Drugs, Pregnancy, And Lactation

OB/GYN News, Feb 1, 2001 by Gerald G. Briggs

[Histamine.sub.2] Blockers and Proton Pump Inhibitors

None of the four [histamine.sub.2] blockers currently available are teratogenic or carcinogenic in animals, nor are they mutagenic. They are rated pregnancy category B drugs, but there are limited or no human data for two of the agents.

There is no evidence that cimetidine (Tagamet) is teratogenic in humans, based on data from a Michigan Medicaid study and studies from Sweden, Italy, and England.

What sets cimetidine apart from the other [H.sub.2] blockers is that it has weak antiandrogenic activity in both humans and animals, and it also reduces cytochrome P450 pathway metabolism, raising concerns about the potential risks of feminization in males and significant drug interactions. Therefore, cimetidine would not be the best [H.sub.2] blocker to use during pregnancy.

Cimetidine is concentrated in human breast milk at up to seven times plasma levels, which doesn't appear to have any clinical significance. The American Academy of Pediatrics (AAP) considers this drug to be compatible with breast-feeding.

Famotidine (Pepcid) is associated with few, if any drug interactions. There is also no evidence that famotidine is teratogenic in humans, but this is based on very few human data. It also concentrates in breast milk, but to a much lesser degree than cimetidine or ranitidine (Zantac), so it would be preferred during breast-feeding.

Nizatidine (Axid) has few, if any drug interactions, but there are almost no pregnancy or breast-feeding data on this drug in humans. Based on animal data and human data on the other [H.sub.2] blockers, nizatidine is probably safe during pregnancy and lactation. If a woman becomes pregnant while taking this drug, there would certainly be little reason for concern.

Ranitidine is not carcinogenic or teratogenic in animals, or mutagenic. There are a few drug interactions with this drug, but their clinical significance appears to be less than those occurring with cimetidine. There has been no evidence in American and European studies that it is teratogenic in humans.

Ranitidine is also concentrated in breast milk at up to seven times plasma levels, but since the AAP considers cimetidine compatible with breast-feeding, I would consider ranitidine to also be compatible.

All four proton pump inhibitors (PPIs) currently available are also not teratogenic in animals. In studies in Europe, there has been no evidence that omeprazole (Prilosec) is a human teratogen. In a Swedish study there was a small cluster (five cases) of congential heart defects in newborns exposed in utero to this drug, but this was not significant and was most likely an errant signal. There is also no evidence that lansoprazole (Prevacid) is a human teratogen, based on studies in Sweden, England, and Denmark.

What distinguishes omeprazole from the other PPIs is a dose-related increase in embryo and fetal mortality in rats and rabbits, which is why this drug is rated a pregnancy category C, and the other PPIs are rated category B.

There are no human pregnancy data on the newer PPIs, pantoprazole (Protonix) and rabeprazole (Aciphex). But based on their lack of animal teratogenicity and the human data available for omeprazole and lansoprazole, inadvertent exposure to these two drugs during pregnancy would not be a concern.

All four PPIs are carcinogenic in animals, and there is some indication there is a potential for carcinogenic effects in human adults who have taken the drug for prolonged periods, as evidenced by precancerous changes.

The carcinogenicity risk in offspring exposed in utero to these drugs has not been studied; this will require long-term follow-up of newborns exposed in utero.

None of the mutagenicity tests that have been performed with omeprazole have been positive, but some of the mutagenicity tests done on the other three were, raising some concern about the use of these drugs during pregnancy and lactation.

There are no human data on these drugs during lactation, but they are concentrated in the breast milk of rats. Based on this information, the mutagenicity and carcinogenicity data, and the potential suppression of gastric acid secretion, these four drugs, if possible, should not be used or started during lactation. This is a conservative approach, which is acceptable when there are no human data on a drug.

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. He is also coauthor of the textbook "Drugs in Pregnancy and Lactation."