This ubiquitous DNA herpesvirus eventually infects most humans. It is the most common cause of perinatal infection, found in 0.2 to 2 percent of all newborn infants. The virus is transmitted horizontally by droplet infection via saliva and urine, as well as vertically from mother to fetus-infant. It can also be transmitted sexually. Daycare centers are a common source of infection. Usually by 2 to 3 years of age, children acquire the infection from one another and then transmit it to their parents.
Following primary infection, the virus becomes latent, and like other herpesvirus infections, there is periodic reactivation with viral shedding despite the presence of serum antibody. Immunosuppressed states increase the propensity for serious cytomegalovirus infection.
There is no evidence that pregnancy increases the risk or clinical severity of maternal cytomegalovirus infection. Most infections are asymptomatic, but about 15 percent of adults have a mononucleosis-like syndrome characterized by fever, pharyngitis, lymphadenopathy, and polyarthritis. The risk of seroconversion among susceptible women during pregnancy is from 1 to 4 percent. Primary infection, which is transmitted to the fetus in approximately 40 percent of cases, more often is associated with severe fetal morbidity. Transmission to the fetus is more likely in the first half of pregnancy than in late gestation.
As with other herpesviruses, maternal immunity to cytomegalovirus does not prevent recurrence (reactivation), nor unfortunately does it prevent congenital infection. Recurrent maternal infection results in fetal infection in 0.15 to 1 percent of cases. In fact, because most infections during pregnancy are recurrent, the majority of congenitally infected neonates are born to these women. Fortunately, congenital infections that result from recurrent infection are less often associated with clinically apparent sequelae than are those from primary infections.
Congenital infection causes cytomegalic inclusion disease, a syndrome that includes low birth weight, microcephaly, intracranial calcifications, chorioretinitis, mental and motor retardation, sensorineural deficits, hepatosplenomegaly, jaundice, hemolytic anemia, and thrombocytopenic purpura. These findings are seen in only 5 to 6 percent of infected neonates.
Primary infection is diagnosed by seroconversion of CMV IgG in paired acute and convalescent sera measured simultaneously or preferentially by detecting maternal IgM cytomegalovirus antibody. Unfortunately, CMV IgM maybe present with primary infection, recurrent infection or reactivation of infection. Figure 86-1 details the algorithm for CMV laboratory diagnosis. CMV IgG avidity testing is valuable in confirming primary CMV infection.
FIGURE 86-1 Algorithm for evaluation of suspected maternal primary cytomegalovirus (CMV) infection in pregnancy. EIA, enzyme immunoassay; IgG, immunoglobulin G; IgM, immunoglobulin M.
In some cases, effects of fetal infection are detected by sonography. Microcephaly, ventriculomegaly, or cerebral calcifications may be seen. Hyperechoic bowel, ascites, hepatosplenomegaly and hydrops have also been described. Amnionic fluid nucleic acid amplification testing is now the gold standard for the diagnosis of fetal infection.
Counseling regarding fetal outcome depends on the stage of gestation during which primary infection is documented. The majority of infants develop normally even with primary infections in the first half of pregnancy.
Currently, there is no effective therapy for maternal infection. Passive immunization with CMV-specific hyperimmune globulin has shown promise in lowering the risk of congenital CMV infection when given to pregnant women with primary disease. Further trials are ongoing.
HUMAN PARVOVIRUS B19
Human B19 parvovirus causes erythema infectiosum, or fifth disease. Parvovirus B19 is a small, single-stranded DNA virus that replicates in rapidly proliferating cells, such as erythroblast precursors. It is transmitted by respirating droplet or hand-to-mouth contact. Viremia occurs during the prodrome, which is followed by clinical features, including a bright red macular rash and erythroderma that affects the face giving a slapped cheekappearance. Adults usually have milder rashes and may develop symmetrical polyarthralgia. In 20 to 30 percent of adults, the infection is asymptomatic.
Maternal infection may be associated with abortion and fetal death, with highest losses when infections occur before 20 weeks. An infected fetus may develop profound anemia with associated high output cardiac failure and nonimmune hydrops. This occurs in 1 percent of infected women.
The management protocol used at Parkland Hospital is depicted in Figure 86-2. Diagnosis is confirmed by parvovirus-specific IgM antibodies. Viral DNA may be detectable in serum during the prodrome but not after the rash develops. For women with positive serology, ultrasonic examination is indicated. If there is hydrops, either fetal transfusion or conservative management is considered. Approximately a third of fetuses with hydrops have spontaneous resolution, and 85 to 95 percent of hydropic fetuses who receive intrauterine transfusion survive.
FIGURE 86-2 Algorithm for evaluation and management of human parvovirus B19 infection in pregnancy. CBC, complete blood count; IgG, immunoglobulin G; IgM, immunoglobulin M; MCA, middle cerebral artery; PCR, polymerase chain reaction; RNA, ribonucleic acid.
