Congenital Fetal Infections - Current Diagnosis & Treatment Obstetrics & Gynecology, 11th Ed.

Current Diagnosis & Treatment Obstetrics & Gynecology, 11th Ed.

15. Congenital Fetal Infections

Unzila Nayeri, MD

Stephen Thung, MD

PARVOVIRUS

ESSENTIALS OF DIAGNOSIS

Caused by parvovirus B19, a single-stranded DNA virus

Clinical manifestations: commonly asymptomatic, erythema infectiosum, systemic symptoms (fever, arthropathy, malaise), or aplastic crises

Complications in pregnancy: fetal demise, fetal anemia, hydrops fetalis

Diagnosis: serologic tests (immunoglobulin [Ig] G and IgM antibodies); serum viral DNA polymerase chain reaction

Antenatal sonographic findings: fetal anemia, hydrops, elevated middle cerebral artery peak systolic velocity

Fetal diagnosis: cordocentesis

Fetal treatment: intrauterine blood transfusion

Pathogenesis

Parvovirus B19 infection, a common childhood infection, tends to be more frequent in late winter or early spring. The infection is caused by a single-stranded DNA virus, the B19 parvovirus, which is transmitted through respiratory secretions and hand-to-mouth contact. The virus has a predilection for rapidly dividing cells such as erythroid progenitor cells.

Prevalence of seropositivity increases with age, and about 50–60% of reproductive-aged women have documented antibodies to parvovirus B19 consistent with prior infection. Immunity is considered lifelong, although reinfection has been documented. The incidence of acute parvovirus infection during pregnancy is 3.3–3.8%. Schoolteachers, day care workers, and homemakers are most susceptible. Nonimmune individuals exposed in a classroom have a 20–30% risk of infection. The secondary attack rate for household members is up to 50%.

During pregnancy, the virus can cross the placenta and infect red cell progenitors in the fetal bone marrow. The virus suppresses erythropoiesis by attaching to the “P” antigen on red cell stem cells. This results in severe anemia and high-output congestive heart failure. In addition to the reduced survival of fetal red blood cells, anemia is further complicated by the increased demands of an expanding intravascular volume and the inability of the immature immune system to control the infection. Additionally, the virus can attack fetal myocardiocytes via the same “P” antigen and cause a cardiomyopathy, further exacerbating the congestive heart failure.

Prevention

Pregnant women who are susceptible to parvovirus B19 should avoid contact with known infected individuals. However, since 20% of infections are subclinical, exposure cannot be eliminated by identifying and excluding individuals with acute parvovirus B19 infection. Additionally, those with infection are infectious prior to the onset of symptoms. Therefore, a policy to routinely remove women from occupations considered high risk, such as day care attendants, is not recommended. On the other hand, patients should be counseled on careful hand washing and avoidance of sharing food and drink.

Clinical Findings

A. Symptoms & Signs (Table 15–1)

Parvovirus B19 causes the common childhood illness erythema infectiosum (also known as “fifth disease”). Erythema infectiosum is characterized by a low-grade fever, malaise, arthralgias, and a “slapped cheek” facial rash. Patients may also present with a “lace-like” erythematous rash on the trunk and extremities. The incubation period for parvovirus is 10–20 days. Although the typical rashes are more common in children, adults may also present with dermatologic manifestations.

Table 15–1. Clinical manifestations of parvovirus.

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Systemic symptoms are noted 1–4 days prior to the onset of the rash. These symptoms include fever, malaise, and arthropathy, which is more common in adults. Patients with hemoglobinopathies such as sickle cell anemia are at risk for aplastic crises, which are usually self-limited. Patients infected with this virus are considered infectious 5–10 days following exposure up to the onset of symptoms. Once the rash presents, individuals are no longer infectious.

B. Laboratory Findings

Serologic testing is used to diagnose maternal parvovirus infection. Immunoglobulin (Ig) M antibody capture radioimmunoassay and enzyme-linked immunosorbent assay (ELISA) are commonly used, with sensitivities ranging from 80–90%. There are various possible combinations of serologic test results that indicate varying disease states (Table 15–2). IgM antibodies are detected 7–10 days after exposure, peak at 10–14 days, and remain positive for several months. Indicating prior infection, IgG antibodies present several days after IgM, plateau at 4 weeks, and persist for many years. When both IgM and IgG are positive, establishing the exact timing of infection is difficult.

Table 15–2. Possible serologic test results for parvovirus.

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Polymerase chain reaction (PCR) assays may also be used to detect viral B19 DNA. In patients with a history of significant exposure and negative IgM serologies, PCR may be used to clarify the diagnosis because it is a sensitive method of detecting small amounts of viral DNA.

Fetal parvovirus infection is diagnosed using PCR analysis of viral B19 DNA in amniotic fluid obtained via amniocentesis. The more invasive method of percutaneous fetal blood sampling can also be used to directly test fetal blood for B19 IgM. This approach is rarely used because it is associated with a fetal loss rate of 1%.

Pregnant patients who have been exposed to parvovirus infection should undergo serologic testing for IgG and IgM antibodies. A woman with a positive IgG and a negative IgM antibody has had a prior infection and is therefore immunized. A positive IgM antibody indicates an acute or subacute parvovirus infection, depending on the IgG status. An infection that occurs during pregnancy and prior to 20 weeks increases the risk for fetal loss. On the other hand, infection after 20 weeks has a lower risk of fetal loss, yet infection remains associated with fetal anemia and hydrops. Patients should undergo serial ultrasound every 2 weeks for at least 10 weeks after the initial exposure to evaluate for evolving fetal hydrops from high-output cardiac failure. The ultrasound should also evaluate the fetus for severe fetal anemia by measuring the middle cerebral artery peak systolic flow (Fig. 15–1).

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Figure 15–1. 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. (Reproduced, with permission, from Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Rouse DJ, Spong CY. Williams Obstetrics. 23rd ed. http://www.accessmedicine.com. Copyright © The McGraw-Hill Companies, Inc. All rights reserved.)

A pregnant woman who is negative for IgG and IgM is susceptible to infection. Therefore, in the case of a recent parvovirus exposure, additional testing with PCR of maternal blood for B19 DNA should be pursued given the possibility of false-negative serologies. The patient should also undergo repeat serologic testing in 3 weeks since IgM antibodies should eventually present in a true infection.

C. Imaging Studies

Ultrasound is a useful tool to screen for fetal anemia and hydrops. Sonographic signs of hydrops include fetal skin edema, ascites, or pleural or pericardial effusions. Doppler velocimetry of the fetal middle cerebral artery is considered an accurate tool to screen for severe fetal anemia (Fig. 15–2). Increases in the peak systolic velocity correlate with worsening fetal anemia. Suspected severe fetal anemia should be confirmed via cordocentesis, at which time therapeutic fetal blood transfusion may be performed.

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Figure 15–2. Middle cerebral artery Doppler images showing elevated peak systolic velocity.

Differential Diagnosis

Rubella

Enteroviruses

Arboviruses

Streptococcal infection

Allergy

Drug reactions

In the setting of fetal hydrops:

Immune hydrops (Rh isoimmunization)

Nonimmune hydrops

Structural defects (cardiac tumors, neck masses, intracranial hemorrhage, etc)

Anemia (due to glucose-6-phosphate dehydrogenase deficiency, fetomaternal hemorrhage etc)

Infection (cytomegalovirus, syphilis, Toxoplasma, etc) Genetic disorders

Placental disorders (chorangioma, chronic vein thrombosis)

Complications

Parvovirus infection in pregnancy has been linked to intrauterine fetal demise in the late second and third trimester. The risk of fetal loss in pregnancies infected prior to 20 weeks of gestation is 11%. The risk dramatically decreases to less than 1% if infection occurs after 20 weeks’ gestation. Experts recommend that a workup for parvovirus be included in the evaluation of these intrauterine fetal demises.

In addition to causing fetal loss, the virus may lead to anemia and subsequent hydrops fetalis. The median interval between diagnosis of maternal infection and hydrops is 3 weeks. Fifty percent of cases occur within 2–5 weeks of maternal infection, and 93% of fetal manifestations occur within 8 weeks. The risk of anemia with hydrops depends on the gestational age at which maternal infection occurs. If infection occurs during the first 12 weeks of pregnancy, the risk of hydrops is 5–10%. This risk decreases to less than 5% if infection develops during weeks 13–20. After week 20 of gestation, the risk of hydrops is less than 1%. Hydropic fetuses with parvovirus are also at risk for severe thrombocytopenia. Despite studies linking parvovirus to teratogenicity in fetal animals and case reports of human infection and subsequent fetal malformations, most data suggest that parvovirus B19 is not a teratogen.

