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Hearing outcomes in children of diabetic pregnancies
Journal Pre-proof Hearing Outcomes in Children of Diabetic Pregnancies Joshua A. Lee, Charmee H. Mehta, Shaun A. Nguyen, Ted A. Meyer PII:
S0165-5876(20)30068-9
DOI:
https://doi.org/10.1016/j.ijporl.2020.109925
Reference:
PEDOT 109925
To appear in:
International Journal of Pediatric Otorhinolaryngology
Received Date: 13 November 2019 Revised Date:
30 January 2020
Accepted Date: 30 January 2020
Please cite this article as: J.A. Lee, C.H. Mehta, S.A. Nguyen, T.A. Meyer, Hearing Outcomes in Children of Diabetic Pregnancies, International Journal of Pediatric Otorhinolaryngology, https:// doi.org/10.1016/j.ijporl.2020.109925. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Elsevier B.V. All rights reserved.
Hearing Outcomes in Children of Diabetic Pregnancies Joshua A. Lee BAa, Charmee H. Mehta MDa, Shaun A. Nguyen, MD FAPCRa, Ted A. Meyer MD PhDa Running Title: Hearing Loss in Children of Diabetic Pregnancies a
Department of Otolaryngology – Head and Neck Surgery, Medical University of South Carolina,
Charleston, SC Conflicts of Interest: none
Corresponding Author Joshua A. Lee [email protected] 135 Rutledge Ave, MSC 550, Charleston, SC 29425 Phone: (843) 876-0112 Fax: (843) 792-0553
Abstract Objective: Children of diabetic pregnancies (CDPs) face numerous risk factors for hearing loss (HL). The objective of this study was to investigate the hearing outcomes of CDPs on a population scale. Methods: Using the Audiological and Genetic Database, the prevalence, severity, and progression of HL in CDPs was compared against children of non-diabetic pregnancies (CNDPs) who served as controls. Results: Among 311 CDPs, 71.1% demonstrated evidence of HL compared to 45.5% in CNDPs (p<0.001). The mean age at which CDPs received audiograms was 3.6 years compared to 5.4 years for CNDPs (p<0.001). Compared to CNDPs, CDPs were similarly affected by common otologic conditions such as acute otitis media (25.7%), chronic otitis media (38.3%), and Eustachian tube dysfunction (41.8%) (all p>0.05). CDPs were more likely to have bilateral HL (81%) and sensorineural hearing loss (SNHL) (8%) relative to CNDPs (p<0.001 and p=0.004, respectively). Rates of conductive HL and mixed HL were not significantly different between groups (p=0.952 and p=0.058, respectively). CDPs were at significant risk for the development of HL (aOR 1.66 [1.28–2.17], SNHL (aOR 1.63 [1.01–2.52], and high-frequency HL (aOR 1.32 [1.03-1.68]). Of the comorbidities evaluated, CDPs with hyperbilirubinemia (aOR 1.85 [1.182.84]), perinatal asphyxia (aOR 1.90 [1.06-3.16]), or congenital heart disease (aOR 1.21 [1.071.37]) demonstrated higher risk of SNHL. Conclusion: Children of diabetic pregnancies face increased risks of developing HL, particularly bilateral and sensorineural hearing loss. Given these findings, we recommend close audiologic follow-up for these children, especially those with complicated birth histories or additional medical problems.
Keywords: Diabetes Mellitus, Gestational; Health of Newborn Infants; Premature Infants; Congenital Heart Defect; Infant of Diabetic Mother; Hearing Loss
1. Introduction Diabetes in pregnancy is an increasingly prevalent condition worldwide. Gestational diabetes (GDM) underlies 99% of diabetic pregnancies and pre-GDM comprises the remaining [1, 2]. In North America, GDM occurs between 7-14% of pregnancies [3, 4]. First-line treatments such as careful glycemic control and lifestyle modifications have only provided moderate disease control [1]. Children of diabetic pregnancies (CDPs) suffer the consequences of suboptimal glycemic control during gestation. Progress in maternal glucose monitoring and diabetes treatments has been made, however birth defects remain elevated in CDPs compared to children of non-diabetic mothers [5]. Both pre-GDM and GDM can cause a range of well-documented anatomic and physiologic abnormalities in the neonate, including preterm birth, congenital malformations, and neonatal respiratory distress [6]. Despite our knowledge of these major complications, the impact of the hyperglycemic in-utero environment on hearing outcomes remains understudied. As such, large-scale studies of this population are needed. In the present investigation, we used the Audiological and Genetic Database (AudGenDB) to evaluate hearing outcomes in CDPs. The AudGenDB is particularly useful in comparing disease associations due to its large sample size and available audiometric data. As a pediatric hearing database however, AudGenDB represents a select cohort of children referred for audiologic evaluation and its data should be interpreted with caution. To our knowledge, the present study is the first of its kind and aims to detail the characteristics of HL and associated risk factors within this growing population of children of diabetic pregnancies.
