teratogenic hearing loss

J Am Acad Audiol 6 : 28-38 (1995)

Teratogenic Hearing Loss Barry Strasnick* John T. Jacobson*

Abstract

Congenital hearing loss continues to be a devastating and disabling affliction in our society. In an effort to promote early recognition and treatment of hearing impairment in children, the Joint Committee on Infant Hearing has established a series of risk factors that place a new-born or infant at risk for hearing loss . These factors have been selected based on either genetic evidence of inherited familial hearing loss, acquired hearing loss from either known or unknown causative agents, or multifactorial inheritance that combines genetic and non-genetic factors . Included in these risk factors are exposures to environmental agents that possess the potential to adversely affect the developing auditory system . In this article, the principal environmental teratogens and their potential impact upon the auditory system will be reviewed .

Key Words : Congenital hearing loss, environmental agents, risk factors for hearing loss, teratogenesis

T

he Joint Committee on Infant Hearing (JCIH, 1991) recognized a series of risk factors that place a newborn or infant at

risk for hearing loss (see Table 1) . Each factor has been carefully selected based on either genetic evidence of inherited familial hearing loss, acquired hearing loss from either known or unknown causative agents, or multifactorial inheritance that combines genetic and non-genetic environmental factors. Of the JCIH risk factors, at least two (congenital infection and oto-toxic drugs) can be considered teratogenic agents, since they can lead to hearing loss as a primary or secondary result of a physical or functional abnormality within the embryonic or fetal envi-ronment during pregnancy. Other risk factors such as craniofacial anomalies that include hear-ing loss may also occur due to exposure to a ter-atogenic agent.

Advanced genetic technology and clinical investigations have demonstrated that congen-ital defects are considerably more frequent than once thought. The overall prevalence of con-genital defects ranges between 1 and 3 percent,

"Eastern Virginia Medical School, DePaul Medical Center, Children's Hospital of the King's Daughters, Norfolk, Virginia

Reprint requests : Barry Strasnick, Eastern Virginia Medical School, 825 Fairfax Avenue, Suite 510, Norfolk, VA 23507

depending on the definition . However, these fig-ures refer to disorders that are generally rec-ognizable at birth, such as malformations or syndromes. More subtle defects such as mental retardation and congenital deafness without syndromic association are therefore less likely to be reported. The purpose of this article is to briefly introduce the area of teratology and dis-cuss the ototoxic teratogenic agents that have potentially deleterious effects on the human auditory system .

EMBRYOLOGIC CONSIDERATIONS

T he embryo is extremely susceptible to ter-atogenesis from the third to ninth week of gestation because it is during this period that the fetal organs are formed out of the germ cell lay-ers (Robbins et al, 1984). An auditory (otic) pla-code first appears in the 3-week-old embryo on the lateral surface of the head and eventually invaginates to form an otic cyst . At 5 weeks, this otic cyst differentiates to form a wide dor-sal (vestibular) part and a more slender ventral (cochlear) part . At 6 weeks, the dorsal portion forms two pouches : a dorsal pouch (horizontal and posterior semicircular canal) and a lateral pouch (lateral semicircular canal) . During week 7, the vestibule divides into a dorsal utricle and a ventral saccule. By 12 weeks, the semicircu-lar canals and utricle are well developed and the

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Teratogenic Hearing Loss/Strasnick and Jacobson

Table 1 High-Risk Criteria for Infant Hearing Loss*

Risk Criteria : Neonates (birth-28 days) . The risk factors that identify those neonates who are at risk for sensorineural hearing impairment include the following : " Family history of congenital or delayed-onset

childhood sensorineural impairment . " Congenital infection known or suspected to be

associated with sensorineural hearing impairment such as toxoplasmosis, syphilis, rubella, cytomegalovirus, and herpes . Craniofacial anomalies including morphologic abnormalities of the pinna and ear canal, absent philtrum, low hairline, etc . Birth weight less than 1500 gms ( 3 .3 Ibs) . Hyperbilirubinemia at a level exceeding indication for exchange transfusion .

0

0 Ototoxic medications including but not limited to the aminoglycosides used for more than 5 days (e .g ., gentamicin, tobramycin, kanamycin, streptomycin) and loop diuretics used in combination with aminoglycosides .

" Bacterial meningitis . " Severe depression at birth, which may include infants

with Apgar scores of 0-3 at 5 minutes, those who fail to initiate spontaneous respiration by 10 minutes, or those with hypotonia persisting to 2 hours of age .

