methanol poisoning during late pregnancy
TRANSCRIPT
Clinical Toxicology, 35(2), 187-191 (1997)
CASE REPORTS
Methanol Poisoning During Late Pregnancy
Philippe Hantson, MD; Jean-Yves Lambermont, MD; Paul Mahieu, MD
Cliniques Universitaires St-Luc. Brussels, Belgium
ABSTRACT
Case Rewrt: A 26-year-old woman ingested 250 to 500 mL methanol during the 38th week of pregnancy. The initial serum methanol concentration was 230 mgldL and fonnate was 33.6 mgldL. A mild metabolic acidosis was present. As gynecologic examination and fetal monitoring failed to detect fetal distress, it was decided to give tocolytic therapy until the treatment of methanol poisoning could be achieved in the mother. Therapy included ethanol infusion, bicarbonate administration and three courses of hemodialysis. Delivery occurred six days after methanol exposure, when methanol was no longer detected in m a t e d blood. No further complications were noted in the mother and her newborn. To our knowledge, there is no other case of methanol poisoning during pregnancy in the literature.
INTRODUCTION Case Report
Methanol poisoning may be complicated by A 26-year-old primigravid woman was admitted to the Emergency Department (day 1; O900) 5 h after having voluntarily ingested 250 to 500 mL methanol. Her past history was negative for drugs and alcohol during pregnancy. According to the date of the last menstrual period, the estimated gestational age was
metabolic acidosis due to the formation of toxic metabolites. This condition can be particularly life- threatening for both the mother and her fetus. We report a case of methanol poisoning occumng in near term pregnancy.
Correspondence: Dr. Philippe Hantson, Department of Intensive Care, Cliniques Universitaires St-Luc, Avenue Hippocrate, 10, 1200 Brussels, Belgium. Tel: 3212-7642743; Fax: 3212-7648928.
187
Copyright cD 1997 by Marcel Dekker, Iuc.
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188 Hantson, Lambermont, and Mahieu
38 weeks. On admission, she was conscious but drowsy. Her vital signs were arterial blood pressure 125/75 mm Hg, heart rate 80 bpm, respiratory rate 16/min. Examination of her optic fundi was normal. She experienced weak and irregular uterine contractions and fetal movements were present. Gynecologic examination showed an absence of cervical dilation. At ultrasonography, the estimated gestational age was 35 weeks, no anomalies were found in the fetus, placenta and amniotic fluid. Fetal heart rate ranged from 120 to 140 bpm. The maternal arterial blood gas analysis revealed pH 7.36, PO2 103 mm Hg, PCO, 24 mm Hg, total C02 14 mmol/L, base deficit -11. Other laboratory values were: urea 12 mg/dL (4.3 mmol/L), creatinine 0.5 mg/dL (44.2 pmol/L) and potassium 3.2 mmol/L. The serum methanol concentration on admission was 230 mg/dL (71.8 pmol/L) and the formic acid concentration was 33.6 mg/dL. Toxicological screening revealed the presence of dipyrone in gastric fluid and blood. Gastric lavage was followed by administration of activated charcoal.
The patient was referred to the Intensive Care Unit (ICU) for further management. We started tocolytic therapy with ritodrine (infusion rate 100 pglmin) in addition to ethanol prescribed to treat methanol poisoning. Ethanol infusion was started immediately and three courses of hemodialysis (4 h period each) were performed over the first 36 h. It was calculated that a total of 2350 mL ethanol 94% (corresponding to 1767 g ethanol) were infused up to delivery. Large doses of sodium bicarbonate were required to keep maternal blood pH near normal: 275 mmol were given over the first day, and 100 mmol during the second day. Arterial blood pH never fell below 7.36. Biological and toxicological data are illustrated in Figure 1.
Fetal heart monitoring failed to reveal any sign of fetal distress during ICU stay (fetal heart rate ranging from 120 to 140 bpm).
At 0200, day 6, the frequency and intensity of uterine contractions increased. The cervix was effaced and fully dilated and a spontaneous rupture of the membranes occurred. The fetus was in left occipital anterior position. Afier one hour of uncomplicated labor, the patient delivered a girl (50 cm height, 3100 g weight, corresponding to percentile 50 for 38 week gestational age) with no signs of distress; the Apgar scores were 9/10 at 1
min, and loll0 after 5 min. Blood was drawn from umbilical artery and vein; the pH of the arterial and venous bloods were 7.29 and 7.36 respectively, and the PC02 were 36 and 39 mm Hg. One hour before delivery, arterial pH was 7.47 and K O 2 30 mm Hg in the mother.
At the time of delivery, the serum ethanol level was 18 mg/dL in the mother and the child and methanol was not detected in either. Formic acid concentration was 0.24 mg/dL in the maternal blood and not measurable in the newborn.
The clinical course was uneventful in the child and the mother. In particular, no visual disturbances developed, with a follow-up of more than ten years for the child.
DISCUSSION
Suicide attempts during pregnancy usually involve medications which are regularly prescribed to preg- nant women. In a series of 11 1 patients, Rayburn et al. found that analgesics, vitamins and iron, anxiolytics and sedative-hypnotic agents accounted for 79% of reported ingestions by pregnant women.2
Ethanol diffuses across the placenta3y4 and may exert teratogenic effects during pregnancy. During pregnancy, it is unlikely that the acute administration of a single large dose of ethanol could result in teratogenic effects, contrasting with the well documented fetal alcohol syndrome, the manifest- ations of which are largely related to chronic alcohol consumption during pregnan~y.~ Methanol has also been found teratogenic in mice and rat^,^,^ but no data are available in humans. However, during pregnancy, the main risk of methanol exposure is undoubtedly the development of a severe metabolic acidosis in the mother and the fetus.
