ANTIBIÓTICOS Y EMBARAZO Antibiotic chemotherapy during pregnancy and lactation period aspects for consideration

Arch Gynecol Obstet (2011) 283:7–18
DOI 10.1007/s00404-010-1646-3
MATERNO-FETAL MEDICINE

Antibiotic chemotherapy during pregnancy and lactation period: aspects for consideration

Ioannis Mylonas

Received: 8 August 2010 / Accepted: 9 August 2010 / Published online: 3 September 2010© Springer-Verlag 2010

AbstractBackground Infections during gestation, delivery and thepostnatal period can jeopardise not only the mother, butalso the child. Along with chromosomal abnormalities andimmunological diseases, infection in early pregnancy repre-sents the most important reason for abortion. During thesecond and third trimester, infections are the principalcause for preterm labour, premature membrane rupture,premature delivery and the resultant complications in thenewborn child. Many pregnant women are very cautiousabout taking antibiotics due to primarily potentially detri-mental eVects on the unborn child. However, there are nocontraindications for antibiotic treatment during pregnancyin the event of a serious infectious disease of the mother.Materials and methods In this review the indications andcontraindications of the administration of antibiotics duringpregnancy are being reviewed.Results Penicillins are a Wrst-line antibiotic treatment dur-ing pregnancy, with the exception of cases in which there isa maternal allergy to penicillin. Cephalosporins are anotherWrst-line antibiotic used during pregnancy. In principle,more commonly used cephalosporins should be given pri-ority. Owing to associated nephrotoxicity and ototoxicity,aminoglycosides should not be prescribed at any time dur-ing pregnancy. Systematic use of aminoglycosides shouldbe considered solely in the event of life-threatening infec-tions with gram-negative pathogens and/or treatment failureof recommended antibiotics during pregnancy. The use of

metronidazole is also permitted during pregnancy, providedthe indications for its use have been strictly veriWed. Linco-samides should be used only if penicillins, cephalosporinsand erythromycin have failed to eradicate infection. Sulfon-amides, trimethoprim and cotrimoxazole are second-lineagents for the use during pregnancy. Tetracyclines shouldnot be administered to pregnant women after the Wfth weekof pregnancy, and are deemed contraindicated. As a precau-tionary measure, gyrase inhibitors are also contraindicatedfor pregnant women, children and young adolescents.Conclusion On the basis of our current state of knowl-edge, the vast majority of antibiotics do not cause seriousharm to the unborn child if used properly and at the appro-priate doses during pregnancy. The treatment with an anti-biotic that is contraindicated does not justify termination ofpregnancy. However, ultimately no medicine, includingantibiotics, can be described as absolutely safe.

Keywords Pregnancy · Antibiotics · Treatment · Contraindication · Adverse outcome

Introduction

Infections during gestation, delivery and the postnatalperiod can jeopardise not only the mother, but also the child[1–4]. Along with chromosomal abnormalities and immu-nological diseases, infection in early pregnancy representsthe most important reason for abortion [5]. During the sec-ond and third trimester, infections are the principal causefor preterm labour, premature membrane rupture, prema-ture delivery and the resultant complications in the new-born child [3, 5].

Many pregnant women are very cautious about takingantibiotics due to potentially detrimental eVects on the

I. Mylonas (&)Division of Infectious Diseases in Gynaecology and Obstetrics, 1st Department of Obstetrics and Gynaecology, Ludwig-Maximilians-University Munich, Maistrasse 11, 80337 Munich, Germanye-mail: [email protected]

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8 Arch Gynecol Obstet (2011) 283:7–18

unborn child. However, it is precisely for the protection ofthe child that antibiotics, particularly suYcient doses ofantibiotics, should not be withheld from the mother.Despite this, studies have shown that mothers are moreprone to take antibiotics when unaware of a pregnancywhen compared with during pregnancy [3, 5, 6].

In this review, the indications and contraindications ofthe administration of antibiotics during pregnancy are beingreviewed. Search strategy and selection criteria for identify-ing relevant data were by performed by searching Medline,Current Contents, Web of Science, Embase and referencesfrom relevant articles. English and German pharmacologi-cal, gynaecological and infectious diseases textbooks werealso reviewed. In addition, numerous articles were identi-Wed through searches of the extensive Wles of the author.Search terms were “pregnancy”, “antibiotic”, “anti-infec-tive drugs” “infection”, “infectious diseases”, “adversepregnancy outcome” and “foetal malformation”. Englishand German language manuscripts were reviewed.

Antibiotic therapy during pregnancy

The administration of antibiotics during pregnancy har-bours several concerns to physicians and patients about therisk of the foetus, since such a treatment should neitherjeopardise pregnancy nor causes harm to the unborn child.However, studies on the safety of antibiotic use duringpregnancy are based on case–control and cohort studies,since placebo-controlled randomised trials are considerednot ethical. Therefore, due to the existing trials, severalproblems on the risk assessment and interpretation exist,such as recall bias, adequate indication and statisticalpower. Moreover, the experience of thalidomide and itsintake during pregnancy with subsequent phokomelia inborn infants is still a matter of discussion and a negativeparadigm in medications used during pregnancy [7]. Inaddition, several reports have raised some concern on theuse of antibiotic treatment during pregnancy. For example,

erythromycin was associated with pyloric stenosis ininfants [8, 9] or even miscarriage after pivmecillinam use[10]. However, according to our current state of knowledgeand experience, the vast majority of antibiotics do not causeserious harm to the unborn child if used and dosed properly[11–15].

