ReviewsAntibiotic Use in Pregnancy and LactationWhat Is and Is Not Known About Teratogenic and Toxic RisksGerard G. Nahum,...
drugs in pregnant and lactating women, as well as           published by the Centers for Disease Control andlimited data p...
Table 1. Description of the Eleven Broad-Spectrum Antibiotics Investigated                                                ...
Table 2. Current Information for Eleven Broad-Spectrum Antibiotics That May Be Used in Pregnant and Lactating Women       ...
Table 2. Current Information for Eleven Broad-Spectrum Antibiotics That May Be Used in Pregnant and Lactating Women (conti...
Table 2. Current Information for Eleven Broad-Spectrum Antibiotics That May Be Used in Pregnant and Lactating Women (conti...
1126                              Table 2. Current Information for Eleven Broad-Spectrum Antibiotics That May Be Used in P...
Table 3. Teratogenic and Toxic Potential of Eleven Broad-Spectrum Antibiotics Based on Available Human and Animal Data    ...
Table 3. Teratogenic and Toxic Potential of Eleven Broad-Spectrum Antibiotics Based on Available Human and Animal Data (co...
Table 3. Teratogenic and Toxic Potential of Eleven Broad-Spectrum Antibiotics Based on Available Human and Animal Data (co...
Table 3. Teratogenic and Toxic Potential of Eleven Broad-Spectrum Antibiotics Based on Available Human and Animal Data (co...
Table 3. Teratogenic and Toxic Potential of Eleven Broad-Spectrum Antibiotics Based on Available Human and Animal Data (co...
Table 3. Teratogenic and Toxic Potential of Eleven Broad-Spectrum Antibiotics Based on Available Human and Animal Data (co...
Drugs in pregnancy
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Antibiotic Use in Pregnancy

Drugs in pregnancy

  1. 1. ReviewsAntibiotic Use in Pregnancy and LactationWhat Is and Is Not Known About Teratogenic and Toxic RisksGerard G. Nahum, MD, CAPT Kathleen Uhl, USPHS, and CAPT Dianne L. Kennedy, USPHSOBJECTIVE: Over ten million women are either pregnant icol, ciprofloxacin, doxycycline, levofloxacin, andor 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 “goodto 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, andgenic 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 thethat can be used to treat routine and life-threatening penicillins, fluoroquinolones and gentamicin, indicatinginfections during pregnancy and lactation. that dosage adjustments for these drugs may be neces- sary. With the exception of chloramphenicol, all of theseDATA 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 ofTeratogenic 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 antibioticsuse of 11 antibiotics in pregnant and lactating women. to assist in making prescribing decisions for pregnant andThe 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 toname] and lactation,” and “[antibiotic name] and breast- protect the health, safety, and survival of individualsfeeding” from January 1940 to November 2005, as well as exposed to pathogenic bacteriologic agents that maystandard 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 concerningnumbers of subjects, methods, and findings to be in-cluded.TABULATION, INTEGRATION, AND RESULTS: The ter- A ntibiotics are among the most commonly pre- scribed prescription medications for pregnant and lactating women.1 More than 10 million womenatogenic potential in humans ranged from “none” (pen- are either pregnant or lactating in the United States aticillin 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 vulnerableU.S. Food and Drug Administration, Rockville, Maryland; FDA Center forDrug Evaluation and Research, Silver Spring, Maryland. population for which the risks of medication use mustPresented in part at the FDA Science Forum in Washington, DC, April 27–28, be separately assessed.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 pregnancythose of the authors only and do not reflect either the policies or positions of the and lactation that can alter the effectiveness of drugs,3Center for Drug Evaluation and Research, the U.S. Food and Drug Adminis- there is the added concern of the possible teratogenictration, or the U.S. Department of Health and Human Services. and toxic effects that medications may have on theCorresponding author: Gerard G. Nahum, MD, FACOG, FACS, Box 2184,Rockville, MD 20847; e-mail: GNahum2003@yahoo.com. developing fetus and newborn. In general, there is a© 2006 by The American College of Obstetricians and Gynecologists. Published dearth of pharmacokinetic and pharmacodynamicby Lippincott Williams & Wilkins. information regarding the use and proper dosing ofISSN: 0029-7844/06 Food and Drug Administration (FDA)–approved1120 VOL. 107, NO. 5, MAY 2006 OBSTETRICS & GYNECOLOGY
