Overall, congenital CMV is estimated to affect 0.4% to 2.3% of all live births (59). It is one of the major nongenetic causes of sensory hearing loss and neurodevelopmental delay (60,61). Of these infants, only approximately 10% are symptomatic at birth or in the neonatal period (49,59). The mortality rate among symptomatic infants varies from 5% to 30% (60). It has been difficult to determine whether there is a difference in risk of disease based on the gestational age of the infant at the time of infection. Congenital CMV is a multisystem disease, and the following are seen in more than 50% of infants affected at birth: hepatosplenomegaly, jaundice, conjugated hyperbilirubinemia, thrombocytopenia, petechiae, microcephaly, seizures, hypotonia, intracranial calcifications, chorioretinitis, and unilateral or bilateral hearing loss (62,63,64). The intracranial calcifications seen in congenital CMV infections tend to be periventricular in location as is seen in Figure 44.1. Other neurologic abnormalities may include intraventricular hemorrhages, periventricular necrosis, cerebral hypoplasia, periventricular leukomalacia, hydrocephalus, and porencephalic cysts. Over time, neuromotor and psychomotor delay is diagnosed in approximately 50% of survivors. Infants with abnormal CT scans at birth have a 90% risk of developing one or more significant long-term neurologic sequelae (significant mental or psychomotor delay, seizures, cerebral palsy, or hearing loss) (65). However, 30% of symptomatic infants with a normal CT scan at birth will do so as well. Cerebral MRI scans may be both more sensitive and specific in predicting ultimate outcomes (66,67,68). Cranial ultrasounds will also detect a large number of abnormalities related to poor prognosis (67). Children who are asymptomatic and remain so until a year of age have similar neurologic testing as uninfected controls. Chorioretinitis is the most frequently diagnosed optic abnormality. Occasionally, this is the only abnormal finding. Although it is usually present at birth, some infants will develop it later in early infancy. Spontaneous resolution has been reported, but it usually progresses to significant visual impairment. Other optic abnormalities include optic atrophy, microphthalmia, cloudy cornea, corneal opacities, optic nerve hypoplasia, optic nerve coloboma, nystagmus, anophthalmia, and cytopia. Hearing loss can vary from mild to profound and occurs in about 50% of symptomatic survivors but also in from 7% to 13% of those with subclinical infections. Bilateral hearing loss is associated with maternal primary infection. It may be present at birth. Hearing deteriorates over the first 18 months in about 50% of infants. Dental defects have been observed in 40%
of surviving symptomatic infants and 5% of asymptomatic ones. In addition, infants infected with CMV may develop pneumonia and/or colitis. A wide variety of other congenital malformations have been described in infants with congenital CMV but not shown to be related to the infection.

The optimal treatment of congenital CMV infection remains to be determined (42). Ganciclovir and valganciclovir are the antiviral agents currently used for the treatment of symptomatic CMV-infected infants (72,73,74,75,76). They are generally recommended for use for viremic infants with a viral sepsis-like syndrome including pneumonitis, refractory thrombocytopenia, sight-threatening retinitis, and colitis. Infants with sensory hearing loss, microcephaly, and other central nervous system (CNS) manifestations, and other congenital CMV-related diseases may benefit from therapy. Determination of the CNS status of infants with CMV infection by cerebral MRI if possible, or CT scan or ultrasound if not, is important both for treatment decisions and for discussions of the infant’s prognosis with parents. Infants should be assessed by an ophthalmologist familiar with the ocular manifestations of congenital CMV. Infants should also have their hearing assessed. In addition, the infant’s complete blood count (CBC), renal and hepatic functions should be determined. Infants with severe congenital CMV can be treated with IV ganciclovir (6 mg/kg/dose administered IV every 12 hours) for 6 weeks; valganciclovir (16 mg/kg/dose administered orally every 12 hours) for 6 weeks or a combination of a short course of ganciclovir IV therapy followed by oral therapy with valganciclovir to complete a 6-week course. Whether a 6-month course of antiviral therapy would provide additional benefit is being studied, and preliminary results indicate that there may be additional benefit from a longer treatment course (75). Generally, CMV viral loads are not monitored during treatment, and viral loads will increase once treatment is discontinued. Infants diagnosed with congenital CMV should have close follow-up with developmental, hearing, and ophthalmologic assessments. Routine IPC precautions are sufficient, but health care providers should be adherent to hand hygiene recommendations.

In pregnant women, the infection is asymptomatic in 80% to 90% (85). Lymphadenopathy is the most common clinical sign among those who do have symptoms (86). The involved lymph nodes are primarily in the head and neck and may often involve a single node. An estimated 1% to 5% of acute infectious mononucleosis is actually toxoplasmosis. Pregnant women may develop hepatitis, pneumonia, myocarditis, encephalitis, and deafness, but these manifestations are rare (87). Ocular involvement does occur, and when it does, it usually involves chorioretinitis and then retinochoroidal scars. Type I T. gondii infections are the ones that have been associated with severe ocular disease in immunocompetent individuals. Psychiatric complications including psychosis resembling schizophrenia, anxiety, and depression have been described in association with T. gondii acute infections. Fulminating disease is common in immunosuppressed patients such as pregnant women with advanced HIV infection (AIDS).

T. gondii causes transplacental infection in the fetus in around 1% if the infection occurred in the months immediately preceding the pregnancy, 10% to 25% of untreated pregnancies with acute infection in the first trimester, 20% to 54% in the second trimester, and 65% to 70% in the third trimester (86,88,89,90). Disease occurs despite the maternal immune response (91). Timely and appropriate maternal therapy reduces the risk of transmission by at least 50%, and the percentage of infants who manifest severe congenital toxoplasmosis is less if the mother receives therapy during pregnancy.

At least two-thirds of infants with congenital toxoplasmosis will not have apparent disease on general examination at birth (77,83,92,93,94,95,96,97). However, if carefully looked for, one-third of these infants will have some abnormality attributable to the infection such as an abnormal cerebrospinal fluid (CSF) examination with pleocytosis and/or elevated protein (20%), chorioretinitis (15%), or intracranial calcifications (10%). Over time, untreated infants will begin to show manifestations of the disease.

