Infections

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Infections during pregnancy have long been recognized as contributors to maternal and infant mortality and morbidity, including long-term neurological impairments. The significant role of infection in early child survival and wellness has led to the development of a number of vaccines. During the later part of the 1990s and in the decade of 2000-2010 the infective process during gestation has received a significant amount of attention.

The route of infection of the fetus following maternal infection is through transplacental transmission or from the genital tract by the cervical amniotic route. The effect of a maternal infection on the fetus may be due to direct actions of toxins or organisms or it can be an indirect consequence of interference with placental or uterine function (Leviton & Gilles, 1996; Leviton & Paneth, 1990). The effect of a specific infection on fetal development is likely to depend on maternal and fetal factors including genetics, nutrition, stage of development, anatomical site of the infection, and the integrity of the placenta. After implantation interaction between the mother and fetus is mediated through the trophoblast, which has distinct immunological characteristics. In addition, the endometrium of pregnancy is unique and the general maternal response to major histocompatability complex (MHC) antigens in the conceptus is downregulated by maternal antifetal HLA (human leukocyte antigen) antibody production (Johnson, 1995). Other factors that influence the outcome include the characteristics of the organism, portal of entry, time of exposure, and dose of the infectious organism. One group of intrauterine infections, which has contributed to MR and other adverse consequences, is collectively known by the acronym TORCH: toxoplasmosis, other, rubella, cytomegalovirus (CMV), and herpes. The impact of these infections is dependent on the time of exposure during gestation.

CMV is one of the most ubiquitous viral infections in humans in the world, with prevalence rates reported from 20 to 95%. In some countries of Southeast Asia, Africa, and the South Pacific islands prevalence rates are reported above 90%, while in the United States and parts of Europe the prevalence is reported to be around 50%. Transmission occurs through shedding of the virus from nasopharyngeal secretions, urine, saliva, tears, genital secretions, breast milk, and blood. Maternal infections usually occur because of sexual transmission, and high number of sexual partners and early age of intercourse are predictors of occurrence of CMV. Perinatal transmission occurs through exposure of the fetus, in utero, to virus from reactivated or acute maternal disease. The virus can remain dormant in the host and cause latent infection and its sequella are exacerbated if the host has immune compromise. Exposure of the fetus to a primary CMV infection poses a risk of adverse outcome at any stage of pregnancy (Peckham, 1991). Approximately 10% of infants with asymptomatic infections at birth develop serious sequella, such as optic atrophy, learning disabilities, and MR (Faro & Soper, 2001). Congenital CMV is reported in 0.2-2.2% of all live births (Baumeister & Woodley-Zanthos, 1996). The mortality rate among symptomatic newborns is about 30%, and more than 90% of survivors have neurological impairments including microcephaly, seizures, MR, and hearing and vision problems. The pathway of transmission of congenital CMV is probably through the placenta and the critical period of exposure appears to be in the first trimester.

Toxoplasmosis is a disease caused by a protozoan, often transmitted through maternal handling of cat feces when changing a litter box or through the ingestion of raw or undercooked meat that contains the protozoa. It can be acquired either pre- or postnatally although the prenatal infection appears to have the most critical impact during the first trimester. Transmission of toxoplasma to the fetus occurs only when the mother has been infected for the first time during gestation, except if the mother has severe immune compromise. The outcomes associated with untreated prenatal exposure to the fetus include microcephaly, hydrocephalus, cerebral palsy, epilepsy, and MR (Baumeister & Kupstas, 1991; Remington, McLeod, & Desmonts, 1995; Roizen, Swisher, & Stein, 1995). Infant se-quella of a maternal infection can be prevented if it is detected and treated with spiramycin early in gestation or with pyrimethamine and sulfadiazine later in gestation. Although prevalence of congenitally infected infants in the United States is not available it has been estimated that 1-10 per 10,000 infants born annually have toxoplasmosis, and the majority is asymptomatic at birth and does not develop the sequella until later in life (Dunn et al., 1999; Guerina et al., 1994; Lebech et al., 1999).

The viral disease rubella has severe consequences when the infection occurs early in pregnancy. When a mother is infected in the first 12 weeks of pregnancy the fetus has an 80% chance of getting the infection, and the rate declines progressively to 25% during the 26th week. In infected fetuses, rubella-associated defects occur in all cases during the first 11 weeks and 35% of cases infected during weeks 13-16; risk to the fetus is negligible after the 16th week (Martin & Schoub, 2000; Morgan-Capner, 1999). The last major epidemic of rubella in the United States occurred in 1964-1965 and resulted in approximately 31,000 cases of rubella and congenital rubella infections. It is reported that 11,000 of these cases resulted in fetal death or therapeutic abortion and 20,000 infants were born with congenital rubella syndrome (CRS). Since 1969 the incidence of rubella declined by more than 99% (Centers for Disease Control and Prevention [CDC], 1997a).