However, untreated infections might themselves harboura substantial risk and treatment might prevent adverse preg-nancy outcome. In general, there are no contraindicationsfor antibiotic treatment during pregnancy in the event of aserious infectious disease in the mother. However, there areseveral classes of antibiotics that are approved and recom-mended for the use during pregnancy (Table 1), approvedwith a restrictive use (Table 2) and contraindicated duringpregnancy and lactation period (Table 3) [4, 11–15]. In thelight of the importance of the beneWcial eVects of breast-feeding, the practice of weaning a child due to antibiotictherapy has largely been abandoned. In terms of obstetricoutcomes, early therapy is crucial for success. Knowledgeof the most important bacterial pathogens, frequent obstet-ric infections and the indications for antibiotic therapy dur-ing pregnancy will facilitate the selection of a suitableantibiotic and subsequent outpatient or inpatient treatmentregimen (Table 4).

Penicillins and cephalosporins

Currently, penicillins constitute the oldest group of eVec-tive antibiotics that are most widely used. Penicillinsbelong to the �-lactam class of antibiotics and act by spe-ciWcally hindering bacterial cell wall synthesis. Penicillinsand �-lactam inhibitors can cross the placental barrier andreach the foetus in quantities suYcient to be detected infoetal blood and amniotic Xuid [16]. At therapeutic doses,penicillins have practically no toxicity in humans [5, 16].Penicillins are eVective against gram-positive streptococ-cal, staphylococcal, enterococcal and meningococcalstrains, and are used primarily for the treatment of syphilis,

Table 1 Antibiotics approved for use during pregnancy [2, 4, 5, 11–16, 21]

Category Comments Recommendations


No indications of foetal impairmentGood placental permeabilityUnder certain circumstances, it may be necessary

to consider an increase in dosage to achieve the desired therapeutic eVect

Penicillins and cephalosporins are Wrst-line antibiotics during pregnancy

More established cephalosporins should be given priority

Macrolides No detrimental eVects on the fetus or the mother have been identiWed to date

More recent erythromycin derivatives such as azithromycin, clarithromycin and roxithromycin should be assessed with caution due to the lack of adequate clinical data

Macrolides may be used during pregnancy if mandated by the bacterial spectrum or in cases of penicillin allergy

Erythromycin estolate should not be administered during the second and third trimesters due to its hepatotoxicity

Spiramycin is the drug of choice for toxoplasmosis during the Wrst trimester

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Arch Gynecol Obstet (2011) 283:7–18 9

gonorrhoea and meningitis [16]. Aminopenicillins are alsoavailable in combination with a �-lactam inhibitor (clavu-lanic acid, sulbactam and tazobactam). To date, no malfor-mations or other undesirable eVects of penicillins have beenreported in studies of either animals or humans [17–20].

Side eVects associated with penicillin are relatively rare.They include immediate or delayed hypersensitivity reac-tions, particularly skin rashes (aVecting 5–10% of patients),fever and anaphylactic shock [5]. Gastrointestinal symp-toms or interstitial nephritis are occasionally reported.When compared with penicillin G, ampicillin causes moresevere side eVects, including nausea, vomiting and diar-rhoea [21]. Because of the lack of serious side eVects, peni-cillins are Wrst-line antibiotics for the use during pregnancy

[2, 4, 16, 17]. In fact, maternal allergy to penicillin repre-sents the only potential therapeutic problem with penicillins[16].

Cephalosporins also have a �-lactam ring structure. Allcephalosporins inhibit the biosynthesis of the bacterial cellwall, thus exerting bactericidal eVects [5, 16]. The pharma-cokinetic proWle of cephalosporins is similar to penicillins[5]. Cephalosporins are also capable of passing through theplacenta and can be detected in bactericidal concentrationsin the amniotic Xuid. Immune haemolytic reactions havebeen observed in patients treated with second- and third-generation cephalosporins, in particular cefotetan [22]. Inrare cases, mothers have experienced oversensitivity reac-tions, such as skin rash and anaphylactic shock. An increase

Table 2 Antibiotics approved for restricted use during pregnancy [2, 4, 5, 11–16, 21]


Aminoglycosides No teratogenic side eVects have been reported to dateThere is evidence of selective uptake of aminoglycosides

by the foetal kidney resulting in damage to immature nephrons

Although an impairment of the 8th cranial nerve has been proven only for streptomycin, this complication cannot be entirely ruled out for other aminoglycosides

All aminoglycosides must be considered potentially nephrotoxic and ototoxic

Prescriptions are restricted to vital indicationsGentamicin is currently considered the

safest choice due to extensive and comprehensive experience with this antibiotic

Therapeutic blood concentrations in the mother do not equate with safety for the foetus

Metronidazole Animal experiments suggest mutagenic and carcinogenic eVects, but no embryo-toxic/teratogenic eVects have been reported in humans

For trichomonas and anaerobic infections

Metronidazole may also be used during pregnancy for appropriate indications

For precautionary reasons, it is currently recommended not to use metronidazole during the Wrst trimester

This also applies to systematic therapy, especially as there are doubts about the eVectiveness of vaginal application

Clindamycin No detrimental eVects to the foetus are currently knownThis antibiotic should only be used speciWcally for

anaerobic infections due to potential maternal side eVects (diarrhoea, pseudomembranous colitis).

