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Anti-infective Agents
Infections may be hazardous to the health of the mother, the course of pregnancy, and the unborn child. They can lead to premature labor or premature rupture of membranes and thereby increase the risk for spontaneous abortion and prematurity. Furthermore, certain germs can pass to the unborn child and harm it directly. Therefore, an anti-infective treatment which should be both effective and safe for the mother and the unborn child is often required. The use of penicillins and older cephalosporins is well documented and considered to be safe. Consequently, they are the drug of choice during pregnancy. In selected cases of bacterial resistance or intolerance to first-line antibiotics, other anti-infective agents might be recommended. Especially for life-threatening infections, a therapy with not so well-tried agents might be needed. The potential benefit of treatment in such cases most often outbalances the potential risk for the unborn child.
2.6.1
Penicillins and β-lactamase inhibitors
Penicillins belong to the β-lactam antibiotics. They inhibit cell-wall synthesis in bacteria and have bactericidal properties. The group of penicillins includes amoxicillin , ampicillin , azidocillin , bacampicillin , benzylpenicillin ( penicillin G ), carbenicillin , cloxacillin , dicloxacillin , flucloxacillin , mezlocillin , oxacillin , phenoxymethylpenicillin ( penicillin V ), piperacillin , pivmecillinam , propicillin , and ticarcillin .
Penicillins cross the placenta and can be detected in the amniotic fluid. In thousands of studied pregnancies over the past decades, no indications were seen to show that treatment with penicillins is embryo- or fetotoxic (e.g. , , , ). Nevertheless, a few studies have discussed an association with cleft palate and maternal use of amoxicillin or ampicillin ( , ). discussed an absolute cleft risk of 2–4 per 1,000, a quite modest increase compared to the background risk. could not find an increased risk for oral clefts after intrauterine amoxicillin exposure; but they saw an increased risk for cleft palate after pivmecillinam exposure in the third month. In one investigation of more than 2,000 pregnant women exposed to pivmecillinam – more than 500 of them in the first trimester – found neither an increased malformation rate nor other abnormalities in the newborns ( ). Pregnant women who are treated with penicillin for syphilis may develop the Jarisch-Herxheimer reaction – a febrile reaction, often with headache and myalgia. Fetal monitoring is recommended in such cases, as uterine contractions may occur ( ). The carboxypenicillins carbenicillin and ticarcillin also did not show any adverse effects in animal experiments, but experience in humans is very limited.
Clavulanic acid , sulbactam , and tazobactam are β-lactamase inhibitors that are prescribed in combination with a penicillin. Fixed combinations are for example, clavulanic acid plus ampicillin, sulbactam plus ampicillin and tazobactam plus piperacillin. Sultamicillin is an orally available prodrug of ampicillin and sulbactam that is rapidly cleaved in the body into both components. So far as studied, β-lactamase inhibitors cross the placenta and reach the fetus in relevant quantities. Malformations have not been observed in animal experiments or in humans ( , ).
In a large, randomized multicenter trial, the prenatal use of ampicillin and clavulanic acid was associated with a significant increase in the occurrence of neonatal necrotizing enterocolitis ( ); other studies could not confirm this concern ( ).
The clearance of penicillin and β-lactamase inhibitors is increased during pregnancy, leading to a discussion that it might be necessary to adjust dose and administration intervals during pregnancy ( ). failed to observe any relevant differences in the pharmacokinetics when studying 17 women who received amoxicillin for premature rupture of membranes.
Recommendation
Penicillins belong to the antibiotics of choice during pregnancy. Where bacterial resistance studies are indicated, penicillins may be combined with clavulinic acid, sulbactam, or tazobactam.
2.6.2
Cephalosporins
Like penicillins, cephalosporins belong to the β-lactam antibiotics. They inhibit the cell wall synthesis of bacteria and have a bactericidal effect. Cephalosporins are classified according to their antimicrobial activity.
Cephalosporins of the first generation include cefadroxil , cefazolin , cephalexin , cephalotin , and cephradine . To the second generation belong cefaclor , cefamandole , cefdinir , cefditoren , cefmetazole , cefotetan , cefotiam , cefoxitin , cefprozil , cefuroxime , and the carbacephem loracarbef that is related to the cephalosporins. The third generation contains cefdinir , cefditoren , cefixim , cefoperazone , cefotaxime , cefpodoxim , ceftazidime , ceftibuten , ceftizoxime , and ceftriaxone . Cefepime and cefpirome are fourth generation cephalosporins. The new cephalosporins ceftaroline and ceftobiprole have been assigned to the fifth generation, and are indicated for severe infections with methicillin-resistant staphylococci (MRSA) and other multi-resistant germs.
Cephalosporins cross the placenta and are detectable in the amniotic fluid at bactericidal concentrations. Elimination in pregnant women is faster, and it may be necessary to adjust dosage ( ). According to observations so far, e.g. about cefuroxim during the first trimester ( ), cephalosporins do not cause teratogenic problems at therapeutic doses ( ). Normal physical and mental development has been confirmed in children up to the age of 18 months, where mothers had been treated with cefuroxim during pregnancy ( ).