Treatment

Mild to moderate anemia is generally well tolerated by the fetus and resolves without sequelae. However, severe anemia can lead to hydrops fetalis and death. If severe anemia is suspected based on elevated Doppler middle cerebral artery peak systolic velocity or signs of hydrops, the fetal hematocrit should be assessed by percutaneous umbilical vein sampling (cordocentesis). Confirmed fetal anemia should be treated with intrauterine blood transfusion. The fetal platelet count should also be determined because the fetus is at risk for thrombocytopenia. Platelets should be available at the time of transfusion. Although there is a risk of fetal death after periumbilical blood sampling, multiple retrospective studies have demonstrated the benefit of such a procedure in hydropic fetuses with parvovirus infection. Usually, only 1 intrauterine transfusion is required because hematopoiesis recovers as the parvovirus infection is cleared.

The delivery of a neonate with hydrops should occur in a tertiary care setting to maximize pregnancy outcome. These infants generally require respiratory assistance with mechanical ventilation and may also require abdominal paracentesis and thoracocentesis of fetal ascites and pleural effusions to aid in resuscitation. Postnatal outcomes depend on gestational age, illness severity, and associated conditions.

Prognosis

Although parvovirus B19 infection during pregnancy is associated with fetal loss and hydrops fetalis, most intrauterine parvovirus infections have an excellent long-term prognosis. Historically, the mortality rate of fetal hydrops was close to 30%. With intrauterine transfusion therapy, over 90% of fetuses who require and survive these transfusions recover within 6–12 weeks with an overall mortality rate of less than 10%. Long-term neurologic and psychomotor outcomes of infants following intrauterine blood transfusion for hydrops have been reported. Most studies are reassuring and suggest no neurodevelopmental abnormalities, although the data are limited.

Borna S, Mirzaie F, Hanthoush-Zadeh S, Khazardoost S, Rahimi-Sharbaf F. Middle cerebral artery peak systolic velocity and ductus venosus velocity in the investigation of nonimmune hydrops. J Clin Ultrasound2009;37:385–388. PMID: 19582828

Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Rouse DJ, Spong CY. Chapter 58: infectious diseases. In Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Rouse DJ, Spong CY (eds). Williams Obstetrics. 23rd ed. http://www.accessmedicine.com/content/aspx?aID=6048859. Accessed October 30, 2010.

de Haan TR, van den Akker ES, Porcelijn L, Oepkes D, Kroes AC, Walther FJ. Thrombocytopenia in hydropic fetuses with parvovirus B19 infection: incidence, treatment and correlation with fetal B19 viral load. BJOG2008;115:76–81. PMID: 18053103.

de Jong EP, de Haan TR, Kroes AC, Beersma MF, Oepkes D, Walther FJ. Parvovirus B19 infection in pregnancy. J Clin Virol 2006;36:1–7. PMID: 16488187.

Duff P, Sweet R, Edwards R. Maternal and fetal infections. In Creasy RK, Resnik R, Iams J, et al (eds). Creasy and Resnik’s Maternal-Fetal Medicine: Principles and Practice. 6th ed. Philadelphia, PA: Saunders Elsevier; 2009:775–776.

Enders M, Weidner A, Zoellner I, Searle K, Enders G. Fetal morbidity and mortality after acute human parvovirus B19 infection in pregnancy: prospective evaluation of 1018 cases. Prenat Diagn. 2004;24:513–518. PMID: 15300741.

Ergaz Z, Ornoy A. Parvovirus B19 in pregnancy. Reprod Toxicol. 2006;21:421–435. PMID: 16580942.

Matsuda H, Sakaguchi K, Shibasaki T, Takahashi H, Kawakami Y, Furuya K. Intrauterine therapy for parvovirus B19 infected symptomatic fetus using B19 IgG-rich high titer gammaglobulin. J Perinat Med2005;33:561–563. PMID: 16318623.

Mendelson E, Aboudy Y, Smetana Z, Tepperberg M, Grossman Z. Laboratory assessment and diagnosis of congenital viral infections: rubella, cytomegalovirus (CMV), varicella-zoster virus (VZV), herpes simplex virus (HSV), parvovirus B19 and human immunodeficiency virus (HIV). Reprod Toxicol 2006;21:350–382. PMID: 16564672.

Nagel HT, de Haan TR, Vandenbussche FP, Oepkes D, Walther FJ. Long-term outcome after fetal transfusion for hydrops associated with parvovirus B19 infection. Obstet Gynecol 2007;109:42–47. PMID: 17197586.

Oepkes D, Seaward PG, Vandenbussche FP, et al. Doppler ultrasonography versus amniocentesis to predict fetal anemia. N Engl J Med 2006;355:156–164. PMID: 16837679.

Riley LE, Fernandez CJ. Parvovirus B19 infection in pregnancy. In: Hirsch MS, Edwards MS, Weisman LE, Lockwood CJ (eds). UpToDate. Waltham, MA: UpToDate; 2010. http://www.utdol.com. Accessed September 20, 2010.

Segata M, Chaoui R, Khalek N, Bahado-Singh R, Paidas MJ, Mari G. Fetal thrombocytopenia secondary to parvovirus infection. Am J Obstet Gynecol 2007;196:61.e1–61.e4. PMID: 17240236.

Servey JT, Reamy BV, Hodge J. Clinical presentations of parvovirus B19 infection. Am Fam Physician 2007;75:373–376. PMID: 17304879.

VARICELLA-ZOSTER VIRUS

ESSENTIALS OF DIAGNOSIS

Caused by varicella-zoster virus (VZV), a single-stranded DNA virus

Clinical manifestations: nonspecific prodromal symptoms and vesicular lesions

Prevention: varicella vaccine; immunity following prior infection

Diagnosis: usually clinical but can be confirmed by serologic tests for anti-VZV IgM

Complications of maternal VZV in pregnancy: pneumonia, respiratory failure

Congenital varicella infection: dermatomal scarring, chorioretinitis, limb hypoplasia, microcephaly, low birth weight

Treatment of pregnant women: oral antivirals and, in the case of maternal complications such as pneumonia, intravenous antiviral therapy

Pathogenesis

The varicella-zoster virus (VZV) is a DNA virus that belongs to the herpesvirus family and causes varicella (chickenpox) and herpes zoster (shingles). Although a majority of infections occur in children, 2% of cases occur in adults. In children, the infection is often benign and self-limited, whereas in adults, it can be devastating. Adults over the age of 20 contribute to over half of varicella-related deaths.

The virus is transmitted by respiratory droplets and direct contact with vesicular lesions. Once droplets enter conjunctiva or nasal/oral mucosa, the virus replicates in regional lymph nodes and spreads to internal organs. Secondary viremia occurs as the virus is released into the bloodstream and attacks cutaneous tissue leading to VZV exanthem. Infectivity is present from 1–2 days prior to the onset of the rash up until the lesions crust over. VZV is highly infectious, with secondary attack rates approximating 90% in susceptible household contacts.

Following a primary VZV infection, the virus remains dormant in dorsal root ganglia. In the setting of impaired immunity, the virus may be reactivated to cause herpes zoster, a vesicular erythematous skin rash that presents along dermatomes. Although there are isolated case reports of reinfection, primary VZV is associated with lifelong immunity.

Prevention

To prevent the complications of VZV in pregnancy, all reproductive-aged women should be vaccinated for varicella if naturally acquired immunity is not present. Varivax, the varicella vaccine, is a live attenuated virus vaccine. The vaccine is contraindicated in pregnancy, immunocompromised states, systemic illnesses, and patients with allergies to neomycin (a component of the vaccine). One dose of the vaccine is sufficient in individuals ages 1–12, and 2 doses, administered 4–6 weeks apart, are required in those over the age of 12. Conception should be delayed until at least 1 month after the second dose. Pregnant patients known to be nonimmune to VZV should be counseled to avoid contact with individuals with varicella.

Clinical Findings

A. Symptoms & Signs (Table 15–3)

The incubation period is 10–21 days after the initial infection. The period of infectivity begins 48 hours prior to the onset of the rash and lasts until the vesicular lesions are crusted over. During this time period, patients experience prodromal symptoms such as fever, malaise, and myalgia. This is followed by a 6- to 10-day vesicular rash on the trunk, face, and scalp. The lesions usually occur in crops and evolve from vesicle to pustule to eventually a crusted over dry scab.

