Toxoplasmosis is caused by the protozoan parasite Toxoplasma gondii and, if acquired prenatally, can cause SNHL. Toxoplasmosis is acquired by exposure to undercooked meat, cat feces, soil, or water containing the parasite. The overall prevalence and incidence of congenital toxoplasmosis varies by region and country. In much of the United States, toxoplasmosis is not considered a reportable disease, making it difficult to get accurate incidence figures. Reporting is seriously hampered by the fact that primary infection in most adults (and therefore pregnant mothers) is asymptomatic. In 2000, the Centers for Disease Control and Prevention (CDC) reported that there were an estimated 400 to 4,000 cases of congenital toxoplasmosis in the United States, based on the seroconversion rate of pregnant mothers (21). Massachusetts began screening newborns for toxoplasmosis in 1986, and in 1994 a study from the New England Regional Newborn Screening Program found the incidence of toxoplasmosis in newborns to be 1/10,000 (22). From 1986 to 1998, a total of 99 cases was detected through this program in Massachusetts, but at least 6 cases eventually diagnosed cases were missed by the screening. The incidence of congenital toxoplasmosis varies outside the United States, estimated at 6 per 1,000 births in France, 2 per 1,000 births in Poland, 7 to 10 per 1,000 births in Colombia, and 3 per 1,000 births in Slovenia (23).The NHANES from 1999 to 2000 reported that of the 2,221 women aged 18 to 49 years tested for IgG antibodies to Toxoplasma 14.9% were positive, meaning that the remainder of the women were susceptible to primary infection. Mothers who become primarily infected with T. gondii have approximately a 30% to 50% chance of transmitting the infection to their fetus. Although the most severe disease is experienced by fetuses becoming infected during the first trimester, transmission of infection, which is transplacental, is much more common later in pregnancy, especially during the third trimester, or during delivery. Eighty-five percent of infants with congenital toxoplasmosis are asymptomatic at birth, with those infected later in pregnancy most likely to be asymptomatic. Although vertical transmission of infection is most likely to occur with primary maternal infection, immunocompromised women with chronic infection may also pass on the disease. If new infection is detected in the mother early in pregnancy, treatment with oral spiramycin, which does not cross the placenta, can prevent transmission to the fetus. If infection occurs later in pregnancy, and/or if the fetus is also infected, treatment with pyrimethamine, sulfadiazine, and folinic acid (pyrimethamine is a folic acid antagonist) may prevent transmission to the infant by treating the mother and may also treat the fetus (24).

The classic symptoms of congenital toxoplasmosis are chorioretinitis, hydrocephalus, and intracranial calcifications. Other symptoms, which can also be seen in other congenital infections including CMV, herpes, and rubella, may include hepatosplenomegaly, jaundice, anemia, microcephaly, and lymphadenopathy. Although a recent systematic review by Brown et al. (25) did not find any cases of hearing loss in infants with congenital toxoplasmosis, others have reported an incidence from 0% to 20%. Earlier studies with a higher incidence of SNHL
often included untreated infants, while most infants in recent studies had been treated, suggesting that adequate treatment decreases the occurrence of SNHL. Treatment of congenitally infected infants with pyrimethamine and sulfadiazine is generally effective, although infants who present without neurologic disease have somewhat better outcomes than those who present with neurologic impairment. In addition, babies asymptomatic at birth may develop signs later in life, including chorioretinitis (25).

Rubella is caused by a togavirus of the genus Rubivirus. Until the introduction of the rubella vaccine, rubella was the most common viral cause of congenital SNHL. The rate of congenital rubella syndrome (CRS) for infants born to women infected during their first 11 weeks of pregnancy is 90%; if infected during the first 20 weeks of pregnancy, it is 20%. The most common features of CRS are cataracts, heart defects, and hearing impairment. During the 1962 to 1965 global rubella pandemic, there were an estimated 12.5 million rubella cases in the United States, and 20,000 infants developed CRS. Following the licensure of live attenuated rubella vaccines in the United States in 1969, the number of reported cases of CRS declined 99%, from 77 cases in 1970 to one imported case in 2004. Although rubella is no longer endemic in the United States, it continues to be endemic in many other countries, where vaccination rates may also not be uniformly high in postpubertal females. Therefore, babies with congenital hearing loss born outside the United States in areas where rubella remains endemic, or born to mothers who may not have been vaccinated, may be more likely to have CRS as a cause of their hearing loss. According to the World Health Organization, the number of countries that have incorporated rubella vaccine into their immunization programs increased from 83 countries (13% of the birth cohort) in 1996 to 127 countries in 2008. In addition, the development of CRS is a theoretical risk in infants of mothers vaccinated during pregnancy, although this has not been reported in the literature. Any infant with CRS can shed the virus for up to 1 year after birth, so that all unvaccinated female caretakers should be aware that they may be at increased risk to become infected (26, 27) (http://www.who.int/immunization/newsroom/Global_Immunization_Data.pdf).

