Abstract

Elevated maternal thyroid autoantibodies during pregnancy are linked to infertility, miscarriage, and neurodevelopmental deficits such as in cognitive function. It has not been established whether autoantibodies to thyroid peroxidase are associated with sensorineural hearing loss (SNHL). The authors tested stored third-trimester maternal serum specimens of 1,736 children for thyroid peroxidase autoantibodies (TPOaAb) by using an enzyme-linked immunosorbent assay technique. The children participated at the Baltimore, Maryland, site of the Collaborative Perinatal Project, which enrolled pregnant women in 1959–1965. An audiology examination was administered to the children at 8 years of age and was used to identify cases of SNHL. Compared with 4.3% of the other children, 22.7% of the children whose mothers had elevated TPOaAb (≥62.5 IU/ml) had SNHL. The difference was significant after controlling for maternal race, age, and hypothyroidism (exact prevalence odds ratio = 7.5, 95% confidence interval: 2.4, 23.3). When a lower cutoff of TPOaAb ≥31.25 IU/ml was used, there continued to be an association with SNHL (exact prevalence odds ratio = 5.7, 95% confidence interval: 2.1, 15.6). The direction and magnitude of the association were similar when an alternative case definition of SNHL was used. These data suggest that antenatal exposure to maternal TPOaAb during the third trimester of pregnancy is associated with impaired auditory development.

Thyroid autoimmunity has been implicated in infertility, fetal loss, preeclampsia, and prematurity, as well as in delayed learning and lowered childhood IQ (1–7). Evidence exists that elevated thyroid peroxidase autoantibodies (TPOaAb) can exert these adverse effects even when the mother is euthyroid in early pregnancy (8–10). It is not fully understood how thyroid autoantibodies interfere with normal pregnancy, nor at what titer or how they affect the developing fetal brain. Population surveys in the United States have noted that some 4–16 percent of women of reproductive age have elevated TPOaAb without presenting clinical disease (11, 12). These surveys showed that the prevalence increased with age and was higher among women of Caucasian origin than other racial/ethnic groupings. Estimates of the proportion of women who have elevated TPOaAb during the first two trimesters of pregnancy range from 1 percent to 2.5–12 percent (10, 13, 14). TPOaAb generally decline as gestation progresses, reportedly falling an average of 50 percent (10, 15) or becoming virtually undetectable by the third trimester (16). Information on variations between different population groups is scant (17).

The etiology of neurodevelopmental events resulting in congenital sensorineural hearing loss (SNHL) remains to be established in over 40 percent of cases (18). The US Preventive Services Task Force estimates that 5,000 infants are born yearly in the United States with moderate, severe, or profound bilateral hearing loss (>40 dB) (19). In addition, minimal or mild (15–40 dB) SNHL—including unilateral and high-frequency-only hearing loss—affects some 5.4 percent of children aged 8–11 years (a prevalence of 2.5 million) (20–22). Mild or minimal SNHL may not be detected in the neonate, or may progress throughout childhood, and can have lifelong effects on language, learning, attention span, school performance, and social interaction (20, 23). Cognitive and hearing deficits often co-occur in iodine-deficient areas (10, 24, 25), cognitive and motor deficits have been observed in children whose mothers have elevated TPOaAb in the first half of pregnancy (6, 26–28, 30), and animal studies have shown that neuronal migration is sensitive to maternal thyroid hormone (31–33). The composite literature led us to hypothesize that elevated maternal TPOaAb during the third trimester would be a sensitive marker for subsequent childhood SNHL.

MATERIALS AND METHODS

Study population

We tested remainder samples from 1,859 previously aliquoted serum specimens that had been stored, frozen at −20°C, at the Johns Hopkins Medical Institutions' Stanley Division of Developmental Neurovirology after they had been obtained from the repository at the National Institute of Child Health and Human Development/National Institutes of Health and tested for selected infectious agents by solid-phase enzyme immunoassay (34). The specimens were originally drawn from pregnant participants enrolled in 1959–1965 at the Baltimore, Maryland, site of the Collaborative Study on Cerebral Palsy, Mental Retardation and Other Neurological and Sensory Disorders of Infancy and Childhood, known as the Collaborative Perinatal Project (CPP). The 12-site CPP was established in 1958 by the National Institute of Neurological and Communicative Disorders and Stroke of the National Institutes of Health and has been described in detail elsewhere (35, 36). Outcome and cofactor data, also stripped of individual identifiers, were obtained from the database maintained for research purposes by the Baltimore CPP Partnership (37). The national database is publicly available at the National Archives. Specimens may be requested from the CPP Serum Bank (Division of Epidemiology, Statistics & Prevention Research/National Institute of Child Health and Human Development/National Institutes of Health).