" Prolonged mechanical ventilation for a duration ? 10 days (e .g ., persistent pulmonary hypertension) .

" Stigmata or other findings associated with a syndrome known to include sensorineural hearing loss (e .g ., Waardenburg or Usher syndrome) .

Risk Criteria : Infants (29 days-2 years) . The factors that identify those infants who are at risk for sensorineural hearing impairment include the following : 0 Parent/caregiver concern regarding hearing, speech,

language, and/or developmental delay . Bacterial meningitis . Neonatal risk factors that may be associated with progressive sensorineural hearing loss (e .g ., cytomegalovirus, prolonged mechanical ventilation, and inherited disorders). Head trauma, especially with either longitudinal or transverse fracture of the temporal bone .

9 Stigmata or other findings associated with syndromes known to include sensorineural hearing loss (e .g ., Waardenburg or Usher syndrome) . Ototoxic medications including but not limited to the aminoglycosides used for more than 5 days (e .g ., gentamicin, tobramycin, kanamycin, streptomycin) and loop diuretics used in combination with aminoglycosides .

0 Children with neurodegenerative disorders such as neurofibromatosis, myoclonic epilepsy, Werdnig-Hoffman disease, Tay-Sach's disease, infantile Gaucher's disease, Nieman-Pick disease, any metachromatic leukodystrophy, or any infantile demyelinating neuropathy. Childhood infectious diseases known to be associated with sensorineural hearing loss (e .g ., mumps, measles) .

'Adapted with permission from Joint Committee on Infant Hearing, 1991 .

cochlear duct has developed its two-and-one-half turns. Elements of the cochlear duct con-tinue to achieve finer differentiation into the sec-ond trimester.

We see then that the vestibular labyrinth, semicircular canals, and utricle (pars superior) develop before the auditory labyrinth, saccule, and cochlea (pars inferior). It has been stated that the older a structure is phylogenetically, the more resistant it is to either developmental or acquired disease. One would therefore anticipate a relative predisposition for teratogenic agents to affect developing structures within the pars inferior more so than those of the pars superior.

TERATOLOGY

T eratology is the area of medical science dedicated to the study of environmental factors contributing to abnormal prenatal growth and development (Smithells, 1980). When present in the fetal environment, a ter-atogenic agent may cause birth defects that include developmental, learning, and behav-ioral disorders and, potentially, fetal death (Gor-lin et al, 1990). Table 2 lists the common causes

and their percentage contribution to the occur-rence of human congenital anomalies, of which perhaps as many as 65 percent are of unknown etiology (Brent, 1986). Approximately 20 percent of all congenital anomalies result from gene mutations, whereas another 5 percent manifest from chromosomal aberrations (Shepard, 1989). Of the remaining identified anomalies, less than 10 percent are known to be due to a ter-atogenic agent (Wilson, 1977).

Interest in the subject of teratology awaited recognition of the successive tragedies of the rubella epidemic in the early 1960s (Cooper, 1968) and thalidomide in the 1970s (Teff and Munro, 1976). The succeeding decades have seen a dramatic growth of clinical and epi-demiologic investigations into the problem of environmental teratogenesis. To date, there have been over 1500 teratogenic agents identi-fied that have produced congenital anomalies in experimental animals. Health care agencies have moved to erect barriers against the intro-duction of potentially teratogenic agents into the pregnant population . With an increasing awareness of the hazards of environmental ter-atogenic exposure, certain generalizations have

Journal of the American Academy of Audiology/Volume 6, Number 1, January 1995

begun to emerge that help us to characterize and recognize such agents .

The severity of congenital infant morbidity and prenatal susceptibility to a teratogenic agent during fetal development is extremely variable . Gorlin and colleagues (1990) have described four factors that account for the wide range of expression encountered among patients who are adversely affected by prenatal exposure to environmental agents . They are:

1. Dosage of the agent. In general, the greater the exposure to a teratogenic agent, the more likely an effect is to occur, and the more likely the effect will be severe .

2 . Developmental timing of the exposure . Most target tissues have relatively specific peri-ods of susceptibility during which they are vulnerable to damage by a particular mech-anism. Thus, the stage of embryonic fetal development at which exposure to a ter-atogen occurs may be of critical importance in determining outcome.