2. Materials and Methods 2.1 Subjects This study was exempt from review by the Institutional Review Board. The AudGenDB stores audiological data of over 175,000 children from Children’s Hospital of Philadelphia, Boston Children’s Hospital, and Vanderbilt University Medical Center. Electronic medical records, radiology reports, audiological testing, and genetic assessments are thoroughly deidentified and compliant with HIPAA. Using International Classification of Diseases 9th and 10th revision (ICD-9 and ICD-10) diagnostic codes or corresponding search terms, we queried the database for patients possessing the diagnosis of infant of a diabetic mother and neonatal hypoglycemia, which hereafter we refer to collectively as CDPs. These selection criteria ensured that patients had clinically significant disease resulting from the diabetic pregnancy. We included only patients who had at least one complete audiogram. Patients who did not meet the above diagnostic criteria for CDP served as controls, hereafter referred to as children of non-diabetic pregnancies (CNDPs) Medical comorbidities were populated for both cohorts using similar search strategies outlined above. The following conditions were queried from the database: congenital heart defect, neural tube defect, fetal macrosomia, preterm delivery, neonatal respiratory distress syndrome (NRDS), mechanical ventilation, sepsis and meningitis within the first 6 months of life, perinatal asphyxia, and hyperbilirubinemia. Common otologic comorbidities were also evaluated, such as acute and chronic otitis media, cholesteatoma, and Eustachian tube dysfunction. The diagnosis of these otologic conditions and assignment of the corresponding ICD code was made in the best judgment of the physician.
2.2 Audiologic Evaluation The present study modified methods for analyzing audiograms and defining HL outcomes detailed in prior AudGenDB studies [7-10]. Pure-tone air- and bone-conduction audiometry as well as sound field testing were used to evaluate hearing outcomes. Throughout the text, the number of ears (n) is used in place of number of patients (N) for outcomes in which these values could differ significantly. When available, ear-specific air-conduction thresholds were collected at octave frequencies of 0.25-8.0 kHz and at interoctave frequencies of 3.0-6.0 kHz. Both masked and unmasked bone conduction thresholds were analyzed at octave frequencies of 0.25-4.0 kHz and an interoctave frequency of 3.0 kHz. The PTA was calculated for air conduction bilaterally using the frequencies 0.5, 1.0, 2.0, and 3.0 kHz, in keeping with the American Academy of Otolaryngology–Head and Neck Surgery guidelines [11]. Where 3.0 kHz was unavailable, hearing levels at 2.0 kHz and 4.0 kHz was averaged instead. In a few cases, a PTA3 based on 0.5, 1.0, and 2.0 kHz substituted for conventional PTA when four thresholds were unavailable. Incomplete audiograms where PTA could not be determined were excluded. HL was defined as a PTA >15 dB for pure-tone audiometry or 20 dB for sound field audiometry at any frequency, or >25 dB at any frequency for infants aged <1 year. Moderate-to-profound HL was defined as a PTA >40 dB [12]. Audiologic patterns were categorized by the presence of HL, type of HL, severity of HL, and laterality of HL (unilateral or bilateral).
2.3 Type of Hearing Loss We classified HL as 1. Conductive (CHL), with an air conduction threshold of >15 dB HL and an air-bone gap of ≥10 dB at any recorded frequency, 2. Sensorineural (SNHL), with an
air-conduction threshold of >15 dB HL and an air-bone gap of <10 dB at any recorded frequency; 3. Mixed, with the presence of both CHL and SNHL at the same or different frequencies; or 4. Undefined, when the type of HL could not be determined due to inadequate data (e.g., audiograms without bone conduction testing or non–ear-specific sound field audiograms). High-frequency HL was defined as loss >20 dB at 4.0, 6.0, or 8.0 KHz.
