Review Article

Acetaminophen Overdose in Pregnancy

Authors: Jason M. Wilkes, MD, Larry E. Clark, MD, Jorge L. Herrera, MD

Abstract

Acetaminophen (APAP) is the most common drug overdose in pregnancy. Available data regarding APAP overdose in pregnancy is limited to case reports and a small prospective case series. APAP has been demonstrated to cross the placenta and in toxic doses may harm the fetal and maternal hepatocytes. Fetal hepatocytes metabolize APAP into both active and toxic metabolites. These toxic metabolites may cause fetal hepatic necrosis. N-acetylcysteine (NAC) has also been demonstrated to cross the placenta and may bind toxic metabolites in both the mother and the fetus. Limited data suggest that the majority of morbidity and mortality from APAP overdose can be averted by initiation of NAC within the first 16 hours of ingestion and possibly even later. NAC may be safely administered during pregnancy and should be initiated early after APAP overdosage. The literature was reviewed through the use of OvidMEDLlNE® database, encompassing 1966 to the present. Searches were conducted using the key words acetaminophen, paracetamol, N-acetylcysteine, overdose, and hepatotoxicity. The search was further refined by selecting articles that contained these search words together with the key word pregnancy. Only English language papers were reviewed. Articles were selected on the basis of relevance to the topic. Pertinent citations found in the selected articles were also reviewed.


Key Points


* Data on acetaminophen overdose and pregnancy are limited.


* Acetaminophen has been demonstrated to cross the placenta and cause toxic metabolites in both the mother and the fetus.


* N-acetylcysteine should be initiated early after acetaminophen overdosage in pregnancy to prevent harm to both the mother and the fetus.

This content is limited to qualifying members.

Existing members, please login first

If you have an existing account please login now to access this article or view purchase options.

Purchase only this article ($25)

Create a free account, then purchase this article to download or access it online for 24 hours.

Purchase an SMJ online subscription ($75)

Create a free account, then purchase a subscription to get complete access to all articles for a full year.

Purchase a membership plan (fees vary)

Premium members can access all articles plus recieve many more benefits. View all membership plans and benefit packages.

References

1.Zimmerman HJ. Acetaminophen hepatotoxicity. Clin Liver Dis 1998;2:523–541.
 
2.Black M. Acetaminophen hepatotoxicity. Annu Rev Med 1984;35:577–593.
 
3.Schiodt FV, Roehling FA, Casey DL, et al. Acetaminophen toxicity in an urban county hospital. N Engl J Med 1997;337:1112–1117.
 
4.Rayburn W, Wible-Kant J, Bledsoe P. Changing trends in drug use during pregnancy. J Reprod Med1982;27:569–575.
 
5.Thomson J, Prescott LF. Liver damage and impaired glucose tolerance after paracetamol overdosage.Br Med J 1966;2:506–507.
 
6.Davidson DGD, Eastman WN. Acute liver necrosis following overdose of paracetamol. Br Med J1966;2:497–499.
 
7.Boyer TO, Routt SL. Acetaminophen-induced hepatic necrosis and renal failure. JAMA 1971;218:440–441.
 
8.Schiodt FV, Atillasoy E, Shakil AO, et al. Etiology and prognosis for 295 patients with acute liver failure. Gastroenterology 1997;112:A1376.
 
9.Marino G, Zimmerman HJ, Lewis JH. Management of drug-induced liver disease. Curr Gastroenterol Rep 2001;3:38–48.
 
10.Byer AJ, Traylor TR, Semmer JR. Acetaminophen overdose in the third trimester of pregnancy.JAMA 1982;247:3114–3115.
 
11.Haibach H, Akhter JE, Muscato MS, et al. Acetaminophen overdose with fetal demise. Am J Clin Pathol 1984;82:240–242.
 
12.Ludmir J, Main OM, Landon MB, et al. Maternal acetaminophen overdose at 15 weeks gestation.Obstet Gynecol 1986;67:750–751.
 
13.Lederman S, Fysh WJ, Tredger M, et al. Neonatal paracetamol poisoning: treatment by exchange transfusion. Arch Dis Child 1983;58:631–633.
 
14.Levy G, Garretson LK, Soda OM. Evidence of placental transfer of acetaminophen. Pediatrics1975;55:895.
 
15.Roberts I, Robinson MJ, Mughal MZ, et al. Paracetamol metabolites in the neonate following maternal overdose. Br J Clin Pharmacol 1984;18:201–206.
 
16.Rayburn W, Shukla U, Stetson P, et al. Acetaminophen pharmacokinetics: comparison between pregnant and nonpregnant women. Am J Obstet Gynecol 1986;155:1353–1356.
 
17.Rollins DE, von Bahr, C, Glauman H, et al. Acetaminophen: potentially toxic metabolite formed by human fetal and adult liver microsomes and isolated fetal liver cells. Science 1979;205:1414–1416.
 