Symptomatic congenital toxoplasmosis can be mild, moderate, or severe at birth (77,98,99). It can involve multiple organ systems or present as an isolated abnormality, specifically hydrocephalus, hepatosplenomegaly, or prolonged hyperbilirubinemia. Between 25% and 50% of symptomatic infants are born prematurely. Only approximately 10% of affected infants have severe disease at birth, of whom 10% die and remainder generally have major neurologic abnormalities including mental retardation, seizures, spasticity, and visual defects. Systemic manifestations of congenital toxoplasmosis include fever, jaundice, anemia, hepatomegaly, splenomegaly, and/or chorioretinitis.

Neurologic abnormalities include encephalitis, seizures, hydrocephalus, and/or intracranial calcifications. CNS involvement is common. Parenchymal brain lesions usually involve a vasculitis of surrounding blood vessels resulting in thrombosis and infarction. If substantial, this can lead to obstruction of the aqueduct of Sylvius resulting in enlargement of the third and lateral ventricles and the development of hydrocephalus. Occasionally, hydrocephalus is the only manifestation of congenital toxoplasmosis. It may present at birth or later and be static or progress to requiring the placement of a shunt. Diffuse intracranial calcifications occur in 10% to 20% of infants but are found in up to 70% of those with symptomatic disease at birth as is seen in Figure 44.2. Although they may increase in number and size in some untreated infants, with treatment, 75% will decrease or totally resolve within a year. Other neurologic findings include bulging fontanelle, encephalitis, hydranencephaly, hypotonia, paralysis, spasticity, opisthotonus, microcephaly, swallowing difficulties, and/or proteinorachia. Radiologic CNS findings may show hydrocephalus, porencephaly, encephalomalacia, and/or cortical atrophy, which are consistent with an old insult during gestation. Alternatively but less commonly, they show single or multiple hypodense lesions with contrast ring enhancement, which imply an acute and active process.

Ocular toxoplasmosis can have a multitude of clinical presentations, which may include chorioretinitis, chorioretinal scars, iritis, leukocoria, microphthalmia, nystagmus, optic atrophy, optic coloboma, retinal folds and traction detachments, granulomas in the posterior pole, strabismus, small cornea, and/or cataracts (100,101,102) (see Fig. 44.3). Chorioretinal scars are the most common finding and are usually detected at the periphery. Macular scars are seen in up to 75% and may be bilateral in one-quarter of cases. These patients have markedly decreased visual acuity.

Unfortunately, most infants with severe symptomatic congenital toxoplasmosis who survive will have significant sequelae despite therapy. This most commonly involves developmental delay and blindness. Those who are born with a subclinical infection and are not treated will all develop eye disease by 10 to 20 years of age and approximately 50% will go on to develop neurologic sequelae (77). Children born with subclinical infection who receive treatment have a better long-term prognosis, but 75% will still have some
evidence of retinal disease although the clinical severity appears to be less. Both untreated and treated infants can have recurrences of ocular toxoplasmosis, but this is less frequent among treated infants (40% to 60% compared to 76% to 82%).

Treatment of acute toxoplasmosis is not usually undertaken except in the case of pregnant women. Women who are diagnosed with toxoplasmosis in the first half of pregnancy may elect to terminate their pregnancy. Although the risk of congenital infection is lower, those who are affected tend to be more severely so.

It is recommended that women, who elect to continue their pregnancy, be treated with spiramycin as soon as possible (89,90,107,113). Spiramycin is a macrolide antibiotic that is active against T. gondii and can cross the placenta and enter the cord blood and the placenta. Side effects are primarily maternal nausea, vomiting, and diarrhea. It is rated as a class c drug in pregnancy and is licensed for use in Canada and Europe in pregnancy and available for special access in the United States. The recommended dose is 1 g three times daily, which unfortunately does not seem to reliably provide antibiotic levels in fetal serum, placental tissue, or the amniotic fluid to inhibit the parasite. Studies of its effectiveness are inconclusive. It is thought to reduce the risk of intrauterine infection to the fetus, but it does not seem to affect the course of infection once it has occurred.

If the fetus has been shown to be infected, additional therapies are suggested for maternal treatment during the pregnancy. Presently, this includes the use of pyrimethamine and sulfadiazine. Pyrimethamine is an antimalarial drug and is a folic acid antagonist. It has a long half-life and achieves high tissue concentrations, particularly in brain. It causes bone marrow suppression that can result in anemia, granulocytopenia, thrombocytopenia, and pancytopenia, which on occasion is severe. Other side effects include a bad taste in the mouth, headache, and gastrointestinal side effects. The drug is known to be teratogenic in animals and so should be avoided in the first 5 months of pregnancy. Sulfadiazine acts synergistically with pyrimethamine against T. gondii and is also a folic acid antagonist. Bone marrow suppression is also a concern with its use, and patients frequently have rashes, crystalluria, hematuria, and renal failure, which is usually reversible with discontinuation of the drug. It is unknown whether this regimen reduces the transmission of T. gondii and, because of the toxicity, is only recommended in an attempt to treat a known infected fetus prenatally. It is thought to reduce the occurrence of severe congenital infection and increase the proportion of infants born with asymptomatic toxoplasmosis. If used, the combination is provided along with leucovorin supplements alternating monthly with spiramycin.