Table 15–3. Clinical manifestations of varicella infection.

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B. Laboratory Findings

Although the diagnosis of varicella is clinical, serologic tests can be performed to confirm the diagnosis in unclear cases. Using ELISA, anti-VZV IgM can be detected 3 days after the onset of symptoms and IgG can be detected 7 days after symptomatology. Immunofluorescence of vesicular lesions and viral cultures or viral DNA PCR of vesicular fluid can also establish the diagnosis.

Prenatal diagnosis of fetal varicella is possible by percutaneous umbilical vein blood sampling (cordocentesis) for identification of viral-specific antibody or DNA. The virus can also be identified by culture, antibody detection or viral DNA PCR in chorionic villi, or amniotic fluid. Although testing may be reassuring if test results are negative, positive test results do not correlate with severity of fetal infection. Invasive testing to make a fetal diagnosis is not routinely recommended.

C. Imaging Studies

Women with VZV who present with respiratory complaints should undergo imaging by chest x-ray. A diffuse or military infiltrative pattern usually distributed in the peribronchial region is suggestive of VZV pneumonia.

Although prenatal ultrasound can be used to look for markers of congenital VZV, the ultrasound is usually unremarkable. Ultrasound findings include hydrops, echogenic foci in liver and bowel, limb deformities, cardiac malformations, microcephaly, ventriculomegaly, and growth restriction.

Differential Diagnosis

Drug eruptions

Viral exanthems

Herpes simplex

Bullous pemphigoid

Dermatitis herpetiformis

Syphilis

Insect bites

Impetigo

Rickettsial disease

Complications

VZV infection occurs in 1–5 cases per 10,000 pregnancies. Pregnancies complicated by VZV infection are associated with maternal, fetal, and neonatal health risks.

Complications of primary VZV infection are more common in adults and include bacterial superinfection of vesicles, pneumonia, glomerulonephritis, myocarditis, adrenal insufficiency, and death. Patients may also experience benign cerebellar ataxia and Guillain-Barré syndrome.

VZV pneumonia occurs in up to 20% of adult cases of VZV and may be more severe in pregnant women. Symptoms include cough, shortness of breath, fever, and tachypnea and typically present within 1 week of the rash. VZV pneumonia is considered a medical emergency because pregnant patients are at risk for respiratory failure.

In terms of adverse effects on the pregnancy, acute VZV infection has been associated with spontaneous abortion, intrauterine fetal death, and congenital VZV syndrome. The risk of congenital VZV syndrome is low, close to 2%, and is limited to VZV exposure during the first 20 weeks of gestation.

Neonatal VZV is associated with up to a 25% mortality rate. Infants born to women who develop acute VZV from 5 days before delivery to 48 hours postpartum are at risk for serious consequences due to immaturity of the neonatal immune system and lack of maternal protective antibodies. Clinical manifestations of neonatal VZV include fever, disseminated vesicular rash, pneumonia, and encephalitis. Complications include dermatomal scarring, ocular abnormalities, chorioretinitis, limb hypoplasia, microcephaly, and low birth weight.

Treatment

At the first prenatal visit, all pregnant women should be questioned about prior VZV infection. About 70–90% of women who are uncertain about their prior history will actually have detectable antibodies and be immune. Patients with a well-defined history of infection should be reassured that second infections are extremely unlikely and that, in these cases, risks to the fetus are insignificant. It is unclear whether antenatal VZV screening of all pregnant women with negative or indeterminate VZV histories is cost effective.

If a susceptible pregnant patient is exposed to VZV, she should be treated within 72–96 hours (Fig. 15–3). Prophylactic intervention with varicella-zoster immune globulin (VZIG) in the incubation period can prevent or attenuate the manifestations of VZV, but it does not prevent fetal infection. Pregnant women who develop VZV despite immunoprophylaxis should be treated with oral acyclovir or valacyclovir for 1 week. Patients with pneumonia, encephalitis, or disseminated infection should have supportive care and be treated with intravenous acyclovir for 10 days.

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Figure 15–3. Management of varicella-zoster infection in pregnancy. (*) If period of exposure is uncertain or diagnostic evaluation is delayed, consider immunoglobulin M (IgM) and serial immunoglobulin G (IgG) testing. Empiric use of VariZIG may be appropriate if susceptibility is suspected. (•) Percutaneous umbilical blood sampling. (Reproduced, with permission, from Riley LE. Varicella-zoster virus infection in pregnancy. In Hirsch MS, Lockwood CJ (eds). UpToDate. Waltham, MA: UpToDate; 2010. http://www.utdol.com.)

Prognosis

Maternal VZV infection is associated with high maternal morbidity and mortality rates. Prognosis is improved with prompt medical attention, supportive care, and treatment of serious conditions such as pneumonia and encephalitis.

The risk of congenital VZV syndrome depends on the gestational age at which exposure occurs. Maternal infection after 20 weeks is not associated with congenital anomalies, and prognosis is favorable, as long as maternal health is optimized. Infection prior to 20 weeks is associated with a low risk of congenital VZV. Prenatal ultrasound diagnosis of fetal anomalies suggestive of congenital VZV syndrome carries a poorer prognosis.

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Tan MP, Koren G. Chickenpox in pregnancy: revisited. Reprod Toxicol 2006;21:410–420. PMID: 15979274.

RUBELLA

ESSENTIALS OF DIAGNOSIS

Caused by an RNA virus transmitted via respiratory droplets

Prevention: rubella vaccine

Clinical manifestations: subclinical infection or mild, self-limited disease

Diagnosis: serologic testing—rubella IgM and IgG antibodies

Congenital rubella syndrome: deafness, ocular defects, central nervous system defects, and cardiac malformations

Pathogenesis

The rubella virus is part of the RNA togavirus family. Commonly referred to as the German measles, the virus is transmitted via respiratory droplets. From the respiratory tract, the virus replicates in lymph nodes and hematogenously disseminates throughout the body. Hematogenous spread of the virus across the placenta leads to fetal infection or congenital rubella syndrome (CRS). The virus causes cytopathic damage to vessels and ischemia in affected organs, leading to the various congenital defects.

Prevention

Primary prevention of rubella is possible through preconceptional vaccination. Since the introduction of the vaccine in 1969, the incidence of rubella in the United States has declined dramatically—from 0.45 per 100,000 in 1990 to 0.1 per 100,000 in 1999. The rubella vaccine consists of a live attenuated virus. Currently, the vaccine is recommended for all children from age 12–15 months and 4–6 years in conjunction with measles and mumps (MMR vaccine). Although it is recommended that women receiving the rubella vaccine delay conception for at least 1 month, there are no data to suggest an increase in complications if inadvertently given during pregnancy.

Reproductive-age women should be tested for immunity to rubella prior to pregnancy. If results indicate susceptibility, these patients should be vaccinated prior to conception. If patients are not seen before conception and instead present at the time of pregnancy, obstetricians should test for rubella at the first prenatal appointment. Susceptible women are counseled to avoid exposure to individuals with viral exanthems.

Pregnant women who are rubella nonimmune should be vaccinated immediately after delivery. Ninety-five percent of individuals receiving the vaccine will seroconvert. Vaccinated women can continue breastfeeding and will not transmit the virus to susceptible contacts. Postpartum vaccination programs have been shown to reduce rubella susceptibility in pregnant nonimmune women. A study in 2004 revealed that one-third of pregnant women are also susceptible to mumps. Therefore, the Centers for Disease Control and Prevention (CDC) recommends that rubella-susceptible women receive the MMR vaccine postpartum.

Clinical Findings

A. Symptoms & Signs (Table 15–4)

Acquired rubella may be subclinical or present as a mild, self-limited disease associated with an exanthem. Although 25–50% of individuals are asymptomatic, symptoms include low-grade fevers, conjunctivitis, cough, and malaise. The incubation period is 2–3 weeks. Symptoms usually last 1–5 days followed by the onset of the rash. The characteristic exanthem of rubella is a nonpruritic, erythematous, maculopapular rash. The rash typically starts on the face and then disseminates to the trunk and extremities lasting 1–3 days. Resolution of the rash follows the same pattern as dissemination. Patients may be contagious for 7–10 days as the virus is present in blood and nasopharyngeal secretions both prior to and following the onset of symptoms. Generalized tender lymphadenopathy, particularly postauricular adenopathy, may also be present. Female adolescents may present with rheumatologic sequelae, including morning stiffness and symmetric joint pain. Rare complications of rubella include thrombocytopenia, hemolytic anemia, and hepatitis.

Table 15–4. Clinical manifestations of rubella.

