Omeprazole

 Risk Factor: CM
 Class: GASTROINTESTINAL AGENTS / Antisecretory Agents

Contents of this page:

Fetal Risk Summary
Breast Feeding Summary
References
Questions and Answers

Fetal Risk Summary

The antisecretory agent omeprazole, a proton pump inhibitor, suppresses gastric acid secretion by a direct inhibitory effect on the gastric parietal cell (1). It is used for the treatment of duodenal and gastric ulcers, erosive esophagitis, and pathologic hypersecretory conditions, such as Zollinger-Ellison syndrome.

In reproductive studies in pregnant rats and rabbits, doses up to approximately 345 and 172 times, respectively, the normal human dose produced no evidence of teratogenicity, but dose-related embryo and fetal mortality was observed (1). A dose-dependent increase in gastric cell carcinoid tumors has been observed in rats (1). The in vitro Ames mutagen assay was negative. Other tests for genotoxicity in mice and rats were either borderline or negative (1).

Omeprazole crosses the placenta to the fetus in sheep (2) and in humans (3). In sheep, the fetal:maternal ratio of total omeprazole, after both low and high dosage, was 0.2, but the ratio of unbound drug was 0.5 (2). Urinary clearance of the drug was low in both the mother and the fetus.

Placental passage of omeprazole in humans was demonstrated in a study published in 1989 (3). Twenty women were administered a single 80-mg oral dose of omeprazole the night before scheduled cesarean sections with a mean dosing-togeneral anesthesia induction time interval of 853 minutes (range of 765977 minutes) (3). At the time of surgery, maternal omeprazole levels ranged from 0 to 271 nmol/L. The drug concentration in 13 of the 20 infants (both arterial and venous umbilical samples were drawn in most cases) was either 0 or below the minimum detection limit (20 nmol/L). In the remaining 7 infants, omeprazole cord blood concentrations ranged from 21 to 109 nmol/L. No adverse effects attributable to the drug were observed either at birth or at follow-up in 7 days.

The FDA has received reports, following pregnancy exposure to omeprazole, of 11 specified birth defects, 4 of which were anencephaly and 1 of which was a hydranencephaly that developed de novo after starting omeprazole in the 13th gestational week (F. Rosa, personal communication, FDA, 1996).

A paper published in 1995 described the use of omeprazole, 20 mg daily for esophageal reflux, by a woman in two consecutive pregnancies that were terminated because of severe congenital anomaliesanencephaly in one and severe talipes in the other (4). The first pregnancy was the result of a gamete intrafallopian transfer (GIFT) procedure, and the second occurred after a natural conception. Both aborted fetuses had normal chromosomal patterns.

A woman with Zollinger-Ellison syndrome was treated in two of her three pregnancies with omeprazole (5). In her first pregnancy, she had been treated with ranitidine (300 mg/day) and other therapy during the 2nd and 3rd trimesters and delivered a healthy, 2560-g boy at 37 weeks' gestation. She then presented at 11 weeks' gestation in her second pregnancy, complaining of abdominal pain and vomiting. Her symptoms were controlled with omeprazole (120 mg/day), which was continued until delivery of a healthy, 2610-g girl. During the third pregnancy, she was treated throughout gestation with omeprazole (180 mg/day) and cimetidine (450 mg/day), delivering a healthy, term 2550-g male infant.

Data from the Swedish Medical Birth Registry were presented in 1998 (6). 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] 1.84.9) compared with the crude malformation rate of 3.9% in the Registry. The odds ration (OR) for a congenital malformation, stratified for birth year, maternal age, parity, and smoking was 0.72 (95% CI 0.411.24) (6). The OR for malformations after proton pump blocker exposure was 0.91 (95% CI 0.451.84) compared with 0.46 (95% CI 0.171.20) for H2-receptor antagonists (OR 0.86, 95% CI 0.332.23; 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 Lansoprazole), whereas only one such defect occurred in those exposed to H2 antagonists. Omeprazole was the only acid-suppressing drug exposure in 262 infants. Twenty other offspring were exposed in utero to omeprazole combined either with cimetidine (2 infants) or ranitidine (18 infants). Eight birth defects (3.1%) were observed in the group where omeprazole was the only acid-suppressing agent used. The defects were ventricular septum defect (N=3), and one each of patent ductus arteriosus, unspecified cardiac defect, urethral valve (detected at 1 month of age), facial anomaly (type not specified), and Down's syndrome. In addition, one infant with hypospadias was observed in a newborn exposed to a combination of omeprazole and ranitidine (6).