  2. 2. drugs in pregnant and lactating women, as well as published by the Centers for Disease Control andlimited data pertaining to the teratogenic potential Prevention in Atlanta.and the fetal or neonatal toxicity of these marketedmedications. Accordingly, sparse information must RESULTSsometimes be assembled from diverse sources to A description of the 11 broad-spectrum antibioticsaddress 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 themedications may be needed.4 Although the possibility fetal compartment. For 5 of these, human umbilicalof a large-scale bioterrorist attack in the United States cord blood levels are of the same order of magnitudeis 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, andprofessionals to be familiar with the risks and benefits vancomycin). For 4, the concentrations are of theof administering antibiotics to pregnant and lactating same magnitude or higher in amniotic fluid as inwomen. 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 breastconsidered in pregnant and lactating women for a milk. Limited information concerning the amount ingroup of 11 broad-spectrum antibiotics (amoxicillin, breast milk was available for 8 antibiotics (ciprofloxa-chloramphenicol, ciprofloxacin, clindamycin, doxy- cin, clindamycin, doxycycline, gentamicin, levofloxa- cin, penicillin G, penicillin VK, and rifampin). Nocycline, 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 terato- genic potential of the 11 antibiotics during humanDATA 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 3Teratogenic 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” forviewed 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 1January 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 Administrationname] 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 Federalaccessed 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 5methods 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 FDAally, 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 toxicity of theseVOL. 107, NO. 5, MAY 2006 Nahum et al Antibiotic Use in Pregnancy 1121
  3. 3. Table 1. Description of the Eleven Broad-Spectrum Antibiotics Investigated Year of Initial FDAAntibiotic Description ApprovalAmoxicillin Semi-synthetic beta-lactam antibiotic. Inhibits the final stage of 1974 bacterial cell wall synthesis, leading to cell lysis.Chloramphenicol Broad-spectrum antibiotic isolated from Streptomyces venezuela in 1950 1947, now synthetically available. Binds to the 50S subunit of bacterial ribosomes, inhibiting peptide bond formation and protein synthesis.Ciprofloxacin Fluoroquinolone antibiotic. Exerts its bactericidal effect by 1987 disrupting DNA replication, transcription, recombination, and repair by inhibiting bacterial DNA gyrase.Clindamycin Antibiotic derived from lincomycin that has wide-ranging 1970 antimicrobial activity. Binds to the 50S ribosomal subunit, thereby inhibiting bacterial protein synthesis.Doxycycline Broad-spectrum antibiotic that binds to the 30S bacterial ribosomal 1967 subunit. Blocks the binding of transfer-RNA to messenger-RNA, thereby disrupting protein synthesis.Gentamicin Aminoglycoside antibiotic with broad-spectrum activity. Binds 1966 irreversibly to 30S bacterial ribosomal subunit, thereby inhibiting protein synthesis.Levofloxacin Fluoroquinolone antibiotic. L-isomer of ofloxacin, which provides 1996 its principal antibiotic effect. Inhibits bacterial DNA replication, transcription, recombination, and repair by inhibiting bacterial type II topoisomerases.Penicillin G Beta-lactam antibiotic that is primarily bactericidal. Inhibits the 1943 final stage of bacterial cell wall synthesis, leading to cell lysis.Penicillin V Naturally derived beta-lactam antibiotic. Inhibits the final stage of 1956 (phenoxymethyl bacterial cell wall synthesis, leading to cell lysis. Considered penicillin) preferable to penicillin G for oral administration because of its superior gastric acid stability.Rifampin Rifamycin B derivative that inhibits bacterial and mycobacterial 1971 DNA-dependent RNA polymerase activity. Used primarily for the treatment of tuberculosis, with additional utility for the treatment of both leprosy and meningococcal carriers.Vancomycin Glycopolypeptide antibiotic. Binds to the precursor units of 1964 bacterial cell walls, inhibiting their synthesis and altering cell wall permeability while also inhibiting RNA synthesis. Because of its dual mechanism of action, bacterial resistance is rare.FDA, U.S. Food and Drug Administration.11 drugs—including idiosyncratic and dose-related lin G, and penicillin VK), lower circulating drugbone marrow suppression with chloramphenicol, ar- concentrations were measured in pregnant womenthropathies and bone and cartilage damage with than nonpregnant, suggesting that a shorter dosingciprofloxacin and levofloxacin, dental staining and interval or increased maternal dose or both may behepatic necrosis with doxycycline, and ototoxicity necessary to obtain similar circulating drug concen-and nephrotoxicity with gentamicin and vancomy- trations as for women in the nonpregnant state. In thecin—none of these toxicities has been documented case of ciprofloxacin and levofloxacin, circulatingin human mothers or offspring either during preg- concentrations were generally reduced in pregnantnancy or breastfeeding with these antibiotics (Table women, also suggesting that an increased maternal3). dose or a shorter dosing interval or both may be Very limited information was available pertain- necessary. In 3 cases (chloramphenicol, gentamicin,ing to maternal pharmacokinetics in pregnancy for 8 and vancomycin), therapeutic drug monitoring ofantibiotics (amoxicillin, ciprofloxacin, clindamycin, serum peak and trough levels is recommended togentamicin, levofloxacin, penicillin G, penicillin VK, assess circulating drug levels. In 1 case (clindamycin),and vancomycin), and none was available for 3 the standard pharmacokinetic parameters did not(chloramphenicol, doxycycline, and rifampin) (Table change appreciably during the first, second, or third2). For 4 antibiotics (amoxicillin, gentamicin, penicil- trimester of pregnancy (Table 2). Very little pharma-1122 Nahum et al Antibiotic Use in Pregnancy OBSTETRICS & GYNECOLOGY
