Pregnant Women and Chemical-Biological Warfare

Shawn P. Stallings, Jason Joseph, Joseph H. Kipikasa, and C. David Adair

There has been increased concern and heightened awareness regarding the possibility of deliberate attacks against susceptible civilian populations with agents of chemical or biological warfare.

GENERAL PREPARATION

All medical facilities and personnel since September 11, 2001 have made prepa­ration for an attack on the general population. While most patients will likely be encountered first by emergency services personnel and first responder physi­cians, the obstetrician should be ready to participate and/or advise in the care of the exposed pregnant patient. Local hospitals, tertiary care centers, and govern­ment agencies have developed a plan for the triage of victims near the site of contact with the harmful substance or for the containment of persons who may have been in contact with a hazardous substance and are now at risk for spread­ing the problem to a wider area. Protocols have been prepared for possible trans­fer of patients to tertiary care centers. In the case of pregnant women, requiring intensive care and having sufficient gestational age for infant survival will likely require facilitation to a tertiary care center. However, this does not alleviate the need for local facilities to be prepared for care and for the possibility that trans­fer may not be possible due to damage in communication lines or transportation modes. Often, the disaster management will be run by a state or local law enforce­ment head, fire chief, or person in charge of emergency services in cases of natu­ral disaster or industrial accident.

In a major event such as bioterrorism, it is important to have protocols for identifying triage victims who are exposed and showing symptoms versus those who are exposed but asymptomatic and may require little intervention or prophy­laxis only. Particularly in a delivery setting, this may be difficult to arrange logisti­cally. This may be further complicated by the fact that most labor and delivery units have little or no facility for negative-pressure respiratory isolation. These negative flow units are usually in medical/surgical floors or ICUs, thus placing the emphasis of care on excellent interteam communication and cooperation. Labor and delivery unit managers need to be prepared to provide fetal monitoring to multiple patients in these remote settings. Such monitoring must be accompanied by preparation of instruments and surgical staff to accomplish emergent deliveries if necessary. Neonatal and anesthesia consultations are required given the increased likelihood of an emergent situation in an area unfamiliar and nontradi- tional for the delivery of child.

BIOLOGICAL AGENTS

Biological agents have received the most attention from the news media as potential weapons of terrorism. The Centers for Disease Control and Prevention (CDC) has designated three different categories for agents that are potential threats for bioterrorism. Category A agents have been chosen because of their ease of dissemination and hig h morbidity a nd mor tality rates or, alternatively, for their potential to cause widespread panic or disruption. These agents include anthrax, small pox, plague, botulism, hemorrhagic fevers, and tularemia. Cate­gory B agents are considered relatively high in priority because of their ease in dissemination; however, they may not cause as widespread injury.

Anthrax

Anthrax is the transmittable disease arising from infection with the Gram-positive, spore-forming bacterium Bacillus anthracis. Humans acquire naturally occurring disease from contact with infected animals or contaminated animal products. The disease more commonly infects herbivores, which ingest the spores from the soil. Animal vaccination is a common practice and has decreased animal mortality from the disease (5). There are three main illnesses in humans depending on the route of contact—cutaneous, inhalational, and gastrointestinal. The cutaneous form is the most common natural disease, although outbreaks of gastrointestinal anthrax are occasionally reported due to the consumption of undercooked, con­taminated meat. Inhalational anthrax is rare but has raised the most concern as a bioterrorist threat because of its high mortality rate and ease of dissemination (5).

The spores of B. anthracis are stable for many years; are resistant to sun­light, heat, and disinfectants; and can be dispersed as a dry or moist aerosol cloud. It is reported that weaponized spores may be disseminated throughout an entire building even after delivery by a contained letter (6). As an example of the deadly nature of the spores, it was reported from the former Soviet Union that an outbreak near one of its weapons facilities in 1979 resulted in 77 cases of inhala­tional anthrax with 66 deaths (85% mortality) (4,6).

The spores germinate in an environment rich in amino acids, nucleic acids, and glucose, such as in mammalian tissues or blood. The bacteria multiply rap­idly and will only form spores again when the nutrients are depleted, such as when contaminated body fluids are discharged and encounter ambient air. The vegetative bacteria do not survive long in ambient conditions unlike their spore form which may remain stable for many years.

Inhalational anthrax begins when inhaled spore particles sized 1 to 5 μ m enter alveolar spaces and are subsequently ingested by macrophages. Spores that survive and are not lysed may travel to the mediastinal lymphatic tissue where they germinate and multiply. The incubation period varies. Most often, incubation occurs within 1 to 7 days but can be delayed as much as 43 days (2,4-6). The replicating B. anthracis produces toxins that carry on cellular damage even if all living bacteria are eradicated with antibiotics (4,5). This ongoing damage results in hemorrhagic lymphadenitis, hemorrhagic medias­tinitis, necrosis, and pleural effusions. The patient may present initially with fever, cough, dyspnea, and malaise. An initial chest radiograph may be abnor­mal with widened mediastinum, infiltrates, and effusion. The more fulminant case progresses rapidly with a continued rise in fever, worsening dyspnea, chest pain, and respiratory failure.

