Metoclopramide Risk Summary

Risk Factor: BM
Class: Gastrointestinal agents / Stimulants

Fetal Risk Summary

Metoclopramide has been used during pregnancy as an antiemetic and to decrease gastric emptying time (1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23 and 24). Reproductive studies in mice, rats, and rabbits at doses up to 250 times the human dose have revealed no evidence of impaired fertility or fetal harm as a result of the drug (25). Metoclopramide (10 mg IV) in pregnant sheep increased maternal heart rate, but had no effect on maternal blood pressure, uterine blood flow, or fetal hemodynamic variables (26).

No congenital malformations or other fetal or newborn adverse effects attributable to the drug have been observed. Except for the one study noted below (7), long-term evaluation of infants exposed in utero to metoclopramide has not been reported.

Metoclopramide crosses the placenta at term (1,2 and 3). Cord:maternal plasma ratios were 0.570.84 after IV doses just before cesarean section. Placental transfer during other stages of pregnancy has not been studied.

Nine reports have described the use of metoclopramide for the treatment of nausea and vomiting occurring in early pregnancy (4,5,6 and 7,20,21,22,23 and 24). Administration of the drug in two of these studies was begun at 78 weeks' gestation (4,5) and at 6 weeks in another (6). The exact timing of pregnancy was not specified in one report (7). Daily doses ranged between 10 and 60 mg. Metoclopramide was as effective as other antiemetics for this indication and superior to placebo (8,9). Normal infant development for up to 4 years was mentioned in one study, but no details were provided (7).

In another case of metoclopramide use for nausea and vomiting, the drug was started at 10 weeks' gestation (20). Dosage was not specified. At 18 weeks, after 8 weeks of therapy, the patient developed a neuropsychiatric syndrome with acute asymmetrical axonal motor-sensory polyneuropathy and marked anxiety, depression, irritability, and memory and concentration difficulties (20). Acute porphyria was diagnosed based on the presence of increased porphyrin precursors in the patient's urine. Metoclopramide was discontinued and the patient was treated with a high-carbohydrate diet. Eventually, a normal, 3500-g infant was delivered at term. The woman recovered except for slight residual weakness in the lower extremities. The investigators speculated that the pregnancy itself, the starvation, the drug, or a combination of these may have precipitated the acute attack (20).

A 1996 report described the use of metoclopramide, droperidol, diphenhydramine, and hydroxyzine in 80 women with hyperemesis gravidarum (21). The mean gestational age at the start of treatment was 10.9 3.9 weeks. All of the women received metoclopramide 40 mg/day orally for approximately 7 days, and 12 (15%) required a second course because of the recurrence of their symptoms of nausea and vomiting. Three of the mothers (all treated in the 2nd trimester) delivered offspring with congenital defects: Poland's syndrome, fetal alcohol syndrome, and hydrocephalus and hypoplasia of the right cerebral hemisphere. Only the latter anomaly is a potential drug effect, but the most likely cause was thought to be the result of an in utero fetal vascular accident or infection (21).

A 2001 study, using a treatment method similar to the above study, described the use of droperidol and diphenhydramine in 28 women hospitalized for hyperemesis gravidarum (22). Pregnancy outcomes in the study group were compared to a historical control of 54 women who had received conventional antiemetic therapy. Oral metoclopramide and hydroxyzine were used after discharge from the hospital. Therapy was started in the study and control groups at mean gestational ages of 9.9 and 11.1 weeks, respectively. The study group appeared to have more severe disease than controls as suggested by a greater mean loss from the prepregnancy weight, 2.07 kg vs. 0.81 kg (n.s.), and a slightly lower serum potassium level, 3.4 vs. 3.5 mmol/L (n.s.). Compared to controls, the droperidol group had a shorter duration of hospitalization (3.53 vs. 2.82 days, p=0.023), fewer readmissions (38.9% vs. 14.3%, p=0.025), and lower average daily nausea and vomiting scores (both p<0.001). There were no statistical differences (p>0.05) in outcomes (study vs. controls) in terms of spontaneous abortions (N=0 vs. N=2 [4.3%]); elective abortions (N=3 [12.0%] vs. N=3 [6.5%]), Apgar scores at 1, 5, and 10 minutes; age at birth (37.3 vs. 37.9 weeks); and birth weight (3114 vs. 3347 g) (22). In controls, there was one (2.4%) major malformation of unknown cause, an acardiac fetus in a set of triplets, and one newborn with a genetic defect (Turner syndrome). There was also one unexplained major birth defect (4.4%) in the droperidol group (bilateral hydronephrosis), and two genetic defects (translocation of chromosomes 3 and 7; tyrosinemia) (22).