A prospective cohort study published in 1998 described the pregnancy outcomes of 113 women exposed to omeprazole (101 during organogenesis) matched to 113 disease-paired controls (exposed to H2-receptor antihistamines) and 113 controls who were exposed to nonteratogenic agents (e.g., dental radiation, acetaminophen) (7). All of the subjects and controls had contacted a teratogen information service to inquire about drug exposures during their pregnancy. Omeprazole-exposed women were from Canada (N=59), Italy (N=41), and France (N=13), whereas all of the 226 controls were from Canada (Motherisk Program in Toronto). There were no significant differences between the groups in alcohol use and smoking. However, omeprazole-exposed women used significantly more antipeptic and prokinetic agents (histamine blockers, antacids, sucralfate, bismuth subsalicylate, calcium carbonate, and cisapride) than women in the two control groups. Pregnancy outcomes were determined from information supplied by the women shortly after delivery. No significant differences between the three groups in terms of live births, spontaneous abortions, elective abortions, gestational age at delivery, preterm delivery, Cesarean section, and birth weight were observed (7). The incidence of major anomalies in live births exposed during the 1st trimester in the three groups were 4 of 78 (5.1%), 3 of 98 (3.1%), and 2 of 66 (3.0%), respectively. The four malformations in omeprazole-exposed infants were ventricular septal defect, polycystic kidneys, ureteropelvic junction stenosis, and patent ductus arteriosus. In disease-paired controls, the three defects were atrial septal defect and two cases of ventricular septal defect, whereas in nonteratogenic controls the two malformations were atrial septal defect with pulmonary stenosis and developmental delay. Although the study lacked the statistical power to detect a small increase in major malformations, the authors concluded that it was unlikely that omeprazole was a major teratogen (7).

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 (8). 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 newborns (10 sets of twins). In addition, two birth defects were observed in aborted fetuses. However, few of the aborted fetuses were examined. Omeprazole was taken during the 1st trimester in five pregnancies. The outcomes of these pregnancies included one elective abortion and four normal, full-term infants (8).

The pregnancy outcomes of nine women who had taken omeprazole (2060 mg/day) during gestation were described in 1998 publication (9). Four of the women took omeprazole during the 1st trimester and five started treatment in the 2nd or 3rd trimesters. No complications or congenital malformations were observed in the offspring or during subsequent follow-up periods ranging from 2 to 12 years (9).

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') (10). 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 the 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. Compared with 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 0.55.2), low birth weight 1.8 (95% CI 0.213.1), and preterm delivery (not adjusted for gestational age) 2.3 (95% CI 0.96.0). 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 (10).

Two databases, one from England and the other from Italy, were combined in a study published in 1999 that was designed to assess the incidence of congenital malformations in women who had received a prescription for an acid-suppressing drug (omeprazole, cimetidine, or ranitidine) during the 1st trimester (11). Nonexposed women were selected from the same databases to form a control group. Spontaneous abortions and elective abortions (except two cases of prenatally diagnosed congenital anomalies that were grouped with stillbirths) were excluded from the analysis. Stillbirths were defined as any pregnancy loss occurring at 28 weeks' gestation or later. Omeprazole was taken in 134 pregnancies, resulting in 139 live births (11 [7.9%] premature), 5 (3.7%) of whom had a congenital malformation. There were no stillbirths or neonatal deaths. The malformations were (shown by system): head/face (tongue tie), heart (septal defects, N=2), muscle/skeleton (dysplastic hip/dislocation/clicking hip), and genital/urinary (congenital hydrocele/inguinal hernia). In addition, three newborns had a small head circumference for gestational age. In comparison, the outcomes of 1,547 nonexposed pregnancies included 1,560 live births (115 [7.4%] premature), 15 stillbirths (includes 2 elective abortions for anomalies), and 10 neonatal deaths. Sixty-four (4.1%) of the newborns had malformations, including defects of the central nervous system (N=2), head/face (N=13), eye (N=2), heart (N=7), muscle/skeleton (N=13), genital/urinary (N=18), gastrointestinal (N=2), and those that were polyformation (N=3) or known genetic anomalies (N=4). There were 21 newborns that were small for gestational age and 78 had a small head circumference for gestational age. The relative risk of malformation (adjusted for mother's age and prematurity) associated with omeprazole was 0.9 (95% CI 0.42.4), with cimetidine 1.3 (95% CI 0.72.6), and with ranitidine 1.5 (95% CI 0.92.6) (11).

