LANSOPRAZOLE

Fetal Risk Summary

Lansoprazole is a proton pump inhibitor that blocks gastric acid secretion by a direct inhibitory effect on the gastric parietal cell (1). It is used for the treatment of gastric and duodenal ulcer, erosive esophagitis, gastroesophageal reflux disease (GERD), and pathologic hypersecretory conditions, such as Zollinger-Ellison syndrome. It is also used in combination with amoxicillin and/or clarithromycin for Helicobacter pylori eradication to reduce the risk of duodenal ulcer recurrence.

Reproductive studies have been conducted in pregnant rats and rabbits at oral doses up to 40 and 16 times, respectively, the recommended human dose based on body surface area (1). No evidence was found that these doses impaired fertility or caused fetal harm. Similar to other proton pump inhibitors, lansoprazole is carcinogenic in mice and rats producing dose-related gastric, testicular, and liver tumors (1). In addition, positive results were seen with lansoprazole in the in vitro human lymphocyte chromosomal aberration assays, but the Ames mutation assay and other genotoxic animal tests were negative (1).

In a study published in 1990, lansoprazole at a dose of 50 or 300 mg/kg was not teratogenic in pregnant rats, but a decrease in fetal weight occurred (2). Schardein also cited a 1990 study, which appears to be similar to the one cited above, that found no evidence of teratogenicity in rats and rabbits (3).

It is not known if lansoprazole crosses the human placenta. The molecular weight (about 369) is low enough, however, that passage to the fetus should be expected. Another proton pump inhibitor, omeprazole, has a molecular weight (about 345) and chemical structure that is very similar to lansoprazole, and it is known to cross the human placenta (see Omeprazole).

A 1998 non-interventional observational cohort study described the outcomes of pregnancies in women who had been prescribed one or more of 34 newly marketed drugs by general practitioners in England (4). Data were obtained by questionnaires sent to the prescribing physicians one month after the expected or possible date of delivery. In 831 (78%) of the pregnancies, a newly marketed drug was thought to had been taken during the 1st trimester with birth defects noted in 14 (2.5%) singleton births of the 557 live newborns (10 sets of twins). In addition, two birth defects were observed in aborted fetuses. However, few of the aborted fetuses were examined. Lansoprazole was taken during the 1st trimester in six pregnancies. Seven healthy newborns (one premature; one set of twins) were delivered (4).

Data from the Swedish Medical Birth Registry were presented in 1998 (5). A total of 553 infants (6 sets of twins) were delivered from 547 women who had used acid-suppressing drugs early in pregnancy. A number of other pharmaceutical agents, identified only by drug category, were also used by these women. Seventeen infants with birth defects were identified (3.1%; 95% Confidence Interval [CI] 1.8–4.9) compared with the crude malformation rate of 3.9% in the Registry. The odds ratio (OR) for a congenital malformation, stratified for birth year, maternal age, parity, and smoking was 0.72 (95% CI 0.41–1.24) (5). The OR for malformations after proton pump blocker exposure was 0.91 (95% CI 0.45–1.84) compared to 0.46 (95% CI 0.17–1.20) for H2-receptor antagonists (OR 0.86, 95% CI 0.33–2.23; p=0.13). Of the 17 infants with birth defects, 10 had been exposed to proton pump blockers, 6 to H2 antagonists, and 1 to both classes of drug. Six of the defects in the proton pump inhibitor group were cardiovascular defects (see also Omeprazole), whereas only one such defect occurred in those exposed to H2 antagonists. Lansoprazole was the only acid-suppressing drug exposure in 13 infants. Two birth defects were observed in this group: atrial septum defect and an undescended testicle (5).

