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Goteborg Pediatric Growth Research Center, Department of Pediatrics, Institute of the Health of Women and Children, Goteborg University (M.-L.B.), 416 85 Goteborg, Sweden; Department of Women’s and Children’s Health, Uppsala University (B.J., T.T., M.L.), 75105 Uppsala, Sweden; and Swedish Armed Forces, Headquarters, Army Safety Inspectorate (P.-A.H.), 10785 Stockholm, Sweden
Address all correspondence and requests for reprints to: Dr. Marie-Louise Barrenäs, Goteborg Pediatric Growth Research Center, Department of Pediatrics, Institute of the Health of the Woman and Child, Goteborg University, 416 85 Goteborg, Sweden. E-mail: marie-louise.barrenas{at}vgregion.se.
Abstract
Background: Several components of the metabolic syndrome coincide with those risk factors linked to sensorineural hearing loss (SNHL). According to the thrifty phenotype hypothesis, the metabolic syndrome can be caused by events during the fetal period. This study tests the thrifty phenotype hypothesis on hearing, using body size at birth and conscription as indirect markers for fetal programming and body mass index as an indicator for the metabolic syndrome.
Methods: Odds ratios were used to analyze birth data regarding body size from birth to conscription as risk factors for hearing loss in 245,092 conscripted Swedish men.
Findings: Compared with conscripts born short for gestational age with catch-up growth, those born short with absence of catch-up growth exhibited 134% higher risk of SNHL. Adult short stature was associated with a 50% increased risk. Compared with conscripts with average body mass index, overweight was associated with 30%, obesity with 99%, and overweight if born light for gestational age with 118% higher risk of SNHL. Conscripts born light for gestational age had a 41% increased risk, independent of the later growth pattern.
Conclusion: The thrifty phenotype hypothesis also seems to be valid for SNHL, meaning that SNHL in adulthood may originate from events during fetal life. SNHL might be a new clinical feature of the metabolic syndrome.
SEARCHING FOR FUTURE therapeutic interventions against the still incurable sensorineural hearing loss (SNHL), Barrenäs et al. (1) suggested that the pathogenesis to SNHL in adulthood may originate in utero due to mechanisms postulated by the thrifty phenotype hypothesis (2). We became interested in this hypothesis because we found inverse associations between SNHL and both short body stature and reduced levels of the IGF-I in women with Turner syndrome (3) and an inverse relationship between final height and SNHL in adult men (1). We also noted the anecdote from 1869 by Banting (4), whose poor hearing was greatly improved after having lost 46 lb by keeping to a low-carbohydrate diet (the precursor to Dr. Aitkin’s diet). Weight reduction might be one possible future treatment intervention.
The thrifty phenotype hypothesis arose from observations that individuals born small for gestational age (SGA) had an increased morbidity in adulthood in certain medical disorders. Such disorders often coincide with those regarded as risk factors for SNHL (5, 6, 7): for example, hypertension, coronary heart disease, dyslipidemia, and diabetes type 2 (8, 9). According to the thrifty phenotype hypothesis, these health problems are triggered by fetal programming, a concept designed to describe how the persistence of the endocrine and metabolic adaptation a fetus makes in response to alterations in the intrauterine environment may induce permanent changes that may lead to dysfunction in adulthood (10). Our working hypotheses are that SNHL is a feature of the metabolic syndrome and that SNHL is imprinted in fetal life along with the thrifty phenotype expression (Fig. 1
). Here we report odds ratios for SNHL in a longitudinal cohort study of 249,000 Swedish conscripts using body size from birth to conscription as an indirect marker for fetal programming, short adult stature as a proxy for absence of height catch-up growth, and body mass index (BMI) as an indicator of the metabolic syndrome.
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Study cohort
Information on Swedish conscripts’ birth characteristics was obtained from the Swedish Birth Register and linked to the Swedish Conscript Register using the males’ unique personal identification numbers. The Swedish Birth Register contains data for more than 99% of all births in Sweden since 1973. In the period from 1973–1978, information about 312,159 live-born male infants was available. Multiple births and infants born to non-Nordic mothers and fathers were excluded (n = 35,957). Moreover, 3,402 males had died before 18 yr of age. Of the remaining 272,800 boys, 21,607 (7.9%) males were not conscripted between January 1991 and January 1997, mainly because of known severe handicaps, including congenital malformations, hearing loss, and chronic diseases (
2.4% in each birth cohort). Audiometry data at conscription were available for 245,092 of the conscripted men, who constituted the studied population (age range, 17–24 yr). The period of follow-up was thus from birth to conscription. The study was approved by the ethics committees at Uppsala University and Goteborg University.