We assessed TPOaAb in specimens from mothers of children delivered during the final trimester of pregnancy. For the purposes of this study, four children born at 191–195 days' gestation were included to capture an additional mother who was positive for elevated TPOaAb (her child did not have SNHL). Twenty-seven specimens corresponding to gestational weeks 17–25 (days 126–182) were excluded. Sample aliquots were coded to mask individual identities, and the TPOaAb assays were conducted prior to linkage to case status. Ninety-six observations were excluded because of incomplete hearing test results. The final analysis included 1,736 children from 1,731 pregnancies among 1,529 mothers.

The study was reviewed and approved by the Johns Hopkins Medical Institutions Institutional Review Board and the Johns Hopkins Bloomberg School of Public Health's Committee on Human Research and the Health Insurance Portability and Accountability Act (HIPAA).

Study design and procedures

The CPP was an observational cohort with follow-up of children from the time that the pregnancy was registered until the children were approximately 8 years of age. Blood samples were taken from the mothers several times during the pregnancy. We assessed TPOaAb concentrations in specimens from the final trimester of pregnancy. Cases of SNHL were identified from results of the audiologic examination administered at 8 years of age.

The incidence of congenital conditions ascertained after birth cannot be determined if the exposure is associated with fetal death, as occurs with TPOaAb. Thus, cases of SNHL reflected prevalent congenital conditions, not incident events, and the measure of association reported here is therefore the prevalence odds ratio (38).

Procedures.

TPOaAb concentrations were assessed at the Center for Autoimmune Disease Research of the Johns Hopkins Medical Institutions by using an indirect microplate enzyme-linked immunoabsorbent assay (QUANTA Lite TPO; INOVA Diagnostics, San Diego, California). The manufacturer's positive concentration standards were 62.5, 125, 250, 500, and 1,000 TPOaAb IU/ml—the range from clinically suspect to strongly positive. We selected a ≥62.5-IU/ml cutpoint, for which the manufacturer reports a specificity of 100 percent with 91 percent sensitivity (39), as the primary threshold. In addition, we used a ≥31.25-IU/ml cutpoint to increase sensitivity as well as to determine whether titers at that level (reflecting concentrations perhaps twofold higher in early pregnancy) (14) were associated with the outcome. This cutoff was generated by extrapolating from the manufacturer's standard curve and is not clinically significant. Concentrations of ≥100 IU/ml often are used to confirm clinical thyroiditis (40), whereas concentrations of <62.5 IU/ml are not considered clinically significant although they may suggest a greater likelihood of future titer elevation (39, 41).

The frozen samples were thawed and diluted by adding 5 μl of serum to 500 μl of horseradish peroxidase diluent provided in the kits. We added 100 μl of the diluted sample to microwells that were precoated with purified human thyroid peroxidase antigen by the manufacturer. After incubation for 30 minutes, washing three times in a diluted horseradish peroxidase wash concentrate provided in the kit, and drying of the plates, 100 μl of horseradish peroxidase immunoglobulin G conjugate was added and three more washings followed another 30-minute incubation period. Lastly, we added 100 μl of 3,31,5,51 tetramethylbenzidine chromogen and incubated the plates in the dark for another 30 minutes. Stop solution was added, and the optical densities were read by using DYNEX MRX Revelation 4.2 equipment (DYNEX Technologies, Chantilly, Virginia). Calibration and control samples for each plate were referenced to the World Health Organization standard (International Reference Preparation Medical Research Council 66/387).

The audiology evaluation at the final CPP follow-up used pure-tone air conduction and bone conduction, methods that remain current today. The right ear was tested first if the child's birthday was an even number; the left ear first, if odd. The opposite ear was masked when the difference between ears was ≥40 dB, and quality control was monitored closely (42, 43). We defined SNHL as an air conduction threshold of >20 dB and an air-bone gap of <10 dB at 500, 1,000, 2,000, or 4,000 Hz in either ear; or a bone conduction threshold of ≥20 dB at the same frequencies in either ear. This case definition includes mixed hearing loss, of which SNHL is a component. We also used a pediatric case definition (bone conduction threshold of ≥15 dB instead of ≥20 dB).

Cofactors potentially associated with TPOaAb, SNHL, or both were screened for independent effects as well as possible effect modification or confounding. Among others, they included maternal age, race, history of thyroid disease, smoking history, reproductive and medical history (including eclampsia, prior miscarriages, stillbirths, and premature deliveries), and socioeconomic status, as well as congenital and neonatal factors, such as gestational age at the time of birth (44) (days from registration to birth, plus gestational age at registration), gestational age at the time of the blood draw (gestational age at birth minus the number of days before the delivery that the sample was drawn), bilirubin levels, respiratory distress, oxygen therapy, low birth weight (<2,500 g), and related neonatal risk factors. The imprecision of gestational age calculations is well discussed (45). We used the CPP gestational age recorded at registration rather than the last menstrual period, which was also available, because the former had been reviewed by a clinician and, mostly, adjusted for erroneous recall.

Statistical methods.