Recommendation
Like penicillins, cephalosporins belong to the antibiotics of choice during pregnancy. Whenever possible, well established cephalosporins should be used preferentially, e.g., cefaclor, cefalexin, and cefuroxim.
2.6.3
Carbapenems and monobactams
Like all β-lactam antibiotics, carbapenems and monobactams inhibit bacterial cell wall synthesis and thus are bactericidal. Generally, they are well tolerated and act as broad-spectrum antibiotics. The carbapenems include doripenem , ertapenem , meropenem , and imipenem . Imipenem can only be obtained in combination with cilastin which itself has no antimicrobic activity. Cilastin specifically inhibits the enzyme dehydropeptidase-1 and blocks the rapid degradation of imipenem. Aztreonam is the first monobactam available for clinical applications.
As far as is known, both carbapenems and monobactams cross the placenta and reach the fetus in relevant quantities ( ). Animal studies and human experience do not show malformations or other undesirable effects; however, systematic investigations have not been conducted. Specifically, there are hardly any experiences in pregnancy with the newer carbapenems – doripenem and ertapenem.
Recommendation
Aztreonam, imipenem, and meropenem may be used when resistance testing indicates that they are needed. Doripenem and ertapenem should only be used in pregnancy when no alternatives are available.
2.6.4
Erythromycin and other macrolides
Pharmacology
Erythromycin and other macrolides inhibit bacterial protein synthesis and are bacteriostatic. Macrolides are primarily applied in the treatment of infections with Gram-positive germs, but are also effective against Haemophilus influenzae and intracellular pathogens such as chlamydia. Macrolides offer an alternative for patients with penicillin allergy.
Erythromycin is the oldest medication of this group. Its resorption can be delayed in the third trimester. Gastrointestinal side effects can lead to lower than therapeutic plasma concentrations, resulting in treatment failure ( ). Only 5–20% of the maternal erythromycin concentration is obtained in the fetus. Therefore, erythromycin is not a sufficiently reliable drug for fetal or amniotic infections.
The newer macrolide antibiotics azithromycin , clarithromycin , dirithromycin , josamycin , midecamycin , roxithromycin and troleandomycin have a similar antibacterial spectrum as erythromycin, but to some degree less gastrointestinal side effects. Spiramycin is used for toxoplasmosis in the first trimester.
Telithromycin is the first ketolide antibiotic for clinical use. It is structurally related to erythromycin.
Toxicology
Erythromycin has always been considered a safe and effective antibiotic during pregnancy. Data on several thousand first trimester exposures do not support an association between erythromycin and congenital malformations (e.g. ). However, an analysis of the data from the Swedish Birth Registry showed a weakly significant increase in malformations in 1,844 children whose mothers took erythromycin in early pregnancy compared to offspring whose mothers used phenoxymethylpenicillin ( ). This was based on an increased rate of cardiovascular malformations, especially ventricular and atrial septal defects. An update of the Swedish data verified an association between the use of erythromycin during early pregnancy and cardiovascular defects ( ). An increased incidence of pyloric stenosis was discussed by the same author ( ). This observation after intrauterine exposure in the first trimester is biologically not plausible; but it should be mentioned that a link has been suggested between a neonatal treatment with erythromycin during the first two weeks and the development of pylorus stenosis (e.g. ). Other studies have failed to find a higher rate of septum defects, pyloric stenosis or other malformations ( , , , , , ). In summary, the experiences argue against an increased embryo- and fetotoxic risk for erythromycin.
There are several reports of maternal hepatotoxic changes when erythromycin estolate was administered in the second half of pregnancy. These women developed a cholestatic icterus during the second week of treatment that abated within weeks when the treatment was discontinued, without evidence of permanent damage or signs of fetal compromise (e.g. ).
Azithromycin , clarithromycin and roxithromycin have also been studied in several publications without any indication of embryo- or fetotoxic effects ( , , , , , ). In the case of clarithromycin, there was some initial concern as animal experiments demonstrated teratogenic effects, and for instance, in some studies cardiovascular defects were induced in rats. Recently a Danish cohort study based on a prescription register observed an increased risk of miscarriage after clarithromycin in early pregnancy, but no increased risk for major malformations ( ).
Experience with dirithromycin , josamycin , midecamycin , spiramycin , and troleandomycin is very limited ( ). Spiramycin has been used in many first trimesters for the treatment of toxoplamosis. Although these reports did not focus on a possible teratogenic effect, numerous normal births after spiramycin exposure are reassuring.
There is no published experience with the use of the ketolide telithromycin in the first trimester. The animal experiments did not show that this agent is teratogenic.
A local treatment with macrolides is quite safe for the fetus. Yet, because resistance develops quickly and allergies are frequent, macrolides should be used with some reservation.
