Pharmacokinetics and Safety of Antimicrobial Agents during Pregnancy Author(s): Anthony W. Chow and Peter J. Jewesson Reviewed work(s): Source: Reviews of Infectious Diseases, Vol. 7, No. 3 (May - Jun., 1985), pp. 287-313 Published by: Oxford University Press Stable URL: http://www.jstor.org/stable/4453624 . Accessed: 13/07/2012 21:21

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http://www.jstor.org REVIEWSOF INFECTIOUSDISEASES ? VOL. 7, NO 3 * MAY-JUNE 1985 ? 1985by The Universityof Chicago.All rightsreserved. 0162-0886/85/0703-0001$02.00

REVIEW ARTICLES

Pharmacokineticsand Safety of AntimicrobialAgents During Pregnancy

Anthony W. Chow and Peter J. Jewesson From the Division of InfectiousDiseases, Departments of Medicineand ClinicalPharmacy, Faculties of Medicineand PharmaceuticalSciences, University of BritishColumbia and VancouverGeneral Hospital, Vancouver,British Columbia,Canada

Theuse of antimicrobialagents during pregnancy poses unique concerns because of both potentialtoxicity and specialpharmacokinetic considerations that haveimportant ther- apeuticimplications for both motherand fetus. Variousphysiologic adaptations occur with advancinggestation, including marked increases in maternalintravascular volume, glomerularfiltration, and hepaticand metabolicactivities; thinning and maturationof the fetomaternalmembrane; and increasesin transplacentaldiffusion capacity. The net resultis that maternalantimicrobial concentrations tend to be 10%-50%lower in late pregnancyand the immediatepostpartum period than in the nonpregnantstate. Placen- tal transferof antimicrobialagents and theirexcretion in amnioticfluid or breastmilk aresimilarly affected by hemodynamicchanges, membrane transport characteristics, and maturationor metabolicactivity of the specificorgans involved. Review of the literature suggeststhat, althoughthe need for cautionin the use of antimicrobialagents during pregnancyhas been well emphasized,firm data on the pharmacokinetics,efficacy, and optimaluse of these drugs in this situationare extremelysparse and urgentlyneeded. However,recommendations regarding the use of specific antibacterial,antifungal, an- tiviral,and antiparasiticagents against selected infections during pregnancy can be made.

Antimicrobialagents are not infrequentlyadmin- humansremains largely unknown. Studies in animals isteredduring the antepartumperiod. The authors havebeen especially unreliable in predictinghuman of several studies have noted that 25%-40% of teratogenicity,and examplesof false-positiveand womensurveyed were exposed to variousantibiot- false-negativepredictions based on thesestudies are ics duringpregnancy [1-6], with as many as 5% of well known [7]. The difficulty of separatingthe pregnantwomen exposed during the first trimester potentialadverse effects of a drugfrom the under- [3]. lying disease process for which the drug was ad- Druguse duringpregnancy poses unique concerns ministeredfurther complicates the issue and often withregard to maternaland fetalsafety, particularly rendersit impossibleto drawvalid conclusionsre- in light of specialpharmacokinetic considerations gardingdrug toxicity [8]. On the other hand, con- that have directrisk-benefit implications for both demnationof usefulagents on the basisof unproven mother and fetus. Although the fetus is generally risks,particularly when therapy is clearlyrequired, consideredto be protectedby the "placentalbarrier" is unjustifiedand disconcerting.Clearly, more ef- of the fetomaternalunit, significantdrug and die- fectivecollection of data and carefullycontrolled, tary substancesdo in fact cross the placenta.The prospective,epidemiologic and statisticalinvestiga- teratogenicpotential of most therapeuticagents in tions of drugsafety during human pregnancy are ur- gently needed. In this review,which is intendedonly as a guide, Receivedfor publicationAugust 18, 1983,and in revisedform we shallconsider the antimicro- March26, 1984. commonlyemployed This workwas supportedin part by grantDG 189 from the bialagents and their use during pregnancy. Our hope MedicalResearch Council of Canadaand grant 6610-1300-47 is thatthe provenand theoretic effects of the antepar- from Healthand WelfareCanada. tum use of these agentson both maternaland fetal Pleaseaddress requests for reprintsto Dr.Anthony W. Chow, outcome will be more readilyrecognized and that Divisionof InfectiousDiseases, Department of Medicine,G. F. more indications will be de- StrongResearch Laboratories, 910 West 10thAvenue, Vancou- precise therapeutic ver, BritishColumbia, Canada V5Z 1M9. veloped.

287 288 Chowand Jewesson

MOTHER PLACENTA FETUS

Locus of Action Tissue Reservoirs Locus of Action Tissue Reservoirs " Free' oBoundB k Free - Bound Free 't Bound Free Bound

Absorption Free Drug -u DlFU i Free Drug (Active Transport)

Boun/d// ~,,B

rud BJ/Drug \Ne \ A F Biotransformation Biotransformati jExcretion - Hemodynamics Amniotic Fluid - Placental thickness & maturation 4 - Metabolic activity - Fetal Gut - Disease states - MW, pk - Lipid solubility - Protein binding Figure 1. Major pathways and interrelations of drug pharmacokinetics in the mother, the fetus, and the placenta.

Antimicrobial Use During Pregnancy degree of protein binding, and vice versa. Ideally, and Puerperium for valid comparisons of antibiotic pharmacokinet- ics in the and states, control PharmacokineticFactors pregnant nonpregnant samples should be obtained from the same women The dynamicinteractions of drug absorption,dis- before and after pregnancy [10]. This approach tribution,receptor activity, metabolism, and elimi- would eliminate the influences of variations in those nationare closely linked in at leastthree major func- pharmacokinetic parameters that are primarily ge- tional compartments:those of the mother, the netically determined. If such an approach is not pos- placenta,and the fetus (figure 1). When the phar- sible, appropriatecontrol samples from nonpregnant macokineticproperties of antimicrobialagents dur- women should at least be matched for age, weight, ing pregnancyare considered,a numberof techni- and (if possible) underlying medical conditions. cal problemsand limitationsbecome apparent. Third, various pharmaceuticalcompounds are of- First, meaningfulinformation can be obtained ten administeredconcomitantly during labor or sur- onlyon agentswhose levels can be accuratelyassayed gery, and the possible influence of these agents on and (if metabolized)whose metabolites can be read- the pharmacokinetics of an antibiotic may be diffi- ily measured.Second, for studiesof antibioticsin cult to evaluate. Fourth, the technical as well as ethi- maternalor fetalplasma or serum,standards should cal problems related to sampling and pharmacoki- preferablybe preparedin correspondingplasma or netic studies of fetal tissue (such as freeing tissue serumfrom age-matched, untreated pregnant women from blood and extractingthe antibiotic) are numer- or fetuses.This requirementis particularlyimpor- ous and immense. These limitations must be care- tant since drugs may bind differentlyin fetal and fully considered if such data are to be interpreted adultplasma and at differentstages of gestation[9, critically and meaningfully. 10].For example,as levels of antibioticsin plasma Finally, the fate of antimicrobial metabolites and or serumare determined in microbiologicassays for the relation of these metabolites to toxicity in the the freeor unboundfractions, samples from a fetus pregnant woman and the fetus remain largely unex- witha low degreeof proteinbinding will givefalsely plored. Even though a metabolite may be microbio- highvalues if comparedwith standards with a higher logically inactive and thereforemay not be measured AntimicrobialDrug Use in Pregnancy 289

by bioassay techniques,it may still possess toxic bumin concentration decreases from a mean of 4.3 potential.This possibilityshould be systematically g/dl in the nonpregnant state to a mean of 3.0 g/dl examinedby modernantimicrobial assay techniques in late pregnancy[15]. This modification may directly (suchas high-pressureliquid chromatography) that affect the ratio of bound to free fractions of many allow simultaneousquantitation of biologicallyin- antimicrobial agents and may ultimately result in a active and biologicallyactive metabolites. lower total serum level of the drug, an increase in Maternalphysiologicconsiderations. During preg- the tissue-to-plasma distribution ratio, and an in- nancya numberof physiologicchanges in themother crease in the rate of drug clearance from the body. may modify the pharmacokineticsof therapeutic Both the tone and the motility of the maternalgas- agents.Important among these arematernal adap- trointestinal tract may be reduced as a consequence tations that serveto increasethe deliveryof blood of physical displacement by the enlarging uterus; and nutrientsto the fetus and to removemetabolic these changes may result in delayed gastric empty- wasteproducts from both motherand fetus [11-13]. ing and prolonged intestinal transit [13]. The latter These adaptationsgenerally result in a markedin- effects may in turn influence either the bioavailabil- creasein both the intravascularand extravascular ity and effectiveness of drugs with acid-labile prop- volumes;the enhancementof cardiacoutput, renal erties or the site-specific absorption of drugs from blood flow, and the glomerularfiltration rate; and the intestinal tract [11, 12]. Finally, progressivethin- the augmentationof hepaticand other metabolic ac- ning of the fetomaternal "barrier"as gestation ad- tivitiesin the mother,the fetus,and the placenta[14]. vances results in increased transplacental diffusion Consequently,the volumeof distribution-as well and alternative routes of drug elimination from the as the metabolicdegradation and renalclearance of mother [14, 16]. These pregnancy-associated physi- the administereddrug-can alter significantlyin ologic changes and their therapeuticimplications are comparisonwith correspondingvalues obtained in summarized in table 1. The net influence of these the nonpregnantstate. Furthermore, the plasmaal- physiologic changes of pregnancy is that maternal