Although there are no clinical controlled trials to guide therapy, treatment protocols have been developed for congenitally infected infants that show effectiveness when compared to historical outcomes (97,101,102,114,115). The treatment of symptomatic infants during the first 12 months of life usually involves the use of pyrimethamine, sulfadiazine, and leucovorin. The dosages usually used are as follows: pyrimethamine 2 mg/kg/d orally for two doses as an initial loading dose following by 1 mg/kg (either daily or divided bid) for the first 6 months after birth and then on alternate days for the next 6 months (months 7 to 12); sulfadiazine 100 mg/kg/d orally divided into bid dosing for 12 months; and leucovorin 10 mg IM three times per week for 12 months. Some centers modify this treatment regime after the first 6 months of therapy so that the therapy from months 7 to 12 after birth involves alternating months of spiramycin therapy of 100 mg/kg/d in divided doses with months of pyrimethamine, sulfadiazine, and leucovorin. Infants with chorioretinitis or CSF protein elevations (≥1 g/dL) also generally receive prednisone or methylprednisolone (1.0 to 1.5 mg/kg/d orally divided bid) to reduce the inflammatory response while on antitoxoplasmosis therapy. Pyrimethamine serum levels do not vary significantly by age; therefore, there is no need to adjust the dosage other than by the weight of the child, which should be done weekly. Infants need to have their CBCs monitored weekly for the first 6 months of therapy and thereafter every other week when receiving pyrimethamine. The dose of leucovorin can be increased if the absolute neutrophil count (ANC) falls below 1,000 × 106/L. The pyrimethamine should be held if the ANC falls below 500 × 106/L. For infants who develop an allergy to sulfadiazine, clindamycin at a dosage of 20 to 30 mg/kg/d can be substituted. The usual presentation of allergy to sulfadiazine is skin rash, such as hives or allergic dermatitis. However, some infants can have sulfadiazine-induced leucopenia that presents with persistent leucopenia despite increased dosing of leucovorin and discontinuation of pyrimethamine. Children with glucose-6-phosphate dehydrogenase (G6PD) deficiency should receive clindamycin in place of sulfadiazine. Treatment of children on medication for seizures may be complicated. Pyrimethamine serum concentrations and half-life is reduced for infants who are also being treated with phenobarbital. Pyrimethamine overdosage can cause seizures. Sulfadiazine may increase the half-life of phenytoin due to interference with hepatic
microsomal enzymes and so dosage adjustment is necessary. Use of sulfadiazine with carbamazepine or clonazepam may exacerbate bone marrow suppression and neutropenia. Finally, sulfadiazine is excreted via the renal system, and dosage adjustment is necessary for infants with renal impairment. Renal and hepatic function should be tested at the beginning of therapy and monitored every few months while on therapy.

Infants who are determined to have congenital toxoplasmosis and who are asymptomatic at birth also should be treated. The recommended treatment involves an initial 6-week course of pyrimethamine, sulfadiazine, and leucovorin in the same doses used for symptomatic infants. They then continue with alternating courses of spiramycin for 6 weeks and pyrimethamine, sulfadiazine and leucovorin for 4 weeks to complete a 1-year course of therapy. Monitoring for drug adverse effects while on pyrimethamine is similar to that described above.

For asymptomatic infants born to mothers with documented gestational toxoplasmosis for whom the suspected diagnosis of congenital toxoplasmosis is not yet confirmed, initial treatment with pyrimethamine, sulfadiazine, and leucovorin can be started while awaiting definitive study results. If the diagnosis is confirmed, then the treatment for asymptomatic congenital toxoplasmosis can be continued.

For healthy infants born to mothers with suspected but not confirmed gestational toxoplasmosis, spiramycin can be started while awaiting the definitive test results.

All infants with congenital toxoplasmosis who survive will need close follow-up in childhood for developmental issues and lifelong for ocular disease regardless of their initial presentation.

In postnatal transmission, the virus initially multiplies in cells of the nasopharynx followed by a period of systemic viremia and shedding from the throat during which the placenta and fetus are infected. The risk of infection to the fetus and its consequences are determined by the serostatus of the mother and the gestation of the pregnancy at the time of the transmission to the fetus. How the fetus sustains such extensive damage is not completely understood. Placental vascular endothelial cells become necrotic and may result in virus-infected emboli (128,129). Thrombosis of the small blood vessels results in hypoxic tissue damage. Rubella-infected cells have reduced mitotic potential as a result of chromosomal breaks. They produce a growth-inhibiting protein and have mitochondrial changes that may result in alterations in cell metabolism. Finally, by altering the actin filament arrangements, the cytoskeletal microtubular system is altered (130). The virus establishes a chronic nonlytic infection of the fetus that can involve any organ system (131). It can induce apoptosis, but the role of this in the teratogenicity of the virus is not established. Focal lysis of cells without associated inflammation is seen and so it is a noninflammatory process resulting in necrosis of the heart, eyes, brain, and ears. The growth restriction seen in rubella is associated with actual reduction in cell numbers (132). Ongoing damage results in late manifestations, which are thought to be viral persistence in association with ineffective immune mechanisms including rubella-specific immune complexes, defective cytotoxic effector cell function, or autoimmunity (133,134,135,136,137). Two rubella-specific proteins (E1 and E2 proteins) found on the viral envelop are thought to be responsible for autoantibody production.

The clinical presentation in postnatal infection may be subclinical seroconversion that occurs in 20% to 50% but which still represents a risk of congenital disease for the fetus (133). For those who develop disease, symptoms start between 12 and 24 days (mean 18) from exposure and begin with a prodrome of malaise. A low-grade fever may be present from 1 to 5 days before the onset of the rash and usually resolves on the first day of the rash presents. The rash is similar to that of measles in that it typically presents of the face or occipital region as a macular papular rash that moves down the body over a 1- to 2-day period. It then disappears after 3 to 5 days. It is not as erythematous as that of measles and there is not the sandpaper feel to the rash as it resolves. There may be an associated conjunctivitis as well as postauricular, suboccipital, and posterior cervical lymphadenopathy. Among adults, arthralgias are also common. Some individuals can have a complicated illness. Pregnancy does not seem to affect the presentation of disease.