Recommendation
Erythromycin, clarithromycin, azithromycin, and roxithromycin may be used in pregnancy when the resistance spectrum requires them, or in cases of an allergy to penicillin. Because of hepatotoxicity, erythomycin estolate should not be given during the second and third trimester. Spiramycin is the treatment of choice for toxoplasmosis in the first trimester. Telithromycin and other makrolides should only be given during pregnancy when no alternatives are available.
2.6.5
Clindamycin and lincomycin
Clindamycin and lincomycin belong to the lincosamide group. They inhibit bacterial protein synthesis and can be bactericidal or bacteriostatic depending on concentration and sensitivity. After an oral dose the resorption is almost complete. About half of the maternal concentration can be attained in the umbilical veins. There were no signs of embryo- or fetotoxic effects in several hundred pregnant women treated with lincomycin at different points in pregnancy ( , ). There were also no problems found for clindamycin. Pseudomembranous enterocolitis is a dangerous maternal complication of clindamycin treatment that may also happen after vaginal application.
Pregnancy complications due to bacterial vaginosis are not sufficiently preventable by vaginal clindamycin therapy ( ). It should be noted though, that other investigators found a reduction in late abortions and prematurity when treating several hundred patients with oral clindamycin for an abnormal vaginal flora ( ).
Recommendation
Clindamycin and lincomycin should only be used when penicillins, cephalosporins and macrolides have failed. Clindamycin should not be routinely used after dental procedures.
2.6.6
Tetracyclines
Pharmacology
The bacteriostatic effect of tetracyclines is based on an inhibition of the bacterial protein synthesis. These broad-spectrum antibiotics, especially tetracycline itself, form stable chelates with calcium ions. The standard agent today is doxycycline . Minocycline is especially lipophilic and displays a somewhat wider antibacterial spectrum than doxycycline. The older derivatives such as oxytetracycline and tetracycline are now rarely used as they are poorly resorbed.
Chlortetracycline , demeclocycline , and meclocycline are only used as local agents.
Tigecycline is a minocycline derivative that belongs to the glycylcyclines; it has a very broad-spectrum and is especially effective against multi-resistant pathogens such as MRSA.
Toxicology
Tetracyclines cross the placenta. According to current knowledge an increased risk of malformation is not expected when tetracyclines are used ( , ). The results of a population-based case-control study suggested that oxytetracycline was associated with an increased incidence of congenital malformations ( ). However, the number of cases in this study was small, and there are no other studies confirming this suspicion. A Danish cohort study found an association between oral clefts and maternal tetracycline exposure in the second month, but this result was based on only two exposed cases ( ).
From the sixteenth week of pregnancy when fetal mineralization takes place, tetracyclines can bind to calcium ions in developing teeth and bones. In the 1950s numerous publications described the brown/yellow discoloration of teeth in children who were prenatally exposed to tetracyclines. Such dental discoloration is the only proven prenatal side effect of tetracyclines in humans. Under discussion were also enamel defects leading to an increased risk of caries, inhibition of the growth of the long bones, specifically the fibula and further, cataracts due to depositions into the lens. As doxycycline has a weaker affinity to calcium ions than the older tetracyclines, the risk appears to be lower for doxycycline exposures.
A discoloration of milk teeth is not to be expected prior to the sixteenth week of gestation. Even thereafter, at worst, only the first molars of the permanent teeth would be affected when the usual therapeutic regimens if current dosings are adhered to. A bigger risk for the described development abnormalities can possibly expected with higher tetracycline doses during the second and third trimester that are necessary, for example, in malaria treatment.
In the past, the use of tetracyclines, especially in high doses or via intravenous administration in the second half of pregnancy, has been associated with severe maternal hepatic toxicity (e.g. ). In most cases these were patients with kidney problems whose serum concentrations were markedly above the therapeutic range.
No untoward effects have been described in pregnant women who applied tetracyclines locally during pregnancy.
There is a lack of experience with tigecycline ; no statement can be made about its tolerance in pregnancy.
Recommendation
All tetracyclines are contraindicated after the fifteenth gestational week. Prior to this, they are antibiotics of second choice. Doxycycline should be preferred in such cases. Inadvertent use of tetracyclines, even after the fifteenth week, is not an indication for termination of pregnancy ( Chapter 1.15 ). If really necessary, a local application to a small area may be conducted throughout pregnancy. Tigecyclin is reserved for special situations when sufficiently tested antibiotic are not effective.
2.6.7
Sulfonamides and trimethoprim
Pharmacology
Sulfonamides have a bacteriostatic effect by inhibiting bacterial folic acid synthesis. Important representatives of this group are sulfadiazine , sulfadoxine , sulfalene , sulfamerazine , sulfamethizole and sulfamethoxazole . For local application silver sulfadiazine is used for burn injuries and sulfacetamide for eye infections.
