PRESCRIBING IN PREGNANCY

0889-8545/97 $0.00

.20

ANTIBIOTIC USE IN PREGNANCY

Jodi S. Dashe, MD, and Larry C . Gilstrap 111, MD

Infections are common during pregnancy, and a significant number of pregnant women are exposed to antibiotics. Urinary tract infections such as bacteriuria, cystitis, and pyelonephritis are among the most common, occurring in 2% to 7% of all pregnant women.32Other frequently encountered infections include community acquired pneumonia, chorioamnionitis, and sexually transmitted diseases. In addition, metritis and mastitis may complicate the postpartum period. Virtually all antibiotics cross the placenta and thus have the potential to affect the fetus adversely. Most are excreted into breast milk and may affect the neonate as well. There are no large scientific studies of the safety of antibiotics in pregnancy. Many agents, however, such as the penicillins and erythromycin, have been used for many years in pregnancy (out of necessity) without apparent adverse fetal effects. Timing the treatment of an infection during pregnancy depends somewhat on its nature and severity. A serious infection such as acute pyelonephritis should be treated as soon as the diagnosis is made. On the other hand, treatment of vaginitis might be delayed until after the first trimester. When giving an antibiotic to a pregnant woman, it is important to be cognizant of the physiologic changes that may alter its pharmacodynamics. The marked increases in blood volume and creatinine clearance that occur in pregnancy typically lead to lower serum concentrations. For example, a given dose of ampicillin or gentamicin will result in 31, 41, 56 lower serum levels in pregnant versus nonpregnant women.15*

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

OBSTETRICS AND GYNECOLOGY CLINICS OF NORTH AMERICA

VOLUME 24 NUMBER 3 * SEPTEMBER 1997

617

618

DASHE & GILSTRAP

Table 1. UMBILICAL CORD BLOOD TO MATERNAL BLOOD RATIOS FOR SOME OF THE PENICILLINS8,33 Antibiotic Ampicillin Ampicillin plus sulbactam Mezlocillin Ticarcillin plus clavulanic acid Cord Blood to Maternal Blood Ratio
0.71 1 .o 0.40

0.8

PENICILLINS Penicillins have been used in clinical practice since the 1940s, and as a group they are probably the safest antibiotics in pregnancy. Each contains a thiazolidine beta-lactam ring, and every type has a different side chain. Penicillins are bactericidal, acting through inhibition of bacterial cell wall synthesis. When given to the mother, significant levels are achieved in the fetus.18,31, 33 Ratios of umbilical cord blood to maternal serum concentrations for some of the penicillins are summarized in Table 1. Pregnant women have been treated with penicillins for many years. Of over 3500 fetuses included in the Collaborative Perinatal Project, there was no increase in congenital anomalies or other adverse effects following exposure to a penicillin in the first t r i m e ~ t e r Despite .~~ the appearance of newer agents, penicillin G remains the drug of choice for syphilis in pregnancy and for group B streptococcal infection. Pregnant women with syphilis who are allergic to penicillins should undergo Ampicildesensitization and then receive treatment with penicillin G.54 lin, an aminopenicillin, is a drug of choice for treatment of enterococcal infection and is part of the recommended regimen for subacute bacterial endocarditis (SBE) prophylaxis. It is also part of triple chemotherapy for the treatment of serious pelvic infections. Some of the more common penicillins are listed in Table 2.

Table 2. SOME OF THE MORE COMMON PENICILLINS Natural penicillins Penicillin G Penicillin V Antistaphylococcal penicillins Methicillin Oxacillin Nafcillin Cloxacillin Dicloxacillin Derivatives of 6-aminopenicillanic acid Ampicillin Amoxicillin Bacampicillin Extended-spectrumpenicillins Carbenicillin Ticarcillin Mezlocillin Piperacillin Azlocillin

Adapted from Far0 S: Penicillins. Obstet Gynecol Clin North Am 16257-269, 1989

ANTIBIOTIC USE IN PREGNANCY

619

Table 3. PENICILLINS PLUS BETA-LACTAMASE INHIBITORS Ticarcillin plus clavulanic acid Amoxicillin plus clavulanic acid Ampicillin plus sulbactam Piperacillin plus tazobactam