Clindamycin and lincomycin should only be used in the event that penicillins, cephalosporins and macrolides are ineVective, i.e. for infections with Bacteroides fragilis and other anaerobic bacteria

Routine prescription of clindamycin after dental procedures is not approved

The use of clindamycin or lincomycin is not a suYcient reason for either a termination of pregnancy or additional diagnostics

Sulfonamides, trimethoprim and cotrimoxazole

If administered shortly before birth, a component of this group of antibiotics (sulfamethoxazole) can cause kernicterus due to the displacement of bilirubin in the newborn

Owing to the mode of action of these antibiotics, damage during the Wrst months of pregnancy cannot be ruled out

Teratogenic eVects have been observed in animal experimentsNo toxic eVects to the embryo or foetus have been

identiWed for trimethoprim to date

Sulfonamides, trimethoprim and cotrimoxazole are second-line antibiotics throughout the pregnancy period

Vancomycin and teicoplanin

No detrimental eVects on the foetus have been identiWed to date

Use only for strictly deWned indications

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in transaminase levels, thrombophlebitis at the injectionsite, haemolysis and bone marrow disorders can also occur[21]. Based on the available data, including the results of aprospective study of cefuroxime use during the Wrst trimes-ter [23], cephalosporin at therapeutic doses is not terato-genic [24]. The results of another study have indicated thatchildren of mothers who received cefuroxime during preg-nancy exhibited normal physical and mental development[25]. Increased clearance of cephalosporins during preg-nancy has been reported; thus, it may be necessary tochange the doses or dosing intervals [16, 26]. Along withpenicillins, cephalosporins are Wrst-line antibiotics for theuse during pregnancy and more commonly used cephalo-sporins should be given priority.

Macrolides

Macrolides are bacteriostatic antibiotics that inhibit proteinbiosynthesis via reversible binding to the bacterial 50Sribosomal subunit. Because of their size, lower levels ofmacrolides are able to reach the foetus [5, 16]. The antibac-terial spectrum of macrolides includes predominantlygram-positive cocci, but also chlamydia, mycoplasma andlegionella, campylobacter as well as coxiella, bartonella,corynebacteria and several mycobacterium species. Macro-lides are suitable alternatives for patients who are allergicto penicillin [2, 4].

Erythromycin is a member of the macrolide group and isdeemed highly safe for the use during pregnancy. In rarecases, temporary impairment of hearing may occur. Othermacrolides include roxithromycin, clarithromycin andazithromycin. These agents are characterised primarily byimproved bioavailability and tolerance, fewer side eVects

(e.g. gastrointestinal side eVects) and an extended antibac-terial spectrum [21]. The activity spectra of these macrolideantibiotics, are similar to erythromycin, but for the mostpart, these agents have fewer gastrointestinal side eVects.To date, there is no evidence that erythromycin [27] orazithromycin, clarithromycin [28, 29], josamycin, roxithro-mycin and spiramycin [30] are teratogenic. However, arecent study based on the data from the Swedish MedicalBirth Registry reported a slightly signiWcant increase in therate of malformations in 1,844 children exposed to macro-lides during early pregnancy when compared with childrenwho were exposed to phenoxymethylpenicillin [31].

In France, toxoplasmosis is treated with spiramycinthroughout pregnancy (from the earliest point of diagnosisuntil delivery). To date, there have been no indications thatthis practice is associated with malformations of newborns.Clarithromycin should be used with caution because it hasbeen shown to have teratogenic eVects in animals and toinduce cardiovascular defects in rats [5, 32].

There have been several reports of liver toxicity inmothers [33] who were treated with erythromycin estolateduring the second half of pregnancy. Cholestatic icteruswas reported in some patients during the second week oftreatment [5, 16]. The condition improved within a fewweeks of withdrawal of the medication without complica-tions or any signs of harm to the foetus.

In conclusion, erythromycin is a safe Wrst-line antibioticfor the use during pregnancy [4, 5, 16]. Caution is advisedsolely for erythromycin estolate due to its potentialhepatotoxicity during pregnancy. More recent erythromy-cin derivatives, such as azithromycin, clarithromycin androxithromycin should be used with caution due to the rela-tive lack of experience with these drugs [5]. Spiramycin isindicated for toxoplasmosis during the Wrst trimester.