Table 1. Pregnancy-associated physiologic changes and their potential influence on antimicrobial pharmacokinetic parameters. Physiologicchange Kineticinfluence(s) Therapeuticimplication(s) References Expandedintravascular volume Increasedvolume of distribution Possibleneed for largerloading [13, 17] (up by 50% by eighthmonth) (decreasedmaternal serum doses concentration) Reducedplasma protein concentra- Possibleunderestimation of serum [15, 18] tion (decreasedtotal drug concen- concentrationof free or active tration, increasedtissue/plasma drug on basis of serumconcen- distribution,increased drug trationof total drug clearance) Possibleneed for more frequent administrationto dampen peak-troughfluctuations Increasedrenal blood flow and Increaseddrug clearance Subtherapeuticdrug concentrations [17, 19] glomerularfiltration rate Possible need for increaseddose (up by 50% by fourth month) and/or decreaseddosing interval Increasedprogesterone-activated Increasedrate of biotransformation Possibleneed for increaseddose [13, 20] hepaticmetabolism to eitheractive or inactive and/or decreaseddosing interval metabolites Decreasedgastrointestinal motility Delayedgastric emptying Reducedrate of absorptionfrom [21, 22] small bowel Unpredictableabsorption of Delayedtransit time Increasedabsorption from orally administereddrugs gastrointestinaltract Increasedthinning of fetomaternal Increasedtransplacental diffusion Possible need for increaseddose [23, 24] barrierwith advancinggestation (increasedfetal serumconcen- and/or decreaseddosing interval tration, decreasedmaternal serum concentration) 290 Chowand Jewesson

antibioticconcentrations tend to be lowerthan those degree.The rate-limitingfactors in the placental reportedafter the administrationof similardoses transferof antibioticsare identical to thosethat gov- to nonpregnantpatients. Overall, drug levels may be ernmembrane diffusion by molecules.Thus, the rate 10%o-50%lower during late pregnancyand the im- of diffusion acrossthe placentalbarrier is directly mediatepostpartum period than in the nonpregnant proportionalto the maternal-fetalconcentration gra- state [16].These effects resulting in lowerdrug con- dientand the surfacearea of the placentaand is in- centrationsin maternalserum have been well recog- verselyproportional to the thicknessof the placental nized for aminoglycosides[25, 26], ampicillin[17], membrane[23, 24]. Earlyin pregnancythe placen- and cefazolin [27]. Otherantibiotics whose mater- tal membraneis relativelythick, and this character- nal serum levels probablydecrease in pregnancy istic tendsto reducepermeability. The thicknessof includemethicillin, cephalexin, cephalothin, eryth- the trophoblasticepithelium decreases in the lasttri- romycin,and nitrofurantoin [16]. Specific data, how- mester(i.e., from 25 im early in gestationto 2 tm ever,are lacking. Antibiotics whose serum levels are at birth [23]), and any passageof drugsis thereby probablyunchanged in pregnancyinclude cephalori- greatlyfacilitated [6, 28]. Variousdisease states, in- dine,clindamycin, thiamphenicol, and trimethoprim- cludingdiabetes and toxemiaof pregnancy,signifi- sulfamethoxazole[16]. cantly alter the permeabilitycharacteristics of the The maternaladaptive changes most likelyto in- placentalmembrane [6]. A drug with a molecular fluencedrug pharmacokinetics are most evidentin weightof <500, a high degreeof lipid solubility,a the third trimesterof pregnancyand immediately low degreeof ionization,and a low affinityfor pro- postpartum;the degreeof changevaries considera- teinbinding thus is ableto traversethe placentamore bly from individualto individual.Precise data on readily.A drug with a molecularweight of >1,000 the time courseof the returnof thesevarious physi- maybe restrictedby its size.Only the unbound(free) ologic adaptationstoward normal during the puer- fractionof a drug is subjectto placentaltransfer; periumare lacking. It is knownthat in the immedi- therefore,the more a drug is bound to maternal ate postpartum period the pattern of maternal plasmaproteins, the less it is availablefor crossing dispositionof drugsremains similar to that during to the fetus [23]. late pregnancydespite the removalof pharmacoki- Although some variationsexist in the placental netic influences from the placentaand the fetus. transferof many antibiotics (such as ampicillin, Thus, the therapeuticimplications of alteredphar- cephalothin,clindamycin, carbenicillin, and the ami- macokinetic properties of antimicrobialagents noglycosides),most followa similarpattern [16]. Af- shouldstill be consideredin the postpartumperiod. tera singleintravenous infusion into the mother,an- Placentaltransfer and excretion in amnioticfluid. tibiotic concentrationsusually peak in umbilical Movementof compounds across the placenta is blood within 30-60 min of the time they peak in generallybidirectional, although the net transferoc- maternalserum. Fetal-to-maternal peak serum level curs from mother to fetus in most instances.The ratioshave ranged between 0.3 and 0.9 for ampicil- transplacentalpassage of an antimicrobialagent is lin, cephalothin,clindamycin, carbenicillin, and the regulatedby many factors,principally the physio- aminoglycosides,while those for erythromycinand logic characteristicsof the maternal-placental-fetal dicloxacillinare more limited ((0.1) [11,16]. The rel- unit andthe physicochemicalproperties of the drug ativeconcentrations of ampicillin,methicillin, and [23]. Physiologicfactors include (1) hemodynamic dicloxacillinin the fetaland maternalcirculation are changesin eitherthe maternalor the fetalcontribu- relatedto the respectivecapacity of these drugsfor tion to total placentalblood flow, (2) the thickness proteinbinding [11]. Ampicillin, which is least pro- andmaturation of the placentalmembranes, and (3) tein bound (20%), reacheshigh levels in the fetus the metabolicactivity of placentaltissues. and in amnioticfluid; in contrast,methicillin (40% Althoughactive and facilitatedtransport of some bound)and dicloxacillin (96% bound) achieve higher substancesacross the placenta has been demon- maternallevels but progressivelylower levels in the strated [6], the transplacentalpassage of an- fetusand amnioticfluid. On this basis dicloxacillin timicrobialagents occurs primarily by simplediffu- may be suitablefor treatmentof a maternalinfec- sion. It follows,therefore, that almost all drugstaken tion but may not be useful for an intrauterine by a pregnantwoman can crossthe placentato some infection. AntimicrobialDrug Use in Pregnancy 291

A considerabletime lag in antibioticpenetration of drugs. It is now known that the fetal liver pos- of the amnioticfluid is noted after intravenousin- sessesmany of the metaboliccapabilities of the adult fusion into the mother.This delay,which may be liver[31a]. Nevertheless, the fetusmay not be capa- severalhours in length,apparently is attributableto ble of metabolizingcertain drugs because of the the fact that antibioticlevels in amnioticfluid dur- immaturemetabolic activity of such enzymes as ing the thirdtrimester are to a great extentdepen- monooxygenases,epoxide hydrase, and glucuronyl- denton antibioticexcretion in fetalurine [16, 28, 29]. transferase[32]. Theamount of drugexcreted in turndepends largely Excretionin breastmilk. The excretionof an- on the maturityand health of the fetus [14].Thus, timicrobialagents in breastmilk is governedby the amnioticdrug levels are much lowerin earlypreg- same principlesthat determineplacental transfer. nancythan at term[29] and arenegligible in the pres- Most drugsenter the mammaryalveolar cells in the ence of intrauterinefetal death [14]. non-ionized,non-protein-bound form [33, 34]. Un- Fetalphysiologic considerations. Antibioticscan dernormal conditions the pH of breastmilk, which reachthe fetus eitherby placentaltransfer into the averages6.8-7.0 (range,6.4-7.6), is lowerthan that fetalcirculation or by the achievementof sufficient of plasma [35]. Thus, weaklybasic antibioticsare concentrationsin the amnioticfluid [29]. The fetal less ionized in maternalplasma, and more non- circulationvaries greatly throughout gestation, and ionizedmolecules are available to pass fromplasma this variation causes significant changes in the into milk [34].Such agents tend to reachhigher con- penetrationand distributionof drugsin fetaltissues. centrationsin breastmilk and lowerconcentrations Since fetal organs,especially those of the gastroin- in maternalserum [16]. When the pH of plasmaand testinaltract, are in directcommunication with am- humanmilk changes,the degreeto whichthe drug niotic fluid, drugs presentin the latter are readily is ionizedand the amountthat will be excretedinto swallowedby the fetusand areavailable for absorp- milkalso change.Drugs with higher volumes of dis- tion fromthe fetalgut. In addition,because of con- tribution tend to reach lower levels in maternal siderableshunting of blood awayfrom the lungs,an- plasmaand, therefore, lower concentrations in breast tibiotic penetrationat this site is particularlypoor milk. Once insidethe alveolarmilk-secreting cells, in the fetus [29]. Conversely,blood flow to the fetal antibioticsreadily enter milk, primarily by diffusion kidneysis excellent,and antibioticsare readilyex- and occasionallyby activetransport or by apocrine cretedin largeamounts in the urine,with subsequent secretion[34]. Lipid-soluble agents appear to reach deliveryto the amnioticfluid. higherpeak levels in milkafter a shorterinterval than The lipid solubility,ionization, and protein-bind- do less lipid-solubleagents [35]. ing characteristicsof antimicrobialagents are im- Althoughessentially all antibioticsadministered portantdeterminants of drug distributionin vari- to the nursingmother can be detectedin her milk, ous fetalcompartments and selectivetissue uptake. deleteriouseffects on the neonatehave only occa- Levelsof highly protein-boundantibiotics tend to sionallybeen encountered[35, 36]. The drug con- be considerablylower in fetal serumthan in mater- centrationto whichthe infantis exposedis usually nal serum;in contrast,fetal levels of antibioticsthat low andrarely either therapeutic or toxic.Moreover, arepoorly protein bound approach maternal levels. drugsmay be excretedin milk as inactivemetabo- Occasionally,drugs such as sulfisoxazole,which is lites (e.g., 50% of chloramphenicolin breastmilk moreextensively bound in umbilicalserum than in is biologicallyinactive), or theymay be ingestedby maternalserum may reachtherapeutic concentra- the infant but then remainunabsorbed or be de- tions in fetalserum despite a relativelyhigh protein- stroyedin the gut [34, 37]. Nevertheless,some an- bindingcharacteristic [30]. As expected,higher con- timicrobialagents passing into milkare very potent, centrationsof antimicrobialagents are generally at- and it is importantto be awareof possibledangers tained in fetal serumand amniotic fluid by bolus to thebreast-fed infant when the mother is givenlarge ratherthan by continuousinfusion of druginto the doses of antibiotics.Such an awarenessis particu- mother[31] and by multiple-doserather than single- larly crucialwhen the nursinginfant is premature dose therapy[9]. or has been born with hereditaryenzyme deficien- Untilrecently, it wasbelieved that the fetuslacked cies and ineffectivemechanisms for hepaticdetox- the necessaryenzymic activity for biotransformation ification or renalclearance (table 2). 292 Chowand Jewesson

TherapeuticImplications of Pregnancy hepatotoxicitywhen administeredduring the latter half of pregnancy[43]. Similarly,tetracycline has Maternal considerations. (1) Adverse effects. beenshown to causea well-definedsyndrome of ful- The overallincidence or severityof adversereactions minanthepatic decompensation that is associated due to antimicrobialtherapy does not appearto be with high mortalityin pregnantpatients [40]. This greaterduring pregnancy than in the nonpregnant syndromeappears to be specificto pregnantwomen state.Caldwell and Cluff [66]studied prospectively who havereduced renal function. Although isonia- the rate of adversereactions due to antimicrobial zid also appears to possess greaterpotential for agentsamong medical and pediatricinpatients. The hepatotoxicityin pregnantthan in nonpregnant overallrate was 4.4% with the followingrates for women,treatment of activetuberculosis should not individualdrugs: streptomycin, 0.9%; cephalospo- be deferred[61, 63]. Someinvestigators have recom- rins,5.2%; ampicillin, 5.7%; gentamicin, 7.7%; and mendedthat if a womanhas a positivetuberculin methicillin,8.5%. Skin rash and renalimpairment skin-testresult or is exposedto tuberculosisduring werethe most commonclinical manifestations. Al- pregnancy(as indicatedby recenttuberculin skin- thoughthese data arenot directlyapplicable to ob- test conversion),she neednot be givenisoniazid un- stetricpatients, they serveto alertthe physicianto til after the pregnancyis terminated[67]. Others, the importanceof a carefulrisk-vs.-benefit consider- however,have suggested that chemoprophylaxis with ation with regardto each courseof therapyin the isoniazidmay be givenin late pregnancy,especially pregnantwoman. in areas with a high endemic incidenceof active Severalagents appear to pose a relativelyhigh risk tuberculosis[68]. For reasonsthat are not entirely of toxicityduring pregnancy and shouldbe avoided clear,the risk of activetuberculosis is greaterdur- or usedonly withgreat caution; these agents, which ing the postpartumperiod than duringpregnancy are listed in table 2, includeerythromycin estolate, [67]. tetracycline,and isoniazid. Erythromycin estolate has (2) Therapeuticefficacy. Apartfrom drug safety been reported to cause a higher incidence of andtolerability, pharmacokinetic characteristics and