Congenital rubella infection may present with a wide variety of clinical findings at birth or the infant may appear normal at delivery
and signs develop over time (118,130,132,134,135,136,137,138,139,140,141,142). The initial characterization of CRS as the triad of heart defects, cataract and hearing defects in association with maternal rubella infection in the first trimester of pregnancy has expanded considerably over time. The most common abnormalities in decreasing order of frequency are: sensorineural hearing loss, mental retardation, cardiac malformations and ocular defects. The development of late-onset CRS manifestations may be related to persistence or reactivation of the viral infection, the immune response, or consequences of vascular damage. Intrauterine growth restriction is present from 50% to 85% of infants. This may be the only initial sign. Most infants also have disturbances in postnatal growth, which is more pronounced among those with other congenital defects. Heart defects are seen more commonly in infants infected in the first trimester. Patent ductus arteriosus is found in 30% of affected infants and which may be associated with other cardiac defects, most commonly pulmonary valvular or artery stenosis. Pulmonary artery stenosis is the next most common heart defect and results from intimal proliferation. Other cardiac defects in CRS include coarctation of the aorta, atrial and ventricular septal defects, tetralogy of Fallot, ventricular aneurysm, myocarditis, and aneurysms of peripheral arteries. Hearing loss is the most common specific congenital defect. It is frequently seen as part of the CRS. It is usually bilateral. It may be present at birth or it may develop over time and be progressive. It is rarely seen if the maternal infection occurred after 17 weeks of gestation. Cataract is found in 35% of infants. It may be either unilateral or bilateral and is seen at birth or shortly thereafter, as part of the routine eye examination for the red reflex. In some cases, it may resolve spontaneously; however, most will require cataract surgery. Depending upon the other manifestations and the age at which the surgery is done, improvement in visual acuity may be disappointing. In addition, retinopathy is found in 35% to 60% of infants. It also may be present at birth or be detected later in life. It is often unilateral and has a distinctive “salt and pepper” appearance. Fortunately, it alone does not appear to affect visual acuity. Some infants may present with a cloudy cornea that usually spontaneously resolves. Glaucoma occurs in less than 10% of infants. It may be bilateral and, like the other ophthalmologic abnormalities, may be either present at birth or diagnosed later. It is important to assess infants over time for this problem as it leads to blindness if not appropriately treated. Many infants with cataract will also have microphthalmia. These infants have a higher risk of glaucoma. Other eye abnormalities that have been observed include iris hypoplasia, strabismus, and iridocyclitis. Approximately 5% in infants will develop an interstitial pneumonia which is thought to be immune mediated and which may be acute, subacute, or chronic. Approximately 20% of infants will have a transient meningoencephalitis, which may manifest with bulging anterior fontanelle, hypotonia, irritability, and seizures. CSF findings show a mononuclear pleocytosis, increased protein content, and rubella virus isolation in 30%. However, in approximately 35%, EEG abnormalities are detectable during the first year of life. Rarely, a progressive rubella panencephalitis can occur. This is a chronic infection that becomes symptomatic in the early teenage years. Some infants will present with microcephaly and/or intracranial calcifications and/or a large anterior fontanelle. Most infants will have neurodevelopmental issues. These range from developmental delay, speech defects in association with hearing loss, and behavior difficulties that may be associated with undiagnosed hearing loss. In approximately 5%, blueberry muffin spots may be transiently seen and some children will have chronic rashes from which rubella virus can be isolated. There are a number of dermatoglyphic abnormalities that serve as a marker for viral teratogenicity. There are also a number of genitourinary malformations that have been seen in CRS. These include cryptorchidism, testicular agenesis, scrotal calcifications, hypospadias, hydroureter, hydronephrosis, ureteral duplication, polycystic kidneys, renal agenesis, and renal artery stenosis with hypertension. Radiolucencies in the distal femur and/or the proximal tibia are found in radiographs in 10% to 20%. These resolve by approximately 3 months of age and are thought to be due to the direct inhibitory effect of rubella virus on bone and cartilage cells. More than 50% of symptomatic infants will have hepatosplenomegaly at birth that resolves over several weeks. Hepatitis may also occur in 5% to 10% which may, or may not, be associated with jaundice. Obstructive jaundice occurs in about 5% of infants. Some infants may have pancreatitis or intra-abdominal calcifications. There may be structural abnormalities of gastrointestinal tract that include esophageal, jejunal or rectal atresia, and some children will have chronic diarrhea. In infants with severe disease, thrombocytopenic purpura occurs at birth from 5% to 10%. Some children will have a transient anemia that may be hemolytic in nature. Rubella virus can infect fetal pancreatic islet cells resulting in the reduction of insulin secretion. Approximately 20% of children with CRS will develop insulin-dependent diabetes by 35 years of age (143,144). The majority of these individuals have circulating pancreatic islet cell cytotoxic or surface antibodies apparently triggered by the rubella virus. Other rare diseases include hypo or dysgammaglobulinemia, thymic hypoplasia, hypothyroidism, hyperthyroidism, thyroiditis, growth hormone deficiency, and precocious puberty.

There is no specific antiviral treatment of rubella. Management of infected individuals is supportive, usually involving multiple medical specialties. CRS patients frequently require corrective surgery. Children diagnosed with CRS or congenital rubella infection or CRS compatible disease should be monitored for the development of late-onset disease manifestations.

Prevention of infection via immunization programs to ensure that the incidence of rubella is low and that pregnant women are not susceptible to rubella is the hallmark of the strategy to combat congenital rubella (118,156,157). The most common vaccine strain used is RA 27/3 attenuated live rubella virus vaccine which is most commonly given in combination with vaccines for measles and mumps (MMR) or newer vaccines that also contain varicella (MMR-V). It produces an antibody response in more than 95% of individuals 12 months of age and older and is 90% effective at preventing disease for at least 15 years after immunization. It is safe to immunize a child or household contact with rubella vaccine if the pregnant mother is susceptible. A booster vaccine is usually given from 3 months to 4 years after the initial immunization as part of the routine childhood immunization schedule in jurisdictions where there is a rubella immunization program. Pregnant women whose rubella immune status has not been established should be screened at the first prenatal visit. Women found to be susceptible should be counseled regarding the risk of rubella and to seek care should they come into contact with another individual suspected or diagnosed with rubella or if they develop a febrile rash illness that is consistent with rubella.

Pregnant women who were seronegative should have rubella immunization immediately in the postpartum period. Immunization during pregnancy is to be avoided. Programs that provide this immunization prior to discharge from hospital are more successful than those that require immunization to be provided at a postpartum clinical visit. Some women may develop postimmunization arthritis or arthralgias in the postpartum period, particularly those with certain human leukocyte antigen class II (HLA-DR) phenotypes, in particular those with DR4 and either DR1 or DR2 (158). The rubella virus may be shed in breast milk and infect the neonate, but this is not a contraindication to postpartum maternal immunization.

Immunization during pregnancy is not advised. Over 700 women have been followed after inadvertently having been immunized either immediately before pregnancy or in the first 12 weeks of pregnancy (159). The vaccine virus was demonstrated to cross the placental barrier in a few cases, but the observed rate of CRS has been zero. In one case though, the infant excreted the vaccine virus for several months. Susceptible pregnant women should avoid contact with children with CRS or congenital rubella infection for the first year of the infant’s life. Infants suspected to have or to have been proven to have congenital rubella should be placed on contact precautions for the first year of life unless they have been shown to have negative rubella cultures on two occasions taken 3 months apart (157).