Prenatal exposure to CMV, a beta-herpes virus, is the most common congenital viral infection and currently the most common viral cause of congenital SNHL. A 2008 study in Dallas, Texas, by Stehel et al. documented a 6% incidence of congenital CMV in babies with confirmed hearing loss. The prevalence of congenital CMV infection is approximately 0.4% to 2.3% of all newborns. If the mother has a primary CMV infection during pregnancy, there is a 40% chance that the infant will become infected, and if she has a reactivation infection, there is about a 2% chance. The chance of transmission of primary infection from mother to child is 25% in the first trimester, 50% in the second, and 75% in the third. However, infants exposed to the virus during the first trimester are the most likely to develop serious neurologic sequelae. Although 90% of infants with congenital CMV are asymptomatic at birth, 10% to 15% will develop hearing loss, while 65% to 70% of infants with symptomatic CMV infection will develop hearing loss. In the study by Stehel et al. (28), 75% of the infants with congenital CMV were only diagnosed because they had hearing loss. However, since CMV hearing loss may be present at birth or it may not develop until later in infancy/childhood, the diagnosis can easily be missed (29). Infants with symptomatic CMV may present at birth with microcephaly, intrauterine growth restriction, developmental delay, hepatosplenomegaly, chorioretinitis, jaundice, petechiae, thrombocytopenia, hyperbilirubinemia, anemia, and hearing loss. The diagnosis of congenital CMV is made in the first few weeks of life by shell vial culture using saliva or urine. Recently, investigators have evaluated CMV polymerase chain reaction (PCR) using dried blood spots, liquid and dried saliva, and dried umbilical cord (30). Although PCR from any of these sources has not been found to be as sensitive as shell vial culture in the newborn period, positive PCR using dried blood spots can confirm a diagnosis of congenital CMV outside the newborn period when shell vial or CMV IgG cannot differentiate between congenital and postnatally acquired infection (31). In addition, PCR technology may be a basis for large-scale screening. Currently, treatment for the hearing loss involves at least 6 weeks of ganciclovir, or, more recently, valganciclovir, a pro drug of ganciclovir (32, 33). The optimal duration of therapy remains unclear, with some evidence supporting a longer course of therapy (up to 6 to 12 months). Although several studies support improved hearing with either of these drug regimens, the numbers of treated patients remain small, the follow-up is variable, and progression of the hearing loss may occur after the drugs are stopped. Side effects of ganciclovir and valganciclovir include bone marrow suppression (neutropenia, thrombocytopenia, anemia) and kidney and liver toxicity. Teratogenesis, mutagenesis, inhibition of spermatogenesis, and impaired fertility have been reported, primarily in animal studies, as a result of exposure to these agents. In addition, treatment of older children with progressive hearing loss due to congenital CMV has not been studied.

Once the baby is out of the newborn period, making a definite diagnosis of congenital CMV is difficult. It can be suspected, however, based on findings of developmental delay, microcephaly, and hearing loss. Visual impairment may be present in 10% to 20% of symptomatic babies and includes strabismus, optic atrophy, macular scarring, pigmentary retinitis, and visual loss. Boppana et al. (34) has reported late onset or reactivation chorioretinitis in 7/31 (23%) of children after 1 to 10 years of age. Imaging findings can help narrow the diagnosis in older children, or
confirm the diagnosis in newborns. Intracranial calcifications, migrational abnormalities (e.g., polymicrogyria), cerebral and cerebellar volume loss, ventriculomegaly, and white matter disease are commonly seen on a combination of ultrasound, magnetic resonance imaging (MRI), and computed tomography (CT). Characteristic imaging findings in association with neurodevelopmental delay strongly suggests a diagnosis of congenital CMV.

The prevention of congenital CMV is a major public health issue. CMV infection in healthy adults and children is common, often silent, and chronic, with viral shedding in urine and saliva continuing for months or years. This makes avoidance of infected individuals by pregnant women, although desirable, almost impossible. The timing of pregnancy related to when the mother developed a primary CMV infection has been found to affect whether subsequent infants develop CMV. Fowler et al. (35) found that for mothers who were initially CMV nonimmune or immune, a shorter interval between the birth at which the mother’s serologic status was established and the subsequent birth was associated with an increased risk of congenital CMV. It was also clear from this study that maternal CMV infection that occurs before getting pregnant still results in a substantial risk of congenital CMV.