  4. 4. Table 2. Current Information for Eleven Broad-Spectrum Antibiotics That May Be Used in Pregnant and Lactating Women Possible Pregnancy Dosage/Schedule Adjustments, Metabolism, Excretion, Microbiologic and Recommendations Antibiotic Spectrum of Activity* Placental Transmission Transmission Into Breast Milk for Monitoring Amoxicillin Gram-positive aerobes, Crosses the human placenta.5–7 Excreted in human breast milk in small amounts.8 Shorter dosing interval and/ most gram-positive Penicillins transferred to the fetus and amniotic Considered “usually compatible with or increased dose have anaerobes, gram- fluid reach therapeutic levels.5 breastfeeding.”9† been suggested during negative aerobes Following therapeutic doses, mean human milk pregnancy to attain similarVOL. 107, NO. 5, MAY 2006 including some enteric concentrations were 0.1–0.6 ␮g/mL.10 plasma concentrations as bacilli, Helicobacter, No adverse effects seen in nursing infants whose for nonpregnant spirochetes, mothers have been treated with amoxicillin. women.6,11 actinomyces* Penicillins are primarily renally excreted via tubular secretion and glomerular filtration. Volume of distribution and renal clearance are increased during the 2nd 13–15 and 3rd trimesters.6,11 Chloramphenicol Gram positives, gram Crosses the human placenta readily. Excreted in human breast milk. Unknown whether dose negatives, anaerobes, Umbilical cord serum concentrations 29–106% In 5 patients with minor obstetrical lacerations adjustments during chlamydia, rickettsiae of maternal levels.12 who received 1 g PO qD for 8 days, mean milk pregnancy are necessary. concentrations were 0.5–2.8 ␮g/mL. In 5 Pharmacokinetics during patients receiving 2 g PO qD for 8 days for pregnancy has not been mastitis, mean milk concentrations were 1.8–6.1 specifically studied. 13 ␮g/mL. Serum concentrations can Human milk concentrations are 51–62% of blood be monitored to keep peak levels.14 and trough levels in the Percentage of administered dose in human breast ranges of 10–20 and 5–10 15 milk per day is 1.3%. ␮g/mL, respectively. CBC Effect on breastfed infants considered “unknown monitored to detect bone but may be of concern.”16 marrow depression. Ciprofloxacin Gram-negative aerobes, Crosses the human placenta and concentrates in Excreted in human breast milk (Product Circulating fluoroquinolone 17 some staphylococci amniotic fluid (Product information Cipro, information Cipro, 2001). concentrations are lower in 17Nahum et al 2001). Considered Љusually compatible with pregnant than in 9† In 20 women at 19–25 weeks of gestation who breastfeeding.” nonpregnant women, but received two 200-mg IV doses q 12 hours, the In 10 women given 750 mg q12 hours PO, serum no specific mean amniotic fluid level 2–4 hours after and milk concentrations were obtained 2, 4, 6, pharmacokinetic data is dosing was 0.12 Ϯ 0.06 ␮g/mL (n ϭ 7; 9, 12, and 24 hours after the 3rd dose. available regarding amniotic fluid: maternal serum concentration Concentrations were 3.79 Ϯ 1.26, 2.26 Ϯ 0.75, ciprofloxacin in pregnant [AF:MS ratio] ϭ 0.57), 0.13 Ϯ0.07 ␮g/mL at 0.86 Ϯ 0.27, 0.51 Ϯ 0.18, 0.20 Ϯ 0.05, and women.19 It is unknown 6–8 hours (n ϭ 7; AF:MS ratio ϭ 1.44), and 0.02 Ϯ 0.006 ␮g/mL at these times and the whether dose adjustments 0.10 Ϯ 0.04 ␮g/mL at 10–12 hours (n ϭ 6; AF: ratios of breast milk: serum concentration were during pregnancy are 17 MS ratio ϭ 10.00). 1.84, 2.14, 1.60, 1.70, 1.67, and 0.85, necessary. 17 respectively. For breastfeeding infants Approximately 50–70% of consuming 150 mL/kg per day, the estimated a dose is excreted in the maximum dose is 0.569 mg/kg per day or urine and, if renal function Յ 2.8% the approved dose for infants of is impaired, the serum half- 18 20 mg/kg per day. life is slightly prolongedAntibiotic Use in Pregnancy (Product information Cipro, 2001). (continued)1123
  5. 5. Table 2. Current Information for Eleven Broad-Spectrum Antibiotics That May Be Used in Pregnant and Lactating Women (continued)1124 Possible Pregnancy Dosage/ Schedule Adjustments, Metabolism, Microbiologic Excretion, and Spectrum of Recommendations for Antibiotic Activity* Placental Transmission Transmission Into Breast Milk MonitoringNahum et al Clindamycin Gram-positive Crosses the human placenta readily.44,20–23 Excreted in human breast milk (Product Pharmacokinetic parameters do anaerobes, gram- In 54 women undergoing cesarean delivery who information Clindamycin, 1970). not change during pregnancy negative anaerobes, received 600 mg IV 30 minutes before surgery, Considered “usually compatible with in women studied during the aerobic gram-positive umbilical cord blood concentrations were 46% of breastfeeding.”9† 1st, 2nd, and 3rd trimesters of cocci, streptococci, maternal serum levels.20 At maternal doses of 150 mg orally to 600 mg gestation.20,24 There are no Clostridia strains After multiple oral doses prior to therapeutic IV, breast milk concentrations range from 0.7 studies to indicate that dosing abortion, fetal blood concentrations were 25% and to 3.8 ␮g/mL (Product information should be modified during amniotic fluid levels were 30% of maternal blood Clindamycin, 1970). pregnancy. levels.21 Cmax and Tmax (after a single standard dose) and Css (after multiple doses) do not change appreciably at any time during pregnancy. Doxycycline Gram-positives, gram- Crosses the placenta (Product information Excreted in human breast milk.25 Unknown whether doseAntibiotic Use in Pregnancy negatives, rickettsiae, Vibramycin, 2001). Use for