Many aerobic and anaerobic bacteria contain beta-lactamase enzymes, which may render a specific antibiotic ineffective. Because of the increasing resistance of bacteria to some of the penicillins, newer agents have been developed that contain a beta-lactamase inhibitor, such as clavulanic acid, sulbactam, and tazobactam (Table 3). They provide excellent coverage against the mixed aerobic and anaerobic polymicrobial infections encountered in women with post-cesarean metritis. While there are no large, epidemiologic studies of the safety of the newer penicillins during pregnancy, it is unlikely that they are teratogenic. They are Food and Drug Administration (FDA) category B drugs, as are all penicillins. Penicillins may cause adverse maternal effects such as hypersensitivity reactions, nausea, diarrhea, central nervous system irritability, and phlebitis. Anaphylaxis occurs in 0.004% to 0.4%, and up to 10% of these patients have a similar reaction to cephalosporins and carbapenems. The Jarisch-Herxheimer reaction is not uncommon following treatment of syphilis in pregnancy, especially primary syphilis infection. CEPHALOSPORINS Cephalosporins are the most commonly prescribed antibiotics. Like penicillins, they contain the four-member beta-lactam ring. They are also bactericidal, acting through inhibition of bacterial cell wall synthesis. Cephalosporins have been classified as first-, second-, and third-genera) . Although there have tion based on their spectrum of activity (Table 4 been no large studies of the safety of cephalosporins in pregnancy, there
Table 4. SOME OF THE COMMONLY USED CEPHALOSPORINS
-~
~

First- and second-generation Cephalothin Cephapirin Cephradine Cefazolin Cefamandole Cefoxitin Cefuroxime Cefonicid Cefaclor Cefmetazole Cefpodoxime Cefprozil

Third-generation Cefotetan Cefotaxime Ceftizoxime Cefoperazone Ceftriaxone Moxalactam Cefmenoxime Cefixime Ceftazidime

620

DASHE & GILSTRAP

have been no embryocidal effects reported, and all of these drugs are listed as FDA category B. They cross the placenta and in most studies their half-life is shorter in pregnancy because of increased renal clear33, 35 First-generation cephalosporins are commonly used for ance.6r post-cesarean delivery prophylaxis and for the treatment of urinary tract infection typically caused by aerobic gram-negative rods. It is important to note that none of the cephalosporins is effective against Enterococcus. Newer cephalosporins, which are third-generation, include cefotetan, cefotaxime, cefoperazone, ceftazidime, ceftizoxime, and ceftriaxone. These agents are at least tenfold less active against Staphylococcus aweus than the first-generation cephalosporins; however, they adequately cover all aerobic streptococci except Enterococcus. They provide excellent coverage against the aerobic gram-negative rods, and several of them are active against gram-positive and gram-negative anaerobes as well. Almost all will cover Pseudomonas sp, with cefotetan being the exception. Cefoperazone, ceftazidime, and ceftriaxone cover Bucteroides fragiZis poorly, and thus may be less effective as single agent treatment for mixed aerobic-anaerobic pelvic infections. Cefoperazone, unlike the others, is cleared principally by biliary excretion. It does not require dose adjustment in the setting of renal insufficiency, and serum levels in pregnancy are similar to those in the nonpregnant state.19Ceftriaxone, which has a shorter half-life in pregnancy, might be an attractive choice because it is one of the few agents tested that does not accumulate in the fetus; however, there has been only limited experience with its use during pregnan~y.2~ The logical use for this class of antibiotics in obstetrics is as singleagent therapy in postpartum metritis. Unfortunately, these agents are expensive and usually have little to offer over standard therapy. They do not cover chlamydia, and several of them do not cover B. fiugilis. Two of the third-generation cephalosporins, ceftriaxone and cefixime, are, however, recommended as single-dose therapy for uncomplicated gonococcal infection. Typical cephalosporin side effects include hypersensitivity and diarrhea. Mild liver function test abnormalities and neutropenia have been reported infrequently. In addition, hypoprothrombinemia and bleeding have been associated with cefoperazone and cefotetan use, especially when high doses are given for prolonged periods or in the setting of underlying renal or hepatic dysfunction or anticoag~lation.~, 24, 44 These two agents have also caused a disulfiram reaction when taken prior to alcohol consumption.28

