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Acetaminophen overdose in pregnancy.

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 OvidMEDLINE[R] 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 Words: acetaminophen, N-acetylcysteine, overdose, pregnancy, toxicity

Introduction

Acetaminophen (APAP), known as paracetamol outside of America, is one of the most widely used over-the-counter medications. (1-3) and has become the most commonly recommended analgesic during pregnancy. (4)

In 1966, the first clinical evidence of the toxicity of APAP appeared in reports of three apparent suicide attempts, two of which were successful as the result of large overdoses. (5,6) The United States did not have its first published report of suicidal overdose until 1971. (7) Since that time, APAP has become the most common drug involved in suicidal overdose and fulminant hepatic failure in the United States. (8,9)

The first reports of APAP overdose in pregnancy resulting in fetal demise were not published until the early 1980s. (10-13) APAP appears to freely cross the placenta (10,14,15) and is in turn metabolized by fetal hepatocytes. Maternal absorption and metabolism of APAP are not affected by pregnancy, (16) and fetal metabolism of APAP occurs. (12,17) Hepatic necrosis may occur in the fetus after maternal overdose if proper treatment is delayed or not given. (18) Therapy for APAP toxicity consists of N-acetylcysteine (NAC). Based on case reports and limited data, NAC appears to be effective also for the treatment of acetaminophen overdose during pregnancy. NAC crosses the placenta and may provide hepatoprotection to the fetus by binding toxic metabolites within the fetal liver. (18,19)

Epidemiology

Approximately 10% of all suicides in the United States are due to APAP overdose. (1) The usual effective suicidal dose is greater than 15 g. Most of these are adolescents or young adults, and 60% are female. Up to 70% of APAP overdoses in the United States are with suicidal intent. The other 30% are accidental and might include overdose caused by carelessness, ignorance of risks, or increased susceptibility plus proper or excessive doses. (2)

Suicide attempts during pregnancy usually present as intentional drug overdoses after interpersonal conflict. (20) The reported frequency of successful suicide (all forms) during pregnancy is one in every 88,000 to 400,000 live births. (20) Approximately 0.07% of all telephone inquiries about drug overdose at a Michigan metropolitan poison control center were related to drug overdose during pregnancy. (20) Among pregnant teenagers in a large American city, in 83% of cases, suicide had not been attempted before the pregnancy. (21)

Over half of the cases occur during the first trimester, with the rest equally divided during the second and third trimesters of pregnancy. Acetaminophen, alone or combined with codeine, was ingested in 20% of drug overdoses during pregnancy. (20) Alcohol abuse and intake of other drugs may be causes of increased susceptibility to APAP toxicity, although this is controversial. (1) Neonates and young children appear to be less susceptible to hepatic injury, presumably because of differences in pharmacokinetics and metabolism of the drug. (17) However, infants and children can convert APAP to its toxic metabolite, and hepatic toxicity may occur, sometimes causing death. (1,10,15) Older children and adolescents are much more likely to intentionally overdose with APAP. (22)

Pathophysiology

In therapeutic doses, adults metabolize APAP predominantly in the liver, rapidly forming nontoxic glucuronides and sulfates that are excreted in urine (1,11) (Fig. 1). Only approximately 4% of the drug is excreted unchanged. Cytochrome P450 enzyme CYP2E1 metabolizes another fraction (~5%) to highly reactive oxides such as the active electrophilic metabolite N-acetyl-p-benzoquinoneimine (NAPQI). Most of NAPQI is bound by reduced glutathione and excreted in the urine as cysteine or mercapturic acid conjugates. Liver cell injury occurs when the amount of the toxic metabolite (NAPQI) formed exceeds the binding capacity of glutathione.

[FIGURE 1 OMITTED]

The percentage of APAP converted to NAPQI by CYP2E1 is increased when APAP conjugation pathways become saturated. Previously, other P450 enzymes such as CYP3A4 and CYP1A2 were thought to contribute, but in vivo studies have shown their contribution to be negligible compared with CYP2E1. (23,24) However, hepatotoxicity developed in CYP2E1 knockout mice given APAP, ethanol, and isopentanol, suggesting the action of other CYP enzymes. (25) One of these enzymes may be CYP2A6, as suggested by recent studies. (26)

Acetaminophen crosses the placenta and is detectable in the neonatal serum after birth. (14) Human fetal microsomes and isolated fetal hepatocytes have been shown to be able to metabolize acetaminophen into NAPQI, although at a slower rate than adults. (17) Glucuronidation, the main metabolic pathway to safely metabolize acetaminophen in adults, is markedly reduced in the neonate, leaving sulfation as the major fetal pathway for acetaminophen metabolism. (17,27) If the fetal circulation becomes saturated with acetaminophen as a result of maternal overdose, oxidation of acetaminophen through the P450 cytochrome system may produce sufficient toxic intermediary to cause hepatic injury in the neonate.