Our aim was to determine whether there was an association between elevated TPOaAb and SNHL. We conducted this analysis conservatively by using several statistical approaches to ensure that the results were robust. Cofactors were assessed individually if they were biologically relevant or their potential effect was indicated (p < 0.20). Confounding and effect modification were evaluated. The final model included cofactors that withstood prior tests and consistently showed a significant association with the outcome or modified the effect of a predictor.

Estimates of binary and unadjusted continuous cofactors were obtained by using exact logistic regression (LogXact, v.7.0 software; Cytel Software Corporation, Cambridge, Massachusetts), which reports conditional maximum likelihood estimates or, when that cannot be accomplished because the estimate of the coefficient is extreme (∞), the maximum unbiased estimate. Continuous covariates were evaluated to determine their distributions, and the mean or median values were tested in association with TPOaAb and SNHL status by using Student's t or Whitney-Wilcoxon tests. Estimates of effect for the whole study population were checked by comparing them with those obtained by excluding siblings (using the first and then the last child only) when more than one child was born to the same mother during the study period. Cofactor collinearity was screened by using univariate correlation computations or multivariate linear regression variable inflation factors. Random-effects logistic regression models (xtreg and xtlogit, Stata v8.2 software; Stata Corporation, College Station, Texas) were used to determine whether there was an unobserved group effect. Multivariate models were compared by using exact logistic regression and logistic regression (logistic, Stata v8.2) with a robust standard error for possible intraclass correlation among siblings. Unadjusted estimates from these two methods were nearly identical, as were those adjusted for binary cofactors. The final analysis used logistic regression with a robust standard error. This method was chosen to permit analysis of multiple cofactors that were computationally too intensive for LogXact and to obtain the more conservative robust standard error to account for any potential intrafamily correlation among siblings, even when the random-effects rho value indicated no such group effect. All p values reported here are two-sided.

RESULTS

Selected baseline characteristics of the study population were compared with those of the larger Baltimore CPP cohort. The populations were similar (table 1).

TABLE 1.

Comparison of baseline characteristics of the Baltimore, Maryland, CPP* and the final study population, 2004–2006

 Baltimore CPP Study population 
  Value 
No. of mothers 3,651 1,529 41.9 
Mean maternal age in years (range) 24.3 (11–46) 24.1 (12–46)  
Median socioeconomic index† 40 40  
    % Married 70.3 70.9  
Mean years of education 9.7 9.7  
Mean weeks of gestation at registration 24.3 20.6  
Mean no. of prior pregnancies 2.8 2.8  
No. of study pregnancies 4,388 1,731 39.5 
No. of surviving children 3,917 1,736 44.3 
    % Black 77.8 82.4  
No. with complete audiometry 3,359 1,736 51.7 
    % Black 82.0 82.4  
 Baltimore CPP Study population 
  Value 
No. of mothers 3,651 1,529 41.9 
Mean maternal age in years (range) 24.3 (11–46) 24.1 (12–46)  
Median socioeconomic index† 40 40  
    % Married 70.3 70.9  
Mean years of education 9.7 9.7  
Mean weeks of gestation at registration 24.3 20.6  
Mean no. of prior pregnancies 2.8 2.8  
No. of study pregnancies 4,388 1,731 39.5 
No. of surviving children 3,917 1,736 44.3 
    % Black 77.8 82.4  
No. with complete audiometry 3,359 1,736 51.7 
    % Black 82.0 82.4  
*

CCP, Collaborative Perinatal Project.

Scores were developed by the CPP to combine correlated measures (family income, educational level, and occupation) reported at the time that the pregnancy was registered. The correlation of CPP and US Census Bureau scores was 0.97.

A total of 1,351 (77.8 percent) of the children were singletons, 10 (0.6 percent) were twins, and, for the remaining 375 (21.6 percent), one to three siblings were born during the study. A total of 1,732 (99.8 percent) of the children were born at ≥196 gestational days, and four (0.2 percent) were born at 191–195 gestational days.

Antenatal maternal TPOaAb

Maternal TPOaAb concentrations averaged 5.2 IU/ml (range, 0.2–640.6 IU/ml). Twenty-two children (1.3 percent) had mothers who tested positive for TPOaAb at ≥62.5 IU/ml, and 32 (1.8 percent) had mothers who tested positive at ≥31.25 IU/ml. The prevalence of elevated TPOaAb did not differ significantly according to gestational age at the time of maternal blood draw (table 2).

TABLE 2.

