Drug Therapy During Labor and Delivery, Part 1

Gerald G. Briggs; Stephanie R. Wan

Disclosures

Am J Health Syst Pharm. 2006;63(11):1038-1047. 

In This Article

Antiinfective Agents During Labor and Delivery

General Considerations

Antibiotic agents are administered during the intrapartum period to prevent and treat maternal infection and to prevent neonatal disease. Short courses of antibiotics are used during the pregnancy puerperium to prevent such infections as group B streptococci (GBS) in newborns, procedure-related bacterial endocarditis, and postpartum endometritis and to treat chorioamnionitis. Many trials have evaluated the use of prophylactic antibiotics to prolong the pregnancy (and subsequently improve neonatal outcomes) after premature rupture of membranes (PROM). In addition, antiretroviral drugs in labor and delivery are used to reduce perinatal transmission from HIV-1-infected mothers.

The selection of the appropriate agent requires consideration of several factors, including the potential pathogens, the emergence of resistant organisms, the risks associated with drug exposure to the fetus and the individual maternal risk stratification. The appropriateness of regimens for those with a history of anaphylactic or allergic reactions to antibiotics must also be considered. Proper antibiotic dosage selection also requires knowledge of the physiological changes in pregnant women that may result in altered pharmacokinetics in pregnancy.

Potential Bacterial Pathogens and the Development of Resistant Organisms

A woman's normal cervical and vaginal flora changes over time in relation to her age and hormonal status. Normal female genital tract flora includes bacteria and fungi. Most infections encountered during pregnancy result from ascending contamination of the lower genital tract flora, most commonly by aerobic and anaerobic organisms. Common bacterial pathogens include gram-positive aerobes (groups A, B, and D streptococci, Streptococcus viridans, enterococci, and Staphylococcus aureus), gram-negative aerobes (Escherichia coli, Klebsiella species, Proteus mirabilis, enterobacter, Morganella morganii, and Gardnerella vaginalis), gram-positive anaerobes (Peptostreptococcus species and Clostridium perfringens), and gram-negative anaerobes (Bacteroides fragilis, Prevotella species, Fusobacterium species, Mycoplasma hominis, Ureaplasma urealyticum, and Mobiluncus species).[2]

The selection of antibiotics is often empirical, with the appropriate regimen targeted against most potential pathogens. While short courses of antibiotics are typically used, the emergence of resistant strains of bacteria is becoming an ever-increasing problem, particularly among hospitalized patients. Several studies have demonstrated postoperative colonization of resistant skin flora in patients given antimicrobial prophylaxis, with evidence existing for both the selection of resistant organisms from the preoperative flora and from the nosocomial environment.[3,4] In addition, the treatment of GBS in penicillin-allergic patients has been complicated by the increasing resistance to clindamycin and erythromycin.[5]

The presence of resistant organisms in the neonate has also been reported with the increasing maternal administration of antibiotics during labor and delivery to reduce neonatal GBS disease and to decrease neonatal morbidity associated with PROM. A study of 5447 very-low-birth-weight (VLBW) infants born between 1998 and 2000 showed a marked reduction in GBS sepsis when compared with VLBW infants born between 1991 and 1993; however, there was also an increase in neonatal E. coli sepsis, with most E. coli isolates from the 1998-2000 birth cohort showing resistance to ampicillin.[6] In this study, ampicillin was the most commonly prescribed antibiotic (49%) during the 1998-2000 period, followed by penicillin (14%) and erythromycin (13%). Another prospective cohort study performed between 1991 and 1996 of 42 cases of early-onset neonatal sepsis concluded that the increased administration of antenatal ampicillin to pregnant women during these years may be responsible for the increased incidence of early-onset neonatal sepsis with non-GBS organisms that are resistant to ampicillin.[7]

Risks of Antibiotic Exposure to the Fetus

When administered to the mother in the antepartum period, all antibiotics are expected to cross the placenta and enter the fetal circulation to some degree. Greater transfer of drugs occurs with advancing gestational age and with agents that are minimally protein bound, as with ampicillin.[8] In general, relatively few antibiotics are contraindicated in pregnancy, and many are considered compatible or likely low risk. Most of the commonly used antibiotics are compatible with pregnancy, including penicillins, cephalosporins, vancomycin, clindamycin, and erythromycin (base, stearate, or ethyl-succinate).[9] Short courses of aminoglycosides at standard doses (e.g., gentamicin 1.5-2 mg [as the sulfate salt]/kg every eight hours) are also compatible, but peak maternal serum concentrations should not exceed normal therapeutic levels because of concerns of fetal toxicity. Since maternal drug concentrations are a major determinant of fetal concentrations, standard dosing is preferred over extended-interval dosing because the latter regimen can result in supratherapeutic peak maternal serum aminoglycoside levels.[10] A recent study of extended-interval versus standard dosing of gentamicin in pregnant women at greater than 34 weeks of gestation demonstrated peak maternal gentamicin serum concentrations ranging from 13 to 25 µg/mL after a dose of 5.1 mg/kg.[10] Although this study showed no adverse fetal effects as a result of the drug in either group, we recommend standard aminoglycoside dosing in pregnant women, as the extended-interval regimen is preferred in those patients with predictable volumes of distribution and drug clearance.

A few antibiotics are either contraindicated or to be used with caution during pregnancy; some are of concern especially when used near term. Tetracyclines are contraindicated in the second and third trimesters secondary to adverse effects on fetal teeth and bones and maternal hepatotoxicity.[9] The use of fluoroquinolones during pregnancy is controversial because of reports of arthropathy in immature animals after fluoroquinolone administration. However, no reports have confirmed this association in humans after in utero exposure, and current human data suggest low risk.[9,11] Human data on nitrofurantoin exposure in the third trimester suggest risk, and it should be avoided near term (38-42 weeks' gestation).[12,13] Nitrofurantoin may induce hemolytic anemia in glucose-6-phosphate dehydrogenase-deficient patients and in patients whose red blood cells are deficient in glutathione, a concern in newborns secondary to their glutathione instability. Sulfonamides should also be avoided near term because of the potential for jaundice and hemolytic anemia in the newborn.[14,15] Dose-related toxicities with streptomycin and kanamycin have been reported, specifically eighth cranial nerve and kidney damage in the mother and neonate[16]; the prolonged use of these agents should be avoided throughout pregnancy.

Pharmacokinetics of Antibiotics During Pregnancy

Pregnancy is associated with marked alterations in maternal physiology. Of particular note are the dramatic changes in renal function. Improved clearance of drugs is attributed to the large expansion of maternal blood volume via increased cardiac output, increased renal blood flow, and increased glomerular filtration rate.[17,18] Combined with greater volume of distribution, increased hepatic metabolism, and sequestration of drugs in the fetal compartment, maternal drug levels are approximately 10-50% lower in late pregnancy and in the immediate postpartum period when compared to nonpregnant women.[19] Medications excreted renally are expected to have shorter half-lives and reach lower peak serum levels in pregnant women. Treatment with penicillins, cephalosporins, aminoglycosides, and erythromycin results (or is thought to result) in abnormally low systemic antibiotic levels in pregnancy.[20] Unfortunately, most of these pharmacokinetic effects have not been extensively studied, and it is unclear what the clinical significance of these decreased drug levels in pregnancy may be.

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