Volume 70, Number 11 OBSTETRICAL AND GYNECOLOGICAL SURVEY Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
CME REVIEW ARTICLE
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CHIEF EDITOR’S NOTE: This article is part of a series of continuing education activities in this Journal through which a total of 36 AMA PRA Category 1 Credits ™ can be earned in 2015. Instructions for how CME credits can be earned appear on the last page of the Table of Contents.
Carbon Monoxide Exposure During Pregnancy Perry Friedman, MD,* Xiaoyue M. Guo, BA,† Robert J. Stiller, MD,‡ and Steven A. Laifer, MD§ *Resident Physician, Department of Obstetrics and Gynecology, Bridgeport Hospital, Bridgeport; †Medical Student, Yale University School of Medicine, New Haven, CT; and ‡Chief Section of Maternal Fetal Medicine and §Chief Section of Obstetrics, Department of Obstetrics and Gynecology, Bridgeport Hospital, Bridgeport, CT Importance: Carbon monoxide (CO) is the leading cause of poisoning in the United States and is associated with high maternal and fetal mortality rates. Given the nonspecific signs and symptoms of toxicity, cases may go unsuspected or attributed to other etiologies. As CO adversely affects both mother and fetus, it is important for practitioners to recognize and treat poisoning in a timely manner. Objective: We seek to assist practitioners with understanding the physiology and recognizing the presentations of both acute and chronic CO poisoning, as well as provide information on diagnosis and treatment options. We also conducted a review of cases described in the literature during the past half century to show varying presentations and treatment methodologies. Evidence Acquisition: A qualitative literature search was conducted using PubMed and Google Scholar for articles published between 1970 and 2014 that assessed cases of CO poisoning during pregnancy. Excluded studies were not in English or contained nonhuman subjects. Results: Nineteen published reports of CO poisoning during pregnancy described in varying levels of detail were found in the literature from 1971 to 2010. Conclusions and Relevance: Carbon monoxide poisoning requires a high degree of suspicion. Diagnosis is made based on initial history and physical evaluation and assessment of environmental CO levels; presenting carboxyhemoglobin levels may be poor indicators of severity of disease. Oxygen therapy should be initiated promptly in all possible cases with consideration of hyperbaric oxygen therapy in cases of significant maternal exposure. Treatment requires a longer duration for fetal CO elimination than in the nonpregnant patients. Importantly, practitioners should educate pregnant patients on prevention. Target Audience: Obstetricians and gynecologists, family physicians Learning Objectives: After completing this activity, the learner will be better able to: describe the basic pathophysiology of carbon monoxide poisoning in the mother and fetus; recognize and diagnose carbon monoxide poisoning in a pregnant patient; explain treatment of carbon monoxide poisoning in pregnancy.
Incidence/Prevalence Carbon monoxide (CO) is an odorless, colorless, and tasteless gas that is a poisonous by-product of combustion. It frequently reaches high ambient concentrations All authors and staff in a position to control the content of this CME activity and their spouses/life partners (if any) have disclosed that they have no financial relationships with, or financial interests in, any commercial organizations pertaining to this educational activity. Correspondence requests to: Perry Friedman, MD, 267 Grant St, Bridgeport, CT 06610. E-mail: [email protected].
in poorly ventilated areas causing signs and symptoms of intoxication.1 Carbon monoxide is responsible for more than half of all fatal poisonings worldwide and is the leading cause of poisoning in the United States,2 accounting for more than 20,000 emergency department visits annually, occurring mostly in the winter months.3 From 1999 to 2010, approximately 500 deaths per year have been attributed to CO poisoning in the United States.3 The case-fatality rate has been reported as high as 30%, although many fatalities are due to intentional exposures for self-harm.4 An estimated 8.5% of pregnant
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women are exposed in some degree to CO.5 Acute CO poisoning in pregnancy has been associated with a maternal mortality rate between 19% and 24%, and a fetal mortality rate between 36% and 67%.6 Because of the nonspecific signs and symptoms, it is possible that these numbers underrepresent the true number of cases, some of which might go unsuspected or be attributed to other etiologies.7 Typical Causes of CO Poisoning Carbon monoxide arises from the combustion of carbon compounds and can either be from exogenous or endogenous sources. Carbon monoxide in its simplest form is an endogenous by-product of normal hemoglobin metabolism of protoporphyrin to bilirubin.8 However, exposure to high concentrations from exogenous sources can be extremely toxic to humans. Carbon monoxide results whenever fuel or other carbon-based materials are burned in oxygen-deprived areas. Accidental household exposure to CO is the most frequent cause of poisoning in pregnancy.9 Examples of potential sources include poorly maintained heating equipment, poorly ventilated gas appliances such as stoves, running vehicles in closed spaces, house fires, clogged chimneys, indoor generators, and so on.10 As such, cities with more significant air pollution have a higher CO burden.11 In the human body, approximately 1% to 3% of hemoglobin is normally bound to CO as carboxyhemoglobin (COHb), with higher amounts found in those with chronic CO exposure, such as smokers (Table 1). In pregnant smokers, COHb levels in the blood can reach 9%. Chronic CO inhalation from tobacco is usually tolerated by pregnant women; however, it may be dangerous if additional sources of CO increase the exposure concentration.11 Average levels in homes without gas stoves vary from 0.5 to 5 ppmv (parts per million volume). Levels near properly adjusted gas stoves are often 5 to 15 ppmv, and those near poorly adjusted stoves may be 30 ppmv or greater.12,13 Physiology of CO in Pregnancy When CO is inhaled, it easily crosses the pulmonary alveoli and combines with hemoglobin to produce TABLE 1 Blood COHb Levels in Different Situations11 State Nonsmoker Smoker Acute poisoning Life threatening
COHb Levels, % 1–3 6–9 30–50 >50
FIG. 1. Oxygen-hemoglobin dissociation curve for adult humans. Competitive binding of CO with hemoglobin causes a left shift of the curve. Reprinted with permission from Elsevier Publishing.14 Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.