Odds ratios for selected predictors of elevated maternal TPOaAb* IU/ml at selected cutpoints,† Collaborative Perinatal Project, Baltimore, Maryland, 2004–2006

 ≥62.5 IU/ml ≥31.25 IU/ml 
 POR* 95% CI* p value POR 95% CI p value 
Gestational age at maternal blood draw (weeks) 0.93 0.83, 1.05 0.24 0.96 0.87, 1.04 0.30 
Maternal age (years) 1.09 1.05, 1.13 0.00 1.08 1.04, 1.12 0.00 
White race 2.04 0.75, 5.60 0.16 2.44 1.10, 5.43 0.03 
 ≥62.5 IU/ml ≥31.25 IU/ml 
 POR* 95% CI* p value POR 95% CI p value 
Gestational age at maternal blood draw (weeks) 0.93 0.83, 1.05 0.24 0.96 0.87, 1.04 0.30 
Maternal age (years) 1.09 1.05, 1.13 0.00 1.08 1.04, 1.12 0.00 
White race 2.04 0.75, 5.60 0.16 2.44 1.10, 5.43 0.03 
*

TPOaAb, thyroid peroxidase autoantibodies; POR, prevalence odds ratio; CI, confidence interval.

Mutually adjusted logistic regression estimate.

Maternal age was significantly associated with elevation of TPOaAb concentrations. Specifically, none of the mothers less than age 20 years (n = 549) was positive at ≥62.5 IU/ml, and only three (0.6 percent) were positive at ≥31.25 IU/ml. Race was not significantly associated with elevated TPOaAb at ≥62.5 IU/ml, although it was at ≥31.25 IU/ml (table 2).

Childhood SNHL at 8 years of age

Seventy-four (4.3 percent) children had SNHL affecting at least one frequency when the criteria for the primary case definition were used. There were 130 cases (7.5 percent) when the pediatric definition was used (table 3).

TABLE 3.

Unadjusted associations of selected baseline factors with SNHL* in the Collaborative Perinatal Project, Baltimore, Maryland, 2004–2006†

 All SNHL No SNHL POR 95% CI* p value 
 No. No. No.    
All children 1,736 100 74 4.3 1,662 95.7    
Sex          
    Boys 876 50.5 36 4.1 840 95.9 0.93 0.57, 1.52 0.84 
    Girls 860 49.5 38 4.4 822 95.6    
Family income          
    >Median 873 50.3 30 3.4 843 96.6 0.64 0.38, 1.06 0.09 
    ≤Median 818 47.1 43 5.3 775 94.7    
    NA* 45 2.6 2.2 44 97.8    
White race 306 17.6 2.9 297 97.1 0.64 0.26, 1.30 0.27 
Black race 1,430 82.4 65 4.5 1,365 95.5    
Premature at birth (length of gestation)          
    <259 days 230 13.3 10 4.4 220 95.6 1.02 0.46, 2.05 1.00 
    ≥259 days 1,506 86.7 64 4.3 1,442 95.7    
    Continuous       1.00 0.99, 1.01 0.83 
Birth weight          
    <2,500g 261 15.0 11 4.2 250 95.8 0.98 0.46, 1.92 1.00 
    ≥2,500g 1,472 84.8 63 4.3 1,409 95.7    
    NA 0.2 100    
Parent          
    Hearing impaired 0.4 100 2.75‡ −∞‡ 1.00‡ 
    Not hearing impaired 1,730 99.6 74 4.3 1,656 95.7    
Mother          
    Smoked 715 41.2 29 4.1 686 95.9 0.94 0.56, 1.55 0.89 
    Did not smoke 1,021 58.8 44 4.3 977 95.7    
Mother          
    Hypothyroid 23 1.3 8.7 21 91.3 2.16 0.24, 9.13 0.52 
    Not hypothyroid 1,707 98.3 72 4.2 1,645 95.8    
    NA 0.4  100.0    
 All SNHL No SNHL POR 95% CI* p value 
 No. No. No.    
All children 1,736 100 74 4.3 1,662 95.7    
Sex          
    Boys 876 50.5 36 4.1 840 95.9 0.93 0.57, 1.52 0.84 
    Girls 860 49.5 38 4.4 822 95.6    
Family income          
    >Median 873 50.3 30 3.4 843 96.6 0.64 0.38, 1.06 0.09 
    ≤Median 818 47.1 43 5.3 775 94.7    
    NA* 45 2.6 2.2 44 97.8    
White race 306 17.6 2.9 297 97.1 0.64 0.26, 1.30 0.27 
Black race 1,430 82.4 65 4.5 1,365 95.5    
Premature at birth (length of gestation)          
    <259 days 230 13.3 10 4.4 220 95.6 1.02 0.46, 2.05 1.00 
    ≥259 days 1,506 86.7 64 4.3 1,442 95.7    
    Continuous       1.00 0.99, 1.01 0.83 
Birth weight          
    <2,500g 261 15.0 11 4.2 250 95.8 0.98 0.46, 1.92 1.00 
    ≥2,500g 1,472 84.8 63 4.3 1,409 95.7    
    NA 0.2 100    
Parent          
    Hearing impaired 0.4 100 2.75‡ −∞‡ 1.00‡ 
    Not hearing impaired 1,730 99.6 74 4.3 1,656 95.7    
Mother          
    Smoked 715 41.2 29 4.1 686 95.9 0.94 0.56, 1.55 0.89 
    Did not smoke 1,021 58.8 44 4.3 977 95.7    
Mother          
    Hypothyroid 23 1.3 8.7 21 91.3 2.16 0.24, 9.13 0.52 
    Not hypothyroid 1,707 98.3 72 4.2 1,645 95.8    
    NA 0.4  100.0    
*

SNHL, sensorineural hearing loss; CI, confidence interval; NA, not available.

