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Lecture 38 TORCH Infection in Pregnant Women

Dr. dr. I.B.G. Fajar Manuaba, Sp.OG, MARS Department Obstetric and Gynaecology of Medical Faculty Udayana University

Abstract

Infections have historically been a major cause of maternal and fetal morbidity and mortality worldwide, and they remain so in the 21st century. The unique maternal-fetal vascular connection in some cases serves to protect the fetus from infectious agents, whereas in other instances it provides a conduit for their transmission to the fetus. TORCH infections include infections associated with Toxoplasma, Other organisms (Parvovirus, human immunodeficiency virus, Epstein-Barr virus, herpesviruses 6 and 8, varicella, syphilis, enteroviruses), Rubella, Cytomegalovirus (CMV), and Hepatitis. Despite the recent emphasis in the screening, antibiotic prophylaxis, and management of early-onset many neonates and children yearly experience the consequences of classic perinatal infections

Introduction

Infections have historically been a major cause of maternal and fetal morbidity and mortality worldwide, and they remain so in the 21st century. The unique maternal-fetal vascular connection in some cases serves to protect the fetus from infectious agents, whereas in other instances it provides a conduit for their transmission to the fetus. Maternal serological status, gestational age at the time infection is acquired, the mode of acquisition, and the immunological status of both the mother and her fetus all influence disease outcome.

TORCH is an acronym for a group of congenitally acquired infections that may cause significant morbidity and mortality in neonates. TORCH infections include infections associated with Toxoplasma, Other organisms (Parvovirus, human immunodeficiency virus, Epstein-Barr virus, herpesviruses 6 and 8, varicella, syphilis, enteroviruses), Rubella, Cytomegalovirus (CMV), and Hepatitis. Despite the recent emphasis in the screening, antibiotic prophylaxis, and management of early-onset many neonates and children yearly experience the consequences of classic perinatal infections.

Toxoplasmosis

The obligate intracellular parasite Toxoplasma gondii has a life cycle with two distinct stages. The feline stage takes place in the cat—the definitive host—and its prey. Unsporulated oocysts are secreted in feces. In the non-feline stage, tissue cysts containing bradyzoites or oocysts are ingested by the intermediate host, including humans. Human infection is acquired by eating raw or undercooked meat infected with tissue cysts or by contact with oocysts from cat feces in contaminated litter, soil, or water. Prior infection is confirmed by serological testing, and its prevalence depends on geographic locale and parasite genotype.

Most acute maternal infections are subclinical and are detected only by prenatal or newborn serological screening. In some cases, maternal symptoms may include fatigue, fever, headache, muscle pain, and sometimes a maculopapular rash and

posterior cervical lymphadenopathy. The incidence and severity of fetal toxoplasmosis infection depend on gestational age at the time of maternal infection. Risks for fetal infection increase with pregnancy duration A metaanalysis estimated the risk to be 15 percent at 13 weeks, 44 percent at 26 weeks, and 71 percent at 36 weeks. Conversely, the severity of fetal infection is much greater in early pregnancy, and these fetuses are much more likely to have clinical findings of infection.

Pregnant women suspected of having toxoplasmosis should be tested. The parasite is rarely detected in tissue or body fluids. Anti-toxoplasma IgG develops within 2 to 3 weeks after infection, peaks at 1 to 2 months, and usually persists for life—sometimes in high titers. Although IgM antibodies appear by 10 days after infection and usually become negative within 3 to 4 months, they may remain detectable for years. Thus, IgM antibodies should not be used alone to diagnose acute toxoplasmosis. IgA and IgE antibodies are also useful in diagnosing acute infection. Toxoplasma IgG avidity increases with time. Thus, if a high-avidity IgG result is found, infection in the preceding 3 to 5 months is excluded. Multiple commercial avidity tests are now available that provide a 100-percent positive predictive value of high avidity confirming latent infection.

No randomized clinical trials have been performed to assess the benefit and efficacy of treatment to decrease the risk for congenital infection. A systematic review of data from 1.438 treated pregnancies found weak evidence for early treatment to reduce congenital toxoplasmosis risks. Treatment has been associated with a reduction in rates of serious neurological sequelae and neonatal demise.