Varicella-zoster virus is a member of the DNA herpesvirus family, and almost 95 percent of adults are immune. Primary infection causes chickenpox, which has an attack rate of 60 to 95 percent in seronegative individuals. In the healthy woman, the typical maculopapular and vesicular rash is accompanied by constitutional symptoms and fever for 3 to 5 days. Varicella infection in adults tends to be much more severe than in children.
Although secondary skin infection with streptococci or staphylococci is the most common complication of chickenpox, varicella pneumonia is the most serious. It develops in about 5 percent of adults. It usually appears 3 to 5 days into the course of the illness and is characterized by tachypnea, a dry cough, dyspnea, fever, and pleuritic chest pain. Chest x-ray discloses characteristic nodular infiltrates and interstitial pneumonitis. In fatal cases, the lungs show scattered areas of necrosis and hemorrhage. Treatment for varicella pneumonia consists of oxygenation, assisted ventilation if necessary, and intravenous acyclovir, 500 mg/m2 or 10 to 15 mg/kg every 8 hours.
Maternal chickenpox during the first half of pregnancy may cause congenital malformations. Some of these include chorioretinitis, cerebral cortical atrophy, hydronephrosis, microcephaly, microphthalmia, dextrocardia, and cutaneous and bony leg defects. Congenital infection is rare if maternal infection occurs after 20 weeks. The highest risk is between 13 and 20 weeks, with an absolute risk of embryopathy of 2 percent.
Fetal exposure to the virus just before or during delivery, and therefore before maternal antibody has been formed, poses a serious threat to the newborn infant. Varicella-zoster immune globulin is administered to the neonate whenever the onset of maternal disease is within about 5 days before or after delivery. This immune globulin, VariZIG, is available through FFF Enterprises under an expanded access protocol.
Management and Prevention
An obstetric protocol for management of varicella exposure is detailed in Table 86-1. Administration of VariZIG will possibly prevent or attenuate varicella infection if given within 96 hours.
TABLE 86-1. Management of Obstetric Patients Exposed to Varicella
An attenuated live-virus vaccine (Varivax) has been available for use since 1995 but is not recommended for pregnant women. The vaccine for the prevention of herpes zoster (Zostavax) licensed in 2006 is not recommended for women younger than 60 years.
Also called German measles, rubella virus typically causes minor infections in the absence of pregnancy. During pregnancy, however, it has been directly responsible for abortion and severe congenital malformations.
Viremia precedes clinically evident disease by about 1 week. Twenty to fifty percent of infected women are asymptomatic. Disease manifests with lymphadenopathy, fever, malaise, and arthralgia. A maculopapular rash may be present, which begins on the face and spreads to the trunk and extremities.
As the duration of pregnancy advances, fetal infections are less likely to cause congenital malformations, with most sequelae seen before 20 weeks. Congenital rubella syndrome includes one or more of the findings listed in Table 86-2. Infants born with congenital rubella may shed the virus for many months and thus be a threat to other infants, as well as to susceptible adults who come in contact with them.
TABLE 86-2. Congenital Rubella Syndrome
The extended rubella syndrome, with progressive panencephalitis and type 1 diabetes mellitus, may not develop clinically until the second or third decade of life. Perhaps as many as a third of infants who are asymptomatic at birth may manifest such developmental injury later in life. Other late sequelae reported are thyroid disease, ocular damage, and mental retardation.
To eradicate the disease completely, the following approach is recommended for immunizing women of childbearing age:
1. Education of health-care providers and the general public on the dangers of rubella infection
2. Vaccination of susceptible women as part of routine gynecological care
3. Vaccination of susceptible women visiting family planning clinics
4. Vaccination of unimmunized women immediately after childbirth or abortion
5. Vaccination of nonpregnant susceptible women identified by premarital serology
6. Vaccination of all susceptible hospital personnel who might be exposed to patients with rubella or who might have contact with pregnant women
Rubella vaccination should be avoided shortly before or during pregnancy because the vaccine contains attenuated live virus. However, there is no evidence that the vaccine induces malformations.
Toxoplasma gondii is transmitted to pregnant women through encysted organisms by eating infected raw or undercooked beef or pork and through contact with oocytes in infected cat feces. The fetus can be infected transplacentally. Maternal immunity appears to protect against fetal infection; thus, for congenital toxoplasmosis to develop, the mother must have acquired the infection during pregnancy.
Symptoms include fatigue, muscle pains, fever, chills, maculopapular rash, and sometimes lymphadenopathy. Most often, toxoplasmosis infection is subclinical. Infection in pregnancy may cause abortion or result in a liveborn infant with evidence of the disease.
