record of safety, with the parent compound penicillin and the aminopenicillins (ampicillin and amoxicillin) having the most robust safety data.5 All penicillins and their derivatives, as well as penicillin combinations with beta-lactamase inhibitors such as clavulanate or sulbactam, have been assigned a Pregnancy Category B rating.19 Pregnant patients with a penicillin allergy diagnosed with syphilis should undergo desensitization followed by penicillin therapy.

Cephalosporins and Cephamycins

Cephalosporins have a long history of documented use in pregnancy.1 Cephalosporins remain a first-line option for many infections in pregnancy with general use reserved for patients allergic or intolerant to penicillin therapy. Cephalosporins have decreased plasma concentrations in pregnant patients because of increased renal elimination; therefore, potential dosage and frequency increases are required.24

All cephalosporins-cephamycins are classified as Pregnancy Category B.19 Findings from a Michigan Medicaid database suggested a potential association between ceftriaxone and cardiac malformation.19 Ceftriaxone remains the drug of choice for the treatment of gonorrhea during pregnancy.25 Ceftriaxone should be used cautiously at term due to the potential risk of kernicterus in neonates. Newly approved agents such as ceftaroline, ceftolozane-tazobactam, and ceftazidime-avibactam are also Pregnancy Category B agents; however, they should be used with caution as there is a lack of published data during pregnancy.26

Carbapenems

There is a paucity of data regarding the use of carbapenems during pregnancy. Ertapenem, meropenem, and doripenem are Pregnancy Category B, while imipenem-cilastatin is Pregnancy Category C.19 Pharmacokinetic changes associated with pregnancy have shown decreased imipenem concentrations.19 Carbapenem therapy should be reserved for pregnant women with infections that are resistant to penicillin and cephalosporin therapy with limited alternatives.

Monobactams

While its lack of cross-reactivity with penicillins and cephalosporins makes aztreonam an appealing choice, there are inconclusive data regarding its safety in pregnancy. Most safety data are in the perinatal period, which supports its Pregnancy Category B rating.19 Aztreonam should be used with caution during the first trimester as data are limited.27 Due to a lack of data at this time, aztreonam use should be restricted to patients with severe penicillin allergy for whom beta-lactam therapy is contraindicated.

Fluoroquinolones

Although fluoroquinolones are classified as Pregnancy Category C, they are generally contraindicated in pregnancy.19 They are widely distributed in the body and routes of elimination differ among the agents.26 Protein binding ranges from 20% to 50%.26 Fluoroquinolones may be safe during the first trimester but are not recommended, as they were associated with fetal harm in previous animal studies4, 5, 28 There is a suggested association with fluoroquinolones and renal toxicity, cardiac defects, and central nervous system toxicity in the fetus.29, 30 Animal data have demonstrated bone and cartilage damage in the fetus.19 Data are inconsistent and more studies are needed to confirm these associations. Authors of a recent literature review concluded that fluoroquinolones may not pose the same risks to humans as they do to animals because of weak study designs, small sample sizes, and confounding variables in the published human studies; however, the data are still not adequate to support their routine use in pregnancy.28 Because of the current evidence, fluoroquinolone use in pregnancy is only recommended if there is no alternative.19, 28

Glycopeptides and Lipoglycopeptides

Vancomycin is a glycopeptide classified as Pregnancy Category B and is thought to be safe for use in pregnancy in the case of serious gram-positive infections, particularly during the second and third trimesters.19 Vancomycin is widely distributed in body tissues, primary eliminated by glomerular filtration in the kidneys, and 55% protein bound, which may lead to alterations in kinetics during pregnancy.26 Vancomycin crosses the placenta and has been found in umbilical cord blood after intravenous administration.5, 6 Despite the absence of robust clinical data, there are reports to suggest that vancomycin is safe to use during pregnancy. In one report, vancomycin was given to 10 pregnant women for infections caused by methicillin-resistant Staphylococcus aureus (MRSA) infections.31 No abnormalities, including hearing loss or nephrotoxicity, were noted in the fetus after at least 1 week of vancomycin therapy during the second or third trimesters. Other cases, where vancomycin was administered for 13 and 28 days, produced similar results, with no ototoxicity or nephrotoxicity in the mother or neonate.6 Because there is limited information available about vancomycin use in the first trimester, caution is warranted during this period.26 In animal trials, no congenital malformations were noted following intravenous administration of vancomycin in rats or rabbits given 1–5 times the maximum recommended human doses.19, 26 When used orally, vancomycin has little systemic absorption, and is not believed to cause adverse effects during pregnancy.5, 19