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B. Laboratory Findings

The diagnosis of rubella is usually established [CD1] by serologic testing of rubella-specific IgG and IgM, via enzyme-linked immunoassays and other serologic tests. IgM antibody concentration reaches a peak 7–10 days after the onset of the infection and decreases over the next 4 weeks. The serum concentration of IgG rises slowly but remains positive over the lifetime of an individual. A rubella PCR or positive culture may also facilitate the diagnosis. The virus may be isolated from blood, nasal cavity, pharynx, or urine.

If rubella exposure occurs in a susceptible woman, serologic tests should be performed. If acute infection is documented with the presence of an IgM antibody, the patient should be counseled regarding the option for prenatal diagnosis. There are various methods to establish the prenatal diagnosis of rubella. Fetal blood via cordocentesis can be tested for rubella-specific IgM concentrations. This is limited in use because fetal immunoglobulins are unlikely to be present prior to 22–24 weeks. PCR can be performed on chorionic villi, fetal blood, and amniotic fluid. Although these tests can determine the presence of rubella in the fetal compartment, the results do not correlate with the level of fetal injury.

Differential Diagnosis

Rubeola

Roseola

Other viral exanthems

Drug reaction

Complications

Although the virus is usually self-limited in adults, rare complications of adult rubella have been reported. These serious complications include encephalitis, thrombocytopenia with hemorrhagic manifestations, neuritis, and conjunctivitis.

The virus can also adversely impact the developing fetus. Pregnant women infected with rubella are at higher risk for spontaneous abortion, fetal infection, growth restriction, and fetal demise. Due to the established rubella vaccination programs in the United States, the incidence of CRS has dramatically decreased, and there are now fewer than 50 cases of CRS each year. However, about 10–20% of reproductiveage women in the United States are not immune, and their fetuses are at risk for CRS. In developing countries without national guidelines for rubella vaccination, the burden of disease is higher, and CRS affects from 10–90 per 100,000 live births.

Rubella is considered one of the most teratogenic viruses during pregnancy. Congenital infection depends on the time of exposure to the virus. About 50–80% of neonates exposed to the virus prior to 12 weeks’ gestation will manifest signs of congenital infection. The risk of CRS decreases with advancing gestational age. CRS is rare if infection occurs beyond 18 weeks’ gestation.

Common anomalies associated with CRS include deafness (60–75%), eye defects such as cataracts or retinopathy (10–30%), central nervous system anomalies (10–25%), and cardiac malformations (10–20%). Other findings include microcephaly, growth retardation, hepatosplenomegaly, hemolytic anemia, and thrombocytopenia. Fetal infection is chronic and persistent after birth. Although most infants with CRS are asymptomatic at birth, they develop signs and symptoms over time. Because of the lack of clinical manifestations at birth and the risk for progression, timely diagnosis is important. Late manifestations of CRS include hearing loss, endocrine disorders, immune defects, and panencephalitis.

Treatment

Treatment for acute rubella infection in children and adults is supportive therapy. Glucocorticoids and platelet transfusion are considered in patients with complications such as thrombocytopenia or encephalopathy. Administration of immune globulin to susceptible women exposed to rubella during pregnancy is controversial. The clinical benefit of immunoglobulins for postexposure prophylaxis of rubella and prevention of fetal infection has yet to be demonstrated.

Prognosis

Pregnant women with rubella have a favorable prognosis when it comes to their health. Unfortunately, the prognosis of CRS is potentially devastating because affected neonates commonly suffer serious sequelae and permanent damage.

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SYPHILIS

ESSENTIALS OF DIAGNOSIS

Caused by the spirochete Treponema pallidum

Stages:

• Primary stage: defined by chancre

• Secondary stage: systemic process involving a maculopapular rash, lymphadenopathy, flu-like symptoms, and condyloma lata

• Latent stage: subclinical infection with positive serologic tests

Early latent syphilis: within 1 year of the initial infection

Late latent syphilis: infection 1 year after the primary infection

• Tertiary stage: systemic disease with cardiovascular, neurologic, and cutaneous manifestations

Diagnosis: direct visualization by dark field microscopy, serologic titers (VDRL and rapid plasma reagin, nonspecific treponemal tests; fluorescent treponemal antibody absorption test, treponemal-specific tests)

Complications in pregnancy: spontaneous abortion, growth restriction, stillbirth, congenital anomalies, preterm delivery, fetal/neonatal infection, and neonatal death

Treatment: penicillin

Pathogenesis

Syphilis is a chronic systemic infection caused by the motile spirochete Treponema pallidum. It is most commonly acquired through direct sexual contact. During pregnancy, infection can also occur via transplacental transmission. Exposure to open lesions containing the organisms facilitates transmission of the spirochete across mucous membranes or skin abrasions. The infection is acquired in 50–60% of partners after a single sexual exposure to an infected lesion. The tissue destruction observed in syphilis infections is a result of the immune response rather than a direct insult from the spirochete itself.

Although the incidence of syphilis steadily declined in the 1990s to early 2000s, there was a notable increase from 2003 to 2005. During this period, there was a parallel rise in the number of diagnosed cases of congenital syphilis (Fig. 15–4).

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Figure 15–4. Congenital syphilis (CS) rate among infants age <1 year and rate of primary and secondary (P&S) syphilis among females age ≥10 years. (Reproduced from Centers for Disease Control and Prevention. National Electronic Telecommunication System for Surveillance, United States, 1995–2008. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5914a1.htm.)

Prevention

Public health strategies, counseling, and education of patients on sexually transmitted infections can help reduce the risk of these infections. Although correct and consistent use of latex condoms may decrease the risk of syphilis transmission, sexual abstinence is the only guaranteed method to avoid transmission. Other risk factors associated with syphilis in pregnancy include poverty, sexual promiscuity, and illicit drug use. Avoiding activities leading to risky behavior, such as alcohol and drug use, may also help prevent transmission. The risk of syphilis can be further modified by early identification of infected patients, screening of high-risk populations, adequate treatment of patients and exposed individuals, and improved access to health care.

Congenital syphilis can be prevented by screening all pregnant women and treating those with evidence of infection. Patients should be encouraged to seek early prenatal care, and all pregnant women should undergo screening at the initial prenatal visit. High-risk patients should be rescreened in the third trimester, around 28 weeks of gestation, and in areas with high rates of congenital syphilis, rescreening upon admission in labor should be considered. Women with an intrauterine fetal demise after 20 weeks of gestation should also be evaluated for syphilis.

Clinical Findings

A. Symptoms & Signs

Syphilis is an infection that presents in different stages over a period of time if untreated. Early syphilis, which occurs within the first year after acquisition of the infection, includes primary and secondary syphilis. Latent syphilis refers to the absence of symptoms in the setting of positive serologies and often follows secondary syphilis. Tertiary or late syphilis, which involves the central nervous and cardiovascular systems, manifests years to decades after the initial infection. Table 15–5 summarizes the clinical manifestations of the various stages of syphilis.

Table 15–5. Clinical manifestations of the various stages of syphilis.

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The chancre, the characteristic lesion of primary syphilis, is a painless, nontender ulcer with an indurated base and raised border. The lesion is found at the site of inoculation. In women, it is most often found on the external genitalia, on the cervix, or in the vagina. Primary syphilis may also manifest with painless inguinal lymphadenopathy. The incubation period varies from 10–90 days, with a mean incubation time of 3 weeks. The primary chancre heals spontaneously in 3–6 weeks in the absence of treatment.

Secondary syphilis is a systemic process characterized by disseminated spread of the infection. This stage typically presents 6 weeks to 6 months after the onset of the primary chancre. Patients present with skin and mucous membrane lesions, along with flu-like symptoms (fever and myalgia) and generalized lymphadenopathy. The generalized maculopapular rash begins on the trunk and proximal extremities and spreads to the entire body, including the palms, soles, and scalp. Condyloma lata are wart-like lesions found in the genital area. The rash usually resolves spontaneously within 2–6 weeks. Patients then enter the latent stage of syphilis.

Patients with latent syphilis are usually asymptomatic with no findings on physical examination. Serologic tests continue to be positive during this time. Latent syphilis is further divided into early and late latent syphilis. If latent infection occurs within 1 year of the initial infection, it is defined as early latent syphilis. Late latent syphilis refers to infection that occurs 1 year after the time of initial infection. A patient can remain in the latent stage for many years.