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

ANTIBIOTIC USE IN PREGNANCY

621

Table 5. MACROLIDE, AMINOGLYCOSIDE, AMINOCYCLITOL, MONOBACTAM, AND CARBAPENEM ANTIBIOTICS Macrolides

Erythromycin Clindamycin Azithrornycin Clarithromycin Streptomycin Gentamicin Tobrarnycin Kanamycin Amikacin Netilrnicin Spectinomycin Aztreonam lmipenern

Aminoglycosides

Aminocyclitol Monobactam Carbapenem

Unlike the vast majority of other antibiotics, erythromycin crosses the placenta minimally. For this reason it is not first-line treatment for syphilis in pregnancy or recommended when a penicillin allergy is present. Erythromycin is FDA category B. Gastrointestinal upset is common with its use. Other side effects include pain at injection sites, hypersensitivity reactions, and infrequent liver function test abnormalities. Clindamycin provides excellent coverage against many anaerobes, including almost all Clostridium sp and most Bacteroides sp, along with many aerobic gram-positive cocci. It does not cover gram-negative rods, and in recent years resistance to some Bacteroides sp has d e v e l ~ p e d . ~ ~ Clindamycin combined with an aminoglycoside is the major regimen used for the treatment of mixed aerobic and anaerobic pelvic infections, with cure rates of approximately 90% to 97%. Its primary obstetric indication is postpartum metritis, and it is also the drug of choice for group B streptococcal prophylaxis in the penicillin-allergic patient. Clindamycin is an FDA category B drug. Side effects include gastrointestinal upset and infrequent liver function test abnormalities. It has been estimated that 1 in 10,000 patients treated with clindamycin will develop pseudomembranous colitis from a toxin produced by Clostridium dificile. Oral vancomycin is the treatment of choice if this complication develops, and metronidazole is an alternate therapy. Azithromycin is a relatively new macrolide with an extended spectrum of activity and a prolonged half-life. It is active against grampositive cocci, some gram-negative rods, and many anaerobes, as well MycopZusrnu and Chlamydia. In one study, in which azithromycin was compared with erythromycin in the treatment of cervical chlamydia infection in pregnant women, azithromycin had equivalent efficacy and significantly fewer side effects.ll Improved intracellular transport compared to erythromycin enhances the effectiveness of azithromycin against the obligate intracellular parasite Chlamydia and allows a single

622

DASHE & GILSTRAP

one-time dosing regimen. Azithromycin and clarithromycin both have good in vitro activity against Borrelia burgdouferi, the tick-borne spirochete known to cause Lyme disease.4,45 They are probably effective treatment for syphilis as well, though this remains to be evaluated. Studies of the safety of azithromycin in pregnant women have not yet been performed. It is listed as FDA category B. Gastrointestinal side effects are less common than with erythromycin, and other reported side effects include headache, dizziness, and mild liver function abnormalities. Clarithromycin is effective against a wide variety of aerobic organIt is most often used during isms as well as Ureaplasma u~eaZyticum.4~ pregnancy for the treatment and prophylaxis of Mycobacterium avium complex (MAC) in women who are HIV positive. There are no large randomized studies of the safety of clarithromycin in pregnancy. It is listed as FDA category C.
AMINOGLYCOSIDES

Aminoglycosides are bactericidal antibiotics that bind the 3 0 s ribosome and inhibit bacterial protein synthesis. Members of this class include streptomycin, gentamicin, tobramycin, kanamycin, amikacin, and netilmicin (see Table 5). Gentamicin is the most widely used aminoglycoside in pregnancy. It covers a wide range of aerobic gram-negative rods, though resistance has developed by some strains of Pseudomonas aeruginosa. Gentamicin also has some activity against S. aureus and is synergistic with ampicillin in the treatment of Enterococcus. Gentamicin rapidly crosses the placenta, with peak cord serum levels approximately 40% of maternal levels in 1 to 2 hours.% The mean concentration ratio between umbilical cord blood and maternal blood for gentamicin is 0.62.18There have been no reported congenital anomalies resulting from gentamicin, and no reports of neonatal ototoxicity or nephrotoxicity following in utero exposure. Gentamicin is an FDA category C drug, and its principal obstetric indication is in combination with clindamycin for treatment of mixed aerobic and anaerobic pelvic infections such as postoperative metritis. It is also the drug of choice given with ampicillin for SBE prophylaxis. Other common uses of ampicillin and gentamicin therapy in pregnancy are chorioamnionitis and pyelonephritis. Graham et aP0 have reported that peak serum levels in pregnant women treated for pyelonephritis are significantly lower than in those who receive gentamicin postpartum. The dosage of any aminoglycoside needs to be reduced in the setting of renal insufficiency. Three major side effects are nephrotoxicity, ototoxicity, and neuromuscular blockade. Nephrotoxicity, which is usually reversible, develops in approximately 2%.4 Ototoxicity may involve either the auditory or vestibular region of the eighth cranial nerve and is, unfortunately, often irreversible. Neuromuscular blockade, a rare complication, may be potentiated by magnesium sulfate and other neu-