COHb, which greatly diminishes hemoglobin’s oxygencarrying capacity. Toxicity occurs because of a combination of tissue hypoxia and direct CO-mediated damage at the cellular level. Hemoglobin’s binding affinity for CO is more than 200 times greater than its affinity for oxygen. A consequence of this competitive binding is a left shift of the oxygen-hemoglobin dissociation curve, and thus, oxygen binds with a greater affinity to hemoglobin, resulting in poorer tissue perfusion as a result of decreased oxygen release to the cells (Fig. 1).15,16 In addition to the resultant tissue hypoxia, a small fraction of free CO in plasma also causes direct tissue injury by disrupting the normal functions of mitochondria, which leads to cell damage.17 During pregnancy, the rate of endogenous CO production increases and then drops rapidly after delivery. This increase is mainly due to progesterone-inducing hepatic microsomal enzymatic activity, although 30% to 40% is from an increase in maternal erythrocyte mass, and 15% is from endogenous fetal production.11 Compared with adult hemoglobin, fetal hemoglobin has a greater affinity for oxygen, which facilitates appropriate physiological maternal-fetal oxygen exchange. Carbon monoxide enters fetal blood after crossing the placenta either by passive diffusion or via a carrier.18 With fetal exposure to CO, the fetal oxygenhemoglobin curve, which typically stands to the left of the maternal oxygen-hemoglobin curve, is further shifted to the left in a more hyperbolic curve; thus, the
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Carbon Monoxide Exposure During Pregnancy • CME Review Article
fetus suffers the same, if not worse, toxic effects because of an even greater tissue hypoxia. Longo8,19 and Longo and Hill8,19 are credited with much of what is known regarding fetal COHb. Having extensively studied CO exposure in maternal and fetal sheep, they have reported that at all levels of CO exposure the fetal COHb concentration initially lags behind that of the mother. Eventually, fetal COHb concentration equals and then surpasses the maternal concentration over time. With initial exposure, maternal COHb levels increase rapidly for the first 2 to 3 hours and then continue to rise over the next 7 to 8 hours. Fetal COHb, on the other hand, initially shows no increase during the first hour; however, over the next 4 to 5 hours, it increases at a slow rate. At 5 to 6, hours it equals maternal concentrations, but continues to rise for 24 hours, eventually reaching a steady state in 36 to 48 hours.8,19 Hill et al20 constructed mathematical models to calculate theoretical relations between fetal-maternal COHb in humans (Fig. 2). Predicted uptake and elimination curves were similar to what was seen in sheep studies. Fetal COHb concentrations would lag behind maternal concentrations, and only after 14 to 24 hours would equilibrium be reached. Of clinical significance, fetal COHb would eventually equilibrate at concentrations 10% to 15% higher than maternal. Fetal CO elimination also significantly lags behind maternal CO elimination, owing to the fact that fetuses cannot increase their tidal volume or ventilation rate. During the washout phase, the approximate time to reach one half of the maximum value was 2 hours for mother and 7 hours for fetus.8 With 100% oxygen, the rate of elimination is greatly increased (Fig. 3);
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FIG. 3. Length of time required to eliminate CO from a mother and fetus when the mother is treated with 100% O2, after prolonged exposures to 30, 50, 100, 200, and 300 ppm inspired CO concentrations, assuming initial equilibrium between fetal and maternal CO. These curves differ from Figure 2 by showing increased rate of CO elimination when 100% oxygen is administered to the mother. Reprinted with permission from Elsevier Publishing.20
nevertheless, fetal elimination time still lags behind maternal, and it has been suggested that in order to normalize fetal COHb a pregnant woman would need to receive 100% oxygen for a duration that is 5 times as long as that required to reduce her own COHb to a normal level.19 Clinically, acute CO poisoning harms both mother and fetus, but chronic exposure may disproportionally harm the fetus during its development.11 Two mechanisms of toxicity have been proposed in the fetus: tissue hypoxia or direct association with the body’s hemecontaining proteins, including intracellular myoglobin, cytochromes a, and p450. Diagnosis and Signs of CO Toxicity for Mother and Fetus
FIG. 2. The predicted time course of human maternal and fetal COHb concentrations during prolonged exposures to 30, 50, 100, 200, and 300 ppm inspired CO concentrations, followed by a washout period when no CO was inspired. Note that fetal COHb concentrations lag behind those of the mother, but eventually reach higher values in most cases. Reprinted with permission from Elsevier Publishing.20
Diagnosing CO poisoning requires a high index of suspicion, given its nonspecific signs and symptoms and the intrinsic properties of CO in being odorless and colorless. Oxygen-dependent organs, such as the heart and brain, show the earliest signs of injury in CO poisoning, but 83% of victims have no or minor symptoms.1 Kao and Nañagas2 dubbed it the “great mimicker” because the clinical signs and symptoms of CO toxicity are largely nonspecific and its presentation depends on the duration and concentration of exposure. As such, it is important for physicians to take a detailed history including symptom duration and correlation with environmental CO concentration. Acute exposure
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TABLE 2 Maternal Symptoms of CO Poisoning According to COHb Levels Stages of CO Poisoning Chronic poisoning
COHb Levels, %
Signs of Poisoning
5–20
Headaches, sensations of weakness, dizziness, sleepiness impaired physical performance, visual difficulties, palpations, nausea, vomiting Tachypnea, tachycardia, fever, vomiting, confusion, disorientation, hypotension, arrhythmia, alteration in consciousness, convulsions, respiratory insufficiency Psychiatric difficulties, apathy, apraxia, disorientation, muscular hypertonia, intestinal problems, urinary or fecal incontinence, alteration in consciousness
Acute poisoning
30–50
Life-threatening poisoning
50–66
Lethal poisoning
>66
Reprinted with permission from BJOG.11
with large concentrations produces symptoms quickly and can lead to death. Maternal symptoms of CO poisoning corresponding to COHb levels are shown in Table 2.11 Early signs and symptoms include headache, nausea and vomiting, increases in blood pressure, tachycardia, and tachypnea, as well as chest pain, shortness of breath, anxiousness, and altered consciousness. Likewise, toxic effects of CO on the developing fetus depend on chronicity of exposure and concentration as well as gestational age (GA).21 The measurement of COHb concentration remains an essential and fundamental component in the evaluation of suspected COHb poisoning (>2% in nonsmokers and ≥9% in smokers).7 Standard pulse oximetry is unable to distinguish between COHb and oxyhemoglobin, but specialized pulse co-oximetry may be useful in rapidly triaging patients with significant exposure.4 Additional studies can also be obtained (Table 3). Additional important laboratory values include arterial and venous partial pressure of oxygen (PO2) levels. Normal arterial PO2 levels are 80 to 100 mm Hg, and venous levels are approximately 25 mm Hg in healthy
nonsmokers. With CO exposures, arterial blood gas PO2 results will typically be normal or low, as they measure dissolved, unbound oxygen. In contrast, venous PO2 results will usually be higher, approximately 30 to 50 mm Hg, given the higher oxygen affinity of COHb and less effective release of oxygen to tissues.21 Cardiac monitoring is also vital because of the potential for dysrhythmias. Brain imaging commonly shows bilateral low-density globus pallidus lesions and/or diffuse, symmetric periventricular white matter lesions after CO poisoning. A neuropsychological screening battery or application of other neuropsychiatric testing methods, such as the Mini-Mental Status Examination, can also be useful for monitoring progress.2 Review of Previous CO Cases in Pregnancy Over the last couple of decades, there have been several published case reports and a few case series of CO exposure during pregnancy and fetal outcomes. Carbon monoxide poisoning in pregnancy was first described in 1859 with the onset of the industrial revolution and
TABLE 3 Recommended Investigations in Women With Suspected CO Poisoning Investigation
Finding/Outcome Measure
1. Measurement of serum COHb 2. Arterial blood gas and lactic acid level 3. Toxic screen 4. Serum CPK and LDL levels 5. Serum ALT and AST 6. Serum glucose level 7. Full blood count 8. ECG 9. Neuropsychological testing 10. CT of the head 11. EEG
Gives an indication of the severity of maternal poisoning and a cruder indication of the degree of fetal poisoning Measure degree of maternal acidosis and hypoxia Another poison could be present Delayed elevation of these enzymes has been described in experimental models Become elevated 1-2 d after severe poisoning Secondary hyperglycemia can sometimes be observed Leukocytosis is common Myocardial ischemia or cardiac arrhythmia may occur Discrete abnormalities of higher cortical function may be sequel To identify cerebral edema or infarction To identify diffuse abnormalities of cerebral electrical activity
Reprinted with permission from BJOG.11 AST indicates aspartate aminotransferase; ALT, alanine aminotransferase; CPK, creatinine phosphokinase; CT, computed tomography; ECG, electrocardiogram; EEG, electroencephalogram; LDL, low-density lipoprotein.