18.Riggs BS, Bronstein AC, Kulig K, et al. Acute acetaminophen overdose during pregnancy. Obstet Gynecol 1989;74:247–253.
 
19.Rivka SH, Dart RC, Jarvie DR, et al. Placental transfer of N-acetylcysteine following human maternal acetaminophen toxicity. J Toxicol Clin Toxicol 1997;35:447–451.
 
20.Rayburn W, Aronow R, Delancey B, et al. Drug overdose during pregnancy: an overview from a metropolitan poison control center. Obstet Gynecol 1984;64:611–614.
 
21.Gabrielson IH, Klerman LV, Currie JB. Suicide attempts in a population pregnant as teenagers. J Public Health 1970;60:2289.
 
22.Meredith TJ, Newman B, Goulding R. Paracetamol poisoning in children. Br Med J 1978;64:611–614.
 
23.Manyike PT, Kharasch ED, Kalhorn TF. Contribution of CYP2E1 and CYP3A to acetaminophen reactive metabolite formation. Clin Pharmacol Ther 2000;67:275.
 
24.Sarich T, Kalhorn T, Magee S, et al. The effect of omeprazole pretreatment on acetaminophen metabolism in rapid and slow metabolizers of S-mephenytoin. Clin Pharmacol Ther 1997;62:21–28.
 
25.Sinclair JF, Szakacs JG, Wood SG, et al. Short-term treatment with alcohols causes hepatic steatosis and enhances acetaminophen hepatotoxicity in CYP2E1 (-I-) mice. Toxicol Appl Pharmacol2000;168:114–122.
 
26.Hazai E, Vereczkey L, Monostory K. Reduction of toxic metabolite formation of acetaminophen.Biochem Biophys Res Commun 2002;291:1089–1094.
 
27.Levy G, Khanna NN, Soda OM, et al. Pharmacokinetics of acetaminophen in the human neonate: formation of acetaminophen glucuronide and sulfate in relation to plasma bilirubin concentration and D-glucaric acid excretion. Pediatrics 1975;55:818–825.
 
28.Burk RF, Hill KE, Hunt RW, et al. Isoniazid potentiation of acetaminophen hepatotoxicity in the rat and 4-methylpyrazole inhibition of it. Res Commun Chem Pathol Pharmacol 1990;69:115–118.
 
29.Hamlyn AN, Douglas AP, James O. The spectrum of paracetamol (acetaminophen) overdose: clinical and epidemiological studies. Postgrad Med J 1978;54:400–404.
 
30.Douglas DR, Sholar JB, Smilkstein MJ. A pharmacokinetic comparison of acetaminophen products (Tylenol Extended Relief vs regular Tylenol). Acad Emerg Med 1996;3:740–744.
 
31.Clements JA, Heading RC, Nimmo WS, et al. Kinetics of acetaminophen absorption and gastric emptying in man. Clin Pharmacol Ther 1978;24:420–431.
 
32.Prescott LF. Paracetamol overdosage: pharmacological considerations and clinical management.Drugs 1983;25:290–314.
 
33.Bizovi KE, Aks SE, Polsucek F, et al. Late increase in acetaminophen concentration after overdose of Tylenol-Extended Relief. Ann Emerg Med 1996;28:549–551.
 
34.Rumack BH, Peterson RG, Koch GG, et al. Acetaminophen overdose: 662 cases with evaluation of oral acetylcysteine treatment. Arch Intern Med 1981;141:380–385.
 
35.Zimmerman HJ. Hepatotoxicity: The adverse effects of drugs and other chemicals ion the liver, ed 2. Philadelphia, Lippincott Williams & Wilkins, 1999.
 
36.Rumack BH, Peterson RG. Acetaminophen overdose: incidence, diagnosis, and management in 416 patients. Pediatrics 1978;62:898–903.
 
37.Wang PH, Yang MJ, Lee WL, et al. Acetaminophen poisoning in late pregnancy: a case report. J Reprod Med 1997;42:367–371.
 
38.Smilkstein MJ, Knapp GL, Rumack BH. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose: analysis of the National Multicenter Study (1976–1985). N Engl J Med1988;319:1557–1562.
 
39.Prescribing Information. Intravenous N-acetylcysteine. Cumberland Pharmaceuticals, NDA 21-539.
 
40.Prescott LF. Treatment of severe acetaminophen poisoning with intravenous acetylcysteine. Arch Intern Med 1981;141:386–389.
 
41.Yip L, Dart RC, Hurlburt KM. Intravenous administration of oral N-acetylcysteine. Crit Care Med1998;26:40–43.
 
42.Smilkstein MJ, Bronstein AC, Linden C, et al. Acetaminophen overdose: a 48-hour intravenous N-acetylcysteine protocol. Ann Emerg Med 1991;20:1058–1063.
 
43.Mokhlesi B, Leikin JB, Murray P, et al. Adult toxicology in critical care, II: specific poisonings. Chest2003;123:897–922.