Table 2. Potential risks posed by selected antimicrobial agents in pregnancy. Type of toxicity Use in Excretion pregnancy,agent Maternal Fetal in milk References Contraindicated Chloramphenicol Marrowaplasia Gray syndrome Yes [29, 38, 39] Tetracycline Hepatotoxicity Tooth discolorationand Yes [40-42] dysplasia Renal failure Inhibitionof bone growth Erythromycinestolate Hepatotoxicity None known Yes [16, 43, 44] Trimethoprim-sulfa- Vasculitis Folate antagonism;congenital Yes [16, 45, 46] methoxazole anomalies Used with caution Aminoglycosides Ototoxicityand Eighth-nervetoxicity Yes [47-49] nephrotoxicity Clindamycin Allergicreactions; pseudo- None known Trace [26, 50, 51] membranouscolitis Nitrofurantoin Neuropathy Hemolyis(G6PD* deficiency) Trace [52-54] Metronidazole Blood dyscrasia None known Yes [55-58] Sulfonamides Allergicreactions Kernicterus;hemolysis (G6PD Yes [30, 59, 60] deficiency) Isoniazid Hepatotoxicity Possibleneuropathy and Yes [61-63] seizures Consideredsafe Penicillins Allergicreactions None known Trace [9, 11, 17] Cephalosporins Allergicreactions None known Trace [27, 64, 65] Erythromycinbase Allergicreactions None known Yes [44, 50] * Glucose-6-phosphatedehydrogenase. AntimicrobialDrug Use in Pregnancy 293

the site and natureof infectionare criticalfactors eitherparent before conception may result in abnor- thatdetermine therapeutic options and ultimate out- mal embryonicdevelopment or intrauterinedeath come. For certaininfections (e.g., those of the uri- [32]. Duringthe first week after conception,prior narytract), the decreasein serumantibiotic concen- to the actual implantationof the fertilizedovum trationsattained during pregnancy may be of little withinthe uterus,potential teratogens probably do consequence,particularly if the site of infectionis exertan all-or-noneeffect; i.e., either the embryodies also the site of drug excretionand local drugcon- or its damagedcells are replaced by undifferentiated centrationsare adequate to producethe desiredther- cells that develop in an entirelynormal fashion. apeutic effect. In infectionsrequiring high serum Differentiationof the embryobegins at two weeks, concentrationsfor therapeuticefficacy (e.g., infec- and it is duringthis period that most major mor- tive endocarditis),much higher dosage schedules phologiccongenital abnormalities may be produced maybe requiredthan those recommendedfor non- [7, 70]. Drugexposure during the fetaldevelopment pregnant patients. Such instances require close periodin the secondand third trimesters is associated monitoringof serumdrug levels to assureadequate witha muchlower risk of majorbirth defects, since dosage and to avoid toxicity to the mother or the at this stagemost majororgan systems are already fetus [1]. well developedand aremuch less susceptibleto ter- Finally,the treatmentof infectionsaffecting both atogeniceffects [6, 7, 70, 71]. Althoughthe overall the motherand the fetusrequires special attention. incidence of major congenital malformationsis In these cases the optimal antimicrobialagent not rv2%-3%oand minordefects may be evidentin as only should cure the infection promptly in the manyas 9% of newborns[70], the contributionof motherbut also shouldbe capableof readilycross- drugexposure to thisproblem is probablyvery small. ing the placentaand achievingbactericidal levels in It is estimatedthat only 10%7of congenitalmalfor- fetaltissues. Such an agentmust be devoidof known mationsare attributable to environmentalcauses, in- teratogeniceffects, have a widemargin of safety,and cludingdrugs, while 25% are due to geneticor chro- possessthe capabilityto cure fetal infectionat any mosomalabnormalities. Fully 65% of all reported stage of gestation[1]. In the treatmentof syphilis, congenitaldefects have no knownidentifiable cause penicillincomes closest to meetingthese ideal criteria [70]. [69].In the treatmentof chorioamnionitis,however, The mechanismsby whicha drugexerts a terato- despiteexcellent maternal and fetal serumconcen- geniceffect arestill poorlyunderstood. Antimicro- trations,ampicillin may be unsatisfactorybecause bial agents may influence fetal developmentin- peaklevels in amnioticfluid remaininadequate un- directlyby their effects on maternaltissues, which til 4-6 hr after initiationof therapy[17]. In addi- includea reductionof the oxygen-carryingcapacity tion, the fetal lung inoculatedby infectedamniotic of blood, the inductionof hypo-or hyperglycemia, fluid would have suboptimalantibiotic concentra- a diminutionof vitaminavailability, or alterations tions becauseblood is shuntedaway from the lung in the supplyof hormones,amino acids, and trace by the fetal circulation.Therefore, antimicrobial elements[7, 72]. Theseagents may also exerta di- treatmentof chorioamnionitisaccompanied by in- rectembryotoxic effect in the intrauterineenviron- trauterinepneumonia is frequentlysuboptimal, and ment. Alternatively,antimicrobial agents may ad- early deliveryof the fetus is recommended[14]. verselyaffect the placentaby interferingwith the Fetalconsiderations. (1) Adverse effects. The ef- normal passage of oxygen, glucose, or other nu- fectsof exposureof the fetusto drugsseldom com- trients[72]. The placenta is an organof majormeta- prisean all-or-nonephenomenon; only rarely do spe- bolic significancesince it is capableof oxidation, cific agentsproduce specific birth defects. There are reduction,conjugation, and hydroxylationreactions five principalperiods of concernwith regardto the [6, 71]. Changesin placentalfunction are expected use of antimicrobialagents during pregnancy; (1) the to influenceadversely the dispositionof manydrugs preconceptionor preimplantationperiod; (2) the and the subsequentdevelopment of the fetus [72]. postimplantationor organogenesisperiod (first tri- (2) Therapeuticefficacy. Although many an- mester);(3) the fetaldevelopment period (second and timicrobialagents cross the placentaand reach mea- thirdtrimesters); (4) the labor and deliveryperiod; surableconcentrations in umbilicalserum or amniotic and (5) the puerperiumand breast-feedingperiod fluid, the administrationof antibioticsto the preg- [7]. Animal studiessuggest that drug treatmentof nant mothermay not be the best wayto treata fetal 294 Chowand Jewesson

Table 3. Therapeutic regimens for common bacterial infections during pregnancy. Reason for therapy First-choiceregimens Alternativeregimens Urinarytract infection Asymptomaticbacteriuria Ampicillin(0.5 g qid po) or cephalexin Nitrofurantoin(100 mg qid po) or sulfisoxazole (0.25-0.5 g qid po) for 7-10 days (0.5 g qid po) for 7-10 days Cystourethritis Ampicillin(0.5 g po) or cephalexin Nitrofurantoin(100 mg po) or sulfisoxazole (0.25-0.5 g po), single dose (2 g po), single dose Pyelonephritis Acute Ampicillin(2 g q6hr iv) or cefazolin Gentamicinor tobramycin(3-5 mg/kg daily (1-2 g q6hr iv) for 7-14 days iv in 3 divideddoses) for 7-14 days Chronic Nitrofurantoin(50-100 mg hs po) Sulfisoxazole(0.5 g bid po) for duration for durationof pregnancy of pregnancy Chlamydiatrachomatis infection Erythromycin(500 mg qid po) Sulfisoxazole(0.5 g qid po) for 10-14 days for 7-14 days Gonorrhea Probenecid(1 g po) plus APPG Spectinomycin(2 g im) or cefoxitin (4.8 MU im), ampicillin(3.5 g po), (2 g im) plus probenecid(1 g po) or amoxicillin(3 g po) Syphilis Primary,secondary, and latent <1 year'sduration Benzathinepenicillin G (2.4 MU im), Erythromycin(500 mg qid po) for 15 days single dose >1 year'sduration Benzathinepenicillin G (2.4 MU APPG (600,000IU im daily) for 15 days im weekly),3 doses (7.2 MU total) (9 MU total) or erythromycin(500 mg qid po) for 30 days Neurosyphilis Aqueouspenicillin G (12-30 MU . . . daily iv) for 10 days, followed by benzathinepenicillin G (2.4 MU im weekly),3 doses; or APPG (2.4 MU im) plus probenecid(500 mg qid po) for 10 days, followed by benzathinepenicillin G (2.4 MU im weekly),3 doses Prolongedmembrane rupture or Ampicillin(2 g iv q6hr iv) for Cefazolin(1 g iv q6hr) for 24-48 hr primarycesarean section 24-48 hr peripartum Chorioamnionitisor puerperal Ampicillinor cefoxitin(1.5-2 g Clindamycin(600 mg q8hr iv) plus gentamicin endometritis q8-6hr iv) for 7-14 days or tobramycin(3-5 mg/kg daily iv) for 7-14 days; moxalactamor cefotaxime (1.5-2 g q8-6hr iv) for 7-14 days Endocarditisprophylaxis for Aqueouspenicillin G (2 MU im or Vancomycin(1 g iv) plus streptomycin deliveryand genitourinary iv); or ampicillin(1 g im or iv) (1 g im ql2hr), 2 doses surgery plus eitherstreptomycin (1 g im ql2hr, 3 doses) or gentamicin (1.5 mg/kg im or iv q8hr, 3 doses), 30 min to 1 hr before procedure NOTE. Abbreviations:hs = at bedtime;APPG = aqueousprocaine penicillin G. infectionin utero [13].Theoretically, antimicrobial Earlydelivery and treatment of the neonateas a sep- drugsthat are intendedfor the fetus should havea aratepatient appears the best approachunder such high index of relativeexposure, which is the ratio circumstances.The efficacy of variousantimicrobial of the total areaunder the drugconcentration time regimensin the treatmentof intrauterinefetal infec- curvefor the fetus to that for the mother.Whereas tion requiresfurther study. high-dose penicillin therapy administeredto the Antimicrobialtherapyfor selected infections dur- motherappears highly effective against congenital ingpregnancy. Theinfections that occur frequently syphilisand neonatalgroup B streptococcalinfec- duringpregnancy and the antimicrobialregimens tion [14,29, 69], it is not veryeffective against fetal recommendedfor their treatment are listed in table3. pneumonia secondary to chorioamnionitis[14]. (1) Urinarytract infection. Urinarytract infec- AntimicrobialDrug Use in Pregnancy 295