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Carbon Monoxide Exposure During Pregnancy • CME Review Article
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TABLE 4 Fetal Complications After CO Toxicity at Different Ages and Dosages11,29,32 Exposure Early General anatomical malformations, especially limb
Late Specifically brain malformations, such as anoxic anencephaly Dosage
Low or Chronic Decreased birth weights and intrauterine growth restriction due to chronic hypoxia
coal-gas exposure.22 In the modern day, however, chronic CO exposure in pregnancy is usually caused by smoking. Tobacco exposure carries with it several additional carcinogens and other short- and long-term effects, some of which have yet to be elucidated. The first connection between premature birth and smoking was made in 1972, and studies since have repeatedly connected cigarette smoking with adverse perinatal and neonatal outcomes in a dose-related manner.23 Reports show increased incidences of fetal wastage, placental abruption, placenta previa, and premature rupture of membranes; decreased birth weight is also directly related to the number of cigarettes smoked. Moreover, long-term effects have been seen of reduced mathematics and reading ability, decreased height, and increased hyperkineticism.22 Acute CO poisoning in the earlier stages of gestation may be associated with anatomical malformations if a viable term fetus results, whereas exposure at a later GA is associated with neurological sequelae of anoxic events, as the fetal brain is more sensitive to CO closer to term.9,24 Cases of fetal demise due to CO intoxication can be diagnosed postmortem, given that fetal COHb is unchanged for days. Toxic levels of COHb in adults are those greater than 25%, and levels greater than 50% may result in death.25 Critical levels of COHb in the developing fetus have been reported to be approximately 60%.26 Thus, mortality rates, while very high in the mother (19%–24%), can be significantly higher in the fetus (36%–67%), depending on GA and severity of maternal poisoning.6 Reported fetal morbidities include preterm delivery, hypoxic ischemic encephalopathy, hypotonia, cerebral palsy, areflexia, persistent seizures, microcephaly, cardiomegaly, limb malformations, and death.11,24,27–29 Autopsies from infants who have died of CO poisoning predominantly show an insult to the basal ganglia, cerebellum, and cerebral cortex,30,31 as well as softening of the lenticular nucleus of the globus pallidus and signs of generalized hypoxic brain
High or Acute Fetal brain dysgenesis including severe hypoxic lesions in the forebrain and basal ganglia at higher dosages Fetal demise
damage with edema and petechial cortical hemorrhage.22 Table 4 describes the fetal complications that occur with exposure at qualitatively different ages and CO dosages. Koren et al32 published the largest series of CO exposures during pregnancy, with follow-up on 38 infants. Of 5 cases with significant maternal exposure (mothers with disorientation, depressed sensorium, or coma), there were 2 fetal deaths and 1 case of cerebral palsy. The 2 remaining cases had maternal COHb levels of 39% and 21% at 27 and 28 weeks, respectively, but promptly received hyperbaric oxygen (HBO) therapy and delivered infants with normal outcomes at 1 year of life. The remaining 35 cases with only mild maternal exposures (headaches, nausea, alert but with mild neurological impairment) delivered infants with normal outcomes. This consisted with the majority of case reports in the literature in that mothers who present with significant CO toxicity, that is, neurologically impaired or comatose, are at increased risk of significant fetal toxicity. However, mild exposures are more common, that is, with symptoms such as headache with/ without nausea and vomiting or altered mental state; in these cases, the reported outcomes have been more favorable.32 Fetal Heart Rate Monitoring Towers and Corcoran27,33 reported 3 cases of CO intoxication in the third trimester with maternal COHb levels of 28% to 36%. Two cases initially demonstrated category II fetal heart rate patterns, showing baseline fetal tachycardia of 160 to 180 beats/min, minimal variability, and the absence of accelerations or decelerations. In the third case, the baseline heart rate was 140 to 150 beats/min, with minimal variability and no fetal heart rate accelerations.27,33 After administering 100% oxygen therapy, there was resolution of the fetal heart rate tracing to a normal baseline and reactive tracing in approximately 60 minutes. Such findings on presentation
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may substantiate the presence of CO toxicity in patients with ambiguous presentations. Treatment of CO Poisoning in Pregnancy As with most poisonings, the initial management involves removing the victim from the source of toxicity and reducing the duration of cellular exposure. When CO intoxication is suspected, initial management should include immediate administration of 15 L/min of 100% oxygen via a nonrebreather mask and obtaining intravenous access.21 Vital signs, including noninvasive pulse co-oximetry testing, and a focused neurologic examination are integral parts of an ongoing evaluation. Patients should be placed on a cardiac monitor as hypoperfusion can lead to myocardial ischemia.4 Laboratory studies should include measurements of COHb level to help diagnose and determine exposure levels.25 However, levels of COHb are only estimates and do not correlate well with exposure and thus should not be used solely to direct treatment.7,25,34 It has also been suggested that any neonate exposed to CO in utero should receive neonatal cranial imaging.29 In cases where patients are brought in by emergency medical services, inquiring about the presence of other victims and their clinical presentation, as well as ambient CO levels obtained at the site, can assist in appropriate triaging of medical resources for patients. Patients should have a full-body examination to evaluate for any superficial epidermal burns, and providers should have high index of suspicion for tracheal burns secondary to hot air/smoke inhalation, depending on the circumstances of exposure. Because of the competitive binding nature of CO to hemoglobin, the treatment for CO toxicity remains 100% oxygen therapy; the goal is to increase FIO2 (fraction of inspired oxygen) to accelerate the dissociation of CO from hemoglobin, therefore shifting the oxygen dissociation curve to the right and eliminating COHb from maternal and fetal circulation as expeditiously as possible.31 Administration of 100% oxygen by face mask alone reduces COHb half-life to approximately 80 to 90 minutes, whereas HBO at 3 atmosphere absolute (ATA) reduces it to 23 minutes.27,31 It is prudent to remember that fetal COHb levels may lag behind that of the mother. Hyperbaric oxygen treatment involves the administration of 100% oxygen at higher than atmospheric pressures within a sealed chamber. The mechanism of action is that a greater amount of a gas, such as oxygen, can be dissolved in a liquid (arterial blood), when the surrounding pressure is higher. For example, at 1 ATA, the dissolved plasma oxygen concentration is
0.3 mL/dL and increases to 1.5 mL/dL with 100% oxygen administration. With HBO at 3 ATA, the plasma oxygen concentration increases to 6 mL/dL.35 The greater oxygen content of blood under hyperbaric conditions helps meet tissue oxygen demands because of its higher oxygen concentration and also facilitates the release of CO from hemoglobin. Hyperbaric oxygen therapy for CO poisoning was first discussed by Haldane in the 1890s but did not see widespread use until the 1960s. The efficacy of this treatment is in reducing CO binding to hemoglobin and other heme-containing proteins including cytochrome a3, but has also been suggested to alter neutrophil adhesion to the endothelium and reduce neurological deficits and overall mortality.2 Although the elimination time of CO is greatly increased with HBO, initial concerns were raised from animal studies regarding adverse outcomes and fetal malformations associated with HBO36,37; these concerns have limited use in pregnancy. However, it is important to note that the combination of ATA pressure and duration of therapy in those earlier animal studies far exceeded those used in clinical practice in humans. This was later corroborated by further research and animal trials by Ferm,36 Cho and Yun,38 and Gilman et al,39 who treated hamsters and pregnant rats with HBO at lower ATA (2–3) pressures and for shorter durations; no deleterious effects to the fetuses were observed. Elkharrat et al6 further showed no evidence of adverse human neonatal outcomes with HBO therapy at 2 ATA for 2 hours’ duration. The only absolute contraindication to HBO therapy is untreated pneumothorax, and most now agree that HBO is appropriate for life-threatening poisoning with COHb greater than 15% to 20% or in patients with a history of loss of consciousness, neurological symptoms, or cardiac compromise.2 Although no human randomized controlled trial data using HBO is available, as pregnancy is frequently an exclusion criterion, rat models have shown that HBO reduces the rate of spontaneous abortion.4 Most centers will offer HBO if COHb levels are greater than 20%, if neurological symptoms are present, or if fetal compromise is suspected.4,16 DISCUSSION/CONCLUSION Acute CO poisoning requires a high index of suspicion. Diagnosis is based on history and physical findings in conjunction with laboratory evidence of elevated COHb levels. Often, the presenting COHb levels are poor indicators of severity of disease, given the significant time lapse from exposure to presentation and partial treatment with some element of oxygen