a short period (1 week) during adjustments during pregnancy chlamydiae, breastfeeding is considered probably safe.9,16 are necessary. mycoplasma, Breast milk concentrations are 30–40% of that Pharmacokinetics during spirochetes, found in maternal blood.25 pregnancy has not been actinomyces specifically studied. Enterohepatically recirculated. Excreted in urine and feces as unchanged drug. From 29% to 55.4% of a dose can be accounted for in the urine by 72 hours (Product information Vibramycin, 2001). Gentamicin Gram-negative aerobic Crosses the human placenta.20,26–28 Excreted in human breast milk.29,30 Increased dosage suggested due rods, many In 2 different studies, peak umbilical cord blood Considered “usually compatible with to decreased serum half-life in streptococci, levels were 34%26 and 42%20 of associated maternal breastfeeding.”9† pregnancy and lower Staphylococcus aureus, blood concentrations. Poorly absorbed from the GI tract.29 Only half maternal serum levels.20,31 mycobacteria of nursing newborns had detectable serum In 54 women undergoing levels, which were low and not likely to cause cesarean delivery, levels were clinical effects.29 No adverse signs or symptoms lower than nonpregnant in nursing infants as a result of maternal women.20 Eliminated mainly treatment.9 by glomerular filtration (Product information Gentamicin, 1966). Clearance decreased in preeclamptic patients.32 Dose/ dosing interval adjusted via peak and trough levels (Product information Gentamicin 1966). (continued)OBSTETRICS & GYNECOLOGY
  6. 6. Table 2. Current Information for Eleven Broad-Spectrum Antibiotics That May Be Used in Pregnant and Lactating Women (continued) Possible Pregnancy Dosage/ Schedule Adjustments, Metabolism, Microbiologic Excretion, and Spectrum of Recommendations for Antibiotic Activity* Placental Transmission Transmission Into Breast Milk Monitoring Levofloxacin Gram-positives and Crosses the human placenta and concentrates in Excreted in human breast milk in high Circulating fluoroquinolone gram-negatives amniotic fluid (based on data for racemic concentrations (based on data for racemic concentrations are lower in ofloxacin) (Product information Levaquin, 1996).17 ofloxacin) (Product information Levaquin, pregnant than in nonpregnant In 20 women at 19–25 weeks of gestation receiving 1996).17 women, but no specificVOL. 107, NO. 5, MAY 2006 two IV 400-mg doses of ofloxacin q12 hours, mean Considered “usually compatible with pharmacokinetic data is amniotic fluid concentration 3–6 hours after dosing breastfeeding.”9† available regarding was 0.25 Ϯ 0.11 ␮g/mL (n ϭ 6; amniotic fluid: In 10 women given 400 mg of ofloxacin q12 levofloxacin in pregnant maternal serum concentration [AF:MS ratio] ϭ hours PO, serum and milk concentrations were women.19 There are no data 0.35), 0.15 Ϯ 0.11 ␮g/mL at 6–10 hours (n ϭ 8; obtained 2, 4, 6, 9, 12, and 24 hours after the to support dosing adjustments AF:MS ratio ϭ 0.67), and 0.13 Ϯ 0.11 ␮g/mL at 3rd dose. Concentrations were 2.41 Ϯ 0.80, during pregnancy. 11–12 hours (n ϭ 6; AF:MS ratio ϭ 2.57).17 1.91 Ϯ 0.64, 1.25 Ϯ 0.42, 0.64 Ϯ 0.21, 0.29 Ϯ 0.10, and 0.05 Ϯ 0.02 ␮g/mL at these times, with breast milk: serum concentration ratios of 0.98, 1.30, 1.39, 1.25, 1.12, and 1.66, respectively.17 For breastfed infants consuming 150 mL/kg per day, the estimated maximum infant dose of ofloxacin is 0.362 mg/kg per day.18 Penicillin G Gram-positive aerobes Crosses the human placenta.5,33,34 Excreted in human breast milk in small amounts Shorter dosing interval and/ or including most Penicillins are transferred to the fetus and amniotic (Product information Bicillin, 2001; product increased dose have been streptococci/ fluid reaching therapeutic levels.5 information Penicillin V, 1997).15 suggested during pregnancy to enterococci, gram- Considered “usually compatible with attain similar plasma positive anaerobes, breastfeeding.”9† concentrations as for spirochetes, In women with serum concentrations of penicillin nonpregnant women.6,11 actinomyces, some ranging from 6 to 120 ␮g/dL, corresponding Penicillins are primarily renally gram negatives* breast milk concentrations were 1.2–3.6 ␮g/dL, excreted via tubular secretion and the amount of the maternal dose appearing and glomerular filtration. in breast milk per day was estimated at 0.03%.15 Volume of distribution and renal clearance are increased during the 2nd and 3rdNahum et al trimesters.6,11 Penicillin VK Gram-positive aerobes Crosses the human placenta readily.5,7,10,33,34,35 Excreted in human breast milk in small amounts Shorter dosing interval and/or including most Penicillins are transferred to the fetus and amniotic (Product information Penicillin V, 1997).15,36 increased dose have been streptococci/ fluid reaching therapeutic levels.5 Considered “usually compatible with suggested during pregnancy enterococci, gram- breastfeeding.”9† to attain similar plasma positive anaerobes, In 18 women, penicillin V milk concentration concentrations as for gram negatives depended on presence of mastitis, with peak nonpregnant women.6,11 levels 2.6–5.4 hours after a single PO 1,320-mg Penicillin V is excreted renally, dose.35 Peak concentration was 30–72 ␮g/dL primarily via tubular with mean concentration 26-37 ␮g/dL. AUC secretion. Volume of over 8 hours after dosing was 2.1–3.0 mg-h/L.35 distribution and renal Estimated dose of penicillin V ingested per day clearance are increased by breastfed infants is 40–60 ␮g/kg, or 0.09– during the 2nd and 3rd 0.14% of maternal dose per kg body weight.35 trimesters.6,11Antibiotic Use in Pregnancy (continued)1125