3. Genetic host susceptibility. Humans vary widely in their genetic control of drug metab-olism, resistance to infection, and other bio-chemical and molecular processes. There-fore, some individuals may be at strikingly

Table 2 Relative Contributions of Various Causes to the Occurrence of Human

Congenital Malformations*

Etiology Malformed Live Births (%)

Cryptogenic (nonfamilial, uncertain etiology) 5

Mendelian Inheritance/ Spontaneous Mutations 15-20

Unknown 65-70 Polygenic Multifactorial Synergism Spontaneous errors of

development

Environmental (exposure of the embryo) Maternal infections (CMV,

rubella, syphilis, 3 herpes, simplex, etc .)

Maternal disease states (diabetes, alcohol, 4 phenylketonuria, nutritional problems, smoking, etc .)

Problems of constraint 2 Drugs, chemicals, irradiation,

hyperthermia <1

*Adapted with permission from Brent, 1986 .

greater risk from a given exposure than the population as a whole. Furthermore, during pregnancy, the susceptibility of two differ-ent individuals, mother and fetus, must be considered.

4. Interactions with other environmental fac-tors . It is common during pregnancy for exposures to more than one agent to occur.

The interrelationship of these contributing fac-tors and their potential role in the development of congenital defects is reflected in the extreme variability of demonstrable birth anomalies. It is obvious then that prediction of possible ter-atogenic-induced birth defects is a difficult task at best .

ENVIRONMENTAL TERATOGEN

T eratogenic agents may be broadly grouped into four categories : (1) infectious agents, (2)

drugs and chemical agents, (3) physical agents, and (4) maternal metabolic and genetic factors. Table 3 lists the various major teratogenic agent categories and their subsets. It should be noted that only a handful of agents have been directly implicated in congenital hearing loss and other craniofacial abnormalities (Table 4) . However, the effects of teratogenic agents on the audi-tory system, while variable, can be potentially devastating. A complete discussion of any one of these agents is beyond the scope of this publi-cation . Furthermore, the reader is cautioned that considerable debate still exists regarding the relative contribution of these offending agents to the development of human birth defects. The following discussion is presented as a general guide to teratogenic agents and their possible impact upon the auditory system . The reader is encouraged to consult standard medical refer-ences for a more thorough discussion of indi-vidual agents . Finally, it is extremely impor-tant to avoid "categorizing" any one particular type or degree of hearing loss with a terato-genic agent. For example, direct association of an audiometric configuration to an infant exposed to a teratogenic agent may be mislead-ing, given the variability of penetrance and expression .

INFECTIOUS AGENTS

Viral Infections

By far, the majority of infections in pregnant women involve the upper respiratory and gas-trointestinal tract. As a rule, these infections

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Table 3 Teratogenic Agents in Humans* Table 4 Selected Teratogenic Agents Associated with Congenital Auditory Physical Agents Malformation and/or Hearing Loss in Humans Radiation (e .g ., atomic, radioiodine, therapeutic)

Hyperthermia Mechanical factors (e .g ., oligohydramnios) Agents Primary Congenital Defect

Infectious Agents Drugs Viruses Alcohol Hearing loss, growth retardation, Cytomegalovirus reduced palpebral fissures, Herpes virus microcephaly, mental retardation Parvovirus B-19 Antibiotics Hearing loss Rubella tetracyclines Bacteria aminoglycosides Syphilis Hydantoin Dysmorphic craniofacial features, Mycoplasma dilantin growth retardation, microcephaly, Parasites mental retardation Toxoplasmosis Retinoic Acid Craniofacial dysmorphism, neural

vitamin A tube defects, abortion Maternal Metabolic and Genetic Factors Thalidomide Ear anomalies, cochlear hypoplasia,

Alcohol girdle hypoplasia, limb reduction Cretinism deformities Diabetes mellitus Folic acid deficiency Infections Hyperthermia Cytomegalovirus Hearing loss, ocular and Nutritional disturbances cardiovascular anomalies, Phenylketonuria microcephaly, growth and mental Rheumatic heart disease and congenital heart block retardation, immune and endocrine Virilizing tumors disturbances

Herpes Simplex Hearing loss, retinal dysplasia, Drugs and Environmental Chemicals microcephaly, possible mental and

