March of Dimes Updates

Smallpox and the smallpox vaccine

From the March of Dimes Birth Defects Foundation

Both smallpox and the vaccine that prevents it have special implications for women of childbearing age and for their health-care providers. Ob/gyns can best serve their patients and themselves by having up-to-date knowledge of the disease, the vaccine, and guidelines for vaccination, including contraindications.

Pregnant women are at special risk from smallpox, if the disease re-emerges as a terrorist weapon—and from adverse effects of the smallpox vaccine. Although a widespread immunization program has begun, there are special considerations for reproductive-aged women. Smallpox vaccine is contraindicated for women who are pregnant or breastfeeding, and for women who are considering becoming pregnant within a month of vaccination.

Current information about smallpox vaccination guidelines is useful to clinicians and available from several sources that are outlined in this article. Also available online is a 1-page information sheet for your patients (Table 1).

TABLE 1
Sources of information on smallpox vaccination

Centers for Disease Control and Prevention (CDC)

Patient Information online at http://www.bt.cdc.gov/agent/smallpox/vaccination/pdf/preg-contra.pdf
For more information visit CDC's smallpox homepage at http://www.cdc.gov/smallpox or call the CDC public response hotline at (888) 246-2675 (English), (888) 246-2857 (Español,) or (866) 874-2646 (TTY).

Professional source for smallpox vaccination issues
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5204a1.htm

American Academy of Pediatrics (AAP)

AAP policy on smallpox immunization of children
http://www.aap.org/advocacy/washing/smallpox_vaccine.htm

March of Dimes

Smallpox vaccination http://www.marchofdimes.com/pnhec/188_4740.asp
Or contact the Pregnancy and Newborn Health Education Center.

Phone: Call the Center between 9:00 am and 8:00 pm Eastern Time, Monday through Friday. Closed most major holidays. Voicemail accepts messages 24 hours a day, 7 days a week. English toll-free number in the United States and Canada: 1-888-MODIMES (888-663-4637). Internationally: 001-914-997-4765 Spanish toll-free number in the United States and Canada: 1-800-925-1855

e-mail: askus@marchofdimes.com

Re-emergence as a public health concern

Declared by the World Health Organization (WHO) to be eradicated in 1980, smallpox (variola) now is deemed a prime candidate for use in biological attack by a rogue state or terrorist group. Vaccination against smallpox began early in 2003 for people in selected military and civilian jobs, initially to include a half-million hospital workers and other members of health-care response teams.

Before its demise, smallpox ranked high among infectious killers. The WHO estimated its average annual, worldwide incidence at 10 to 15 million cases, one quarter of them fatal, before the late 1960s, when intensified international vaccination programs began its extinction.¹

Variola virus belongs to a large family of poxviruses that infect species ranging from moths to mankind, but variola has no known, nonhuman host in nature. This fact seemed to ensure that human disease would be permanently eradicated by vaccination in the 1970s, unless the virus was reintroduced by human error or malice. A main reason for today's concern about reintroduction is that Russian stores of the virus, and scientists who worked with it at a major laboratory in Siberia for possible use as a weapon, could not be accounted for after the breakup of the Soviet Union.² Variola virus is a top candidate for biologic warfare because of its high contagion and case-fatality rate. Each index case caused up to five secondary cases, in times when there was substantial population immunity, and might cause 10 such cases in today's more susceptible population. General case-fatality rates have reached 25% in modern times, and have been substantially higher in pregnant women.^1,3

The last naturally acquired case of smallpox occurred in 1977, when a hospital cook in Somalia survived it. In 1978 two people in England died after accidental release of the virus in a research laboratory. Literature on epidemiology, morbidity, mortality, and prevention of smallpox, including adverse effects of the vaccine, is based mainly on experience in the 1960s. Certain factors that have changed since then weaken predictions based on such experience.

Routine vaccination in this country ended in 1972, and vaccination of military personnel ended in 1989. Because vaccine-induced immunity wanes, there is no longer a large percentage of people whose immunity could prevent their transmitting the disease to others. Also, immune system impairment is more prevalent in the population today, due to such factors as HIV and wider use of cancer chemotherapy, radiation therapy, and immunosuppressive treatment for autoimmune disease or organ transplants. A likely consequence is an increased frequency of severe disease and death in any outbreak of smallpox, but also an increased frequency of severe adverse effects of vaccination.³ There is also concern that any variola virus strain used as a biologic weapon may have been altered to make it more dangerous than the natural strains that once circulated—for example, by designing it to evade conventional immunization. On the plus side, some of today's antiviral drugs might attenuate the disease.

Those caveats aside, there is a solid body of clinical information, with special relevance to women of childbearing age, on smallpox and the efficacy and adverse effects of the vaccine.