Varicella and herpes zoster are different manifestations of the same virus. The primary infection produces chickenpox during childhood in the United States, although varicella is a disease of the reproductive years in subtropical and tropical climate countries. Chickenpox is a highly contagious disease and humans are the only reservoir. It is transmitted by droplets from vesicular fluid or secretions from the upper respiratory tract. There are approximately 1-7 cases per 10,000 pregnancies (Freij & Sever, 1997; Gilstrap, 1997; Paryani & Arvin, 1986; Preblud, Cochi, & Orenstein, 1986). The manifestations of congenital varicella include cortical atrophy and other neurological findings. Varivax, the live attenuated varicella vaccine, was approved in the United States in 1995 (Gibbs & Sweet, 1999).

Another important maternal infection that has consequences for the developing fetus is urinary tract infection. Urinary tract infections represent the most common medical complication of pregnancy, occurring in approximately 4-7% of all pregnancies. When all potentially offending genitourinary pathogens are included, and when the spectrum of asymptomatic bacteriuria is considered, these factors may increase the frequency of maternal bacteriuria to 25%. Recent research using an inception cohort design with Medicaid maternal and infant-linked records and Vital Records for 41,090 pregnancies during 1995-1998 found the relative risk

(RR) for MR or developmental delay among children of mothers with urinary tract infection without an antibiotic (i.e., based on Medicaid pharmacy reimbursement claims) was significantly elevated compared to the group without an urinary tract infection and compared to children of mothers with urinary tract infection and an antibiotic claim. Similar analyses of the National Collaborative Perinatal Project provide comparable results (McDermott, Callaghan, Szwejbka, Mann, & Daguise, 2000; McDermott, Daguise, Mann, Szwejbka, & Callaghan, 2001).

There is an increasing body of evidence suggesting that prematurity is a consequence of maternal infections including those that are sexually transmitted: gonorrhea, Group B streptococcus, Chlamydia trachomatis, trichomonas vaginalis, bacterial vaginosis, and herpes simplex virus. Premature rupture of the membranes (PROM), a precursor of early delivery, is often accompanied by the presence of one of these organisms, which could cause the fetal membranes in utero to weaken and rupture. Thus it is often suggested that PROM is a symptom of an existing infection, which was not treated (Creasy & Iams, 1999; Iams, Talbert, Barrows, & Sachs, 1985). Bacteria in amniotic fluid are found in approximately 10% of women with PROM and PROM occurs in approximately 5% of all pregnancies (Aries, Rodriquez, Rayne, & Kraus, 1993; Romero, Yoon, et al., 1993).

Worldwide another serious and widespread threat to cognitive development results from the transmission of human immunodeficiency virus (HIV) infection from the mother to the developing fetus. Perinatally acquired HIV infection and pediatric autoimmune deficiency syndrome (AIDS) emerged as a cause of MR in the late 1980s (Boylan & Stein, 1991). AIDS has become a major public health problem in many countries of Africa, where high HIV prevalence among childbearing women is combined with lack of access to antenatal antiretroviral therapy and cesarean delivery, causing vertical transmission of HIV (intrauterine, intrapartum, or neonatal) (European Mode of Delivery Collaboration, 1999). The neurodevelopmen-tal effects of pediatric AIDS include microcephaly and significant delays in cognitive and motor development (Belman, 1992; Macmillan et al., 2001). These effects have been reported to be greater when transmission of the virus from mother to child occurs in utero versus during parturition (Smith et al., 2000). In developed countries, improvements in postnatal treatment and survival of children with HIV may be associated with a reduction in adverse neurodevelopmental outcomes. One U.S. study of HIV infected children aged 3-5 years found no detriment in verbal or performance IQ when compared to controls matched on ethnicity and prenatal drug exposure (Fishkin et al., 2000). Another study, without controls, of children with AIDS surviving to school age in Philadelphia, found no more than 12% to have developmental scores in the range for MR (Mialky, Vagnoni, & Rutstein, 2001). Estimates are not available of the prevalence of pediatric HIV-associated neurodevelopmental disorders from low-income countries, where the vast majority of HIV-infected children reside but where few have access to antiretroviral therapy. In addition to direct effects of AIDS on the developing nervous system, the AIDS epidemic may be a causal factor in mild MR to the extent that it increases children's exposure to social, emotional, and economic deprivation during critical periods of development. Cost-effective and accessible methods of prevention and treatment of HIV in developing countries are needed to control this emerging cause of MR. Although administration of antiretroviral therapy and other medications to the pregnant woman can dramatically reduce HIV transmission, this form of treatment and preventive intervention is not widely practiced in the continents of Asia and Africa, due to poverty and political will (Amar, Ho, & Mohan, 1999; Boylan & Stein, 1991). In low-income countries which include the majority of HIV-infected women worldwide and in which prenatal screening, counseling, and treatment options are limited, the probability of vertical transmission from mother to infant is 30-40%.

In addition to infections known to directly damage the developing nervous system, other prenatal and perinatal infections associated with perinatal complications may contribute to developmental disabilities either directly or indirectly. Perinatal complications that occur more frequently in the presence of maternal and fetal infections include premature birth, low birth weight, intrauterine growth restriction, and asphyxia (Donders, Desmyter, De Wet, & Ban Assche, 1993). Infants born with perinatal complications, in turn, are at increased risk for developmental disabilities (Broman, Nichols, Shaughnessy, & Kennedy, 1987). The role of maternal and intrauterine infections in the etiology of perinatal brain disorders is an area of active investigation (O'Shea & Dammann, 2000).

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