Aminopterin and methylaminopterin growth deficiency Androgenic hormones Rubella Hearing loss, ocular and Busulfan cardiovascular anomalies, Chlorobiphenyls microcephaly, hydrocephaly, Coumarin anticoagulants possible mental and growth Cyclophosphamide deficiency Diethylstilbestrol Syphilis Hearing loss, mental retardation, Diphenylhydantoin and trimethadione skeletal malformation Lithium Toxoplasmosis Hearing loss, vestibular Mercury abnormalities, ocular anomalies, Methimazole microcephaly, hydrocephaly, Penicillamine mental and growth deficiency Tetracyclines Varicella-Zoster Hearing loss, ocular anomalies, Thalidomide microcephaly, growth and mental Trimethadione retardation, neurogenic muscle Valproic acid atrophy

'Adapted with permission from Shepard, 1989 .

remain localized and have no apparent effect upon the developing fetus . Occasionally, infec-tious agents do gain access to the blood stream, leading to transplacental infection of the fetus. Many of these potentially teratogenic infectious agents go unrecognized due to a relative paucity of clinical symptoms in the host . Examples include rubella and cytomegalovirus (CMV) infections, which often go undetected in the pregnant mother. Serologic methods are often not helpful in diagnosing maternal-fetal infec-tion unless the patient is examined during the acute phase of the illness when a rising antibody titer is elicited . Retrospective analysis can only

Agents are typically classified into four major groups, but two (drugs and infections) are primarily associated with auditory deficits . The list is not inclusive of all teratogenic agents (adapted with permission from Sever and Brent, 1986).

determine whether an infection has taken place, not the time of its occurrence .

Rubella

Maternal rubella infection within the first 3 months of pregnancy poses a serious risk to the developing fetus. Risk figures for congeni-tal rubella have been reported as high as 50 per-cent for the first month and 10 to 15 percent for the third month, with significant risk extend-ing up to the sixteenth week . Common mani-


festations include heart disorders, low birth weight, mental retardation, visual loss, and sensorineural hearing impairment (Hanshaw and Dridgeon, 1978). It is estimated that as a result of the last epidemic of rubella in the United States in the 1960s, over 25,000 infants were born with congenital rubella. The inci-dence of rubella has dramatically decreased since the introduction of the rubella vaccine; however, there are still approximately 50 infants per year born with congenital rubella syndrome and hearing loss .

Hearing loss is the most common of all the rubella-associated defects, occurring in 50 per-cent of surviving infants afflicted in the first trimester (Davis, 1983). The prevalence of hear-ing loss decreases to less than 20 percent when maternal rubella is contracted during the sec-ond or third trimester. Hearing defects often occur in the absence of other diagnostic find-ings . Most of these children tend to have bilat-eral sensorineural hearing loss that may be asymmetric and progressive in one-quarter of the children with the syndrome (Bordley and Alford, 1970). Audiograms typically demon-strate a flat or gradually sloping severe to pro-found sensorineural loss (Fraser, 1976; Anvar et al, 1984). In addition to inner ear defects, central auditory processing disorders with asso-ciated speech delay may occur due to cerebral involvement (Ames et al, 1971). The middle ear is usually spared .

Temporal bone findings in patients with congenital rubella typically reveal cochleosac-cular degeneration with collapse of Reissner's membrane and the saccular wall . The vestibu-lar apparatus is generally unaffected. It is impor-tant to note that despite substantial evidence implicating the rubella virus in congenital deaf-ness, the virus itself has not been isolated from the inner ear of any affected individuals.

In general, rubella vaccination offers ade-quate protection against the disease. Bottiger (1979) reportedly found no cases of rubella infec-tion in appropriately immunized women, whereas 15 percent of nonvaccinated women had contracted the disease. In contrast to rubella vaccination, the value of passive immunization with immunoglobulin remains doubtful .

Cytomegalovirus

CMV a virus of the herpes group, is the leading cause of fetal viral infection in the US, and accounts for over 4000 cases of sensorineural hearing loss per year (Reynolds et al, 1974).

The infection is most often asymptomatic in the mother. Because of difficulties in determining the time of maternal infection, it is unclear which stage of intrauterine development is most sus-ceptible to CMV infection.