Once the spirochete crosses the placental barrier, it widely disseminates throughout the fetus (164). The manifestations of congenital syphilis are a result of the host responses to T. pallidum (165,166,167). Regardless of the organ system involved, the pathologic appearance of infected tissue shows perivascular infiltration by lymphocytes, plasma cells, and histiocytes-producing obliterative endarteritis and extensive fibrosis. Placentas in which the pregnancy is complicated by syphilis tend to be relatively large with focal villitis and, in those infants who are symptomatic at birth, a necrotizing funisitis (168). A few infected live born infants may have clear manifestations of illness at birth, usually presenting with vesicular or bullous skin lesions and/or hepatosplenomegaly. Most infants though are asymptomatic in the early neonatal period. Approximately 60% of affected infants will develop some clinical manifestation of congenital syphilis by 3 months of life. The development of “snuffles,” a thick purulent nasal discharge that is highly infectious and teeming with spirochetes, along with palmar and plantar bullae (also highly infectious) and splenomegaly is a highly suggestive clinical presentation of congenital syphilis and usually is seen beginning around week 3 of life. Osteochondritis and periostitis may be seen in the long bones or in the ribs. This may be present at birth in an otherwise asymptomatic infant. In some instances, this may result in fracture, and the infant will decline to move the affected limb (pseudoparalysis of Parrot). Other signs are less specific and include fever, lymphadenopathy, pneumonitis, irritability, meningitis, hepatosplenomegaly, hepatitis, jaundice, pancreatitis, glomerulonephritis or nephrotic syndrome, hemolytic anemia, disseminated intravascular coagulation (DIC), thrombocytopenia, and failure to thrive. Pneumonia due to syphilis classically shows complete opacification of both lung fields if not treated (pneumonia alba). The hemolytic anemia may be associated with cryoglobulinemia, immune complex formation, and macroglobulinemia and be refractory to treatment and last for months. The hepatosplenomegaly is caused by extramedullary hematopoiesis and inflammation. The associated jaundice is caused by hemolysis and/or hepatitis. The hepatitis associated with syphilis usually has high alkaline phosphatase, transaminases, and γ-glutamyl transferase concentrations that worsen transiently but significantly with penicillin treatment. Some children may have fulminant sepsis like presentations with hypoglycemia, lactic acidosis, encephalopathy, and DIC in association with hepatic failure. Hepatic abnormalities may persist for up to a year after treatment. Premature infants are more likely to develop severe early disease than are term infants. However, signs may not develop until puberty in some infected children. These late signs include alterations of the permanent teeth (Hutchinson teeth—peg-shaped and notched upper central incisors; mulberry molars—multicuspid first molars), interstitial keratitis, secondary glaucoma, eighth nerve deafness, saddle nose deformity due to scarring by syphilitic rhinitis, cranial nerve palsies, developmental delay, hydrocephalus, epilepsy, optic nerve atrophy, frontal bossing, saber shins (anterior bowing of the mid tibia), and Clutton joints (synovial effusions of the knees).

The clinical presentation of untreated Lyme disease after the neonatal period involves three general stages (175). The first stage occurs within 7 to 28 days of the tick bite and involves the development of a characteristic rash, erythema migrans (EM), at the tick bite site. This occurs in approximately 80% of infected patients. The second stage involves early dissemination of the spirochete and is manifested by multiple EM lesions along with neurologic and/or cardiac findings. The neurologic findings may include meningitis, unilateral or bilateral facial nerve palsies, and peripheral motor and/or sensory neuropathies. The cardiac findings usually involve first-degree atrioventricular block. During the first and second stages, the spirochete can be recovered from the blood in up to 50% of cases. Late Lyme disease may develop months to years after the initial infection and is characterized by intermittent or persistent arthritis usually involving one or more large joints, specifically the knee, along with subtle cognitive disturbances, which may indicate encephalopathy, or polyneuropathy involving spinal radicular pain or distal paresthesias. B. garinii may be responsible for a more severe form of chronic encephalomyelitis. Some patients demonstrate a prolonged post-Lyme disease syndrome that can be debilitating and for which the cause and treatment has not yet clearly been determined. Re-infections can occur with subsequent bites by infected ticks among individuals who have been appropriately treated during previous primary or secondary stages of illness.

Since Borrelia are spirochetes and a blood borne phase with dissemination clearly occurs, there is concern of transplacental transmission to the fetus during those times. At present, there has not been a congenital Lyme disease syndrome identified. Specifically, studies done in highly endemic areas involving more than 3,700 pregnancies have not shown an association with maternal-positive Lyme serology and/or history of tick bite in pregnancy with adverse pregnancy outcomes including fetal malformations (176,177,178,179). However, the spirochete can be transmitted to the fetus when the mother is not treated, and there is one case report in which this occurred despite penicillin therapy in the first trimester (180,181). Postnatally, there is no evidence of mother-to-child transmission through breast milk or close contact.

The treatment of pregnant women found to have clinical Lyme disease depends upon the stage of the disease and whether neurologic involvement is present (175). For primary illness involving EM, oral amoxicillin 500 mg three times daily for 14 to 21 days or cefuroxime axetil 500 mg twice daily for the same time period if allergic to amoxicillin. For those with neurologic symptoms, either intravenous ceftriaxone (2 g daily) or cefotaxime (2 g three times a day) for 14 to 28 days is recommended. Pregnant women whose only neurologic manifestation is facial nerve palsy could be treated with oral amoxicillin. Arthritis is treated with either oral or intravenous antibiotics for 30 to 60 days. Women who are found to be seropositive for Lyme disease in pregnancy and are asymptomatic do not require treatment. Women who have had a recent tick bite do not require antibiotic prophylaxis.

There are no management or treatment guidelines for the infant found to be infected with B. burgdorferi. Consultation with a specialist in pediatric infectious diseases would be recommended.

Pregnant women should be counseled regarding prevention of tick bites by avoiding tick-infested areas or, if this is not possible, reducing the risk of contact by using protective clothing, insect repellants (DEET containing repellants are considered to be safe in pregnancy), and by daily complete examination of the body for ticks and rapid removal of any found to be attached.

In postnatal transmission, VZV is transmitted from infectious secretions through either the conjunctiva or nasal/oral mucosa (184,187,191). Primary infection of the respiratory tract is followed by viral replication in the regional lymph nodes and tonsils for 4 to 6 days and is then spread systemically to other internal organs. There is then a secondary viremia, which is associated with cutaneous involvement and the development of the characteristic rash. In pregnancy, infection of the fetus occurs during either the first or second viremic stage. The sites of infection in the fetus are not clear. Fetal chickenpox is thought to occur based on the findings of cutaneous scars. After resolution, there is subsequent infection of the dorsal root ganglia, which may result in cell destruction of the nerve tissue.