Sulfonamides attain 50–90% of the maternal concentration in the fetus and compete with bilirubin for binding sites on albumin. Today, sulfonamides are seldom used as monotherapy because their spectrum is limited and resistance develops rapidly. Combined with a folate antagonist such as trimethoprim or pyrimethamine (Section 2.6.16 ), sulfonamides are indicated among others in the treatment of toxoplasmosis and malaria. The fixed combination of the sulfonamide sulfamethoxazole and trimethoprim is available as co-trimoxazole . Both agents in this combination are not subject to pregnancy-induced variation in clearance that would require dose modifications. Trimethoprim is effective as a monotherapy in uncomplicated urinary tract infections with sensitive pathogens.
Toxicology
To date, there are no indications that sulfonamides, trimethoprim, and their combinations have a teratogenic potential in humans ( , ). An embryotoxic potential has been discussed from time to time, because antagonists to folic acid can lead to malformations in animal experiments, and in humans the spontaneous incidence of neural tube defects (spina bifida) can be decreased by the administration of folic acid during early pregnancy ( Chapter 2.18 ). The fact that human folic acid reductase is much less sensitive to trimethoprim than the bacterial enzyme, could explain that teratogenic problems have so far not been documented in humans when antibiotics with folic acid antagonists were used.
Trimethoprim has been used for many decades in pregnant women. At present, there is an ongoing discussion concerning the association between the use of folic acid antagonists and an increased risk of congenital malformations. A retrospective case-control study discusses the causal relationship between treatment with trimethoprim and other folic acid antagonists, and the development of neural tube defects, cardiovascular abnormalities, cleft lip and palate, and urinary tract anomalies ( ). Authors’ views on a preventative dose of multivitamin and folic acid preparations vary. Additional case-control studies, some of them with notable methodological problems, found weakly significant evidence for the development of cardiovascular defects, urinary tract anomalies, anencephaly, limb defects, and orofacial clefts (e.g. , , ). An increased risk for preterm birth and low birth weight has also been observed after exposure to trimethoprim/sulfamethoxazole ( , ). A Danish cohort study based on a prescription register found a doubling of the hazard of miscarriage after trimethoprim exposure in the first trimester ( ). Based on the same prescription register, an increased risk of heart and limb defects was observed after preconceptional exposure (during the 12 weeks before conception) to trimethoprim ( ). Beside methodological problems, such an association seems unlikely because a short-term therapy with trimethoprim does not usually lead to a relevant folic acid deficiency as a possible cause for birth defects. Trimethoprim and sulfonamides are not drugs of first choice, but they exhibit no established teratogens. According to current knowledge the teratogenic risk of a trimethoprim and sulfonamide therapy is negligible. Actually, there are no sufficiently convincing arguments to support the recommendation of an additional folic acid administration during an antibiotic therapy with the discussed medications, see Chapter 2.18.8 for additional discussion concerning folic acid usage.
Extensive, generally reassuring experiences in the use of co-trimoxazole for common urinary tract infections during pregnancy, do not include the conclusion that this medication is safe when used at a much higher dose for opportunistic infections such as a Pneumocystis pneumonia in the context of an HIV infection. So far, there have been no reports of malformations when such therapy was used in pregnant women.
There are no systematic studies about the local application of sulfonamides during pregnancy.
Neonatal toxicity
As sulfonamides compete with bilirubin for binding sites with plasma proteins, it has been argued that the risk of neonatal kernicterus is increased when sulfonamides are given at the end of gestation. With current surveillance, the danger of kernicterus is not tangible. However, a rise in bilirubin, especially in premature infants, cannot be excluded when sulfonamides have been used until birth. A Danish population-based study could not find an association between sulfamethoxzole exposure near term and an increased risk of neonatal jaundice ( ).
Recommendation
Sulfonamides, trimethoprim, and co-trimoxazole are antibiotics of second choice throughout pregnancy. If high dose co-trimoxazole is used for a Pneumocystis pneumonia during the first trimester, based on theoretical grounds, folic acid should be supplemented and a detailed ultrasound examination should be offered to ascertain the normal development of the fetus. If a premature birth is threatening, sulfonamides should be avoided in view of the bilirubin levels of the newborn. A short-term local treatment is acceptable, especially if the site is small.
2.6.8
Quinolones
Quinolones inhibit the bacterial enzymes topoisomerase II and IV that are important for the nucleic acid metabolism of bacteria. Quinolones have a high affinity for cartilage and bone tissue which is highest in immature cartilage.
Pipemidic acid and nalidixid acid belong to the group of older quinolones. They have been displaced by the newer fluoroquinolones. The most important fluoroquinolones include ciprofloxacin , enoxacin , levofloxacin , moxifloxacin , norfloxacin , and ofloxacin . Several substances have been removed from the market because of severe side effects. Garenoxacin , lomefloxacin , pefloxacin , rosoxacin , and sparfloxacin are still available in some countries. Gatifloxacin and nadifloxacin are only used as local agent.
Quinolones cross the placenta and are found in the amniotic fluid at low concentrations.When moxifloxacin is used about 8% of the maternal serum concentration can be measured in the amniotic fluid, and with lovofloxacin about 16% ( ).
