BISMUTH SUBSALICYLATE

Fetal Risk Summary

Bismuth subsalicylate (bismuth salicylate) is hydrolyzed in the gastrointestinal tract to bismuth salts and sodium salicylate (1,2). Two tablets or 30 mL suspen sion of the compound yields 204 mg and 258 mg, respectively, of salicylate. Inorganic bismuth salts, in contrast to organic complexes of bismuth, are relatively water-insoluble and poorly absorbed systemically, but significant absorption of salicylate does occur (1,2). A brief 1992 study found minimal absorption of bismuth (exact serum concentrations not specified) from bismuth subsalicylate in 12 healthy subjects as opposed to a peak serum level of 0.050 µg/mL after a dose of 216 mg of colloidal bismuth subcitrate in a single patient (3). Some bismuth absorption was documented across the normal gastric mucosa, but the primary absorption occurred from the duodenum (3). Others believe, however, that the design of the study produced the observed results, and that bismuth absorption occurs only in the gastric antrum, not in the gastric body or duodenum (4).

Although absorption of inorganic bismuth salts is negligible, in a study of chronic administration of bismuth tartrate 5 mg/kg/day, one of four lambs born of treated ewes was stunted, hairless, and exophthalmic, and a second was aborted (5). Moreover, in one case report, the use of an extemporaneously compounded antidiarrheal mixture containing bismuth subsalicylate was associated with bismuth encephalopathy in a 60-year-old man who took an unknown amount of the preparation for a period of 1 month (6). Encephalopathy was diagnosed by an electroencephalogram characteristic of bismuth toxicity and a blood bismuth level of 72 ng/mL (upper limit of normal is 5 ng/mL).

No reports of adverse fetal outcome after the use of commercially available bismuth subsalicylate have been located for humans. The Collaborative Perinatal Project recorded 15 1st trimester exposures to bismuth salts (bismuth subgallate N= 13, bismuth subcarbonate N=1, and milk of bismuth N=1), but none to bismuth subsalicylate (7, pp. 384–7). These numbers are small, but no evidence was found to suggest any association with congenital abnormalities. For use anytime during pregnancy, 144 mother-child pairs were exposed to bismuth subgallate and 5 of the in utero exposed infants had inguinal hernia, a hospital standardized relative risk (SRR) of 2.6 (7, pp. 442,497). A causal relationship, however, cannot be determined from these data.

In contrast to bismuth, salicylate is rapidly absorbed with more than 90% of the dose recovered in the urine. Data on the use of salicylates in human pregnancy, primarily acetylsalicylic acid (aspirin), is extensive. The main concerns from exposure to this drug during pregnancy include congenital defects, increased perinatal mortality from premature closure of the ductus arteriosus in utero, intrauterine growth retardation, and salicylate intoxication (see Aspirin). An increased risk of intracranial hemorrhage in premature or low-birth-weight infants is a potential complication of aspirin exposure near delivery, but other salicylates, including sodium salicylate, probably do not present a risk because the presence of the acetyl moiety seems to be required to suppress platelet function (8,9 and 10).

In summary, inorganic bismuth salts, formed from metabolism of bismuth subsalicylate in the gastrointestinal tract, apparently present little or no risk to the fetus from normal therapeutic doses, but the data available for bismuth in pregnancy are poor and the actual fetal risk cannot be determined (11). On the other hand, the potential actions of salicylates on the fetus are complex. Although the risk for toxicity may be small, significant fetal adverse effects have resulted from chronic exposure to salicylates. Because of this, the use of bismuth subsalicylate during gestation should be restricted to the first half of pregnancy, and then only in amounts that do not exceed the recommended doses.

Breast Feeding Summary

The excretion of large amounts of bismuth obtained from bismuth subsalicylate into breast milk is not expected because of the poor absorption of bismuth into the systemic circulation. Salicylates, however, are excreted in milk and are eliminated more slowly from milk than from plasma with milk:plasma ratios rising from 0.03–0.08 at 3 hours to 0.34 at 12 hours (12). Because of the potential for adverse effects in the nursing infant, the American Academy of Pediatrics recommends that salicylates should be used cautiously during breast feeding (13). A recent review also states that bismuth subsalicylate should be avoided during lactation because of systemic salicylate absorption (14).

References

1. Pickering LK, Feldman S, Ericsson CD, Cleary TG. Absorption of salicylate and bismuth from a bismuth subsalicylate-containing compound (Pepto-Bismol). J Pediatr 1981;99:654–6.
2. Feldman S, Chen S-L, Pickering LK, Cleary TG, Ericsson CD, Hulse M. Salicylate absorption from a bismuth subsalicylate preparation. Clin Pharmacol Ther 1981;29:788–92.
3. Menge H, Brosius B, Lang A, Gregor M. Bismuth absorption from the stomach and small intestine. Gastroenterology 1992;102:2192.
4. Nwokolo CU, Pounder RE. Bismuth absorption from the stomach and small intestine. Reply. Gastroenterology 1992;102:2192–3.
5. James LF, Lazar VA, Binns W. Effects of sublethal doses of certain minerals on pregnant ewes and fetal development. Am J Vet Res 1966;27:132–5.
6. Hasking GJ, Duggan JM. Encephalopathy from bismuth subsalicylate. Med J Aust 1982;2:167.
7. Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA:Publishing Sciences Group, 1977.
8. O'Brien JR. Effects of salicylates on human platelets. Lancet 1968;1:779–83.
9. Weiss HJ, Aledort ML, Shaul I. The effect of salicylates on the haemostatic properties of platelets in man. J Clin Invest 1968;47:2169–80.
10. Bleyer WA. Maternal ingested salicylates as a cause of neonatal hemorrhage. J Pediatr 1974;85:736–7.
11. Friedman JM, Little BB, Brent RL, Cordero JF, Hanson JW, Shepard TH. Potential human teratogenicity of frequently prescribed drugs. Obstet Gynecol 1990;75:594–9.
12. Findlay JWA, DeAngelis RL, Kearney MF, Welch RM, Findley JM. Analgesic drugs in breast milk and plasma. Clin Pharmacol Ther 1981;29:625–33.
13. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137–50.
14. Anderson PO. Drug use during breast feeding. Clin Pharm 1991;10:594–624.