Abstract
Despite evidence of fetal safety, most antiemetics are contraindicated in pregnancy. We summarise a risk-benefit analysis of the literature on safety and effectiveness of pharmacotherapy and nontraditional therapy for nausea and vomiting of pregnancy (NVP) to provide evidence-based guidelines on the management of NVP.
The medical literature was scanned for controlled studies on the human teratogenicity and effect of various antiemetics in pregnant women. Data were pooled based on drug/therapy class and summarised to determine relative risk with 95% confidence interval (for malformations and failure rates for NVP) and homogeneity (chi-square test).
Evidence from controlled trials has demonstrated the safety and efficacy of the following drugs for the treatment of varying degrees of NVP: doxylamine/pyridoxine±dicycloverine (dicyclomine), antihistamine H1 receptor antagonists, and phenothiazines (as a group). However, pooled data for doxylamine/ pyridoxine±dicycloverine, H1 antagonists and phenothiazines were not homogeneous. Other therapies, such as pyridoxine alone, metoclopramide, ondansetron and the corticosteroids may be beneficial in managing NVP. However, limited efficacy studies and the paucity of well-controlled safety studies may limit the use of some of these agents among patients not responsive to first-line agents. Well-controlled safety and effectiveness trials in patients with NVP are lacking for nonpharmacological treatments (e.g. acupressure).
NVP can be managed safely and effectively. Further trials must be conducted in order to determine the true effectiveness of certain agents in patients with NVP.
Similar content being viewed by others
References
Gadsby R, Barnie-Adshead AM, Jagger C. A prospective study of nausea and vomiting during pregnancy. Br J Gen Pract 1993; 43: 245–8
Vellacott ID, Cooke EJA, James CE. Nausea and vomiting in early pregnancy. Int J Gynecol Obstet 1988; 27: 57–62
De la Ronde SK. Nausea and vomiting in pregnancy. J Soc Obstetricians Gynaecologists Can 1994; 16: 2035–41
Depue RH, Bernstein L, Ross RK, et al. Hyperemesis gravidarum in relation to estroadiol levels, pregnancy outcome, and other maternal factors: a seroepidemiologic study. Am J Obstet Gynecol 1987; 157: 1137–41
Kimura M, Amino N, Tamakai H, et al. Gestational thyrotoxicosis and hyperemesis gravidarum: possible role of HCG with higher stimulating activity. Clin Endocrinol (Oxf) 1993; 38: 345–50
Wilson R, McKillop JH, MacLean M, et al. Thyroid function tests are rarely abnormal in patients with severe hyperemesis gravidarum. Clin Endocrinol (Oxf) 1992; 37: 331–4
Shulman A, Shapiro MS, Bahary C, et al. Abnormal thyroid function in hyperemesis gravidarum. Acta Obstet Gynecol Scand 1989; 68: 533–6
Jeffcoate WJ. Recurrent pregnancy-induced thyrotoxicosis presenting as hyperemesis gravidarum: case report. Br J Obstet Gynaecol 1985; 92: 413–5
Koch KL, Stern RM, Vasey M, et al. Gastric dysrhythmias and nausea of pregnancy. Dig Dis Sci 1990; 35(8): 961–8
Deuchar N. Nausea and vomiting in pregnancy: a review of the problem with particular regard to psychological and social aspects. Br J Obstet Gynaecol 1995; 102: 6–8
Callahan E, Burnett M, DeLawyer D, et al. Behavioural treatment of hyperemesis gravidarum. J Psychosomat Obstet Gynecol 1986; 5: 187–96