tions arethe most commoninfectious complications is high [69]. Penicillinremains the most effective among pregnantwomen. Acute cystourethritisoc- agent for the preventionand treatmentof both cursin vlMoof pregnantwomen. Treatment is simi- maternaland congenital syphilis. Because an entirely lar to that of asymptomaticbacteriuria, which oc- satisfactoryalternative regimen is lacking, a full curs in 4%o-6%oof pregnantwomen but has been evaluationof the validityof a historyof penicillin reportedin as manyas 21%in some series [73]. If allergyis essentialbefore alternativeregimens are asymptomaticbacteriuria goes untreated, 20%-40% considered[69]. of infected pregnant women will develop pye- (5) Chorioamnionitisand puerperalendometri- lonephritis,a major complicationassociated with tis. Chorioamnionitisresults from ascending infec- a risk of bacteremiaas well as pretermlabor and tion by endogeneous,commensal vaginal organisms delivery[16]. Treatment is best providedin a hospi- throughthe cervix.Factors that favorthe develop- tal setting. Most instancesof acute pyelonephritis mentof chorioamnionitisand puerperalendometri- can be preventedby screeningfor bacteriuriadur- tis includeprolonged labor or ruptureof membranes ing earlypregnancy and againin the thirdtrimester and poor aseptic technique.Use of intrauterine and effective treatmentof any women with con- cathetersand fetal scalpelectrodes are otherpossi- firmedbacteriuria. Low-dose suppressive therapy for ble sourcesof infection.Fetal aspiraton or ingestion the durationof pregnancyis occasionallyrecom- of infectedamniotic fluid mayresult in severepneu- mendedafter treatmentof acuteinfection in order monitisand intrauterinedeath [74]. Both penicillins to reducethe rateof recurrentpyelonephritis, which andcephalosporins reach the fetusand the amniotic may be as high as 30%-40% [16]. fluidwhen large doses are administered parenterally (2) Chlamydiatrachomatis infection. The re- to the mother.Ampicillin and cefoxitinare consid- portedincidence of cervicalinfection with C. tracho- eredthe drugsof firstchoice because of theirbroad matis in pregnancyranges from 3%0to 25%7o.If un- spectrumof activityand lack of toxicity[74]. How- treated,maternal infection of the cervixmay result ever,if fetaldistress is presentand intrauterine pneu- in a high incidenceof verticaltransmission to the monitisis suspected,active steps should be takento neonate:conjunctivitis has beenreported in 50%of facilitatedelivery of the fetus as soon as possible. newbornswith infected mothers and pneumonitisin Thisdecision is importantbecause, even though high 10%-20% [16, 69]. Neonatal conjunctivitisas- concentrationsof ampicillin can be achieved in sociatedwith chlamydialinfection usually develops maternaland fetal serum, peak levels in amniotic fiveto 14days after delivery. A mild, mucopurulent fluid mayremain inadequate for 4-6 hr afterinitia- discharge typically resolves spontaneously after tion of therapy[17]. In addition,as has alreadybeen severalweeks to months,although persistent infec- mentioned,the fetallung inoculated by infectedam- tion may lead to trachomalikelesions. Chlamydial nioticfluid may have suboptimal antibiotic concen- neonatalpneumonitis generally manifests itself two trationsbecause blood is shuntedaway from the lung to threemonths after birth. Infants are afebrilebut by the fetal circulation[14]. tachypneicand often have a distinctivestaccato Endometritismay become established during la- cough [69]. bor or immediatelyin the postpartumperiod [74]. (3) Gonorrhea. The reportedincidence of gonor- The incidenceof infectionis 1%-4%after normal rheain pregnancyranges from 0.5% to 10%[16, 69]. labor [75].Infection is most commonafter assisted Sincethe majorityof cases areasymptomatic, rou- deliveryor trauma,especially after emergencyce- tine screeningfor gonorrheaat the initial prenatal sarean section. There is usually a mild fever as- visitand again in the thirdtrimester is recommended sociatedwith uterinetenderness and foul-smelling [16]. Positive cervical culturesat deliveryare as- lochia.Serious septicemia and pelvicperitonitis de- sociatedwith an increasein the incidenceof chori- velop occasionally. Initial antibacterialtherapy oamnionitis, prematurerupture of membranes, shouldbe with ampicillinor a cephalosporin.If re- pretermdelivery, and gonococcalophthalmia neo- tained placental tissue is suspectedor persistent natorum[69]. bleedingis noted,the uterinecavity must be explored (4) Syphilis. In someareas an increasedincidence and emptiedonce parenteralantimicrobial therapy of syphilishas been reportedin the past five years. has been administeredfor at least 6 hr [74]. If the infectionremains untreated during pregnancy, (6) Prematurerupture of membranesand primary the rateof perinatalmortality and congenital syphilis cesareansection. Sincethe rateof postpartumfe- Table 4. Pharmacokinetic and toxicologic characteristics of selected antimicrobial agents during pregnancy.

Percentage proteinprotein Degree of Fetal/maternal Pharmacokinetics* Potential toxicity bound placental serum level Excretion Group, agent (maternal) transfer ratio Maternal Fetal/neonatal in milk Maternal Fetal/neonatal

Penicillins [10, 14, 161 Variable [78] Moderate to high 0.1-0.7 [11] SSerum level; texcretion; Probably unchanged Absent or trace Allergic reactions Allergic reactions [11, 16] tVD; t?z [16, 24] [11, 79] [33, 80, 81] [82]; safe [82]; safe [9, 16] [35, 83] Benzathine G [11, 84] 50 ... 0.1-0.7 ...... 0.01-0.04 .. . . /g/ml Phenoxymethyl [33] 80 ...... 0.03-0.2. . . /gg/ml Oxacillin [85] 94 . . . Low tExcretion; tVD . . . Absent ... .. Dicloxacillin [86, 87] 98 . . . Low (0.1-0.3) . .. .. Absent .... Methicillin [9, 88] 37 High High (0.8-1.4) SSerum level . . . Trace .. Nafcillin [89] 90 ...... 68% protein bound Absent ... .. [79] Ampicillin [17, 90] 22 High High (0.3-0.9) . . . 10% protein bound 0.07 pg/ml WUrinaryestra- Diarrhea, [79] diol excretion candidiasis Carbenicillin [80] 50 ...... 0.3 /jg/ml Cephalosporins [10, 64] Variable [91] Moderate to high 0.2-1 [92] 1Serum level; texcretion; Probably unchanged Absent or trace Cross-hypersensi- Allergic reactions [64] tVD; St?z [9, 10, 16] [80, 81] tivity with pen- [82]; safe icillin [82]; safe Cephalothin [64, 93] 72 Moderate 0.1 SSerum level . . . Absent ... .. Cefazolin [27, 64] 80 Moderate 0.3 SSerum level; S?tz ... 1.5 gg/ml ... .. Cephradine [10, 94] 10 High 0.1-0.4 1Serum level; texcretion; ...... tVD; Itl/ Cephalexin [65] 12 Moderate . . . SSerum level . . . Absent ... .. Cefoxitin [95] 70 High 0.6 4Serum level . . . Absent Cefuroxime [10, 96] 33 High 0.3 iSerum level; texcretion; ...... Probably safe tVD; tl/i Moxalactam [92, 97] 40 High 0.4 St?2 [92] ...... Probably safe Cefotaxime [98] 37 High 0.2 ...... Probably safe Tetracyclines Variable High 0.5-0.7 [99] Probably unchanged Probably unchanged Low bioavail- Hepatotoxicity; Tooth discolora- [40, 41, 59, 99] (35-93) ability (che- pancreatitis; tion and dys- lated with renal failure plasia; inhibi- milk calcium) [40, 41] tion of bone [33, 35] growth [59, 81] Oxytetracycline [100] 35 High 0.5-0.7 ...... 2-3 Mg/ml As above As above Tetracycline [40, 41, 65 High 0.6 ... .. 0.5-3 pg/ml As above As above 99] (70% of serum level) (continued) Demethylchlortetra- 91 High 0.5-0.7 ...... 0.1-1.4 jg/ml As above As above cycline [101] (70% of serum level) ' Doxycycline [102] 93 ...... 0.4-0.8 jg/ml As above As above (30%-40% of serum level) Minocycline [103] 76 ...... 0.2-0.8 jg/ml As above As above Chloramphenicol [38, 50 High [104] 0.7-1.0 [104] Unchanged [104] $Hepatic conjuga- 1-3.5 jg/ml Bone marrow Bone marrow 39, 104] tion (50% present [33, 105] depression; depression; as inactive aplastic Gray syndrome metabolite) anemia [104] [38, 39, 106] Metronidazole [56-58, 20 High [107] High [58] Probably unchanged [56] Probably unchanged 1-7.7 pg/ml Blood dyscrasia; No known tera- 107, 108] (100% of neuropathy; togenicity in serum level) intolerance to humans but [33] alcohol [107] avoidance probably prudent [57] Erythromycin base and 70-75 Low [50] Low (0.02) $Serum level; labsorp- Low penetration 3-6 ig/ml Allergic reactions Safe estolate [43, 44, 50] [50] tion [50] [50] (50%-100% (base); chole- of serum static hepatitis level) [33] (estolate) [43, 82] Lincomycin and clinda- 90 Moderate [26, 50] 0.4-0.5 [26] Serum level unchanged; Unchanged [50] 2-4 jg/ml Allergic reactions; Safe [51, 109] mycin [26, 50, 51] ?tV2[50] (10%-20% diarrhea and of serum pseudomem- level) [33] branous colitis [51, 82] Sulfonamides 40-90 High 0.1-0.9 [45] Serum level unchanged; Unchanged 5-90 jg/ml Allergic reactions; Kernicterus; it/2 [79] [33, 80] crystalluria hemolysis [82] (G6PDt defi- ciency) [37, 59] Sulfisoxazole [110] 85 High . . . Serum level unchanged 65%-70% protein High (similar As above As above bound; tVD to serum level) Sulfamethoxazole 70 High 0.7-1.0 (1.5- Serum level unchanged; 57% protein bound; . . . As above As above [45, 111] 1.8 when ?tV2[79] tVD used with trimethoprim) Sulfamethoxydiazine 80 High ...... 57% protein bound; 10-27 jg/ml As above As above [112] tVD (10%-22% of serum level) [79]

(continued) Table 4 (continued).