Approximately 3 percent of pregnant women and 1 to 2 percent of newborns demonstrate evidence of CMV infection (Hanshaw, 1971). Clinical manifestations include microcephaly, mental retardation, hepatosplenomegaly, and deafness . Over 97 percent of congenitally infected infants show no sign of disease in the neonatal period. However, there is a growing body of evidence to suggest that a number of infants, asymptomatic at birth, will eventually develop neurologic abnormalities that become apparent in later life . In fact, 10 to 15 percent of infected children will eventually demonstrate adverse sequelae such as mental retardation, coordination disturbances, and hearing loss (Reynolds, 1974 ; Stagno et al, 1977a) . The preva-lence of sensorineural hearing loss in infants who are symptomatic at birth may be as great as 50 percent (Pass et al, 1980; Hanshaw, 1982). The diagnosis of congenital CMV infection can-not be made on clinical grounds alone and must be based on isolation of the virus from fresh urine or tissue during the first week of life . Alternatively, a variety of serologic tests are available to detect CMV antibody to document the presence of infection. Owing to the limited period during which proper diagnosis can be made, it is likely that many cases of congenital deafness today classified as of unknown etiol-ogy can be ascribed to congenital CMV infection. There is no consistent pattern or degree of severity of hearing loss in infants with CMV infection. Hearing loss may be symmetric with primarily high-frequency impairment (Pappas, 1985). Asymmetric or unilateral hearing loss has also been reported (Stagno et al, 1977a) . The incidence of hearing loss in congenital CMV has been reported as high as 40 percent in sur-viving neonates (Davis, 1981). In contrast, John-son and colleagues (1986) evaluated 40 prema-ture infants having perinatal-acquired CMV In this group, only one infant (3.75%) was reported to demonstrate high-frequency sen-sorineural hearing loss . The prevalence of hear-ing loss did not differ from a matched control group, and the authors suggested that signifi-cant sensorineural hearing loss may not be identified in premature infants through the age of 3 years. Pappas (1985) recommends careful audiometric follow-up in children with asym-metric hearing since progressive hearing loss is

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prevalent in this group. This degenerative process may be due to reactivation of viral dis-ease following a period of latent infection (Dahle et al, 1974), which may last throughout the first decade of life (Hanshaw, 1971).

Temporal bone histopathology in infants with CMV infection reveals infected epithelial cells within the cochlea, saccule, utricle, and semicircular canals (Meyers and Stool, 1968). Hydrops of the cochlea and saccule have also been observed (Davis and Johnson, 1983). Vestibular pathology may occur as a result of infection of the vestibular apparatus (Davis et al, 1977).

There is presently no safe method for vac-cination against CMV infection. Furthermore, naturally acquired infection may not produce a significant protective effect . Primary preven-tion of CMV infection thus consists mainly of avoidance of exposure during pregnancy.

Other Viral Infections

Numerous other viral infections including polio virus, varicella, measles, and mumps have been implicated as potentially teratogenic agents . However, a direct causal relationship between viral infection and associated congenital defects remains largely unproven . Careful epidemio-logic studies are necessary before the role of any of these viral agents in the development of congenital defects, including hearing loss, can be firmly established.

Bacterial Infections

While a host of bacterial agents are capable of infecting the fetus antenatally, only syphilis is thought to have a significant teratogenic potential.

Syphilis

In 1958, Hutchinson described the classic triad of congenital syphilis : notched incisor teeth, interstitial keratitis, and sensorineural hear-ing loss . Congenital syphilis may manifest either as secondary syphilis in the first 2 years of life or as tertiary syphilis between ages 8 to 20 years. There may be a substantial time period between the onset of ocular disease and the onset of hearing loss .

Syphilitic infection of the labyrinth or acoustic nerve may result in sudden, progres-sive, or fluctuating sensorineural hearing loss . In secondary syphilis, early acquired hearing


loss is common and is typically sudden, bilateral, and progressive. Delayed acquired hearing loss is usually associated with luetic labyrinthitis occurring during the tertiary stage of syphilis . Auditory deficits tend to manifest as a severe, bilateral, and progressive sensory loss . Speech recognition deteriorates in concert with decreases in auditory sensitivity. Middle ear mobility is unaffected, although acoustic reflex patterns reflect bilateral sensorineural pathol-ogy. Early-onset syphilitic hearing loss has the potential for reversibility with early detection and prompt treatment with high-dose intra-venous penicillin and oral steroids . In more advanced cases, however, hearing loss is gen-erally permanent (Balkany and Dans, 1978; Pillsbury and Shea, 1979) .