ANTIBIOTIC USE IN PREGNANCY

623

romuscular blockers used during general anesthesia. This effect can be reversed by anticholinesterases and calcium administration. AMINOCYCLITOL Spectinomycin is an aminocyclitol antibiotic related to the aminoglycosides. It may be beneficial in the treatment of N. gonorrhoeae infection in patients who are allergic to penicillins and cephalosporins. Penicillinase-producing strains of gonorrhea resistant to spectinomycin have been reported. There have been no teratogenic or adverse fetal effects documented. Spectinomycin is listed as FDA category B. MONOBACTAM Aztreonam is a monobactam antibiotic, and is the first and only agent in this class to become clinically available. Although it is a betalactam, like the penicillins, it is resistant to hydrolysis by beta-lactamase and has not been found to induce beta-lactamase production. Aztreonam covers most aerobic gram-negative rods, but is ineffective against grampositives and anaerobes. Its spectrum is thus similar to the aminoglycosides, and it remains effective in an anaerobic environment (which aminoglycosides do not), making it an excellent choice for combination therapy with clindamycin for treatment of an abscess. The combination of aztreonam and clindamycin has also been found equivalent to gentamicin and clindamycin for metritis.I7 Aztreonam has a wide margin of safety and is not nephrotoxic or ototoxic like the aminoglycosides, though it accumulates in renal insufficiency and must be dosed accordingly. While studies in pregnant women are limited, it is not teratogenic in rodents. Aztreonam is listed as FDA category 8.Side effects, which are uncommon, include rashes and transaminase elevations. CARBAPENEMS Imipenem is the first of a new class of antibiotics, the carbapenems, to become clinically available. It is administered in combination with cilastatin, a dipeptidase inhibitor that prevents nephrotoxicity. Imipenem has a broader spectrum than any other beta-lactam, covering grampositive cocci, gram-negative rods, and anaerobe^.^^ Only methicillinresistant S. aureus, MycopZasma, and Chlamydia are resistant, and resistance of P. aeruginosa has emerged during therapy. Imipenem has been reported to be highly effective in the treatment of postpartum infection.36 While it is rarely a first-line agent, it may be beneficial if organisms are resistant to other antibiotics. In pharmacokinetic studies, its peak serum levels are considerably lower in pregnancy.22 There is limited experience with the safety of imipenem during pregnancy, and it has few, if any,

624

DASHE & GILSTRAP

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

VANCOMYCIN

Vancomycin is a glycopolypeptide that is bactericidal because it inhibits the synthesis and assembly of bacterial cell wall polymers. Though it has a limited spectrum of activity, there are several infections for which it remains the drug of choice. These include the treatment of C. difficile-induced pseudomembranous colitis, for which it may be given orally, and the treatment of methicillin-resistant S. uureus. In penicillinallergic patients, vancomycin is the drug of choice for treatment of Enterococczis and for prophylaxis of subacute bacterial endocarditis.' There has been controversy in the past regarding the potential for fetal ototoxicity or nephrotoxicity with this agent.47Although it appears that standard doses of vancomycin pose no threat to the fetus, it is listed as FDA category C. The dose should be decreased in those with renal insufficiency.