2.4 Progression of Hearing Loss Initial severity of HL was calculated using the PTA of the earliest and most complete audiogram demonstrating HL. Final severity of HL was calculated using the PTA of the last available complete audiogram. Progression of HL was measured by calculating the difference between the initial PTA showing HL and the final PTA.
2.5 Statistical Analysis Statistical analyses were performed with R version 3.5.2 (R Institute for Statistical Computing, Vienna, Austria). Categorical variables were summarized by frequency and percentage. Continuous variables were summarized by mean ± standard deviation or median and interquartile range (IQR: 75th and 25th) where appropriate. All continuous variables were assessed for normality using the Shapiro-Wilk test. Comparisons of patient characteristics and outcomes (categorical variables) were performed using a Fisher’s exact test or Pearson’s Chisquare test. For continuous variables, an independent t-test or Mann-Whitney test was used to compare the two groups. A correlation model was used to determine the relationships among all outcome variables. All independent variables that showed a significant correlation at an α level of < 0.10 with dependent variables were placed in a multivariate regression analysis. Adjusted
odds ratio (aOR) and its confidence interval [95%CI] were obtained from the final model as a measure of the association between the independent predictors (age of first audiogram, sex, race, ethnicity, comorbidities, and common otolaryngologic conditions) and the dependent responses (different hearing patterns, SNHL). Cohen’s effect sizes (ES) estimates with 95% confidence intervals (CI) were calculated using contingency tables of outcome data for comorbid variables. Effect size is represented by standardized mean difference (SMD), a unitless numerical value also known as Cohen’s d, which assesses the magnitude and certainty of benefit [13, 14]. Positive values indicate a positive effect on outcome interpretation being suggested by Cohen: 0.25 small effect, 0.55 medium effect, and 0.85 large effect [13]. A P value <.05 was considered to indicate a statistically significant difference for all statistical tests.
3. Results 3.1 Patient Demographics Our search strategy of the AudGenDB yielded 311 CDPs as well as 102,995 CNDP patients who served as our control group. African Americans comprised a greater proportion of CDPs (19.6%, p=0.035) as did children with Hispanic ethnicity (11.3%, p=0.025) compared to CNDPs. The male to female ratio did not differ significantly between CDPs and the control group (p=0.160). Compared to controls, CDPs were significantly more likely to have a history of congenital heart anomalies (40.5% vs. 4.9%), preterm delivery (53.4% vs. 4.3%), NRDS (27.3% vs. 0.4%), perinatal asphyxia (7.1% vs. 0.2%), and hyperbilirubinemia (34.4% vs 0.4%) (p<0.001 for all comparisons). Sepsis (37.6%) and meningitis (4.8%) within the first 6 months of life affected CDPs at a tremendously higher rate compared to CNDPs (0.5% and 0.1%, p<0.001). While CDPs had an increased prevalence of fetal macrosomia (1.0%) and neural tube defects
(1.3%) relative to controls (both p<0.001), the event rate was small and not included in subsequent multivariable analysis. Common otolaryngologic conditions associated with HL, such as acute otitis media, chronic otitis media, cholesteatoma, and Eustachian tube dysfunction, affected both cohorts similarly (p=0.492, p=0.364, p=0.408, p=0.458, respectively). Table 1 summarizes patient demographics.
3.2 Prevalence and Laterality of Hearing Loss Among the 311 CDPs, 71.1% children demonstrated evidence of HL whereas 45.5% CNDPs had HL (p<0.001). CDPs were also more likely to have bilateral HL (81% ears) compared to CNDPs (68.5% ears) (p<0.001). CDPs also had higher odds of having HL on multivariable analysis (aOR 1.66 [1.28-2.17]) (Figure 1).
3.3 Patterns of Hearing Loss High-frequency HL affected a greater proportion of CDPs compared to controls (44.1% vs. 33.2%, p<0.001). Similarly, a greater prevalence of moderate-to-profound HL was found in CDPs relative to CNDPs (20.9% vs 12.6%, p<0.001). Concerning the type of HL (CHL, SNHL, or mixed HL), only SNHL affected CDPs at a significantly higher rate compared to controls (8% vs. 4.5%, p=0.004). On multivariable analysis, CDPs were independently associated with having high-frequency HL (aOR 1.32, [1.03-1.68]) and SNHL (aOR 1.63 [1.01-2.52]) (Figure 1). Comorbidities such as congenital heart disease (aOR 1.21 [1.07-1.37]), perinatal asphyxia (aOR 1.90 [1.67, 3.16]), and hyperbilirubinemia (aOR 1.85 [1.18, 2.84]) were significantly associated with SNHL on multivariable analysis (Figure 2).