Malagelada JR, Camilleri M. Unexplained vomiting: a diagnostic challenge. Ann Intern Med 1984; 101: 211–8
Einarson TR, Leeder JS, Koren G. A method for meta-analysis of epidemiological studies. Drug Intell Clin Pharm 1988; 22: 813–23
Newman V, Fullerton JT, Anderson PO. Clinical advances in the management of severe nausea and vomiting during pregnancy. J Obstet Gynecol Neonatal Nurs 1993; 22: 483–90
Shaw J, Brooks PM, McNeil JJ, et al. The management of nausea and vomiting during pregnancy. Med J Aust 1987; 147: 290–1
de la Ronde S, Thirsk J, the SOGC Clinical Practice — Obstetrics Committee. Committee opinion: guidelines for the management of nausea and vomiting in pregnancy. J Soc Obstetricians Gynaecologists Can 1996; 18(3): 255–7
Jewell D, Young G. Treatments for nausea and vomiting in early pregnancy. In: Neilson JP, Crowther CA, Hodnett ED, et al., editors. Pregnancy and childbirth module of The Cochrane Database of Systematic Reviews, [updated 04 March 1997]. Available in The Cochrane Library [database on disk and CDROM]. The Cochrane Collaboration; Issue 2. Oxford: Update Software; 1997. Updated quarterly
Briggs GG, Freeman RK, Yaffe SJ, editors. Drugs in pregnancy and lactation. 5th ed. Baltimore: Williams and Wilkins, 1998
O’Brien B, Naber S. Nausea and vomiting during pregnancy: effects on the quality of women’s lives. Birth 1992; 19(3): 138–43
Erick M. Battling morning (noon and night) sickness: new approaches for treating an age-old problem. J Am Diet Assoc 1994; 94: 147–8
Tufts University Diet and Nutrition Letter 1994; 11 (1): 6–7
General Practitioner Research Group. General practioner clinical trials: drugs in pregnancy survey. Practitioner 1963; 191: 775–80
Bunde CA, Bowles DM. A technique for controlled survey of case records. Curr Ther Res 1963; 5: 245–8
Greenberg G, Inman WHW, Weatherall JAC, et al. Maternal drug histories and congenital abnormalities. BMJ 1977; 2: 853–6
Heinonen OP, Slone D, Shapiro S. Birth defects and drugs in pregnancy. Littleton (MA): Publishing Sciences Group, 1977
Newman NM, Correy JF, Dudgeon GI. A survey of congenital abnormalities and drugs in private practice. N Z J Obstet Gynecol 1977; 17: 156–9
Smithells RW, Sheppard S. Teratogenicity testing in humans: a method demonstrating safety of Bendectin. Teratology 1978; 17: 31–5
Michaelis J, Gluck E, Michaelis H, et al. Does Lenotan have teratogenic effects? Dtsh Arztedl 1980; 23: 1527–9
Jick H, Holmes LB, Hunter JR, et al. First-trimester drug use and congenital disorders. JAMA 1981; 246(4): 343–6
Fleming DM, Knox JDE, Crombie DL. Debendox in early pregnancy and fetal malformation. BMJ 1981; 283: 99–101
Gibson GT, Colley DP, McMichael AJ, et al. Congenital anomalies in relation to the use of doxylamine/dicyclomine and other antenatal factors. Med J Aust 1981; 1: 410–4
Eskenazi B, Bracken MB. Bendictin (Debendox) as a risk factor for pyloric stenosis. Am J Obstet Gynecol 1982; 144: 919–24
Morelock S, Hingson R, Kayne H, et al. Bendectin and fetal development. Am J Obstet Gynecol 1982; 142: 209–13
Aselton P, Jick H, Milunsky A, et al. First-trimester drug use and congenital disorders. Obstet Gynecol 1985; 65(4): 451–5
Shiono PH, Klebanoff MA. Bendectin and human congenital malformations. Teratology 1989; 40: 151–5
Erikson JD. Risk factors for birth defects: data from the Atlanta Birth Defects Case-Control Study. Teratology 1991; 43: 41–51