Cochlear histopathology includes atrophy of the organ of Corti along with degeneration of the fibers of the cochlear nerve (Karmody, 1966). Antenatal or perinatal diagnosis can be made by serologic testing or pathologic examination for identification of the organism . All women should be screened for syphilis during pregnancy since prompt treatment may be curative and prevent the serious sequelae of intrauterine infection.

Parasites

Toxoplasmosis

Toxoplasmosis is caused by the protozoan parasite Toxoplasma gondii, and the infection is usually asymptomatic in the mother. The incidence of intrauterine toxoplasmosis aver-ages one case per 750 deliveries in the US . Infection during the first trimester appears most likely to lead to an enhanced risk of severe fetal consequences, whereas later infections in pregnancy appear to result in clinically asymp-tomatic disease.

Congenital toxoplasmosis commonly man-ifests with central nervous system involvement including microcephaly, intracranial calcification, mental retardation, and seizures . In addition, ocular disease, including cataracts, choriore-tinitis, and microphthalmia, is seen .

In children with more subtle disease in the newborn period, long-term follow-up has revealed a high incidence of sensorineural deafness that is usually severe and bilateral (Alford et al, 1974). In some instances, serologic testing among deaf individuals has supported a direct causal relationship between congenital toxoplasmosis infection and hearing loss . Temporal bone stud-ies, however, have failed to isolate the putative


organism within the auditory system . Vaccina-tion against toxoplasmosis is not presently avail-able . Therefore, preventative measures consist of avoidance of infection during pregnancy. Meth-ods for prevention include avoiding ingestion of the oocysts contained in raw meat and eggs or exposure to infected materials such as cat feces.

DRUGS AND CHEMICAL AGENTS

t has been reported that, on average, women receive three or more medications, both pre-

scribed and nonprescribed, during pregnancy (Nora et al, 1967) . The mechanisms by which drugs and chemical agents produce birth defects remain largely unknown, and, in many instances, their association with risk to the developing fetus is conjectural at best . Proposed mechanisms include cell death, alteration of cellular growth, and derangement of morpho-genetic processes.

Nonprescription Drugs

Thalidomide

The most tragic evidence of drug-induced birth defects occurred in the 1960s when Euro-pean drug manufacturers released thalidomide as an over-the-counter sedative preparation. It has been estimated that between 1958 and 1963, over 10,000 children were damaged by this drug world-wide (Swinyard, 1978). Thalidomide was rather convincingly shown to be teratogenic when taken even in a single dose during the sus-ceptible period of fetal development (days 20 to 35). A variety of defects were produced includ-ing phocomelia, esophageal atresia, renal age-nesis, facial hemangiomas, and external ear anomalies . In 1963, Miehlke and Partsch described a syndrome associated with thalido-mide use that consisted of anomalies of the ears and paralysis of the facial and abducens nerves. Thalidomide has been shown to produce abnor--mal cochlear development, and, in these instances, severe sensorineural hearing loss is a common outcome.

Ethyl Alcohol

Ethyl alcohol continues to be one of the most abused drugs that is consumed through-out the world. It is estimated that approximately 2 per 1000 children suffer from fetal alcohol syndrome (FAS). Epidemiologic studies indicate that almost 1 out of every 30 pregnant women

abuse alcohol and that approximately 6 percent of their children demonstrate clinical features of FAS . Initially coined by Jones and Smith (1973), FAS describes a series of irreversible congenital anomalies observed in the offspring of alcoholic mothers. FAS is recognized as the leading cause of mental retardation in the west-ern world, exceeding disorders such as Down syn-drome and cerebral palsy.

With the progressive rise of maternal alco-hol abuse, the prevalence of FAS has become a major universal health concern. However, FAS has not been a well-recognized clinical entity, and there remains a wide variance in the reported incidence of this syndrome . This variance is likely due to the reluctance of mothers to admit to substance abuse and the fact that congenital severity appears related to the amount and period of chronic consumption (Little and Streissguth, 1981). Furthermore, recognition of the syndrome may not occur at birth, and typi-cal congenital facial characteristics are not always recognized .

The actual reported prevalence of FAS ranges between 1:500 to 1 :2500 term pregnan-cies (Streissguth et al, 1980 ; Sokol, 1981; Smith, 1982), with apparent regional concentrations (Little and Streissguth, 1981). This higher inci-dence (e.g., Sweden, 1:600) may be attributed to the nature of the health care systems and track-ing methods. As many as one half of all infants born to chronic alcoholics may present with some diagnostic feature of FAS.