The Pharmaco-Epidemiological Prescription Database of North Jutland County (Denmark) identified 309 women with singleton pregnancies who filled prescriptions for metoclopramide during a 6-year period (19911996) (23). The pregnancy outcomes of this group were compared to 13,327 women who did not receive prescriptions of any kind during pregnancy. The mean birth weights of the metoclopramide and control groups were nearly identical, 3480 g vs. 3470 g, respectively. No significant differences were found between the groups in terms of congenital malformations (odds ratio [OR] 1.11, 95% confidence interval [CI] 0.62.1), low birth weight (OR 1.79, 95% CI 0.83.9), or preterm delivery (OR 1.02, 95% CI 0.61.7) (23).

A brief 2000 communication examined the outcome of 126 women who had received metoclopramide for nausea and vomiting of pregnancy during the 1st trimester (24). The pregnancy outcomes of these women, who had called one of five teratogen information centers (one each in Italy and Brazil and three in Israel), were compared with a control group of 126 women who had contacted the centers for information on nonteratogenic and nonembryotoxic drug exposures, matched for age, smoking status, and alcohol use. The pregnancy outcomes were similar between the groups in terms of live births, spontaneous abortions, gestational age at delivery, rate of prematurity, birth weight, fetal distress, and major malformations. Both groups had five infants with major birth defects. In the metoclopramide group, two infants had patent ductus arteriosus, two had ventricular septal defects (VSD), and one had hypospadias. The birth defects in the infants born to the control group were two cases of VSD and one each of bilateral syndactyly of the foot, hypospadias, and an inguinal hernia. The gross motor development (as measured by the Denver Development Scale) of the infants in the two groups at ages 4 to 15 months were also similar (24).

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 192 newborns had been exposed to metoclopramide during the 1st trimester (F. Rosa, personal communication, FDA, 1993). Ten (5.2%) major birth defects were observed (eight expected), including (observed/expected) 1/2 cardiovascular defects and 1/1 polydactyly. No anomalies were observed in four other defect categories (oral clefts, spina bifida, limb reduction defects, and hypospadias) for which specific data were available. These data do not support an association between the drug and congenital defects.

A 1997 case report described the signs and symptoms of acute intermittent porphyria in a 29-year-old woman at 13 weeks' gestation (27). The patient presented with abdominal pain, constipation, and vomiting and was treated with IV metoclopramide. Her symptoms worsened with treatment and included weakness of the lower extremities and a severe neuropsychiatric syndrome consisting of both autonomic and neurologic functions. Metoclopramide was stopped and she was treated with high-dose IV glucose and a high carbohydrate diet. Evaluation of urine and stool porphyrin precursors confirmed the diagnosis. She eventually delivered a normal, 2760-g infant at term. The authors concluded that the severe maternal symptoms were brought on by metoclopramide, a porphyrinogenic agent, and starvation resulting from hyperemesis (27).