McKeigne PM, Lam SH, Linn S, et al. Bendectin® and birth defects: I. A meta-analysis of the epidemiologic studies. Teratology 1994; 50: 27–37
Geiger CJ, Fahrenbach DM, Healey FJ. Bendectin® in the treatment of nausea and vomiting in pregnancy. Obstet Gynecol 1959; 14: 688–90
McGuinness BW, Taylor Binns D. ‘Debendox’ in pregnancy sickness. J R Coll Gen Pract 1971; 21: 500–3
Wheatley D. Treatment of pregnancy sickness. Br J Obstet Gynaecol 1977; 84: 444–7
Bendectin Peer Group. Bio/Basics International Peer Group Report. Merrell Dow Pharmaceuticals Inc., March 14, 1975: 559–637
Cartwright EW. Dramamine in nausea and vomiting of pregnancy. West J Surg 1951; 59: 216–34
King AG. The treatment of pregnancy nausea with a pill. Obstet Gynecol 1955; 6: 332–8
Conklin FJ, Nesbitt REL. Buclizine hydrochloride for nausea and vomiting of pregnancy. Obstet Gynecol 1958; 11: 214–9
Diggory PLC, Tomkinson JS. Nausea and vomiting in pregnancy. A trial of meclozine dihydrochloride with and without pyridoxine. Lancet 1962; II: 370–2
Baum G, Boxer EL, Davidson JH, et al. Meclozine and pyridoxine in pregnancy sickness. Practitioner 1963; 190: 251–3
Erez S, Schifrin BS, Dirim O. Double-blind evaluation of hydroxyzine as an antiemetic in pregnancy. J Reprod Med 1971; 7: 57–9
Lask S. Treatment of nausea and vomiting of pregnancy with anti-histamines. BMJ 1953; 1: 652–3
Fitzgerald JPB. The effect of promethazine in nausea and vomiting of pregnancy. N Z Med J 1955; 54: 215–8
Newlinds JS. Nausea and vomiting in pregnancy: a trial of triethylperazine. Med J Aust 1964; 51: 234–6
Winters HS. Anti-emetics in nausea and vomiting of pregnancy. Obstet Gynecol 1961; 18: 753–6
Sahakian V, Rouse D, Sipes S, et al. Vitamin B6 is effective therapy for nausea and vomiting of pregnancy: a randomized, double-blind placebo-controlled study. Obstet Gynecol 1991; 78: 33–6
Vutyavanich T, Wongtra-ngan S, Ruangsri R. Pyridoxine for nausea and vomiting of pregnancy: a randomized, double-blind, placebo-controlled trial. Am J Obstet Gynecol 1995; 173: 881–4
Ylikorkala O, Kauppila A, Ollanketo ML. Intramuscular ACTH and placebo in the treatment of hyperemesis gravidarum. Acta Obstet Gynecol Scand 1979; 58: 453–5
Safari HR, Fassett MJ, Souter IC, et al. The efficacy of methyl-prednisolone in the treatment of hyperemesis gravidarum: a randomized, double-blind, controlled study. Am J Obstet Gynecol 1998; 179: 921–4
Czeizel AE, Dudas I, Fritz G, et al. The effect of periconceptional multivitamin-mineral supplementation on vertigo, nausea and vomiting in the first trimester of pregnancy. Arch Gynecol Obstet 1992; 251: 181–5
Schatz M, Petitti D. Anti-histamines and pregnancy. Ann Allergy Asthma Immunol 1997; 78: 157–9
Seto A, Einarson T, Koren G. Pregnancy outcome following first trimester exposure to anti-histamines: meta-analysis. Am J Perinatal 1997; 14(3): 119–24
Mellin GW, Katzenstein M. Meclozine and foetal abnormalities. Lancet 1963; 26: 222–3
Nelson MM, Forfar JO. Associations between drugs administered during pregnancy and congenital abnormalities of the fetus. BMJ 1971; 1: 523–7
Saxen I. Cleft palate and maternal diphenhydramine intake. Lancet 1974; I: 407–8
Kullander S, Kallen B. A prospective study of drugs and pregnancy. II. Anti-emetic drugs. Acta Obstet Gynecol Scand 1976; 55: 105–11