Cutaneous anthrax occurs following the deposition of the spores in cuts or abrasions of the skin. Subsequently, germination occurs in the skin, and toxin production proceeds to local tissue edema and necrosis. A skin vesicle typically forms which then dries to form a black eschar. Antibiotic therapy will not alter the course of skin destruction and eschar resolution, but it will decrease the localized edema and the risk of systemic spread. Systemic spread may be possi­ble, and untreated mortality is reported to be as high as 20% (4-7). Gastrointes­tinal anthrax may be contracted from ingestion of contaminated meat. Spores may germinate in either the upper or the lower intestinal tract. Ulcer formation in the mouth or esophagus may lead to regional lymphadenitis. In the lower tract, intestinal anthrax may lead to nausea, vomiting, acute abdomen, ascites, mesenteric lymphadenopathy, bowel edema, and bloody diarrhea. In both cases, death may occur due to systemic illness, and mortality as high as 25% to 60% has been reported (2,5-7). Unfortunately, there is limited information available on anthrax infection during pregnancy, but in general, usual nonpregnant thera­peutic guidelines are employed given the high morbidity and mortality to the untreated patient let alone the treated individual (8).

It is important to remember that casual contact or respiratory droplets from coughing or sneezing do not spread anthrax.

Prophylactic antimicrobial therapy is not needed unless law enforcement and public health officials document an actual exposure. It is recommended that the primary care women’s health provider not initiate the therapy unless directed to do so by the appropriate public health officials (9). Screening may be performed by way of nasal swab, but due to potential error, postexposure prophylaxis is recommended only after a confirmed exposure or high-risk encounter (9).

The current CDC guidelines were based on susceptibilities determined from anthrax isolates from the intentional exposures in 2001 (7). These isolates were found to be sensitive to penicillin, amoxicillin, ciprofloxacin, doxycycline, chloramphenicol, clindamycin, tetracycline, rifampin, clarithromycin, and van­comycin. Adult exposure prophylaxis is typically given with ciprofloxacin 500 mg orally every 12 hours for 60 days or doxycycline 100 mg orally every 12 hours for 60 days (2). The recommendation is the same for pregnant and lactating women. The potential morbidity and mortality from anthrax are felt to outweigh the his­torical and theoretical concerns regarding these medications (9). If the anthrax isolate in a current case is found to be sensitive to penicillin, the pregnant or lactating patient should be switched to amoxicillin 500 mg orally three times a day for the remainder of the prophylaxis period (9).

Vaccination against anthrax may be performed. The vaccine, called anthrax vaccine adsorbed (AVA), is a cell-free product given in a six-dose series over 18 months (5). While there has been significant media coverage of concerns over side effects of the vaccine following the US military’s mandated vaccination of active-duty and reserve-duty personnel, AVA is thought to be acceptably safe (5). Due to the potential for spores to remain dormant in tissues for prolonged peri­ods despite antibiotic prophylaxis, there has been interest in the use of AVA for postexposure prophylaxis in conjunction with antibiotics (5,8). The vaccine should theoretically be safe for use during pregnancy due to a lack of an active organism. No published experience is available on the use of the vaccine during pregnancy, but the potential benefits may outweigh the risk associated with sys­temic diseases in the event of a large-scale exposure. Experience from the mili­tary vaccination program suggests no adverse effect on pregnancy outcomes for women vaccinated prior to becoming pregnant (10).

Smallpox

Smallpox is caused by the DNA virus known as variola. It is easily transmitted from person to person by respiratory droplets. In addition, the virus may remain stable on fomites for up to 1 week (6). The virus replicates in respiratory epithe­lia and then migrates to regional lymph nodes. An initial viremia, accompanied by mild fever and malaise, will lead to introduction of the virions to a variety of tissues, resulting in localized infections in the kidneys, lungs, intestines, skin, and lymphoid tissues. After an incubation of 7 to 17 days, a second viremia occurs with high fevers, headache, backache, rigors, and vomiting. A rash is usu­ally apparent within 48 hours of this new phase. The rash is initially maculo­papular but changes soon to a vesicular eruption. The characteristic smallpox appearance is reached when the vesicles become pustules. Viral shedding may occur from the time of the rash until the lesions have crusted and separated. Death may occur in this phase due to overwhelming viremia and multiple organ failure (6).