Several studies have examined the effect of metoclopramide on gastric emptying time during labor for the prevention of Mendelson's syndrome (i.e., pulmonary aspiration of acid gastric contents and resulting chemical pneumonitis and pulmonary edema) (1,3,10,11,12,13,14,15 and 16,28,29). Gastroesophageal reflux was decreased, as was the gastric emptying time. The drug was effective in preventing vomiting during anesthesia. No effects were noted on the course of labor or the fetus. Apgar scores and results of neurobehavioral tests did not differ from those of controls (1,3,10,16), nor did newborn heart rates or blood pressures (1).

The effect of metoclopramide on maternal and fetal prolactin secretion during pregnancy and labor has been studied (2,17,18). The drug is a potent stimulator of prolactin release from the anterior pituitary by antagonism of hypothalamic dopaminergic receptors. However, transplacentally acquired metoclopramide did not cause an increased prolactin release from the fetal pituitary, nor did maternal prolactin cross the placenta to the fetus (2,17). In two other studies, 10 mg of intravenous metoclopramide administered during labor did not affect the levels of maternal or fetal thyroid-stimulating hormone or thyroid hormones (19), or maternal growth hormone concentrations (30).

Breast Feeding Summary

Metoclopramide is excreted into human breast milk. Because of ion trapping of the drug in the more acidic (as compared with plasma) milk, accumulation occurs with milk:plasma ratios of 1.81.9 after steady-state conditions are reached (31,32 and 33).

Several studies have examined the effect of metoclopramide as a lactation stimulant in women with inadequate or decreased milk production (31,32,33,34,35,36,37,38,39,40,41,42 and 43). One study involved 23 women who had delivered prematurely (mean gestational length, 30.4 weeks) (41). The drug, by stimulating the release of prolactin from the anterior pituitary, was effective in increasing milk production with doses of 2045 mg/day (9,32,33,34,35,36,37,38,39,40,41 and 42). Doses of 15 mg/day were not effective (37). In one study, metoclopramide caused a shift in the amino acid composition of milk, suggesting an enhanced rate of transition from colostrum to mature milk (38). No effect on the serum levels of prolactin, thyroid-stimulating hormone, or free thyroxin was observed in nursing infants in a 1985 study of 11 women with lactational insufficiency (39). A 1994 investigation found a positive response in 78% (25 of 32) of treated women, but the increase in daily milk production was inversely correlated with maternal age (43).

The total daily dose that would be consumed by a nursing infant during the maternal use of 30 mg/day has been estimated to be 145 g/kg/day (31,32 and 33). This is much less than the maximum daily dose of 500 g/kg recommended in infants (9) or the 100 g/kg/day dosage that has been given to premature infants (44). Metoclopramide was detected in the plasma of one of five infants whose mothers were taking 10 mg 3 times daily (32,33). Adverse effects have been observed in only two infantsboth with mild intestinal discomfort (36,37). In one case the mother was consuming 30 mg/day (36) and in the other, 45 mg/day (37).

In summary, metoclopramide apparently does not present a risk to the nursing infant with maternal doses of 45 mg/day or less. One review has stated that the drug should not be used during breast feeding because of the potential risks to the neonate (45), but there are no published studies to substantiate this caution. Although no adverse effects in the nursing infant have been reported, the American Academy of Pediatrics considers the use of metoclopramide during lactation to be of concern because of the potent central nervous system effects that the drug is capable of producing (46).