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Carbon Monoxide Exposure During Pregnancy • CME Review Article
therapy prior to COHb measurement.27 In addition, fetal status and COHb levels are often far worse than what the maternal symptoms indicate as a result of the slower fetal elimination rate. Oxygen therapy should be initiated promptly. The risks and benefits of treatment with HBO compared with the consequences of injury from CO poisoning, that is, teratogenesis, neurological insult, and increased risk of intrauterine fetal death, should be considered. Although in some cases HBO has been initiated regardless of presenting COHb concentration or symptoms, the general consensus across the literature is as follows: HBO therapy is appropriate in the setting of maternal COHb levels greater than 20%, if there are signs of neurological compromise in the mother, or if signs of fetal hypoxia are present, such as tachycardia with minimal variability consistent with history of exposure, irrespective of COHb levels.6,16,27 Pregnant women should generally receive oxygen therapy 5 times the length of treatment required to reduce her own COHb.19 For patients with symptoms of mild CO intoxication, the fetal outcomes are generally good after receiving oxygen therapy. For those patients with life-threatening CO poisoning, the fetal consequences can be significant with high rates of fetal mortality. The importance of prevention cannot be overstated. Adequate education about sources of CO exposure and safe heating practices, as well as proper use of CO detectors, can help reduce the risk of accidental CO poisoning. REFERENCES 1. Centers for Disease Control and Prevention. Carbon monoxide. Workplace Safety & Health Topics. 2013. Available at: http:// libguides.edgewood.edu/content.php?pid=436846&sid=3575160. Accessed December 1, 2014. 2. Kao LW, Nañagas KA. Carbon monoxide poisoning. Med Clin North Am. 2005;89:1161–1194. 3. Carbon monoxide exposures—United States, 2000–2009. MMWR Morb Mortal Wkly Rep. 2011;60:1014–1017. Available at: http:// www.cdc.gov/mmwr/. Accessed December 1, 2014. 4. Nikkanen H, Skolnik A. Diagnosis and management of carbon monoxide poisoning in the emergency department. Emerg Med Pract. 2011;13:1–14; quiz 14. 5. Greingor JL, Tosi JM, Ruhlmann S, et al. Acute carbon monoxide intoxication during pregnancy. One case report and review of the literature. Emerg Med J. 2001;18:399–401. 6. Elkharrat D, Raphael JC, Korach JM, et al. Acute carbon monoxide intoxication and hyperbaric oxygen in pregnancy. Intensive Care Med. 1991;17:289–292. 7. Hampson NB, Hauff NM. Carboxyhemoglobin levels in carbon monoxide poisoning: do they correlate with the clinical picture? Am J Emerg Med. 2008;26:665–669. 8. Longo LD. The biological effects of carbon monoxide on the pregnant woman, fetus, and newborn infant. Am J Obstet Gynecol. 1977;129:69–103. 9. Norman CA, Halton DM. Is carbon monoxide a workplace teratogen? A review and evaluation of the literature. Ann Occup Hyg. 1990;34:335–347.
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10. Centers for Disease Control and Prevention. Carbon monoxide poisoning. 2012. Available at: http://ephtracking.cdc.gov/ showCarbonMonoxideLanding.action. Accessed December 1, 2015. 11. Aubard Y, Magne I. Carbon monoxide poisoning in pregnancy. BJOG. 2000;107:833–838. 12. Agency for Toxic Substances and Disease Registry. Toxicology profile for carbon monoxide. US Department of Health and Human Services: Public Health Service. 2012. Available at: http:// www.atsdr.cdc.gov/toxprofiles/tp201.pdf. Accessed December 27, 2014. 13. US Environmental Protection. Carbon monoxide. An introduction to indoor air quality (IAQ). 2013. Available at: http://www.epa.gov/ iaq/co.html. Accessed December 27, 2014. 14. Oxygen and carbon dioxide transport. In: Berne RM, Levy MN, Koeppen BM, et al., eds. Physiology. Philadelphia, PA: Mosby/ Elsevier; 2009:775. 15. Rodkey FL, O’Neal JD, Collison HA, et al. Relative affinity of hemoglobin S and hemoglobin A for carbon monoxide and oxygen. Clin Chem. 1974;20:83–84. 16. Silverman RK, Montano J. Hyperbaric oxygen treatment during pregnancy in acute carbon monoxide poisoning. A case report. J Reprod Med. 1997;42:309–311. 17. Ernst A, Zibrak JD. Carbon monoxide poisoning. N Engl J Med. 1998;339:1603–1608. 18. Longo LD. Carbon monoxide in the pregnant mother and fetus and its exchange across the placenta. Ann N Y Acad Sci. 1970; 174:312–341. 19. Longo LD, Hill EP. Carbon monoxide uptake and elimination in fetal and maternal sheep. Am J Physiol. 1977;232:H324–H330. 20. Hill EP, Hill JR, Power GG, et al. Carbon monoxide exchanges between the human fetus and mother: a mathematical model. Am J Physiol. 1977;232:H311–H323. 21. Goldstein M. Carbon monoxide poisoning. J Emerg Nurs. 2008; 34:538–542. 22. Copel JA, Bowen F, Bolognese RJ. Carbon monoxide intoxication in early pregnancy. Obstet Gynecol. 1982;59(suppl 6): 26S–28S. 23. Astrup P, Olsen HM, Trolle D, et al. Effect of moderate carbonmonoxide exposure on fetal development. Lancet. 1972;2: 1220–1222. 24. Yildiz H, Aldemir E, Altuncu E, et al. A rare cause of perinatal asphyxia: maternal carbon monoxide poisoning. Arch Gynecol Obstet. 2010;281:251–254. 25. Hall J, Schmidt G, Wood L. Principles of Critical Care. New York: McGraw-Hill; 1992. 26. Farrow JR, Davis GJ, Roy TM, et al. Fetal death due to nonlethal maternal carbon monoxide poisoning. J Forensic Sci. 1990;35: 1448–1452. 27. van Hoesen KB, Camporesi EM, Moon RE, et al. Should hyperbaric oxygen be used to treat the pregnant patient for acute carbon monoxide poisoning? A case report and literature review. JAMA. 1989;261:1039–1043. 28. Brown DB, Mueller GL, Golich FC. Hyperbaric oxygen treatment for carbon monoxide poisoning in pregnancy: a case report. Aviat Space Environ Med. 1992;63:1011–1014. 29. Alehan F, Erol I, Onay OS. Cerebral palsy due to nonlethal maternal carbon monoxide intoxication. Birth Defects Res A Clin Mol Teratol. 2007;79:614–616. 30. Muller GL, Graham S. Intrauterine death of the fetus due to accidental carbon monoxide poisoning. N Engl J Med. 1955;252: 1075–1078. 31. Gabrielli A, Layon AJ. Carbon monoxide intoxication during pregnancy: a case presentation and pathophysiologic discussion, with emphasis on molecular mechanisms. J Clin Anesth. 1995; 7:82–87. 32. Koren G, Sharav T, Pastuszak A, et al. A multicenter, prospective study of fetal outcome following accidental carbon monoxide poisoning in pregnancy. Reprod Toxicol. 1991;5:397–403.
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33. Towers CV, Corcoran VA. Influence of carbon monoxide poisoning on the fetal heart monitor tracing: a report of 3 cases. J Reprod Med. 2009;54:184–188. 34. Caravati EM, Adams CJ, Joyce SM, et al. Fetal toxicity associated with maternal carbon monoxide poisoning. Ann Emerg Med. 1988;17:714–717. 35. Leach RM, Rees PJ, Wilmshurst P. Hyperbaric oxygen therapy. BMJ. 1998;317:1140–1143. 36. Ferm VH. Teratogenic effects of hyperbaric oxygen. Proc Soc Exp Biol Med. 1964;116:975–976.
37. Fujikura T. Retrolental fibroplasia and prematurity in newborn rabbits induced by maternal hyperoxia. Am J Obstet Gynecol. 1964;90:854–858. 38. Cho SH, Yun DR. The experimental study of the effect of hyperbaric oxygen on the pregnancy wastage of rats with acute carbon monoxide poisoning. Seoul J Med. 1982;23: 67–75. 39. Gilman SC, Greene KM, Bradley ME, et al. Fetal development: Effects of simulated diving and hyperbaric oxygen treatment. Undersea Biomed Res. 1982;9:297–304.