METRONIDAZOLE

Metronidazole is a nitroimidazole antibiotic whose mode of action is not completely understood. It is the only available antibiotic effective in treating Trichomonas vaginalis. Its spectrum includes many of the obligate anaerobes such as Bacteroides sp, Fusobacterium, and Clostridia sp, as well as the anaerobic protozoa, Entamoeba histolytica and Giardia lamblia. Metronidazole crosses the placenta, and at term fetal cord blood concentrations are approximately equivalent to those in maternal serum.3 Use of metronidazole in pregnancy is somewhat controversial. While the reduced form of the drug is mutagenic in bacteria, mammals are not capable of reducing metronidazole and should not be at risk.'* Metronidazole in high doses is carcinogenic in rodents, but has not been found to be carcinogenic in other animal models.7,49 It has not been reported to be teratogenic in animal studies. A review of nearly 600 pregnant women given metronidazole for trichomoniasis found no evidence of terat~genicity.~~ Although it has not been associated with adverse fetal effects, it is currently recommended for use in the second and third trimesters only.5uIt is FDA category B. Side effects, which are uncommon unless therapy is prolonged, include gastrointestinal upset, metallic taste, headache, vertigo, and somnolence. After large doses, reversible peripheral neuropathy and encephalopathy have been reported. A disulfiram-like reaction to alcohol has been well described.38

ANTIBIOTIC USE IN PREGNANCY

625

FLUOROQUINOLONES

Fluoroquinolones are a class of bactericidal antibiotics that act at the level of bacterial DNA gyrase to inhibit DNA synthesis.13They are derived primarily from nalidixic acid. Fluoroquinolones are effective treatment for urinary tract infection, bacterial diarrhea, respiratory infection, bone and joint infection, and gonococcal infe~ti0n.l~ Examples of antibiotics in this class include norfloxacin, ciprofloxacin, ofloxacin, and enoxacin. There are no large epidemiologic studies of the use of the fluoroquinolones in pregnancy, but these agents have been reported to cause irreversible arthropathy in immature animals.48Thus, this class of antibiotics should be avoided if possible during pregnancy and in breastfeeding mothers.
SULFONAMIDES

Sulfonamides are the oldest class of antibiotics, introduced in the 1930s. They are bacteriostatic and interfere with bacterial synthesis of folate. Their action is potentiated by trimethoprim, which inhibits bacterial dihydrofolate reductase. The primary use of sulfonamides in pregnancy is the treatment of uncomplicated urinary tract infection. While they were once active against most gram-positive cocci and gram-negative rods, many strains have become resistant, so susceptibility should be tested before treating chronic or recurrent infection. Typical agents include sulfisoxazole or the combination of trimethoprim-sulfamethoxazole. Sulfonamides cross the placenta, and fetal levels reach 70% to 95% of maternal levels within several hours. If given shortly before delivery, sulfonamides can bind albumin and displace bilirubin, and this has been reported to result in neonatal hyperbilirubinemia with kernicterus.26 However, one study in which 94 infants were exposed to sulfadiazine in utero for maternal rheumatic fever prophylaxis found no increased Hemolytic anemia has also risk of hyperbilirubinemia or kerni~terus.~ been reported in a fetus born to a mother homozygous for glucose-6phosphate dehydrogenase deficiency who happened to be taking sulfis o ~ a z o l eSince . ~ ~ trimethoprim is a folate antagonist (at least in bacteria), it is generally not recommended for use in pregnancy. Nonetheless, in studies involving almost 300 pregnant women, trimethoprim was not 56 The combinaassociated with any teratogenic or adverse fetal effects.lo, tion of trimethoprim plus sulfasoxazole may be indicated for Pneumocysfis carinii pneumonia prophylaxis in pregnant women who are infected with HIV. Sulfonamides are FDA category B drugs, and trimethoprim is FDA category C . NITROFURANTOIN Nitrofurantoin is used primarily for the treatment of urinary tract infections during pregnancy. This drug has not been reported to be

626

DASHE & GILSTRAP

associated with teratogenic or adverse fetal effects. While nitrofurantoin may cause hemolytic anemia in women with glucose-6-phosphate dehydrogenase defi~iency:~ it has not been reported to do so in the fetus. Nitrofurantoin has also been associated with a pneumonitis if given for protracted periods. In the authors experience of over 1000 pregnant women receiving this antibiotic, neither pneumonitis nor hemolytic anemia has occurred. In a small meta-analysis on the safety of nitrofurantoin during the first trimester of pregnancy, there was no increase in congenital malformations (OR 1.29; 95% CI 0.25-6.57).8 It is listed as FDA category C. TETRACYCLINES Tetracyclines are bacteriostatic antibiotics that reversibly bind the 3 0 s ribosome and inhibit bacterial protein synthesis. They have a broad spectrum of activity against many gram-positive and gram-negative aerobes and anaerobes, including chlamydia, mycoplasma, and the spirochetes. Tetracyclines cross the placenta and deposit in fetal decidual teeth causing yellow-brown discoloration if given after 5 months gestation.21, 27, 30, % Despite earlier reports, they do not lead to an increase in tooth enamel hypoplasia or caries, and they do not inhibit fibula growth in the preterm infant.42 However, tetracyclines are FDA category D, and should be avoided in pregnancy unless no alternative is available. One potential indication is in the treatment of syphilis in a penicillin-allergic patient who cannot be desensitized. Tetracycline at doses of more than 2 grams per day has been reported to cause acute fatty degeneration of the liver, particularly in those treated for pyel0nephritis.5~ The tetracyclines are listed in Table 6. ANTITUBERCULOUS AGENTS