APAP metabolism is unchanged in pregnant versus non-pregnant women. (16) It has been shown that the human fetus metabolizes APAP after placental transfer, and its metabolites are excreted in urine in the same manner as adults. (14) Since NAPQI is a reactive metabolite that exerts most of its effects at the level of the hepatocyte, it is unlikely that any significant amount crosses the placenta. Since APAP crosses the placenta, the ability of the fetus to metabolize APAP is the primary determinant of the degree of fetal hepatocyte damage that occurs after maternal APAP overdose. The ability to metabolize APAP begins at approximately 18 weeks' gestation and continues to increase through 23 weeks. (12,17) Oxidation by the fetal liver is approximately 10 times slower than by the adult liver, but it is unknown how much this rate increases as the fetus continues to develop. Therefore, the fetus is also at risk for hepatotoxicity after maternal overdose of APAP; however, current knowledge does not allow us to quantify the risk to the fetus or to determine if the risk is different at different gestational ages.

The total quantity of APAP ingested, the resulting blood level, the activity of the cytochrome P450 system (especially CYP2E1), the adequacy of glutathione (GSH) stores, the effectiveness of glucuronidation, and the promptness of appropriate therapy (Table) are all important factors affecting the toxicity of the intentional ingestion of a single large dose of APAP. (1,2,28) Other factors that modulate the toxicity of APAP ingestion include acute or chronic alcohol ingestion, the use of medications that affect the P450 cytochrome system, and the age of the patient, with children appearing to be less susceptible. The role of these factors in predicting fetal morbidity or mortality after maternal acetaminophen overdose has not been studied. Hepatic injury or even death may occur in 80% of APAP doses that exceed 15 g; however, doses as large as 75 g have been followed by instances of recovery. (29)

Since the absorption of APAP is rapid, achieving peak values in 1 to 2 hours, (30) the 4-hour blood level is used as a prognostic measure and guide to therapy in adults. (31,32) However, large doses of APAP may delay gastric emptying, and extended release preparations may cause a delay in the peak level as well. (31,33) Rumack, Matthews, Vale, and Prescott have developed nomograms that correlate the likelihood of liver damage with blood levels of APAP during the first 16 or even 24 hours after taking a single overdose of the drug (34) (Fig. 2). Patients with levels above 300 [micro]g/mL at 4 hours have development of overt, often fatal hepatic injury in 90% of cases. This nomogram is predictive of hepatic injury in pregnant women as well, but it is impossible to exactly correlate the effect on the fetus since fetal ability to metabolize APAP is unpredictable and reported experience is case-based only. (12,16,17) It should be noted that the nomogram applies only to a single time-point ingestion of an overdose and cannot be used to predict hepatic toxicity in subjects chronically ingesting excessive amounts of acetaminophen.

Clinical Features

The outcome of the mother will generally reflect the outcome of the fetus. (18) The clinical course of APAP toxicity caused by intentional overdose is triphasic. (9,35) The first phase, which begins within several hours of ingestion, includes anorexia, nausea, vomiting, and rarely shock. This phase generally lasts less than 12 hours. The second phase occurs over the next 24 to 48 hours. During the second phase, gastrointestinal symptoms improve and biochemical evidence of hepatic injury appears.

The third phase, usually 3 to 5 days after ingestion, is the time when overt hepatic damage and jaundice may appear. The severity of hepatic injury is variable. Up to one third of patients who had presumably not been treated in time may progress to fulminant hepatic failure, evidenced by coagulopathy, and hepatic encephalopathy. Ideally, therapy should be delivered during the first phase or early into the second phase of the intoxication.

Treatment

In September 1976, the Food and Drug Administration gave an Investigational New Drug License to the Rocky Mountain Poison and Drug Center for the use of oral NAC in the treatment of APAP poisoning. (18) The treatment protocol for oral NAC was a loading dose of 140 mg/kg orally followed by 17 maintenance doses of 70 mg/kg orally every 4 hours. If the patient's history indicated ingestion of 7.5 g or more and an APAP level was not available immediately, the recommendation was to initiate treatment and then discontinue it later if the level was determined to be nontoxic. One hundred thirteen women who were reported to be in various stages of pregnancy were entered into the study protocol from 1976 to 1985. Follow-up, including appropriate laboratory and pregnancy outcome data, was available in 60 cases, 24 of which had APAP levels above the APAP overdose nomogram line. Ten were treated within 10 hours of ingestion, 10 were treated 10 to 16 hours after ingestion, and 4 were treated 16 to 24 hours after ingestion. Of the 10 who were treated within 10 hours of ingestion, 8 delivered normal infants and 2 had elective abortions. Of the 10 patients receiving NAC 10 to 16 hours after ingestion, 5 delivered viable infants, 2 had elective abortions, and 3 had spontaneous abortions. Of 4 women receiving NAC 16 to 24 hours after ingestion, 3 patients had hepatotoxicity and 1 patient died. There was one spontaneous abortion, one stillbirth, one elective abortion, and one delivery. There was a significantly increased probability of fetal death if the mother received the loading dose of NAC late after ingestion (P = 0.002) or if she took an overdose early in pregnancy (P = 0.014). However, it is important to note that the study group was a small number of patients who were neither randomly selected nor part of a case-control study. This study in addition to other case reports supports the early administration of NAC in APAP overdose in pregnancy. (36,37)