Exact logistic estimates of the prevalence odds ratio (POR).

When the ß values are extreme, as in this instance (−∞), the exact logistic regression software provides a median unbiased point estimate, which has no meaningful interpretation.

Maternal TPOaAb and SNHL

None of the baseline characteristics assessed was independently associated with SNHL (table 3). Having elevated maternal TPOaAb during the third trimester was associated with an increased risk of SNHL in the children (table 4). Of the 22 children whose mothers tested positive at ≥62.5 IU/ml, five (22.7 percent) had SNHL, whereas six (18.8 percent) of the 32 children whose mothers were positive for TPOaAb at ≥31.25 IU/ml did. These rates of SNHL were significantly greater than among children of TPOaAb-negative mothers (p < 0.05).

TABLE 4.

Prevalence and unadjusted exact odds ratios of SNHL* in association with maternal TPOaAb* at selected cutpoints, Collaborative Perinatal Project, Baltimore, Maryland, 2004–2006

 All SNHL No SNHL POR* 95% CI* p value 
 No. No. No.    
All children 1,736 100 74 4.3 1,662 95.7    
TPOaAb IU/ml          
    ≥62.5 22 1.3 22.7 17 77.3 6.99 1.96, 20.51 0.004 
    ≥31.25 32 1.8 6
 
18.8
 
26
 
81.3
 
5.54 1.81, 14.38 0.004 
   Pediatric SNHL
 
No pediatric SNHL
 
   
All children 1,736 100 130 7.5 1,606 92.5    
TPOaAb IU/ml          
    ≥62.5 22 1.3 27.3 16 72.7 4.80 1.51, 13.20 0.009 
    ≥31.25 32 1.8 25.0 24 75.0 4.32 1.64, 10.19 0.004 
 All SNHL No SNHL POR* 95% CI* p value 
 No. No. No.    
All children 1,736 100 74 4.3 1,662 95.7    
TPOaAb IU/ml          
    ≥62.5 22 1.3 22.7 17 77.3 6.99 1.96, 20.51 0.004 
    ≥31.25 32 1.8 6
 
18.8
 
26
 
81.3
 
5.54 1.81, 14.38 0.004 
   Pediatric SNHL
 
No pediatric SNHL
 
   
All children 1,736 100 130 7.5 1,606 92.5    
TPOaAb IU/ml          
    ≥62.5 22 1.3 27.3 16 72.7 4.80 1.51, 13.20 0.009 
    ≥31.25 32 1.8 25.0 24 75.0 4.32 1.64, 10.19 0.004 
*

SNHL, sensorineural hearing loss; TPOaAB, thyroid peroxidase autoantibodies; POR, prevalence odds ratio; CI, confidence interval.

Effect of maternal clinical thyroid disease

Twenty-three children had mothers with a history of hypothyroidism during the pregnancy, of which 11 responded clinically to the l-thyroxine treatment they all received. Two of these mothers had TPOaAb titers of >100 IU/ml; one had a child with SNHL, the other did not. When history of hypothyroidism was adjusted for or excluded from the analysis, estimates of the association between elevated maternal TPOaAb and SNHL did not change materially (table 5). Seven children had mothers with hyperthyroidism before or during the study pregnancy. None of the mothers had elevated TPOaAb, and none of the children had SNHL.

TABLE 5.

Association of elevated maternal TPOaAb* with childhood SNHL,* Collaborative Perinatal Project, Baltimore, Maryland, 2004–2006†