Historical series of pregnant women affected by smallpox describe very high rates ofprematurity and fetal loss (11). In addition, pregnant women appear more susceptible to the disease, with case-fatality rates as high as 61% among unvac­cinated individuals and mortality rates of 27% even among vaccinated pregnant women. This compares with commonly reported mortality rates in nonpregnant adults of 3% when vaccinated and 30% among unvaccinated patients (2,11). Preg­nant women develop the hemorrhagic form of the disease with increased fre­quency compared with nonpregnant women and men (8,11). This hemorrhagic form of smallpox is characterized by fever, backache, abdominal pain, and a dif­fuse red rash. Historically, spontaneous epistaxis, ecchymoses, and bleeding into various organs led to rapid patient deterioration. The case-fatality rate among women with hemorrhagic smallpox was 100% in one series. Congenital smallpox among live born infants has been reported to occur in as many as 9% to 60% cases, with a very high mortality rate (8,11).

Infected patients should be isolated in negative-pressure rooms. Anyone who has had direct contact with and infected person should undergo strict quar­antine with respiratory isolation for 17 days (4). Especially in the setting of large numbers of infected individuals, quarantine and separate physical facilities may be required to minimize further disease spread. Airborne and body fluid contact precautions must be utilized. All discarded laundry or waste should be placed in biohazard bags and autoclaved prior to disposal (6). A certain number of hospital personnel may need to be vaccinated in advance in order to provide care in the event of a deliberate infection. Hospitals with maternity services should antici­pate the need to designate obstetrical and neonatal physicians and nurses for a team response.

Cidofovir has been tried with success against other pox viruses and has been reported to show in vitro activity against variola, but it cannot yet be rec­ommended as treatment (2,4). The principles of managing an outbreak of small­pox will be isolation and supportive care of infected patients and postexposure vaccination for contacts. Vaccination against smallpox is by inoculation of the related Orthopoxvirus, vaccinia. Vaccination is moderately effective at aborting or attenuating the disease if given within 4 days of an exposure (2,4). Complica­tions from widespread vaccination with vaccinia in the past included localized dermal reactions, vaccinia gangrenosa (with local extensive skin necrosis at the site of inoculation), eczema vaccinatum (a super infection of eczema with the vaccinia virus), progressive vaccinia, and postvaccinial encephalitis (11). While pregnant mothers may be vaccinated, there is a low risk of a potentially fatal fetal infection from the vaccinia virus. Therefore, routine vaccination of pregnant women in nonemergent settings is not recommended. In the event of an actual bioterrorism event, a pregnant woman at risk for exposure must weigh the risks of adverse effect from the vaccine against the devastating outcomes associated with smallpox infection in pregnancy (11).

Tularemia

Tularemia is a bacterial zoonosis first isolated by McCoy and Chapin in Tulare County, CA, in 1912 while searching for the causative agent of a disease affecting ground squirrels in the region. Documentation of this disease dates back to the 16th century in Norway and has been described throughout the northern hemi­sphere. Shortly after its isolation, Tularemia was recognized as a potential agent of severe and possibly fatal disease. A number of countries have done extensive research on its possible application as a biological weapon including Japan, Russia, and the United States. In the 1950s and 1960s, the US military developed weapons that could deliver aerosolized Francisella tularensis (12). Along with stock piling of weaponized F. tularensis, a live attenuated vaccine was developed that could partially protect against the virulent SCHU S4 strain and research was performed with various antibiotic regimens including streptomycin, tetra­cyclines, and chloramphenicol. With the termination of its biological weapons development program by executive order in 1970, all supplies were subsequently destroyed by 1973. Parallel efforts by the former Soviet Union continued into the 1990s with strains engineered that are resistant to vaccines and antibiotics (12). The impact of a weaponized release of Tularemia was estimated by the WHO in 1969 that aerosol dispersal of 50 kg of virulent F. tularensis over a metropolitan area with 5 million inhabitants would result in 250,000 incapacitation casualties including 19,000 fatalities (12).

The epidemiology of Tularemia is extremely complex. The organism has been isolated from over 200 animal species, including warm- and cold-blooded vertebrates, invertebrates, and numerous arthropods (13). Transmission can occur through several routes, including direct contact with the infected ani­mals, arthropod vectors such as fleas and ticks, inhalation, and ingestion. In the United States, ticks are responsible for 75% of cases (14). Inhalational tularemia is extremely rare in the United States and should raise the suspicion of inten­tional use via aerosolized attack. Any case of tularemia is reportable to the CDC, but the inhalational form should be extremely concerning (14).

