Antibiotics use in pregnancy
Introduction
During pregnancy, untreated sexually transmitted or urinary tract infections are associated with significant morbidity, including low birth weight, preterm birth, and spontaneous abortion. 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. See, Figure 1 of FDA pregnancy risk classification system.
| Table (1). Antibiotic safety during pregnancy | |||
|---|---|---|---|
| Antibiotics | FDA Category | Notes | |
| Aminoglycosides | D | Streptomycin is linked to hearing loss in newborns and should be avoided, unless specific benefit is 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) | B | Generally safe to use; use ceftriaxone with caution at term due to risk of kernicterus | |
| Carbapenems | |||
| Doripenem, ertapenem, and meropenem | B | Use with caution only when penicillins or cephalosporins not an option | |
| Imipenem‐cilastatin | C | ||
| Aztreonam | B | Use only if severe allergy to beta‐lactams | |
| Fluoroquinolones | C | Avoid in pregnancy unless benefits outweigh risks | |
| Glycopeptides | |||
| Vancomycin | B | Appears to be safe and effective | |
| Macrolides | |||
| Azithromycin, erythromycin | B | Generally safe to use azithromycin; use erythromycin and clarithromycin with caution and only if benefits outweigh risks | |
| Clarithromycin | C | ||
| Telithromycin | C | May use if benefits outweigh risks | |
| Oxazolidinones | |||
| Linezolid | 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 | Hepatic enzymes should be monitored closely during pregnancy while on tuberculosis therapy. Pyridoxine (B6) should be given with INH during pregnancy |
|
| Ethambutol | B | ||
| Pyrazinamide | C | ||
| Rifampin, rifabutin | C | ||
| Bedaquiline | B | ||
| Ceftolozane‐tazobactam and ceftazidime‐avibactam were recently approved at the time of this manuscript, but also carry a Pregnancy Category B rating. Pregnancy rating categories were current as of summer of 2015. New guidelines will require a change in pregnancy warning language. |
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Antibiotics
Aminoglycosides
Amikacin, gentamicin, streptomycin, and tobramycin are the most commonly prescribed aminoglycosides. Aminoglycosides have shorter serum half‐life, clearance is increased and a larger volume of distribution in pregnant women. Aminoglycosides cross the placenta and may result in toxicities, especially if administered in the first trimester of pregnancy. Use of streptomycin in the first trimester may cause irreversible bilateral congenital deafness, leading to a boxed warning and FDA Pregnancy Category of D. Due to the risks specifically associated with streptomycin use, this agent should be avoided. Other aminoglycosides have NOT commonly been associated with similar hearing loss; however, if hearing abnormalities did occur, symptoms were mild without clinical significance. 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.
Beta-lactams
- Penicillins and their newer derivatives are the most safe and widely prescribed antimicrobial class during pregnancy.
- Penicillins and their newer derivatives may require increased doses and/or frequency due to increased plasma volume and creatinine clearance in pregnant women and serum penicillin concentrations may be decreased by as much as 50%.
- The aminopenicillins (ampicillin and amoxicillin) having the most robust safety data.
- 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.
- Cephalosporins are considered to be safe in pregnancy. 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. All cephalosporins are classified as Pregnancy Category B.
- Findings from a Michigan Medicaid database suggested a potential association between ceftriaxone and cardiac malformation. Ceftriaxone remains the drug of choice for the treatment of gonorrhea during pregnancy.
- 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.
- Carbapenems include ertapenem, meropenem and doripenem are Pregnancy Category B, while imipenem‐cilastatin is Pregnancy Category C. Pharmacokinetic changes associated with pregnancy have shown decreased imipenem concentrations.
- Carbapenem therapy should be reserved for pregnant women with infections that are resistant to penicillin and cephalosporin therapy with limited alternatives.
- Monobactams include aztreonam is Pregnancy Category B rating. Aztreonam should be used with caution during the first trimester as data are limited.
- 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.
Quinolones
Fluoroquinolones are classified as Pregnancy Category C. They are generally contraindicated in pregnancy. They are widely distributed in the body and routes of elimination differ among the agents. Fluoroquinolones may be safe during the first trimester but are not recommended, as they were associated with fetal harm in previous animal studies.