About one-third of individuals with untreated syphilis will progress to the tertiary stage. Widespread tissue destruction in the tertiary stage results in cardiovascular disease, neurosyphilis, and cutaneous and osseous lesions. Obliterative endarteritis occurs as the spirochete develops a predilection for arterioles. Cardiovascular syphilis manifests with aortic aneurysms, aortic insufficiency, and coronary stenosis. Neurosyphilis is characterized by paralysis, paresthesias, tabes dorsalis, blindness, gait abnormalities, confusion, and dementia.

The Argyll-Robertson pupil (pupil that does not react to light but is able to accommodate) is pathognomonic for tertiary syphilis. Gummas are classic dermatologic manifestations. These gummas consist of necrosis surrounded by an inflammatory infiltrate encapsulated by proliferating connective tissue and form reddish-brown nodular lesions in the skin.

B. Laboratory Findings

Testing for syphilis can be performed either with direct visualization of the organism or by direct serologic testing. Using dark field microscopy, spirochetes can be identified in bodily fluid or lesions. More recently, direct fluorescent antibody stains have replaced dark field microscopy, but technicians still require a fluorescent microscope to visualize the organism. Serologic tests may initially return negative in the early stages of chancre formation. Therefore, these lesions should be sampled for detection of spirochetes and undergo dark field examination.

Serologic testing consists of a nonspecific screening test followed by a confirmatory treponemal antibody test. The nontreponemal screening tests include the Venereal Disease Research Laboratories (VDRL) test, rapid plasma reagin (RPR) test, or automated reagin test. Reported as a titer, these tests use cardiolipin antigens to detect circulating antibodies and can be used to follow response to treatment. In certain patients, however, a low titer may persist for a long period of time. Due to the nonspecific nature of these tests, false-positive results are not uncommon (0.2–3.2%) and may occur in a multitude of settings including various infections, malignancies, connective tissue diseases, and chronic liver disease.

The fluorescent treponemal antibody absorption test (FTA-ABS) is the most commonly used confirmatory test that detects antibodies specifically directed to treponemal cellular components. Because these tests remain positive even after treatment, they are not used to follow response to treatment. In pregnancy, seropositive women should be considered infected unless a treatment history is well documented and subsequent serologic antibody titers have declined.

Less than 10% of patients with untreated syphilis progress to symptomatic late neurosyphilis. In the absence of clinical signs or symptoms of neurologic involvement, the CDC does not recommend routine lumbar puncture in primary and secondary syphilis. However, in patients with latent syphilis, lumbar puncture should be performed if there are signs of neurologic involvement, evidence of active tertiary syphilis, treatment failure, or HIV infection. The diagnosis of neurosyphilis depends on a combination of tests including reactive serologies, abnormal cerebrospinal fluid (CSF) cell count, elevated protein, and/or reactive CSF VDRL.

Serial quantitative VDRL titers facilitate the diagnosis of reinfection or persistence of active syphilis. With adequate treatment, VDRL titers decrease and become negative within 6–12 months in early syphilis and within 12–24 months in late syphilis. Further diagnostic tests (such as lumbar puncture) and appropriate treatment are needed if titers continue to rise.

Congenital syphilis is diagnosed easily in the setting of a fetus with clinical manifestations of syphilis, placentomegaly, and positive laboratory studies confirming the infection. However, many neonates do not manifest signs and symptoms of congenital infection. Although cord blood may return positive for nonspecific tests for syphilis, the diagnosis is difficult due to the transplacental transfer of maternal nontreponemal and treponemal IgG antibodies to the fetus. In these complicated situations, treatment must be based on the diagnosis of syphilis in the mother, treatment status of the mother, comparison of maternal and infant nontreponemal serologic titers at the time of delivery, and presence of clinical findings of syphilis in the infant. Infants with positive VDRL tests results with no clinical evidence of syphilis should have monthly VDRL titers for at least 9 months; rising titers indicate the need for therapy.

Differential Diagnosis

Primary Syphilis

Granuloma inguinale

Lymphogranuloma venereum

Herpes simplex

Chancroid

Carcinoma

Trauma

Lichen planus

Psoriasis

Mycotic infections

Bowen’s disease

Secondary Syphilis

Drug eruptions

Psoriasis

Lichen planus

Pityriasis rosea

Tinea versicolor

Parasitic infections

Viral exanthems

Rocky Mountain spotted fever

Complications

In addition to the aforementioned manifestations of the various stages of syphilis, complications of congenital syphilis result in significant neonatal morbidity. Although vertical transmission can occur at any time during pregnancy and at any stage of syphilis, the risk of congenital infection is greater in the earlier stages of the disease. Women with primary or secondary syphilis are more likely to transmit the disease to their fetuses than are women with latent disease. Maternal primary syphilis and secondary syphilis are associated with a 50% risk of congenital syphilis, whereas early latent syphilis carries a 40% risk of congenital syphilis. The risk of congenital syphilis is even lower, close to 10%, among patients with late latent syphilis. Although serious adverse outcomes are more likely to occur with transmission in the earlier stages, most pregnant women are in the latent stage of syphilis at the time of diagnosis and have had the infection for more than 1 year.

Although the spirochete can cross the placenta and infect the fetus as early as the sixth week of gestation, clinical manifestations do not appear until after the 16th week. By this time, the fetal immune system has matured and can respond to the spirochete. It is the immune reaction to the infection that is responsible for tissue destruction rather than direct injury by the spirochete. The risk of congenital syphilis is increased with infection late in pregnancy, treatment less than 30 days before delivery, inappropriate treatment of the mother, and the lack of prenatal serologic testing.

Untreated syphilis is associated with significant adverse effects on the pregnancy including spontaneous abortion, intrauterine growth restriction, fetal demise, congenital anomalies, preterm delivery, and neonatal death. Stillbirth rates range from 10–35%. Fetuses with congenital infections exhibit hepatosplenomegaly, ascites, polyhydramnios, placental thickening, and hydrops.

Congenital syphilis is divided into 2 clinical syndromes: early and late congenital syphilis (Table 15–6). Early congenital syphilis refers to the manifestations of syphilis within the first 2 years of life. These infants can present with a maculopapular rash, snuffles (flu-like syndrome associated with nasal discharge), mucous lesions, hepatosplenomegaly, jaundice, anemia, lymphadenopathy, chorioretinitis, and iritis. Late congenital syphilis presents after 2 years of age. Findings consistent with late congenital syphilis include frontal bossing, short maxilla, saddle nose, saber shins, high palatal arch, Hutchinson teeth, interstitial keratitis, and eighth nerve deafness. Infants may also have other neurologic manifestations such as mental retardation, hydrocephalus, and optic nerve atrophy.

Table 15–6. Signs and symptoms of congenital syphilis.

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Treatment

Pregnant women with a history of sexual contact with a person with documented syphilis, positive dark field microscopic visualization of spirochetes, positive serologies via a specific treponemal test, or evidence of reinfection should be treated. Penicillin G is the treatment of choice for all stages of syphilis and is effective in treating maternal disease, preventing fetal transmission, and treating fetal disease (Table 15–7). Although alternatives to penicillin are available to treat nonpregnant penicillin-allergic patients, parenteral penicillin G is the only therapy with documented efficacy for syphilis during pregnancy because it crosses the placenta in adequate amounts, effectively treating the fetus. Therefore, it is recommended that patients with known penicillin allergy undergo desensitization followed by subsequent treatment with penicillin. Although erythromycin was previously used for treatment of syphilis in pregnancy, its efficacy for treatment of the fetus and prevention of transmission is inadequate. Doxycycline and tetracycline may be used to treat nonpregnant patients. The efficacy of antibiotics such as ceftriaxone and azithromycin is currently under investigation.

Table 15–7. CDC-recommended treatment of syphilis during pregnancy.

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Desensitization can occur in an oral or intravenous manner. Regardless of the route, patients should undergo desensitization in a hospital setting due to potential serious IgE-mediated allergic reactions.

Early disease, with documentation that the initial infection occurred within the past year, is treated with a single dose of benzathine penicillin. Because of treatment failures even after adherence to recommended guidelines, some experts recommend additional therapy with a second dose of penicillin G 1 week after the initial dose. Despite adequate therapy, risk factors for treatment failure include high VDRL titers at the time of diagnosis, unknown duration of infection, treatment within 4 weeks of delivery, and ultrasound signs of fetal syphilis.

Late latent syphilis, latent syphilis of unknown duration, and tertiary syphilis should be treated with 3 doses of benzathine penicillin at weekly intervals. Neurosyphilis requires more intensive treatment with high doses of intravenous aqueous crystalline penicillin or intramuscular procaine penicillin for 10–14 days.