Table 3 Contraindicated antibiotics during pregnancy [2, 4, 5, 11–16, 21]


Tetracyclines Tetracyclines can disturb the development of teeth and bones

A link between the use of tetracyclines and lethal liver damage in mothers cannot be ruled out

Contraindicated starting from the 16th week of pregnancy until the age of seven due to tooth discoloration

All tetracyclines are contraindicated after the 16th week of pregnancy

Prior to the 16th week, they are considered second-line antibiotics

Accidental administration of tetracycline after the 16th week of pregnancy does not justify termination of pregnancy

No additional prenatal diagnostic measures are necessary, especially for doxycycline

Chinolones Causes severe cartilage damage in animals Gyrase inhibitors must be avoided during pregnancyIn well-founded cases, it is possible to use gyrase

inhibitors that have been tested on a large number of pregnant patients (e.g. norXoxacin or ciproXoxacin)

Rifampicin and streptomycin

Not permitted for the treatment of tuberculosis during the Wrst 3 months of pregnancy

Spiramycin is the drug of choice for the treatment of toxoplasmosis during the early stages of pregnancy

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Lincosamines

Lincosomide antibiotics, such as lincomycin and clindamy-cin are similar to macrolides in their spectrum of activityand mechanism of action [5]. In addition to a high level ofeYcacy against gram-positive bacteria [with the exceptionof methicillin-resistant Staphylococcus aureus (MRSA)],clindamycin is active against all anaerobic bacteria, as wellas actinomycetes and nocardia. Cross-resistance to clinda-

mycin and erythromycin is in the range of approximately20% [16].

There are no known teratogenic eVects of this group ofantibiotics in humans [5]. Resorption after oral administra-tion is almost complete and clindamycin can be used duringany trimester. Another advantage of clindamycin is itsspeciWc pharmacokinetic proWle, which includes not onlyplacental permeability, which is important for treatingmaternal–foetal infections, but also accumulation in granu-

Table 4 Frequently occurring diseases and their causes during pregnancy and lactation [1–3]

Disease Bacterial causes Primary treatment options

Endometritis postpartum Chlamydia trachomatisGonococci

Penicillins

Colpitis Streptococci (Group A)Staphylococcus aureusTrichomonas

Penicillins and cephalosporinsMetronidazole (trichomoniasis)

Mastitis Staphylococcus aureus

Puerperal sepsis Streptococci (Group A) Penicillins

Vulvitis Streptococci (Group A)Staphylococcus aureus


Wound infection Staphylococcus aureusStreptococci (Group A)EnterobacteriaAnaerobic bacteriaChlamydia trachomatis (perihepatitis)

Antibiotic prophylaxis for caesarean section

CephalosporinsAmpicillin/amoxicillin

Cervicitis GonococciChlamydia trachomatis

MacrolidesAmoxicillin

Cystitis and pyelonephritis Mostly Escherichia coli (»80%)Proteus mirabilis (10–15%)Other enterobacteriaStaphylococcus saprophyticus

(young and sexual active women)Rarely Pseudomonas spp. and

Staphylococcus aureus

Penicillins and cephalosporins are suYcient in most cases

Premature rupture of membranes (PROM)

Many bacteria Ampicillin/amoxicillinMacrolides

Prevention of premature birth Many bacteria Ampicillin/amoxicillinCephalosporinsMacrolides

Asymptomatic vaginal streptococci infection

Streptococci (Group B) PenicillinsMacrolides

Trichomoniasis Trichomonas vaginalis MetronidazoleTinidazole after the 20th

week of pregnancy

Chorioamnionitis Many bacteria Ampicillin/amoxicillinCephalosporins

Listeriosis Listeria monocytogenes Ampicillin/amoxicillin

Lues Treponema pallidum Penicillins

Pneumonia Streptococcus pneumoniae (¡30%)Haemophilus inXuenzae (¡5%)Staphylococcus aureus (¡5%)Mycoplasma pneumoniae (¡10%)Chlamydia pneumoniaeKlebsiella pneumoniae

Penicillins and cephalosporins are suYcient in most cases

Toxoplasmosis—primary infection

Toxoplasma gondii Spiramycin up to the 15th week of pregnancyAfterwards sulfonamides and pyrimethamine

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locytes (e.g. abscess pus). One potential risk that isobserved in 2–10% of all cases is the occurrence of pseudo-membranous colitis after several weeks of treatment, aswell as upon vaginal application [34]. Pregnancy complica-tions as a consequence of bacterial vaginosis cannot besuYciently prevented or treated via vaginal clindamycintherapy [35].

Aminoglycosides

Aminoglycosides have a narrow spectrum of activity, tar-geting gram-negative bacteria. They are bactericidal, andact by inhibiting protein synthesis. This group of antibiot-ics, includes amikacin, gentamicin, kanamycin, neomycin,netilmicin, paromomycin, spectinomycin, streptomycin andtobramycin [4].

Prenatal streptomycin or kanamycin injections are asso-ciated with impaired hearing of exposed children, with aparticularly sensitive phase up to approximately the fourthmonth of pregnancy [16, 32]. Thus, aminoglycosidesshould generally not be administered during the Wrst4 months of pregnancy due to potential ototoxicity andnephrotoxicity. Although the risk of damage to the eighthcranial nerve has only been described for isolated cases offoetal exposure to kanamycin and streptomycin [5], thiscomplication cannot be entirely ruled out for other amino-glycosides. A retrospective case–controlled study failed toestablish an increased rate of malformations after oral neo-mycin and parenteral gentamycin treatment [36].