 SNHL (n = 74) Pediatric SNHL (n = 130) 
 POR* 95% CI* p value < POR 95% CI p value < 
TPOaAb ≥62.5 IU/ml       
    Unadjusted 7.01 2.34, 21.02 0.001 4.81 1.77, 13.08 0.002 
    Adjusted       
        TPOaAb 7.50 2.41, 23.33 0.000 5.15 1.81, 14.67 0.002 
        Maternal age (year increase) 0.98 0.95, 1.02 0.33 0.99 0.96, 1.02 0.38 
        White race 1.35 0.77, 2.37 0.29 1.68 1.11, 2.54 0.01 
        Maternal hypothyroidism diagnosis 1.85 0.42, 8.12 0.42 1.06 0.25, 4.44 0.94 
    Excluding 23 with hypothyroidism       
        TPOaAb 6.61 1.85, 23.63 0.004 4.47 1.42, 14.11 0.01 
        Maternal age (year increase) 0.98 0.95, 1.02 0.40 0.99 0.96, 1.02 0.45 
        White race 1.39 0.79, 2.44 0.26 1.71 1.13, 2.59 0.01 
TPOaAb ≥31.25 IU/ml       
    Unadjusted 5.55 2.07, 14.89 0.001 4.31 1.83, 10.15 0.001 
    Adjusted       
        TPOaAb 5.73 2.10, 15.62 0.001 4.39 1.84, 10.50 0.001 
        Maternal age (year increase) 0.98 0.95, 1.02 0.33 0.99 0.96, 1.02 0.37 
        White race 1.32 0.76, 2.32 0.33 1.65 1.10, 2.50 0.02 
        Maternal hypothyroidism diagnosis 2.0 0.46, 8.54 0.36 1.11 0.27, 4.63 0.89 
    Excluding 23 with hypothyroidism       
        TPOaAb 5.7 1.68, 15.34 0.004 3.93 1.55, 9.98 0.004 
        Maternal age (year increase) 0.99 0.95, 1.02 0.40 0.99 0.96, 1.02 0.44 
        White race 1.36 0.78, 2.40 0.28 1.69 1.12, 2.55 0.01 
 SNHL (n = 74) Pediatric SNHL (n = 130) 
 POR* 95% CI* p value < POR 95% CI p value < 
TPOaAb ≥62.5 IU/ml       
    Unadjusted 7.01 2.34, 21.02 0.001 4.81 1.77, 13.08 0.002 
    Adjusted       
        TPOaAb 7.50 2.41, 23.33 0.000 5.15 1.81, 14.67 0.002 
        Maternal age (year increase) 0.98 0.95, 1.02 0.33 0.99 0.96, 1.02 0.38 
        White race 1.35 0.77, 2.37 0.29 1.68 1.11, 2.54 0.01 
        Maternal hypothyroidism diagnosis 1.85 0.42, 8.12 0.42 1.06 0.25, 4.44 0.94 
    Excluding 23 with hypothyroidism       
        TPOaAb 6.61 1.85, 23.63 0.004 4.47 1.42, 14.11 0.01 
        Maternal age (year increase) 0.98 0.95, 1.02 0.40 0.99 0.96, 1.02 0.45 
        White race 1.39 0.79, 2.44 0.26 1.71 1.13, 2.59 0.01 
TPOaAb ≥31.25 IU/ml       
    Unadjusted 5.55 2.07, 14.89 0.001 4.31 1.83, 10.15 0.001 
    Adjusted       
        TPOaAb 5.73 2.10, 15.62 0.001 4.39 1.84, 10.50 0.001 
        Maternal age (year increase) 0.98 0.95, 1.02 0.33 0.99 0.96, 1.02 0.37 
        White race 1.32 0.76, 2.32 0.33 1.65 1.10, 2.50 0.02 
        Maternal hypothyroidism diagnosis 2.0 0.46, 8.54 0.36 1.11 0.27, 4.63 0.89 
    Excluding 23 with hypothyroidism       
        TPOaAb 5.7 1.68, 15.34 0.004 3.93 1.55, 9.98 0.004 
        Maternal age (year increase) 0.99 0.95, 1.02 0.40 0.99 0.96, 1.02 0.44 
        White race 1.36 0.78, 2.40 0.28 1.69 1.12, 2.55 0.01 
*

TPOaAB, thyroid peroxidase autoantibodies; SNHL, sensorineural hearing loss; POR, prevalence odds ratio; CI, confidence interval.

Logistic regression with robust standard error, unadjusted and adjusted for maternal age, race, and treated clinical hypothyroidism.

In an additional probe, children with one or more siblings born during the study (n = 385) were excluded from analysis. The association between TPOaAb and SNHL remained significant (prevalence odds ratio = 5.3, 95 percent confidence interval: 1.5, 18.2; p < 0.01; data not shown).

Neither maternal age nor race was independently associated with the primary case definition of SNHL (table 5). However, White children were significantly more likely than Black children to have SNHL when the pediatric case definition was used (table 5). The higher prevalence of SNHL among White children was independent of maternal TPOaAb status.

DISCUSSION

When a convenience sample of banked serum specimens from the Baltimore CPP was used, we found that elevation of maternal TPOaAb during the third trimester of pregnancy was associated with a higher prevalence of childhood SNHL after adjusting for important cofactors, including maternal age, race, and hypothyroidism. The association remained significant when two different exposure cutpoints and two case definitions were used.

Most of the study population was not exposed to elevated maternal TPOaAb; the overall prevalence was 1.3 percent and 1.8 percent at the ≥62.5-IU/ml and ≥31.25-IU/ml cutoffs, respectively, and was 1.9 percent and 2.4 percent, respectively in children whose mothers were at least 20 years of age (n = 1,187). These rates are lower than those reported in the general population and early pregnancy (10–12), but they are consistent with the young average age and late pregnancy status (and perhaps predominant race) of the mothers from whom the specimens were obtained. The finding that increased maternal age was strongly associated with elevation of TPOaAb confirms observations from most other studies (11, 12, 40).