Clinically, tularemia can present in several forms, including ulceroglandu- lar, oculoglandular, oropharyngeal, inhalational, typhoidal, and septic forms (12-14). Manifestations of the disease vary and are dependent on the route of exposure, dose, and virulence. In general, infection occurs 3 to 5 days after expo­sure with symptoms including abrupt onset of fever, chills headache, coryza, sore throat, myalgia, arthralgia, and fatigue (12). Hematogenous spread may also occur, causing meningitis, pericarditis, pneumonia, hepatitis, peritonitis, endocarditis, ataxia, osteomyelitis, sepsis, rhabdomyolysis, and acute renal failure (13). Ulceroglandular disease is the most common form of naturally pre­senting infection. Usual presentation includes the development of a tender pru­ritic papule at the site of infection. Progression to a painful ulcer and regional lymphadenitis occurs several days later. Over time, if not treated, spontaneous drainage of lymph nodes will occur. Oropharyngeal tularemia should be suspected in patients developing ulcerative pharyngitis or tonsillitis. Oculoglan- dular disease presents as a unilateral conjunctivitis with periauricular lymph­adenitis. Inhalational tularemia will present like other pnuemonias with symptoms such as fever, nonproductive cough, dyspnea, and pleuritic chest pain. Radiographic examination of the chest may find peribronchial infiltrates, bronchiolar pneumonia in one or two lobes, pleural effusions, and hilar lymph­adenopathy. Typhoidal tularemia describes systemic illness in the absence of localizing symptoms. Sepsis from tularemia is potentially fatal. Nonspecific findings of fever, abdominal pain, diarrhea, and vomiting may be present early. An individual with sepsis from tularemia will appear toxic and may develop confusion and coma. Prompt treatment is imperative with the possibility of shock, DIC, ARDS, and multisystem organ failure if treatment is delayed.

Diagnosis is first and foremost accomplished by a physician with a high index of clinical suspicion. Physicians that suspect tularemia should promptly collect specimens of respiratory secretions and blood. Specimens should be han­dled with care by laboratory personnel. Microscopic identification ofE tularensis may be accomplished with fluorescent-labeled antibodies. This is a rapid diag­nostic procedure that is performed by laboratories in the National Public Health Laboratory Network (12). Culture is the definitive means of confirmatory testing and can be performed from pharyngeal washings, sputum, fasting gastric aspi­rates, and rarely from blood.

In the event of encountering a release of aerosolized tularemia, standard precautions can be used due to the highly unlikely transmission from human to human. Decontamination of spills or areas containing infected persons can be accomplished with a 10% bleach solution followed by a solution of 70% alcohol (13). Persons with exposure to aerosols containing tularemia should wash them­selves and contaminated clothing with soap and water. Municipal water sources should remain safe secondary to their standard levels of chlorine. Public educa­tion should include avoidance of sick or dead animals and include precautions to take appropriate measures to avoid arthropod bites (13).

Antibiotic therapy for the general population can be determined by the classification of the cases as either contained- or mass-casualty situation. For isolated cases in adults, a regimen of streptomycin 1g IM or gentamicin 5mg∕kg should be administered for 10 days. With a mass-casualty exposure, doxycycline 100 mg orally twice daily for 14 days and ciprofloxacin 500 mg orally for 10 days are recommended. In the pregnant population, a course of gentami­cin is recommended in the contained-casualty situation and is likely to pose a low risk to the fetus. In the event of a mass-casualty exposure, the recommended regimen consists of oral ciprofloxacin. Prophylactic antibiotic treatment is rec­ommended to persons who are asymptomatic. In the pregnant female, a 14-day course of ciprofloxacin is recommended.

Plague

Plague has held a special place in world history with multiple pandemics, lead­ing to the death of millions of people. The bacillus, Yersinia pestis, is generally transmitted to humans from a rodent host by way of a flea vector. However, direct host-to-host transmission may occur by way of an infectious aerosol from affected individuals. This makes the disease extremely contagious. The disease is rapidly fatal in the absence of an appropriate antibiotic treatment (6). There have been attempts in the past to create a weapon out of plague; however, most such attempts have met with limited success. Still, plague represents a potential bioterrorism threat by way of an aerosol or inhalational route.

Typical bubonic plague is acquired from the bite of a flea, which regur­gitates the Y. Pestis from its foregut. The organisms rapidly multiply and spread to regional lymph nodes within 1 to 8 days. The infection of lymph nodes creates a characteristic bubo, which is a large tender area of inflamma­tion within the regional lymph node. From there, the patient may become septic within several days. Some patients will develop pneumonia and begin to shed Yersinia organisms in their cough droplets. Patients typically develop a productive cough with blood-tinged sputum within 24 hours of the onset of symptoms (6). Plague can also be ingested from a contaminated food source. The gastrointestinal form of the disease also follows a rapid course with the buboes developing in mesenteric drainage sites. Persons infected by the inha­lation route may not develop the typical buboes but may progress rapidly to septicemia.