Telavancin, oritavancin, and dalbavancin are lipoglycopeptides with gram-positive activity similar to that of vancomycin.26 Similar to vancomycin, telavancin is primarily excreted by the kidneys. All three are highly protein bound (85–93%) and widely distributed to tissues, which may mean altered kinetics during pregnancy.26 While there are no human data in pregnancy available for telavancin, animal data suggest that telavancin may cause harm (Pregnancy Category C).19 In rat, rabbit, and minipig studies, telavancin caused limb and skeletal malformations and fetal weight loss. The manufacturer recommends that women of childbearing potential have a serum pregnancy test prior to beginning therapy with telavancin and placed on effective contraception for the duration of therapy. There are no human data available for the use of oritavancin or dalbavancin in pregnancy, and animal studies found no fetal toxicity at doses comparable to human doses (Pregnancy Category C).26 With oritavancin, doses of approximately 25% of the human dose showed no evidence of harm to the fetus in rat and rabbit studies, while higher doses have not been tested. After dalbavancin exposures of 3.5 times the human dose, rats were found to have increased embryo lethality and offspring death.26 Telavancin, oritavancin, and dalbavancin should be avoided in pregnancy unless the benefits of treatment outweigh the risk to the fetus.

Macrolides and Ketolides

Data regarding the safety of macrolides in pregnancy are widely variable.32 Given the relatively low protein binding, large volumes of distribution, and hepatic metabolism, one would anticipate that the physiologic changes in pregnancy should have less effect on the kinetics of these agents.26 The first associations of erythromycin (Pregnancy Category B) exposure with cardiovascular defects and pyloric stenosis in offspring occurred in 2003, although later studies did not corroborate these results.33, 34 In a retrospective cohort, investigators recorded the presence of congenital malformations, pyloric stenosis, or intussusceptions in order to determine the effect of macrolides on fetal development.32 In 1033 women exposed to macrolides (erythromycin, azithromycin, clarithromycin, or roxithromycin), there was no association with the development of major malformation in the fetus. In addition, exposure in the third trimester was not associated with pyloric stenosis or intussusception.32 In a review of maternal erythromycin exposure over 15 years, erythromycin was persistently associated with cardiovascular defects (risk estimate 1.70; 95% CI 1.26–2.39).33 Most defects were considered mild. In infants with congenital heart disease and pyloric stenosis, there was no association with macrolide exposure compared to nonexposed controls.34 Any product containing erythromycin should be used with caution in pregnancy and only when benefit outweighs risk.

Azithromycin has generally been considered safe for use in pregnancy and is Pregnancy Category B.19 In rats and mice, azithromycin at two to four times the human dose was not associated with any evidence of fetal harm.35 In a comparison of women exposed to azithromycin versus other antibiotics or nonteratogens, no differences were found in the rates of major malformations between groups.36 Similar to erythromycin, data from studies of clarithromycin (Pregnancy Category C) have been conflicting. In animal studies, some rats exposed to clarithromycin in the first trimester did not result in teratogenicity, while other rats showed low incidences of cardiac abnormalities after clarithromycin exposure.35 Other data report cleft palate in murine studies and retarded fetal growth in monkeys.35 In clinical reports, including a prospective controlled study, clarithromycin exposure has not been associated with increased incidence of major malformations.23, 37, 38 Although data are conflicting, it is generally thought that azithromycin is safe to use in pregnancy, while clarithromycin should be used with caution and only when benefit outweighs risk.

Telithromycin is a ketolide antibacterial with similar structure and activity as the macrolides. There are no human data for the use of telithromycin in pregnancy, and it is Pregnancy Category C.26 In rats and rabbits, telithromycin was not teratogenic at doses ranging from 0.5 to 1.8 times the human doses. At higher doses, delayed fetal maturation was observed, possibly related to maternal toxicity. Given its relative limited utility and potential risks, telithromycin should be avoided in pregnancy.