In summary, aminoglycosides and in particular kanamy-cin and streptomycin, should not be administered parenter-ally during pregnancy due to potential ototoxicityassociated with these agents [4, 5, 16]. Aminoglycosidesshould be used systematically solely for life-threateninginfections with gram-negative pathogens when treatmentwith Wrst-line antibiotics fails to achieve the desired eVect.Serum concentrations must be monitored regularly for theduration of therapy. Overall, the risks associated with thetreatment with aminoglycosides do not justify terminationof pregnancy. Depending on the extent of parenteral ther-apy, the hearing ability of the child must be veriWed earlyduring the postpartum period [16].

Metronidazole and derivates

Metronidazole and other nitroimidazoles (e.g. ornidazole)act by inhibiting DNA synthesis, thus they are bactericidalin nature. This group of antibiotics targets anaerobic bacte-ria, including bacteroides fragilis and protozoans (amoebasand lamblia). These agents are used primarily in combina-tion with other antibiotics (e.g. aminoglycosides, amino- or

acylureidopenicillin and clindamycin). Metronidazole has awide therapeutic spectrum. The preferred route of adminis-tration is oral or local application for the treatment of trich-omonas or anaerobic infections. Several groups haverecommended metronidazole for the prevention of prema-ture birth due to bacterial vaginosis [35]. Some of the sideeVects to be considered include gastrointestinal disordersand more rarely, changes in blood count and allergies, aswell as central nervous system disorders, which aVect pre-dominantly alcoholics and patients with medication with-drawal symptoms [37].

Following oral and intravenous administration, theconcentration of metronidazole in the developing embryofrequently reaches higher levels than in the mother [5]. Rel-evant quantities also reach the foetus upon vaginal applica-tion. The results of animal studies have raised somequestion about the potential mutagenic and carcinogeniceVects of metronidazole, but these have not been conWrmedin humans [16, 38]. The results of a retrospective study ofmetronidazole during pregnancy showed an associationbetween prenatal exposure to metronidazole and childhoodneuroblastoma, but this association was not statistically sig-niWcant [39]. Another study conducted over a period ofmore than 20 years yielded no indication of an increasedrisk of malignancy after metronidazole administration [40].Based on the results of analysis of over 3,000 pregnancies,it appears that metronidazole is not teratogenic in humans[16, 38, 41, 42]. Although there is insuYcient data to makeconclusive statements about nimorazole, ornidazole andtinidazole, which are used for the oral treatment of tricho-monas, amoeba and bacterial vaginosis, there are no indica-tions to date that these agents are teratogenic [16, 32].

In summary, the use of metronidazole during pregnancyis permitted only if the indications for use have been strictlyveriWed. Trichomonas infection should be treated with asingle oral dose of 2 g [5]. Parenteral administration isadvisable only for dangerous anaerobic infections. Pro-tracted vaginal application should be avoided, as it is notconsidered suYciently eVective and may also lead to pro-longed exposure of the foetus [5]. Metronidazole should beused over nimorazole and tinidazole. Termination of preg-nancy or further diagnostics is not indicated.

Sulfonamides and cotrimoxazole

Sulfonamides are synthetic, bacteriostatic, broad-spectrumantibiotics that are amongst the oldest anti-infective drugs.Today, sulfadiazin and sulfalen are oVered as single-agenttherapies; however, the importance of sulfonamides for thetreatment of bacterial infections has diminished signiWcantlyover the past several years. This is due in part to the factthat many microorganisms have developed resistance to

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sulfonamides, and because bactericidal penicillins andcephalosporins are more eVective and have no associatedtoxicity in the developing embryo or foetus [5, 21]. Sulfon-amides are eVective against most gram-positive and manygram-negative bacteria. However, several gram-negativebacteria have developed resistance to sulfonamides and thisclass of antibiotics is used only in very speciWc cases, i.e.urinary tract infections, treatment of meningococcal strainsand as a preventative against rheumatic fever. Side eVects,such as gastrointestinal disorders and oversensitivity mayoccur [21].

To date, there is no evidence that sulfonamides, trimeth-oprim and combined preparations have teratogenic poten-tial in humans [5, 6, 16, 43]. A study of the CollaborativePerinatal Project [44] looked at data from 1,455 childrenborn to mothers who were treated with sulfonamides duringthe Wrst trimester. Data from an additional 5,689 childrenwhose mothers received sulfonamide at various times dur-ing pregnancy were also analysed. No reliable associationbetween sulfonamide treatment and foetal malformationswas established in either of these settings; thus, sulfona-mides should be considered non-teratogenic, and termina-tion of pregnancy after sulfonamide intake during gestationis not supported [4, 16]. Nonetheless, potential toxicity toembryos remains to be a topic of discussion, because folicacid antagonists have been shown to have teratogeniceVects in animal experiments. However, human folic acidreductase is much less sensitive to trimethoprim than thebacterial homologues [5]. The increased risk of kernicterusin newborns associated with sulfonamide therapy is alsofrequently addressed, since unfavourable eVects on biliru-bin concentration in newborns due to sulfonamide treat-ment up to delivery cannot be completely ruled out. Despitethe possibility, the risk of kernicterus should be consideredlow [1, 5].