3.4 Progression of Hearing Loss CDPs obtained their first complete audiogram at an earlier mean age of 3.6 years (range 0.08-14.9) as compared to CNDPs at 5.4 years (0.0-18.0) (p<0.001). Among ears of children with hearing loss, initial PTAs were extracted based on the first audiograms demonstrating any HL. In our cohorts of interest, initial median PTA was 21.3 dB (IQR 18.8-36.3) for CDPs and 25.0 dB (IQR 19.4-37.5) for CNDPs (p<0.004). Follow-up data were available for 137 CDPs and 31,091 CNDPs, with a median follow-up duration of 1.0 year (IQR 0.2 – 3.4). In both groups, for individual ears, hearing improved approximately 5dB at their last complete audiogram (p=0.1002). Among the 10 children with SNHL and follow-up data, one experienced worsened hearing while the remaining 9 did not demonstrate any change in hearing. Table 3 summarizes patient details by type of HL.
4. Discussion Diabetes in pregnancy remains an increasingly prevalent medical condition worldwide and in the United States [1, 3, 4]. While major associated fetal abnormalities have been well documented, the effect of maternal diabetes on childhood hearing remains understudied. Existing literature has shown little consensus on the association of hearing loss in CDPs. Studies comparing audiometric testing from CDP versus CNDPs show conflicting results [15-18]. On the other hand, reports have demonstrated the association of maternal diabetes with failure on newborn hearing screening [19] as well as with craniofacial conditions affecting hearing [20-24]. Thus, hearing outcomes of CDPs deserve further investigation.
4.1 Characteristics of HL
Our evaluation of the AudGenDB revealed that HL affected significantly more CDPs compared to CNDPs. Of note, CDPs demonstrated increased risk of HL on multivariate analysis, suggesting that diabetes in pregnancy might represent a primary risk factor. CDPs with HL were more likely to present with bilateral loss, at high frequencies, and with moderate-to-profound severity than CNDPs. Sensorineural hearing loss occurred in a significantly greater proportion of CDPs compared to controls. Mixed HL also occurred in a greater proportion of CDPs compared to CNDPs, though this difference did not reach statistical significance. In contrast, CDPs showed similar rates of CHL relative to controls. This result was consistent with our finding that rates of otitis media, cholesteatoma, and Eustachian tube dysfunction were similar between CDPs and CNDPs. The literature also suggests potential mechanisms of the development of SNHL in CDPs. Authors have hypothesized that poor gestational glycemic control causes vascular damage in the developing inner ear [25, 26]. Other theories have suggested that increased glucose metabolism can disrupt organogenesis or produce reactive oxygen species resulting in improper gene expression [5]. Additionally, one study proposed that higher levels of insulin-like growth factor1 can alter cochlear morphogenesis [27]. Along with findings from the present study, these proposed mechanisms might indicate that diabetes in pregnancy impacts children globally and impairs sensorineural components of hearing.
4.2 Progression of Hearing Progression of hearing represents one of the most clinically relevant outcomes obtainable from a pediatric hearing database. However, we encountered some discrepancies in hearing
progression. For instance, despite having a greater proportion of HL, CDPs appeared to have less hearing loss (better initial PTA) and similarly better final PTA compared to controls. As reported in our study, initial PTA selects the first audiogram capturing any hearing loss. Because CDPs received their first audiogram at an earlier age, HL might have presented in a milder form compared to controls who were assessed at a later point. With respect to final PTA, poor followup might account for the similar performance between cohorts. In total, these limitations preclude our ability to draw informative conclusions on progression of hearing loss.