The definitive diagnosis is made by a sputum Gram stain showing Gram­negative coccobacilli with bipolar “safety pin” staining. The chest radiograph may show consolidating lobar pneumonia. Further tests include an IgM enzyme immunoassay, antigen detection, and polymerase chain reaction (2). These tests are available typically through state health departments and the CDC. This approach requires a high index of suspicion to obtain these tests early enough to involve state organizations in containment. Patients with suspected bubonic plague should be separated from other patients, preferably under negative­pressure conditions, and body fluid precautions followed until at least 3 days of appropriate antibiotics have been completed (6). Patients who are suspected of being septic, having respiratory symptoms, or are diagnosed with pneumonic plague should be maintained under respiratory droplet precautions including negative-pressure isolation until the completion of at least four or more days of antibiotic therapy (6).

Standard therapy is 10 days of intravenous antibiotic, which may be switched to oral therapy when patients begin to improve. For nonpregnant adults, the recommended treatment is streptomycin 1 mg intramuscularly twice a day or gentamicin 5 mg∕kg IM or IV every 24 hours. Other choices include chloramphenicol or fluoroquinolones. For patients with suspected meningitis, chloramphenicol is considered mandatory because of its superior penetration of the CNS. The dose is 50 to 75 mg/kg per day (2,6).

It is thought that the major determinant of outcome for the mother and child is the timing of antibiotic administration (6). The fetus is susceptible to exposure to Y. pestis in utero or through contact with maternal blood. Histori­cally, plague acquired during pregnancy led to nearly universal fetal loss and could be especially severe in the pregnant woman (8). Gentamicin should be sub­stituted for streptomycin in the case of pregnancy. Chloramphenicol should be used with caution in pregnant women due to potential adverse effects on fetus and newborn. Doxycycline and ciprofloxacin have also been considered as alter­native regimens. Their use in this situation would represent a choice between benefits from treating the infection and potential risks of medication exposure to the fetus (8). Empiric treatment of the newborn following delivery of an infected mother should also be considered. In the event of a bioterrorist attack, it is thought that postexposure prophylaxis would be necessary to prevent rapid spread of the disease within the population. The decision would have to be made whether or not to place pregnant patients on the recommended prophylaxis of doxycycline 100 mg twice a day based on the risk of exposure and spread of the disease (8). Again, timely treatment with the appropriate antibiotics is very important in affecting the maternal outcome in pregnancy. Untreated, the mortality from plague is estimated at close to 100%. Even in treated cases, pneumonic plague is highly lethal with up to 50% to 60% mortality despite appropriate antibiotic therapy. In general, given the immunosuppressed state and normal physiological adaptations of pregnancy, a higher mortality would be anticipated. Thus, the dilemma of treating pregnant women with medications such as doxycycline, which are not typically used in the pregnant population, emphasizes the importance of carefully evaluating the exposure risk and the need for ongoing assessment and coordination of the disaster event with local, state, and federal authorities.

Q Fever

Q fever is caused by a small intracellular bacterium known as Coxiella burnetii. This agent would be attractive for use in bioterrorism because of the ease with which it causes infection since a single viable organism is adequate (4). Most immunocompetent persons have a self-limited infection without serious long­term complications, although chronic infection and endocarditis may occur in a small portion of infected individuals and can be debilitating. Hepatic transami­nase levels are frequently elevated and the peripheral white blood cell count is normal (4). An intentional release of Q fever would more likely be intended to cause disruption and psychological effects rather than mass casualties with overall mortality as low as 2.4% (4). The organism has long been known for its association with infection leading to abortion in animals. More recent informa­tion suggests that an effect on fetal loss is true in humans as well.

Q fever is generally obtained through inhalation of Coxiella organisms. The organisms are carried in body fluids such as the amniotic fluid of farm animals. A spore-like form can survive heat and drying with the capability to spread in the air (4). The incubation period is between 2 and 14 days. The clinical manifes­tations are similar to other nonspecific viral illnesses with fever, chills, and headache. The patient may also experience malaise, anorexia, and weight loss. More serious complications include neurological derangements in at least 23% of acute cases (2).

The diagnosis is generally made by the clinical complaints along with patchy infiltrates on chest x-ray, no cough, and a history consistent with exposure (4). Serology for IgG and IgM to Coxiella can be identified with antibodies appearing during the 2nd week of the illness. Convalescent titers usually show a fourfold increase after 2 to 3 months (4). The typical treatment for uncomplicated i nfections or prophylaxis for a nonpregnant adult is with doxycycline twice a day for 5 to 7 days. Chronic infections may require prolonged combination therapy (4). Fluoroquinolones may also be considered for empiric therapy. The dis­ease is not thought to be contagious from person to person (2). A vaccine is exten­sively used in Australia, but it is not approved for use in the United States (15).