Sulfasalazine, a combination of the sulfonamide sulfa-pyridine and 5-aminosalicylic acid, is often prescribed dur-ing pregnancy. It is a proven remedy for chronicinXammatory bowel diseases, such as morbus crohn andcolitis ulcerosa [1]. 5-aminosalicylic acid (also known asmesalazine) is also used alone as an antiphlogistic. Toxo-plasmosis [45, 46], nocardiosis and pneumocystis cariniipneumonia are other important indications for sulfonamidetreatment during pregnancy.

In summary, sulfonamide, trimethoprim and cotrimoxaz-ole are second-line agents for the use throughout pregnancy[5]. When there is a relevant indication, for example, uri-nary tract infection, treatment with cotrimoxazol is sup-ported, even during the Wrst trimester. For patients withacquired immunodeWciency syndrome (AIDS) who need toundergo high-dose antibiotic therapy for pneumocystiscarinii pneumonia during the Wrst trimester, folic acid sup-plements should be incorporated into treatment, due to the-

oretical considerations [16]. If there is a risk of pretermdelivery, sulfonamides should be avoided due to concernsabout the bilirubin concentration of the newborn.

Glycopeptides

Glycopeptide antibiotics inhibit the synthesis of peptido-glycans involved in stabilizing the bacterial cell wall. Theirspectrum of the activity includes all gram-positive patho-gens, with problematic pathogens frequently being suscep-tible as well. The two currently available representatives ofthis class of antibiotic, vancomycin and teicoplanin, areused predominantly for infections with MRSA and entero-coccal infections [5, 16, 21]. Glycopeptides should alwaysbe regarded as a reserve antibiotic and used accordinglyduring the pregnancy [5]. Limited data on the side eVectproWle (including nephrotoxicity and neurotoxicity) andteratogenic potential of glycopeptides supports the cautioususe of these agents during pregnancy.

Tetracyclines

Tetracyclines inhibit protein synthesis through inhibition ofthe bacterial ribosome; hence, they are bacteriostatic. Tetra-cyclines are a broad-spectrum class of antibiotics [1, 16]used for the treatment of acne, pelvic infections, urinarytract infections, bronchitis and borreliosis [1, 21].

During the 1950s, tetracyclines were some of the morecommonly used antibiotics. At the time, numerous publica-tions reported a yellowing of the teeth of children who wereexposed prenatally to tetracyclines, a side eVect that standsas the only proven pre-birth side eVect of this class of anti-biotics in humans. Tetracyclines cross the placental barrierand can accumulate in developing long tubular bones andteeth [5, 6, 16, 21]. This can lead to tooth discoloration,ranging from yellow to dark brown. In addition, there havebeen reports of tooth enamel defects, increased susceptibil-ity to dental caries, growth inhibition of the long tubularbones, particularly the Wbula after long-term treatment andpremature birth, as well as cataracts due to the accumula-tion of the antibiotic in eye lenses [5, 6, 16]. There havealso been several reports of additional maternal risks, suchas fatty liver and nephropathies following tetracycline treat-ment during pregnancy [47, 48]. Several reports have docu-mented severe and sometimes even fatal tetracycline-conditioned liver damage in the mother [33].

Owing to the reported risks associated with tetracyclinetreatment during pregnancy, this class of antibiotics mustnever be administered to pregnant women after the Wfthweek of pregnancy [4, 5, 11]. That being said, terminationof pregnancy due to treatment with tetracyclines is not

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supported, given that an increased risk of malformations ofthe child has not been deWnitively proven [5]. One case–controlled study reported an increased rate of malforma-tions after administration of oxytetracycline during the sec-ond month of pregnancy [49]. These results, however, haveyet to be veriWed in other settings by other investigators.Young women who are being treated with extended tetracy-cline therapy for acne are particularly at risk, and shoulduse reliable contraception methods [5].

Chinolones (gyrase inhibitors)

Chinolones (4-chinolones) are gyrase antagonists that actby inhibiting bacterial topoisomerase (gyrase), which isessential for nucleic acid metabolism. Human topoisomer-ase is not aVected by therapeutic gyrase inhibitors. To avoidthe build-up of resistance, this group of agents should beused exclusively for enterobacterial infections, includinginfection by Pseudomonas that cannot be treated with clas-sical antibiotics [16].

When administered to young experimental animals (bea-gle dogs), chinolones caused arthropathy, the pathogenesisof which remains unclear. Doses that substantially exceedthe therapeutic range can result in abortion, retardation andreduced ossiWcation in experimental animal models [50].No such teratogenic eVects are associated with typical ther-apeutic doses. In humans, irreversible joint cartilage defectshave not been detected among prepartally exposed children[51]. A study from the European Network of TeratologyInformation Services examining data on over 700 exposedpregnant women did not identify any notable risk of mal-formation associated with chinolones [16, 52]. Similarresults were obtained in two other studies that examined asmaller number of patients [53, 54].

