Antibiotic Use in Pregnancy

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PRESCRIBING IN PREGNANCY 0889-8545/97 0.00 + .20

ANTIBIOTIC USE IN PREGNANCYJodi S. Dashe, MD, and Larry C . Gilstrap 111, MD

Infections are common during pregnancy, and a significant numberof pregnant women are exposed to antibiotics. Urinary tract infectionssuch as bacteriuria, cystitis, and pyelonephritis are among the mostcommon, occurring in 2% to 7 of all pregnant women.32Other fre-quently encountered infections include community acquired pneumonia,chorioamnionitis, and sexually transmitted diseases. In addition, metritisand mastitis may complicate the postpartum period.Virtually all antibiotics cross the placenta and thus have the poten-tial to affect the fetus adversely. Most are excreted into breast milk andmay affect the neonate as well. There are no large scientific studies ofthe safety of antibiotics in pregnancy. Many agents, however, such asthe penicillins and erythromycin, have been used for many years inpregnancy (out of necessity) without apparent adverse fetal effects.Timing the treatment of an infection during pregnancy depends some-what on its nature and severity. A serious infection such as acutepyelonephritis should be treated as soon as the diagnosis is made. Onthe other hand, treatment of vaginitis might be delayed until after thefirst trimester.When giving an antibiotic to a pregnant woman, it is important tobe cognizant of the physiologic changes that may alter its pharmacody-namics. The marked increases in blood volume and creatinine clearancethat occur in pregnancy typically lead to lower serum concentrations.For example, a given dose of ampicillin or gentamicin will result inlower serum levels in pregnant versus nonpregnant women.15*1 41 6

From the Department of Obstetrics and Gynecology, University of Texas SouthwesternMedical Center, Dallas, Texas (JSD); and the Department of Obstetrics, Gynecology,and Reproductive Sciences, University of Texas at Houston Health Science Center,Houston, Texas (LCG)

OBSTETRICS AND GYNECOLOGY CLINICS OF NORTH AMERICAVOLUME 4 NUMBER 3 * SEPTEMBER 1997 617


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Table 1. UMBILICAL CORD BLOOD TO MATERNAL BLOOD RATIOS FOR SOME OFTHE PENICILLINS8,33

Antibiotic Cord Blood toMaternal Blood RatioAmpicillinAmpicillin plus sulbactamMezlocillinTicarcillin plus clavulanic acid

0.711 o0 400 8

PENICILLINSPenicillins have been used in clinical practice since the 1940s, andas a group they are probably the safest antibiotics in pregnancy. Eachcontains a thiazolidine beta-lactam ring, and every type has a differentside chain. Penicillins are bactericidal, acting through inhibition of bacte-rial cell wall synthesis. When given to the mother, significant levels areachieved in the fetus.18, 1, 33 Ratios of umbilical cord blood to maternalserum concentrations for some of the penicillins are summarized inTable 1.Pregnant women have been treated with penicillins for many years.Of over 3500 fetuses included in the Collaborative Perinatal Project,

there was no increase in congenital anomalies or other adverse effectsfollowing exposure to a penicillin in the first t r i m e ~ t e r . ~ ~espite theappearance of newer agents, penicillin G remains the drug of choice forsyphilis in pregnancy and for group B streptococcal infection. Pregnantwomen with syphilis who are allergic to penicillins should undergodesensitization and then receive treatment with penicillin G 54Ampicil-lin, an aminopenicillin, is a drug of choice for treatment of enterococcalinfection and is part of the recommended regimen for subacute bacterialendocarditis SBE) prophylaxis. It is also part of triple chemotherapyfor the treatment of serious pelvic infections. Some of the more commonpenicillins are listed in Table 2.