The incidence and severity of congential infection depends on gestation age. The risk of fetal infection increases as pregnancy advances, but the severity decreases. Overall, less than a fourth of infected newborns with congenital toxoplasmosis have evidence of clinical illness at birth. Later, however, most go on to develop some sequelae of infection. Clinically affected infants at birth usually have evidence of generalized disease with low birth weight, hepatosplenomegaly, icterus, and anemia. Some primarily have neurological disease, with convulsions, intracranial calcifications, mental retardation, and hydrocephaly or microcephaly. Almost all infected infants eventually develop chorioretinitis.
Routine screening for toxoplasmosis in the United States is not recommended, except for pregnant women with human immunodeficiency virus (HIV) infection. Antitoxoplasma IgG develops and persists for life. IgG avidity testing is useful to determine how recent the infection occurred. Antitoxoplasma IgM may remain positive for years. The best testing regimen is obtained using a Toxoplasma Serologic Profile performed at the Palo Alto Medical Foundation Research Institute (1-650-853-4828). Prenatal diagnosis is performed using amniotic fluid DNA amplification techniques and sonographic evaluation.
For women thought to have active toxoplamosis, antimicrobial treatment is recommended. Spiramycin is thought to reduce the risk of congenital infection but not to treat established fetal infection. Treatment with pyrimethamine, sulfonamides, and folinic acid is used to treat fetal infection.
Listeria monocytogenes is an uncommon but underdiagnosed cause of neonatal sepsis. This gram-positive, aerobic, motile bacillus can be isolated from soil, water, and sewage. One to five percent of adults carry Listeria in their feces. Food-borne transmission is important, and outbreaks of listeriosis have been reported from raw vegetables, coleslaw, apple cider, melons, smoked fish, delicatessen meats, milk, and fresh Mexican-style cheese.
Listeriosis during pregnancy may be asymptomatic or cause a febrile illness that is confused with influenza, pyelonephritis, or meningitis. Occult or clinical infection also may stimulate labor and be a cause of fetal death. Maternal lister-emia causes fetal infection that characteristically produces disseminated granulomatous lesions with microabscesses in the placenta.
The newborn infant is particularly susceptible to infection, and mortality approaches 20 percent. Early-onset neonatal sepsis presents with respiratory distress, fever and/or neurological abnormalities. Late-onset listeriosis manifests after 5 to 7 days of life as meningitis.
The diagnosis relies on clinical suspicion and positive blood cultures.
A combination of ampicillin and gentamicin is usually recommended because of proven synergism. Trimethoprim-sulfamethoxazole is also effective and should be given to penicillin-allergic women. Antimicrobial treatment may also be effective for treatment of fetal infection.
There are four species of Plasmodium that cause human malaria: vivax, ovale, malariae, and falciparum. Organisms are transmitted by the bite of the female Anopheles mosquito. Nearly 350 to 500 million persons worldwide are infected at any given time, and the disease causes 1 million deaths annually.
Malarial episodes increase by three- to fourfold during the latter two trimesters of pregnancy and 2 months postpartum. Pregnancy enhances the severity of falciparum malaria, especially in nonimmune, nulliparous women. The incidence of abortion and preterm labor is increased with malaria. Stillbirths may be caused by placental and fetal infection. The malaria parasites have an affinity for decidual vessels and may involve the placenta extensively without affecting the fetus. Neonatal infection is uncommon, with congenital malaria developing in up to 7 percent of neonates born to nonimmune mothers.
The disease is characterized by fever and flu-like symptoms, including chills, headaches, myalgia, and malaise, which may occur at intervals. Symptoms are less severe with recurrences. Malaria may be associated with anemia and jaundice, and falciparum infections may cause kidney failure, coma, and death.
The diagnosis is based on clinical features and the identification of the intracellular malaria organisms on a blood smear.
Commonly used antimalarial drugs are not contraindicated during pregnancy. Some of the newer antimalarial agents have anti–folic acid activity and may theoretically contribute to the development of megaloblastic anemia; however, in actual practice, this does not appear to be the case. Chloroquine is the treatment of choice for all forms of sensitive plasmodium species. For women with chloroquine-resistant infection, quinine plus clindamycin is currently recommended. Mefloquine or atovaquone-proguanil are not currently recommended for treatment during pregnancy, although mefloquine is still recommended for chemoprophylaxis. The Centers for Disease Control and Prevention maintain a malaria hotline for treatment recommendations (770-488-7788).
Chemoprophylaxis is recommended for pregnant women traveling to areas in which malaria is endemic. If chloroquine-resistant malaria has not been reported, prophylaxis is initiated 1 to 2 weeks before the endemic area is entered. Chloroquine, 300 mg of base (500 mg salt), is given orally once a week, and this is continued until 4 weeks after return to nonendemic areas. Travel to areas endemic for chloroquine-resistant strains is discouraged during early pregnancy, after which mefloquine prophylaxis may be given.
For further reading in Williams Obstetrics, 23rd ed.,
see Chapter 58, “Infectious Diseases.”