A 1998 case report described a 41-year-old woman with refractory gastroesophageal reflux disease (GERD) who was treated with omeprazole (20 mg/day) starting at 29 weeks' gestation (12). Previous treatment with ranitidine (late 1st trimester), cisapride (2nd trimester), or a combination of the two had been unsuccessful. A slightly premature male child (birth weight not given) with fetal bradycardia was delivered in the 36th week with Apgar scores of 6 and 9 at 1 and 5 minutes, respectively. He was doing well at 1 year of age (12).

Several investigations have studied the effect of omeprazole for prophylaxis against aspiration pneumonitis in emergency cesarean section (13,14,15,16,17 and 18). No adverse effects were noted in the newborns.

In summary, the lack of teratogenicity in animals and the bulk of the human 1st-trimester exposure data indicate that omeprazole is not a major human teratogen. None of the cohort studies measured a significant increase in the rates of major birth defects, but they lacked the power to detect small increases in birth defects or rare malformations. The small cluster of cardiac defects observed in one study after omeprazole exposure appears to be an errant signal as it was not confirmed in other studies. Most likely, cardiac and other defects observed in all studies were the result of many factors, including possibly the severity of the disease and concurrent use of other drugs. The data, however, 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 of the data collection. The gastric tumors observed in rats are a potential concern for human offspring, but the dose-related nature of the tumors and the limited in utero exposure during gestation probably indicates a negligible risk. However, as with all drug therapy, avoidance of omeprazole during pregnancy, especially during the 1st trimester, is the safest course. If omeprazole 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

Only one report describing the use of omeprazole during human lactation has been located. A woman with refractory GERD was treated with omeprazole (20 mg/day) for 78 weeks before delivering a premature male infant (birth weight not given) at 36 weeks' gestation (see above) (12). Treatment was continued after birth during breast feeding. During this time, she fed her infant son just before taking her dose at 8 AM, refrained from nursing for 4 hours, then expressed and discarded her milk at 12 noon. At 3 weeks postpartum, blood and milk samples were obtained at 8 AM and then every 30 minutes for 4 hours (i.e., until 12 noon). The milk was obtained by expressing but the volume of the samples was not specified. Maternal serum concentrations began to rise 90 minutes after the dose, reached 950 nM at 12 noon, and appeared to be still rising. Breast milk levels also began to rise at 90 minutes and peaked at 180 minutes at 58 nM. The infant was doing well at 1 year of age.

The above case report estimated a maximum daily omeprazole exposure of 4 g, but the calculation was based on a consumption of only 200 mL of milk/day for a 5-kg infant (40 mL/kg/day). A more acceptable value is 150 mL/kg/day (19). Moreover, the milk samples were obtained by expression and the volumes expressed were not given. This is clinically relevant because hindmilk obtained at the end of a feeding is 45 times higher in fat than foremilk (20). For lipid-soluble drugs, such as omeprazole, hindmilk would be expected to contain most of the drug in milk.

In concurrence with the above case report, the relatively low molecular weight of omeprazole (about 345) predicts that it will be excreted into human milk. In rats, administration of omeprazole at a dose 35345 times the human dose during late gestation and lactation resulted in decreased pup weight gain (1). The clinical significance of this for nursing human infants is unknown.

One source has stated that the safety of a drug during breast feeding can be arbitrarily defined as no more than 10% of the adult dose standardized by weight if a therapeutic dose for infants is not known (13). Until additional studies show that omeprazole meets this criterion, the use of omeprazole during breast feeding should probably be avoided. Other concerns, such as the carcinogenicity observed in animals and the potential for suppression of gastric acid secretion in the nursing infant, also warrant further study.

References

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3. Moore J, Flynn RJ, Sampaio M, Wilson CM, Gillon KRW. Effect of single-dose omeprazole on intragastric acidity and volume during obstetric anaesthesia. Anaesthesia 1989;44:55962.
4. Tsirigotis M, Yazdani N, Craft I. Potential effects of omeprazole in pregnancy. Hum Reprod 1995;10:21778.
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