[FIGURE 2 OMITTED]

When a patient presents with a probable toxic ingestion of APAP, blood should be drawn for measurement of APAP level and treatment started immediately. (1,32) If the level during the initial period of 4 to 16 hours is found to be predictive of no liver injury, NAC may be stopped. If the level is borderline or predictive of injury, treatment should be completed. As with all patients ingesting toxic quantities of APAP, the best outcomes occur in patients who receive NAC within 16 hours of ingestion. Treatment 16 to 24 hours after ingestion and perhaps longer is still indicated, even though it may be less effective. (38)

There may be occasions in which oral NAC may not be feasible because of nausea, vomiting, anorexia, and/or altered mental status. Nasogastric tube administration may be considered for these patients. This still may not be possible for all cases. In the United Kingdom and Canada, NAC has been available as an intravenous preparation. (1) In January 2004, the Food and Drug Administration approved the use of intravenous NAC (Acetadote[R]) for use within 8 to 10 hours after ingestion of a potentially hepatotoxic quantity of acetaminophen. The most frequently reported adverse events attributed to intravenous acetylcysteine administration include rash, urticaria, and pruritus, with frequency between 0.2% and 20.8%, and may be particularly severe in cases with preexisting bronchospasm. (39) Systemic anaphylaxis may also occur in response to intravenous NAC. Circumstances in which intravenous administration of NAC would be advantageous include inability to tolerate oral NAC, coingestion with other noxious product necessitating ongoing gastrointestinal lavage, gastrointestinal bleeding or obstruction, APAP toxicity presenting as encephalopathy, neonatal APAP toxicity from maternal overdose, and medical or surgical conditions precluding oral NAC administration. (40-43) Data are limited regarding the safety and efficacy of intravenous acetylcysteine in pregnant women. No serious toxicity inherent to pregnancy has been reported in the few cases treated so far, but experience is very limited.

Conclusion

APAP toxicity in pregnancy is not rare and can result in significant morbidity and mortality in both the mother and the fetus. APAP crosses the placenta and may be metabolized by the fetal liver into active and toxic metabolites. Fetal hepatic necrosis caused by these toxic metabolites may occur from maternal APAP overdose. NAC also crosses the placenta and may bind toxic metabolites in both the mother and the fetus. Limited data based mainly on case reports suggests that NAC may be safely administered during pregnancy and should be initiated early after APAP overdosage. Because the safety profile of oral or intravenous acetylcysteine has not been adequately studied in pregnancy, consideration should be given to obtaining informed consent before administration during pregnancy. Acetaminophen overdose during pregnancy is not an infrequent occurrence, and further investigation is necessary in relation to this field.

References

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All the money you make will never buy back your soul.
--Bob Dylan


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

From the Division of Gastroenterology, University of South Alabama College of Medicine, Mobile, AL.

Reprint requests to Jorge L. Herrera, MD, Division of Gastroenterology, 5600 Girby Road, Mobile, AL 36693. Email: jherrera@usouthal.edu

Accepted June 8, 2005.

RELATED ARTICLE: 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.
Table. Factors affecting outcome after acetaminophen overdose

 Suicidal intention single dose
Dose over 15 g in 95% of cases.

Blood levels Blood level between 4 and 16 h after ingestion
 is a useful predictor of hepatic injury.
Cytochrome P450 activity Increased activity of CYP2E1 enhances toxicity
 of APAP.
Glutathione stores Depletion of glutathione stores during
 conditions such as fasting, or concomitant
 use of carbazepine and phenytoin decreases
 detoxifying ability enhancing toxicity.
Nutritional status Fasting enhances toxicity by leading to
 decreased glucuronidation, leading to
 enhanced production of toxic metabolite.
 Fasting may also contribute to glutathione
 depletion.
Alcohol and drugs Alcohol induces CYP2E1 as well as 3A4,
 increasing conversion of APAP to NAPQI.
 Alcohol also leads to decreased synthesis of
 glutathione and to impaired nutrition
 contributing to depletion of glutathione.
 Phenytoin, carbamazepine and phenobarbital
 induce CYP3A4 leading to increased
 production of NAPQI.
 Zidovudine may impair glucuronidation leading
 to APAP hepatotoxicity with therapeutic
 doses.
Age Children are less susceptible, because of
 lesser production of toxic metabolites and
 greater degree of conjugation.
Gender Greater proportion of females in suicidal
 exposure.
Promptness of treatment Treatment given within 16 hours of ingestion
 is more likely to prevent severe
 hepatotoxicity.

APAP, acetaminophen; NAPQI, N-acetyl-p-benzoquinoneimine.
*Adapted from Zimmerman HJ. Acetaminophen hepatotoxicity. Clin Liv Dis
1998;2:528, with permission.
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Title Annotation:Review Article
Author:Herrera, Jorge L.
Publication:Southern Medical Journal
Date:Nov 1, 2005
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