However, because preconception maternal CMV immunity may confer a significant degree of protection against vertical transmission of the virus compared to primary infection during pregnancy, vaccination of young women before they get pregnant is an obvious route to protection (35). Although the development of an effective CMV vaccine has been difficult, Schleiss (36) has recently reported interim results of a phase II trial of a deoxyribonucleic acid (DNA) vaccine against CMV in a guinea pig model. Further population-based studies of transmission rates, severity of disease related to when the mother and fetus become infected, and vaccine development will be key to decreasing the overall prevalence and transmission of CMV in the population.

Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) are double-stranded DNA viruses that commonly infect humans (37). Neonatal HSV infections occur in approximately 1/3,200 births in the United States, with the majority being HSV-2 (37). Kimberlin (38) reported that 85% of transmission is peripartum, 10% is postnatal, and 5% is in utero, with primary maternal infection resulting in a higher transmission rate than reactivation disease. Approximately 50% of neonatal HSV infections have central nervous system (CNS) involvement. The incidence of hearing loss in children with neonatal HSV is unclear. A recent systematic review of the incidence of SNHL in neonates exposed to HSV was published in 2008 (39). They found that SNHL occurs rarely in infants with exposure to HSV and that there was no evidence of delayed onset of SNHL in infants with asymptomatic perinatal HSV infection. The few papers that reported audiometric data found hearing loss in association with intrauterine HSV-2 infection 0% to 33% of the time, with all infants also having severe CNS disease. However, all studies were small and audiometric techniques varied. The standard treatment for symptomatic perinatal HSV infection is acyclovir, but the effect of treatment on hearing loss is unclear. Based on the limited information available, Westerberg et al. (39) did not find that routine serologic screening for HSV infection in otherwise asymptomatic neonates with SNHL was justified.

Transplacental mother-to-child transmission of syphilis has been recognized since the 15th century. Congenital syphilis (CS) and syphilis acquired after birth are caused by Treponema pallidum, a gram-negative spirochete bacterium. Worldwide, 2 million mothers test positive for syphilis during pregnancy, comprising 1.5% of all pregnancies, and can lead to stillbirths and neonatal death. In the United States, however, CS is uncommon, with the result that hearing loss due to CS may be missed. A systematic review of CS cases and articles contained in multiple databases, including Medline (1950 to March 2008), EMBASE (1980 to March 2008), CINAHL (1982 to March 2008), BIOSIS Previews (1969 to March 2008), and Cochrane databases, was published in 2009 (40). These authors found no reported cases of SNHL in infants with CS born to mothers with syphilis acquired during pregnancy in any of the articles they reviewed. Between 2003 and 2005, the number of CS cases reported annually in the United States declined from 10.6 cases per 100,000 live births in 2003 to 8.2 in 2005, but then increased back to 10.1 per 100,000 live births in 2008. This increase in CS followed a 38% increase in the primary and secondary syphilis rate among US females from 2004 to 2007. In 2008, infants born to black mothers accounted for 50% of CS cases, infants of Hispanic mothers for 31% of cases, and infants of white, Asian/Pacific Islander, and American Indian/Alaskan Native mothers for 15%, 2%, and 1%, respectively. Despite this recent increase, however, CS remains uncommon in the United States, and therefore CS and any associated hearing loss may not be as readily recognized as in countries where it is more common. Hutchinson described the classic triad of late CS as interstitial keratitis, notched incisors, and SNHL (41). In 1970, Fiumara and Lessell (42) added to this triad Clutton joint (symmetrical hydrarthrosis especially of the knees) and mulberry molars (malformed first molar resembling a mulberry). Although any infant who presents with nonimmune hydrops, osteochondritis, periosteitis, hepatosplenomegaly, jaundice, rhinitis, mucocutaneous skin rash, and/or pseudoparalysis of an extremity should be suspected of having CS, there are no studies looking at the array of symptoms in infants who are actually serologically positive, raising the question whether hearing loss could be the only symptom of CS. Prenatal diagnosis involves testing pregnant mothers, with nearly complete elimination
of any serious complications in the baby if the mother is treated before 24 weeks gestation. For babies with CS identified after birth, appropriate treatment with penicillin (dose and duration dependent on formulation) usually results in a cure. If there is uncertainty about whether the mother has been adequately treated, evaluation of both the mother and infant should be undertaken shortly after birth. Syphilis acquired after birth may present as progressive and/or sudden hearing loss or vertigo. Therefore, the diagnosis of acquired syphilis should be considered in any sexually active patient who presents with recent onset hearing loss and/or vertigo, as these symptoms often improve with penicillin and steroids.