Oxazolidinones

Currently, there are a lack of pharmacokinetic and controlled studies of linezolid and tedizolid in pregnant women. Linezolid distributes well into tissue and has 31% protein binding, whereas tedizolid is highly protein bound (70–90%).26 Positive maternal outcomes without fetal teratogenesis were detailed in a case report of 4 weeks of linezolid use starting at 14 weeks of pregnancy.39 Both agents are Pregnancy Category C and animal studies in mice, rats, and rabbits have not shown teratogenic effects.19 However, in rats, linezolid and tedizolid resulted in mild fetal toxicities, including decreased fetal body weight and reduced ossification of the sternebrae at maternally toxic doses.26 A reduction in fetal weight and increase in costal cartilage abnormalities were seen with tedizolid use in mice with the absence of maternal toxicities (4-fold increase in the estimated human exposure based on area under the concentration curve [AUC]).26 Fetal weight loss and maternal toxicity were identified with tedizolid use in rabbits. However, in a prenatal and postnatal toxicity study of rats, no offspring defects were documented with tedizolid used at the highest tested dose equivalent to the plasma AUC exposure of the 200 mg/day clinical human dose.26 Oxazolidinones could be considered for use during pregnancy when potential benefits outweigh the risks.

Tetracyclines

Labeled as Pregnancy Category D, tetracyclines have proven teratogenicity in humans.19 They are associated with congenital defects, with large doses being linked to maternal liver toxicity.19 In general, tetracyclines penetrate into tissues and body fluids with the degree of penetration correlated to lipid solubility (minocycline > doxycycline > tetracycline).26 Routes of elimination differ by agent and protein binding widely ranges by agent.26 Tetracyclines cross the placenta and when used beyond the second trimester, they can bind to calcium in the developing fetus and cause permanent discoloration of bones and teeth. They are contraindicated past the fifth week of pregnancy.19 Tetracyclines should be used with extreme caution, if at all, in pregnancy, and only when a clear benefit has been established. In rare cases, doxycycline may be considered in pregnant women who have life-threatening tick-borne illnesses.

Miscellaneous Antibiotics

Clindamycin

Clindamycin is a lincosamide antibiotic, crosses the placenta, and is classified as Pregnancy Category B.19 Clindamycin is widely distributed into most body tissues and is highly plasma protein bound (92–94%).26 It is excreted in the urine as 10% active drug and metabolites, 3.6% in the feces, with the remainder excreted as inactive metabolites.26 A study of 647 newborns that had been exposed to clindamycin in the first trimester did not support an association between the drug and congenital defects.19 Evidence is lacking for using oral clindamycin late in pregnancy. In contrast, vaginal clindamycin is not recommended due to systemic absorption (up to 30%), increased risk of adverse neonatal outcomes (neonatal infection and low birth weight), and lack of efficacy.19, 25 Late clindamycin use (up to 32 wks' gestation) is associated with adverse outcomes and the Centers for Disease Control and Prevention Sexually Transmitted Diseases Treatment Guidelines recommend avoiding vaginal clindamycin in the latter half of pregnancy.25, 40

Daptomycin

Daptomycin is Pregnancy Category B.19 It is highly protein bound (90–93%), has a volume of distribution of 0.1 L/kg, and is primarily excreted by the kidneys.26 There are no controlled trials with daptomycin (a cyclic lipopeptide) during pregnancy. However, isolated reports suggest that daptomycin may be safe to use.41, 42 In the first report, a woman in the third trimester was successfully treated with daptomycin 4 mg/kg for 14 days for vancomycin- and ampicillin-resistant Enterococcus faecium pyelonephritis.41 In another report, a 14-week pregnant patient with a history of drug abuse was successfully treated with daptomycin 6 mg/kg for 6 weeks for tricuspid valve endocarditis.42 No adverse effects were noted in the patient or in the neonate at birth in either report. In animal studies, daptomycin was administered to rats and rabbits at doses 2–4 times human doses with no evidence of harm to the fetus. Daptomycin should be used in pregnancy only if the benefit outweighs the risk.

