Antibiotic Use in Pregnancy and Lactation What Is and Is Not Known About Teratogenic and Toxic Risks

Reviews Antibiotic Use in Pregnancy and Lactation What Is and Is Not Known About Teratogenic and Toxic Risks Gerard G. Nahum, MD, CAPT Kathleen Uhl, USPHS, and CAPT Dianne L. Kennedy, USPHS OBJECTIVE: Over ten million women are either pregnant icol, ciprofloxacin, doxycycline, levofloxacin, and or lactating in the United States at any time. The risks of rifampin) to “undetermined” (clindamycin, gentamicin, medication use for these women are unique. In addition and vancomycin). Assessments were based on “good to normal physiologic changes that alter the pharmaco- data” (penicillin G and VK), “fair data” (amoxicillin, chlor- kinetics of drugs, there is the concern of possible terato- amphenicol, ciprofloxacin, doxycycline, levofloxacin, and genic and toxic effects on the developing fetus and rifampin), “limited data” (clindamycin and gentamicin), newborn. This article reviews the risks and pharmacoki- and “very limited data” (vancomycin). Significant phar- netic considerations for 11 broad-spectrum antibiotics macokinetic changes occurred during pregnancy for the that can be used to treat routine and life-threatening penicillins, fluoroquinolones and gentamicin, indicating infections during pregnancy and lactation. that dosage adjustments for these drugs may be neces- sary. With the exception of chloramphenicol, all of these DATA SOURCES: Information from the U.S. Food and antibiotics are considered compatible with breastfeed- Drug Administration (FDA) product labels, the Teratogen ing. Information Service, REPROTOX, Shepard’s Catalog of Teratogenic Agents, Clinical Pharmacology, and the peer- CONCLUSION: Health care professionals should con- reviewed medical literature was reviewed concerning the sider the teratogenic and toxic risk profiles of antibiotics use of 11 antibiotics in pregnant and lactating women. to assist in making prescribing decisions for pregnant and The PubMed search engine was used with the search lactating women. These may become especially impor- terms “[antibiotic name] and pregnancy,” “[antibiotic tant if anti-infective countermeasures are required to name] and lactation,” and “[antibiotic name] and breast- protect the health, safety, and survival of individuals feeding” from January 1940 to November 2005, as well as exposed to pathogenic bacteriologic agents that may standard reference tracing. occur from bioterrorist acts. (Obstet Gynecol 2006;107:1120–38) METHODS OF STUDY SELECTION: One hundred twen- ty-four references had sufficient information concerning numbers of subjects, methods, and findings to be in- ntibiotics are among the most commonly pre- cluded. Ascribed prescription medications for pregnant TABULATION, INTEGRATION, AND RESULTS: The ter- and lactating women.1 More than 10 million women atogenic potential in humans ranged from “none” (pen- are either pregnant or lactating in the United States at icillin G and VK) to “unlikely” (amoxicillin, chloramphen- any one time, and they are administered antibiotics for many reasons.2 Because of the special consider- From the Department of Obstetrics and Gynecology, Uniformed Services Uni- ations associated with fetal and newborn develop- versity of the Health Sciences, Bethesda, Maryland; Office of Women’s Health, ment, these women constitute a uniquely vulnerable U.S. Food and Drug Administration, Rockville, Maryland; FDA Center for Drug Evaluation and Research, Silver Spring, Maryland. population for which the risks of medication use must be separately assessed. Presented in part at the FDA Science Forum in Washington, DC, April 27–28, 2005. In addition to the pharmacokinetic and pharma- The views, opinions, interpretations, and conclusions expressed in this article are codynamic changes that may occur during pregnancy those of the authors only and do not reflect either the policies or positions of the and lactation that can alter the effectiveness of drugs,3 Center for Drug Evaluation and Research, the U.S. Food and Drug Adminis- there is the added concern of the possible teratogenic tration, or the U.S. Department of Health and Human Services. and toxic effects that medications may have on the Corresponding author: Gerard G. Nahum, MD, FACOG, FACS, Box 2184, Rockville, MD 20847; e-mail: [email protected]. developing fetus and newborn. In general, there is a dearth of pharmacokinetic and pharmacodynamic © 2006 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. information regarding the use and proper dosing of ISSN: 0029-7844/06 Food and Drug Administration (FDA)–approved 1120 VOL. 107, NO. 5, MAY 2006 OBSTETRICS & GYNECOLOGY drugs in pregnant and lactating women, as well as published by the Centers for Disease Control and limited data pertaining to the teratogenic potential