Mitchell AA, Schwingl PJ, Rosenberg L, et al. Birth defects in relation to Bendectin® use in pregnancy. II. Pyloric stenosis. Am J Obstet Gynecol 1983; 147(7): 737–42
Einarson A, Bailey B, Jung G, et al. Prospective controlled study of hydroxyzine and cetirizine in pregnancy. Ann All Asthma Immunol 1997; 78: 183–6
Milkovich L, Van den Berg BJ. An evaluation of the teratogenicity of certain antinauseant drugs. Am J Obstet Gynecol 1976; 125: 244–8
American Hospital Formulary Service. Drug Information 1990. Bethesda (MD): American Society of Hospital Pharmacists, 1990: 2116–8
Gant H, Reinken L, Dapunt O, et al. Vitamin B6 depletion in women with hyperemesis gravidarum. Wien Klin Wochenschr 1975; 87: 510–7
Willis DM, O’Grady JP, Faber JJ, et al. Diffusion of permeability of cyanocobalamin in human placenta. Am J Physiol 1986; 250 (3 Pt 2): R459–64
Mills JL, McPartlin JM, Kirke PN, et al. Homocysteine metabolism in pregnancies complicated by neural-tube defects. Lancet 1995; 345: 149–51
Ho CK, Kaufman RL, McAlister WH. Congenital malformations. Cleft palate, congenital heart disease, absent tibiae, and polydactyly. Am J Dis Child 1975; 129: 714–6
Farag RA, Ananth J. Thanatophoric dwarfism associated with prochlorperazine administration. N Y State J Med 1978; 78: 279–82
Freeman R. Limb deformities: possible association with drugs. Med J Aust 1972; 1: 606–7
Hall G. A case of phocomelia of the upper limbs. Med J Aust 1963; 1: 449–50
Rafla N. Limb deformities associated with prochlorperazine [letter]. Am J Obstet Gynecol 1987; 156: 1557
Brambati B, Lanzani A, Sanchioni L, et al. Conjoined twins and in utero early exposure to prochlorperazine. Reprod Toxicol 1990; 4: 331–2
Rumeau-Rouquette C, Goujard J, Huel G. Possible teratogenic effect of phenothiazines in human beings. Teratology 1976; 15: 57–64
Moriarty AJ, Nance MR. Trifluoperazine and pregnancy. Can Med Ass J 1963; 88: 375–6
Shepard TH. Catalog of teratogenic agents. 7th ed. Baltimore (MD): John Hopkins University Press, 1992
Nageotte MP, Briggs GC, Towers CV, et al. Droperidol and diphenhydramine in the management of hyperemesis gravidarum. Am J Obstet Gynecol 1996; 174(6): 1801–6
Brunton LL. Agents affecting gastrointestinal water flux and motility; emesis and antiemetics; bile acids and pancreatic enzymes. In: Hartman JG, Gilman AG, Limbird LE, editors. The pharmacological basis of therapeutics. 9th ed. New York (NY): McGraw-Hill 1996: 917–36
Einarson A, Koren G, Bergman U. The treatment of nausea and vomiting in pregnancy. Eur J Obstet Gynecol Reprod Biol 1998; 76(1): 1–3
Sidhu MS, Lean TH. The use of metoclopramide (Maxolon) in hyperemesis gravidarum. Proc Obstet Gynaecol Soc Singapore 1970; 1: 43–6
Pinder RM, Brogden RN, Sawyer PR, et al. Metoclopramide, a review of its pharmacological properties. Drugs 1976; 12: 81–131
Tucker ML, Jackson MR, Scales MDC, Ondansetron: pre-clinical safety evaluation. Eur J Cancer Clin Oncol 1989; 25 Suppl. 1: S79–S93
Guikontes E, Spantideas A, Kiakakis J. Ondansetron and hyperemesis gravidarum [letter]. Lancet 1992; 340: 1223
World MJ. Ondansetron and hyperemesis gravidarum [letter]. Lancet 1993; 341: 185
Tincello DG, Johnstone MJ. Treatment of hyperemesis gravidarum with the 5-HT3 antagonist ondansetron (Zofran). Postgrad Med J 1996; 72(853): 688–9