The incidence of tuberculosis in pregnancy is increasing, and it has been reported to be as high as 0.1% in endemic areas of the United States.%The American Thoracic Society and Centers for Disease Control have recommended that initial treatment for pregnant women with tuberculosis consist of isoniazid and rifampin. Ethambutol is also suggested if there is concern for isoniazid resistance.*All three agents cross the placenta. In a review of 15 studies involving over 400 pregnancies exposed to rifampin, over 600 exposed to ethambutol, and almost 1500
Table 6. THE TETRACYCLINES
Tetracycline Demeclocycline Doxycycline Oxytetracycline Minocycline

ANTIBIOTIC USE IN PREGNANCY

627

Table 7. ANTITUBERCULOUS AGENTS

lsoniazid Rifampin Ethambutol Streptomycin Pyrazinamide Ethionamide Cycloserine

exposed to isoniazid, the rate of congenital malformations was not increased over that of the general p ~ p u l a t i o nPyridoxine .~~ (vitamin B6) is recommended for pregnant women receiving isoniazid to prevent neuropathy. Isoniazid and rifampin are listed as FDA category C , whereas ethambutol is an FDA category B drug. Streptomycin, an aminoglycoside antibiotic, is not recommended for use in pregnancy, as eighth cranial nerve abnormalities have been identified in up to 15%of exposed infants. The potential teratogenicity of the other antituberculous agents, pyrazinamide, ethionamide, and cycloserine, has not yet been adequately evaluated, and their use should also be avoided in pregnancy.2,16 The antituberculous agents are listed in Table 7. SUMMARY With a few notable exceptions, most antibiotics can be used with relative safety during pregnancy. Moreover, none of the antibiotics to date has been shown to be teratogenic, although tetracycline may cause yellow-brown discoloration of the deciduous teeth (a fetal effect). Thus, antibiotics should not be withheld from the pregnant woman, especially when indicated for serious, life-threatening infections. References
1. American Heart Association Committee on Prevention of Bacterial Endocarditis: Prevention of bacterial endocarditis. Circulation 56139A, 1977 2. American Thoracic Society: Treatment of tuberculosis and tuberculosis infection in adults and children. Am J Respir Crit Care Med 1491359, 1994 3. Amon K, Amon I, Huller H: Maternal-fetal passage of metronidazole. In Advances in Antimicrobial and Antineoplastic Chemotherapy. Proceeding of the VII International Congress of Chemotherapy, Prague, Urban and Schwarzenberg, 1971 4. Appel GB, Neu HC: The nephrotoxicity of antimicrobial agents (part 2 of 3). N Engl J Med 296:7, 1977 5. Baskin CG, Law S, Wenger N K Sulfadiazine rheumatic fever prophylaxis during pregnancy: Does it increase the risk of kemicterus in the newborn? Cardiology 65:222, 1980 6. Bawdon RE, Cunningham FG, Quirk JG, et al: Maternal and fetal pharmacokinetics of moxalactam given intrapartum. Am J Obstet Gynecol 144:54, 1982 7. Beard CM, Noller KL, OFallon WM, et al: Cancer after exposure to metronidazole. Mayo Clin Proc 63147, 1988 8. Ben David S, Einarson T, Ben David Y, et al: The safety of nitrofurantoin during the first trimester of pregnancy: Meta-analysis. Fundam Clin Pharmacol 9:503, 1995