Prevention in Atlanta. and the fetal or neonatal toxicity of these marketed medications. Accordingly, sparse information must RESULTS sometimes be assembled from diverse sources to A description of the 11 broad-spectrum antibiotics address these issues. and their general modes of action are provided in Recently, the threat of bioterrorism has expanded Table 1. the context in which the potential use of antibiotic All 11 antibiotics cross the placenta and enter the medications may be needed.4 Although the possibility fetal compartment. For 5 of these, human umbilical of a large-scale bioterrorist attack in the United States cord blood levels are of the same order of magnitude is unlikely, the potential for widespread antibiotic use as circulating maternal blood concentrations (chlor- in this situation emphasizes the need for health care amphenicol, clindamycin, gentamicin, rifampin, and professionals to be familiar with the risks and benefits vancomycin). For 4, the concentrations are of the of administering antibiotics to pregnant and lactating same magnitude or higher in amniotic fluid as in women. maternal blood (ciprofloxacin, clindamycin, levo- This article reviews the available information floxacin, and vancomycin) (Table 2). concerning the risks and special circumstances to be All 11 antibiotics are excreted in human breast considered in pregnant and lactating women for a milk. Limited information concerning the amount in group of 11 broad-spectrum antibiotics (amoxicillin, breast milk was available for 8 antibiotics (ciprofloxa- chloramphenicol, ciprofloxacin, clindamycin, doxy- cin, clindamycin, doxycycline, gentamicin, levofloxacin, penicillin G, penicillin VK, and rifampin). No cycline, gentamicin, levofloxacin, penicillin G, peni- quantitative data concerning breast milk concentra- cillin VK, rifampin, and vancomycin). By using this tions were available for 3 (amoxicillin, chloramphen- information, better choices can be made for the icol, and vancomycin) (Table 2). treatment of different types of bacterial pathogens in Using the Teratogen Information Service clas- these particularly vulnerable populations. sification system for teratogenic risk,44 the teratogenic potential of the 11 antibiotics during human DATA SOURCES AND METHODS OF STUDY pregnancy ranged from “none” in 2 cases (penicil- SELECTION lin G and VK) to “unlikely” in 6 (amoxicillin, Information from FDA-approved product labels, the chloramphenicol, ciprofloxacin, doxycycline, levo- Teratogen Information Service, Shepard’s Catalog of floxacin, and rifampin) to “undetermined” in 3 Teratogenic Agents, REPROTOX, Clinical Pharma- (clindamycin, gentamicin, and vancomycin). As- cology, and the peer-reviewed literature were re- sessments were based on data that were “good” for viewed for information concerning the use of 11 2 (penicillin G and VK) to “fair” for 6 (amoxicillin, antibiotics in pregnant and lactating women. The chloramphenicol, ciprofloxacin, doxycycline, levo- medical literature was queried with the PubMed floxacin, and rifampin) to “limited” for 2 (clinda- search engine. Papers searched were published from mycin and gentamicin) to “very limited” for 1 January 1940 to November 2005, in any language. (vancomycin). A summary of the human and ani- The search terms “[antibiotic name] and pregnancy,” mal data contributing to these assessments is shown “[antibiotic name] and lactation,”, and “[antibiotic in Table 3. The Food and Drug Administration name] and breastfeeding,” were used, as was standard Pregnancy Category classifications for the 11 anti- reference tracing. A total of 124 references were biotics (as defined under 21 CFR [Code of Federal accessed through these sources that contained suffi- Regulations] 201.57 for the A, B, C, D, X Preg- cient information concerning the numbers of subjects, nancy Category system) (Table 4) were “B” in 5 methods of investigation, and findings to be useful for cases (amoxicillin, clindamycin, penicillin G, peni- the purpose of drawing conclusions concerning phar- cillin VK, and vancomycin), “C” in 5 cases (chlor- macokinetic parameters, teratogenic potential, and amphenicol, ciprofloxacin, gentamicin, levofloxa- toxicity assessments of these drugs. All materials were cin, and rifampin), and “D” in 1 case (doxycycline) restricted to information from nonproprietary sources (Table 3). In addition to the published literature, that were available in the public domain. Addition- proprietary data were used to establish the FDA ally, information concerning the potential treatment pregnancy category for these drugs. options for exposures and diseases caused by possible Despite numerous concerns regarding the poten- agents of bioterrorism were obtained from materials tial for maternal and fetal or neonatal

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