- There is a suggested association with fluoroquinolones and renal toxicity, cardiac defects, and central nervous system toxicity in the fetus. Animal data have demonstrated bone and cartilage damage in the fetus. Data are inconsistent and more studies are needed to confirm these associations.
- 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.
- Because of the current evidence, fluoroquinolone use in pregnancy is only recommended if there is no alternative.
Vancomycin
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. Because there is limited information available about vancomycin use in the first trimester, caution is warranted during this period.
Macrolides
Erythromycin is Pregnancy Category B. In general, erythromycin is considered to be safe during pregnancy. It may be associated with cardiovascular defects and pyloric stenosis, although later studies did not corroborate these results.
- Azithromycin has generally been considered safe for use in pregnancy and is Pregnancy Category B.
- 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.
Although data are conflicting, it is generally thought that azithromycin is safe to use in pregnancy, while clarithromycin should be used with caution (especially during 1st trimester) and only when benefit outweighs risk (safe during 2nd and 3rd trimesters).
Linezolid
Linezolid is Pregnancy Category C and animal studies in mice, rats, and rabbits have not shown teratogenic effects. Linezolid could be considered for use during pregnancy when potential benefits outweigh the risks.
Tetracyclines
Tetracyclines labeled as Pregnancy Category D, tetracyclines have proven teratogenicity in humans. They are associated with congenital defects, with large doses being linked to maternal liver toxicity. 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. 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.
Other antibiotics
- Clindamycin is a lincosamide antibiotic, crosses the placenta, and is classified as Pregnancy Category B. Clindamycin appears safe and effective
- Fosfomycin (Pregnancy Category B) is generally well tolerated. 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.
- Metronidazole is classified as Pregnancy Category B; however, it is contraindicated in the first trimester of pregnancy.
- Vaginal metronidazole should be used with caution during pregnancy, as a potential link with congenital hydrocephalus has been suggested.
- Metronidazole also remains a guideline‐recommended therapy for bacterial vaginosis and Trichomonas infections in pregnancy.
- Nitrofurantoin is an antibacterial specific to the urinary tract, nitrofurantoin is considered Pregnancy Category B. Nitrofurantoin is commonly used in UTI management in pregnant women.
- Nitrofurantoin may increase the risk of hemolytic anemia in pregnant patients with severe glucose‐6‐phosphate dehydrogenase deficiency.
- Nitrofurantoin remains an option for treatment of UTI and prevention of recurrent UTI in pregnant women.
- Polymyxins (Polymyxin B and polymyxin E) are considered Pregnancy Category C. Due to the limited use in pregnant women and high potential for adverse events, strong caution is advised prior to use.
- Sulfamethoxazole‐Trimethoprim are rated FDA Pregnancy Category C. They are bound to plasma proteins (sulfamethoxazole > trimethoprim) and eliminated renally primarily through glomerular filtration and renal tubular secretion.
- 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. 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.
- 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 is a glycylcycline that crosses the placenta and is classified as Pregnancy Category D. 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
Considerations for treatment of tuberculosis during pregnancy and lactation. With the exception of streptomycin (Pregnancy Category D), first-line anti-tuberculosis drugs are considered safe for use in pregnancy including (all Pregnancy Category C): isoniazid, rifampin, pyrazinamide AND ethambutol.
Streptomycin is ototoxic to the fetus and should not be used during pregnancy. Recommended treatment regimen during pregnancy includes isoniazid, rifampin, and ethambutol for 9 months. Consider supplementation with pyridoxine 25 mg/day in pregnant and breastfeeding women taking isoniazid.
References
- Bookstaver PB, Bland CM, Griffin B, Stover KR, Eiland LS, McLaughlin M. A Review of Antibiotic Use in Pregnancy. Pharmacotherapy. 2015;35(11):1052-1062.
- Medication and Drug Exposure in Pregnancy. Dynamed.com. (2020). [online] Available at: https://www.dynamed.com/drug-review/medication-and-drug-exposure-in-pregnancy.