References

1. Bylsma-Howell M, Riggs KW, McMorland GH, Rurak DW, Ongley R, McErlane B, Price JDE, Axelson JE. Placental transport of metoclopramide: assessment of maternal and neonatal effects. Can Anaesth Soc J 1983;30:48792.
2. Arvela P, Jouppila R, Kauppila A, Pakarinen A, Pelkonen O, Tuimala R. Placental transfer and hormonal effects of metoclopramide. Eur J Clin Pharmacol 1983;24:3458.
3. Cohen SE, Jasson J, Talafre M-L, Chauvelot-Moachon L, Barrier G. Does metoclopramide decrease the volume of gastric contents in patients undergoing cesarean section? Anesthesiology 1984;61:6047.
4. Lyonnet R, Lucchini G. Metoclopramide in obstetrics. J Med Chir Prat 1967;138:3525.
5. Sidhu MS, Lean TH. The use of metoclopramide (Maxolon) in hyperemesis gravidarum. Proc Obset Gynaecol Soc Singapore 1970;1:14.
6. Guikontes E, Spantideas A, Diakakis J. Ondansetron and hyperemesis gravidarum. Lancet 1992;340:1223.
7. Martynshin MYA, Arkhengel'skii AE. Experience in treating early toxicoses of pregnancy with metoclopramide. Akush Ginekol 1981;57:445.
8. Pinder RM, Brogden RN, Sawyer PR, Speight TM, Avery GS. Metoclopramide: a review of its pharmacological properties and clinical use. Drugs 1976;12:81131.
9. Harrington RA, Hamilton CW, Brogden RN, Linkewich JA, Romankiewicz JA, Heel RC. Metoclopramide: an update review of its pharmacological properties and clinical use. Drugs 1983;25:45194.
10. McGarry JM. A double-blind comparison of the anti-emetic effect during labour of metoclopramide and perphenazine. Br J Anaesth 1971;43:6135.
11. Howard FA, Sharp DS. Effect of metoclopramide on gastric emptying during labour. Br Med J 1973;1:4468.
12. Brock-Utne JG, Dow TGB, Welman S, Dimopoulos GE, Moshal MG. The effect of metoclopramide on the lower oesophageal sphincter in late pregnancy. Anaesth Intensive Care 1978;6:269.
13. Hey VMF, Ostick DG. Metoclopramide and the gastro-oesophageal sphincter. Anaesthesia 1978;33:4625.
14. Feeney JG. Heartburn in pregnancy. Br Med J 1982;284:11389.
15. Murphy DF, Nally B, Gardiner J, Unwin A. Effect of metoclopramide on gastric emptying before elective and emergency caesarean section. Br J Anaesth 1984;56:11136.
16. Vella L, Francis D, Houlton P, Reynolds F. Comparison of the antiemetics metoclopramide and promethazine in labour. Br Med J 1985;290:11735.
17. Messinis IE, Lolis DE, Dalkalitsis N, Kanaris C, Souvatzoglou A. Effect of metoclopramide on maternal and fetal prolactin secretion during labor. Obstet Gynecol 1982;60:6868.
18. Bohnet HG, Kato K. Prolactin secretion during pregnancy and puerperium: response to metoclopramide and interactions with placental hormones. Obstet Gynecol 1985;65:78992.
19. Roti E, Robuschi G, Emanuele R, d'Amato L, Gnudi A, Fatone M, Benassi L, Foscolo MS, Gualerzi C, Braverman LE. Failure of metoclopramide to affect thyrotropin concentration in the term human fetus. J Clin Endocrinol Metab 1983;56:10715.
20. Milo R, Neuman M, Klein C, Caspi E, Arlazoroff A. Acute intermittent porphyria in pregnancy. Obstet Gynecol 1989;73:4502.
21. Nageotte MP, Briggs GG, Towers CV, Asrat T. Droperidol and diphenhydramine in the management of hyperemesis gravidarum. Am J Obstet Gynecol 1996;174:18016.
22. Turcotte V, Ferreira E, Duperron L. Utilit du dropridol et de la diphenhydramine dans l'hyperemesis gravidarum. J Soc Obstet Gynaecol Can 2001;23:1339.
23. Sorensen HT, Nielsen GL, Christensen K, Tage-Jensen U, Ekborn A, Baron J, and the Euromap study group. Birth outcome following maternal use of metoclopramide. Br J Clin Pharmacol 2000;49:2648.