  7. 7. 1126 Table 2. Current Information for Eleven Broad-Spectrum Antibiotics That May Be Used in Pregnant and Lactating Women (continued)Nahum et al Possible Pregnancy Dosage/ Schedule Adjustments, Metabolism, Microbiologic Excretion, and Spectrum of Recommendations for Antibiotic Activity* Placental Transmission Transmission Into Breast Milk Monitoring Rifampin Mycobacteria, Neisseria Crosses the human placenta (Product information Excreted in human breast milk (Product Unknown whether dosing meningitidis, S aureus, Rifampin, 1971).37–39 information Rifampin, 1971).15,40,41 adjustments during pregnancy Haemophilus influenzae, Umbilical cord concentrations between 12% and Considered “usually compatible with are necessary. Legionella pneumophila, 33% of maternal blood levels, with peak levels breastfeeding.”9† Pharmacokinetics during Chlamydia occurring concurrently after drug administration.37–39 After a single oral dose of 600 mg, a nursing pregnancy has not been infant would ingest approximately 0.05% of the specifically studied. maternal dose per day, or approximately 0.3 Hepatically deacetylated toAntibiotic Use in Pregnancy mg/day.15,40,41 active metabolite. Parent compound and metabolites excreted via biliary elimination (60%). Enterohepatic re-circulation; plasma levels elevated in hepatic disease. Up to 30% excreted in urine; renal clearance is 12% of GFR.38 Vancomycin Gram positives, S aureus, Crosses the human placenta (Product information Excreted in human breast milk when There are no studies to indicate Staphylococcus Vancomycin, 1964).42,43 administered IV (Product information that vancomycin dosing epidermidis, Appears in umbilical cord blood after IV maternal Vancomycin, 1964).42 should be modified during streptococci, treatment (Product information Vancomycin, When administered orally, vancomycin is poorly pregnancy. enterococci, 1964).42,43 Amniotic fluid and umbilical cord blood absorbed from the GI tract (Product Volume of distribution and Clostridium, Coryne- concentrations during the early 3rd trimester information Vancomycin, 1964). It is, therefore, plasma clearance both bacterium comparable to maternal blood levels (fetal-maternal not likely to cause adverse effects in nursing increased, but half-life similar serum concentration ratio of 0.76).43 infants. to that for nonpregnant women (4.55 versus 4–6 hours) in a woman administered IV vancomycin twice daily from 26–28 weeks of pregnancy.43 CBC, complete blood count; AF, amniotic fluid; MS, maternal serum; GI, gastrointestinal; AUC, area under the curve; GFR, glomerular filtration rate. * Listed in the product label and the clinical pharmacology monograph as active against most strains; bacterial resistance occurs commonly in some species of otherwise susceptible bacteria due to beta-lactamase production. † Based on assessment by the American Academy of Pediatrics.OBSTETRICS & GYNECOLOGY
  8. 8. Table 3. Teratogenic and Toxic Potential of Eleven Broad-Spectrum Antibiotics Based on Available Human and Animal Data Magnitude of Human FDA Animal Data: Teratogenic Teratogenic Fetal Risk Pregnancy Antibiotic Human Data: Teratogenic and Toxic Effects and Toxic Fetal Effects (Based on TERIS Assessment)44 Category* Amoxicillin OR for major congenital anomalies ϭ 1.4 (95% CI 0.9–2.0) for No increased congenital Increased risk of teratogenicity is B women using amoxicillin ϩ clavulanic acid during malformations in mice treated “unlikely,” based on “fair” data. pregnancy in a case-control study of 6,935 malformed infants with 3–7 times the maximum (no increased risk).45 human therapeutic dose of OR (adjusted) for congenital anomalies ϭ 1.16 (95% CI 0.54– amoxicillin.54 2.50) in a Danish study (1991–2000) of 401 primiparous No adverse reproductive effectsVOL. 107, NO. 5, MAY 2006 women who filled prescriptions for amoxicillin during in rats given amoxicillin- pregnancy (rate ϭ 4.0%) compared with 10,237 controls who clavulanic acid at doses of 400 did not redeem any prescription drug (rate ϭ 4.1%).46 and 1,200 mg/day prior to No increased rate of congenital malformations among 147 fertilization and during the women who received prescriptions for amoxicillin during the first 7 days of gestation 1st trimester.46 (Product information Amoxil, No increased rate of congenital anomalies among 284 infants 2001).55 whose mothers were administered amoxicillin or ampicillin No adverse fetal effects in pigs during the 1st trimester, or in 1,060 infants whose mothers given amoxicillin with were treated at any time during pregnancy.47 clavulanic acid at doses of 600 No significantly increased rate of major or minor anomalies in mg/kg on days 12–42.56 the children of 14 women treated with amoxicillin and Increased frequency of probenecid during the first 14 weeks of gestation or among embryonic death in mice 57 women treated after the 14th week in a controlled clinical treated with amoxicillin at 6–7 trial on the treatment of gonorrhea during pregnancy.48 times the maximum No adverse effects in offspring exposed to amoxicillin during therapeutic human dose.54 the 2nd and 3rd trimesters in 3 controlled clinical trials of antibiotic treatment for premature preterm rupture of membranes.49–51 An association of necrotizing enterocolitis in newborns and maternal amoxicillin and clavulanic acid treatment duringNahum et al the 3rd trimester was observed in a randomized controlled