Patients may develop the Jarisch-Herxheimer reaction within several hours after treatment. Symptoms last for 12–24 hours and include fever, chills, myalgias, vasodilation, mild hypotension, and tachycardia. In addition to the symptoms present in nonpregnant individuals, women undergoing treatment in the second trimester are at risk for preterm contractions, preterm labor (highest risk 48 hours after treatment), decreased fetal movement, fetal distress, and fetal death. Patients improve with supportive therapy because the Jarisch-Herxheimer reaction is usually self-limited and resolves by 24–36 hours.

Response to therapy should be monitored with clinical and serologic examination at 1, 3, 6, 12, and 24 months after treatment. Titers usually decline at least 4-fold within 12–24 months of treatment. Patients with persistent clinical symptoms or with sustained 4-fold increases in the nontreponemal test titer have either failed therapy or become reinfected. These patients need retreatment, CSF analysis, and HIV testing. Pregnant women treated for syphilis need repeat serologic titers at 28–32 weeks of gestation and at delivery. Women at high risk for reinfection may have serologies checked monthly.

After adequate treatment, nontreponemal serologic tests often become negative. The treponemal test results usually remain positive for life. Certain patients may have positive nontreponemal tests despite treatment. In these cases, titers are usually not higher than 1:8.

Prognosis

The number of cases of early syphilis has recently been rising, particularly among intravenous drug users and the HIV population. The syphilis rate among women increased from 1.1 cases per 100,000 females in 2007 to 1.5 cases per 100,000 females in 2008. Women of reproductive age make up 80% of the female population with syphilis. Therefore, syphilis is an important health concern. Serious sequelae for the fetus and neonate are due to the failure to diagnose or adequately treat maternal disease.

The efficacy of penicillin for treatment of syphilis in pregnancy ranges from 95–100%. Prognosis is usually favorable once the patient is adequately treated. However, pregnant patients require close follow-up because treatment failure may result in a congenitally infected fetus and neonate.

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CYTOMEGALOVIRUS

ESSENTIALS OF DIAGNOSIS

Caused by double-stranded DNA herpes virus

Prevention: strict personal hygiene

Diagnosis: serologic testing in adults; amniotic fluid PCR for prenatal diagnosis

Antenatal sonographic findings: microcephaly, ventriculomegaly, intracranial calcifications, hydrops, growth restriction, placentomegaly, and echogenic bowel

Pathogenesis

Cytomegalovirus (CMV) is a double-stranded DNA virus that belongs to the herpesvirus family. It has the ability to establish lifelong latency in the host after primary infection and can periodically reactivate with shedding of virus. CMV is the most common congenital infection. Birth prevalence estimates range from 0.2–2.5%.

Horizontal transmission of CMV results from transplantation of infected organs, blood transfusions, sexual contact, or contact with contaminated saliva or urine. Vertical transmission is due to transplacental infection, ingestion of genital tract secretions during delivery, or breastfeeding. Because the virus has the potential to remain latent in host cells after resolution of initial infection, CMV infections in pregnant women are either primary or recurrent. If the initial infection occurs during pregnancy, it is considered a primary infection. A recurrent infection refers to an infection in which maternal CMV antibodies are present prior to conception.

CMV seropositivity increases with age. In the United States, approximately 50–80% of adult women have serologic evidence of prior CMV infection. Although maternal pre-existing immunity decreases the risk of intrauterine transmission, the presence of antibodies is not absolutely protective against either reinfection or vertical transmission. The rate of seroconversion in pregnancy is about 1–4%.

Hematogenous spread of the virus across the placenta is responsible for congenital infection. Dissemination is more likely during primary infection. In the case of primary infection in pregnancy, there is a 50% risk of fetal infection. The rate of transmission increases as the pregnancy progresses, with the highest risk of transmission in the third trimester. However, the severity of fetal injury is greatest if maternal primary infection occurs in the first trimester. In the setting of recurrent infection, the risk of fetal transmission is overall lower, with a 5–10% risk.

Prevention

There is no vaccine to prevent CMV infection, and there is a lack of data to suggest that treatment of maternal infection prevents the risk of congenital CMV infection. For these reasons, routine prenatal screening for CMV is not recommended. Preventive measures, such as careful handwashing techniques, should be employed to decrease the risk of CMV infection during pregnancy. Susceptible individuals should avoid sharing food or drinks with young children. Seronegative pregnant women should also be transfused with CMV-negative blood products and counseled regarding safe sexual practices if not in a monogamous relationship.

Clinical Findings

A. Symptoms & Signs (Table 15–8)

Clinical manifestations of CMV depend on the integrity of the host immune system. Immunocompromised individuals are at risk for severe infection and may present with complications such as myocarditis, hepatitis, pneumonitis, retinitis, and/or meningoencephalitis. In pregnant women, CMV infections are either subclinical or consist of mild nonspecific symptoms. Fever, flu-like symptoms, or mild hepatitis are more likely to occur in individuals with primary infections rather than reinfection or reactivation. The incubation period for CMV is 1–2 months.

Table 15–8. Clinical manifestations of cytomegalovirus.

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B. Laboratory Findings

Maternal infection during pregnancy is diagnosed by serologic testing. Primary infection is confirmed in the setting of seroconversion of CMV-specific IgG in paired acute and convalescent sera. Serum samples are collected 3–4 weeks apart and tested in parallel for anti-CMV IgG. Seroconversion from negative to positive or a significant increase in anti-CMV IgG titers is consistent with infection. IgM titers are not reliable in diagnosing CMV because the sensitivity of CMV IgM assays ranges from 50–90%. Additionally, IgM titers can remain positive for more than a year and revert from negative to positive in women with reactivation or reinfection with a different strain. Positive IgM titers decline over a period of 30–60 days. When CMV-specific IgG and IgM are both positive, CMV IgG avidity testing can be performed to confirm primary CMV infection. A low-avidity CMV IgG test is suggestive of CMV infection occurring in the preceding 6 months. Alternatively, a high-avidity test virtually excludes the possibility of a primary CMV infection occurring within the previous 4 months. Avidity testing is performed in the United States by Focus Diagnostics, a reference laboratory in California. Figure 15–5 depicts a management strategy for suspected maternal CMV infection.

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Figure 15–5. Algorithm for evaluation of suspected maternal primary cytomegalovirus (CMV) infection in pregnancy. EIA, enzyme immunoassay; IgG, immunoglobulin G; IgM, immunoglobulin M. (Reproduced, with permission, from Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Rouse DJ, Spong CY. Williams Obstetrics, 23rd ed. http://www.accessmedicine.com. Copyright © The McGraw-Hill Companies, Inc. All rights reserved.)

The diagnosis of CMV can also be made by PCR antigen identification and viral culture. The highest concentrations of virus are found in urine, seminal fluid, saliva, and breast milk. Although viral cultures can be positive within 72–96 hours, a minimum of 21 days is required before the culture is reported as negative.

The preferred method for diagnosing congenital CMV is via PCR identification of CMV in amniotic fluid. Sensitivities of PCR range from 70–100%. Data suggest that sensitivities are higher if the testing is performed after 21 weeks’ gestation and after a 6-week lag time between maternal infection and the procedure. This period allows sufficient time for the virus to infect the placenta and fetus with subsequent replication of the virus in the fetal kidney followed by excretion into the amniotic fluid. Therefore, if an amniocentesis is performed soon after infection and returns negative, the procedure should be repeated later in pregnancy. Identification of the virus or the viral load in the amniotic fluid does not correlate with the severity of fetal injury.

C. Imaging Studies

Prenatal ultrasound may help diagnose congenital CMV. Sonographic findings concerning for severe injury include microcephaly, ventriculomegaly, intracranial calcifications, hydrops, growth restriction, and oligohydramnios. Other ultrasound markers suggestive of infection include placentomegaly, echogenic bowel, meconium peritonitis, ascites, and pleural effusions. A normal ultrasound does not exclude the possibility of infection and sequelae.

Differential Diagnosis

Epstein-Barr virus

Acute hepatitis

Acute HIV

Human herpesvirus-6

Herpes simplex virus

Rubella

Enteroviral infections

Lymphocytic choriomeningitis virus

Toxoplasmosis

Complications

Congenital CMV is more likely in the setting of primary infection acquired earlier in the pregnancy. Approximately 5–15% of infants who develop congenital CMV are symptomatic at birth. Severe clinical manifestations include hepatosplenomegaly, intracranial calcifications, jaundice, growth restriction, microcephaly, chorioretinitis, hearing loss, thrombocytopenia, and hepatitis (Table 15–8). The most severely affected infants have a mortality rate of about 30%. Deaths are usually secondary to liver dysfunction, bleeding, disseminated intravascular coagulation, or secondary bacterial infections. Eighty percent of survivors have serious morbidity. Of the 85–90% of neonates who are asymptomatic at birth, 10–15% will develop hearing loss, chorioretinitis, or dental defects by the age of 2.

