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Infect Med 12(11): 600-602, 606, 618, 1995.
Safety and Toxicity of Antimicrobials During Pregnancy
Authors: Joette M. Meyer, PharmD, University of Illinois at Chicago, College of Pharmacy; Keith A. Rodvold, PharmD, FCP, FCCP, University of Illinois at Chicago, Colleges of Pharmacy and Medicine
[abstract] Antimicrobial agents are used frequently during pregnancy. Unfortunately, only a few antimicrobials have been shown to be completely nontoxic when given to pregnant women. Antimicrobial agents and their potential use during pregnancy are discussed; however, the current information available is often limited. Potential side effects of antimicrobial agents must be considered in the selection of optimal therapy for the pregnant patient.
* Abstract & Keywords
* Periods and Levels of Risk
* Penicillins, Cephalosporins, and Other Beta-Lactams * Macrolides
* Trimethoprim and Sulfonamides
* Drugs Mentioned in This Article
Many antimicrobial agents are capable of crossing the placenta, which has important toxicologic implications for the fetus. Only a few antimicrobials have been shown to be completely nontoxic when given to pregnant women. Unfortunately, the teratogenic potential of the majority of antimicrobial agents is unknown and, consequently, they are avoided during pregnancy. Studies in animal models offer some information but may be unreliable in predicting human teratogenicity. Avoiding useful agents on the basis of insufficient data may not be in the patient's best interest, especially when alternative antimicrobial agents are limited.
Periods and Levels of Risk
There are 5 major periods of concern when considering use of an antimicrobial agent, or other drug, during pregnancy. The preconception period is important for both males and females because drug administration to either gender in animal models can affect embryonic development or result in embryonic death. Use of drugs during the first 7 days after conception probably represents an all-or-none effect on the fertilized ovum: Either the damage is so great that the embryo dies, or the damaged cells are replaced by undifferentiated cells that develop normally. Once implantation occurs, after 14 days, differentiation of the embryo begins. This is the period of time when most drug-associated congenital abnormalities are produced. Therefore, it is recommended to avoid any unnecessary use of medications during the first trimester.
Exposure during the second and third trimesters presents a smaller risk because most organ systems are developed by this time. Instead, it is the metabolic processes that are at most risk. Labor and delivery represents a relatively short period of time but should not be overlooked. The last period of concern is during breast-feeding. Almost all antimicrobial agents administered to the lactating mother can be detected in her milk, but detrimental effects have only occasionally been encountered. Nonetheless, there are possible dangers, especially when large doses of antimicrobial agents are given to premature infants or to those with impaired drug elimination pathways.
The Food and Drug Administration (FDA) has established a Fetal Risk Summary, which divides drugs into categories based on accumulated safety data from animal and human studies (Table I).[3,4] Category A drugs represent no fetal risk. Currently, there are no antimicrobial agents that fall into this category. Category B drugs are relatively safe to use during pregnancy. If possible, agents should be selected from this category. A designation of category C means that the fetal risk is unknown. These agents should be used only when there is no safer alternative, or when the benefit outweighs the risk. Although there is some evidence of fetal risk in category D, it may be necessary to use these drugs for life-threatening or serious infections for which safer drugs cannot be used, or prove ineffective. Drugs listed as category X cause abnormalities and are contraindicated for use in pregnancy. The risk of using these antimicrobial agents in pregnant women clearly outweighs any possible benefit.
Penicillins, Cephalosporins, and Other Beta-Lactams
The penicillins are probably the most frequently prescribed antimicrobial agents used in pregnancy and appear to be relatively safe. All penicillins cross the placenta, but due to their low lipid solubility and high ionization, therapeutic levels are not achieved in the fetus unless large doses are given. One study of more than 3000 mothers found no teratogenic effects when penicillin derivatives were taken during the first trimester of pregnancy. Penicillins are considered safe to use during pregnancy and are listed as FDA category B (Table II). Beta-lactamase inhibitors (e.g., sulbactam, clavulanate, and tazobactam) have not been reported to cause direct fetal toxicity, although they can cause a positive Coombs' test.
Cephalosporins and aztreonam (a monobactam) are also considered category B and thus safe to use during pregnancy. There is no report of a cephalosporin causing birth defects. Immature male rats exposed to cefoperazone, cefotetan, moxalactam, and cefamandole (these agents all contain the methlytetrathiazole [MTT] side chain) became infertile. However, no human study has ever documented a cephalosporin causing infertility in a human fetus.
The carbapenem imipenem-cilastatin is category C, and no teratogenic or adverse fetal effects have been documented for either moiety; however, data are limited.