trial including 4,826 pregnant patients.52,53 Chloramphenicol OR for major congenital anomalies ϭ 1.7 (95% CI 1.2–2.6) for No increased congenital Increased risk of teratogenicity is C oral administration at any time during pregnancy in a case- anomalies in monkeys.60 “unlikely,” based on “fair” data. control study of 22,865 malformed infants (risk marginally No teratogenicity in mice or “Therapeutic doses of chloramphenicol increased).57 rabbits at 10–40 times the are unlikely to pose a substantial RR for congenital malformations ϭ 1.19 (95% CI 0.52–2.31) in recommended human dose.61 teratogenic risk.” 348 offspring born to women who took chloramphenicol at No teratogenicity in rats at 2–4 any time during pregnancy (no statistically increased risk).58 times the usual human dose,62 Potential for both dose-related and idiosyncratic bone marrow but various fetal anomalies at toxicity. Caution should be used near term, during labor, 10–40 times the human and while breastfeeding due to the possibility of inducing dose.61,63Antibiotic Use in Pregnancy “gray-baby” syndrome.59 Increased fetal death and decreased fetal weight in mice, rats, and rabbits.61–631127 (continued)
  9. 9. Table 3. Teratogenic and Toxic Potential of Eleven Broad-Spectrum Antibiotics Based on Available Human and Animal Data (continued)1128 Magnitude of Human FDA Animal Data: Teratogenic Teratogenic Fetal Risk Pregnancy Antibiotic Human Data: Teratogenic and Toxic Effects and Toxic Fetal Effects (Based on TERIS Assessment)44 Category* Ciprofloxacin Congenital malformation rate ϭ 4.0% and spontaneous No detectable adverse effects on Increased risk of teratogenicity is C abortion rate ϭ 10.7% among liveborns to 56 women who embryonic or fetal “unlikely,” based on “fair” data.Nahum et al continued their pregnancies after exposure to ciprofloxacin development in monkeys.69 “Therapeutic doses of ciprofloxacin (ENTIS registry, 1986–1994). Rates of spontaneous No evidence of teratogenicity in during pregnancy are unlikely to pose abortion/fetal death, post-natal disorders, prematurity and the offspring of mice, rats, and a substantial teratogenic risk, but the intra-uterine growth retardation did not exceed background rabbits.70 data are insufficient to state that there rates.64 is no [increased] risk”. In a prospective registry of 116 pregnancies exposed to ciprofloxacin, 91 resulted in live births and 69% of these were exposed during the 1st trimester. Six liveborns were malformed (congenital malformation rate ϭ 6.6%). There was no pattern of minor or major malformations.64 OR for major congenital anomalies ϭ 0.85 (95% CI 0.21– 3.49) in a controlled, prospective, observational study ofAntibiotic Use in Pregnancy 200 human pregnancies exposed to fluoroquinolones during the 1st trimester (2.2% rate versus 2.6% in controls) [53% ciprofloxacin exposures, with 68% during the 1st trimester] (no increased risk).65 No clinically significant musculoskeletal or developmental dysfunctions in offspring.65 No congenital malformations and no increase in musculoskeletal problems in offspring of 28 pregnant women exposed to ciprofloxacin during the 1st trimester.65 Permanent quinolone-induced cartilage or bone damage has not been documented in humans.66,67 Seven women exposed to ciprofloxacin during 2nd or 3rd trimester delivered healthy, normal babies. Motor, adaptive, social, and language milestones were consistent with age, and there was no evidence of cartilage damage on regular clinical assessments up to 5 years of age.68 Clindamycin Major congenital anomalies in 31 of 647 infants (4.8%) whose No increased congenital Increased risk of teratogenicity is B mothers were given prescriptions for clindamycin during malformations in mice and “undetermined” based on “limited” the 1st trimester of pregnancy; expected rate 4.3%.71 rats given 1–12 times the data. No increased rate of congenital malformations in 104 women therapeutic human dose.77,78 “Although a small [increased] risk treated with clindamycin during the 2nd or 3rd trimester of cannot be excluded, a high risk of pregnancy for the prevention of preterm delivery.72 congenital anomalies in the children No increased rate of congenital anomalies in 65 infants born of women treated with clindamycin to women who received clindamycin and quinine during during pregnancy is unlikely”. the 2nd or 3rd trimester of pregnancy for the treatment of malaria.73 (continued)OBSTETRICS & GYNECOLOGY
  10. 10. Table 3. Teratogenic and Toxic Potential of Eleven Broad-Spectrum Antibiotics Based on Available Human and Animal Data (continued) Magnitude of Human FDA Animal Data: Teratogenic Teratogenic Fetal Risk Pregnancy Antibiotic Human Data: Teratogenic and Toxic Effects and Toxic Fetal Effects (Based on TERIS Assessment)44 Category* Clindamycin No congenital malformations among 16 children of women (continued) treated with clindamycin during the 1st trimester of pregnancy for attempted prevention of recurrent miscarriage.74 Can be a causative factor in the development of pseudomembranous colitis due to overgrowth of ClostridiumVOL. 