Sullivan CA, Johnson CA, Roach H, et al. A pilot study of intravenous ondansetron for hyperemesis gravidarum. Am J Obstet Gynecol 1996; 174(5): 1565–8
Bailey B, Addis A, Lee A, et al. Cisapride use during human pregnancy: a prospective controlled study. Dig Dis Sci 1997; 42(9): 1848–52
Wells CN. Treatment of hyperemesis gravidarum with cortisone. Am J Obstet Gynecol 1953; 66: 598–601
Parry H, Martin K. Single dose iv dexamethasone: an effective anti-emetic in cancer chemotherapy. Cancer Chem Pharmacol 1991; 28: 231–2
Fainstat T. Cortisone-induced congenital cleft palate in rabbits. Endocrinology 1954; 55: 502
Mogadam M, Dobbins WO, Korelitz BI, et al. Pregnancy in inflammatory bowel disease: effect of sulfasalazine and corticosteroid on fetal outcome. Gastroenterology 1981; 80(1): 72–6
Popert AJ. Pregnancy and adrenocortical hormones. BMJ 1962: 967–72
Warrell DW, Taylor R. Outcome for the fetus of mothers receiving prednisolone during pregnancy. Lancet 1968; I(534): 117–8
Mintz G, Niz J, Gutierrez G, et al. Prospective study of pregnancy in systemic lupus erythermatosus. Results of a multi-disciplinary approach. J Rheumatol 1986; 13(4): 732–9
Jacobson SJ, Pastuszak A, Koren G. Effects of prenatal exposure to prednisone; a prospective study [abstract]. Ped Research 1997; 41 (4 Pt 2): 348A
Czeizel C, Rockenbauer M. Population-based case-control study of teratogenic potential of corticosteroids. Teratology 1997; 56: 335–40
Richards ID. A retrospective inquiry into possible teratogenic effects of drugs in pregnancy. Drugs Teratol Dev 1971: 441–55
Park-Wyelie L, Mazzotta P, Pastuszak A, et al. Birth defects following maternal exposure to corticosteroids: a prospective cohort study, and a meta-analysis of epidemiological studies. Teratology. In press
Robert E, Vollset SE, Botto L, et al. Malformation surveillance and maternal drug exposure: the MADRE project. Int J Risk Saf Med 1994; 6: 75–118
Rodriguez-Pinilla E, Martinez-Firas ML. Corticosteroids during pregnancy and oral clefts: a case-control study. Teratology 1998; 58: 2–5
Taylor R. Successful management of hyperemesis gravidarum using steroid therapy. Q J Med 1996; 89(2): 103–7
Nelson-Piercy C, de Swiet M. Corticosteroids for the treatment of hyperemesis gravidarum. Br J Obstet Gynecol 1994; 101: 1013–5
Nelson-Piercy C, de Sweit M. Complications of the use of corticosteroids for the treatment of hyperemesis gravidarum. Br J Obstet Gynecol 1995; 102: 507–9
Magee LA, Redman CWG. An N-of-1 trial for treatment of hyperemesis gravidarum. Br J Obstet Gynecol 1996; 103: 478–80
Fischer-Rasmussen W, Kjaer SK, Dahl C, et al. Ginger treatment of hyperemesis gravidarum. Eur J Obstet Gynecol Reprod Biol 1990; 38: 19–24
Sallan SE, Zinberg NE, Frei E. Anti-emetic effect of delta-9-tetrahydrocannabinol in patients receiving cancer chemotherapy. N Engl J Med 1975; 293: 795–7
Chang AE, Shiling DJ, Stillman RC, et al. Delta-9-tetrahyrdocannibinol as an anti-emetic in cancer patients receiving high dose methotrexate; a prospective randomized evaluation. Ann Intern Med 1979; 91: 819–24
Ekert K, Waters KD, Jurk IH. Amelioration of cancer chemotherapy-induced nausea and vomiting by delta-9-tetra-hydrocannbinol. Med J Aust 1979; 2: 657–9
De Aloysio D, Penacchioni P. Morning sickness control in early pregnancy by Neiguan point acupressure. Obstet Gynecol 1992; 80: 852–4