Erythromycin crosses the placenta, but fetal concentrations are generally low due to erratic absorption from the maternal gastrointestinal tract and unpredictable transplacental passage. Erythromycin is also a category B drug -- the base and succinate forms are considered safe for use during pregnancy. However, erythromycin estolate should not be used during pregnancy because it has been associated with a 10% to 15% incidence of reversible hepatotoxicity in mothers during the second half of pregnancy.
Less is known about the newer macrolides. Azithromycin (category B) has shown no teratogenic effects in animal studies, but there are no adequate controlled studies in pregnant women. Clarithromycin has been shown to cause teratogenic effects in animals, but its effects in humans are unknown. Clarithromycin has been placed into FDA category C (Table II).
There are limited data on the transplacental passage of aminoglycosides. Only gentamicin is listed in category C. The other agents (e.g., tobramycin, amikacin, netilmicin, streptomycin, kanamycin) are category D because eighth cranial nerve damage has been reported in children whose mothers received streptomycin as long-term therapy for tuberculosis. No cases of deafness have been reported for gentamicin, tobramycin, or amikacin. However, there is still potential for ototoxicity, so these agents should be avoided during pregnancy. If gentamicin is used, patients should be monitored using serum gentamicin concentrations (concentrations in amniotic fluid range from 30% to 50% of maternal concentrations). Renal function also should be assessed periodically by monitoring serum creatinine. Data regarding safety of once-daily
aminoglycoside dosing in pregnant patients have not been reported.
Tetracyclines cross the placenta readily and are in category D because they are known teratogens. They exert their adverse effects by inhibiting protein synthesis and by competing with calcium for incorporation into bone. Thus, tetracycline can deposit in growing bones and may disturb longitudinal growth. These agents can also cause a yellow-brown discoloration of teeth, hypoplasia, and enamel defects. Incorporation of tetracycline into deciduous ("baby") teeth and bone begins in the second trimester and can continue throughout the third trimester
into the postnatal period. The effects are most dramatic, however, with mid-trimester exposure.
Lethal fatty liver degeneration and pancreatitis have been reported in pregnant women taking large doses of intravenous tetracycline. The danger to the mother may be greatest during the third trimester.
Fluoroquinolones are in FDA category C and are not recommended for use in pregnancy because they have been shown to cause arthropathy in weight-bearing joints as well as noninflammatory joint effusions, fluid-filled blisters, fissures, erosions, and clusters of chondrocytes in immature animals. It is hypothesized that the fluoroquinolones may impair skeletal development in fetuses and infants, especially in their weight-bearing joints.
One study of 38 patients exposed to norfloxacin and ciprofloxacin during pregnancy failed to show any adverse effects on the musculoskeletal system. The majority of women took these agents during the first trimester of pregnancy. Assessment was based on information obtained about the child from mothers and physicians; however, no diagnostic procedures, such as MRI, were done.
Transplacental passage of clindamycin occurs and concentrations accumulate in fetal tissues. Clindamycin is in category B, and there are no records of teratogenic effects associated with its use. Clostridium difficile-induced colitis is a concern, but it does not develop more frequently during pregnancy.
Metronidazole, listed as category B, is carcinogenic in rodents and mutagenic for certain bacteria. Peterson and colleagues reported an increase in the incidence of congenital anomalies among infants of women treated with metronidazole during the first trimester. Other investigators have found no evidence of teratogenicity, still-births, or premature births. It is recommended that the drug not be given during the first trimester, unless it is absolutely necessary. Use of this drug during the second and third trimesters is still being debated.
The clinical use of chloramphenicol (category C) during pregnancy has been limited because of the serious adverse hematologic reactions (including aplastic anemia) and the development of gray-baby syndrome. (Gray-baby syndrome occurs because of inadequate routes of elimination of unconjugated chloramphenicol in immature infants. This excessive drug accumulation leads to a syndrome of toxicity, including vasomotor collapse, hypothermia, cyanosis, and an ashen-gray color.) Most clinicians prefer to use alternative antimicrobial agents such as beta-lactams.
Trimethoprim and Sulfonamides
Trimethoprim is in category C. There is very little placental transfer of the drug, but it is generally avoided because it inhibits folic acid metabolism, as does methotrexate, which is a known teratogen. Pyrimethamine is also avoided because it has the same mechanism of action.
Sulfonamides are category B but should be avoided near the end of gestation (third trimester) because of the increased risk of kernicterus in the infant. Kernicterus is thought to occur when the sulfonamide competes with bilirubin for albumin binding, thus causing hyperbilirubinemia. The free bilirubin diffuses into the central nervous system. The placenta can clear unconjugated bilirubin, but once the infant is born, it has no elimination mechanism. Infants with glucose-6-phosphate deficiency (G6PD) can develop hemolytic anemia if the mother takes sulfonamides late in pregnancy. At high doses, gross fetal malformations have been reported in animals, but in humans only 2 studies suggest an association between these drugs and birth defects.[25,26]
Trimethoprim/sulfamethoxazole (TMP/SMX) is not recommended because it is a combination product; however, sulfa drugs can be used when necessary during the first or second trimesters.