Both the association of TPOaAb titer with maternal age and the observed prevalence during the third trimester are consistent with the stability of TPOaAb over time. Optical densities for all wells were well within the manufacturer's range, and all other quality control criteria were met (39). Immunoglobulin G antibodies, such as TPOaAb, generally have been found to be quite stable in sera that have been stored frozen for long periods, even if thawed and refrozen several times (46–48). In this study, samples had been stored, thawed, and refrozen, and then rethawed and tested in identical fashion. SNHL status was determined separately and linked after the laboratory assays had been conducted. Even in the event that some degradation did occur, therefore, differential degradation of TPOaAb is not likely.

A total of 1,721 (99.1 percent) of the specimens were drawn at ≥196 gestational days and 15 (0.9 percent) taken at 158–193 gestational days, by which time it would be expected that the TPOaAb titers would have declined an average of 50 percent (49). Given the substantial literature on the association of elevated TPOaAb with infertility and miscarriage, we would not anticipate as high a prevalence during the third trimester as would be found among the general, nonpregnant female population.

The observed 4.3–7.5 percent prevalence of childhood SNHL (including mixed hearing loss) also is in line with rates cited in the literature (20). The basis of the association between elevated maternal TPOaAb and SNHL in the offspring requires further exploration. A substantial literature exists on the essential role that maternal thyroid hormone (thyroxine, or T4) plays in regulating neurodevelopment and demarcates large gaps in our understanding of the specific mechanisms (24, 32, 50, 51). When TPOaAb persist throughout pregnancy, maternal levels of thyroxine sometimes decline, as does free thyroxine, or fT4 (50, 52, 53). It is possible that the presence of elevated autoantibodies inhibits the enzymatic activity of thyroid peroxidase (without which thyroxine cannot be formed), induces thyroid cytotoxicity, alters signals for the maturation and function of the fetal thyroid gland, marks a pathology of infectious origin, or signals autoimmune copathologies affecting the auditory pathway (53–55). Both thyroxine and TPOaAb cross the placenta (56). It is not known whether elevated maternal TPOaAb constitute a neurodevelopmental risk factor that is independent of thyroxine (57).

The human inner and middle ear is formed during the first and early second trimesters, and maturation continues until birth (51, 58). Maternal hypothyroxinemia impairs its proper development, although the pathways and timing are not fully understood (25, 31, 33, 59–65). Even when the thyroxine deficit is mild and transient, it may irreversibly alter radial neuronal migration, neocortex cytoarchitecture, and response to acoustic stimuli in animals (32). Research indicates that thyroxine also regulates the transcription of prestin, the protein involved in the ear's outer hair cell ability to change lengths (66).

Current understanding (49) suggests that the TPOaAb titers detected in this study are likely to represent higher levels in early pregnancy, a phase of thyroid hormone-dependent neurodevelopment during which deficits are likely to be more severe and irreversible (49, 51, 58, 67). It is possible that we observed an association specifically related to autoantibody elevation in late pregnancy or to the prolonged duration of elevated concentrations. We do not know whether the association observed here was due to TPOaAb as a proxy for progressive, undetected hypothyroxinemia, another TPOaAb mechanism, or both (68). We did not assay for thyroxine or other measures of thyroid function because our hypothesis was that the TPOaAb themselves would be a sensitive marker for SNHL. Moreover, we would not have had sufficient serum volume to run the other assays even if we had set out to. The role of TPOaAb is far from understood, and an international conference sponsored by the Centers for Disease Control and Prevention and the American Thyroid Association called for research to elucidate “postpregnancy outcomes” associated with TPOaAb (69). To our knowledge, this study is the first to evaluate the association of SNHL with TPOaAb, and the findings suggest that confirmation and exploration of the mechanisms involved are warranted.

The literature on TPOaAb and neurodevelopment in humans has focused on motor skills and cognitive function. Other studies have evaluated the effect of hypothyroxinemia on hearing development (70), but none to our knowledge has examined the association of TPOaAb with SNHL. The one clinical trial that did implicate TPOaAb in potential hearing loss was small (n = 691) and lacked a proper control group (71). It implied that the main effect was in reducing thyroxine availability. It is possible, however, that elevated TPOaAb mark additional pathologies.

Variability in autoimmune suppression occurs during pregnancy, as does variation in TPOaAb epitopes and their respective inhibitory and cytotoxic effects (53), the effect on serum thyroxine levels, placental and/or fetal gland function, inherited susceptibilities, and dietary iodine or selenium content, among other environmental exposures (1, 72, 73). It is possible that our results were affected by these or other factors we did not measure, or whose role remains unknown (74).