Quinolones have not been found to be teratogenic in animals but severe, irreversible damage to joint cartilages was noted in young dogs treated after birth with quinolones (e.g. ). Such alterations have not been described in prenatally exposed children. Many publications failed to show indications of joint cartilage damage or an increased risk of malformations ( , , , , , ). One study expressed concern that the prenatal use of fluoroquinolones may be associated with an increased risk of bone malformations ( ). Although not resembling each other, in three out of four birth defects the skeleton was affected. However, in this study of 130 women who redeemed a prescription for fluoroquinolones during the first trimester, or 30 days before conception, the total malformation rate was not increased ( ). In a prospective cohort study with 949 women who were exposed to a fluorquinolone during the first trimester, neither the rate of major birth defects, nor the risk of spontaneous abortion were increased compared to a control group ( ). Altogether, most data are available for norfloxacin and ciprofloxacin and, to a lesser extent, for levofloxacin, moxifloxacin, ofloxacin and pefloxacin. There are few or no data for the other fluoroquinolones.
There have been no reports of undesirable side effects after topical use of quinolones during pregnancy.
Recommendation
Quinolones are antibiotics of second choice during pregnancy. In well-founded situations, when better studied antibiotics are ineffective, those quinolones that are well documented may be preferred such as norfloxacin or ciprofloxacin. A detailed ultrasound examination may be offered after exposure with the other fluoroquinolones during the first trimester. Local treatment with quinolones is acceptable throughout pregnancy.
2.6.9
Nitrofurans and drugs for urinary tract infections
Nitrofurantoin is a chemotherapeutic agent for drug-resistant urinary tract infections (UTIs) and for the prevention of recurrent UTIs. It acts as a bacteriostatic, but is also bactericidal at higher concentrations. Details of its mechanism of action remain to be clarified. After an oral dose, therapeutic effective levels are attained only in the urinary tract.
Several publications do not support an association between nitrofurantoin and congenital malformations ( , , , ), although in a number of studies, some of them with methodological faults, weakly significant findings were noted for craniosysnostosis, ophthalmic malformations, oral clefts, and cardiovascular defects ( , , ). A case-control study observed an increased risk of craniosynostosis after intrauterine exposure to nitrosatable drugs ( ).
As nitrofurantoin lowers the activity of glutathione reductase, discussions arise periodically as to whether an intrauterine exposure could trigger a fetal hemolysis. reported a mature newborn with hemolytic anemia whose mother took nitrofurantoin during the last gestational month. Nitrofurantoin is often used during pregnancy, and fetal hemolysis has not been commonly observed; therefore, a relevant risk is not likely. However, observed an increased risk of neonatal jaundice after maternal nitofurantoin treatment in the last 30 days before delivery.
There is a case report of a pregnant woman who developed a toxic hepatitis after having been exposed to nitrofurantoin in her thirty-sixth week ( ). In another case a woman took nitrofurantoin in her thirty-third week and was interpreted to present a gestational nitrofurantoin-induced pneumonia ( ).
The nitrofurantoin derivative nifuroxazide is used for the treatment of diarrhea. There are no documented reports of its tolerance in pregnancy nor evidence of effectiveness.
Nifurtimox is a nitrofuran used for treatment of Chagas disease. Experience for pregnancy is very limited and the World Health Organization recommends that nifurtimox should not be taken by pregnant women ( ). One study about safety included 14 pregnant women, but did not give information about the pregnancy outcome ( ).
For local treatment the nitrofurans furazolidone , nitrofural , and nifuratel are available. There has been no evidence of embryo- or fetotoxic risk in local applications. The use of local nitrofurans, especially as vaginal therapy, remains controversial and needs to be critically assessed not only during pregnancy.
Methenamine is a UTI medication that releases the antiseptic formaldehyde into the urine. Methenamine mandelate had been used for chronic UTIs due to E. coli and unproblematic germs. Effectiveness and tolerance of the agent remain controversial. Embryo- or fetotoxic problems have not been reported.
There are no reports about the use of the hydroxy-quinolone derivative nitroxoline in pregnancy.
Fosfomycin
Fosfomycin is a broad-spectrum antibiotic that is bactericidal by inhibiting the synthesis of the bacterial cell wall. It is used as an intravenous injectable and as a reserve antibiotic in severe infections such as osteomyelitis. Fosfomycin tromethamine is an orally taken salt of fosfomycin used for the treatment of uncomplicated UTIs. Some authors also recommend the oral use during pregnancy (e.g. , ). These studies, however, are primarily focused on the effectiveness of fosfomycin tromethamine, not on the risk for the newborn. Overall, the experience argues against a teratogenic and fetotoxic potential in humans.
Recommendation
Nitrofurantoin can be given during pregnancy to treat urinary tract infections when the antibiotics of choice have been ineffective. If possible, it should be avoided towards the end of pregnancy. The use of nifuroxazide, nifurtimox, local nitrofurans, methenamine, and nitroxoline should be avoided during pregnancy.
When the antibiotics of choice in pregnancy cannot be used, fosfomycin tromethamine may be used to treat urinary tract infections in pregnancy. The intravenous application of fosfomycin should be restricted to severe bacterial infections with problematic germs.