Percentage protein Degree of Fetal/maternal Pharmacokinetics* Potential toxicity bound placental serum level Excretion Group, agent (maternal) transfer ratio Maternal Fetal/neonatal in milk Maternal Fetal/neonatal

Trimethoprim [45, 111, 44 High [45, 46] 0.7-0.8 Serum level unchanged; Serum level un- 1.8-5.5 jig/ml Allergic reactions Folate anta- 113] [45, 46] t?V[45, 111] changed; \tV2 [113] gonism; ker- [45, 79] nicterus; hemo- lysis (G6PD deficiency); potentially teratogenic [16, 33, 46] Nitrofurantoin [52-54] 60 High [52] >1.0 [52] &Serumlevel; texcretion tExcretion 0.5 tg/ml Neuropathy; Hemolysis [52] [80] hemolysis (G6PD (G6PD deficiency) deficiency) [54, 114] Nalidixic acid [115, 116] >93 Low . . . Probably unchanged tt?l [79] 4 Mg/ml Toxic psychosis Hemolysis [34] and convulsions (G6PD) deficiency) [115, 116] Methenamine mandelate . . . Probably low . . . Unknown Unknown Trace [33] Probably safe Probably safe [117] [117] [117] Aminoglycosides [48] 0-6 Low to moderate 0.2-0.5 [26] iSerum level; tVD; tVD; texcretion Trace (poorly Nephrotoxicity Eighth-nerve [25, 26, 118] texcretion [10, 26] [48] absorbed and ototoxicity toxicity; pos- from gastro- sible alteration intestinal of intestinal tract) [34, flora [48, 81] 109] Streptomycin [119, 120] 5 Moderate ...... As above As above Gentamicin [26, 118] 0 Moderate 0.4 ~Serum level ...... As above As above Tobramycin [121] 0 Moderate 0.5 i Serum level; t?2 ...... As above As above unchanged Kanamycin [25] 0-5 Moderate 0.3-0.5 ~Serum level; t/ . . . 2 jig/ml As above As above unchanged Amikacin [122] 2-6 Moderate 0.2 ISerum level; t ...... As above As above Spectinomycin [123, 124] "Weakly" ...... Serum level [124] Unknown . . . Probably safe Probably safe protein bound

Vancomycin [125, 126] 55 ...... Unknown Unknown . . . Ototoxicity and Unknown nephrotoxicity (continued) Antituberculous Drugs Isoniazid [67, 127] 0 Yes [59] High [16] Serum level unchanged Unchanged 6-12 pg/ml tHepatotoxicity Neuropathy and in rapid convulsion acetylators Ethambutol [128, 129] 40 Unknown . . . tExcretion Unknown Unknown Retrobulbar Probably safe ~ neuritis Rifampin [59, 61] 85 High [59] 0.3 Serum level unchanged Probably unchanged 1-3 Mg/ml [34] Hepatotoxicity; No known tera- hypoprothrom- togenicity in binemia and humans; bleeding probably safe ;' Antifungal drugs Amphotericin B 91-95 Yes [130] 0.3-1.0 Probably unchanged Unknown Unknown Hepatotoxicity; Reversible azo- 9 [130, 131] [131] hypokalemia; temia and hy- : anemia; idio- pokalemia; no syncratic known tera- reactions togenicity Flucytosine [132, 133] 4 Unknown . . . Probably unchanged Unknown Unknown Hepatotoxicity; Potentially marrow aplasia teratogenic Miconazole [134-136] >90 Unknown . . . Unknown Unknown Unknown Hyperlipidemia; Safety not hyponatremia, established and thrombo- cytosis Ketoconazole [134, 137] 99 Unknown . . . Unknown Unknown Unknown Hepatitis Safety not established Griseofulvin [138, 139] . . . Yes 0.5-1.0 iSerum level . . Unknown Allergic reactions; Teratogenic in hepatotoxicity mice; safety not established Antiviral drugs Amantadine [140, 141] . . . Unknown . . . Unknown Unknown Trace Anxiety, halluci- Teratogenic in nations, and animals; rare psychosis report of car- diovascular lesion Vidarabine [140] 20-30 Unknown . . . Unknown Unknown Unknown Neurotoxicity Teratogenic and with tremor carcinogenic in and hallucina- animal species tions; throm- bocytopenia and leukopenia Acyclovir [142-144] 9-22 [143] Unknown . . . Unknown tt/2 Unknown Nephrotoxicity No known tera- with de- togenicity but hydration safety not established

NOTE. Relevant reference numbers are listed inside brackets. Ellipsis points indicate either no published data or no information known to authors. , * Symbols and abbreviations: $ = decreased; t = increased; VD = volume of distribution; tV2 = half-life. t G6PD = glucose-6-phosphate dehydrogenase. 300 Chowand Jewesson

brile morbidityand endometritisis relativelyhigh This apparentlack of toxicityhas led to a moreex- among women experiencingpremature membrane tensivepharmacokinetic investigation of the penicil- ruptureor primarycesarean section (20%-40%), lins than of any other group of antibiotics. prophylacticantibiotics are often recommended All penicillin derivativesappear to cross the priorto deliveryand for 24-48 hr afterdelivery [74]. placenta.However, since these agentstend to have Althoughseveral prospective studies of prophylac- a low degreeof lipid solubilityand a high degreeof tic antibiotics in primary cesarean section have ionization, the administrationof large doses to a demonstratedthe efficacy of such managementin pregnantwomen is requiredif therapeuticlevels are reducingmaternal febrile morbidity and woundin- to be achievedin the fetus [17, 145].Penicillins with fection,considerable disagreement remains regard- a high levelof proteinbinding (e.g., oxacillin,clox- ing the optimal prophylacticregimen and the risk acillin,dicloxacillin, and nafcillin)reach lower lev- of unnecessaryexposure of the fetusto antimicrobial els in fetaltissues and amniotic fluid than do poorly agents.Some authors prefer withholding prophylaxis bound pencillins(e.g., ampicillinand methicillin). in primarycesarean section until after the cord is Fetaldrug concentrations are almost nil duringthe clamped[76]. The valueof prophylacticantibiotics first trimesterand arehighest near term. Amniotic in reducingperinatal morbidity and mortality is even fluidconcentrations may also varywith the stageof less certain. gestationand the timeelapsed since maternal inges- (7) Prophylaxisforbacterial endocarditis. Infec- tion. Levelsin maternalserum vary widely with the tive endocarditisis one of the most seriouspoten- dosage and are usuallylower than those in the se- tial complicationsof cardiacdisease in pregnancy. rum of nonpregnantpatients, as the rate of renal Prophylaxisis recommendedfor those situations that clearanceincreases throughout pregnancy [9, 10]. are likelyto be associatedwith bacteremia,such as Many penicillin derivativesare excretedin small dentalmanipulations, prolonged rupture of mem- amountsin breastmilk [33, 34, 80]. branes,operative delivery, manual removal of the Lessinformation is availableconcerning the safety placenta,and genitourinarytract surgery[16, 31]. of the cephalosporinsduring pregnancy,but the Womenwith congenital heart disease (other than un- pharmacokineticsof this class of agents is similar complicatedostium secundum atrial-septal defects), to that of the penicillins.Levels in maternalserum rheumaticvalvular heart disease, and acquiredval- arelower and eliminationhalf-lives shorter than in vularheart disease should be consideredcandidates nonpregnantpatients, while rates of renalclearance for prophylaxisprior to these procedures.In cases are higher [10, 64, 65, 92, 95, 96]. The safety of of mitralvalve prolapse, only womenwith a mitral second-and third-generation cephalosporins during regurgitationmurmur (and not those with isolated pregnancyhas not beenthoroughly examined. These clicks)require prophylaxis for infectiveendocardi- agentsare, however, expected to be as safe as their tis [77]. predecessors.

Specific Antimicrobial Agents in Pregnancy Tetracyclines,Chloramphenicol, and Metronidazole Currentinformation on the pharmacokineticand Tetracyclines.Oxytetracycline, demethylchlor- toxicologic characteristicsof many antimicrobial tetracycline,and tetracyclineall cross the placenta agentsduring pregnancy is summarizedin table 4. readilyand appearin cord blood [146].These anti- bioticsare specifically contraindicated during preg- nancybecause of adverseeffects on the motherand Penicillinsand Cephalosporins the fetus [14,29, 40, 47]. Pregnantwomen with un- Penicillinshave provento be the safest antibiotics derlyingrenal dysfunction or pyelonephritisappear for useduring pregnancy. Although allergic reactions to be particularlyat risk for developingacute fatty to any of the penicillins can occur in pregnant necrosisof the liverand renal failure when given large women,there are no otherknown contraindications intravenousdoses [40, 41]. Theseadverse reactions for the use of this groupof drugs [14, 29]. No ter- appearto be dose relatedand are associatedwith atogeniceffects were found in a majorstudy involv- high mortality[14, 29, 41]. Adverseeffects on the ing over 3,000 motherswho ingestedpenicillin de- fetus,particularly when a tetracyclineis administered rivativesduring the firsttrimester of pregnancy[2]. duringthe secondand third trimesters of pregnancy, AntimicrobialDrug Use in Pregnancy 301

include discolorationand severedysplasia of the ing 30%-150% of simultaneousmaternal levels teethand inhibition of bone growth[16, 28, 42, 47]. [104].Although chloramphenicol is secretedin breast Fetalreactions to tetracyclineare mediatedby two milk, the quantitiesare insufficient to induceGray mechanisms:interference with protein synthesis and syndrome. chelationwith calcium and other cationic substances. Metronidazole. Metronidazolereadily crosses Congenitallimb abnormalitiesand cataractshave the placenta[42]. Serumlevels of this drugduring also been observedin infants of mothersreceiving pregnancyare comparable to those in nonpregnant largedoses of the drugduring the first 12 weeksof women, and fetal serum concentrationsapproach pregnancy[29, 59]. Tetracyclineschelate calcium in maternallevels [42]. Although metronidazolehas a dose-dependentmanner and arefound in develop- been foundto be carcinogenicin rodentsand muta- ing long bones andteeth. These effects appear early genicfor certainbacteria [107, 147], there is no firm in the secondtrimester, when ossification centers be- evidencefor teratogenicityor an increasedrate of gin to develop,and inhibitionof bone growthcan congenitalbirth defects after administration to preg- continue six months into the postnatal period. nant women [55-58]. Nevertheless,most obstetri- Hypoplasiaof the deciduousand permanentteeth, cians refrainfrom using this drug duringthe first with brownor purplediscoloration, may occur up trimesterand, whenpossible, during the lasttrimes- to six to eight yearsof age if exposureis continued. ter and breast-feeding.Metronidazole may cause a The absorptionof tetracyclineby the infant via numberof adversereactions in pregnantwomen, in- ingestionof breastmilk is minimaldue to chelation cludingconvulsions, peripheral neuropathy, revers- withmilk calcium [35]. The riskof tooth discolora- ible neutropenia,and intoleranceto alcohol [107]. tion in this situationis consideredminimal [35]. However,these reactionswould not be expectedto Chloramphenicol.Chloramphenicol is generally occur more often than in nonpregnantpatients. reservedfor the treatmentof seriousinfections when alternative are not available.Its use agents during Macrolidesand Lincosamides pregnancyis usually avoidedbecause of potential blood dyscrasiasand aplastic anemia. The well- Macrolides. The macrolideantibiotics include describedcomplications of "Gray"syndrome have erythromycinbase and its varioussalts. Levelsof been reportedin prematureinfants given chloram- theseagents in maternalserum are lower than those phenicolpostnatally. Gray syndromeis character- in the serumof nonpregnantindividuals, probably izedby the rapiddevelopment of pallidcyanosis, ab- because of inconsistentabsorption from the gas- dominal distention,flaccidity, vomiting, irregular trointestinaltract during pregnancy [50]. Although respiration,hypothermia, and acute respiratory fail- erythromycincrosses the placenta, transplacental ure [29, 38, 39]. It is causedby a toxicaccumulation passageis unpredictable,and levels in fetal serum of chloramphenicol,particularly in the pretermin- as wellas in amnioticfluid are typically low [16,44]. fant, who lacks both the enzyme responsiblefor Erythromycinbase has been widely used during preg- glucuronylconjugation and the functionallymature nancy with no known deleteriouseffects to the renalsystem required for effectivetubular excretion motheror the fetus [29, 59]. Use of the estolatesalt, of the free drug [29, 106]. The serum half-life of however,is contraindicatedduring pregnancy [43]. chloramphenicolis markedlyprolonged in thesene- Erythromycinestolate has beenassociated with sub- onates.The mortalityassociated with this syndrome clinicalbut reversiblehepatotoxicity in 10%-15%of maybe as highas 40% [29].No characteristicpatho- womengiven the drugduring late pregnancy [29, 43]. logic featuresare noted postmortem. Although the- Hepatotoxicitytypically begins after 10 days of ther- oreticallya risk,the developmentof Graysyndrome apy but may occur with more rapidonset (two to following maternalingestion of chloramphenicol threedays) in patientswho had previouslyreceived duringthe thirdtrimester has not beendocumented. erythromycinestolate. Symptoms consist of nausea, All reportedcases have occurred in pretermneonates vomiting,and rightupper quadrant pain, followed given chloramphenicolafter delivery. by jaundice,fever, and liverdysfunction suggestive Serum levels of chloramphenicolin pregnant of cholestatichepatitis. This complicationappears womenare comparable to those in nonpregnantin- to be a hypersensitivityreaction, since it may rap- dividuals[104]. Transplacental passage of the drug idly recurif the drug is administeredagain. occursreadily, with fetal serum concentrations reach- Lincosamides. Thisgroup of antibioticsincludes 302 Chowand Jewesson