Despite the fact that both the exposure and outcome were rare, they occurred among 1,736 children, a relatively large study population that was well characterized. The association was robust across the multiple analytic approaches used. Nonetheless, it is possible that at least some of the cases of SNHL assessed at the age of 8 years were not congenital. This possibility would bias our estimates if other causes of childhood SNHL such as noise, head trauma, meningitis, ototoxic drugs, or others selectively affect children of mothers with elevated TPOaAb (75, 76). If a shared genetic trait is associated with both elevated maternal TPOaAb and congenital SNHL, the association we detected would be confounded.

While neonatal screening programs are critical to mitigating the effects of SNHL as early as possible, they cannot reverse it. The elucidation of risk factors for SNHL—a lifelong impairment with multiple attendant disadvantages even when minimal or mild—is warranted in its own right.

The observed association of SNHL with TPOaAb at cutoffs that, in early pregnancy, could be below the 100 IU/ml often used to confirm thyroiditis suggests that what is clinically unexceptional for the mother may not be acceptable for the well-being of the developing child. This observation implies that additional studies of pregnant women with elevated TPOaAb are warranted, including those who are positive below 100 IU/ml. TPOaAb positivity may not only predict an increased risk of clinical thyroid disease in the women themselves (77, 78) but also mark preventable neurodevelopmental deficits in their children. From a policy perspective, these results could provide insights regarding the type and timing of thyroid tests advisable during pregnancy (15). Although confirmatory studies are required, the observations reported here provide an evidentiary basis in support of proposals to screen mothers at the onset of pregnancy for both TPOaAb and fT4 and adhere to a monitoring algorithm throughout pregnancy for those testing positive for TPOaAb even if thyroid-stimulating hormone values are normal (79).

Abbreviations

    Abbreviations
  • CPP

    Collaborative Perinatal Project

  • SNHL

    sensorineural hearing loss

  • TPOaAb

    thyroid peroxidase autoantibodies

This study was conducted as Ellen E. Wasserman's doctoral dissertation at the Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, which provided a grant to support the research. INOVA Diagnostics donated the assay kits for the analysis of thyroid autoantibodies. The tests were supported by the Johns Hopkins Center for Autoimmune Disease Research. The National Institute of Child Health and Human Development/National Institutes of Health repository provided serum specimens to the Stanley Division of Developmental Neurovirology, Johns Hopkins Medical Institutions, from which samples were obtained. The Stanley Medical Research Institute provided financial support to procure the samples from the National Institutes of Health repository. The National Institute of Mental Health/National Institutes of Health supported CPP database maintenance (“Pilot Studies for Baltimore CPP/Pathways Followup,” grant MH 070333).

The authors are grateful to Dr. Douglas Forrest, National Institute on Deafness and Other Communication Disorders/National Institutes of Health, for his encouragement and thoughtful questions; Dr. Janet Hardy, one of the original Baltimore CPP investigators, for her early guidance on the CPP; Dr. David Irani, Johns Hopkins Medical Institutions, for his insights and counsel on issues related to embryonic brain development; Dr. Mark Klebanoff, National Institute of Child Health and Human Development/National Institutes of Health, for his comments on the draft manuscript; and Bodgana Krivogorsky, Stanley Division of Developmental Neurovirology, for aliquotting and labeling the samples. The authors extend special thanks to Dr. Frank M. Lassman, an original NCPP investigator now at the University of Minnesota, for his thoughtful suggestions and background information; Dr. Matthew Longnecker, National Institute of Environmental Health Sciences/National Institutes of Health, for his critiques along the way; Dr. Jon Samet, Johns Hopkins Bloomberg School of Public Health, for reviewing the initial proposal and providing methodological guidance; Dr. Steve Selvin, University of California Berkeley, for his thoughts and suggestions regarding early visual data explorations; Dr. Lori Sokoll, Johns Hopkins Medical Institutions, for contributing her time and laboratory services to attempting fT4 assays; Dr. Donna Strobino, Johns Hopkins Bloomberg School of Public Health, for comments on neonatal matters in an early draft of the proposal; Dr. Grant Tao, Johns Hopkins Medical Institutions, for his advice regarding the design of the study and his critical analyses of the draft manuscript; Dr. Susan Tonascia, Johns Hopkins Bloomberg School of Public Health, for providing comments and suggestions regarding the logistics of data linkage and study planning; Dr. Robert F. Vogt, Jr., National Center for Environmental Health/Centers for Disease Control and Prevention, for thoughtful conversations and comments on an earlier draft of the manuscript; and Dr. Clare Weinberg, National Institute of Environmental Health Sciences/National Institutes of Health, for her time and thoughts regarding early methodological approaches. In addition, Mark F. Prummel's dedicated work is acknowledged as an inspiration and guide. His untimely death is lamented.

Conflict of interest: none declared.

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