Table 2. SOME OF THE MORE COMMON PENICILLINSNatural penicillins

Antistaphylococcal penicillinsPenicillin GPenicillin VMethicillinOxacillinNafcillinCloxacillinDicloxacillin

Derivativesof 6-aminopenicillanic acidAmpicillinAmoxicillinBacampicillinCarbenicillinTicarcillinMezlocillinPiperacillinAzlocillin

Extended-spectrumpenicillins

Adapted from Far0 S: Penicillins bstet Gynecol Clin North Am 16257-269 1989


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ANTIBIOTIC USE IN PREGNANCY 619Table 3. PENICILLINS PLUS BETA-LACTAMASE INHIBITORS

Ticarcillin plus clavulanic acidAmoxicillin plus clavulanic acidAmpicillin plus sulbactamPiperacillin plus tazobactam

Many aerobic and anaerobic bacteria contain beta-lactamase en-zymes, which may render a specific antibiotic ineffective. Because of theincreasing resistance of bacteria to some of the penicillins, newer agentshave been developed that contain a beta-lactamase inhibitor, such asclavulanic acid, sulbactam, and tazobactam (Table 3 . They provideexcellent coverage against the mixed aerobic and anaerobic poly-microbial infections encountered in women with post-cesarean metritis.While there are no large, epidemiologic studies of the safety of thenewer penicillins during pregnancy, it is unlikely that they are terato-genic. They are Food and Drug Administration (FDA) category B drugs,as are all penicillins.Penicillins may cause adverse maternal effects such as hypersensi-tivity reactions, nausea, diarrhea, central nervous system irritability, andphlebitis. Anaphylaxis occurs in 0.004% to 0.4 , and up to 10% of thesepatients have a similar reaction to cephalosporins and carbapenems. TheJarisch-Herxheimer reaction is not uncommon following treatment ofsyphilis in pregnancy, especially primary syphilis infection.

CEPHALOSPORINSCephalosporins are the most commonly prescribed antibiotics. Likepenicillins, they contain the four-member beta-lactam ring. They are alsobactericidal, acting through inhibition of bacterial cell wall synthesis.Cephalosporins have been classified as first-, second-, and third-genera-tion based on their spectrum of activity (Table4 .Although there havebeen no large studies of the safety of cephalosporins in pregnancy, there

Table 4. SOME OF THE COMMONLY USED CEPHALOSPORINS~ ~First- and second-generationCephalothinCephapirinCephradineCefazolinCefamandoleCefoxitinCefuroxime

CefonicidCefaclorCefmetazoleCefpodoximeCefprozil

Third-generationCefotetanCefotaximeCeftizoximeCefoperazoneCeftriaxoneMoxalactamCefmenoximeCefiximeCeftazidime


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have been no embryocidal effects reported, and all of these drugs arelisted as FDA category B. They cross the placenta and in most studiestheir half-life is shorter in pregnancy because of increased renal clear-ance.6r 33 35 First-generation cephalosporins are commonly used forpost-cesarean delivery prophylaxis and for the treatment of urinary tractinfection typically caused by aerobic gram-negative rods. It is importantto note that none of the cephalosporins is effective against Enterococcus.Newer cephalosporins, which are third-generation, include cefo-tetan, cefotaxime, cefoperazone, ceftazidime, ceftizoxime, and ceftriax-one. These agents are at least tenfold less active against Staphylococcusa w e u s than the first-generation cephalosporins; however, they ade-quately cover all aerobic streptococci except Enterococcus. They provideexcellent coverage against the aerobic gram-negative rods, and severalof them are active against gram-positive and gram-negative anaerobesas well. Almost all will cover Pseudomonas sp, with cefotetan being theexception. Cefoperazone, ceftazidime, and ceftriaxone cover Bucteroidesfragi is poorly, and thus may be less effective as single agent treatmentfor mixed aerobic-anaerobic pelvic infections. Cefoperazone, unlike theothers, is cleared principally by biliary excretion. It does not requiredose adjustment in the setting of renal insufficiency, and serum levelsin pregnancy are similar to those in the nonpregnant state.19 Ceftriaxone,which has a shorter half-life in pregnancy, might be an attractive choicebecause it is one of the few agents tested that does not accumulate inthe fetus; however, there has been only limited experience with its useduring pregnan~y.2~The logical use for this class of antibiotics in obstetrics is as single-agent therapy in postpartum metritis. Unfortunately, these agents areexpensive and usually have little to offer over standard therapy. Theydo not cover chlamydia, and several of them do not cover B. fiugilis.Two of the third-generation cephalosporins, ceftriaxone and cefixime,are, however, recommended as single-dose therapy for uncomplicatedgonococcal infection. Typical cephalosporin side effects include hyper-sensitivity and diarrhea. Mild liver function test abnormalities and neu-tropenia have been reported infrequently. In addition, hypoprothrombi-nemia and bleeding have been associated with cefoperazone andcefotetan use, especially when high doses are given for prolonged peri-ods or in the setting of underlying renal or hepatic dysfunction oranticoag~lation.~,4, 44 These two agents have also caused a disulfiramreaction when taken prior to alcohol consumption.28