Treatment

Supportive therapy and symptomatic relief are recommended in infected immunocompetent pregnant women. Antiviral drugs, such as ganciclovir, should be used in immunocompromised patients with CMV because these medications decrease mortality and morbidity associated with serious CMV infections. Antiviral drugs have not been shown to decrease the risk of congenital CMV. Until recently, there has been no promising effective treatment for congenital CMV. More recent data suggest improved outcomes when using hyperimmune globulin as treatment and prophylaxis for congenital CMV infection. However, the study was limited in that it was neither randomized nor controlled, and therefore, its findings must be interpreted with caution.

Prognosis

Immunocompetent pregnant women with CMV have a favorable prognosis. However, congenital CMV poses a threat to infants and children and is, in fact, the most common congenital infection. It can be potentially devastating and is a major cause of permanent auditory, cognitive, and neurologic impairment.

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TOXOPLASMOSIS

ESSENTIALS OF DIAGNOSIS

Caused by an intracellular parasite

Transmitted following consumption of undercooked meat or contact with oocysts from infected cat feces

Clinical manifestations vary depending on the integrity of the immune system

Diagnosis

• Serologic testing in adults

• DNA PCR of amniotic fluid for prenatal diagnosis

Congenital toxoplasmosis: chorioretinitis, hydrocephalus, ventriculomegaly, and periventricular calcifications

Treatment during pregnancy

• Spiramycin therapy in women with documented acute toxoplasmosis

• Therapy with pyrimethamine, sulfadiazine, and leucovorin if fetal diagnosis is confirmed

Pathogenesis

Toxoplasma gondii is an obligate intracellular parasite with 3 distinct life forms: trophozoite, cyst, and oocyst. Wild and domestic cats are the only known host for the oocyst. The oocyst is formed in the intestine and then shed in cat feces. The oocysts become infective 1–5 days later and may remain infectious for over a year. Other animals, such as cows, ingest the oocyst. The oocyst then becomes the invasive trophozoite, which then spreads throughout the body forming cysts in brain and muscle.

In developed countries, the prevalence of infection has declined over the last 30 years. Higher rates of infection are present in less developed countries and those with tropical climates where undercooked meats and unfiltered water are more prevalent. Ten to 50% of adults have evidence of previous infection. Maternal infection results from consumption of uncooked or undercooked meat or contact with oocysts from the feces of an infected cat. Following primary maternal infection, fetal infection occurs after transmission of parasites across the placenta. The trophozoite forms tissue cysts in the brain and muscle and can remain dormant for years.

About 50% of adults in the United States have developed immunity to Toxoplasma, and this immunity is generally lifelong, mediated by T lymphocytes, except in the case of immunocompromised patients. In the setting of primary infection, the overall rate of fetal infection is one-third. Although the risk of fetal infection increases with gestational age at seroconversion, severe infection is more likely with infection in the first trimester. The rate of vertical transmission increases from 10–15% in the first trimester, to 25% in the second trimester, and to more than 60% in the third trimester. Reinfection leading to congenital toxoplasmosis is exceedingly uncommon.

Prevention

Prevention of toxoplasmosis is extremely important in pregnancy. Pregnant women should avoid contact with cat litter. If cat litter is handled, gloves should be worn and hands should be thoroughly washed. Conscientious hand hygiene is also important following the preparation of meat. Fruits should be washed, and meat should be cooked thoroughly (to 152°F/66°C). Women should also avoid drinking unfiltered water and ingesting soil by observing strict hand hygiene after contact with soil.

Clinical Findings

A. Symptoms & Signs (Table 15–9)

Table 15–9. Clinical manifestations of toxoplasmosis.

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Immunocompetent individuals with an acute infection may be either asymptomatic or present with vague nonspecific symptoms such as fatigue, fever, and myalgias. These patients may also present with lymphadenopathy. Immunocompromised patients, on the other hand, can have devastating consequences following infection. Neurologic dysfunction is not uncommon and includes encephalitis, meningoencephalitis, and intracerebral abscesses. Other manifestations include myocarditis and pneumonitis.

B. Laboratory Findings

Maternal diagnosis of toxoplasmosis is confirmed by serologic testing. Anti-Toxoplasma antibody can be detected using indirect fluorescent antibodies, indirect hemagglutination and agglutination tests, and ELISA. IgM-specific antibodies suggest acute infection. Diagnosis of an infection during pregnancy is most precise when 2 blood samples, greater than 2 weeks apart, document seroconversion from negative to positive Toxoplasma-specific IgM or IgG. In certain parts of Europe, women undergo serial testing with the goal of detecting early infection. However, the benefit of routine testing is controversial given the lack of data suggesting that treatment improves clinical outcomes. In the United States, diagnosis of a recent Toxoplasma infection is challenging in the setting of a single sample. IgM can remain positive for 10–13 months, and there is substantial variation among individuals. Twenty-five percent of women will have persistently positive IgM lasting years, and in certain patients, low IgG avidity will also remain positive for years. Rising IgG titers are also not useful due to the variation among laboratories. In the setting of a positive IgM and a negative IgG result with both tests positive 2 weeks later, recent infection is likely.

To confirm primary Toxoplasma infection, an avidity test for Toxoplasma IgG antibody is performed. In the setting of high-avidity IgG testing, infection within the previous 3–5 months is excluded. The functional avidity of IgG is low in the case of primary infection. In the United States, serologic diagnosis of an acute infection should be confirmed by the Palo Alto Medical Foundation Research Institute, a reference laboratory. The laboratory runs a panel of tests known as the Toxoplasma Serologic Profile, which includes the Sabin Feldman dye test, double-sandwich IgM ELISA, IgA and IgG ELISA, and a differential agglutination test.

The diagnosis of congenital toxoplasmosis is confirmed by identification of PCR toxoplasmic DNA in amniotic fluid. The sensitivity and specificity of real-time PCR are 92.2% and 100%, respectively. However, false-positive and false-negative tests do occur. Although the presence of Toxoplasma-specific IgM in fetal blood is extremely sensitive for diagnosis, due to the risk of fetal loss, cordocentesis is not widely used.

C. Imaging Studies

Ultrasonography is helpful in providing prognostic information. The most commonly noted abnormalities include intracranial calcifications and ventriculomegaly. These findings are usually seen after 21 weeks’ gestation.

Differential Diagnosis

CMV

Disseminated tuberculosis

Acute HIV

Epstein-Barr virus (mononucleosis)

Brain abscess

Leukemia

Lymphoma

Pneumocystis pneumonia

Progressive multifocal leukoencephalopathy

Sarcoidosis

Syphilis

Cryptococcus neoformans

Aspergillus

Complications

Although Toxoplasma infection is usually benign in immunocompetent pregnant women, infection in pregnancy can have serious consequences for the neonate. Approximately 3 per 1000 infants demonstrate evidence of congenital toxoplasmosis, with clinically significant infection present in 1 per 1000 pregnancies. Approximately 20% of neonates born to mothers with acute toxoplasmosis have clinical manifestations in infancy. These infants can present with hepatosplenomegaly, disseminated purpuric rash, ascites, and chorioretinitis. Central nervous system (CNS) manifestations include periventricular calcifications, ventriculomegaly, seizures, and mental retardation. The classic triad of congenital toxoplasmosis includes chorioretinitis, hydrocephalus, and periventricular calcifications.

Untreated asymptomatic infants at birth are at high risk for subsequently developing abnormalities. The most common delayed complication is chorioretinitis, which can result in vision loss. Additional sequelae that may manifest later in life include mental retardation, deafness, and seizures. Recent data do not suggest an association between congenital toxoplasmosis and reduced birth weight or small for gestational age infants.

Treatment

Toxoplasmosis infection in the immunocompetent adult is usually asymptomatic or self-limited and does not require treatment. Immunocompromised patients, on the other hand, should be treated with oral sulfadiazine and pyrimethamine.