4.3 Medical Comorbidities Common fetal consequences of GDM include fetal macrosomia, congenital malformations, cardiomyopathies, preterm birth, and neonatal respiratory distress. Other disturbances include hypoglycemia, polycythemia, and hyperbilirubinemia [6]. While our study showed that CDPs were at increased risk of developing HL and SNHL, multiple evaluated comorbidities also contributed significantly to hearing outcomes (see Figure 2). The most prominent variables were congenital heart defects, perinatal asphyxia, hyperbilirubinemia, mechanical ventilation, and sepsis. Studies have validated the association between hyperbilirubinemia and SNHL as well as further exacerbations in hearing function after exchange transfusion [28, 29]. Mechanical ventilation and sepsis have been associated with failure on hearing screening tests, especially among preterm infants [30]. These factors are particularly relevant to our study as over half of CDPs were delivered prematurely. GDM has also been shown to increase rates of perinatal asphyxia [6], which can expose the cochlea and neural pathways of hearing to hypoxic injury [31].
40.5% of CDPs in our study possessed a congenital heart defect, which is not surprising given its high association with diabetes in pregnancy [32]. Children with congenital heart defects are also at risk of HL [33]. However, unifying explanations for the coexistence of both HL and cardiac anomalies due to maternal diabetes are lacking. A prior study of the AudGenDB examined rates of HL in children with velocardiofacial syndrome [10], whose association with maternal diabetes has been implicated [34, 35]. Interestingly, CHL represented the predominant type of HL (32.5%) which the authors attributed to recurrent middle ear infections in the setting of immunodeficiency. In contrast, the present study found that the study population was predisposed to SNHL. Altogether, these important comorbidities might present risks of HL to CDPs that is in addition to risks conferred by diabetic pregnancy.
4.4 Limitations This study was limited by the biases inherent in a retrospective study, including the demonstration of association without causation. Our results might also overestimate the prevalence of HL as AudGenDB collects data from children referred for audiologic examination. Additionally, the reason for referral cannot be determined. Confounding interventions and comorbid variables without an ICD-9 or ICD-10 code could not be assessed in this study, including the use of ototoxic antibiotics [36]. Despite these limitations, we succeeded in obtaining a valid internal control group against which CDPs could be compared. Importantly, our study draws attention to an understudied subject and identifies further areas of investigation.
5. Conclusion
Diabetes mellitus and gestational diabetes remain an increasingly prevalent public health concern. Children of diabetic pregnancies face significant risk of developing HL, particularly SNHL. Along with providing preventive measures and prenatal counseling to mothers, close audiologic follow-up in CDPs, especially in those with complicated birth histories, might reduce the risk of HL and provide opportunity for early intervention.
Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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Figure Captions Figure 1. Patterns of Hearing Loss Associated with Children of Diabetic Pregnancies Figure 2. Variables Associated with Sensorineural Hearing Loss
Table 1. Patient Characteristics CDP, N (%)
CNDP, N (%)
p-value†
311
102,995
-
195 (62.7)
60363 (58.6)
Race White African American Other
152 (63.7) 61 (19.6) 52 (16.7)
66200 (64.3) 15476 (15.0) 21319 (20.7)
Ethnicity Hispanic Non-Hispanic Other§
35 (11.3) 210 (67.5) 66 (21.2)
7625 (7.4) 74574 (72.4) 20796 (20.2)
Comorbidities Congenital Heart Defect Neural Tube Defect Fetal Macrosomia Preterm Delivery NRDS Mechanical Ventilation Sepsis Meningitis Perinatal Asphyxia Hyperbilirubinemia
126 (40.5) <10‡ <10‡ 166 (53.4) 85 (27.3) <10‡ 117 (37.6) 15 (4.8) 22 (7.1) 107 (34.4)
5038 (4.9) 292 (0.3) 37 (0.0) 4406 (4.3) 361 (0.4) 79 (0.1) 519 (0.5) 137 (0.1) 177 (0.2) 387 (0.4)
Demographic Variable Total children Sex Male Female
Effect Size [95% CI]
0.160
0.09 [-0.03 – 0.22]
0.035
-0.20 [-0.32 - -0.08]
0.025
-0.06 [-0.17 – 0.06]
<0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
1.42 [1.30 – 1.55] 0.84 [0.29 – 1.39] 1.82 [1.17 – 2.47] 1.79 [1.66 – 1.91] 2.58 [2.43 – 2.72] 1.69 [1.18 – 2.19] 2.64 [2.50 – 2.77] 2.01 [ 1.71 – 2.31] 2.09 [1.84 – 2.34] 2.72 [2.58 - 2.86]
Otologic Comorbidities Acute otitis media 80 (25.7) 28459 (27.6) 0.492 -0.05 [-0.19 – 0.09] Chronic otitis media 119 (38.3) 42189 (41.0) 0.364 -0.06 [0.19 – 0.06] Cholesteatoma <10‡ 2189 (2.1) 0.408 -0.28 [-0.82 – 0.26] Eustachian tube 130 (41.8) 40765 (39.6) 0.458 0.05 [-0.07 – 0.18] dysfunction Abbreviations: Children of Diabetic Pregnancies (CDP), Children of Non-diabetic Pregnancies (CNDP), Neonatal Respiratory Distress Syndrome (NRDS) † P-value for univariate chi-square tests. Any outcomes significant at p<0.10 were further assessed on multivariable analysis § Ethnicity is unknown, missing, or not revealed ‡ Exact value of less than 10 is censored per AudGenDB policy to protect patient identity.
