I frequently get calls from physicians who have questions about the safety of different anti-infectives during pregnancy or breast-feeding. In this and future columns, I will review what is known about this large class of drugs when used in these two situations.

* Penicillins. There is

no evidence that exposure to penicillins during any stage of pregnancy is associated with birth defects or direct fetal toxicity. All are rated pregnancy category B and cross the placenta throughout pregnancy. Products that combine a penicillin with a [beta]-lactamase inhibitor, such as clavulanate with amoxicillin (Augmentin) or ticarcillin (Timentin) and sulbactam with ampicillin (Unasyn), also appear to be safe during pregnancy.

When used near term, however, indirect toxicity may occur with extended-spectrum penicilins. Ampicillin has been linked to an increased risk of ampicillin-resistant Escherichia coli sepsis in newborns, so many centers no longer use it for pregnant women who carry group B streptococci. Instead, they use the more narrow-spectrum penicillin G.

A recent study found an increased incidence of necrotizing enterocolitis in newborns exposed to amoxicillin/clavulanate in utero, attributed to antibiotic-induced abnormal colonization of the neonatal intestinal tract with Clostridium difficile. However, further study is needed to confirm this association.

All penicillins are excreted into breast milk but are compatible with breastfeeding. Nursing infants exposed to these agents should be observed for possible adverse effects such as diarrhea, thrush, and allergic reactions.

* Cephalosporins. Cephalosporins, rated category B, are believed to cross the placenta and are excreted into breast milk. There is no evidence of indirect or direct toxicities to the embryo, fetus, or newborn exposed to any cephalosporin, or of any problems reported with exposure through breast milk. Cephalosporins are compatible with nursing, but the infant should be monitored for adverse effects similar to those caused by the penicillins.

* Tetracyclines. All are rated D. They are not teratogenic or embryo-fetotoxic in the first trimester. But starting in the second trimester, they are rapidly taken up by mineralizing tissue such as the teeth or bone, causing discoloration of the deciduous teeth. This process also inhibits fetal skeletal growth but is clinically insignificant because skeletal growth undergoes a catch-up phase when exposure stops. Women who are breast-feeding can take tetracycline. A very small amount is excreted into breast milk, but it is bound with calcium so that only a negligible amount is absorbed by the newborn.

* Macrolides. Their safety during pregnancy and lactation varies. Erythromycin is rated B and is the best macrolide to use during pregnancy because of the amount of human data and experience with this drug. There's no evidence of fetal or embryo teratogenicity in humans or toxicity to the embryo or fetus with exposure at any stage of gestation with the base or various salt forms. The exception is the estolate salt, which has been associated with maternal hepatotoxicity when used during the second trimester and should be avoided during pregnancy Erythromycin is excreted into breast milk and is considered compatible with breast-feeding.

Azithromycin (Zithromax) is rated B. There is no evidence of teratogenicity or embryo-fetal harm when used at any stage during pregnancy, but this is based on fewer than 100 exposed pregnancies reported in the literature. Azithromycin accumulates in breast milk, so I would be cautious about its use during breast-feeding.

Clarirhromycin (Biaxin) is rated C. What sets it apart is that in some rat and mice studies there was a low incidence of cardiovascular anomalies and cleft palate at doses close to human doses. There have been no such reports in humans, but human data are limited. One 1998 study found a significant increase in spontaneous abortions in women exposed to this agent during the first trimester in comparison with a control group. Although this needs to be confirmed, the safest course would be to avoid prescribing this drug until after the first trimester.

There are no reports of use during breast-feeding, but clarithromycin accumulates in rat milk, which raises some concern.

Dirithromycin (Dynabac) is rated C. In mice and rat studies, it was not teratogenic but was associated with fetal growth retardation at doses dose to those used in humans. There are no reports of use during pregnancy or breastfeeding in humans. Since this is a relatively new drug, I recommend caution until more information is available.

GERALD G. BRIGGS is clinical pharmacist, Women's Hospital, Long Beach Memorial Medical Center; clinical professor of pharmacy University of California, San Francisco; and adjunct associate professor of pharmacy University of Southern California, Los Angeles.