Data collection
Gestational age was estimated from the date of the last menstrual period of the subject’s mother and was stratified into very preterm (<32 wk completed), moderately preterm (32–36 wk), and term (
37 wk) births. Birth weight for gestational age was categorized into three categories. Light or heavy for gestational age was defined as more than 2 SD scores (SDS) below or above the mean birth weight for gestational age, and appropriate weight for gestational age (AGA) as birth weight between –2 and 2 SDS (11). Birth length and head circumference were defined analogously. SGA was defined as less than –2 SDS for either birth length or weight for gestational age and was divided into three different subgroups: born short only, born light only, and born both short and light for gestational age (12). The birth weight distribution was the same for all six birth cohorts. Height at conscription was recorded in centimeters without shoes and weight in kilograms in light indoor clothes. Adult height SDS was computed as (individual measurement minus cohort mean measurement)/cohort SD, and stratified into short adult stature (less than –2 SDS), normal adult stature (–2 to 2 SDS), and tall adult stature (>2 SDS). Conscripts born SGA and who were above –2 SDS in height at conscription were categorized as exhibiting a linear catch-up in height. BMI was calculated as the ratio between adult weight and squared adult height. Normal BMI was defined as BMI between 18.5 and 24.9, overweight as BMI greater than 25, and obesity as BMI greater than 30, as suggested by the World Health Organization (13). Hearing measurements were conducted according to standard audiometric procedures. High and midfrequency hearing losses were defined as having at least one hearing threshold below (poorer than) 20 dB at 3, 4, and 6 kHz or 1 and 2 kHz, respectively.
Statistical analysis
The statistical analysis of risks was performed using multiple logistic regression analyses in the standard statistical package SPSS (version 11.5, SPSS, Inc., Chicago, IL) for Windows. A two-tailored P < 0.05 was considered significant. Odds ratios were presented with 95% confidence intervals. The adjustments used in the multivariate analyses for possible confounders are presented in the tables.
Results
Short for gestational age and short stature at conscription
Hearing loss in either mid- or high frequencies was found in 4.0% of the total study sample, in 5.7% of non-SGA with a short adult stature, and in 7.1% of SGA with no catch-up growth and therefore a short adult stature (P < 0.005). Final height, however, was negatively associated with increased risk of hearing loss, with short adult stature exhibiting a 50% increased risk of hearing loss at high frequencies (Table 1). Being born short for gestational age was not found to be associated with a significantly increased risk of hearing loss unless catch-up growth was absent (Tables 1–3). Among men born short, lack of catch-up growth resulting in short adult stature was associated with a 134% risk increase of hearing loss at high frequencies compared with men born short with normal adult stature. Similar results were found among men born AGA or born both short and light without catch-up growth (51% and 75% higher risks, respectively).
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Compared with boys with AGA, low birth weight for gestational age was associated with a slightly increased risk of a hearing loss at high frequencies (30%; Table 1
). When analyzing different subgroups of men born SGA, a 41% increased risk of hearing loss was found among conscripts born light for gestational age compared with men born AGA (Table 2). Being born both short and light was associated with a slightly increased risk (28%) compared with men who were not born SGA. Relative to conscripts with average BMI, overweight was found to be associated with a 30–40% increased risk of hearing loss and obesity with a doubled risk (Tables 1 and 3). The association between BMI at conscription and hearing loss among the subgroups of men born SGA was also studied (Table 3). Overall, the risk of hearing loss among men in the different SGA subgroups tended to be higher if they attained overweight, especially if born light (a 118% risk increase). However, the numbers were small, obese and overweight cases were not separated, and statistical significance was not always obtained. Also, low BMI was associated with a risk increase (Table 3). This observation was consistent also for all but one of the six subgroups, and that subgroup was extremely small (n = 6). Therefore, this may be important despite a lack of statistical significance in the small cells.
Discussion
The most important new finding from this large young male cohort when searching for therapeutic strategies to treat SNHL in a short-term perspective was that conscripts with obesity constituted a doubled risk of SNHL, overweight produced only a 30–40% risk increase, but overweight if born SGA light again caused a doubled risk compared with conscripts with normal BMI. These findings imply that SNHL may be involved in the metabolic syndrome, possibly by sharing the same etiology. Fetal programming of the hypothalamic-pituitary-axis could be one possibility. This view is contradictory to the current opinion in audiological science, i.e. that SNHL in adulthood is caused by hypertension, obesity, cardiovascular disease, or hypercholesterolemia per se. Our main arguments for this paradigm shift were that SNHL has been associated with all major clinical features of the metabolic syndrome, including IGF-I (3), and, according to the present study, also to SGA, obesity, and absence of catch-up in height. Moreover, this is the first time a U-shaped association was reported between BMI and hearing loss. This result does not contradict the Barker hypothesis, because the association between BMI and cardiovascular disease was also U-shaped (14). Another possibility was that the adipocytes produced or released some toxic substance. For example, increased TNF-
, IL-6, and complement component 3 levels have been reported in both SNHL and obesity (15, 16). From this point of view, a most interesting study will be to follow the effects of low-carbohydrate diet and weight reduction on hearing in obese patients with SNHL.