Nitrofurantoin is often an alternative to TMP/SMX for the prophylaxis and treatment of lower urinary tract infections during pregnancy. Nitrofurantoin has low serum concentrations and, to a very small extent, crosses the placenta. Nitrofurantoin is an FDA category-B agent. Teratogenicity or fetal adverse effects have not been observed in animal studies. Several clinical reports support the safety of nitrofurantoin use during pregnancy.[27,28]
Nitrofurantoin can induce acute hemolytic anemia in patients with G6PD deficiency or with glutathione-deficient red blood cells. No instances of hemolytic anemia have been reported in newborns. However, the manufacturer cautions the use of nitrofurantoin in pregnant women at term and in infants less than 1 month of age.
Vancomycin is considered a category-C agent. Transplacental passage of vancomycin has been documented in animal models. There are minimal clinical data available concerning its effects in humans, but no adverse fetal effects have been reported. The potential risk of maternal ototoxicity and nephrotoxicity is similar in pregnant and nonpregnant patients receiving this agent.
Clearly, some antimicrobial agents, such as tetracyclines, should be avoided during pregnancy. However, accumulated data show that penicillins, cephalosporins, and erythromycin can be safely administered to pregnant women. Unfortunately, there are many agents whose safety is unknown. More data regarding the safety of antimicrobial agents during pregnancy are needed. The current information is often scarce and probably does not allow optimal use of these agents. In order to best treat the pregnant patient, clinicians must weigh the effects of the infection against the potential side effects of the antimicrobial agent to mother and child.
Table I - Pregnancy Categories*
A. Controlled studies fail to demonstrate a risk to the fetus in the first trimester (and there is no evidence of risk in later trimesters); the possibility of fetal harm appears remote.
B. Fetal risk not demonstrated in animal studies, but there are no controlled studies in pregnant women, or animal reproduction studies have shown an adverse effect that was not confirmed in controlled studies in women during the first trimester (and there is no evidence of a risk in later trimesters).
C. Either animal studies have revealed adverse effects on the fetus (teratogenic, embryocidal, or other) and there are no controlled human studies, or studies in animals and women are not available.
D. There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective). X Studies in animals or humans have demonstrated fetal abnormalities or there is evidence of fetal risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.
*Adapted from Briggs et al and Mandell et al.
Table II - Safety and Toxicity of Antimicrobial Agents During Pregnancy
Category in Maternal Fetal/Neonatal
Antimicrobial Agent Pregnancy Toxicities Toxicities
AminoglycosidesD (except Ototoxicity, Eighth gentamicin, cranial category C) nephrotoxicitynerve toxicity
AztreonamB Phlebitis; mild None known GI distress
CephalosporinsB Allergic None known reactions
ChloramphenicolC Bone marrow Gray-baby depression, syndrome including aplastic anemia
ClindamycinB PseudomembranousNone known colitis
FluoroquinolonesC GI distress; CNS Animal studies reactions suggest possible arthropathy18 in developing bone and cartilage Macrolides
Erythromycin base B GI distress No known teratogenicity in humans
Erythromycin estolateB Cholestatic clarithromycin hepatitis shown to be teratogenic
Erythromycin base B GI distress in animals)
AzithromycinB GI distress
ClarithromycinC GI distress; taste perversion
MetronidazoleB Disulfiram-like May or may not be reaction; teratogenic
blood dyscrasiasin humans[21,22]
NitrofurantoinB GI distress; Hemolytic anemia pulmonary reactions
PenicillinsB (except Allergic None known - cilastatin, reactions category C)
Sulfonamides B Allergic Kernicterus, reactions hemolysis (in G6PD deficiency) TetracyclinesD Hepatoxicity[19,20]; Tooth pancreatitis; discoloration; renal failure inhibition of bone growth
TrimethoprimC Allergic reactions Folate antagonist, potential therefore teratogen
TMP/SMXC Megaloblastic Kernicterus, anemia hemolysis (in G6PD deficiency)
VancomycinC Ototoxicity; Possible oto- and nephrotoxicitynephrotoxicity
TMP/SMX = trimethoprim/sulfamethoxazole.
Drugs Mentioned in This Article
Ampicillin Amikin, Generic
Erythromycin (base, succinate, estolate) Generic
Trimethoprim/sulfamethoxazole Bactrim, Cotrim, Septra, Generic
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