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CME REVIEW ARTICLE
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CHIEF EDITOR’S NOTE: This article is part of a series of continuing education activities in this Journal through which a total of 36 AMA PRA Category 1 Credits ™ can be earned in 2015. Instructions for how CME credits can be earned appear on the last page of the Table of Contents.
Carbon Monoxide Exposure During Pregnancy Perry Friedman, MD,* Xiaoyue M. Guo, BA,† Robert J. Stiller, MD,‡ and Steven A. Laifer, MD§ *Resident Physician, Department of Obstetrics and Gynecology, Bridgeport Hospital, Bridgeport; †Medical Student, Yale University School of Medicine, New Haven, CT; and ‡Chief Section of Maternal Fetal Medicine and §Chief Section of Obstetrics, Department of Obstetrics and Gynecology, Bridgeport Hospital, Bridgeport, CT Importance: Carbon monoxide (CO) is the leading cause of poisoning in the United States and is associated with high maternal and fetal mortality rates. Given the nonspecific signs and symptoms of toxicity, cases may go unsuspected or attributed to other etiologies. As CO adversely affects both mother and fetus, it is important for practitioners to recognize and treat poisoning in a timely manner. Objective: We seek to assist practitioners with understanding the physiology and recognizing the presentations of both acute and chronic CO poisoning, as well as provide information on diagnosis and treatment options. We also conducted a review of cases described in the literature during the past half century to show varying presentations and treatment methodologies. Evidence Acquisition: A qualitative literature search was conducted using PubMed and Google Scholar for articles published between 1970 and 2014 that assessed cases of CO poisoning during pregnancy. Excluded studies were not in English or contained nonhuman subjects. Results: Nineteen published reports of CO poisoning during pregnancy described in varying levels of detail were found in the literature from 1971 to 2010. Conclusions and Relevance: Carbon monoxide poisoning requires a high degree of suspicion. Diagnosis is made based on initial history and physical evaluation and assessment of environmental CO levels; presenting carboxyhemoglobin levels may be poor indicators of severity of disease. Oxygen therapy should be initiated promptly in all possible cases with consideration of hyperbaric oxygen therapy in cases of significant maternal exposure. Treatment requires a longer duration for fetal CO elimination than in the nonpregnant patients. Importantly, practitioners should educate pregnant patients on prevention. Target Audience: Obstetricians and gynecologists, family physicians Learning Objectives: After completing this activity, the learner will be better able to: describe the basic pathophysiology of carbon monoxide poisoning in the mother and fetus; recognize and diagnose carbon monoxide poisoning in a pregnant patient; explain treatment of carbon monoxide poisoning in pregnancy.
Incidence/Prevalence Carbon monoxide (CO) is an odorless, colorless, and tasteless gas that is a poisonous by-product of combustion. It frequently reaches high ambient concentrations All authors and staff in a position to control the content of this CME activity and their spouses/life partners (if any) have disclosed that they have no financial relationships with, or financial interests in, any commercial organizations pertaining to this educational activity. Correspondence requests to: Perry Friedman, MD, 267 Grant St, Bridgeport, CT 06610. E-mail: [email protected].
in poorly ventilated areas causing signs and symptoms of intoxication.1 Carbon monoxide is responsible for more than half of all fatal poisonings worldwide and is the leading cause of poisoning in the United States,2 accounting for more than 20,000 emergency department visits annually, occurring mostly in the winter months.3 From 1999 to 2010, approximately 500 deaths per year have been attributed to CO poisoning in the United States.3 The case-fatality rate has been reported as high as 30%, although many fatalities are due to intentional exposures for self-harm.4 An estimated 8.5% of pregnant
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women are exposed in some degree to CO.5 Acute CO poisoning in pregnancy has been associated with a maternal mortality rate between 19% and 24%, and a fetal mortality rate between 36% and 67%.6 Because of the nonspecific signs and symptoms, it is possible that these numbers underrepresent the true number of cases, some of which might go unsuspected or be attributed to other etiologies.7 Typical Causes of CO Poisoning Carbon monoxide arises from the combustion of carbon compounds and can either be from exogenous or endogenous sources. Carbon monoxide in its simplest form is an endogenous by-product of normal hemoglobin metabolism of protoporphyrin to bilirubin.8 However, exposure to high concentrations from exogenous sources can be extremely toxic to humans. Carbon monoxide results whenever fuel or other carbon-based materials are burned in oxygen-deprived areas. Accidental household exposure to CO is the most frequent cause of poisoning in pregnancy.9 Examples of potential sources include poorly maintained heating equipment, poorly ventilated gas appliances such as stoves, running vehicles in closed spaces, house fires, clogged chimneys, indoor generators, and so on.10 As such, cities with more significant air pollution have a higher CO burden.11 In the human body, approximately 1% to 3% of hemoglobin is normally bound to CO as carboxyhemoglobin (COHb), with higher amounts found in those with chronic CO exposure, such as smokers (Table 1). In pregnant smokers, COHb levels in the blood can reach 9%. Chronic CO inhalation from tobacco is usually tolerated by pregnant women; however, it may be dangerous if additional sources of CO increase the exposure concentration.11 Average levels in homes without gas stoves vary from 0.5 to 5 ppmv (parts per million volume). Levels near properly adjusted gas stoves are often 5 to 15 ppmv, and those near poorly adjusted stoves may be 30 ppmv or greater.12,13 Physiology of CO in Pregnancy When CO is inhaled, it easily crosses the pulmonary alveoli and combines with hemoglobin to produce TABLE 1 Blood COHb Levels in Different Situations11 State Nonsmoker Smoker Acute poisoning Life threatening
COHb Levels, % 1–3 6–9 30–50 >50
FIG. 1. Oxygen-hemoglobin dissociation curve for adult humans. Competitive binding of CO with hemoglobin causes a left shift of the curve. Reprinted with permission from Elsevier Publishing.14 Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.