The second new finding was the strong association with growth retardation, implying that SNHL may originate in utero due to fetal programming by mechanisms previously described to underlay the thrifty phenotype hypothesis. The effect of absence of linear catch-up growth on hearing was crucial, indicating that hearing is dependent on GH. It is known that the length of the human organ of Corti varies among individuals (17), that reduced IGF-I levels affect the size and function of the cochlea, and that low IGF-I levels are involved in intrauterine and postnatal growth retardation and the metabolic syndrome (8, 18). Possibly SNHL occurred more frequently among short conscripts born SGA short who lacked catch-up growth because their IGF-I levels were lower. This might have reduced the replication of cells in the cochlea, causing SNHL because the number of auditory sensory cells was smaller as the organ of Corti was shorter.
This is the first study on hearing using the categorization by SGA and catch up in height, which might explain why previous studies have failed to show a relationship between hearing loss and short birth length. Other strengths of this study lie in the facts that birth data were collected prospectively and there was a large sample size, which permitted powerful comparisons between different subgroups of SGA because each SGA subgroup contained about 3000 infants. The main shortcomings of this study were the lack of serum level markers such as IGF-I as well as data concerning parental height; the timing of a possible negative event during pregnancy; the age when obesity, hearing loss, and catch up in height occurred; and the conscripts’ health behavior. However, the present results were consistent with previous studies of both the thrifty phenotype hypothesis and the metabolic syndrome in general and previous results on the present cohort in particular, i.e. that conscripts born SGA who lack catch-up growth had higher systolic blood pressure, higher BMI, and subnormal intellectual, psychological, and physical performances (19, 20). Heredity and chromosomal aberrations are well-known causes of both hearing loss among young people and fetal growth retardation, and relationships between hearing loss and low birth weight (21, 22, 23, 24), low body weight at 1 yr of age (25), and short adult stature (1, 3) have been reported previously. Accordingly, we see no reason why audiometric measurement errors should differ systematically with regard to birth characteristics or adult height or weight, or why exposure to noise should differ between short and tall conscripts. Because confusion has arisen about catch up when used for both weight and height (26), we emphasize the importance of separating height catch up (an established definition for compensatory linear growth) from an increase in weight, because height catch up relates positively to improvements in health and not the opposite, i.e. health hazards (19, 20). The terminology for increase in weight should be overweight and obesity, as defined by the World Health Organization (13). In the present study, obesity was associated with a doubled risk of SNHL, and height catch up was related to a substantial risk reduction.
In conclusion, the present results support the view that the thrifty phenotype hypothesis as well as the metabolic syndrome may be appropriate explanations for SNHL, implying that SNHL could have the same underlying causes as growth retardation in utero and obesity. The overall implication of these findings is to increase awareness among medical professionals and researchers that SNHL might be another clinical feature of the metabolic syndrome. A fast track could be to include hearing in the large on-going multicenter studies on obesity, the metabolic syndrome, and cardiovascular disease, either by audiometry or a standardized yes/no question. For example, "can you without difficulty hear what is said in a conversation among several persons, without using a hearing aid," an item used by the National Bureau of Statistics in Sweden when estimating health over time. Another robust variable is hearing aid usage (yes/no). Indeed, the cost in Europe for occupational noise-induced SNHL was estimated to 12 billion euros/yr at minimum (27), and the overall prevalence for SNHL by age 80 yr was 50% (28, 29). Moreover, hearing aids (which are stigmatizing and cosmetically annoying) do not offer sufficient amplification when most needed, i.e. when background noise is present. Our next task is to study the effects of weight reduction and maintenance of serum IGF-I concentrations on SNHL.
Footnotes
First Published Online May 31, 2005
Abbreviations: AGA, Appropriate weight for gestational age; BMI, body mass index; SDS, SD score; SGA, small for gestational age; SNHL, sensorineural hearing loss.
Received February 22, 2005.
Accepted May 25, 2005.
References
80 years of age. Prevalence of problems and sensitivity. Scand Audiol 26:99–106[Medline]This article has been cited by other articles:
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  Joint Committee on Infant Hearing Year 2007 Position Statement: Principles and Guidelines for Early Hearing Detection and Intervention Programs Pediatrics, October 1, 2007; 120(4): 898 - 921. [Full Text] [PDF]
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 Y. J. Cheng, E. W. Gregg, H. S. Kahn, D. E. Williams, N. De Rekeneire, and K. M. V. Narayan Peripheral Insensate Neuropathy--A Tall Problem for US Adults? Am. J. Epidemiol., November 1, 2006; 164(9): 873 - 880. [Abstract] [Full Text] [PDF]
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