Clinical picture and diagnosis

Surveillance for an outbreak depends heavily on suspicion of the disease by astute clinicians.

Symptoms typically appear 7 to 19 days after exposure, starting with fever, chills, headache, backache, and vomiting. Two or 3 days later a rash emerges, sometimes starting with fleeting, generalized erythema, and progresses from macules to papules to vesicles to pustules. The vesicular stage may suggest chickenpox, but tends to cause more lesions on the face and limbs, including palms and soles, than the mainly truncal pattern of chickenpox. Smallpox lesions also differ in that they develop at the same stage all over the body, rather than in the coexisting crops of new and old lesions that typify chickenpox. In the pustular stage, smallpox lesions are more deep-seated than they look, rolling around under palpation as if they were small, round foreign bodies. This is said to be a distinctive feature of the disease. Definitive diagnosis requires viral DNA analysis at a top-level containment laboratory, using samples collected by vaccinated individuals.

Presumptive diagnosis can be elusive in cases of atypical smallpox, such as the mild "modified" form in people with partial immunity from old vaccination, the slowly developing "malignant" or "flat," velvet-skinned form with up to 95% mortality, and the rapidly developing hemorrhagic form with up to 99% mortality. In any possible smallpox outbreak, preventing epidemic spread will depend importantly on clinicians' diagnostic suspicion of "modified" disease in patients whose age or military or travel history points to prior vaccination that may disguise mild but dangerously contagious disease.

The largest reported series of pregnancies complicated by smallpox—almost 400—comes from India in the 1960s. Pregnant women were at greatly increased (up to 25%) risk for hemorrhagic smallpox. Its hallmarks are subconjunctival hemorrhages, bleeding from the nose and gums, hemoptysis, hematemesis, hematuria, vaginal bleeding, petechiae and ecchymoses, and bloody pustules on the skin and mucosae. Overall maternal mortality was 27% in vaccinated and 61% in unvaccinated women. There were very high rates of fetal loss, preterm birth, and neonatal death.³ It is unclear how relevant data from 40 years ago in India are to any smallpox scenario in the United States today.

Prevention

The mainstay of prevention is vaccination. The vaccine contains live vaccinia virus, which is related to variola virus and to the virus that causes cowpox. A single dose elicits antibody titers of at least 1:10 in more than 95% of individuals.⁴ It is not known what antibody level reliably prevents infection.⁴ Immunization is highly preventive for about 5 years, and protective against severe disease for more than 10 years. Only an estimated 10% of people vaccinated before 1970 have any remaining protection.³

Vaccination within 2 to 3 days after exposure is highly protective against disease, and within 4 to 5 days, may prevent death.³ There is no absolute contraindication to emergency vaccination after high-risk exposure to smallpox.⁴

Pregnancy and other contraindications to vaccination

Relative contraindications to vaccination of women include current pregnancy, intended conception within 28 days, and current breastfeeding. The same applies to anyone in close (especially home) contact with a woman who is pregnant or intending conception, but not to contacts of nursing mothers.⁴ In the absence of a smallpox outbreak, therefore, pregnant or nursing women and women who are considering pregnancy within the next month, should not receive the smallpox vaccine.⁵ If there is an outbreak of smallpox, guidelines may change and new guidelines should be followed at that time.

A chief concern for pregnant women is the rare occurrence of fetal vaccinia. The live vaccine virus occasionally infects a fetus, and when it does, often causes fetal or newborn death. Because data were not systematically gathered in the smallpox era, risk figures are not available. The Centers for Disease Control and Prevention has created a case registry for reporting pregnancy exposures to vaccinia virus (see "The National Smallpox Vaccine in Pregnancy Registry: keeping track of rare complications").

Other relative contraindications include having any of the following conditions, or having a close contact with any of them. Those include past or present eczema; active acute, chronic, or exfoliative conditions that disrupt the epidermis; and immune system compromise due to disease (such as leukemia, HIV infection, or congenital immune deficiency) or treatment that impairs immune defenses (such as cancer chemotherapy or radiotherapy, or immunosuppressive medications for autoimmune disease or organ transplants).⁴

Contraindications that apply only to vaccination candidates include allergy to smallpox vaccine components, current use of ocular topical steroid medication, any moderate-to-severe short-term illness, and age less than 1 year. (The CDC's Advisory Committee on Immunization Practices "does not recommend" nonemergency vaccination of anyone younger than age 18.) As of April, the CDC recommended temporary deferral of vaccination for anyone with: (1) known heart disease, including congestive heart failure, cardiomyopathy, history of angina or heart attack, or other evidence of coronary artery disease; (2) history of stroke or transient ischemic attack; or (3) three or more of these risk factors: hypertension, hypercholesterolemia, hyperglycemia or diabetes, current smoking, and having a parent or sibling with heart disease before the age of 50.⁶

Other adverse effects of smallpox vaccine

In a 1968 survey recently cited by the CDC, adverse events considered serious but not life-threatening occurred in about one in 1,000 first-time vaccinees.⁴ More than half were inadvertent transmissions to contacts. Generalized vaccinia, an extensive but nontoxic rash, affected about 1/4,000 vaccinees. Erythema multiforme affected 1/6,000.