The metabolism of ethanol and methanol is dependent upon the activity of alcohol and aldehyde dehydrogenase. Little is known about the activity of these enzymes in human fetal liver. Experimental models in rats suggest that the activity of fetal liver alcohol dehydrogenase is very low.8 In perfused livers obtained from 10- to 16-week-old human fetuses, Pikkarainen et al. found that the activity of fetal alcohol dehydrogenase is only 10% of adult level^.^ The activity probably increases with time. Acetaldehyde and formaldehyde are small liposoluble molecules which are able to cross membranes by
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Methanol Poisoning in Pregnancy 189
7 3
7.45
7,4
7.35
7.3
7.25 ~ ~ ~ 8 8 ~ ~ 8 8 8 8 ~ ~ ~ 8 8 8 ~ 8 8 8 8 8 ~ ~ ~ 8 8 8 ~ ~
- : & - ( n m l c r r z : z - r - N - r N - -
r - N
pH 7,36 7,41 7,43 7,45 7.45 7.46 7,45 7.42 7.43 7.44 7.47 1.43 22 22 totalCO2(nunoVL) 14 15 21 26 21 23 22 22 22 22
lactate (xrunoYL) 2.05 3,6 3.5 2.25 fonNc acld (mgidLJ 33.6 33 0.28 0.24
30
25
20
15
10
Figure 1. Biological and toxicological data including serum methanol, formic acid and ethanol determinations.
simple diffusion. In rats, in the late pregnancy, aldehyde dehydrogenase activity is present in placenta and fetal liver at lower value than in liver from the adult rat. It seems that there is an acetaldehyde threshold above which the capacity of acetaldehyde metabolism by the fetoplacental unit could be surpassed. lo
Extrapolation of these data to methanol intoxication in humans is difficult. It is very likely that methanol crosses the placenta resulting in an equilibrium between maternal and fetal blood. If fetal liver alcohol dehydrogenase activity is weak, the biotransformation of methanol to formaldehyde would occur only in the mother. Formaldehyde could also cross the placenta. It is not known whether fetal liver aldehyde dehydrogenase could metabolize significant amounts of formaldehyde into formic acid. In the present case, formic acid could
not be found in fetal blood, while a very low concentration was still detected in the mother.
The management of methanol exposure in a pregnant woman should follow the principles proposed for nonpregnant patients. In all cases in which the blood methanol level exceeds 25 mg/dL, ethanol followed by hemodialysis remains the mainstay of treatment.
Some aspects of ethanol therapy during pregnancy have to be discussed. Ethanol has been used in the past to prevent premature delivery. However, in comparison with other therapeutic agents (beta- adrenergic drugs), ethanol therapy is poorly effective and can be complicated by severe maternal and neonatal adverse effects. IV administration of ethanol to the mother near term results in the drug readily crossing the placenta with the development of significant ethanol concentrations in the newborn
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190 Hantson, Lambermont, and Mahieu
infant. * l2 Ethanol concentration should be monitored closely in the maternal blood to avoid complications during the perinatal period which include premature births, neonatal depression, lethargy, apnea, poor muscle tone and abnormal reflexes. All of these have been noted in infants delivered during a maternal ethanol infusion or within 12 h after its termination. Hypoglycemia, metabolic acidosis and even death have also been reported.13 The recommended serum ethanol concentration for the treatment of methanol poisoning is 100 to 150 mg/dL. Despite the administration of usual doses of ethanol, this level was not reached in the present case. The final serum ethanol concentration can not always be readily predicted by the ethanol infusion rate, and especially during hemodialysis. We were hesitant to use large doses of ethanol in order to avoid complications in the fetus. However, metabolic acidosis did not progress in the mother and serum formic acid concentration decreased rapidly. This suggests that the combination of ethanol and hemodialysis was effective.
Hemodialysis should be performed on any methanol poisoned patient who is symptomatic, has a significant metabolic acidosis, has a blood level of methanol greater than 25 mg/dL, or has renal compromise. l 4 Concentrations of formate in excess of 20 mg/dL can be expected to produce ocular injury and a metabolic acidosi~. '~ Hemodialysis is effective in removing methanol and its toxic metab- olite, formic acid, and is useful for the correction of metabolic acidosis. Hemodialysis durin pregnancy has been previously documented. 16.1' Special attention should be given to the control of blood pressure and to the prompt diagnosis and treatment of bleeding disorders.
Heparin does not cross the placenta in significant quantities. l 8 However, anticoagulant therapy increases the risk of postpartum bleeding and heparin therapy should be monitored closely.
Among other treatments, the use of 4-methyl- pyrazole, a competitive inhibitor of alcohol dehydrogenase, is currently under investigation in animals and humans as an alternative to ethanol therapy after methanol or ethylene glycol poisoning.19 However, its clinical use is not approved by the FDA and it is prohibited in pregnant women. In our patient, the toxicological screening
revealed the presence of dipyrone and the possible protective effect of this pyrazole derivative remains speculative.m
Several reasons led us to consider the prolongation of pregnancy. The gestational age was uncertain as there was a discrepancy between ultrasonography findings and the term predicted by the date of the onset of the last menstrual period. Also, the patient was admitted before significant amounts of methanol were transformed into toxic metabolites making it unlikely that the fetus was exposed to severe acidosis. We thought therefore that it was safer to promote the elimination of methanol in the fetomatemal compartment before delivery because ethanol infusion and hemodialysis is difficult in the newborn.
In conclusion, we report a case of methanol poisoning occurring during near term pregnancy and we are not aware of similar cases in the literature. Despite the high initial blood concentration of methanol in the mother, therapy with ethanol infusion and hemodialysis was safe and effective for both the mother and the newborn.
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