PROTOCOLS OB/GYN INFECTION

Measles in pregnancy

By Bryan Larsen, PhD

Gestational measles can cause maternal death, fetal loss, and prematurity. Our overview discusses vaccination options, diagnostic tests, and management during pregnancy.

Measles (rubeola) is a highly contagious infection. It is typically acquired by nonimmune children, and infection among inadequately immunized adolescents remains a problem, even in developed countries. In the United States, many cases are imported from endemic areas, occur in groups that reject vaccination on religious or philosophic grounds, and, more frequently than in the past, involve young adults. Humans and monkeys are the only hosts for the virus and in the absence of vaccination or prior infection, human susceptibility is universal.

The World Health Organization estimates that measles is responsible for more than 1 million deaths annually worldwide, making it the sixth to seventh largest killer among infectious diseases—it shares this rank with HIV/AIDS. In 1995, the US had a historically low incidence of disease, although there had been a resurgence between 1989 and 1991. In 1968, incidence reached an all-time high of 152,209 cases, but by 1990 annual incidence had dropped to 27,786. In 1995, only 309 cases were reported to the Centers for Disease Control and Prevention. This sharp decrease is due to improved immunization practices.

As with any disease that has become uncommon as a result of successful vaccine strategies, the medical community still needs to be vigilant and familiar with the manifestations of measles. Complacency about vaccination could lead to a resurgence, and unfamiliarity with the symptoms of uncomplicated measles or its more serious sequelae can lead to poor management.

Pathophysiology

Measles enters by droplets or by fomites through the upper respiratory tract, with initial replication taking place locally and in regional lymph nodes. Then, primary viremia sets in and infects the reticuloendothelial system. After 5 to 7 days, secondary viremia follows. An incubation period of 9 to 12 days culminates in fever, upper respiratory symptoms, and pathognomonic Koplik's spots (red spots with bluish to white centers on the buccal mucosa), followed 1 to 2 days later by a rash that begins on the head and descends to the trunk and limbs. Invasion of the respiratory, urinary, and gastrointestinal tracts, as well as the CNS, leads to a variety of symptoms. Sequelae can be acute or chronic.

Diagnosis

Clinical observation is the primary means of diagnosing measles, although atypical manifestations may be difficult to recognize. Immunohistochemistry will reveal viral antigens, in the forms of fluorescent antibody-staining cells, in nasal secretions, urine, or skin biopsy specimens. Histologic or cytologic specimens may reveal multinucleated giant cells suggestive of measles virus infection. These indicators decline within a few days of the onset of the rash.

Viral RNA can be detected by suitably equipped laboratories that use reverse transcriptase polymerase chain reaction (PCR) testing. PCR testing is particularly useful when there are chronic complications, but few intact viral particles are present. In cases involving subacute sclerosing panencephalitis (SSPE), very high IgG levels are found in the cerebrospinal fluid (CSF). Serodiagnosis is usually accomplished by demonstrating IgM antibodies in acute serum samples taken 2 to 3 days after the onset of rash and rising IgG antibodies in later samples. Antibodies in CSF demonstrate CNS involvement.

For assessing the level of protection in previously vaccinated in-dividuals, antibody measurement by means of enzyme-linked immunosorbent assay (ELISA) can be useful. In most cases revaccination is more cost-effective, however, because the presence of protective antibody is not a contraindication to vaccination.

Virology

The measles virus belongs to the genus Morbillivirus of the Paramyxovirus family. Its genome is a single strand of negative-sense RNA, and it carries two proteins required for viral replication with its protein nucleocapsid. During the process of maturation, the nascent virus acquires a lipid bilayer envelope that contains some host and some viral components. Host cells may be destroyed by viral replication, but some cells can instead become persistently infected.

Viral replication occurs in a number of cell types, such as epithelium, endothelium, and lymphoid cells, including macrophages and monocytes. Although intact viral particles can be removed from the bloodstream by serum antibodies, incomplete virus in the form of ribonucleoprotein may persist in gray and white matter, leading to a chronic condition that is unlike a primary measles infection.

Immunity

A single antigenic type of virus is responsible for natural infection, and infection confers lifelong immunity through the serum antibody response. Antibodies passively transferred at low titers (transplacentally derived or parenterally administered) probably do not prevent measles, but may permit a milder form of the disease. Recent studies from endemic populations suggest that transplacental antibodies from mothers with prior natural infection live longer in infants, compared with antibodies from mothers who had measles vaccination. Passive immunization is used in measles-exposed populations at risk of serious illness, including immunosuppressed or immunodeficient individuals. It should also be used when protection is needed during pregnancy.

The active vaccine has been available since 1963 and is based on a live-attenuated virus strain usually given as part of the measles-mumps-rubella regimen during the first 12 to 18 months of life. Live vaccine is contraindicated during pregnancy, however. Active vaccination should precede conception by at least 3 months. Postpartum vaccination of a woman susceptible to rubella provides an opportunity to offer measles vaccine as well. In the absence of a clear history of previous vaccination, the live virus may still be used, since an increased incidence of adverse reactions has not been documented in already immune individuals.