628

DASHE & GILSTRAP

9. Bruch K Hypoprothrombinemia and cephalosporins. Lancet 1:535,1983 10. Brumfitt W, Purse11 R Trimethoprim/sulfamethoxazole in the treatment of bacteriuria in women. J Infect Dis 128:657, 1973 11. Bush MR, Rosa C: Azithromycin and erythromycin in the treatment of cervical chlamydial infection during pregnancy. Obstet Gynecol 8461, 1994 12. Charles D Chloramphenicol, clindamycin and metronidazole. In Ledger WJ (ed): Antibiotics in Obstetrics and Gynecology. The Hague, Martinus Nijhoff, 1982, pp 159217 13. Christian 1s:The quinolone antibiotics. Prim Care Update in Obstetrics and Gynecology 3:87, i996 14. Dinsmoor MI, Gibbs R S The role of the newer antimicrobial aaents in obstetrics and gynecology. Clin Obstet Gynecol31:423, 1988 15. Duff P, Jorgensen JH, Alexander G, et a1 Serum gentamicin levels in patients with post-cesarean endomyometritis. Obstet Gynecol 61:723, 1983 16. Fleischman JK, Greenberg HE, Kanengiser LC, et a1 Tuberculosis. Prim Care Update Ob/Gyn 1:227, 1994 17. Gibbs RS, Blanco JD, Lipscomb KA, et a1 Aztreonam versus gentamicin, each with clindamycin, in the treatment of endometritis. Obstet Gynecol 65:285, 1985 18. Gilstrap LC, Bawdon RE, Burris J: Antibiotic concentration in maternal blood, cord blood and placental membranes in chorioamnionitis. Obstet Gynecol 72:124, 1988 19. Gonik B, Feldman S, Pickering LK, et al: Pharmacokinetics of cefoperazone in the parturient. Antimicrob Agents Chemother 30:874, 1986 20. Graham JM, Blanco JD, Oshior BT, et al: Gentamicin levels in pregnant women with pyelonephritis. Am J Perinatol 11:40, 1994 21. Harcourt JK, Johnson NW, Storey E: In vivo incorporation of tetracycline in the teeth of man. Arch Oral Biol 7431, 1962 22. Heikkila A, Renkonen 0, Erkkola R Pharmacokinetics and transplacental passage of imipenem during pregnancy. Antimicrob Agents Chemother 36:2652, 1992 23. Heinonen CP, Slone D, Shapiro S Birth Defects and Drugs in Pregnancy. Littleton, MA, Littleton Publishing Sciences Group, 1977 24. Holt J: Hypoprothrombinemia and bleeding diathesis associated with cefotetan therapy in surgical patients. Arch Surg 123:523, 1988 25. Kafetzis DA, Brater DC, Fanourgakis JE, et a1 Ceftriaxone distribution between maternal blood and fetal blood and tissues at parturition and between blood and milk postpartum. Antimicrob Agents Chemother 23:870, 1983 26. Kantor HI, Sutherland DA, Leonard JT, et a1 Effect on bilirubin metabolism in the newborn of sulfisoxazole administration to the mother. Obstet Gynecol 17494, 1961 27. Kline AH, Blattner RJ, Lunin M Transplacental effects of tetracyclines on teeth. JAMA 188:178, 1964 28. Kline SS, Mauro VF, Forney RB, et al: Cefotetan-induced disulfiram-type reactions and hypoprothrombinemia. Antimicrob Agents Chemother 31:1328,1987 29. Kropp H, Gerckens L, Sundelof JG, et al: Antibacterial activity of imipenem: The first thienamycin antibiotic. Reviews of Infectious Diseases 7(suppl):389,1984 30. Kutscher AH, Zegarelli EV, Tovell HM, et al: Discoloration of deciduous teeth induced by administration of tetracycline antepartum. Am J Obstet Gynecol96291, 1986 31. Landers DV, Green JR, Sweet RL: Antibiotic use during pregnancy and the postpartum period. Clin Obstet Gynecol 26:391, 1983 32. Lucas MJ, Cunningham FG: Urinary tract infections complicating pregnancy. In Williams Obstetrics, 19th ed. Norwalk, CT, Appkton & Lange [suppl5], 1994 33. Maberry M, Trimmer K, Bawdon R, et al: Antibiotic concentrations in maternal blood, cord blood, and placental membranes in women with chorioamnionitis (Abstract #453). Presented at the Society for Gynecologic Investigation, St. Louis, MO, March 1990 34. Margono F, Mroueh J, Garley A, et al: Resurgence of active tuberculosis among pregnant women. Obstet Gynecol83:911, 1994 35. Martens MG: Cephalosporins. Obstet Gynecol Clin North Am 16:291, 1989 36. Matsuda S, Suzuki M, Oh K, et a1 Pharmacokinetic and clinical studies of imipenem/ cilastatin sodium in the perinatal period. A study of imipenem/cilastatin sodium in the Perinatal Co-Research Group. Jpn J Antibiot 41:1731, 1988
A