COHb, which greatly diminishes hemoglobin’s oxygencarrying capacity. Toxicity occurs because of a combination of tissue hypoxia and direct CO-mediated damage at the cellular level. Hemoglobin’s binding affinity for CO is more than 200 times greater than its affinity for oxygen. A consequence of this competitive binding is a left shift of the oxygen-hemoglobin dissociation curve, and thus, oxygen binds with a greater affinity to hemoglobin, resulting in poorer tissue perfusion as a result of decreased oxygen release to the cells (Fig. 1).15,16 In addition to the resultant tissue hypoxia, a small fraction of free CO in plasma also causes direct tissue injury by disrupting the normal functions of mitochondria, which leads to cell damage.17 During pregnancy, the rate of endogenous CO production increases and then drops rapidly after delivery. This increase is mainly due to progesterone-inducing hepatic microsomal enzymatic activity, although 30% to 40% is from an increase in maternal erythrocyte mass, and 15% is from endogenous fetal production.11 Compared with adult hemoglobin, fetal hemoglobin has a greater affinity for oxygen, which facilitates appropriate physiological maternal-fetal oxygen exchange. Carbon monoxide enters fetal blood after crossing the placenta either by passive diffusion or via a carrier.18 With fetal exposure to CO, the fetal oxygenhemoglobin curve, which typically stands to the left of the maternal oxygen-hemoglobin curve, is further shifted to the left in a more hyperbolic curve; thus, the
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Carbon Monoxide Exposure During Pregnancy • CME Review Article
fetus suffers the same, if not worse, toxic effects because of an even greater tissue hypoxia. Longo8,19 and Longo and Hill8,19 are credited with much of what is known regarding fetal COHb. Having extensively studied CO exposure in maternal and fetal sheep, they have reported that at all levels of CO exposure the fetal COHb concentration initially lags behind that of the mother. Eventually, fetal COHb concentration equals and then surpasses the maternal concentration over time. With initial exposure, maternal COHb levels increase rapidly for the first 2 to 3 hours and then continue to rise over the next 7 to 8 hours. Fetal COHb, on the other hand, initially shows no increase during the first hour; however, over the next 4 to 5 hours, it increases at a slow rate. At 5 to 6, hours it equals maternal concentrations, but continues to rise for 24 hours, eventually reaching a steady state in 36 to 48 hours.8,19 Hill et al20 constructed mathematical models to calculate theoretical relations between fetal-maternal COHb in humans (Fig. 2). Predicted uptake and elimination curves were similar to what was seen in sheep studies. Fetal COHb concentrations would lag behind maternal concentrations, and only after 14 to 24 hours would equilibrium be reached. Of clinical significance, fetal COHb would eventually equilibrate at concentrations 10% to 15% higher than maternal. Fetal CO elimination also significantly lags behind maternal CO elimination, owing to the fact that fetuses cannot increase their tidal volume or ventilation rate. During the washout phase, the approximate time to reach one half of the maximum value was 2 hours for mother and 7 hours for fetus.8 With 100% oxygen, the rate of elimination is greatly increased (Fig. 3);
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FIG. 3. Length of time required to eliminate CO from a mother and fetus when the mother is treated with 100% O2, after prolonged exposures to 30, 50, 100, 200, and 300 ppm inspired CO concentrations, assuming initial equilibrium between fetal and maternal CO. These curves differ from Figure 2 by showing increased rate of CO elimination when 100% oxygen is administered to the mother. Reprinted with permission from Elsevier Publishing.20
nevertheless, fetal elimination time still lags behind maternal, and it has been suggested that in order to normalize fetal COHb a pregnant woman would need to receive 100% oxygen for a duration that is 5 times as long as that required to reduce her own COHb to a normal level.19 Clinically, acute CO poisoning harms both mother and fetus, but chronic exposure may disproportionally harm the fetus during its development.11 Two mechanisms of toxicity have been proposed in the fetus: tissue hypoxia or direct association with the body’s hemecontaining proteins, including intracellular myoglobin, cytochromes a, and p450. Diagnosis and Signs of CO Toxicity for Mother and Fetus
FIG. 2. The predicted time course of human maternal and fetal COHb concentrations during prolonged exposures to 30, 50, 100, 200, and 300 ppm inspired CO concentrations, followed by a washout period when no CO was inspired. Note that fetal COHb concentrations lag behind those of the mother, but eventually reach higher values in most cases. Reprinted with permission from Elsevier Publishing.20
Diagnosing CO poisoning requires a high index of suspicion, given its nonspecific signs and symptoms and the intrinsic properties of CO in being odorless and colorless. Oxygen-dependent organs, such as the heart and brain, show the earliest signs of injury in CO poisoning, but 83% of victims have no or minor symptoms.1 Kao and Nañagas2 dubbed it the “great mimicker” because the clinical signs and symptoms of CO toxicity are largely nonspecific and its presentation depends on the duration and concentration of exposure. As such, it is important for physicians to take a detailed history including symptom duration and correlation with environmental CO concentration. Acute exposure
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TABLE 2 Maternal Symptoms of CO Poisoning According to COHb Levels Stages of CO Poisoning Chronic poisoning
COHb Levels, %
Signs of Poisoning
5–20
Headaches, sensations of weakness, dizziness, sleepiness impaired physical performance, visual difficulties, palpations, nausea, vomiting Tachypnea, tachycardia, fever, vomiting, confusion, disorientation, hypotension, arrhythmia, alteration in consciousness, convulsions, respiratory insufficiency Psychiatric difficulties, apathy, apraxia, disorientation, muscular hypertonia, intestinal problems, urinary or fecal incontinence, alteration in consciousness
Acute poisoning
30–50
Life-threatening poisoning
50–66
Lethal poisoning
>66
Reprinted with permission from BJOG.11
with large concentrations produces symptoms quickly and can lead to death. Maternal symptoms of CO poisoning corresponding to COHb levels are shown in Table 2.11 Early signs and symptoms include headache, nausea and vomiting, increases in blood pressure, tachycardia, and tachypnea, as well as chest pain, shortness of breath, anxiousness, and altered consciousness. Likewise, toxic effects of CO on the developing fetus depend on chronicity of exposure and concentration as well as gestational age (GA).21 The measurement of COHb concentration remains an essential and fundamental component in the evaluation of suspected COHb poisoning (>2% in nonsmokers and ≥9% in smokers).7 Standard pulse oximetry is unable to distinguish between COHb and oxyhemoglobin, but specialized pulse co-oximetry may be useful in rapidly triaging patients with significant exposure.4 Additional studies can also be obtained (Table 3). Additional important laboratory values include arterial and venous partial pressure of oxygen (PO2) levels. Normal arterial PO2 levels are 80 to 100 mm Hg, and venous levels are approximately 25 mm Hg in healthy
nonsmokers. With CO exposures, arterial blood gas PO2 results will typically be normal or low, as they measure dissolved, unbound oxygen. In contrast, venous PO2 results will usually be higher, approximately 30 to 50 mm Hg, given the higher oxygen affinity of COHb and less effective release of oxygen to tissues.21 Cardiac monitoring is also vital because of the potential for dysrhythmias. Brain imaging commonly shows bilateral low-density globus pallidus lesions and/or diffuse, symmetric periventricular white matter lesions after CO poisoning. A neuropsychological screening battery or application of other neuropsychiatric testing methods, such as the Mini-Mental Status Examination, can also be useful for monitoring progress.2 Review of Previous CO Cases in Pregnancy Over the last couple of decades, there have been several published case reports and a few case series of CO exposure during pregnancy and fetal outcomes. Carbon monoxide poisoning in pregnancy was first described in 1859 with the onset of the industrial revolution and
TABLE 3 Recommended Investigations in Women With Suspected CO Poisoning Investigation
Finding/Outcome Measure
1. Measurement of serum COHb 2. Arterial blood gas and lactic acid level 3. Toxic screen 4. Serum CPK and LDL levels 5. Serum ALT and AST 6. Serum glucose level 7. Full blood count 8. ECG 9. Neuropsychological testing 10. CT of the head 11. EEG
Gives an indication of the severity of maternal poisoning and a cruder indication of the degree of fetal poisoning Measure degree of maternal acidosis and hypoxia Another poison could be present Delayed elevation of these enzymes has been described in experimental models Become elevated 1-2 d after severe poisoning Secondary hyperglycemia can sometimes be observed Leukocytosis is common Myocardial ischemia or cardiac arrhythmia may occur Discrete abnormalities of higher cortical function may be sequel To identify cerebral edema or infarction To identify diffuse abnormalities of cerebral electrical activity
Reprinted with permission from BJOG.11 AST indicates aspartate aminotransferase; ALT, alanine aminotransferase; CPK, creatinine phosphokinase; CT, computed tomography; ECG, electrocardiogram; EEG, electroencephalogram; LDL, low-density lipoprotein.