Very few postnatal varicella infections are subclinical; however, infections in young children less than a year of age may be missed as they tend to have very few lesions. Typically in the postnatal period, the illness consists of fever, malaise, and a distinctive pruritic rash (191). There may be a prodromal period of fever, malaise, and/or myalgia 1 to 4 days before the development of the rash. The rash usually starts of the face and trunk and moves outward to the extremities. It is characterized by successive crops of macules that develop into papules and then into vesicles. The initial vesicles are classically described as “teardrops on a red base.” Over the next 24 hours, they gradually crust over. The rash characteristically shows a combination of vesicles, papules, and crusted lesions of different sizes seen at the same time. New lesions appear daily over 3 to 5 days. Once the lesions are crusted over and no new lesions have appeared over a 24- to 48-hour period, the individual is no longer considered to be infectious. Morbidity and mortality increases with age. Although adults account for only about 2% of clinical varicella cases, 25% of the mortality due to varicella occurs in this age group. Complications include the development of varicella pneumonia which is described more frequently among pregnant women, encephalitis, bleeding diathesis, and secondary bacterial skin infections, particularly necrotizing fasciitis due to GAS.

Zoster tends to initially present with nerve root pain along a dermatome followed within days to weeks by the appearance of a papular/vesicular rash. It is usually unilateral and involves one or two adjacent dermatomes. Rash extending beyond two dermatomes implies a disseminated VZV reactivation.

VZV transmission occurs to the fetus via the transplacental route. There is some in vitro evidence that it may result in chromosomal breaks in the fetal cells, in particularly fetal leukocytes (192). There is also suspicion that there is an increase in the incidence of leukemia among infants exposed to varicella in gestation; however, the numbers involved are too small to confirm the association (193).

The congenital abnormalities associated with gestational varicella are primarily cutaneous, musculoskeletal, neurologic, and ocular (183,189,190). The most common skin abnormalities are cicatricial lesions. Limb abnormalities include hypoplasia, atrophy, and/or paresis. Limb hypoplasia is usually unilateral involving the leg. However, involvement of the arm, mandible, or hemithorax has been described. Rudimentary digits can be seen. The pathophysiology of the limb abnormalities is thought to be as a consequence of a neuropathy resulting from damage to the dorsal ganglia and anterior columns of the spinal cord. Cutaneous scars are found on hypoplastic limbs, the trunk, or the opposite extremity (see Fig. 44.4). CNS findings more commonly include microcephaly, cortical and cerebral atrophy, psychomotor retardation, seizures, and foal brain calcifications. Other findings that have been observed include low birth weight, autonomic dysfunction manifesting as loss of bowel and urinary sphincter control, dysphagia, intestinal obstruction,
and Horner syndrome. Unilateral or bilateral ocular abnormalities are also common. These include optic nerve atrophy, cataracts, chorioretinitis, microphthalmos, and/or nystagmus. The mortality rate during the first few months of life among infants with congenital varicella syndrome is reported to be 30%. Among the survivors, 15% will develop zoster sometime in the first 4 years of life.

Treatment considerations of varicella have evolved over the past 10 years (182,195). Children receiving treatment with oral acyclovir will have a shortened course of illness and period of infectivity. Pregnant women with varicella pneumonia or other varicellarelated complications need admission to hospital and treatment with IV acyclovir (10 mg/kg every 8 hours). There have not been any controlled studies addressing the treatment of uncomplicated varicella in pregnancy. The American Academy of Pediatrics does not recommend treatment with acyclovir in this situation citing safety concerns. However, acyclovir has been used frequently to treat varicella, zoster, and herpes simplex infections in pregnancy without significant adverse effects. Therefore, many experts would recommend the treatment of any pregnant women with uncomplicated varicella with oral acyclovir (20 mg/kg four times daily for 5 days). Whether treatment would reduce the risk or the severity of congenital varicella syndrome is unknown.

At this time, there are no recommendations for routine serologic screening of pregnant women. Many obstetricians obtain a verbal history of exposure and do serologic testing of those who are unsure of their status. Varicella vaccine should not be given in pregnancy, but it can be safely used in the postpartum period. Mothers who do not know whether they have had varicella or varicella vaccine should be tested for IgG antibodies to VZV if a known or suspected exposure has occurred. The majority will likely be found to be immune. Those found to be nonimmune and who have a known exposure to VZV can be provided with varicella immune globulin if the exposure was within 10 days. The current formulation in the United States and Canada is VariZIG, and the adult dose is 625 units, given IM. If VariZIG or a similar product is not available, IVIG at a dose of 400 mg/kg has been used. Whether the use of either of these products will prevent congenital varicella syndrome is unknown.

There are no antiviral treatment recommendations for children born with congenital varicella syndrome.

It is the causative agent for fifth disease or erythema infectiosum, a syndrome usually seen in children associated with a characteristic immune-mediated “slapped cheek” rash (196,197). The rash is lacy or reticulated, spreads to the trunk and extremities, and may last up to 2 weeks. It also may reappear with exposure to sunlight, temperature changes, or emotional stress. There may also be a number of other rash presentations associated including erythema multiforme. Some adults will have an influenza-like illness, and there is also frequently an associated immune-mediated symmetrical arthritis usually involving the hands but may also involve the wrists, ankles, and knees. However, half of infected adults have a subclinical presentation. It is associated with aplastic crisis in sickle-cell anemia and other hemolytic diseases and, importantly for neonatology, hydrops fetalis. It produces a lytic infection in human erythroid progenitor cells due to tropism for erythrocyte P antigen (globoside). Individuals who are “p” phenotype are naturally resistant to Parvovirus B19 infection (estimated to be 1 per 200,000) (196,202). Globoside is also found on megakaryocytes, endothelial cells, placenta, fetal liver, and heart cells. B19 also binds to other glycophospholipids found on granulocytes as well as kidney, liver, heart, and bowel cells. Therefore, infection with this virus tends to involve multiple organ systems. For infants, the suppressed fetal bone marrow leads to chronic anemia, which is not well tolerated by the fetus, and congestive heart failure develops leading to severe anemia. Parvovirus B19 may also directly affect the cardiac muscle function, which may also contribute to the disease (203). A number of other congenital abnormalities have been reported among infants with Parvovirus B19 infection, but causation has not been established.