2.6.10
Nitroimidazole antibiotics
Nitroimidazoles are effective bactericidal agents against anaerobes and protozoa. They are converted into metabolites that impede intracellular bacterial DNA synthesis. The main representative of the nitroimidazoles is metronidazole . Metronidazole is now being recommended by some investigators for the treatment of bacterial vaginosis in pregnancies at high risk for preterm delivery, as a strategy to decrease this risk (review by ). Others, however, failed to notice an improvement in the incidence of prematurity ( , , ).
After oral and intravenous administration, concentrations as high as those in the mother are reached in the embryo/fetus. Significant systemic absorption occurs after vaginal application, exposing the fetus as well. The pharmacokinetic profile of metronidazole did not change at the different time points assessed during pregnancy, and did not differ from nonpregnant patients ( ).
Like all nitroimidazoles, metronidazole displays an experimentally mutagenic and cancerogenic potential (review by ) that has not been confirmed in humans. An investigation that ranged over 20 years did not show any indication of an increased risk of cancer when metronidazole was used ( ).
On the basis of over 3,000 analyzed pregnancies, it can be stated that metronidazole has no teratogenic potential in humans (e.g. , , ). Suggestions from the Hungarian Malformation Registry of a link between vaginal therapy with metronidazole and miconazole during the second and third month, and an increased appearance of syndactylies and hexadactylies have not been confirmed by other investigators ( ).
Nimorazole and tinidazole , both registered for the treatment of trichomonas infections, amebiasis, and bacterial vaginosis, cannot be evaluated sufficiently because of the lack of human data – the same applies to ornidazole . So far, there are no reports of human teratogenicity.
Recommendation
Metronidazol may be used in pregnancy when indicated. A single oral dose of 2 g is preferable to vaginal administration spread over several days, particularly as there are doubts about the effectiveness of the vaginal application. A parenteral administration is only indicated for a serious anaerobic infection. Metronidazole is to be preferred to the less examined nitroimidazoles.
2.6.11
Aminoglycosides
The aminoglycoside antibiotics amikacin , framycetin , gentamicin , kanamycin , neomycin , netilmicin , paromomycin , ribostamycin , streptomycin , and tobramycin inhibit protein synthesis and are bactericidal primarily for Gram-negative germs. After oral administration only a minimal portion of aminoglycosides is resorbed. After parenteral administration of about 20–40% of the maternal plasma concentration is detectable in the fetus. Spectinomycin is an aminocyclitol antibiotic closely related to the aminoglycosides.
Oto- and nephrotoxic side effects are also known to occur in nonpregnant patients when aminolgycosides are used parenterally. There are case reports about the parenteral use of kanamycin and streptomycin during pregnancy describing auditory problems, even deafness, in children exposed in utero (e.g. , , ). A similar case was reported in connection with gentamicin ( ). An investigation of the hearing ability of 39 children whose mothers had received gentamicin intravenously during pregnancy found no deficiencies. This argues against a major ototoxic risk of gentamicin when used in pregnancy ( ).
Theoretically, a fetal nephrotoxic risk exists because aminoglycosides concentrate in the fetal kidneys. A case report about a connatal kidney dysplasia after maternal gentamicin therapy ( ) does not prove a clinically relevant human risk, nor does a case of a hydronephrosis and suspected stenosis at the uteropelvic junction with lethal outcome, where the mother had been treated for UTI first with ciprofloxacin and then with gentamicin at weeks 4–5 ( ).
Except for these case reports, studies argue against a high oto- or nephrotoxic risk of gentamicin in the fetus and newborn. There has been no increase in the observation of malformations ( ). No untoward effects have been described with aminoglycosides as local treatment during pregnancy.
Experience with spectinomycin is insufficient to analyze a risk in pregnancy.
Recommendation
Aminoglycosides should only be used parenterally in life-threatening infections with difficult Gram-negative pathogens and when first-choice antibiotics fail. The serum levels need to be monitored regularly during the treatment. A risk-based termination of pregnancy or invasive diagnostic are not required ( Chapter 1.15 ). If the parenteral therapy had been extensive, renal function should be monitored in the neonate and an auditory test should be performed. If local or oral application of aminoglycosides is indicated, they can be given because systemic absorption is minimal by these routes.
2.6.12
Glycopeptide and polypeptide antibiotics
Glycopeptide antibiotics
The glycopeptides vancomycin and teicoplanin are bactericidal only for Gram-positive pathogens by inhibiting their cell wall synthesis. They are considered reserve antibiotics to be used against MSRA and multi-resistant enterococci. To avoid the development of resistance, their application should be critically appraised, and possibly limited only to fighting problematic pathogens. Oral glycopeptides are hardly resorbed. This is useful when treating pseudomembranous enterocolitis with vancomycin. However, in this situation metronidazole (Section 2.6.10 ) should be considered as an alternative, as vancomycin therapy is more expensive, and to prevent the selection for vancomycin-resistant enterococci.