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TABLE 4 Fetal Complications After CO Toxicity at Different Ages and Dosages11,29,32 Exposure Early General anatomical malformations, especially limb
Late Specifically brain malformations, such as anoxic anencephaly Dosage
Low or Chronic Decreased birth weights and intrauterine growth restriction due to chronic hypoxia
coal-gas exposure.22 In the modern day, however, chronic CO exposure in pregnancy is usually caused by smoking. Tobacco exposure carries with it several additional carcinogens and other short- and long-term effects, some of which have yet to be elucidated. The first connection between premature birth and smoking was made in 1972, and studies since have repeatedly connected cigarette smoking with adverse perinatal and neonatal outcomes in a dose-related manner.23 Reports show increased incidences of fetal wastage, placental abruption, placenta previa, and premature rupture of membranes; decreased birth weight is also directly related to the number of cigarettes smoked. Moreover, long-term effects have been seen of reduced mathematics and reading ability, decreased height, and increased hyperkineticism.22 Acute CO poisoning in the earlier stages of gestation may be associated with anatomical malformations if a viable term fetus results, whereas exposure at a later GA is associated with neurological sequelae of anoxic events, as the fetal brain is more sensitive to CO closer to term.9,24 Cases of fetal demise due to CO intoxication can be diagnosed postmortem, given that fetal COHb is unchanged for days. Toxic levels of COHb in adults are those greater than 25%, and levels greater than 50% may result in death.25 Critical levels of COHb in the developing fetus have been reported to be approximately 60%.26 Thus, mortality rates, while very high in the mother (19%–24%), can be significantly higher in the fetus (36%–67%), depending on GA and severity of maternal poisoning.6 Reported fetal morbidities include preterm delivery, hypoxic ischemic encephalopathy, hypotonia, cerebral palsy, areflexia, persistent seizures, microcephaly, cardiomegaly, limb malformations, and death.11,24,27–29 Autopsies from infants who have died of CO poisoning predominantly show an insult to the basal ganglia, cerebellum, and cerebral cortex,30,31 as well as softening of the lenticular nucleus of the globus pallidus and signs of generalized hypoxic brain
High or Acute Fetal brain dysgenesis including severe hypoxic lesions in the forebrain and basal ganglia at higher dosages Fetal demise
damage with edema and petechial cortical hemorrhage.22 Table 4 describes the fetal complications that occur with exposure at qualitatively different ages and CO dosages. Koren et al32 published the largest series of CO exposures during pregnancy, with follow-up on 38 infants. Of 5 cases with significant maternal exposure (mothers with disorientation, depressed sensorium, or coma), there were 2 fetal deaths and 1 case of cerebral palsy. The 2 remaining cases had maternal COHb levels of 39% and 21% at 27 and 28 weeks, respectively, but promptly received hyperbaric oxygen (HBO) therapy and delivered infants with normal outcomes at 1 year of life. The remaining 35 cases with only mild maternal exposures (headaches, nausea, alert but with mild neurological impairment) delivered infants with normal outcomes. This consisted with the majority of case reports in the literature in that mothers who present with significant CO toxicity, that is, neurologically impaired or comatose, are at increased risk of significant fetal toxicity. However, mild exposures are more common, that is, with symptoms such as headache with/ without nausea and vomiting or altered mental state; in these cases, the reported outcomes have been more favorable.32 Fetal Heart Rate Monitoring Towers and Corcoran27,33 reported 3 cases of CO intoxication in the third trimester with maternal COHb levels of 28% to 36%. Two cases initially demonstrated category II fetal heart rate patterns, showing baseline fetal tachycardia of 160 to 180 beats/min, minimal variability, and the absence of accelerations or decelerations. In the third case, the baseline heart rate was 140 to 150 beats/min, with minimal variability and no fetal heart rate accelerations.27,33 After administering 100% oxygen therapy, there was resolution of the fetal heart rate tracing to a normal baseline and reactive tracing in approximately 60 minutes. Such findings on presentation
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may substantiate the presence of CO toxicity in patients with ambiguous presentations. Treatment of CO Poisoning in Pregnancy As with most poisonings, the initial management involves removing the victim from the source of toxicity and reducing the duration of cellular exposure. When CO intoxication is suspected, initial management should include immediate administration of 15 L/min of 100% oxygen via a nonrebreather mask and obtaining intravenous access.21 Vital signs, including noninvasive pulse co-oximetry testing, and a focused neurologic examination are integral parts of an ongoing evaluation. Patients should be placed on a cardiac monitor as hypoperfusion can lead to myocardial ischemia.4 Laboratory studies should include measurements of COHb level to help diagnose and determine exposure levels.25 However, levels of COHb are only estimates and do not correlate well with exposure and thus should not be used solely to direct treatment.7,25,34 It has also been suggested that any neonate exposed to CO in utero should receive neonatal cranial imaging.29 In cases where patients are brought in by emergency medical services, inquiring about the presence of other victims and their clinical presentation, as well as ambient CO levels obtained at the site, can assist in appropriate triaging of medical resources for patients. Patients should have a full-body examination to evaluate for any superficial epidermal burns, and providers should have high index of suspicion for tracheal burns secondary to hot air/smoke inhalation, depending on the circumstances of exposure. Because of the competitive binding nature of CO to hemoglobin, the treatment for CO toxicity remains 100% oxygen therapy; the goal is to increase FIO2 (fraction of inspired oxygen) to accelerate the dissociation of CO from hemoglobin, therefore shifting the oxygen dissociation curve to the right and eliminating COHb from maternal and fetal circulation as expeditiously as possible.31 Administration of 100% oxygen by face mask alone reduces COHb half-life to approximately 80 to 90 minutes, whereas HBO at 3 atmosphere absolute (ATA) reduces it to 23 minutes.27,31 It is prudent to remember that fetal COHb levels may lag behind that of the mother. Hyperbaric oxygen treatment involves the administration of 100% oxygen at higher than atmospheric pressures within a sealed chamber. The mechanism of action is that a greater amount of a gas, such as oxygen, can be dissolved in a liquid (arterial blood), when the surrounding pressure is higher. For example, at 1 ATA, the dissolved plasma oxygen concentration is
0.3 mL/dL and increases to 1.5 mL/dL with 100% oxygen administration. With HBO at 3 ATA, the plasma oxygen concentration increases to 6 mL/dL.35 The greater oxygen content of blood under hyperbaric conditions helps meet tissue oxygen demands because of its higher oxygen concentration and also facilitates the release of CO from hemoglobin. Hyperbaric oxygen therapy for CO poisoning was first discussed by Haldane in the 1890s but did not see widespread use until the 1960s. The efficacy of this treatment is in reducing CO binding to hemoglobin and other heme-containing proteins including cytochrome a3, but has also been suggested to alter neutrophil adhesion to the endothelium and reduce neurological deficits and overall mortality.2 Although the elimination time of CO is greatly increased with HBO, initial concerns were raised from animal studies regarding adverse outcomes and fetal malformations associated with HBO36,37; these concerns have limited use in pregnancy. However, it is important to note that the combination of ATA pressure and duration of therapy in those earlier animal studies far exceeded those used in clinical practice in humans. This was later corroborated by further research and animal trials by Ferm,36 Cho and Yun,38 and Gilman et al,39 who treated hamsters and pregnant rats with HBO at lower ATA (2–3) pressures and for shorter durations; no deleterious effects to the fetuses were observed. Elkharrat et al6 further showed no evidence of adverse human neonatal outcomes with HBO therapy at 2 ATA for 2 hours’ duration. The only absolute contraindication to HBO therapy is untreated pneumothorax, and most now agree that HBO is appropriate for life-threatening poisoning with COHb greater than 15% to 20% or in patients with a history of loss of consciousness, neurological symptoms, or cardiac compromise.2 Although no human randomized controlled trial data using HBO is available, as pregnancy is frequently an exclusion criterion, rat models have shown that HBO reduces the rate of spontaneous abortion.4 Most centers will offer HBO if COHb levels are greater than 20%, if neurological symptoms are present, or if fetal compromise is suspected.4,16 DISCUSSION/CONCLUSION Acute CO poisoning requires a high index of suspicion. Diagnosis is based on history and physical findings in conjunction with laboratory evidence of elevated COHb levels. Often, the presenting COHb levels are poor indicators of severity of disease, given the significant time lapse from exposure to presentation and partial treatment with some element of oxygen