While Q fever has long been implicated as a cause of low birth weight and abortion in farm animals, more recent data from France suggest that it has a significant role in human pregnancy as well (16). Acute infection during the first trimester leads to a very high rate of spontaneous abortion in untreated patients. Acute infection in the second or third trimester is less commonly associated with fetal loss but can be associated with low birth weight and premature delivery. The recommended treatment is trimethoprim 320mg with sulfame­thoxazole 1,600 mg daily for the duration of the pregnancy. Chronic infection is more common in women who develop the acute infection during pregnancy as compared to acquisition in the nonpregnant patient. This is thought to be related to the relatively immunocompromised state of pregnancy (16). The use of trimethoprim/sulfamethoxazole during pregnancy reduces the frequency of abortion as well as reduces the number of women with identifiable Coxiella in the placenta at delivery (16). Such treated patients are still at risk for early delivery and low birth weight. Long-term treatment after delivery for the woman is also recommended to resolve the chronic infection. The recommended postpartum regimen is doxycycline 100 mg twice daily and hydroxychloroquine 600 mg daily for 1 year following the pregnancy. For women who are appropriately treated, subsequent pregnancies seem to be unaffected. Similarly, women who acquire and resolve the acute infection prior to becoming pregnant also do not show a lasting effect on pregnancy outcomes (16). Breastfeeding is not recommended for women with acute Q fever.

Ricin

Ricin is a potent toxin easily derived from the beans of the castor plant (Ricinus communis). The toxin received media attention as an agent of bioterrorism through the arrest of six persons in Manchester, England, in December of 2002, who allegedly produced the toxin in their apartment as part of a potential attack. The discovery of powdered ricin in the mailroom serving former US Senate Majority Leader Bill Frist’s office in February, 2004, resulted in renewed fears regarding vulnerability to an attack with this toxin. The potential for ricin to be a weapon of mass destruction rests in the ease of producing the toxin and its stability, which allows for relatively easy dissemination with low risk of detec­tion. The amount of ricin necessary to produce the effects is also very small.

The protein is derived in the processing of castor beans, the oil of which is used in industrial settings, including a component of brake or hydraulic fluid (17). The waste mash or aqueous phase of the oil production is 5% to 10% ricin, which can then be isolated through the common technique of chromatography. The toxins RCL III and RCL IV are relatively small dimeric proteins consisting of an “A” chain and a “B” chain. After entry to the cell by binding to cell surface glycoproteins, the toxins inhibit the 60S ribosomal subunit, preventing contin­ued protein synthesis. The interruption of protein synthesis eventually leads to cell death (17).

In the event of inhalational exposure, symptoms are related to irritation of the lungs. Respiratory symptoms will begin usually 4 to 8 hours after the expo­sure. Early symptoms can include fever, chest tightness, cough, and dyspnea. Within 1 to 2 days, severe inflammation of the respiratory tract, cell death, and the development of acute respiratory distress syndrome may be expected. The treatment consists only of respiratory support with mechanical ventilation. (2,3). There has been fear that ricin might be used also to contaminate the water or food supply. This seems to be more difficult considering the large lethal dose extrapolated for humans (15). In the event of a gastrointestinal exposure, symp­toms would be expected from necrosis of the gastrointestinal epithelium as well as damage to spleen, liver, and kidneys. Symptoms might manifest as abdominal cramps and nausea, as well as high output gastrointestinal fluid loss. Ricin is thought to be much less toxic when ingested rather than inhaled, although a large gastrointestinal exposure could lead to enough necrotic multiorgan damage to produce hemorrhage and hypovolemic shock (2,3).

The diagnosis may be confirmed by ELISA testing, although this is not widely available (4). Patients should be treated by decontamination with removal of garments and cleansing with soap and water. Outside of contact with residual, undetected toxin remaining on the victim, there is thought to be little secondary risk to emergency department personnel; however, as with all patients, the observation of universal contact precautions is prudent. There is no direct anti­dote to the toxin, although gastric decontamination with charcoal has been reported to be potentially of benefit in some cases (2-4,15). Supportive care is the main approach to management. In the case of a pregnancy, the size of the toxin makes it unlikely to readily cross with ease to the fetus. The outcome for the baby will depend on the supportive care of the mother.

TOXINS OR CHEMICALS

There are several compounds that may be encountered as either the result of an intentional release, such as in the case of the release of nerve gas on a Japanese sub­way, or in the event of an industrial accident. For the most part, care of the pregnant patient will differ little from the nonpregnant patient. The lethal agents are classi­fied into four categories: nerve agents or anticholinesterases, vesicants or blistering agents, choking or pulmonary agents, and cyanogens or “blood” agents (18).