The exact amount of alcohol necessary to produce fetal damage has not been well docu-mented ; however, many studies suggest that consumption of two or more drinks per day dur-ing pregnancy is associated with an increased risk of fetal insult . Furthermore, fetal suscep-tibility to ethyl alcohol appears to occur through-out the majority of intrauterine life with the degree of malformation related to the amount of alcohol consumption.

The exact mechanism of teratogenesis seen with ethyl alcohol use during pregnancy remains uncertain. Alcohol has been shown to adversely affect cellular metabolism both directly as well as through its metabolites. Additionally, malnutrition and vitamin defi-ciency commonly seen in alcoholics likely con-tribute to adverse fetal outcome.

Prenatal use of ethyl alcohol can result in a wide spectrum of fetal abnormalities . The FAS includes dysmorphic facial features along with a series of neurologic, behavioral, and other physical anomalies. Typically, infants are

34


born with craniofacial dysmorphogenesis . Char-acteristics include microcephaly, short palpebral fissures, hypoplastic philtrum, thinned upper lip, ptosis, low nasal bridge, epicanthal folds, micrognathia, and midface hypoplasia (Jung, 1989). Other structural, otolaryngologic deficits include cleft palate and pinna abnormalities (Jones and Smith, 1973 ; Toutant and Lipp-mann, 1980 ; Smith, 1982). Posterior rotation of the auricle as well as a poorly formed concha may be evident.

Although ethanol has been reported to be ototoxic (Gieldanowski, 1965 ; Morizono and Sikora, 1981 ; Church, 1987), there is little agreement with regard to its effects on the developing auditory system . Church (1987) and Church and Gerkin (1988) reported the results of 14 children with FAS. Thirteen children (93%) had clinically significant histories of bilateral recurrent serous otitis media and four children (29%) had concurrent permanent bilat-eral sensory hearing loss . This reported high incidence of middle ear effusion confirms ear-lier cited evidence (Johnson et al, 1981 ; Streissguth et al, 1985). The presence of cleft lip and palate may account for this high rate of occurrence . In 1980, Toutant and Lippmann found hearing loss in one of six siblings with FAS ; however, the specific type of hearing dis-order was not reported .

Audiologic and otologic management of FAS demands early recognition and therapeutic treat-ment, including that of recurrent serous otitis media. Because speech and language disorders have been reported (Isoub et al, 1981), appro-priate referral is also an important considera-tion in the overall FAS management .

Prescription Drugs

Aminoglycosides

There have been numerous reports describ-ing the potential deleterious effects of amino-glycosides on the developing auditory system . Aminoglycosides infiltrate the perilymph and endolymph of the inner ear, resulting in higher local concentrations of the drug than typically seen in the peripheral blood. Since aminoglyco-sides are administered intramuscularly or intra-venously and excreted through the kidneys, the degree of ototoxic danger appears to be primar-ily related to the blood level of the drug and its duration in the circulation . Aminoglycosides may be toxic to both the neuroepithelium of the

vestibular system, as well as the sensory hair cells of the cochlea.

Transplacental transfer of aminoglycoside antibiotics has been well demonstrated in humans (Neinsterm et al, 1976). The majority of reports considered women with tuberculosis who were treated with streptomycin or dihy-drostreptomycin. For example, in a study by Conway and Burt (1965), streptomycin was shown to cross the placenta, resulting in labyrinthine damage and high-frequency hear-ing loss in the fetus. Of note, when auditory changes were reported in the offspring of moth-ers who received aminoglycoside antibiotics, the ototoxicity occurred independently of ototoxicity in the mother.

Intrauterine ototoxicity has also been reported for newer aminoglycosides, including kanamycin and gentamicin . Most of these stud-ies, however, are retrospective and lack data describing duration of therapy and serum lev-els of drugs employed . Furthermore, combina-tions of aminoglycosides and diuretics such as furosemide or ethacrynic acid demonstrate syn-ergism with regard to ototoxicity. The treat-ment of a pregnant woman with aminoglyco-sides may subject the developing fetus to the risk of ototoxicity similar to that seen in adults and children . However, a true postnatal teratogenic effect on the developing fetal auditory system remains to be proven .