lincomycinand clindamycin. Since lincomycin offers TMP-SMZhas been reportedto cause congenital no therapeuticadvantages over its derivative,it has anomaliessuch as cleft palatesin rats [16, 46], al- now becomeobsolete and has been-replacedby clin- though no cases of human birth abnormalities damycin.Serum levels of clindamycinin pregnant relatedto maternalingestion have been recorded. womenare reportedto be similarto those in non- Sinceboth constituentsof TMP-SMZreadily cross pregnantpatients, although the serum half-life is the placentaand reachlevels in fetalserum and am- usuallyshorter during pregnancy [50]. Transplacental niotic fluid that approachthose in maternalserum passageof clindamycinoccurs rapidly, and adequate [45],the riskof kernicterusand hemolysisfrom rel- levelsare achieved in fetaltissues [50]. Clindamycin ativeG6PD and glutathionedeficiency in the fetus has become popular in the treatment of drug- theoretically exists [29]. TMP-SMZ may cause resistantanaerobic infections during the peripartal megaloblasticanemia during pregnancy as a result period,particularly intraamniotic and postpartum of antifolateeffects. This reaction can be prevented infections[16]. Although fetal toxicitydue to clin- by the concomitantadministration of folinic acid, damycinhas not beendocumented to date,the poten- which does not interferewith the antibacterialac- tially seriouscomplication of pseudomembranous tivity of TMP-SMZ[28]. colitis in the mother must be considered. Nitrofurantoin,nalidixic acid, and methenamine salts. Serum levels of nitrofurantoinhave been to decrease This Sulfonamides,Trimethoprim-Sulfamethoxazole, and reported duringpregnancy [9, 10]. agenthas also beenshown to crossthe and UrinaryAntiseptics placenta achievea high fetal-maternalserum concentration Sulfonamides. Sulfonamidesare commonly em- ratio[52]. Although the placentais readilybreached, ployedfor the treatmentof asymptomaticbacteri- therapeuticlevels are not maintainedin cordserum, uria and cystourethritisduring pregnancy. All sul- probablybecause of rapid renal excretion.Nitro- fonamidepreparations readily cross the placentaand furantoindoes not appearto reachsignificant con- enterboth the fetalcirculation and the amnioticfluid centrationsin the amnioticfluid, and its excretion [45,46, 59]. Passageinto the breastmilk also occurs in breastmilk is clinicallyinsignificant [59]. This [34, 37]. drugis frequentlychosen for the treatmentof uri- Directtoxic effects of sulfonamideson the fetus narytract infections in womenduring pregnancy; it arenot welldocumented. A theoreticrisk of hemol- appearsto be safe for both the motherand the fetus ysis from sulfonamidesexists because of a relative [53].There is a theoreticrisk of hemolysisin the fe- deficiency of fetal glucose-6-phosphatedehydro- tus andneonate, with relative G6PD deficiency [114]. genase (G6PD) and glutathione[37, 59]. Sulfona- Nalidixicacid crosses the placenta.It is highlypro- mides competewith bilirubinfor albumin-binding teinbound and is excretedin bothamniotic fluid and sites [30]. In the fetus this competitionis probably breastmilk [115,116]. The incidenceof adversereac- unimportant,as the placentais fullycapable of clear- tions to nalidixicacid is low, althoughthe drugoc- ing unconjugatedbilirubin [60]. Once the fetus is casionallycauses toxic psychosisand convulsions born, however,the protectionof the placentais no and shouldbe avoidedin patientswith seizuredis- longeravailable, and the presenceof long-actingsul- orders.This agent has been reportedto cause in- fonamides may predispose the infant to hyper- creasedintracranial pressure, papilledema, and bulg- bilirubinemiawith diffusion of free bilirubininto ing fontanellesin the newborninfant [148]. Nalidixic the centralnervous system, causing kernicterus [59]. acid shouldbe used with cautionduring pregnancy Therefore,long-acting sulfonamides, such as sul- and avoidedaltogether during the firsttrimester; its famethoxydiazine,should not be administereddur- use is not recommendedin nursingmothers and in- ing termpregnancy since levels may remain signifi- fants under three months of age. cant in the fetus for four to six daysafter maternal Methenaminemandelate is absorbedrapidly fol- ingestion [37, 59, 60]. lowingoral administration. Its distributionin mater- Trimethoprim-sulfamethoxazole. Trimetho- nal and fetal tissues and in amnioticfluid has not prim-sulfamethoxazole(TMP-SMZ) is best avoided beenwell studied. Nevertheless, it appearsto be safe during pregnancy,especially during the first and duringpregnancy and can be used as a urinaryan- thirdtrimesters. Folic acid antagonists are known ter- tisepticfor the treatmentof bacteriuria[149]. No in- atogens and wereformerly used as abortifacients. creasedrisk to the fetushas beenreported [73, 117]. AntimicrobialDrug Use in Pregnancy 303

Insignificantamounts of methenamineare excreted of spectinomycininto fetal tissues,amniotic fluid, in breastmilk [33]. or breastmilk has not beenadequately studied. Un- likethe aminoglycosides,spectinomycin does not ap- pearto be toxic in termsof cochlear,vestibular, or Aminoglycosides,Spectinomycin, and Vancomycin renalfunction. Availabledata do not suggestthat Aminoglycosides. The aminoglycosideantibiot- spectinomycinis teratogenicor poses uniquerisks ics are frequentlyused for the treatmentof serious to eithermother or fetus[123]. It is presentlythe drug infectionsduring pregnancy; these agentsare often of choice in pregnantwomen with uncomplicated combinedwith penicillins or clindamycinwhen used gonorrheawho areallergic to penicillinor whosein- againstpyelonephritis, septic abortion, or chorioam- fectionis causedby penicillinase-producingstrains nionitis. Limited pharmacokineticdata indicate of Neisseriagonorrhoeae [69, 123]. transplacentalpassage of all aminoglycosides[25, Vancomycin. Vancomycinis glycopolypeptide 26, 48, 59, 122].Serum concentrations of gentami- antibioticuseful for the treatmentof a varietyof se- cin, kanamycin,and amikacin are consistently lower rious infections, including endocarditis, shunt- in pregnantthan in nonpregnantpatients [25, 118, associatedor prostheticinfections, staphylococcal 122].Only a smallamount of activedrug is detected enterocolitis,and antibiotic-associatedpseudomem- in the amnioticfluid [14],although concentrations branouscolitis [125]. Although unrelated to the ami- in fetal serum may reach 30%-50% of those in noglycosides,vancomycin can also cause ototoxic- maternalserum [16, 118].Marked concentration of ity andnephrotoxicity. Studies in animals,including aminoglycosidein fetal renaltissue has been noted pregnantrabbits and cats, indicate that vancomycin [121]. Studies in animals and humans have not crossesthe placentaand penetratesinto fetalserum, demonstratedincreased teratogenicity with these amniotic fluid, and breast milk [126]. Data from agents [2, 150]. Ototoxicityhas been reportedin a studiesin humans,however, are lacking. The use of numberof neonateswhose mothersreceived strep- vancomycinduring pregnancy should be restricted tomycinand dihydrostreptomycinduring pregnancy to cases of life-threateninginfections for whichno for the treatmentof tuberculosis[48]. In spiteof the alternativeantibiotics are available. widespreaduse of theseagents, very few cases of neo- natal havebeen recorded following short- ototoxicity Antituberculous termmaternal administration during late pregnancy Drugs [47, 49]. With rareexceptions, however, only small Since the outcome of pregnancyamong women groups of patientshave been closely studied,and receivingantituberculous therapy with the first-line bothcochlear and vestibular toxicity are particularly agents (includingisoniazid, ethambutol,and rif- difficult to monitorduring early infancy [48]. ampin)does not differsignificantly from that among Althoughototoxicity related to short-termther- the generalpopulation, the use of these agentsdur- apyis infrequent,aminoglycosides should be avoided ing pregnancyis not contraindicated[61, 63]. Isonia- if at all possible during pregnancy.In situations zid appearsto be the safest and most effectiveof whereuse of aminoglycosidesis indicatedbecause the availableantituberculous agents and is relatively of severeinfection and lack of suitablealternatives, welltolerated during pregnancy. It readilycrosses the caution should be exercised,especially if preterm placentaand is excretedin breastmilk [16,59, 61]. deliveryis anticipated.Careful monitoring of mater- Isoniazidis potentiallyhepatotoxic; it has beensug- nal serum levels throughout therapy is strongly gestedthat this riskis increasedin rapidacetylators recommendednot only to minimizefetal exposure (e.g.,Orientals and Eskimos) and in pregnantwomen to excessivedrug levels but also to ensurethe op- [67].For this reason,unless active infection is pres- timal outcomeof treatmentthrough the avoidance ent, some authorshave recommendedthat isonia- of subtherapeuticlevels in the mother. zid prophylaxisfor recenttuberculin skin-test con- Spectinomycin. Spectinomycin is an aminocy- versionbe delayeduntil after delivery [67]. However, clitolantibiotic structurally and biochemically differ- otherauthorities have suggested that such treatment ent from the aminoglycosides.It is currentlyused may be given in late pregnancy,especially in areas exclusivelyfor the treatmentof gonorrhea[123]. The with a high endemicincidence of activetuberculo- drugis rapidlyabsorbed after intramuscularinjec- sis [68]. tion and is weaklyprotein bound. The penetration Ethambutolhas also been used extensivelydur- 304 Chowand Jewesson