107, NO. 5, MAY 2006 difficile. Occurs infrequently and no more common among pregnant women using clindamycin than nonpregnant.75 Has occurred with use of nearly all antibacterial agents, including clindamycin (Product information Clindamycin, 1970). An infant developed bloody stools after exposure to clindamycin and gentamicin in breast milk; no blood and breast milk samples were obtained and a causative relationship was not established.76 Doxycycline OR for major congenital anomalies ϭ 1.6 (95% CI 1.1–2.3) No increase in congenital Increased risk of teratogenicity is D for women receiving doxycycline at any time during anomalies in mice treated with “unlikely,” based on “fair” data. pregnancy in a case-control study of 18,515 infants with 2–6 times the maximum “Therapeutic doses of doxycycline are congenital abnormalities (risk marginally increased).79 human dose.87 unlikely to pose a substantial risk of OR of 1.6 was not significantly increased (95% CI 0.8–3.6) for Increased skeletal anomalies and fetal malformations, but the data are a separately analyzed subgroup exposed during decreased fetal weight in mice insufficient to state that there is no organogenesis (2–3 months of pregnancy).79 at 17 times the maximum [increased] risk.” No association of congenital malformations with doxycycline human dose.87 Increased risk of dental staining is exposure for any of 6 anomalies (cardiovascular defects, No teratogenicity in rabbits “undetermined” based on “very oral clefts, spina bifida, polydactyly, limb reduction defects, given 2–17 times the limited” data. and hypospadias) among 1,795 doxycycline-exposed maximum human dose, but pregnancies in 229,101 completed pregnancies in a decreased fetal weight and surveillance study of Medicaid recipients.71 increased fetal death at higherNahum et al All mothers reported that exposed infants were normal at 1 doses.87,88 year of age in a prospective study of 81 pregnancies treated No teratogenicity in rats or with doxycycline for 10 days during the early 1st monkeys at more than 100 trimester.80 times the human dose.89 Tetracycline class antibiotics may induce hepatic necrosis in Delayed long bone skeletal some pregnant women.81–83 differentiation in albino rats Some tetracyclines can cause cosmetic staining of primary given 8 mg/kg of doxycycline dentition for exposures during the 2nd or 3rd trimester,84,85 intraperitoneally from and there is some concern about possible enamel gestational day 8 to 19.90 hypoplasia and reversible depression of fetal bone growth.86 Delayed appearance of No staining from doxycycline has been documented in primary ossification centers in humans. the humerus, ulna, radius,Antibiotic Use in Pregnancy femur, tibia, and fibula compared with controls (P Ͻ .001).901129 (continued)
  11. 11. Table 3. Teratogenic and Toxic Potential of Eleven Broad-Spectrum Antibiotics Based on Available Human and Animal Data (continued)1130 Magnitude of Human FDA Animal Data: Teratogenic Teratogenic Fetal Risk Pregnancy Antibiotic Human Data: Teratogenic and Toxic Effects and Toxic Fetal Effects (Based on TERIS Assessment)44 Category* Gentamicin OR for major congenital anomalies ϭ 1.7 (95% CI 0.9–3.2), Mice given 1–12 times the Increased risk of teratogenicity is C in a case-control study of 22,865 infants with congenital maximum human dose had a “undetermined” based on “limited”Nahum et al anomalies (no increased risk); included 19 critical slight statistically data. exposures, with the majority occurring during the 2nd or nonsignificant increase in the “A small [increased] risk cannot be 3rd month of pregnancy.91 rate of congenital anomalies at excluded, but there is no indication A randomized trial of 3 parenteral antibiotic regimens showed lower doses, but not higher that the risk of malformations in no congenital abnormalities among 57 infants whose ones.95 Fetal deaths were children of women treated with mothers were treated with gentamicin during the 1st or 2nd increased.95 gentamicin during pregnancy is likely trimesters.92 In mice treated with 11–18 times to be great.” The frequency of newborn hearing screening failures was not the maximum human dose, different between 46 infants whose mothers were treated dose-dependent ultrastructural with gentamicin during pregnancy and 92 unexposed vestibular system damage was control infants.93 demonstrated in offspring.96 Renal cystic dysplasia was reported in a child whose mother In rats treated systemically withAntibiotic Use in Pregnancy was given gentamicin during the 7th week of pregnancy.94 daily doses up to 500 times There is no proof of a causal relationship between the the maximum human gentamicin treatment and the nephrotoxicity, but it cannot ophthalmic dose, gentamicin be excluded.94 depressed median glomerular No ototoxicity or nephrotoxicity has been documented in counts and kidney and body human fetuses.44 weights in newborns (Product information Gentamicin, 1966). Rats given 9–25 times the maximum human dose had nephrotoxicity in offspring of type typically expected from aminoglycoside exposure.97 Levofloxacin No well-controlled studies of the safety and efficacy of No teratogenicity in rats at oral There are no well-controlled studies of C levofloxacin in pregnant or lactating women have been doses up to 810 mg/kg per the safety and efficacy of levofloxacin reported. day (9.4 times the maximum in pregnant or lactating women. human dose based on BSA) or Comprehensive reviews of published IV doses up to 160 mg/kg per data concerning norfloxacin and day (1.9 times the maximum ciprofloxacin (2 related human dose) (Product fluoroquinolone antibiotics) conclude information Levaquin, 1996). that an increased risk of teratogenicity is “unlikely” based on “fair” data. (continued)OBSTETRICS & GYNECOLOGY