Dundee JW, Sourial FBR, Ghaly RG, et al. P6 acupressure reduces morning sickness. J R Soc Med 1988; 81: 456–7
Hyde E. Acupressure therapy for morning sickness: a controlled clinical trial. J Nurse Midwifery 1989; 34(4): 171–8
Belluomini J, Litt RC, Lee KA, et al. Acupressure for nausea and vomiting of pregnancy: a randomized, blinded study. Obstet Gynecol 1994; 84: 245–8
O’Brien B, Relyea MJ, Taerum T. Efficacy of P6 acupressure in the treatment of nausea and vomiting during pregnancy. Am J Obstet Gynecol 1996; 174: 708–15
Evans AT, Samuels SN, Marshall C, et al. Suppression of pregnancy-induced nausea and vomiting with sensory afferent stimulation. J Reprod Med 1993; 38(8): 603–6
Bayreuther J, Lewith GT, Pickering R. A double-blind crossover study to evaluate the effectiveness of acupressure at pericardium 6 (P6) in the treatment of early morning sickness (EMS). Complement Ther Med 1994; 2: 70–6
Kroger W, DeLee S. The psychosomatic treatment of hyperemesis gravidarum by hypnosis. Am J Obstet Gynecol 1946; 51: 544–52
Giorlando S, Mascola R. The treatment of hyperemesis gravidarum with hypnotherapy. Am J Obstet Gynecol 1957; 73: 444–7
Henker III FO. Psychotherapy as adjunct in treatment of vomiting during pregnancy. South Med J 1976; 69(12): 1585–7
Smallwood RA, Berlin RG, Castagnoli N, et al. Safety of acid-suppressing drugs. Dig Dis Sci 1995; 40 Suppl. 2: 63S–80S
Dordevic M, Beric B. Our experience in the treatment of pyrosis in pregnancy with Kompensan. Med Preg 1972; 25: 277–9
Jacobs D. Maternal drug ingestion and congenital malformations. S Afr Med J 1975; 49: 2073–80
Lewis JH, Weingold AAB. The use of gastrointestinal drugs during pregnancy and lactation. Am J Gastroenterol 1985; 80: 912–23
Jones DGC, Langman MJS, Lawson DH, et al. Post-marketing surveillance of the safety of cimetidine: twelve-month morbidity report. Q J Med 1985; 54(215): 253–68
Magee LA, Inocencion G, Kamboj L, et al. Safety of first trimester exposure to histamine H2-blockers: a prospective cohort study. Dig Dis Sci 1996; 41(6): 1145–9
Lalkin A, Loebstein R, Addis A, et al. Safety of omeprazole during pregnancy: a multi-centre prospective cohort study. Am J Obstet Gynecol. 1998 Sep; 179 (3 Pt 1): 727–30
Schardein JL, Furuhashi T, Ooshima Y. Reproductive and developmental toxicology studies of lansoprazole (AG-1749) in rats and rabbits. Yakuri Chiryo 1990; 18 (Suppl. 10): 119–29
Koren G, Bologa M, Long D, et al. Perception of teratogenic risk by pregnant women exposed to drugs and chemicals during the first-trimester. Am J Obstet Gynecol 1989; 160(5): 1190–4
Koren G, Pastuszak A, Ito S. Drugs in pregnancy. New Engl J Med 1998; 338(16): 1128–37
Acknowledgements
Special thanks to Dr Benoit Bailey, Dr Peter von Dadelszen and Dr Gideon Koren for their valuable clinical input into the preparation of this paper. This paper was partially funded by the Motherisk Research Grant. Motherisk receives an annual educational grant from Duchesnay, Incorporated.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Mazzotta, P., Magee, L.A. A Risk-Benefit Assessment of Pharmacological and Nonpharmacological Treatments for Nausea and Vomiting of Pregnancy. Drugs 59, 781–800 (2000). https://doi.org/10.2165/00003495-200059040-00005
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003495-200059040-00005