ing pregnancy[61, 128].Although congenital anoma- teinsis negligible,and it penetratestissues well [133]. lies such as cleft palate have been reported in ex- Among the antifungalimidazoles, only micona- perimental animals, no increased risk of toxicity or zole and ketoconazoleappear to be useful against teratogenicity has been established in humans given systemicmycoses. Miconazole has thus far failedto this drug [63, 129]. Inadequate data are currently play a majorrole in antifungalchemotherapy, pri- available regarding the penetration of ethambutol marilybecause of its toxicity[134]. Its safetyduring into amniotic fluid, fetal tissues, or breast milk. pregnancyhas not beenestablished. When used top- Rifampin rapidlycrosses the placenta during term ically, miconazoleis absorbedfrom the vaginain pregnancy, and appreciable amounts of the drug traceamounts, and the benefits of its use in preg- reach the fetal blood and amniotic fluid [59]. Only nancyshould be carefullyweighed against the poten- trace amounts are detected in human breast milk tial risks [135,136]. Ketoconazole is the first of the [34]. The safety of rifampin in pregnancy is less well antifungalimidazoles to be well absorbedorally. It established than that of isoniazid [16, 63]. Available is effectiveagainst infections caused by diversefungi data neither refute nor confirm the suspicion of ter- (includingdermatophytes) and against mucocutane- atogenicity in humans. Limb reduction has been ous candidiasisand deep mycosis[134]. The phar- reported, but the incidence is not statistically differ- macokineticproperties of ketoconazoleare incom- ent from the expected background rate [61]. A the- pletelydefined. The drug is highly proteinbound oretic risk of hypoprothrombinemia and bleeding andextensively metabolized. It has surprisinglyfew during the perinatal period -resulting either from adverseeffects when administeredorally, although hepatic enzyme induction or from drug interactions both hepatitisand adrenalsuppression have been with rifampin- has been suggested [61] but requires reported[137]. The degreeto whichketoconazole is further investigation. absorbedby fetal tissues and amnioticfluid is un- The increased risk of ototoxicity in infants of known,and its safetyin pregnancyhas not beenes- mothers who receiveprolonged courses of streptomy- tablished. cin during pregnancy has been previously discussed Griseofulvinis an antimicrobialagent with limited (see section on aminoglycosides). Streptomycinis no fungicidalactivity that is usedprimarily for the treat- longer considered a first-line antituberculous agent. ment of dermatophyticinfections of the scalp and nails.It is inconsistentlyabsorbed from the gastroin- testinaltract and is extensivelymetabolized in the AntifungalDrugs liver.Griseofulvin crosses the placentapoorly and Little has been documented about the use of sys- is not detectedin amnioticfluid [138].It has been temic antifungal drugs during pregnancy.Ismail and foundto be embryotoxicand teratogenicwhen ad- Lerner [130] recently reviewed the published ex- ministeredto pregnantmice [139]and is not recom- perience with amphotericin B among 21 pregnant mendedfor use in human pregnancy. women. The adverse effects of amphotericin B, such as nephrotoxicity with azotemia and hypokalemia, AntiviralDrugs seem to be no worse in pregnant than in nonpreg- nant patients. No increase in the incidence of ter- In contrastto the remarkableprogress made in the atogenesis or of persistent toxic effects on the fetus treatmentof bacterialinfections in the past fourde- or the neonate was found. Amphotericin B crosses cades, only a few major advances in antiviral the placenta and reaches concentrations in fetal se- chemotherapyhave developed.These few include rum that are approximatelyone-third as high as those the use of amantadineand its derivativesfor the in maternal serum [130]; fetal serum levels may ap- prophylaxisand treatmentof influenza,the use of proach maternal levels near delivery [131]. Inade- vidarabineand acyclovirfor the treatmentof life- quate data exist regarding the penetration of this threateningherpes simplex and varicella-zosterin- agent into amniotic fluid [130]. fections,and the use of acyclovirfor the treatment Flucytosine is teratogenicin rats [132, 133] and for of genitalherpes simplex infection [140].Idoxuri- this reason is contraindicatedduring pregnancy.This dine and cytarabineare too toxic for systemicuse agent is water soluble and is absorbed intact from and are reservedprimarily for topical treatmentof the gastrointestinal tract. Its binding to plasma pro- herpeskeratitis. AntimicrobialDrug Use in Pregnancy 305

Amantadine is absorbed rapidly and completely of some of these infectionsduring pregnancy and after oral administration. It is not metabolized in the antiparasiticdrugs that should specificallybe humans, and 90% of the administered dose is ex- avoidedduring pregnancy are listed in table 5. creted unchanged in the urine. The drug is also ex- Antiprotozoal drugs. (1) Malaria. Since the creted in milk, but its other pharmacokinetic prop- contractionof malariaduring pregnancy represents erties during pregnancy in humans are unknown. a significantrisk to the fetus as well as the mother Because amantadine in large doses has been found [151],both treatmentand prophylaxis are clearly in- to be embryotoxic and teratogenic for certain labo- dicated.Chloroquine is generallysafe in pregnant ratory animals, its use in pregnant women should womenand poses little teratogenicrisk [152];thus, be avoided [140]. it is the drug of choice for chloroquine-sensitive Vidarabine is poorly water soluble, and large malaria acquiredduring pregnancy.Chloroquine volumes of fluids are required for intravenous ad- crossesthe placentaand accumulatesin fetalocular ministration by continuous infusion. This agent is tissue [157];it producescochleovestibular damage rapidly deaminated to arabinosylhypoxanthine, if administeredon a long-termbasis in largedoses which also has antiviral activity [140]. Vidarabine [153, 154].However, this drughas not been found is teratogenic in laboratory animals, and its use in to haveany harmfuleffect on the fetus when used pregnant women should be reserved for life- in the dosages recommendedfor malariaprophy- threatening herpes infections. laxis [152]. Acyclovir is only partially absorbed when ad- In relapsingmalaria due to Plasmodiumvivax or ministered orally. When infused intravenously, it is Plasmodium ovale, primaquineis recommended widely distributed in tissues and body fluids [142]. along with chloroquinein nonpregnantpatients. Acyclovir is primarily excreted by glomerular filtra- However,since fetal red blood cells are relatively tion and tubular secretion. Extensive studies have deficientin G6PD and glutathione,the fetus is at failed to demonstrate embryotoxicity or teratogen- increased risk for intravascularhemolysis and esis of acyclovir in laboratory animals [143]. methemoglobinemia[42]. Primaquine, therefore, is Nevertheless, its safety in pregnancy has not yet not recommendedduring pregnancy.Pregnant been established. As a general rule, systemic an- womenfor whom radicalcure or terminalprophy- tiviral agents should be avoided in pregnancy, par- laxiswith primaquine is otherwiseindicated should ticularly during the first trimester, except in the receiveonly chloroquineonce weeklyuntil delivery. presence of life-threatening infections in the Primaquinecan then be administeredafter delivery mother. Whether treatment with antiviral agents [152]. near term is safe for the fetus or can prevent dissem- Treatment and prophylaxis of choroquine- inated herpes simplex infection in the newborn re- resistantmalaria in pregnantwomen pose a special mains to be determined. dilemma,since a numberof antimalarialagents ef- fectivefor this purposeare contraindicatedduring pregnancy(table 5). Pyrimethamine,a folic acid AntiparasiticDrugs antagonist, is teratogenicin laboratoryanimals, With the current ease of global travel and the recent and its safetyin humanpregnancy has not been es- influx of immigrants from tropical into nontropical tablished[157]. This drugshould be avoided,espe- countries, the need to consider the use of various cially in the first trimesterof pregnancy[152]. In antiparasitic agents during pregnancy has become addition,the use of long-actingsulfonamides late much more imminent. Unfortunately, reliable data in pregnancymay be associatedwith neonatal jaun- addressing the toxic or teratogenic potential of dice and kernicterus.Therefore, women who are many of these agents in humans are not available. pregnantor are likely to become so should not Furthermore,the natural history and consequences travelto areaswhere the presenceof chloroquine- of parasitic infections in both the mother and the resistant malaria requires prophylaxis with fetus are not well understood. In this section only pyrimethamine-sulfadoxine.Pregnant women who therapy for the more common protozoal and hel- cannot avoid exposure to these malarial strains minthic infections in temperate climates will be shouldbe informedof the possiblerisks of fetalter- considered. The agents of choice for the treatment atogenicityand neonataljaundice before they take Table 5. Recommendations regarding the use of antiparasitic drugs during pregnancy. Potential toxicity Type of parasite, Recommendation on use infection, drug during pregnancy* Excretion in milk Maternal Fetal/neonatal Protozoal Malaria [151, 152] Chloroquine Prophylaxis: 300 mg of base po weekly; Minimal [33, 80] Ototoxicity [153, 154] None at recommended doses treatment: 600 mg of base po, then [152] 300 mg in 6 hr, then 300 mg daily for 2 days Quinine Life-threatening infections only: 650 <1 Ig/ml [81] Cinchonism; hemolysis; renal Optic nerve hypoplasia and mg of base po every 8 hr for failure [155] congenital deafness [32] 10-14 days Primaquine Contraindicated; delay treatment until Unknown Hemolysis [156] Hemolysis [156] after delivery Pyrimethamine-sulfadoxinet Contraindicated 3 pg/ml [33, 35] Allergic reactions [152] Potentially teratogenic; kernicterus [152, 157] Pyrimethamine-dapsonet Contraindicated Yes [33] Hemolysis; agranulocytosis Hemolysis and methemo- [156] globinemia [156] Toxoplasmosis [158] Spiramycin 2-4 g po daily for 3-4 weeks Unknown None [158] No known teratogenicity [159] Pyrimethamine-sulfadiazine Contraindicated High [33] Allergic reactions Potentially teratogenic; kernicterus [160] Amebiasis [161, 162] Symptomatic Metronidazole 750 mg po tid for 5-10 days, used High [81] Neuropathy; granulocyto- No known teratogenicity along with diiodohydroxyquin penia; alcohol intolerance in humans [57] Diiodohydroxyquin 650 mg po tid for 10 days, used along Unknown Iodine hypersensitivity [163] None known with metronidazole Emetine Contraindicated Unknown Cardiotoxicity [161] Fetal damage [161] Asymptomatic Diiodohydroxyquin 650 mg po tid for 20 days Unknown Iodine hypersensitivity [163] None known Diloxanide Contraindicated Unknown None Safety not established [161] Giardiasis [161] Metronidazole 250 mg po tid for 7 days Yes [81] Neuropathy; granulocyto- No known teratogenicity penia; alcohol intolerance in humans [57] Paromomycin 10 mg/kg po tid for 5-10 days Unknown None (not absorbed) None known [161] Quinacrine Contraindicated Unknown Hemolysis; toxic psychosis Safety not established [161] Furazolidone Contraindicated Unknown Agranulocytosis; hemolysis Potentially teratogenic [161] [163] ______[16 ]______o ? 0

Table 5 (continued). Potential toxicity c> Type of parasite, Recommendation on use Ptni t infection, drug during pregnancy* Excretion in milk Maternal Fetal/neonatal Trichomoniasis [56, 108] Metronidazole 1 g po bid for 2 doses or 250 mg Yes [81] Neuropathy; granulocyto- No known teratogenicity po tid for 7-10 days penia; alcohol intolerance in humans [57] Nematodal Ascariasis [160] Piperazine 4 g po, single dose Unknown Seizures [164] None reported Mebendazole Contraindicated; delay treatment until Unknown . . . Potentially teratogenic [165] after delivery Hookworm, enterobiasis, trichuriasis [160] Mebendazole Contraindicated; delay treatment until Unknown . . . Potentially teratogenic [165] after delivery Strongyloidiasis [164] Thiabendazole 25 mg/kg po bid for 2-5 days Unknown Allergic reactions; drowsi- Safety not established ness; nausea and vomiting [164] Cestodal Taenia solium, Taenia saginata, Diphyllobothrium latum [164] Niclosamide 2 g po, single dose Unknown None [164] Safety not established Mebendazole Contraindicated; delay treatment until Unknown . . . Potentially teratogenic [165] after delivery Cysticercosis [164] Praziquantel 5-10 mg/kg po, single dose Yes [141] None [141] Safety not established NOTE. Relevant reference numbers are listed inside brackets. Ellipsis points indicate either no published data or no information known to authors. t The trade name for this drug is Fansidar. t The trade name for this drug is Maloprim.