The reported incidence of hearing loss asso-ciated with aminoglycoside antibiotics ranges from 10 to 16 percent (Quick, 1986 ; Lerner and Matz, 1980). The affects of aminoglycosides on the auditory system typically include bilateral, symmetrical, high-frequency sensorineural hear-ing loss . Typical reductions in speech recogni-tion are demonstrated with a concomitant decrease in pure-tone sensitivity. Middle ear mobility is normal, although acoustic reflex patterns are consistent with sensory hearing loss . The degree of severity and the audiomet-ric configuration are typically related to the type of drug, its dosage, and duration in the sys-tem and drug interaction .

Chloroquine

Chloroquine, an antimalarial drug, has been associated with an increased risk of auditory and optic abnormalities. Deafness from direct VIIIth nerve damage has been reported . However, the overall risk when standard doses are used dur-ing pregnancy appears to be relatively low.


PHYSICALAGENTS

A variety of physical agents have been impli-cated as being potentially teratogenic to

the fetus. The most notable agents include radi-ation and thermal energy.

Concern over potential teratogenic effects of high-dose radiation arose from experimental observations of the offspring of survivors of nuclear explosions during World War II . Abnor-malities including growth retardation, central nervous system damage, and ocular defects were noted. It is thought that even low-dose radiation associated with natural exposure may contribute to an enhanced rate of embryonic mutations. Concern over the carcinogenic poten-tial of intrauterine radiation exposure also appears valid.

Prolonged exposure of the fetus to high ther-mal environmental temperatures such as during bathing or sauna has been questioned as being potentially teratogenic . Animal studies support the notion that heat may act as a teratogen dur-ing initial stages of neural tube development. However, similar evidence of a direct teratogenic effect in man is lacking (Edwards, 1977).

At the present time, evidence is inadequate to invoke a direct causal relationship between intrauterine exposure to thermal or radiation energy and auditory disabilities in the new-born . However, it would appear prudent to avoid either prolonged thermal exposure or inadver-tent radiation exposure during the first trimester of pregnancy.

MATERNAL METABOLIC AND GENETIC FACTORS

A Ithough not strictly environmental, meta-bolic and/or genetic factors within the mother may alter the fetal intrauterine envi-ronment. Examples include diabetes mellitus, maternal myotonic dystrophy, and maternal phenylketonuria . While not directly implicated in auditory malformation, there is sufficient evidence to suggest that intrauterine exposure to maternal alterations in these and other meta-bolic/genetic factors can lead to fetal wastage along with a variety of abnormalities including microcephaly, neural tube defects, and mental retardation. In addition, the data suggest that control of these factors, particularly in the first few weeks of pregnancy, may be associated with a somewhat lower risk of fetal malformations (Shepard, 1989).

TERATOGENIC HEARING LOSS: GENERAL CONSIDERATIONS

C onsiderable debate still exists regarding the role of environmental agents in the development of birth defects in our population. However, it is becoming abundantly clear that genetic factors alone cannot account for the alarming number of fetal abnormalities identi-fied . With these observations comes an increas-ing emphasis on identification and prevention of teratogenic exposures.

The primary means of prevention of birth defects from teratogenic exposures is the elim-ination of the potential teratogen from the prenatal environment. Toward this end, it is incumbent upon all medical professionals to be aware of the teratogenic potential of a mul-titude of environmental agents and offer appropriate counseling and treatment alter-natives, particularly during the early months of pregnancy.

The evaluation and treatment of a child suspected of having been exposed to a poten-tially teratogenic agent begins with a high index of suspicion. A careful review of the pre-natal history should be performed along with an in-depth examination to search for abnor-malities known to be associated with terato-genic exposure . A careful otologic examination, as well as objective electrophysiologic testing to accurately determine the extent and type of hearing loss is indicated. If hearing loss is dis-covered, prompt medical or surgical interven-tion is warranted. Appropriate amplification is critical to the intellectual, social, and emo-tional development of these children . Parents must also be educated to inform them as to their role in the rehabilitation of the hearing-impaired child.

CONCLUSION

n view of the large number of drugs, infec-tions, and physical agents that the fetus may

be exposed to in utero, it is remarkable that so few have thus far proven to be teratogenic. Per-haps this merely reflects our present inability to recognize the complicated relationships between various exogenous agents and their clinical consequences . Until complete charac-terization of such agents is available, emphasis should be placed on strict avoidance of potentially hazardous agents whenever possible during pregnancy.


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