Although there is no strong evidence demonstrating the efficacy of prenatal treatment, certain data suggest that prenatal therapy may reduce, but not eliminate, the risk of congenital infection. Therefore, therapy is usually offered to pregnant women diagnosed with acute infection. Treatment usually consists of spiramycin, a macrolide antibiotic that has the potential to concentrate in the placenta and, therefore, prevent fetal transmission. Because it does not cross the placenta, it is not used to treat fetal infection. Spiramycin is used commonly in Europe with favorable outcomes and is available in the United States through the CDC.

Pyrimethamine and sulfadiazine are folic acid antagonists that can be used to treat documented fetal infection. Pyrimethamine is teratogenic in animals, and both medications can cause bone marrow suppression. Due to the adverse effects of these medications, these drugs should only be used if fetal infection is confirmed. As of yet, there are no clinical trials to clearly demonstrate that the regimen is more effective than spiramycin. Leucovorin calcium (folinic acid) is added to the regimen to prevent bone marrow suppression. The efficacy and safety of other drugs such as azithromycin and clarithromycin in treating toxoplasmosis is currently under investigation.

Aggressive early treatment of neonates with congenital infection is recommended and includes therapy with pyrimethamine, sulfadiazine, and leucovorin for 1 year. Early therapy decreases the risk of late complications of toxoplasmosis.

Prognosis

Infection in immunocompetent women has a favorable prognosis. The prognosis of congenital toxoplasmosis is variable and depends on the clinical sequelae, which range from an asymptomatic state to severe neurologic morbidity.

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LISTERIA

ESSENTIALS OF DIAGNOSIS

Caused by gram-positive motile Bacillus

Preventive measures: thoroughly cooking raw meets, washing raw vegetables, avoiding unpasteurized foods

Clinical manifestations in healthy pregnant women: asymptomatic, vague, flu-like symptoms including fever, chills, malaise, and myalgias

Complications in pregnancy: fetal death, premature delivery, neonatal infection

Diagnosis: cultures on blood, amniotic fluid, placenta

Treatment: penicillin/ampicillin with or without gentamicin for synergistic effect

Pathogenesis

Listeria monocytogenes is a food-borne gram-positive motile Bacillus capable of causing life-threatening infections in humans. It is a facultative intracellular parasite that primarily inhabits soil and decaying vegetative matter. Animals carrying the organism contaminate foods of animal origin such as meat and dairy products. Although there are multiple species of Listeria, L monocytogenes is the only species that is considered pathogenic in humans. The organism’s virulence is attributed to listeriolysin O, a pore-forming toxin, that enables the pathogen to suppress antigen-induced T-cell activation. Most Listeriainfections in adults are due to oral ingestion followed by intestinal mucosal penetration and subsequent systemic infection.

Annually, there are approximately 1600 cases of listeriosis in the United States, with a 16% mortality rate. About 1 in 6 cases of listeriosis occurs during pregnancy. Recent data show that the overall incidence of listeriosis is decreasing, with a 26% decrease noted by the CDC from 1998 to 2009. Human listeriosis can occur as either a sporadic illness or an epidemic. The sporadic form occurs more commonly than the epidemic form (responsible for >95% of cases). The epidemic form is due to widespread contamination of food products. High-risk foods include unpasteurized soft cheeses, processed/delicatessen meats, hot dogs, smoked seafood, and pâtés. Several outbreaks of listeriosis in the United States have been associated with Mexican-style soft cheeses made from unpasteurized milk.

Although L monocytogenes can be isolated from the feces of 1–5% of healthy adults, systemic infections usually occur in individuals with predisposing conditions such as pregnancy, old age, and immunocompromised states. Decreased cell-mediated immunity in pregnancy is believed to be the cause of increased susceptibility of pregnant women to listeriosis. Subsequent fetal and/or neonatal infection most likely occurs from hematogenous dissemination of the organism through the placenta, although ascending infection from cervical colonization with L monocytogenes may also play a role.

Prevention

Prevention of Listeria infections is important on a legislative as well as individual level. Government agencies such as the US Department of Agriculture (USDA) have instituted policy changes to reduce L monocytogenescontamination. Large-scale producers of ready-to-eat meat have been required to develop L monocytogenes control programs and institute various measures such as postpackaging pasteurization.

Individuals can prevent infection with Listeria by following certain recommendations. Recommendations include thoroughly cooking raw meats; carefully washing raw vegetables; avoiding unpasteurized milk or products made from unpasteurized milk; keeping uncooked meats and poultry separate from vegetables and from cooked foods and ready-to-eat foods; washing hands, knives, countertops, and cutting boards after handling and preparing uncooked foods; and consuming perishable and ready-to-eat foods as soon as possible. Pregnant women should also avoid soft cheeses such as feta, brie, and queso fresco and delicatessen meats.

Clinical Findings

A. Symptoms & Signs

In immunocompromised, elderly, and pregnant patients, Listeria can lead to invasive disease, such as meningitis and sepsis. In healthy adults, if ingested in high numbers, the organism can cause febrile gastroenteritis. The incubation period for Listeria is generally 6–90 days, but may be only 24 hours during widespread epidemics of gastroenteritis.

Listeriosis in pregnancy is most common in the third trimester. Although many pregnant infected women are asymptomatic, about two-thirds manifest nonspecific flulike symptoms characterized by fever, chills, myalgias, malaise, and upper respiratory complaints. Infection is usually mild and self-limited, but pregnant women may present with signs and symptoms of sepsis. Listerial CNS infection in pregnancy is generally rare. Maternal listeriosis can lead to serious consequences such as fetal death, premature delivery, and neonatal infection.

B. Laboratory Findings

There are no specific clinical manifestations that help distinguish listeriosis from other infections that manifest with fever and nonspecific flu-like symptoms. Therefore, blood cultures are necessary in establishing the diagnosis. Routine cerebrospinal fluid analysis is limited because pregnant women do not usually present with CNS infections. Although routine stool cultures are not helpful in diagnosing systemic listeriosis, stool cultures using selective media may be valuable in patients with Listeria gastroenteritis. Amniocentesis may be performed to help diagnose fetal listerial infection. Additionally, cultures obtained from the uterus or placenta may also establish the diagnosis.

C. Imaging Studies

Magnetic resonance imaging (MRI) is superior to computed tomography scan for detecting Listeria lesions in the CNS. It is recommended that patients with Listeria meningitis or systemic listeriosis with CNS signs and symptoms undergo an MRI.

Differential Diagnosis

Maternal

Influenza

Urinary tract infection

Pyelonephritis

Meningitis

Fetal

Group B Streptococcus

Escherichia coli

Klebsiella pneumoniae

Complications

Maternal listeriosis is associated with fetal loss, premature delivery, neonatal infection, and neonatal death. In a review of 222 cases of maternal infection, the pregnancy was complicated by abortion or stillbirth in 20% of cases, while neonatal sepsis resulted in 68% of surviving neonates. Neonatal listeriosis has been divided into 2 distinct clinical and serologic entities: early-onset and late-onset disease. Early-onset disease occurs in infants infected in utero with signs of infection presenting soon after birth; it presents as diffuse sepsis with multiorgan involvement including liver, lungs, and CNS. Early-onset disease is associated with a high rate of fetal demise and neonatal mortality. Granulomatosis infantiseptica refers to a severe in utero infection in which disseminated abscesses and/or granulomas are present in multiple internal organs. Late-onset neonatal disease presents in term infants who present with signs and symptoms of infection days to weeks after delivery. These neonates usually present with meningitis and long-term neurologic sequelae such as mental retardation. Intrapartum transmission or nosocomial infection after delivery is usually responsible for late-onset disease. Both types of neonatal listeriosis are associated with a high neonatal mortality rate.

Treatment

Parenteral ampicillin or penicillin G is the recommended antibiotic regimen for treatment of listeriosis. Listerial microbial resistance to penicillins or derivatives of penicillins has not been described under natural conditions. Dose and duration of therapy depend on age and type of infection. Pregnant women are usually treated with ampicillin 2 g intravenously every 4–6 hours; this dose provides adequate transplacental penetration. Optimal duration of therapy in pregnancy has not been established and varies between 2 and 4 weeks. When complicated listerial infections are present—involving the CNS, endocarditis, or infections in neonates and immunocompromised adults—gentamicin may be added to ampicillin for a synergistic effect. Trimethoprim-sulfamethoxazole is effective in patients allergic to penicillins.

Prognosis

Although maternal prognosis after listerial infection is generally favorable, fetal and neonatal infection can be severe with perinatal case fatality rates ranging from 22–45%. Listeriosis carries a poorer prognosis for fetuses affected at earlier gestations. Prompt diagnosis and proper antibiotic therapy can significantly reduce the fetal and neonatal complications associated with maternal listeriosis.

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