After vaccination, declining but protective titers remain for about 18 years, with natural exposure boosting the immune response somewhat. Because a small percentage of primary vaccinations are ineffective, some countries recommend revaccination to anticipate this possibility. In the US, many colleges mandate revaccination before entrance. Table 1 presents a summary of vaccine recommendations.

Table 1
Recommendations for measles vaccination (non-childhood)*

Revaccinate persons immunized before their first birthday (provide second dose of live measles vaccine).

Revaccinate if primary vaccination was given with immunoglobulin (provide second dose of live measles vaccine).

Revaccinate if primary vaccination used killed vaccine (available between 1963 and 1967). Provide two doses of vaccine separated by more than 1 month to prevent severe atypical measles.

Revaccinate persons immunized with unknown vaccine type between 1963 and 1967.

Revaccinate if primary vaccination was killed vaccine followed within 3 months by live vaccine (provide two doses of vaccine).

Although the humoral immune response to measles has received the most attention, the virus itself interacts with cell-mediated responses during active disease. Transitory losses of hypersensitivity reactions have been blamed on the invasion of T and B lymphocytes by the measles virus. A recent report suggests that the mechanism may involve a down-regulation of interleukin-12 (IL-12) production by monocytes through interaction with CD46, which serves as the measles virus receptor. Suppressed cell-mediated immunity is important because it may cause increased susceptibility to secondary infections, which are responsible for more measles-related deaths than the primary viral disease itself. Other forms of immune compromise may also be a risk factor.

The complications of measles

Measles can be complicated by acute or chronic conditions. The presence of co-morbid illness increases the risk of complications. For example, in individuals with tuberculosis, measles may follow a more virulent course and can exacerbate the tuberculosis.

Individuals who are immunosuppressed are at risk of severe viral illness. Sometimes-fatal giant cell pneumonia may occur in the absence of a rash in immunocompromised children, for instance. Inadequate vitamin A nutrition has also been associated with increased susceptibility to complications—particularly among children in developing countries. This has prompted the use of vitamin A in the treatment of measles.

Approximately one quarter of infected individuals experience complications such as diarrhea (9%), bacterial or viral otitis and pneumonitis (each about 7%), and postmeasles encephalitis, which occurs in 50 to 400 of every 10,000 measles cases. Because of its significant mortality (20%) and riskof permanent neurologic sequelae (20% to 40%), encephalitis is the most compelling reason for vigorous vaccination campaigns. The mechanism of pathology in encephalitis cases is believed to be an allergic inflammatory reaction.

Early use of killed vaccines has also left an unfortunate legacy, namely atypical measles syndrome. This is an allergic response consisting of fever, an urticarial rash that spreads from limbs to trunk, and atypical pneumonia in young adults.

The most serious complication, however, is subacute sclerosing panencephalitis (SSPE), a delayed sequel of measles seen mainly in children 5 to 10 years of age. It occurs 5 to 7 years after the primary measles infection. A recent report describes a 16-year-old gravida with a fatal case of SSPE. This degenerative disease is associated with the persistence of mutant viral forms from infected cells, which produce significant quantities of ribonucleoprotein in the CNS. Its early symptoms are personality change, intellectual decline, and inappropriate behavior, followed by progressive mental deterioration and motor dysfunction, culminating in seizures, coma, and death within a few years. The estimated rate of this complication is 0.5 to 2 for every 100,000 cases.

Pregnancy and measles

When measles reached the previously unexposed population of Greenland in 1951, a nearly threefold greater mortality was observed in pregnant women, compared with nonpregnant women. In addition, measles produces high rates of fetal loss, although the mechanism appears to be placental compromise rather than fetal damage or viral teratogenicity, as shown by Moroi and co-workers. These investigators found measles virus antigen in syncytial trophoblast and decidua, but not in the fetus, in a case of fetal death at 25 weeks' gestation.

Declining rates of measles in the US have reduced the number of gestational measles cases, but the resurgence of measles in the early 1990s and continued problems with measles in other parts of the world demonstrate the potential for adverse pregnancy outcomes. In 1993, Eberhart-Phillips and colleagues reported on 53 cases of gestational measles, in which there were two maternal deaths and a high rate of fetal loss and prematurity. In 1992, Atmar and colleagues described 12 gravid women with measles and one newly parturient patient whose illnesses suggested a virulent disease course, with one maternal death and seven instances each of maternal hepatitis and pneumonitis. In this series there were four cases of premature labor and one spontaneous abortion. Likewise Stein and Greenspoon reported three cases of bacterial pneumonia complicating gestational measles in 1991; one of these patients successfully underwent tocolysis for premature labor but had an unexplained stillbirth 7 weeks later.

Vaccination

Ideally, of course, we want to prevent measles through vaccination. As noted above, the vaccine must be given when a patient is not pregnant, although vaccination of her young children will not threaten a pregnant mother (Table 2). Vaccination against all preventable diseases should be promoted, and the overriding concern about rubella and its dangers should not divert attention from other diseases such as measles. If you have a patient who expresses religious or philosophical aversion to vaccination, be especially diligent in maintaining contact, since outbreaks of disease are more likely in such individuals and their families.