ANTIBIOTIC USE IN PREGNANCY

629

37. Morgan IFK Metronidazole treatment in pregnancy. In Phillips I, Collier J (eds): Metronidazole Proceedings, Geneva, April 25-27. New York, Academic Press, 1979 38. Penick SB, Carrier RN, Sheldon J B Metronidazole in the treatment of alcoholism. Am J Psychiatr 125:1063, 1969 39. Perkins RP: Hydrops fetalis and stillbirth in a male glucose-6-phosphate dehydrogenase-deficient fetus possibly due to maternal ingestion of sulfisoxazole. Am J Obstet Gynecol 11:379, 1971 40. Peters DH, Clissold SP: Clarithromycin: A review of its antimicrobial activity, pharmacokinetic properties, and therapeutic potential. Drugs 44:117, 1992 41. Philipson A: Pharmacokinetics of ampicillin during pregnancy. J Infect Dis 136:370, 1977 42. Porter PJ, Sweeney EA, Golan H, et al: Controlled study of the effect of prenatal tetracycline on primary dentition. In Antimicrobial Agents and Chemotherapy-1965: Proceedings of the 5th Interscience Conference on Antimicrobial Agents and Chemotherapy and IVth International Congress of Chemotherapy, Washington DC, 1965, p 668 43. Powell RD, DeGowin RL, Alving A S Nitrofurantoin induced hemolysis. J Lab Clin Med 62:1002,1963 44. Quintiliani R Bleeding disorders associated with newer cephalosporins. Clin Pharm 2:360. 1983 45. Reisner DP: Uses of macrolide antibiotics in obstetrics and gynecology. Prim Care Update Ob/Gyn 3122, 1996 46. Rendle-Short TJ: Tetracycline and teeth and bone. Lancet 1:1188, 1962 47. Reyes MP, Ostrea EM, Cabinian AE, et al: Vancomycin during pregnancy: Does it cause hearing loss or nephrotoxicity in the infant? Am J Obstet Gynecol 161:977, 1989 48. Rodondi LC: Quinolones, an update. The Bulletin of the Hospital Pharmacy and Drug Information Analysis Service. Pharmacy and Therapeutics Forum, University of California, San Francisco, 35:4, 1987 49. Roe FJC: Metronidazole: A review of uses and toxicity. J Antimicrob Chemother 3:205, 1977 50. Simms-Cendan JS: Metronidazole. Prim Care Update Ob/Gyn 3:153, 1996 51. Snider DE, Layde PM, Johnson MW, et al: Treatment of tuberculosis during pregnancy. Am Rev Respir Dis 122:65,1980 52. Turgeon P, Turgeon V, Gordeau M, et al: Longitudinal study of susceptibilities of species of the Bacteroides fragilis group to five antimicrobial agents in three medical centers. Antimicrob Agents Chemother 38:2276, 1994 53. Weinstein AJ, Gibbs RS, Gallagher M Placental transfer of clindamycin and gentamicin in term pregnancy. Obstet Gynecol 124:688, 1976 54. Wendel GD, Stark BJ, Jamison RB, et a 1 Penicillin allergy and desensitization in serious maternal/fetal infections. N Engl J Med 312:1229, 1985 55. Whalley PJ, Adams RH, Combes B: Tetracycline toxicity in pregnancy: Liver and pancreatic dysfunction. JAMA 189:357, 1964 56. Williams JR, Cordie AP, Brumfitt W, et al: The treatment of bacteriuria in pregnant women with sulphamethoxazole and trimethoprim [suppl]. Postgrad Med J 45:71,1969 57. Zaske DE, Cipolle RJ, Strate RG, et al: Rapid gentamicin elimination in obstetric patients. Obstet Gynecol 56559, 1980

Address reprint requests to Jodi S. Dashe, MD Department of Obstetrics and Gynecology University of Texas Southwestern Medical Center 5323 Harry Hines Boulevard Dallas, TX 75235-9032