MACROLIDESThe macrolides-erythromycin, clindamycin, azithromycin, andclarithromycin-are bacteriostatic antibiotics that work by attaching tothe 50s ribosome and inhibiting bacterial protein synthesis (Table 5).Erythromycin covers most aerobic gram-positive cocci, and it is a drug ofchoice for Legionella Mycoplasma and Chlamydia infection in pregnancy.


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Table 5 MACROLIDE, AMINOGLYCOSIDE, AMINOCYCLITOL, MONOBACTAM, ANDCARBAPENEM ANTIBIOTICS

Macrolides

Aminoglycosides

AminocyclitolMonobactamCarbapenem

ErythromycinClindamycinAzithrornycinClarithromycinStreptomycinGentamicinTobrarnycinKanamycinAmikacinNetilrnicinSpectinomycinAztreonamlmipenern

Unlike the vast majority of other antibiotics, erythromycin crosses theplacenta minimally. For this reason it is not first-line treatment forsyphilis in pregnancy or recommended when a penicillin allergy ispresent. Erythromycin is FDA category B. Gastrointestinal upset is com-mon with its use. Other side effects include pain at injection sites,hypersensitivity reactions, and infrequent liver function test abnormali-ties. Clindamycin provides excellent coverage against many anaerobes,including almost all Clostridium sp and most Bacteroides sp, along withmany aerobic gram-positive cocci. It does not cover gram-negative rods,and in recent years resistance to some Bacteroides sp has dev e l~ pe d . ~~Clindamycin combined with an aminoglycoside is the major regimenused for the treatment of mixed aerobic and anaerobic pelvic infections,with cure rates of approximately 90% to 97%. Its primary obstetricindication is postpartum metritis, and it is also the drug of choicefor group B streptococcal prophylaxis in the penicillin-allergic patient.Clindamycin is an FDA category B drug. Side effects include gastrointes-tinal upset and infrequent liver function test abnormalities. It has beenestimated that 1 n 10,000patients treated with clindamycin will developpseudomembranous colitis from a toxin produced by Clostridium dificile.Oral vancomycin is the treatment of choice if this complication develops,and metronidazole is an alternate therapy.Azithromycin is a relatively new macrolide with an extended spec-trum of activity and a prolonged half-life. It is active against gram-positive cocci, some gram-negative rods, and many anaerobes, as wellMycopZusrnu and Chlamydia. In one study, in which azithromycin wascompared with erythromycin in the treatment of cervical chlamydiainfection in pregnant women, azithromycin had equivalent efficacy andsignificantly fewer side effects.ll Improved intracellular transport com-pared to erythromycin enhances the effectiveness of azithromycinagainst the obligate intracellular parasite Chlamydia and allows a single


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one-time dosing regimen. Azithromycin and clarithromycin both havegood in vitro activity against Borrelia burgdouferi the tick-borne spiro-chete known to cause Lyme disease.4,45 hey are probably effectivetreatment for syphilis as well, though this remains to be evaluated.Studies of the safety of azithromycin in pregnant women have not yetbeen performed. It is listed as FDA category B. Gastrointestinal sideeffects are less common than with erythromycin, and other reportedside effects include headache, dizziness, and mild liver function abnor-malities.Clarithromycin is effective against a wide variety of aerobic organ-isms as well as Ureaplasma u~eaZ yticum.4~t is most often used duringpregnancy for the treatment and prophylaxis of Mycobacterium aviumcomplex (MAC) in women who are HIV positive. There are no largerandomized studies of the safety of clarithromycin in pregnancy. It islisted as FDA category C.