Table 2
Precautions for measles vaccine use

The current live virus-containing vaccines are provided in three forms: monovalent (measles), MR (measles-rubella), and MMR (measles-mumps-rubella). Although the measles vaccine is highly effective, a second dose is mandatory to ensure an adequate level of protection. Table 1 emphasizes the importance of providing two doses of live virus vaccine and lists special situations requiring revaccination.

Measles vaccine has an excellent record of safety but may induce some side effects. As many as 45% of those vaccinated develop a temperature of 103°F (39.4°C) or higher, beginning at about 42 days after vaccination. Transient rashes are reported in 5% of patients, while CNS problems occur in fewer than one per million.

Management during pregnancy

When a pregnant woman gets measles near the time of delivery, the fetus may become infected at birth or within 12 days after delivery. Children born to infected mothers who have measles in the last week of pregnancy or first week postpartum should be treated with immune globulin. Immune globulin (0.25 mL/kg IM) is also administered to modify the course of measles in the susceptible gravida within 6 days of exposure to the virus. Between 5 and 9 days after exposure, this treatment will not prevent secondary viremia, but may reduce the severity of disease.

Bacterial complications should be treated with appropriate antimicrobial therapy, although there is no reliable therapy for measles encephalitis. Therefore, management should employ supportive therapy—especially in pregnancy, where symptoms may be exaggerated and may lead to prematurity or loss of the fetus.

SUGGESTED READING

Advisory Committee on Immunization Practices (ACIP). General recommendations on immunization. MMWR. 1994;43(RR-1):1-38.

Advisory Committee on Immunization Practices (ACIP). Update: Vaccine side effects, adverse reactions, contraindications, and precautions. MMWR. 1996;45(RR-12):2.

American Academy of Pediatrics Committee on Infectious Diseases. Vitamin A treatment of measles. Pediatrics. 1993;91:1014-1015.

American College of Obstetricians and Gynecologists. Immunization during pregnancy. ACOG Technical Bulletin Number 160-October 1991. Int J Gynaecol Obstet. 1993;40:69-79.

ANON. Measles—United States. MMWR. 2000;49:557-560.

Atmar RL, Englund JA, Hammill H. Complications of measles during pregnancy. Clin Infect Dis. 1992;14:217-226.

Eberhart-Phillips JE, Frederick PD, Baron RC, et al. Measles in pregnancy: a descriptive study of 58 cases. Obstet Gynecol. 1993;82:797-801.

Enders G. Paramyxoviruses. In: Baron S, ed. Medical Microbiology. 4th ed. Galveston, Tex: University of Texas Medical Branch; 1996.

Fawzi WW, Chalmers TC, Herrera MG, et al. Vitamin A supplementation and child mortality. A meta-analysis. JAMA. 1993;269:898-903.

Handal GA. Adolescent immunization. Adolesc Med. 2000;11:439-452.

Kacica MA, Venezia RA, Miller J, et al. Measles antibodies in women and infants in the vaccine era. J Med Virol. 1995;45:227-229.

Karp CL, Wysocka M, Wahl LK, et al. Mechanism of suppression of cell-mediated immunity by measles virus. Science. 1996;273:228.

Modlin JF. Measles virus. In: Belshe RB, ed. Human Virology. Littleton, Mass: PSG Publishing; 1984:333-360.

Moroi K, Saito S, Kurata T, et al. Fetal death associated with measles virus infection of the placenta. Am J Obstet Gynecol. 1991;164:1107-1108.

Nagai K, Mori T. Acute disseminated encephalomyelitis with probable measles vaccine failure. Pediatr Neurol. 1999;20:399-402.

Naniche D, Yeh A, Eto D, et al. Evasion of host defenses by measles virus: wild-type measles virus infection interferes with induction of Alpha/Beta interferon production. J Virol. 2000;74:478-484.

Ohsaki M, Tsutsumi H, Takeuchi R, et al. Recent increase in the frequency of infant measles in Japan. Pediatr Int. 2000;42:233-235.

Pardi DS, Tremaine WJ, Sandborn WJ, et al. Early measles virus infection is associated with the development of inflammatory bowel disease. Am J Gastroenterol. 2000;95:1480-1485.

Peltola H, Heinonen O. Frequency of true adverse reactions to measles-mumps-rubella vaccine: a double-blind placebo-controlled trial in twins. Lancet. 1986;1:939-942.

Stein SJ, Greenspoon JS. Rubeola during pregnancy. Obstet Gynecol. 1991;78:925-929.

Tomkins A. Malnutrition, morbidity and mortality in children and their mothers. Proc Nutr Soc. 2000;59: 135-146.

Dr. Larsen is Professor, Department of Obstetrics and Gynecology and Microbiology, and Dean for University Research, Des Moines University, Des Moines, Iowa.

Adapted from Mead PB, Hager WD, Faro S, eds. Protocols for Infectious Disease in Obstetrics and Gynecology. 2nd ed. Malden, Mass: Blackwell Science Inc; 2000.

 

Bryan Larsen. OB/GYN Infection: Measles in pregnancy. Contemporary Ob/Gyn 2000;11:103-115.