Prenatal treatment is based on two regimens—spiramycin alone or a pyrimethamine– sulfonamide combination with folinic acid. These two regimens have also been used consecutively. Little evidence supports the use of a specific regimen. That said, most experts will use spiramycin in women with acute infection early in pregnancy. Pyrimethamine–sulfadiazine with folinic acid is selected for maternal infection after 18 weeks or if fetal infection is suspected.

with folinic acid is selected for maternal infection after 18 weeks or if fetal infection is
Parvovirus Human parvovirus B19 causes erythema infectiosum, or fifth disease. The B19 virus is a

Parvovirus

Human parvovirus B19 causes erythema infectiosum, or fifth disease. The B19 virus is a small, single-stranded DNA virus that replicates in rapidly proliferating cells such as erythroblast precursors. This can lead to anemia, which is its primary fetal effect. Only individuals with the erythrocyte globoside membrane P antigen are susceptible. In women with severe hemolytic anemia—for example, sickle-cell disease— parvovirus infection may cause an aplastic crisis.

In 20 to 30 percent of adults, infection is asymptomatic. Fever, headache, and flu-like symptoms may begin in the last few days of the viremic phase. Several days later, a bright red rash with erythroderma affects the face and gives a

slappedcheekappearance. The rash becomes lacelike and spreads to the trunk and extremities. Adults often have milder rashes and develop symmetrical polyarthralgia that may persist several weeks.

There is vertical transmission to the fetus in up to a third of maternal parvovirus infections Fetal infection has been associated with abortion, nonimmune hydrops, and stillbirth. In a review of 1089 cases of maternal B19 infection from nine studies, Crane (2002) reported an overall fetal loss rate of 10 percent. It was 15 percent for infections before 20 weeks but was only 2.3 percent after 20 weeks.

Depending on gestational age, fetal transfusion for hydrops may improve outcome in some cases. Mortality rates as high as 30 percent have been reported in hydropic fetuses without transfusions. With transfusion, 94 percent of hydrops cases resolve within 6 to 12 weeks, and the overall mortality rate is < 10 percent. Most fetuses require only one transfusion because hemopoiesis resumes as infection resolves.

There is currently no approved vaccine for human parvovirus B19, and there is no evidence that antiviral treatment prevents maternal or fetal infection. Decisions to avoid higher-risk work settings are complex and require assessment of exposure risks. Pregnant women should be counseled that risks for infection approximate 5 percent for casual, infrequent contact; 20 percent for intense, prolonged work exposure such as for teachers; and 50 percent for close, frequent interaction such as in the home. Workers at day-care centers and schools need not avoid infected children because infectivity is greatest before clinical illness. Finally, infected children do not require isolation.

Finally, infected children do not require isolation. Rubella—German Measles This RNA togavirus typically causes

Rubella—German Measles

This RNA togavirus typically causes infections of minor importance in the absence of pregnancy. Rubella infection in the first trimester, however, poses significant risk for abortion and severe congenital malformations. Transmission occurs via nasopharyngeal secretions, and the transmission rate is 80 percent to susceptible individuals. The peak incidence is late winter and spring.

Maternal rubella infection is usually a mild, febrile illness with a generalized maculopapular rash beginning on the face and spreading to the trunk and extremities.

Other symptoms may include arthralgias or arthritis, head and neck lymphadenopathy,and conjunctivitis. The incubation period is 12 to 23 days. Viremia usually precedes clinical signs by about a week, and adults are infectious during viremia and through 5 to 7 days of the rash. Up to half of maternal infections are subclinical despite viremia that may cause devastating fetal infection.

Rubella may be isolated from the urine, blood, nasopharynx, and cerebrospinal fluid for up to 2 weeks after rash onset. The diagnosis is usually made, however, with serological analysis. Specific IgM antibody can be detected using enzyme-linked immunoassay from 4 to 5 days after onset of clinical disease, but it can persist for up to 6 weeks after appearance of the rash. Importantly, rubella reinfection can give rise to transient low levels of IgM. Serum IgG antibody titers peak 1 to 2 weeks after rash onset. This rapid antibody response may complicate serodiagnosis unless samples are initially collected within a few days after the onset of the rash. If, for example, the first specimen was obtained 10 days after the rash, detection of IgG antibodies would fail to differentiate between very recent disease and preexisting immunity to rubella. IgG avidity testing is performed concomitant with the serological tests above. High- avidity IgG antibodies indicate an infection at least 2 months in the past.