AMINOGLYCOSIDESAminoglycosides are bactericidal antibiotics that bind the 30s ribo-some and inhibit bacterial protein synthesis. Members of this classinclude streptomycin, gentamicin, tobramycin, kanamycin, amikacin,and netilmicin (see Table 5). Gentamicin is the most widely used amino-glycoside in pregnancy. It covers a wide range of aerobic gram-negativerods, though resistance has developed by some strains of Pseudomonasaeruginosa. Gentamicin also has some activity against S. aureus and issynergistic with ampicillin in the treatment of Enterococcus. Gentamicinrapidly crosses the placenta, with peak cord serum levels approximately40% of maternal levels in 1 to 2 hours.% The mean concentration ratiobetween umbilical cord blood and maternal blood for gentamicin is

0.62.18There have been no reported congenital anomalies resulting fromgentamicin, and no reports of neonatal ototoxicity or nephrotoxicityfollowing in utero exposure.Gentamicin is an FDA category C drug, and its principal obstetricindication is in combination with clindamycin for treatment of mixedaerobic and anaerobic pelvic infections such as postoperative metritis. Itis also the drug of choice given with ampicillin for SBE prophylaxis.Other common uses of ampicillin and gentamicin therapy in pregnancyare chorioamnionitis and pyelonephritis. Graham et aP0 have reportedthat peak serum levels in pregnant women treated for pyelonephritisare significantly lower than in those who receive gentamicin postpartum.The dosage of any aminoglycoside needs to be reduced in the setting ofrenal insufficiency. Three major side effects are nephrotoxicity, ototoxi-

city, and neuromuscular blockade. Nephrotoxicity, which is usuallyreversible, develops in approximately 2 .4 Ototoxicity may involve ei-ther the auditory or vestibular region of the eighth cranial nerve andis, unfortunately, often irreversible. Neuromuscular blockade, a rarecomplication, may be potentiated by magnesium sulfate and other neu-


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romuscular blockers used during general anesthesia. This effect can bereversed by anticholinesterases and calcium administration.

AMINOCYCLITOLSpectinomycin is an aminocyclitol antibiotic related to the aminogly-cosides. It may be beneficial in the treatment of N. gonorrhoeae infectionin patients who are allergic to penicillins and cephalosporins. Penicil-linase-producing strains of gonorrhea resistant to spectinomycin havebeen reported. There have been no teratogenic or adverse fetal effectsdocumented. Spectinomycin is listed as FDA category B.

MONOBACTAMAztreonam is a monobactam antibiotic, and is the first and onlyagent in this class to become clinically available. Although it is a beta-lactam, like the penicillins, it is resistant to hydrolysis by beta-lactamaseand has not been found to induce beta-lactamase production. Aztreonamcovers most aerobic gram-negative rods, but is ineffective against gram-positives and anaerobes. Its spectrum is thus similar to the aminoglyco-sides, and it remains effective in an anaerobic environment (which

aminoglycosides do not), making it an excellent choice for combinationtherapy with clindamycin for treatment of an abscess. The combinationof aztreonam and clindamycin has also been found equivalent to genta-micin and clindamycin for metritis.I7 Aztreonam has a wide margin ofsafety and is not nephrotoxic or ototoxic like the aminoglycosides,though it accumulates in renal insufficiency and must be dosed accord-ingly. While studies in pregnant women are limited, it is not teratogenicin rodents. Aztreonam is listed as FDA category 8 ide effects, whichare uncommon, include rashes and transaminase elevations.

CARBAPENEMSImipenem is the first of a new class of antibiotics, the carbapenems,to become clinically available. It is administered in combination withcilastatin, a dipeptidase inhibitor that prevents nephrotoxicity Imipenemhas a broader spectrum than any other beta-lactam, covering gram-positive cocci, gram-negative rods, and anaerobe^.^^ Only methicillin-resistant S. aureus MycopZasma and Chlamydia are resistant, and resis-tance of P. aeruginosa has emerged during therapy. Imipenem has been

reported to be highly effective in the treatment of postpartum infection.36While it is rarely a first-line agent, it may be beneficial if organisms areresistant to other antibiotics. In pharmacokinetic studies, its peak serumlevels are considerably lower in pregnancy.22There is limited experiencewith the safety of imipenem during pregnancy, and it has few, if any,


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indications for use. No teratogenicity has been reported, and it is FDAcategory C Side effects include hypersensitivity reactions, nausea, andphlebitis, and it should not be given to those allergic to penicillins.