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Carbon Monoxide Exposure During Pregnancy • CME Review Article
therapy prior to COHb measurement.27 In addition, fetal status and COHb levels are often far worse than what the maternal symptoms indicate as a result of the slower fetal elimination rate. Oxygen therapy should be initiated promptly. The risks and benefits of treatment with HBO compared with the consequences of injury from CO poisoning, that is, teratogenesis, neurological insult, and increased risk of intrauterine fetal death, should be considered. Although in some cases HBO has been initiated regardless of presenting COHb concentration or symptoms, the general consensus across the literature is as follows: HBO therapy is appropriate in the setting of maternal COHb levels greater than 20%, if there are signs of neurological compromise in the mother, or if signs of fetal hypoxia are present, such as tachycardia with minimal variability consistent with history of exposure, irrespective of COHb levels.6,16,27 Pregnant women should generally receive oxygen therapy 5 times the length of treatment required to reduce her own COHb.19 For patients with symptoms of mild CO intoxication, the fetal outcomes are generally good after receiving oxygen therapy. For those patients with life-threatening CO poisoning, the fetal consequences can be significant with high rates of fetal mortality. The importance of prevention cannot be overstated. Adequate education about sources of CO exposure and safe heating practices, as well as proper use of CO detectors, can help reduce the risk of accidental CO poisoning. REFERENCES 1. Centers for Disease Control and Prevention. Carbon monoxide. Workplace Safety & Health Topics. 2013. Available at: http:// libguides.edgewood.edu/content.php?pid=436846&sid=3575160. Accessed December 1, 2014. 2. Kao LW, Nañagas KA. Carbon monoxide poisoning. Med Clin North Am. 2005;89:1161–1194. 3. Carbon monoxide exposures—United States, 2000–2009. MMWR Morb Mortal Wkly Rep. 2011;60:1014–1017. Available at: http:// www.cdc.gov/mmwr/. Accessed December 1, 2014. 4. Nikkanen H, Skolnik A. Diagnosis and management of carbon monoxide poisoning in the emergency department. Emerg Med Pract. 2011;13:1–14; quiz 14. 5. Greingor JL, Tosi JM, Ruhlmann S, et al. Acute carbon monoxide intoxication during pregnancy. One case report and review of the literature. Emerg Med J. 2001;18:399–401. 6. Elkharrat D, Raphael JC, Korach JM, et al. Acute carbon monoxide intoxication and hyperbaric oxygen in pregnancy. Intensive Care Med. 1991;17:289–292. 7. Hampson NB, Hauff NM. Carboxyhemoglobin levels in carbon monoxide poisoning: do they correlate with the clinical picture? Am J Emerg Med. 2008;26:665–669. 8. Longo LD. The biological effects of carbon monoxide on the pregnant woman, fetus, and newborn infant. Am J Obstet Gynecol. 1977;129:69–103. 9. Norman CA, Halton DM. Is carbon monoxide a workplace teratogen? A review and evaluation of the literature. Ann Occup Hyg. 1990;34:335–347.
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10. Centers for Disease Control and Prevention. Carbon monoxide poisoning. 2012. Available at: http://ephtracking.cdc.gov/ showCarbonMonoxideLanding.action. Accessed December 1, 2015. 11. Aubard Y, Magne I. Carbon monoxide poisoning in pregnancy. BJOG. 2000;107:833–838. 12. Agency for Toxic Substances and Disease Registry. Toxicology profile for carbon monoxide. US Department of Health and Human Services: Public Health Service. 2012. Available at: http:// www.atsdr.cdc.gov/toxprofiles/tp201.pdf. Accessed December 27, 2014. 13. US Environmental Protection. Carbon monoxide. An introduction to indoor air quality (IAQ). 2013. Available at: http://www.epa.gov/ iaq/co.html. Accessed December 27, 2014. 14. Oxygen and carbon dioxide transport. In: Berne RM, Levy MN, Koeppen BM, et al., eds. Physiology. Philadelphia, PA: Mosby/ Elsevier; 2009:775. 15. Rodkey FL, O’Neal JD, Collison HA, et al. Relative affinity of hemoglobin S and hemoglobin A for carbon monoxide and oxygen. Clin Chem. 1974;20:83–84. 16. Silverman RK, Montano J. Hyperbaric oxygen treatment during pregnancy in acute carbon monoxide poisoning. A case report. J Reprod Med. 1997;42:309–311. 17. Ernst A, Zibrak JD. Carbon monoxide poisoning. N Engl J Med. 1998;339:1603–1608. 18. Longo LD. Carbon monoxide in the pregnant mother and fetus and its exchange across the placenta. Ann N Y Acad Sci. 1970; 174:312–341. 19. Longo LD, Hill EP. Carbon monoxide uptake and elimination in fetal and maternal sheep. Am J Physiol. 1977;232:H324–H330. 20. Hill EP, Hill JR, Power GG, et al. Carbon monoxide exchanges between the human fetus and mother: a mathematical model. Am J Physiol. 1977;232:H311–H323. 21. Goldstein M. Carbon monoxide poisoning. J Emerg Nurs. 2008; 34:538–542. 22. Copel JA, Bowen F, Bolognese RJ. Carbon monoxide intoxication in early pregnancy. Obstet Gynecol. 1982;59(suppl 6): 26S–28S. 23. Astrup P, Olsen HM, Trolle D, et al. Effect of moderate carbonmonoxide exposure on fetal development. Lancet. 1972;2: 1220–1222. 24. Yildiz H, Aldemir E, Altuncu E, et al. A rare cause of perinatal asphyxia: maternal carbon monoxide poisoning. Arch Gynecol Obstet. 2010;281:251–254. 25. Hall J, Schmidt G, Wood L. Principles of Critical Care. New York: McGraw-Hill; 1992. 26. Farrow JR, Davis GJ, Roy TM, et al. Fetal death due to nonlethal maternal carbon monoxide poisoning. J Forensic Sci. 1990;35: 1448–1452. 27. van Hoesen KB, Camporesi EM, Moon RE, et al. Should hyperbaric oxygen be used to treat the pregnant patient for acute carbon monoxide poisoning? A case report and literature review. JAMA. 1989;261:1039–1043. 28. Brown DB, Mueller GL, Golich FC. Hyperbaric oxygen treatment for carbon monoxide poisoning in pregnancy: a case report. Aviat Space Environ Med. 1992;63:1011–1014. 29. Alehan F, Erol I, Onay OS. Cerebral palsy due to nonlethal maternal carbon monoxide intoxication. Birth Defects Res A Clin Mol Teratol. 2007;79:614–616. 30. Muller GL, Graham S. Intrauterine death of the fetus due to accidental carbon monoxide poisoning. N Engl J Med. 1955;252: 1075–1078. 31. Gabrielli A, Layon AJ. Carbon monoxide intoxication during pregnancy: a case presentation and pathophysiologic discussion, with emphasis on molecular mechanisms. J Clin Anesth. 1995; 7:82–87. 32. Koren G, Sharav T, Pastuszak A, et al. A multicenter, prospective study of fetal outcome following accidental carbon monoxide poisoning in pregnancy. Reprod Toxicol. 1991;5:397–403.
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33. Towers CV, Corcoran VA. Influence of carbon monoxide poisoning on the fetal heart monitor tracing: a report of 3 cases. J Reprod Med. 2009;54:184–188. 34. Caravati EM, Adams CJ, Joyce SM, et al. Fetal toxicity associated with maternal carbon monoxide poisoning. Ann Emerg Med. 1988;17:714–717. 35. Leach RM, Rees PJ, Wilmshurst P. Hyperbaric oxygen therapy. BMJ. 1998;317:1140–1143. 36. Ferm VH. Teratogenic effects of hyperbaric oxygen. Proc Soc Exp Biol Med. 1964;116:975–976.
37. Fujikura T. Retrolental fibroplasia and prematurity in newborn rabbits induced by maternal hyperoxia. Am J Obstet Gynecol. 1964;90:854–858. 38. Cho SH, Yun DR. The experimental study of the effect of hyperbaric oxygen on the pregnancy wastage of rats with acute carbon monoxide poisoning. Seoul J Med. 1982;23: 67–75. 39. Gilman SC, Greene KM, Bradley ME, et al. Fetal development: Effects of simulated diving and hyperbaric oxygen treatment. Undersea Biomed Res. 1982;9:297–304.
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