The data notwithstanding, administration of gyraseinhibitors to pregnant women, children and young adoles-cents is deemed contraindicated as a precautionary measure[5, 11, 16]. In well-founded and life-threatening cases,where other common antibiotics are ineVective, it is advis-able to use only norXoxacin or ciproXoxacin, which havebeen tested in a large number of pregnant patients [16]. Theintake of gyrase antagonists does not justify either a risk-based pregnancy termination or invasive diagnostics [5].

Tuberculostatics

Tuberculostatics are agents that are used selectively for thetreatment of tuberculosis. This class of antibiotics includesisoniazid, pyrazinamide, ethambutol, rifampicin and strep-tomycin, with isoniazid and ethambutol being consideredthe safest for use during pregnancy [4, 5, 16, 55]. Rifampi-

cin, a partially synthetic reserve antibiotic that is bacterici-dal and acts by inhibiting bacterial RNA synthesis, iscontraindicated in patients with liver disease and those thatare breast feeding. Indications for the use during pregnancymust be strictly deWned. Since treatment with these antibi-otics stimulates liver activity, weakening of the eVects of anumber of other drugs (including �-blockers, cyclosporin,glucocorticoids and phenytoin) must be considered.

Novel antibiotics—linezolid, daptomycin, tigecycline, doripenem

Linezolid is eVective in vitro against multi-resistant gram-positive bacteria (especially MRSA and glycopeptide-resis-tant enterococci). It is suitable for targeted therapy of infec-tions caused by methicillin-resistant or glycopeptide-gram-positive cocci and is also an alternative for the treatment ofnocardiosis and listeriosis. As there are still insuYcient dataregarding administration during pregnancy, this antibioticis not recommended during pregnancy.

Daptomycin is a cyclic lipopeptide, which is only eVectiveagainst gram-positive bacteria. In contrast to the glycopep-tides, daptomycin is bactericidal and shows a synergism invitro with aminoglycosides and rifampicin. As there are stillinsuYcient data regarding administration during pregnancy,this antibiotic is not recommended during pregnancy.

Tigecycline is a derivative of minocycline, a tetracycline.It is eVective against gram-positive and gram-negativepathogens, even against those that are resistant to tetracy-cline. Tigecycline has bacteriostatic properties and showsno activity against Pseudomonas, Serratia, Proteus andMorganella. There are still insuYcient data regarding preg-nancy. However, this antibiotic, like other tetracyclins, iscontraindicated during pregnancy.

Doripenem is a new carbapenem with greater stabilityagainst renal dehydropeptidasen. The spectrum of activitysimilar to that of imipenem and meropenem, and is eVectiveagainst Pseudomonas unlike other carbapenems. As there arestill insuYcient data regarding administration during preg-nancy, this antibiotic is not recommended during pregnancy.

Practical points

When there are compelling reasons for the prescription ofantibiotics to a pregnant patient, the following consider-ations should be taken into consideration [2, 4, 5]:

• No medication should be prescribed without a compel-ling indication (adequate risk/beneWt assessment).

• During the selection of an antibiotic, it is important tochoose the drug with the best proven tolerance.

123


Table 5 Overview of antibiotic and their approved usage during pregnancy and lactation period [2, 4, 5, 11–15]

Pregnancy Lactation period

Crossing placental barrier

FDA ADEC German classiWcation

DiVusion breast milk

German classiWcation

Amikacin + C/D D CI + CI

Amoxicillin ++ B A AM + SI

Amoxicillin/clavulanic acid ? B B1 AM + SI

Ampicillin +++ B A AM + SI

Ampicillin/sulbactam ? B - SI + SI

Azithromycin + B B1 SI + SI

Aztreonam + B B1 CI + CI

Benzylpenicillin +++ B A AM + SI

Cefaclor ? B B1 SI + SI

Cefadroxil +++ B ¡ SI + SI

Cefalexin +++ B ¡ SI + SI

Cefazolin +++ B B1 SI + SI

Cefepim ++ B ¡ SI + SI

CeWxim +++ B ¡ SI + SI

Cefotaxim + B B1 SI + SI

Cefotiam ? ¡ ¡ SI + SI

Cefoxitin +++ B B1 SI + SI

Cefpodoxim–proxetil ? B B1 SI + SI

Ceftazidim ++ B B1 SI + SI

Ceftibuten ? B ¡ SI + SI

Ceftriaxon + B B1 SI + SI

Cefuroxime ? B ¡ SI + SI

Cefuroximaxetil + B ¡ SI + SI

Chloramphenicol +++ C A CI + CI

CiproXoxacin +++ C B3 CI ? CI

Clarithromycin ? C B3 SI + SI

Clindamycin ++ B A CI + CI

Cotrimoxazole +++ C C SI + SI

Doxycycline ++ D D CI + CI

Ertapenem ? B ¡ SI + CI

Erythromycin ? B A SI + SI

Ethambutol +++ B A SI + SI

Flucloxacillin ++ B B1 AM + SI

Fosfomycin ++ B ¡ SI + SI

Gentamicin ++ C D CI + CI

Imipenem/cilastatin +++ C B3 CI ? CI

Isoniazid +++ B/C A SI ? SI

Josamycin ? ¡ ¡ SI ++ SI

LevoXoxacin +++ C B3 CI + CI

Linezolid ? C ¡ CI SI

Loracarbef + B ¡ SI + SI

Meropenem ? B B2 SI + SI

Metronidazole +++ B B2 CI/SI + CI/SI

Mezlocillin +++ B B1 AM + SI

Minocycline ? D D CI + CI

123


• Groups of antibiotics that have been on the market for along time and for which there are adequate empiricaldata should be given priority.