Vancomycin crosses the placenta reaching the fetus in relevant quantities ( ). It has not shown teratogenic effects in animal studies. Experience with treatment in human pregnancy is limited to a few case reports. There were no observations of malformations, kidney damage, or hearing deficits ( ).
Experience with teicoplanin and the new lipoglycopeptides dalbavancin , oritavancin and telavancin is insufficient to analyze a risk in pregnancy. In vitro telavancin crosses the human placenta, with fetal concentrations reaching less than 3% of maternal concentrations ( ).
Recommendation
Glycopeptides should only be used in cases of life-threatening bacterial infections; vancomycin should then be preferred.
Lipopeptide antibiotics
Daptomycin belongs to a new class of cyclic lipopeptides and is effective exclusively against Gram-positive bacteria. It works by interfering with the bacterial cell membrane and protein synthesis, and is indicated to treat complicated infections with difficult pathogens. In animal experiments, daptomycin crossed the placenta and was not teratogenic. Two children whose mothers took daptomycin in the fourteenth and twenty-seventh weeks were unremarkable ( , ).
Recommendation
The use of daptomycin is limited to cases of life-threatening bacterial infections.
Polypeptide antibiotics
Polymyxins belong to the polypeptide antibiotics that are bactericidal by interfering with the transport mechanism of the cell wall. While the polymyxin colistin is today mostly used locally, it can also be applied parenterally where there is an infection with multi-resistant Gram-negative germs. In patients with mucoviscidosis it is used as an inhalative. Enterally colistin is not resorbed; therefore its oral administration is used to selectively decontaminate the intestinal tract.
The polypeptide antibiotics bacitracin , polymyxin B , and tyrothricin are used locally. Only limited experience is available in the application of polypeptide antibiotics during pregnancy and do not indicate a substantial risk ( ).
Recommendation
The parental use of colistin is limited to cases of life-threatening bacterial infections. The local and oral application of polypeptide antibiotics need to be critically assessed.
2.6.13
Other antibiotics
Chloramphenicol
Chloramphenicol and Tiamphenicol inhibit bacterial protein synthesis and have bacteriostatic activity. Chloramphenicol is relatively toxic, and can cause severe agranulocytosis. It crosses the placenta well and can reach therapeutic concentrations in the fetus. In premature and term births it may lead to the grey baby syndrome. Chloramphenicol can reach toxic levels in the neonate even when only the mother has been treated. There have been no suggestions of malformations ( ).
Experience with thiamphenicol is insufficient to analyze a risk in pregnancy.
Recommendation
The systemic use of chloramphenicol and thiamphenicol is contraindicated throughout pregnancy. Exceptions are life-threatening maternal infections that do not respond to less toxic antibiotics. When systemic treatment is absolutely necessary before birth, it is important to observe the newborn for toxic symptoms. A local application is also to be avoided during pregnancy.
Dapsone
Dapsone , used among other indications against leprosis, apparently has no teratogenic potential (e.g. , ). However, cases of hemolytic anemia have been reported in mothers and newborns. As dapsone bears a structural similarity to the sulfonamides, it has been argued that it might compete with bilirubin for protein binding, and thus could lead to hyperbilirubinemia in the newborn.
Recommendation
During pregnancy, dapsone should be reserved for specific indications. If treatment took place in the first trimester, a detailed ultrasound examination should be offered to ascertain the normal development of the fetus.
Fidaxomicin
Fidaxomicin is a macrocyclic antibiotic which is approved for the treatment of infections with Clostridium difficile. Enterally fidaxomicin is very poorly resorbed. No experiences have been reported about its use during pregnancy.
Recommendation
Fidaxomicin should be avoided in pregnancy. If treatment took place in the first trimester, a detailed ultrasound examination should be offered to ascertain the normal development of the fetus.
Linezolid
Linezolid is a member of the oxazolidinone class, a new group of antibiotics. It acts bactericidally by inhibiting bacterial protein synthesis and is indicated in the treatment of multi-resistant pathogens. There is just one case report about the use of linezolid during pregnancy. After intrauterine exposure from gestational weeks 14 to 18 a healthy infant was delivered at term ( ).
Recommendation
With the lack of experience, linezolid should only be used for severe infections with problematic germs. If treatment took place in the first trimester, a detailed ultrasound examination should be offered to ascertain the normal development of the fetus.
Pentamidine
The antiprotozoal agent pentamidine , among others effective in Pneumocystis pneumonia, has not been evaluated sufficiently in pregnancy to estimate its embryotoxic potential for humans. Usually it can be replaced by other antibiotics, e.g. co-trimoxazole (Section 2.6.7 ).
Recommendation
Pentamidine is to be reserved in pregnancy for special situations when better tested antibiotics are not effective. If treatment took place in the first trimester, a detailed ultrasound examination should be offered to ascertain the normal development of the fetus.
Rifaximin
Rifaximin is an antibiotic to treat travelers’ diarrhea. There is not enough experience regarding its use in pregnancy. Minimal enteral resorption and negative animal testing suggest that a high embryotoxic risk is unlikely.