There is no specific treatment for Parvovirus B19. Although there was one published case in which IVIG was successfully used, this is not currently a recommended therapy (205). Essentially, the management of the hydropic fetus may include in utero blood transfusions (196). Postnatally, treatment is supportive and involves partial exchange transfusions or simple transfusions of packed red cells until the hemoglobin is stabilized. Infants diagnosed with hydrops fetalis should be delivered in a facility with neonatal tertiary care. These infants are difficult to manage in the early neonatal period. The majority will need respiratory assistance and mechanical ventilation, and this may be complicated by the presence of pulmonary edema as well as large pleural effusions and peritoneal ascites. These may need drainage urgently to facilitate resuscitation. The clinical criteria for deciding to do intrauterine fetal blood transfusion is complex as approximately two-thirds of infants diagnosed with Parvovirus B19-associated hydrops fetalis will have the hydrops resolve without specific treatment. Most of these were not those severely affected. Approximately one-third of affected fetuses also have thrombocytopenia. Therefore, if intrauterine transfusions are done, it is important to check the fetal platelet count and be prepared to administer platelets as exsanguination can occur during the procedure if the fetus is thrombocytopenic. In general, there are no long-term sequelae for those infants who recover, although there have been recent reports of adverse neurodevelopmental outcome although it is not clear whether this is related to the severity of illness in the neonatal period. They are not at risk of chronic infection. Individuals with active Parvovirus B19 infections should be placed on droplet precautions. Congenitally infected infants do not need to be put on additional precautions if the hydrops has resolved by the time of birth (206).

The degree of illness associated with malaria is based on the degree of parasitemia during the erythrocyte phase, which is, in turn, related to the species of parasite with P. falciparum producing the highest parasite load, the degree of previous specific immunity to the parasite and the status of the immune system in general. Pregnant women have a greater risk than do nonpregnant women. Pregnant women who are also HIV seropositive have an even greater risk of severe disease (214,215,216). Women who live in highly endemic regions are more likely to have experienced one or more episodes of malaria and so are more likely to be partially immune. They are still at risk of acquiring malaria but are less likely to have severe disease. Women who leave areas of high endemic activity lose this partial immunity over time and are therefore more susceptible if they return. The reason that primigravida women have a great risk of severe disease in highly endemic regions is that, at least for P. falciparum, there is a pregnancy-specific immunity to malaria. Erythrocytes infected with certain clones of P. falciparum have the ability to sequester in the intervillous spaces of the placenta (217). Placental malaria occurs in approximately 40% of affected primigravida pregnancies (range 16% to 63%) compared with approximately 20% in multigravidas (range 12% to 33%) (218,219). Placental infection can be detected even in the situation where peripheral smears do not yield the parasite. Pregnancy tends to select for those clones that have the ability to infect the placenta (pregnancy-associated malaria), and with successive pregnancies in endemic areas, women become partially immune to these clones. Interestingly, women make specific antibodies to these clones while men do not. These specific P. falciparum clones express a class of variant surface antigens (VSAs) that result in the parasite-infected erythrocytes having the ability to adhere to chondroitin sulfate A, found on the syncytiotrophoblast lining, leading to syncytial degradation and occasionally localized villus destruction. Placental infection can also occur with P. vivax, but the mechanism appears to be different (220). Placental infection with P. falciparum has been suspected to influence neonatal immune responses to malarial challenge in the first year of life along with altered susceptibility to other pathogens and some vaccines (21). Infants born to primigravida mothers with placental malaria have a more balanced general Th1/Th2 immune response to antigen challenges over all compared with other infants. Placental malaria appears to affect transplacental antibody transfer and so infants have lower titers of antibodies at birth to a number of viral and bacterial pathogens, thus increasing their susceptibility to them earlier in the neonatal period. Interestingly, it is the infants of multiparous mothers who developed placental infection in more than one pregnancy who appear to have the greatest altered response to malaria during infancy resulting in increased susceptibility and risk of more severe disease. It may be that there is a genetic factor at play here as well.

The symptoms of malaria in the pregnant woman are similar to those of the nonpregnant adult (207,221). Almost all nonimmune individuals will present with fever. Once established, the fevers may be clearly periodic and reflect the cyclical release of parasites from the infected erythrocytes into the blood, which tends to become synchronized after the first few cycles. The time periods then reflect the species involved with periods of fever being every 24 hours for infection with P. knowlesi, 48 hours for P. falciparum, P. vivax, and P. ovale, and 72 hours for P. malariae. Frequently, the patient has chills, sweats, headaches, myalgias, fatigue, nausea, abdominal pain, vomiting, diarrhea, and/or cough in association with the fever spikes. Pregnant women are more likely to have severe hypoglycemia (58%) compared with nonpregnant women (8%). In the situation of severe malaria, there is significant anemia, jaundice, sequestration of erythrocytes in the brain (cerebral malaria) and kidney (black water fever) leading to death (222,223). Mothers remain at higher risk of severe disease for 2 to 3 months after delivery. However, in situations where the mother is partially immune, the infection may be asymptomatic with only anemia as a clinical sign that the infection has occurred. For the fetus, maternal infection can result in low birth weight (10% to 20%) or fetal loss (6% to 8%).

Congenital infection can occur with all species, but P. falciparum and P. vivax are the two species in which this has been described most frequently. For mothers who are partially immune, the actual risk of transmission to the fetus is low (0.1% to 1.5%); however, it may be as high as 10% for previously nonimmune mothers. In endemic areas, distinguishing congenital infection from mosquito-borne disease is not always possible. In nonendemic areas, that a mother had malaria is not always appreciated. Infants with congenital malaria generally present in the first 2 months of age with irritability, fever, anemia, thrombocytopenia, hyperbilirubinemia, splenomegaly, hepatomegaly, feeding difficulties with vomiting, and/or diarrhea. Infants with congenital P. vivax malaria may present at several months of age.

Treatment choices of malaria in pregnancy depend on the suspected or identified species, the degree of parasitemia if P. falciparum is suspected, and the clinical illness (226). Adverse effects in pregnancy of most antimalarial drugs have not been extensively studied. However, the potential severity of the disease and risk of maternal and fetal mortality dictate that treatment with these compounds should not be withheld. In general, management of a pregnant woman with malaria residing in nonendemic regions should be done in consultation with an infectious disease specialist or travel medicine specialist. Treatment protocols vary over time as resistance patterns change. The CDC Web site is a reference source most commonly used to help guide therapy based on prevalence of various malarial species and the antimalarial resistance patterns in the regions (http://www.cdc.gov/malaria). However, pregnant women with severe disease due to P. falciparum are usually treated with
therapy that may include clindamycin with either artesunate or quinine (227). Quinine is associated with hypoglycemia, which can adversely affect the fetus. Chloroquine can be used for chloroquinesensitive malarial strains. The use of doxycycline and primaquine is generally contraindicated in pregnancy and while breastfeeding.