Rubella is one of the most complete teratogens, and sequelae of fetal infection are worst during organogenesis. Pregnant women with rubella infection and a rash during the first 12 weeks of gestation have a fetus with congenital infection in up to 90 percent of cases At 13 to 14 weeks’ gestation, this incidence was 54 percent, and by the end of the second trimester, it was 25 percent. Defects are rare after 20 weeks.

There is no specific treatment for rubella. Droplet precautions for 7 days after the onset of the rash are recommended. Primary prevention relies on comprehensive vaccination programs. To eradicate rubella and prevent congenital rubella syndrome completely, a comprehensive approach is recommended for immunizing the adult population. MMR vaccine should be offered to nonpregnant women of childbearing age who do not have evidence of immunity whenever they make contact with the health-care system. Vaccination of all susceptible hospital personnel who might be exposed to patients with rubella or who might have contact with pregnant women is important. Rubella vaccination should be avoided 1 month before or during pregnancy because the vaccine contains attenuated live virus. Although there is a small overall theoretical risk of up to 2.6 percent, there is no observed evidence that the vaccine induces malformations. MMR vaccination is not an indication for pregnancy termination. Prenatal serological screening for rubella is indicated for all pregnant women. Women found to be nonimmune should be offered the MMR vaccine postpartum.

Cytomegalovirus This ubiquitous DNA herpes virus eventually infects most humans. Cytomegalovirus (CMV) is the most

Cytomegalovirus

This ubiquitous DNA herpes virus eventually infects most humans. Cytomegalovirus (CMV) is the most common perinatal infection in the developed world. Specifically, some evidence of fetal infection is found in 0.2 to 2.5 percent of all neonates. The virus is secreted into all body fluids, and person-to-person contact with viral-laden saliva, semen, urine, blood, and nasopharyngeal and cervical secretions can transmit infection. The fetus may become infected by transplacental viremia, or the neonate is infected at delivery or during breast feeding.

Primary maternal CMV infection is transmitted to the fetus in approximately 40 percent of cases and can cause severe morbidity. In contrast, recurrent maternal infection infects the fetus in only 0.15 to 1 percent of cases. A review of nine studies of CMV vertical transmission rates reported first-trimester transmission in 36 percent, second- trimester in 40 percent, and third-trimester in 65 percent. Naturally acquired immunity during pregnancy results in a 70-percent risk reduction of congenital CMV infection in future pregnancies. However, as noted earlier, maternal immunity does not prevent recurrences, and maternal antibodies do not prevent fetal infection. Also, some seropositive women can be reinfected with a different viral strain that can cause fetal infection and symptomatic congenital disease. Routine prenatal CMV serological screening is currently not recommended. Pregnant women should be tested for CMV if they present with a mononucleosis-like illness or if congenital infection is suspected based on abnormal sonographic findings. Primary infection is diagnosed using CMV-specific IgG testing of paired acute and convalescent sera. CMV IgM does not accurately reflect timing of seroconversion because IgM antibody levels may be elevated for more than a year. Moreover, CMV IgM may be found with reactivation disease or reinfection with a new strain. Thus, specific CMV IgG avidity testing is valuable in confirming primary CMV infection. High anti-CMV IgG avidity indicates primary maternal infection > 6 months before testing. Finally, viral culture may be useful, although a minimum of 21 days is required before culture findings are considered negative.

Several fetal abnormalities associated with CMV infection may be seen with sonography, computed tomography, or magnetic resonance imaging. In some cases, they are found at the time of routine prenatal sonographic screening, but in others they are part of a specific evaluation in women with CMV infection. Findings include microcephaly, ventriculomegaly, and cerebral calcifications; ascites, hepatomegaly, splenomegaly, and hyperechoic bowel; hydrops; and oligohydramnios.