VANCOMYCIN

Vancomycin is a glycopolypeptide that is bactericidal because itinhibits the synthesis and assembly of bacterial cell wall polymers.Though it has a limited spectrum of activity, there are several infectionsfor which it remains the drug of choice. These include the treatment ofC. difficile-induced pseudomembranous colitis, for which it may be givenorally, and the treatment of methicillin-resistant S. uureus. In penicillin-allergic patients, vancomycin is the drug of choice for treatment ofEnterococczis and for prophylaxis of subacute bacterial endocarditis.'There has been controversy in the past regarding the potential for fetalototoxicity or nephrotoxicity with this agent.47Although it appears thatstandard doses of vancomycin pose no threat to the fetus, it is listed asFDA category C. The dose should be decreased in those with renalinsufficiency.

METRONIDAZOLE

Metronidazole is a nitroimidazole antibiotic whose mode of actionis not completely understood. It is the only available antibiotic effectivein treating Trichomonas vaginalis. Its spectrum includes many of theobligate anaerobes such as Bacteroides sp, Fusobacterium and Clostridiasp, as well as the anaerobic protozoa, Entamoeba histolytica and Giardialamblia. Metronidazole crosses the placenta, and at term fetal cord bloodconcentrations are approximately equivalent to those in maternal serum.3Use of metronidazole in pregnancy is somewhat controversial. Whilethe reduced form of the drug is mutagenic in bacteria, mammals arenot capable of reducing metronidazole and should not be at risk.'*Metronidazole in high doses is carcinogenic in rodents, but has not beenfound to be carcinogenic in other animal models.7, 9 It has not beenreported to be teratogenic in animal studies. A review of nearly 600pregnant women given metronidazole for trichomoniasis found no evi-dence of ter at~g en ic it y.~~lthough it has not been associated with ad-verse fetal effects, it is currently recommended for use in the secondand third trimesters only.5u t is FDA category B. Side effects, which areuncommon unless therapy is prolonged, include gastrointestinal upset,metallic taste, headache, vertigo, and somnolence. After large doses,reversible peripheral neuropathy and encephalopathy have been re-ported. A disulfiram-like reaction to alcohol has been well described.38


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ANTIBIOTIC USE IN PREGNANCY 6 5

FLUOROQUINOLONESFluoroquinolones are a class of bactericidal antibiotics that act atthe level of bacterial DNA gyrase to inhibit DNA synthesis.13They are

derived primarily from nalidixic acid. Fluoroquinolones are effectivetreatment for urinary tract infection, bacterial diarrhea, respiratory infec-tion, bone and joint infection, and gonococcal infe~ti0n.l~xamples ofantibiotics in this class include norfloxacin, ciprofloxacin, ofloxacin, andenoxacin. There are no large epidemiologic studies of the use of thefluoroquinolones in pregnancy, but these agents have been reported tocause irreversible arthropathy in immature animals.48Thus, this classof antibiotics should be avoided if possible during pregnancy and inbreastfeeding mothers.SULFONAMIDES

Sulfonamides are the oldest class of antibiotics, introduced in the1930s. They are bacteriostatic and interfere with bacterial synthesis offolate. Their action is potentiated by trimethoprim, which inhibits bacte-rial dihydrofolate reductase. The primary use of sulfonamides in preg-nancy is the treatment of uncomplicated urinary tract infection. Whilethey were once active against most gram-positive cocci and gram-nega-tive rods, many strains have become resistant, so susceptibility shouldbe tested before treating chronic or recurrent infection. Typical agentsinclude sulfisoxazole or the combination of trimethoprim-sulfamethoxa-zole.Sulfonamides cross the placenta, and fetal levels reach 70 to 95%of maternal levels within several hours. If given shortly before delivery,sulfonamides can bind albumin and displace bilirubin, and this has beenreported to result in neonatal hyperbilirubinemia with kernicterus.26However, one study in which 94 infants were exposed to sulfadiazinein utero for maternal rheumatic fever prophylaxis found no increasedrisk of hyperbilirubinemia or kerni~terus.~emolytic anemia has alsobeen reported in a fetus born to a mother homozygous for glucose-6-phosphate dehydrogenase deficiency who happened to be taking sulfi-s o ~ a z o l e . ~ ~ince trimethoprim is a folate antagonist (at least in bacteria),it is generally not recommended for use in pregnancy. Nonetheless, instudies involving almost 300 pregnant women, trimethoprim was notassociated with any teratogenic or adverse fetal effects.lo,6 The combina-tion of trimethoprim plus sulfasoxazole may be indicated for Pneumo-cysfis carinii pneumonia prophylaxis in pregnant women who are in-fected with HIV. Sulfonamides are FDA category B drugs, andtrimethoprim is FDA category C .NITROFURANTOIN