Nerve Agents—Acetylcholinesterase Inhibitors

These are organophosphorus compounds and include tabun, sarin, soman, GF, and VX. Their primary mechanism of action is through the inhibition of acetylcholinesterase at synapses and neuromuscular junctions. The tyrylcholin- esterase in plasma and acetylcholinesterase in the red blood cell are also inhibited. The result is an excess of acetylcholine leading to hypersecretion and bronchoconstriction in airways, mental status changes, nausea, vomiting, and muscle fasciculation and weakness (18). A large exposure may be rapidly fatal with loss of consciousness, seizures, and apnea from respiratory muscle paraly­sis and central nervous system depression. The agents are usually clear and colorless and may be disseminated as either a vapor or a liquid. Exposure may be through skin absorption, inhalation, or gastrointestinal ingestion. Inhalation is more effective than absorption through intact skin (19).

Patients with a large exposure or significant symptoms should be treated with atropine and pralidoxime (2-PAM) (18). Atropine competes with the accu­mulated acetylcholine and diminishes the cholinergic effects. Pralidoxime dis­sociates the nerve agent from the cholinesterase and is excreted in the urine as a complex with the agent (19). Atropine is commonly given as a 2-mg intramuscu­lar or intravenous dose and is sometimes available for self-administration via an auto-injector. The patient should be reevaluated every 10 to 15 minutes, and a repeat dose given until secretions decrease or breathing becomes easier (19). Pralidoxime also can be given as 600 to 1,000mg intramuscularly or as a slow intravenous dose. Timing of administration is important as the cholinesterase enzyme will dissociate less easily from the organophosphate as time passes. The aging time is different for each nerve agent (19). If severe respiratory distress is apparent, intubation should be accomplished. In addition, severely injured victims should be given a benzodiazepine (diazepam, lorazepam, or midazolam) to raise the seizure threshold and help prevent secondary anoxic brain injury (18,19). Successfully treated patients should begin to recover within a few hours, but neurological symptoms may persist for weeks.

There is little information available on the fetal effects of such an exposure. The fetus will be particularly susceptible to any respiratory depression or anoxia in the mother. Theoretically, the compounds may be able to reach the fetal brain with some behavioral depression likely, which may alter fetal biophysical or non­stress testing or maternal perception of fetal activity. Ultimately, fetal survival will depend on the expeditious and appropriate care of the mother.

Vesicants and Pulmonary Agents

The vesicants, such as mustard gas and lewisite, are easily absorbed through the skin and mucous membranes. The damage may not be evident until 2 to 12 hours after contact (19). Damage is caused by cross-linking and methylation of DNA. Blisters may form on the skin in the early stages. Skin sloughing will later place the patient at risk for secondary infection. Wounds should be cared for the same way as scald burns; systemic antibiotics are not necessary (19). Similarly, the damage to lung tissues results in a chemical pneumonia that may also lead to secondary infection. Mortality is generally low from an acute attack with overall mortality rates at 2% to 5%, but the number of people affected may be high and caring for the high morbidity will consume a large amount of medical resources and health care dollars (18,19).

Similarly, pulmonary agents, such as phosgene and chlorine, lead to dam­age in the respiratory tract within hours of exposure. Hydrolysis of the inhaled gas produces hydrochloric acid that mediates the local tissue toxicity (19). The effect with this agent involves damage to the alveolar-capillary membrane and subsequent reactionary pulmonary edema. The lung’s ability to clear the excess fluid will be overcome and dyspnea will result. There can be a delay in the onset of lung failure up to 48 hours. Victims usually require mechanical ventilation, but survival past 48 hours generally suggests that recovery is likely and purports a favorable long-term outcome (18,19). Care is supportive and early tracheotomy is advisable for severe exposure. Preventive antibiotics are not indicated and will only result in microbial selection. Some degree of lung fibrosis and pulmonary restriction can be seen in severe cases (19).

RADIATION

Public concern over radiation exposure has been elevated by worries about the safety of nuclear power facilities, the transport and disposal of nuclear waste, or the threatened use of radiation-contaminated weapons—so-called dirty bombs. Much is known about the consequences of inadvertent exposure. Damage can range from skin reddening to cancer induction and death. Particularly relevant to pregnancy is the fact that rapidly growing fetuses and children are more sus­ceptible to the subtle effects of radiation exposure than are adult tissues (20,21). Damage is also cumulative, with increasing or repetitive exposures resulting in more severe damage (20).