  12. 12. Table 3. Teratogenic and Toxic Potential of Eleven Broad-Spectrum Antibiotics Based on Available Human and Animal Data (continued) Magnitude of Human FDA Animal Data: Teratogenic Teratogenic Fetal Risk Pregnancy Antibiotic Human Data: Teratogenic and Toxic Effects and Toxic Fetal Effects (Based on TERIS Assessment)44 Category* Levofloxacin No teratogenicity or adverse (continued) effects on fertility in rats at oral doses up to 360 mg/kg per day.91 Decreased fetal body weight and increased fetal mortality in rats givenVOL. 107, NO. 5, MAY 2006 810 mg/kg per day, with retardation of fetal skeletal ossification/skeletal variations (Product information Levaquin, 1996).98 No teratogenicity in rabbits given up to 50 mg/kg per day orally (1.1 times the maximum recommended human dose based on BSA), or IV at doses up to 25 mg/kg per day (0.5 times the highest recommended human dose) (Product information Levaquin, 1996).98 Penicillin G OR for major congenital anomalies ϭ 1.3 (95% CI 1.1–1.5) No teratogenicity in mice Increased risk of teratogenicity is “none” B for women who used penicillin G during pregnancy in a administered up to 500 units/g based on “good” data. case-control study (1980-1996) of 22,865 malformed infants on gestation day 14.103 (marginally increased risk suggested attributable to recall No teratogenicity or increased bias by the authors).99 abortions in rabbits RR for congenital malformations ϭ 0.92 (95% CI 0.78–1.10) maintained on 100 mg/kg perNahum et al among 7,171 infants whose mothers were treated with a day during pregnancy.104 penicillin derivative at any time during pregnancy (no No teratogenicity or impaired increased risk).58 fertility in mice, rats and The frequency of 1st-trimester penicillin use was no greater rabbits (Product information than expected in a prospective study of 194 infants with Bicillin, 2001). major malformations born in Sweden (1963–1965).100 OR for neural tube defects ϭ 0.90 (95% CI 0.37–2.17). Rate of 1st-trimester penicillin use was no greater than expected in a case-control study of 538 infants with neural tube defects and 539 controls in California from 1989 to 1991 (no increased risk).101 No adverse effects noted in offspring despite widespread useAntibiotic Use in Pregnancy of penicillins during pregnancy.10,44,58,99,102 (continued)1131
  13. 13. Table 3. Teratogenic and Toxic Potential of Eleven Broad-Spectrum Antibiotics Based on Available Human and Animal Data (continued)1132 Magnitude of Human FDA Animal Data: Teratogenic Teratogenic Fetal Risk Pregnancy Antibiotic Human Data: Teratogenic and Toxic Effects and Toxic Fetal Effects (Based on TERIS Assessment)44 Category* Penicillin VK OR for congenital anomalies ϭ 1.25 (95% CI 0.84–1.86) (not No evidence of impaired fertility Increased risk of teratogenicity is “none” B increased) among 654 users of penicillin VK with or without or harm to the fetus due to based on “good” data.Nahum et al other drug use during the 1st trimester (1991–1998). The rate penicillin in reproduction of congenital anomalies (4.6%) was no greater than for 9,263 studies in mouse, rat, and controls who did not redeem any prescription drug during rabbit (Product information pregnancy (3.6%).105 Nine cardiovascular abnormalities Penicillin V, 1997). occurred in the group exposed to penicillin VK (OR 1.74; 95% CI 0.83–3.65) (not statistically increased).105 OR for congenital anomalies ϭ 1.3 (95% CI 1.1–1.6) in a case- control study (1980–1996) of 22,865 infants with congenital anomalies (173 [0.8%] treated with penicillin V during pregnancy). Adjusted OR for medically documented penicillin V use during the 1st trimester showed no significant association between maternal exposure and congenitalAntibiotic Use in Pregnancy anomalies.106 Rifampin In a meta-analysis of case reports (1971–1977; 15 different No increased rate of congenital Increased risk of teratogenicity is “unlikely” C authors),111 congenital malformations among 410 offspring in anomalies in rats or mice based on “limited to fair” data. 442 gravidas treated with rifampin—usually in combination treated with 2.5–10 times the “The data are insufficient to state that there with other drugs—was 3.3% and no higher than expected for usual human dose.112 is no [increased] risk”. human populations.44,107 Exposure was during the first 4 In rats and mice treated months in 109 cases. The spontaneous abortion rate ϭ 1.7% with Ն 15 times the human was below expected for a general obstetrical population.108 dose (Ն 150 mg/kg per day), In 226 women exposed during 229 conceptions, 9 offspring had there was an increased rate of congenital malformations among 207 births (4.3%)37,109; this spina bifida, cleft palate, and was no greater than the historical rate for women afflicted nonossified skeletal elements with tuberculosis.37,109 The spontaneous abortion rate ϭ 2.4% (Product information and was below expected for general obstetric populations.108 Rifampin, 1971).37,109 The No congenital anomalies in the offspring of 13 women treated malformation rate was dose- with rifampin for leprosy,110 or 18 women treated for dependent. No increase in rate brucellosis.111 Treatment occurred during all trimesters. of congenital anomalies in rabbits treated with similar doses (200 mg/kg per day). No fetal malformations in rabbits administered doses of 50 mg/ kg per day for 20 days beginning on day 2.113 In rabbits given doses of up to 20 times the usual human dose, imperfect osteogenesis and embryotoxicity were reported (Product information Rifampin, 1971).OBSTETRICS & GYNECOLOGY (continued)

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