The management of the immunocompetent pregnant woman with primary or recurrent CMV is limited to symptomatic treatment. If recent primary CMV infection is confirmed, amnionic fluid analysis should be offered. Counseling regarding fetal outcome depends on the gestation age during which primary infection is documented. Even with the high infection rate with primary infection in the first half of pregnancy, most fetuses develop normally.

There is no CMV vaccine. Prevention of congenital infection relies on avoiding maternal primary infection, especially in early pregnancy. Basic measures such as good hygiene and hand washing have been promoted, particularly for women with toddlers in day-care settings. Although there may be sexual transmission from infected partners, there are no data on the efficacy of preventive strategies.

there are no data on the efficacy of preventive strategies. Hepatitis B Chronic hepatitis B virus

Hepatitis B

Chronic hepatitis B virus (HBV) infection is estimated to affect >350 million people worldwide and represents a significant cause of morbidity and mortality related to cirrhosis and hepatocellular carcinoma. Mother-to-child transmission (MTCT) of HBV remains an important source of incident cases of HBV. Current barriers to eradication of incident HBV infections via MTCT include underutilization of immunoprophylaxis with hepatitis B vaccination and hepatitis B immune globulin in certain endemic regions as well as failure of immunoprophylaxis.

Hepatitis B perinatal transmission remains a common mode of viral transmission, especially in highly endemic areas globally.The availability over the past decade of effective oral agents that suppress viral replication has allowed the consideration of thirdtrimester treatment to reduce the risk of this transmission. This is important, particularly in pregnant women with very high viral levels (>108 copies/mL or 2 × 107 IU/mL), in whom the risk is highest, but transmission can occur even at levels >200

000 IU/mL. Treatment decisions necessitate careful discussion of risks and benefits as emerging data suggest some possible effect on bone mineral concentration in tenofovir-exposed pregnant women, which must be balanced by a nearly 10% risk of chronic infection with an incurable virus. Pregnant women with HBV must be monitored for clinical flares, with or without medications, and breastfeeding should be allowed as well.

In the absence of HBV immunoprophylaxis, 10 to 20 percent of women positive for HBsAg transmit viral infection to their infant. This rate increases to almost 90 percent if the mother is HBsAg and HBeAg positive. Immunoprophylaxis and hepatitis B vaccine given to infants born to HBV-infected mothers has decreased transmission dramatically and prevented approximately 90 percent of infections.

Hepatitis C

Hepatitis C virus (HCV) is a well known cause of chronic liver disease in adults, but the burden of HCV in pregnant women and children is underappreciated. The leading route of HCV acquisition in children is vertical transmission.

Women with chronic HCV infection often have uneventful pregnancies without worsening of liver disease or other maternal or infant adverse effects; some women mayeven have improvement. For example, in a series of 266 pregnant women infected with HCV, elevated serum alanine aminotransferase (ALT) levels were detected in 56% of women at the beginning of pregnancy but only 7% during the third trimester. However, 55% of women returned to elevated ALT levels by 6 months postpartum. Such changes may be due to the significant changes in the maternal immune system during pregnancy.

Infants born to women infected with HCV were more likely to be low birth weight, small for gestational age, and require neonatal intensive care and assisted ventilation. In the same cohort, women infected with HCV had an increased risk for gestational diabetes but only when combined with excessive gestational weight gain.

There is currently no licensed vaccine for HCV prevention. The chronic HCV infection treatment has traditionally included alpha interferon (standard and pegylated), alone or in combination with ribavirin. This regimen is contraindicated in pregnancy because of the teratogenic potential of ribavirin in animals.

Learning task

1. What is IgG avidity ? Who important this result for the treatment scenario ?

2. Describe about indication, side effect, effective dose, contra indication of spiramycin ?

3. How to protect pregnant women from Parvovirus infection ?

4. Describe about MMR vaccination ?

5. How to protect pregnant women from Cytomegalovirus infection ?

Self assement

1. Explain how to manage pregnant women with human immunodeficiency virus ?

2. Explain how to manage pregnant women with Epstein-Barr virus ?

3. Explain how to manage pregnant women with herpesviruses 6 and 8 ?

4. Explain how to manage pregnant women with varicella ?

5.

Explain how to manage pregnant women with syphilis ?

6. Explain how to manage pregnant women with enteroviruses ?