0> 308 Chowand Jewesson

this medication[152]. Since pyrimethamineis ex- anddiloxinide are contraindicated during pregnancy cretedin significantamounts in breast milk [35], becauseof potentialfetal danger. pyrimethamine-sulfadoxineshould also be avoided (3) Toxoplasmosis.Toxoplasmosis acquired dur- by mothers who breast-feedin the postpartum ing pregnancymay lead to spontaneousabortion, period. prematurebirth, stillbirth,and (most importantly) Dapsonein combinationwith pyrimethamine has congenitalmalformations [158]. The fetusis not af- been useful for the treatmentand prophylaxisof fectedby maternalinfection acquired prior to preg- chloroquine-resistantfalciparum malaria. However, nancy,as it is protectedby transplacentalpassage this sulfone induceshemolytic anemia and methe- of maternalantibodies [160]. Furthermore, women moglobinemia,and several cases of agranulocytosis givingbirth to an affectedchild are unlikely to have havebeen reportedin associationwith its use as an recurrentproblems in subsequent pregnancies. antimalarialagent [156].Like pyrimethamine-sul- Womenwho acquirethe diseaseduring pregnancy, fadoxine, pyrimethamine-dapsoneis not recom- especiallyduring the first five months, should be mendedfor use duringpregnancy. treatedto preventfetal and congenital complications. Both tetracyclineand quinineare contraindicated In nonpregnantpatients pyrimethamine plus sulfadi- in pregnancyunless they are requiredto treat life- azineis the preferredcombination. Because of pos- threateninginfections in the mother[152]. Quinine sibleteratogenic effects of pyrimethamineand poten- in largedoses wasat one time widelyused to induce tial toxic effects of sulfonamideson the fetus, abortion[70, 157].Hypoplasia of the opticnerve and however,this regimencannot be advocatedduring congenitaldeafness have both been reportedafter pregnancy[160]. Spiramycin, a macrolideantibiotic failureof attemptsto terminatepregnancy [70]. Qui- similarto erythromycin,is the drug of choice for ninehas also been reported to causemassive intravas- treatmentof toxoplasmosisduring pregnancy [159] cularhemolysis followed by acutetubular necrosis and is impressivein reducingthe overallfrequency and renal failureduring pregnancy [155]. of fetal infectionwhen administeredto the mother (2) Amebiasis. Experiencesin Africa and India [158].Spiramycin is absorbedincompletely and ir- suggestthat amebiasismay run a more fulminant regularlywhen administered orally. It doesnot cross courseand that latentinfections may be exacerbated the placentafreely [158] and is not knownto be ter- duringpregnancy [160]. Treatment of amebiasisdur- atogenic [159]. ing pregnancyis thereforegenerally warranted. Di- (4) Giardiasis. Infectioncaused by Giardialam- iodohydroxyquin,a luminalamebicide, is the agent blia is often asymptomatic.Few studies of giardia- of choice for asymptomaticinfection. Its main ad- sis duringpregnancy have been reported.Patients verseeffects include iodine hypersensitivity and gas- with symptomaticinfection should be givenmetro- trointestinalupset [163].Subacute myelo-optic neu- nidazole[160]. Quinacrine is not recommendedbe- ropathyhas beenreported with diiodohydroxyquin, cause it crossesthe placentaand becomesa poten- althoughonly when the drug was administeredin tial hazard to the fetus [164]. Furazolidone,a doses largerthan that recommendedfor amebiasis. nitrofuraneffective in the treatmentof giardiasis, This complicationis not as frequentwith diiodo- is also best avoidedduring pregnancy since it can hydroxyquinas with iodochlorhydroxyquin[163]. cause agranulocytosisand acutehemolysis in indi- Diloxanidefuroate is an alternativeluminal amebi- vidualswith G6PD deficiency[163]. Paromomycin, cide [163].Its safetyduring pregnancy has not been an aminoglycoside,is not systemicallyabsorbed from determined,and it should thereforebe avoidedin the gastrointestinaltract and is a useful alternative this situation [160]. agent for treatmentof symptomaticgiardiasis dur- Symptomaticamebic disease during pregnancy ing pregnancy. should be treatedwith metronidazoleplus diiodo- (5) Trichomoniasis. Trichomonasvaginalis is a hydroxyquin.The potentialteratogenicity and car- common protozoan found in the vagina of cinogenicityof metronidazolein rodentshas already 10%-25%of all women[160]. This flagellate is iden- been discussed.Although there is no firmevidence tifiedin ~5%oof infantsborn of untreated,infected of teratogenicityin humans,the use of metronida- mothersbut only rarelycauses symptomatic disease zole in pregnantwomen should be carefullyconsid- [160].In womenwith trichomonal vaginitis, metro- eredand if possibleavoided during the firstand last nidazoleis highlyeffective. The low riskof teratoge- trimestersor duringbreast-feeding. Both emetine nicityor carcinogenicityin humanssuggests that this AntimicrobialDrug Use in Pregnancy 309

drug can be administeredduring pregnancy when ter oraladministration, and no seriousadverse reac- therapyis clearlyindicated [56, 108].Treatment of tions have been reported [164]. Since tapeworm asymptomaticinfection, however, is not recommended. infectionsgenerally are not life-threatening,however, Anthelmintic drugs. (1) Nematodes (round- it is recommendedthat treatment of pregnantwomen worms). The rationaluse of anthelminticagents be postponeduntil after delivery.Cysticercosis due duringpregnancy requires an understandingof the to T solium larvaeis best treatedby surgicalresec- uniquehost-parasite relationship. First, in most hel- tion. Praziquantel,a newanticestodal drug, appears minthic infections, human morbidity is directly promising,particularly in neurocysticercosis.The proportionalto wormburden. Second, with rare ex- drugis absorbedrapidly, distributed throughout all ception,helminths do not multiplyin the humanhost tissues,metabolized completely, and excretedread- [165].Thus, roundworm infestations other than as- ily [141].It is not knownto haveany teratogenic, em- cariasisand strongyloidiasisare seldom significant bryotoxic,or mutageniceffects [141]. duringpregnancy, and treatmentis usuallyunwar- ranteduntil after delivery.For enterobiasis,trichu- Summaryand Conclusions riasis, and hookworminfections, the treatmentof choicefollowing delivery is mebendazole[165]. This In this reviewwe have examinedthe pharmacoki- agenthas broad-spectrumactivity against a variety neticand therapeuticimplications of antimicrobial of nematodes.Although it is poorlyabsorbed after therapyduring pregnancy. While the needto evalu- oraladministration, mebendazole is contraindicated ate criticallythe safetyand potentialteratogenicity duringpregnancy since it is teratogenicand embryo- of all therapeuticagents administered during preg- toxic when used in pregnantrats [165]. nancy has been emphasized,the informationcur- Ascaris lumbricoidesoccasionally causes severe rentlyavailable to assurethe optimalusage of these disease,particularly during larval migration to ex- drugsduring the antenatalperiod is sparse.Precise traintestinal sites. Treatmentduring pregnancy pharmacokineticdata, particularlyon the newer should be limitedto cases of heavy infestationor antifungal,antiviral, and antiparasiticagents, are symptomaticdisease [160]. The treatmentof choice lacking. While it is clear that all antimicrobial for intestinalinfection is piperazine;no harmfulef- agentsare potentially harmful to the fetusand that fectson the fetushave been reported following mater- their administrationduring pregnancymust be nal administrationof this drug [116,164]. limitedto specific indicationsin both the mother Strongyloidiasiscarries a seriouspotential risk and and the fetus,a greaterunderstanding of the nature shouldalways be treated,even when asymptomatic. and consequencesof various infectious processes If an infectionis not treated,cyclic autoinfection may duringpregnancy is needed.The potential risks and develop,allowing larvae to penetratethe colon or benefitsof antimicrobialtherapy must be assessed the perianalmucosa, migrate through the systemic individuallyon the basis of relevantclinical and circulation,and reenterthe intestine.Severe autoin- pharmacologicdata that areappropriate to the spe- fectioncan be fatal, especiallyin patientsreceiving cific clinicalsetting of both motherand fetus.Only corticosteroidsor other immunosuppressivedrugs. in this mannercan a moreeffective approach to an- Thiabendazoleis the treatmentof choice for stron- timicrobialtherapy be developedfor the pregnant gyloidiasis.It is well absorbedafter oral adminis- patient. tration,and most of the drugis metabolizedand ex- cretedin the urinewithin 24 hr [164].The safetyof thiabendazoleduring pregnancy and breast-feeding, References has not been established. however, 1. Schwarz Cestodes Cestodiasis RH, CrombleholmeWR. Antibiotics in preg- (2) (tapeworms). during nancy.South Med J 1979;72:1315-8 pregnancycauses no seriouscomplications; mater- 2. HeinonenOP, SloneD, ShapiroS. Antimicrobialand an- nal diseaseis of concernonly whencysticercosis de- tiparasiticagents. Birth defects and drugsin pregnancy. velops following infestation by Taenia solium. Littleton, Mass.: Publishing Sciences Group, 1977; Niclosamideis the for the treatment 296-313 preferredagent 3. Forfar Nelson MM. of infectionswith the andfish JO, Epidemiologyof drugstaken by beef,pork, tapeworms pregnantwomen: drugs that may affect the fetus ad- (i.e., Taenia saginata, T solium, and Diphyl- versely.Clin PharmacolTher 1973;14:632-42 lobothriumlatum). Niclosamide is not absorbedaf- 4. BodenforferTW, Briggs GG, Gunning JE. Obtainingdrug 310 Chowand Jewesson

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