“Dirty bombs” are typically intended to spread radiation in such a way as to make areas unusable. Depending on the source, the amount of radiation released from such a weapon is unlikely to cause severe forms of acute radiation syn­drome (20). From the United Nations’ report of Iraq’s testing of dirty bombs in 1987, the Iraqis deemed that radiation levels achieved were too low to cause

Biological Effects of Total Body Irradiation

Source: Ref. 20.

significant damage and the project was abandoned. In a modern context, such weapons would likely be used to disrupt routines and generate fear in the general public (Table 10.1).

The management of the initial exposure to radiation adheres to the princi­ples of decreasing the time near the source, increasing the distance from the source, and the use of physical barriers, such as glass or concrete to shield an individual from exposure (20,22). In the event of an exposure, it is recommended to leave the area on foot. Do not take cars or public transit that may harbor con­taminated dusts. Make use of barriers by entering buildings. Clothes are to be removed and bagged for later disposal. A shower may remove contaminated dust or debris from the skin (20).

Radiation exposure can result in significant dysfunction to many organs within the body. Depending on the dose and length of time of exposure, as well as the mechanism of exposure, injury may range from a local injury such as a burn to a more widespread injury such as the acute radiation syndrome (ARS) (22,23). A local injury often involves exposed contact areas like the hands and face. Patients may present with erythema, blistering, desquamation, and ulceration of the skin. The patient may or may not realize when the exposure might have occurred. For example, handling an unknown metallic object might be the source of exposure. Such injuries generally evolve slowly and the full extent of injury may not be known for several weeks. Conventional wound management may be ineffective (23).

The ARS is a quickly developing illness caused by a total body exposure to radiation. It is characterized by damage of several organ systems due to the effect of ionizing radiation, leading to a deficiency in cell numbers or cell function. Radioac­tive sources provoking ARS might consist of machines that emit gamma rays, x-rays, or neutrons. There are four phases ofARS (23). The first is a prodromal phase in which a patient might experience nausea, vomiting, and loss of appetite. Gener­ally, these symptoms disappear within 1 to 2 days and a symptom-free latency period may follow. The length of the latent period may vary depending on the radiation dose. A period of full-blown illness may then follow with electrolyte imbalances, diarrhea, hematologic abnormalities, and even CNS changes. The overt illness results either in death or in slow, eventual recovery (23). Severe organ dysfunction that may be noticed includes low white blood cell count leading to immunodeficiency. A gastrointestinal syndrome also may occur with loss of the cells lining the gut, leading to water and electrolyte loss through vomiting, diar­rhea, and impaired nutrient absorption. The patient may also demonstrate

confusion and disorientation resulting from the dramatic changes in dehydration and electrolyte imbalance. These mental status changes, including periods of unconsciousness, are generally considered a poor prognostic sign (22,23). Full recovery is possible and may occur over a prolonged period of time, from several weeks to 2 years.

The initial management of a large radiation exposure includes treating traumatic injuries (fractures, lacerations) as they would normally be managed. In addition, care should be taken to remove external contaminants. The history should focus on details of the source of exposure including the type of radiation, the prox­imity to the source, and the length of time of the exposure (23). A careful medical history should be obtained and, in the case of pregnant women, an estimate of the gestational age and a summary of pregnancy history included. Diagnosis of ARS may be aided by following the complete blood count every 4 to 6 hours. A significant drop in the absolute lymphocyte count and platelet count may aid in timing the exposure (22,23). Suspected exposures and Gynecologists, 2004. Available at: http://www.acog.org/publications/committee_opinions/co299.cfm. Retrieved May 25, 2009.

22. Flyn DF, Goans, nuclear terrorism: triage and medical management of radiation and combined-injury casualties. Surg Clin North Am. 2006;86:601-636.

23. Oak Ridge Institute for Science and Education, Radiation Emergency Assistance Center/Training Site. Guidance for radiation accident management. Managing radi­ation emergencies: acute radiation syndrome. Available at: http://www.orau.gov/ reacts/syndrome.htm#Acute. Retrieved March 7, 2004.

24. Centers for Disease Control. Emergency preparedness & response. Radiation emer­gencies: potassium iodide. Available at: http://www.bt.cdc.gov/radiation/ki.asp. Cited May 25, 2009.

25. Mushtaq, A, El-Azizi, M, Khardori N. Category C potential bioterrorism agents and emerging pathogens. Infect Dis Clin North Am. 2006;20:423-441.

26. Koirala, J. Plague: disease, management, and recognition of act of terrorism. Infect Dis Clin North Am. 2006;20:273-287.

27. Cono J, Cragan JD, Jamieson DJ, Rasmussen SA. Prophylaxis and treatment of pregnant women for emerging infections and bioterrorism emergencies. Medscape published 11/21/2006. Cited May 25, 2009.