• Priority should be given to antibiotics that are not associ-ated with risks to the mother or foetus (i.e. those with no

or minimal potential toxic side eVects) based on the latestscientiWc knowledge.

• Treatment should be monitored and doses adjusted asneeded.

• Monotherapy is preferable to combination therapy.

Table 5 continued

+ denotes minor crossing of the placental barrier/diVusion into breast milk

++ denotes moderate crossing of the placental barrier/diVusion into breast milk

+++ denotes distinct crossing of the placental barrier/diVusion into breast milk

? denotes unknown

FDA classiWcation [Food and Drug Administration (FDA); http://www.fda.gov]: A controlled human studies show no foetal risks; these drugs arethe safest, B animal studies show no risk to the foetus and no controlled human studies have been conducted, or animal studies show a risk to thefoetus but well-controlled human studies do not, C no adequate animal or human studies have been conducted, or adverse foetal eVects have beenshown in animals but no human data are available, D evidence of human foetal risk exists, but beneWts may outweigh risks in certain situations(e.g., life-threatening disorders, serious disorders for which safer drugs cannot be used or are ineVective), X proven foetal risks outweigh any pos-sible beneWt

ADEC classiWcation (Australian Drug Evaluation Committee; http://www.tga.gov.au/docs/html/adec/adec.htm): Category A drugs which havebeen taken by a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformationsor other direct or indirect harmful eVects on the foetus having been observed, Category B1 drugs which have been taken by only a limited numberof pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful eVectson the human foetus having been observed, Studies in animals have not shown evidence of an increased occurrence of foetal damage, CategoryB2 drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequencyof malformation or other direct or indirect harmful eVects on the human foetus having been observed. Studies in animals are inadequate or may belacking, but available data show no evidence of an increased occurrence of foetal damage, Category B3 drugs which have been taken by only alimited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirectharmful eVects on the human foetus having been observed. Studies in animals have shown evidence of an increased occurrence of foetal damage,the signiWcance of which is considered uncertain in humans, Category C drugs which, owing to their pharmacological eVects, have caused or maybe suspected of causing, harmful eVects on the human foetus or neonate without causing malformations. These eVects may be reversible. Accom-panying texts should be consulted for further details, Category D drugs which have caused and are suspected to have caused or may be expectedto cause, an increased incidence of human foetal malformations or irreversible damage. These drugs may also have adverse pharmacologicaleVects. Accompanying texts should be consulted for further details, Category X drugs which have such a high risk of causing permanent damageto the foetus that they should not be used in pregnancy or when there is a possibility of pregnancy

German classiWcation (,,Rote Liste”;http://www.rote-liste.de): SI strict indication, CI contraindication, AM approved medication

Pregnancy Lactation period

Crossing placental barrier

FDA ADEC German classiWcation

DiVusion breast milk

German classiWcation

MoxiXoxacin ? C ¡ CI + CI

Netilmicin + C/D D CI ? CI

NorXoxacin ? C B3 CI ? CI

OXoxacin ? C B3 CI ?

Oxacillin + B B3 AM + SI

Phenoxymethylpenicillin ? B A AM + SI

Piperacillin + B B1 AM + SI

Piperacillin/tazobactam ? B B1 SI ? SI

Pyrazinamide ? C B2 SI + SI

Quinupristin/dalfopristin ? B ¡ SI ? CI

Rifabutin ? C C SI ? SI

Rifampicin ++ B/C C CI + SI

Roxithromycin ? B B1 SI + SI

Teicoplanin ? C B3 CI ? CI

Telithromycin ? ¡ ¡ CI ? CI

Tobramycin +++ C/D D CI + CI

Trimethoprim +++ C B3 CI + CI

Vancomycin +++ C B2 SI + SI

123

http://www.fda.gov

http://www.tga.gov.au/docs/html/adec/adec.htm

http://www.rote-liste.de


• Whenever possible, oral therapy should be given priorityover infusion therapy.

• Placental permeability and elimination of the antibioticshould be taken into consideration (Table 5).

According to our current state of knowledge, the vastmajority of antibiotics do not cause serious harm to theunborn child if used and dosed properly. Even in cases inwhich a contraindicated antibiotic has been administered,the risks do not justify termination of the pregnancy. Thatbeing said, no medicine, including antibiotics, can bedescribed as absolutely safe during pregnancy [4, 5, 16].

Acknowledgments The author would like to thank Prof. Dr. E.-R.Weissenbacher and Prof. Dr. K. Friese for their helpful discussionregarding antibiotic treatment during pregnancy and lactation period.The author does not have any Wnancial, personal, political, intellectualor religious interests in publishing this article.

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