Fidaxomicin

Although fidaxomicin, a nonabsorbable macrocyclic antibiotic, is Pregnancy Category B, there are no published documented cases of use in pregnant women.26 Reproductive studies in rats and rabbits at doses 66–200 times the exposure expected in humans at standard dosing revealed no harm to the fetus. Systemic exposure to fidaxomicin is minimal with plasma concentrations falling below the level of detectability in most patients.43

Fosfomycin

Fosfomycin (Pregnancy Category B) is generally well tolerated, and although it crosses the placental barrier, no adverse events in the fetus or infant have been reported.44 In Europe, it is used with caution in pregnancy as an injectable agent, which is not available in the United States44 Oral fosfomycin, for the treatment of UTIs, may be recommended for use due to its high sensitivity, ease of use, activity against multidrug-resistant organisms, and safety in pregnancy.45

Metronidazole

Metronidazole is classified as Pregnancy Category B; however, it is contraindicated in the first trimester of pregnancy.19 Several trials have linked metronidazole use in asymptomatic Trichomonas vaginalis infection or increased fetal fibronectin concentrations with increased preterm birth (PTB) rates.46, 47 Multivariate analysis showed no relationship between metronidazole exposure at any time during pregnancy with PTB, low birth weight, or congenital abnormalities.48 Vaginal metronidazole should be used with caution during pregnancy, as a potential link with congenital hydrocephalus has been suggested.49 Metronidazole also remains a guideline-recommended therapy for bacterial vaginosis and Trichomonas infections in pregnancy; however, risk of repeat exposure during pregnancy is unknown and a reduced risk of PTB has not been clearly established.25

Nitrofurantoin

An antibacterial specific to the urinary tract, nitrofurantoin is considered Pregnancy Category B.19 Animals exposed to doses 25 times that of normal human administration did not result in teratogenic effects. Because of limited systemic exposure and its relatively benign adverse effect profile combined with proven effectiveness, nitrofurantoin is commonly used in UTI management in pregnant women. A recent meta-analysis of eight studies did not demonstrate any association of nitrofurantoin exposure in women with major congenital malformation.50 The meta-analysis did include three case-controlled studies that revealed a significant increase (OR 1.22; 95% CI 1.02–1.45) in malformations, including an increased risk in hypoplastic left heart (OR 3.07).50 Although not commonly reported, nitrofurantoin may increase the risk of hemolytic anemia in pregnant patients with severe glucose-6-phosphate dehydrogenase deficiency as indicated by one case report.51 Although there may be some concern in the recent meta-analysis requiring further investigation of possible teratogenic effects, nitrofurantoin remains an option for treatment of UTI and prevention of recurrent UTI in pregnant women.50

Polymyxins

Polymyxin B and polymyxin E are considered Pregnancy Category C.19 In the few published cases and single database examined, there does not appear to be an increased risk of PTB, low birth weight or congenital abnormalities, although the data are quite limited.52 In an animal model examining risk during pregnancy, polymyxin B demonstrated toxic effects to the embryo in a dose-dependent manner. This was hypothesized to be due to its effects on reduction in metabolism, heart loss or neuromuscular blockade.53 Due to the limited use in pregnant women and high potential for adverse events, strong caution is advised prior to use.

Sulfamethoxazole-Trimethoprim

Sulfamethoxazole and trimethoprim are both rated FDA Pregnancy Category C.19 They are bound to plasma proteins (sulfamethoxazole > trimethoprim) and eliminated renally primarily through glomerular filtration and renal tubular secretion.26 Animal studies have demonstrated teratogenic effects. Sulfamethoxazole and trimethoprim both cross the placenta and should be avoided in the first trimester due to the mechanism of trimethoprim as a folate antagonist. Exposure during this period can significantly increase the risk of major congenital malformations, primarily neural tube and cardiac defects.54 Trimethoprim has also been associated with an increase in cleft palates with first trimester use.55 Approximately 2-fold increases in cardiac and limb malformations were seen with trimethoprim use 12 weeks prior to conception.56 However, maternal folic acid supplementation reduces the risk of major fetal malformations from trimethoprim. Sulfonamides should not be used in the third trimester as they theoretically result in an increase of unbound bilirubin due to competitive protein binding. Sulfamethoxazole-trimethoprim use during the first trimester has been also associated with a 3-fold increase in urinary tract defects and its use during the last two trimesters has been associated with small for gestational age newborns.54, 57 Overall, sulfamethoxazole-trimethoprim should be avoided in the first trimester and after 32 weeks' gestation if other treatment options are available. In the second and third trimesters, use in pregnant women should be limited to those situations when the benefits outweigh the potential risks.