24. Berkovitch M, Elbirt D, Addis A, Schuler-Faccini L, Ornoy A. Fetal effects of metoclopramide therapy for nausea and vomiting of pregnancy. N Engl J Med 2000;343:4456.
25. Product information. Reglan. A.H. Robins, 1997.
26. Eisenach JC, Dewan DM. Metoclopramide exaggerates stress-induced tachycardia in pregnant sheep. Anesth Analg 1996;82:60711.
27. Shenhav S, Gemer O, Sassoon E, Segal S. Acute intermittent porphyria precipitated by hyperemesis and metoclopramide treatment in pregnancy. Acta Obstet Gynecol Scand 1997;76:4845.
28. Orr DA, Bill KM, Gillon KRW, Wilson CM, Fogarty DJ, Moore J. Effects of omeprazole, with and without metoclopramide, in elective obstetric anaesthesia. Anaesthesia 1993;48:1149.
29. Stuart JC, Kan AF, Rowbottom SJ, Yau G, Gin T. Acid aspiration prophylaxis for emergency caesarean section. Anaesthesia 1996;51:41521.
30. Robuschi G, Emanuele R, d'Amato L, Salvi M, Montermini M, Gnudi A, Roti E. Failure of metoclopramide to release GH in pregnant women. Horm Metab Res 1983;15:4601.
31. Lewis PJ, Devenish C, Kahn C. Controlled trial of metoclopramide in the initiation of breast feeding. Br J Clin Pharmacol 1980;9:217,219.
32. Pelkonen O, Arvela P, Kauppila A, Koivisto M, Kivinen S, Ylikorkala O. Metoclopramide in breast milk and newborn. Acta Physiol Scand 1982;(Suppl 502):62 (Abstract).
33. Kauppila A, Arvela P, Koivisto M, Kivinen S, Ylikorkala O, Pelkonen O. Metoclopramide and breast feeding: transfer into milk and the newborn. Eur J Clin Pharmacol 1983;25:81923.
34. Sousa PLR. Metoclopramide and breast-feeding. Br Med J 1975;1:512.
35. Guzman V, Toscano G, Canales ES, Zarate A. Improvement of defective lactation by using oral metoclopramide. Acta Obstet Gynecol Scand 1979;58:535.
36. Kauppila A, Kivinen S, Ylikorkala O. Metoclopramide increases prolactin release and milk secretion in puerperium without stimulating the secretion of thyrotropin and thyroid hormones. J Clin Endocrinol Metab 1981;52:4369.
37. Kauppila A, Kivinen S, Ylikorkala O. A dose response relation between improved lactation and metoclopramide. Lancet 1981;1:11757.
38. de Gezelle H, Ooghe W, Thiery M, Dhont M. Metoclopramide and breast milk. Eur J Obstet Gynecol Reprod Biol 1983;15:316.
39. Kauppila A, Anunti P, Kivinen S, Koivisto M, Ruokonen A. Metoclopramide and breast feeding: efficacy and anterior pituitary responses of the mother and the child. Eur J Obstet Gynecol Reprod Biol 1985;19:1922.
40. Gupta AP, Gupta PK. Metoclopramide as a lactogogue. Clin Pediatr 1985;24:26972.
41. Ehrenkranz RA, Ackerman BA. Metoclopramide effect on faltering milk production by mothers of premature infants. Pediatrics 1986;78:61420.
42. Budd SC, Erdman SH, Long DM, Trombley SK, Udall JN Jr. Improved lactation with metoclopramide. Clin Pediatr 1993;32:537.
43. Toppare MF, Laleli Y, Senses DA, Kitaper F, Kaya IS, Dilmen U. Metoclopramide for breast milk production. Nutrition Res 1994;14:101929.
44. Sankaran K, Yeboah E, Bingham WT, Ninan A. Use of metoclopramide in preterm infants. Dev Pharmacol Ther 1982;5:1149.
45. Lewis JH, Weingold AB, The Committee on FDA-Related Matters, American College of Gastroenterology. The use of gastrointestinal drugs during pregnancy and lactation. Am J Gastroenterol 1985;80:91223.
46. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:13750.

Continue reading here: Tetracycline Risk Summary

Was this article helpful?

0 0