In a study published in 1999, investigators linked data from a Danish prescription database to a birth registry to evaluate the risks of proton pump inhibitors for congenital malformations, low birth weight, and preterm delivery (<37 weeks') (6). From a total of 51 women who had filled a prescription for these drugs sometime during pregnancy, 38 (omeprazole N=35, lansoprazole N=3) had done so during the interval of 30 days before conception to the end of the 1st trimester. A control group, consisting of 13,327 pregnancies in which the mother had not obtained a prescription for reimbursed medication from 30 days before conception to the end of her pregnancy, was used for comparison. The prevalence of major congenital anomalies in controls was 5.2%. Three major birth defects (7.9%), two of which were cardiovascular anomalies, were observed from the 38 pregnancies possibly exposed in the 1st trimester (specific drug exposure not given): ventricular septum defect; pyloric stenosis; and one case of patent ductus arteriosus, atrial septum defect, hydronephrosis, and agenesis of the iris. In comparison to controls, the adjusted (for maternal age, birth order, gestational age, and smoking, but not for alcohol abuse) relative risks for the three outcomes were congenital malformations 1.6 (95% CI 0.5–5.2), low birth weight 1.8 (95% CI 0.2–13.1), and preterm delivery (not adjusted for gestational age) 2.3 (95% CI 0.9–6.0). Although the study found no elevated risks for the three outcomes, the investigators cautioned that more data were needed to assess the possible association between proton pump inhibitors and cardiac malformations or preterm delivery (6).

In summary, the lack of teratogenicity in animals is reassuring, but the limited human pregnancy experience prevents an assessment of the risk from this drug. Birth defects, including cardiac defects, have been reported in pregnancies exposed to a proton pump inhibitor (see also Omeprazole), but there is no evidence of a causal association. Most likely, the observed defects were the result of many factors, including possibly the severity of the disease and concurrent use of other drugs. The data do warrant continued investigation. In addition, the studies lacked the sensitivity to detect minor anomalies because of the absence of standardized examinations. Late appearing major defects may also have been missed due to the timing of some data collection. The carcinogenicity data are a potential concern, but the dose-related nature of the tumors and the presumable limited in utero exposure to the drug during human gestation probably indicates a negligible risk. However, as with all drug therapy, avoidance of lansoprazole during pregnancy, especially during the 1st trimester, is the safest course. If lansoprazole is required or if inadvertent exposure does occur early in gestation, the known risk to the embryo/fetus appears to be low. Long-term follow-up of offspring exposed during gestation is warranted.

Breast Feeding Summary

No reports describing the use of lansoprazole during human lactation have been located. Both lansoprazole and its metabolites are excreted in the milk of lactating rats (1), and their excretion in human milk should be expected. Because of the carcinogenicity observed in animals, and the potential for suppression of gastric acid secretion in the nursing infant, the use of lansoprazole during lactation should probably be avoided.

References

1. Product information. Prevacid. Tap Pharmaceuticals, 2001.
2. Schardein JL, Furuhashi T, Ooshima Y. Reproductive and developmental toxicity studies of lansoprazole (ag-1749) in rats and rabbits. Yakuri to Rinsho 1990;18:S2773–83. As cited by Shepard TH. Catalog of Teratogenic Agents. 8th ed. Baltimore:Johns Hopkins University Press, 1995:245.
3. Schardein JL, Furuhashi T, Ooshima Y. Reproductive and developmental toxicity studies of lansoprazole (AG-1749) in rats and rabbits. Jpn Pharmacol Ther 1990;18(Suppl 10):119–29. As cited by Schardein JL. Chemically Induced Birth Defects. 2nd ed. New York:Marcel Dekker, 1993:447.
4. Wilton LV, Pearce GL, Martin RM, Mackay FJ, Mann RD. The outcomes of pregnancy in women exposed to newly marketed drugs in general practice in England. Br J Obstet Gynaecol 1998;105:882–9.
5. Kallen B. Delivery outcome after the use of acid-suppressing drugs in early pregnancy with special Reference to omeprazole. Br J Obstet Gynaecol 1998;105:877–81.
6. Nielsen GL, Sorensen HT, Thulstrup, Tage-Jensen U, Olesen C, Ekbom A. The safety of proton pump inhibitors in pregnancy. Aliment Pharmacol Ther 1999;13:1085–9.