Tigecycline

Tigecycline is a glycylcycline that crosses the placenta and is classified as Pregnancy Category D.19 Animal data have demonstrated adverse outcomes, including fetal loss in maternal toxic doses and possible discoloration of infants' teeth. Although no human studies exist to date, this medication should only be used when the benefit outweighs the risk to the fetus.

Antimycobacterial Agents

First-line therapy for tuberculosis (TB) in pregnant women is consistent with the nonpregnant populations and includes isoniazid (INH), rifampin, ethambutol, and pyrazinamide.58, 59 A systematic review demonstrated overall safety of first-line therapy comparable to the general population.59 Of note, many patients were not exposed to anti-TB medications during the first trimester, representing the most critical time of fetal development and risk of abnormalities. INH, Pregnancy Category C, has not produced a signal of increased fetal abnormalities in animal or human data.59, 60 A nonsignificant increase in hepatitis has been observed in pregnant women receiving INH, particularly in those with preexisting liver disease and HIV.60 Monitoring of liver enzymes is important and is recommended throughout pregnancy.59, 60 An elevation of 3–5 times the upper limit of normal may prompt discontinuation of anti-TB therapy. INH is also recommended for latent TB infection (LTBI) in pregnancy as a first-line treatment. Low-risk patients may be advised to defer treatment of LTBI until after pregnancy because of concerns about medication exposure. High-risk patients (e.g., HIV) should be initiated on INH therapy. Pyridoxine (B₆) daily oral supplementation (25–50 mg/day) is advised in all pregnant women receiving INH to mitigate neurologic complications in the mother and newborn.59, 60

Rifampin use in animals at up to ten times the normal human dose did not produce any fetal abnormalities; however, increasing the dose to 15 times human exposure at the time of conception was associated with significant fetal malformations.60 Use of rifampin in more than 2000 pregnant women has not produced an increase in fetal abnormalities.60 Rifampin has a Pregnancy Category C rating.19 INH coupled with rifampin is known to increase liver enzymes additively; thus, careful monitoring is advised. An association between rifampin and newborn bleeding has been described, so prophylactic vitamin K may be necessary.60 Data on alternative rifamycins―rifabutin and rifapentine―are limited in pregnancy and should be used with caution.58 They are considered Pregnancy Category C and not recommended in the current guidelines.19, 58

Ethambutol is Pregnancy Category B and is generally considered safe in pregnancy.19, 58 It is associated with retrobulbar neuritis in the general population; however, there has not been an associated increase in either pregnant mothers or infants born to mothers exposed to ethambutol during pregnancy.60 There are no controlled studies to date investigating pyrazinamide (PZA) use in pregnant animals or humans, but literature is available documenting use without fetal or maternal harm.19 PZA may be associated with increased risk of hepatotoxicity, especially in combination with INH and/or rifampin. In general, PZA is thought to be safe in pregnancy (Pregnancy Category C), while careful risk assessment is needed and enhanced monitoring, specifically of uric acid and liver enzymes, is suggested.58

Fluoroquinolones, which may be used in multidrug resistant TB, should be generally avoided in pregnancy as discussed previously. The risks and benefits should be weighed in using aminoglycosides in management of TB or other non-MTB infections in pregnancy.58, 59 The newest anti-TB agent, bedaquiline, is considered Pregnancy Category B.26

Conclusions

The use of antibiotics in pregnancy requires careful assessment and a discussion of risk versus benefit to mother and fetus, both short and long term. In general, many antibiotics are considered safe in pregnancy, especially beta-lactams, macrolides, clindamycin, and fosfomycin; however, additional data are needed for the majority of antibiotic classes. Emerging antibiotic resistance will certainly play a role in future use of broad-spectrum and alternative agents in pregnancy. Pharmacists play a prominent role in risk assessment and evaluation of available evidence for optimal antibiotic selection, dosing, duration of therapy, and monitoring. Pharmacists should also be aware of the new detailed product labeling for pregnancy that was implemented in the summer of 2015.

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