Nitrofurantoin is used primarily for the treatment of urinary tractinfections during pregnancy. This drug has not been reported to be


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associated with teratogenic or adverse fetal effects. While nitrofurantoinmay cause hemolytic anemia in women with glucose-6-phosphate dehy-drogenase defi~iency:~ t has not been reported to do so in the fetus.Nitrofurantoin has also been associated with a pneumonitis if given forprotracted periods. In the authors experience of over 1000 pregnantwomen receiving this antibiotic, neither pneumonitis nor hemolytic ane-mia has occurred. In a small meta-analysis on the safety of nitrofurantoinduring the first trimester of pregnancy, there was no increase in congeni-tal malformations OR 1.29; 95% CI 0.25-6.57).8 It is listed as FDAcategory C.

TETRACYCLINESTetracyclines are bacteriostatic antibiotics that reversibly bind the

3 s ribosome and inhibit bacterial protein synthesis. They have a broadspectrum of activity against many gram-positive and gram-negativeaerobes and anaerobes, including chlamydia, mycoplasma, and the spi-rochetes. Tetracyclines cross the placenta and deposit in fetal decidualteeth causing yellow-brown discoloration if given after 5 months gesta-tion.21,7 30 Despite earlier reports, they do not lead to an increase intooth enamel hypoplasia or caries, and they do not inhibit fibula growthin the preterm infant.42However, tetracyclines are FDA category D, andshould be avoided in pregnancy unless no alternative is available. Onepotential indication is in the treatment of syphilis in a penicillin-allergicpatient who cannot be desensitized. Tetracycline at doses of more than2 grams per day has been reported to cause acute fatty degeneration ofthe liver, particularly in those treated for pyel0nephritis.5~The tetracy-clines are listed in Table 6.

ANTITUBERCULOUS AGENTS

The incidence of tuberculosis in pregnancy is increasing, and it hasbeen reported to be as high as 0.1% in endemic areas of the UnitedStates.%The American Thoracic Society and Centers for Disease Controlhave recommended that initial treatment for pregnant women withtuberculosis consist of isoniazid and rifampin. Ethambutol is also sug-gested if there is concern for isoniazid resistance.* All three agents crossthe placenta. In a review of 15 studies involving over 400 pregnanciesexposed to rifampin, over 600 exposed to ethambutol, and almost 1500

Table 6. THE TETRACYCLINESTetracycline OxytetracyclineDemeclocycline MinocyclineDoxycycline


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Table 7 ANTITUBERCULOUS AGENTSlsoniazidRifampinEthambutolStreptomycin

PyrazinamideEthionamideCycloserine

exposed to isoniazid, the rate of congenital malformations was notincreased over that of the general p ~ p u l a t i o n . ~ ~yridoxine (vitamin B6is recommended for pregnant women receiving isoniazid to preventneuropathy. Isoniazid and rifampin are listed as FDA category Cwhereas ethambutol is an FDA category B drug. Streptomycin, anaminoglycoside antibiotic, is not recommended for use in pregnancy, aseighth cranial nerve abnormalities have been identified in up to 15%ofexposed infants. The potential teratogenicity of the other antituberculousagents, pyrazinamide, ethionamide, and cycloserine, has not yet beenadequately evaluated, and their use should also be avoided in preg-nancy.2,16 he antituberculous agents are listed in Table 7.

SUMMARY

With a few notable exceptions, most antibiotics can be used withrelative safety during pregnancy. Moreover, none of the antibiotics todate has been shown to be teratogenic, although tetracycline may causeyellow-brown discoloration of the deciduous teeth (a fetal effect). Thus,antibiotics should not be withheld from the pregnant woman, especiallywhen indicated for serious, life-threatening infections.

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Update Ob/Gyn 3122, 1996

Address reprint requests toJodi S . Dashe, MDDepartment of Obstetrics and GynecologyUniversity of Texas Southwestern Medical Center5323 Harry Hines BoulevardDallas, TX 75235-9032

Antibiotic Use in Pregnancy

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