Recommendation
If possible, rifaximin should be avoided during pregnancy.
Streptogramins
Streptogramins are a group of cyclic peptide antibiotics that inhibit, like macrolides and lincosamides , the synthesis of bacterial proteins. They are derivatives of the naturally occurring pristinamycin . The later developed derivatives quinupristin and dalfopristin are used in a fixed combination. Streptogramins should only be applied as reserve antibiotics for infections with highly resistant Gram-positive germs. Reports about use in pregnancy have not been available.
Recommendation
Streptogramins are to be avoided during pregnancy. If treatment took place in the first trimester, a detailed ultrasound examination should be offered to ascertain the normal development of the fetus.
2.6.14
Tuberculosis and pregnancy
Active tuberculosis (TB) requires treatment in pregnancy, as the disease endangers not only the mother, but also the fetus. Pregnancy does not seem to affect the course of TB. The prevalence of congenital TB is less than 1% where no treatment is initiated. investigated 761 newborns of mothers who had received treatment for TB during the gestation. Their children were smaller and had lower birth weights than the control group of children of healthy mothers.
There are slight differences in the recommendations of the different organizations in the world, such as the , the International Union against Tuberculosis and Lung Disease (IUATLD), and several national organizations (e.g. ). Treatment considerations depend on disease status and drug resistance. First-line drugs for the treatment of TB during pregnancy are isoniazid (+ pyridoxine ), rifampicin , ethambutol and pyrazinamide . These standard medications have not shown teratogenic or fetotoxic effects in humans (e.g. ). As far as we know today, TB drugs reach the fetus in relevant quantities. An increasing development of resistance makes it harder to choose the right medication in pregnancy. Pregnant women with multidrug-resistant TB (MDR-TB) may also require second-line antituberculous drugs; the necessity for treatment should be weighed against the risk for the fetus on an individual base. Current experiences in the management of MDR-TB argue against a high risk of the reserve drugs for the newborn ( , ). Streptomycin, however, should be avoided because of its ototoxic potential.
Ethambutol
Ethambutol is a bacteriostatic drug used against tuberculosis. It can cross the placenta, but the risk of congenital malformations when used during pregnancy appears to be low. There are no reports indicating that ethambutol can cause ocular toxicity in the fetus, as it does in adults, when given in higher doses.
Recommendation
Ethambutol is a first-line drug for treatment of tuberculosis during pregnancy.
Isoniazid
Isoniazid (INH) has proven to be a highly effective drug against many strains of mycobacterium, and can be used for tuberculous prophylaxis and for treatment of an active disease during pregnancy. Although INH can cross the placenta, it does not appear to be teratogenic, even when given during the first trimester. The older literature contains case reports of different malformations and neurological damages in prenatally exposed children. INH intake, lack of pyridoxine, co-medication, and even the TB disease itself was blamed. Newer publications did not confirm a teratogenic risk (e.g. , ). In summary, experiences speak against a major risk. INH increases pyridoxine metabolism, which may be responsible for CNS toxicity. To prevent a possible vitamin B6 deficiency, INH should be given during pregnancy in combination with pyridoxine .
Recommendation
Isoniazid is a first-line drug for treatment of tuberculosis during pregnancy. It needs to be given together with pyridoxine.
Pyrazinamide
Pyrazinamide (PZA) is an antibiotic with specific effectiveness against Mycobacterium tuberculosis. As its structure resembles nicotinamide, it is assumed that it intervenes with the nucleic acid metabolism of the bacterial cell. PZA has effective bactericidal properties. Systematic studies of its tolerance in pregnancy are lacking. So far, there has been no evidence of embryo- or fetotoxic effects in humans. The use of PZA during pregnancy is recommended in several guidelines (e.g. ). The American Thoracic Society recommends in its guidelines to hold PZA as a reserve drug during pregnancy, as there are currently insufficient data about its teratogenicity ( ). If PZA is not used, treatment may be prolonged.
Recommendation
Pyrazinamide may be used during pregnancy to treat active TB.
Rifampicin
Rifampicin also called rifampin , inhibits bacterial RNA polymerase and is effective as a bactericidal agent against different pathogens, particularly mycobacteria. Rifampicin can cross the placenta. In animal experiments, teratogenic effects were seen with doses 5–10 times higher than in human treatment. Because rifampicin inhibits DNA-dependent RNA polymerase, there has been concern that it might interfere with fetal development. Until now, no reports in the literature have confirmed this fear. There is apparently no increased risk of malformations. A long-term therapy of the mother could result in inhibition of vitamin K synthesis, and result in a higher bleeding tendency in neonates.
Recommendation
Rifampicin is a first-line drug for treatment of tuberculosis during pregnancy. When used near term the newborn should receive an extended vitamin K prophylaxis ( Chapter 2.9 ). Regarding other infections such as MRSA, rifampicin should only be administered when the drugs of first choice for pregnancy cannot be used.
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