There are limited clinical studies to guide therapy (226). As stated previously, the choice of medications is dependent on the malarial species. One suggested treatment guideline is as follows, but treatment of an infant with congenital malaria is best done in consultation with an expert in infectious diseases:

Supportive therapy includes hydration and monitoring for hypoglycemia.

Preventive strategies include deferment of travel by pregnant women to areas in which malaria is endemic. If travel is necessary, then measures should be taken to reduce exposure to mosquitoes, along with use of insect repellent and malaria chemoprophylaxis. Pregnant women should be advised to seek medical assessment if signs or symptoms compatible with malaria occur. Women should also be advised to report the details of any travel to a malarial area (both travel previous to and during the pregnancy) when presenting for delivery.

The pathophysiology of tuberculosis in pregnancy is similar to that of the nonpregnant woman (232). Pregnant women are no more likely to contract tuberculosis or reactivate latent disease more frequently than those who are not pregnant. The usual route of infection is inhalation of the bacteria with deposition in the lung. The actual infectious dose is not known but may be as low as 10 organisms. Replication in the lung occurs over several weeks. Some bacteria spread to regional lymph nodes via infected macrophages and from there may be disseminated to other areas in the body including the genital area and the placenta, if a woman is pregnant. After 1 to 3 months, the body can mount a cell-mediated immune response and control the infection. At that point, the tuberculin skin test becomes positive. The affected regions in the lung are essentially walled off by deposition of fibrin and calcium, but viable M. tuberculosis bacteria remain. At this stage, the individual is considered to have latent tuberculosis (LTBI). These bacteria are responsible for reactivation tuberculosis if the individual becomes immune suppressed. Congenital tuberculosis occurs through two mechanisms (233). The first is dissemination to the placenta if a woman is infected during her pregnancy or if she develops reactivation disease during her pregnancy. Primary infection of the mother during pregnancy tends to result in more severe disease for the fetus. The second mechanism is by direct infection from previously established maternal genitourinary tuberculosis. Infection can start at the time of menarche and may be asymptomatic for a long period. The ovaries, fallopian tubes, the uterus, and the cervix can all be infected. The most common symptom is infertility and so this route of infection for the infant occurs less often.

Maternal primary infection with M. tuberculosis is commonly asymptomatic or the illness produced is so mild that it is unrecognized (234,235). Only approximately 30% will have any pulmonary symptoms, which is usually just nonspecific cough. Some will develop retrosternal or pleural chest pain. Fever can be present and usually occurs as low-grade increases in temperature occurring for several days or weeks. Malaise, and fatigue and weight loss can occur, but these symptoms may not be easily distinguished in early pregnancy. In primary pulmonary tuberculosis, the chest radiograph may be normal, just show hilar adenopathy, show hilar adenopathy with a collapsed right middle lobe or show a pneumonia with or without hilar adenopathy and with or without pleural effusion. The changes in the chest radiograph take months to resolve. Maternal reactivation disease may only present with weight loss, cough, and fatigue. Over time, fever and night sweats occur in approximately 50%, chest pain in 30%, dyspnea in 30%, and hemoptysis in 25%. Chest radiographs are helpful in the diagnosis as most patients will have abnormalities present and so are appropriate to do in pregnant women as part of the investigation of potential tuberculosis (236). In tuberculosis reactivation, infiltrates are classically seen in the apical-posterior segments of the lungs in 80% to 90% of cases. Alternatively, infiltrates are seen in the superior segment of the lower lobes or the anterior segment of the upper lobes. Cavitation occurs in 20% to 40%. Granulomas due to M. tuberculosis can occur in other organs in addition to the genitourinary system, particularly bone and brain.

Congenital tuberculosis can present at birth or in the first few weeks of life (233). The clinical signs are related to the location and the size of the granulomatous lesions. Approximately 75% will have hepatomegaly in association with liver function abnormalities. A primary complex in the liver or caseating hepatic granuloma is diagnostic of congenital tuberculosis. Around 70% will have respiratory symptoms, most with an abnormal chest radiograph with infiltrates and 50% with a miliary pattern of disease. Occasionally, an infant will have a rapidly progressive pulmonary illness with the development of cavitary lesions. Other nonspecific findings include fever in approximately 50%, lymphadenopathy in approximately 40%, abdominal distention in 25%, and lethargy in 20%. One feature that has been described in from 15% to 20% of congenitally infected infants is tuberculosis of the ear presenting with chronic discharge. In approximately 10%, papular skin lesions will be seen. Other abnormalities that occur less frequently are apnea, vomiting, jaundice, seizures, cyanosis, and petechiae.

Asymptomatic pregnant women who are diagnosed with LTBI may, or may not, be offered therapy during pregnancy depending upon the risk assessment that is made as to whether she is likely to progress to active disease (237). For those not treated during pregnancy, treatment is usually deferred for 3 months after delivery to reduce the risk of maternal hepatitis. At the time of starting treatment in the postpartum period, the mother should be reassessed for the development of active, contagious disease. For women treated for LTBI in pregnancy, the usual medications that are given include isoniazid with pyridoxine supplementation or rifampin. The most common complication of these medications is hepatitis, and women should be monitored regularly for this. Other rarer complications include neuropsychiatric problems that can involve mania, depression and memory problems, peripheral neuritis, seizures, thrombocytopenia, hemolytic anemia, fever, and rash.

Women with uncomplicated active tuberculosis in pregnancy are treated in the same manner as nonpregnant women with the use of isoniazid, rifampin, and ethambutol as the first-line drugs (238,239). In the situation where there may be drug-resistant tuberculosis or the mother is coinfected with HIV, alternative regimens may be used, and their care is usually done in conjunction with an expert in tuberculosis and/or HIV care. Isoniazid, rifampin, and ethambutol are considered to be acceptable for use in pregnant women as there have not been any associated teratogenic effects. Hemorrhagic disease in the infant has been reported with rifampin use in pregnancy (240

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