Life-threatening complications affected 1/20,000. These included encephalitis (1/80,000), disseminated disease among people with immune deficiencies (1/666,000) and eczema vaccinatum among those with histories of eczema and related conditions (1/26,000). The overall death rate was 1/666,000.

In a recent vaccination trial, minor, expected vaccine reactions included fatigue in 50% of vaccinees, headache (40%), muscle aches and chills (20%), nausea (20%), and fever (100°F or higher) in 10%. About one third of vaccinees reported trouble sleeping, or having missed work, school, or recreational activities.⁴

Work in progress

For more than 2 years a CDC team has collaborated with the National Institutes of Health and other resources in smallpox research. Efforts include development and production of safer vaccines and evaluation of certain antiviral drugs, such as cidofovir and its analogs, for treatment of severe adverse effects of smallpox vaccination and of smallpox itself. Achievement of those goals may benefit from the recent establishment of smallpox infections in cynomolgus monkeys. Other goals are rapid and accurate assays for diagnosis of smallpox infection in its earliest stages and comprehensive study of genetic diversity of the virus as a basis for rational design of vaccines and drugs.

The CDC continually updates guidelines as new information becomes available. Its smallpox home page (see Table 1) has links to Web pages for clinicians, health officials, and the public.

REFERENCES

1. World Health Organization 2001. http://www.who.int/emc/diseases/smallpox/factsheet.html

2. CBRNE – smallpox. eMedicine 2003. http://www.emedicine.com/emerg/topic885.htm

3. CDC. Smallpox vaccination and adverse reactions. MMWR. 2003;52(No. RR-4). http://www.cdc.gov/mmwr/PDF/RR/RR5204.pdf .

4. CDC. Vaccinia (smallpox) vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2001. MMWR Recomm Rep. 2001;50(RR-10). http://www.cdc.gov/mmwr/PDF/RR/RR5010.pdf .

5. CDC. Pregnancy and breastfeeding mean you should not get smallpox vaccine. http://www.bt.cdc.gov/agent/smallpox/vaccination/pdf/preg-contra.pdf .

6. CDC. People who should not get the smallpox vaccine (unless they are exposed to smallpox). http://www.bt.cdc.gov/agent/smallpox/vaccination/contraindications-public.asp .

The National Smallpox Vaccine in Pregnancy Registry: keeping track of rare complications

Smallpox vaccine is known to cause fetal vaccinia, a very rare, but serious complication that can result from exposure to smallpox vaccine during pregnancy. Fewer than 50 cases have been reported in the world literature, three of which occurred in the United States in 1924, 1959, and 1968.^1-3 Affected pregnancies have been reported in women vaccinated in all three trimesters, in primary vaccinees as well as in those being revaccinated, and in nonvaccinated contacts of vaccinees. Because a risk of infection to the fetus is known to exist, smallpox vaccination is not recommended among pregnant women or anyone with close physical contact to a pregnant woman (such as a household member or sex partner).

The CDC has established the National Smallpox Vaccine in Pregnancy Registry, a surveillance system to monitor the outcomes in women who inadvertently received smallpox vaccine during pregnancy, became pregnant within 28 days after vaccination, or were in close contact with a vaccinee within 28 days. Exposed pregnant women should contact their health-care providers or their state health department for assistance in enrolling in the Registry. Health-care providers and staff from state health departments are encouraged to report all exposed pregnant women to the Registry. Reports should be routed through the CDC's Clinician Information Line at 877-554-4625 or CDC at 404-639-8253.

REFERENCES

1. Lane JM, Millar JD, Neff JM. Smallpox and smallpox vaccination policy. Annu Rev Med. 1971;22:251-272.

2. CDC. Smallpox vaccine: recommendations of the Public Health Service Immunization Practices Advisory Committee. MMWR. 1978:27:156-158, 163-164.

3. CDC. Adverse reactions to smallpox vaccination—1978. MMWR. 1979;28:265-267.

 

Ellen Fiore. Smallpox and the smallpox vaccine. Contemporary Ob/Gyn Oct. 1, 2003;48:85-91.