Table 2. Hearing Outcomes in Children of Diabetic Pregnancies vs. Controls Hearing Outcome Mean age of audiogram (range)
†
CDP 3.6 (0.08-14.9)
CNDP 5.4 (0.0-18.0)
p-value <0.001
Effect Size [95% CI] 0.40 [0.28 – 0.51]
221 (71.1)
46879 (45.5)
< 0.001
0.59 [0.46 – 0.73]
Unilateral HL
42 (19.0)
14758 (31.5)
<0.001
-0.37 [-0.56 – 0.19]
Bilateral HL
179 (81.0)
32121 (68.5)
High-Frequency HL, N (%)
137 (44.1)
34210 (33.2)
<0.001
0.25 [0.13 – 3.77]
Prevalence of CHL, N (%)
60 (19.3)
19566 (19.0)
0.952
0.01 [-0.15 – 0.17]
Prevalence of SNHL, N (%)
25 (8.0)
4612 (4.5)
0.004
0.34 [0.12 - 0.57]
Prevalence of Mixed HL, N (%)
65 (20.9)
17226 (16.7)
0.058
0.15 [0.00 – 0.30]
Prevalence of Undefined HL, N (%)
71 (22.8)
5475 (5.3)
<0.001
0.92 [0.77 – 1.06]
Median initial PTA (IQR), dB
21.3 (18.8-36.3)
25.0 (19.437.5)
0.004
NR
Median final PTA (IQR), dB
20.0 (13.8-29.3)
0.066
NR
65 (20.9)
20.0 (11.926.5) 13004 (12.6)
<0.001
0.33 [0.18 – 0.48]
5.0 (0.6-10.6)
5.0 (0.0-13.1)
0.1002
NR
HL Prevalence, N (%) Laterality, N (%)
Severity
Moderate to profound HL, N (%) ‡
Progression Improvement in PTA (IQR), dB
Abbreviations: conductive hearing loss (CHL), hearing loss (HL), children of diabetic pregnancies (CDP), children of non-diabetic pregnancies (CNDP), interquartile range (IQR), not reportable (NR), number of children (N), number of ears (n), pure-tone audiometry (PTA), sensorineural hearing loss (SNHL). † P-value for univariate chi-square tests. Any outcomes significant at p<0.10 were further assessed on multivariable analysis ‡ HL improvement was calculated by ears (n) rather than by child (N) due to discrepancies in improvement between ears
Table 3. Patient Characteristics within Types of Hearing Loss CHL SNHL Median Age of CDP (IQR) 5.9 (4.4-8.5) 8.6 (5.5-12.7)
Mixed HL 7.8 (5.3-11.9)
Undefined HL 3.2 (1.8-5.4)
Children Included in Hearing Loss Progression Analysis (N) CDP 21 10 20 86 CNDP 9523 1142 6933 13493 Abbreviations: conductive hearing loss (CHL), hearing loss (HL), children of diabetic pregnancies (CDP), children of non-diabetic pregnancies (CNDP), interquartile range (IQR), number of children (N), sensorineural hearing loss (SNHL)
Pattern of HL
Any HL
1.66 [1.28, 2.17]
SNHL
1.63 [1.01, 2.52]
Moderate-toprofound HL
1.26 [0.93, 1.70]
High-Frequency HL
1.32 [1.03, 1.68]
0.8
1
1.2
1.4
1.6
1.8 2 2.2 OR (95% CI)
Abbreviations: Hearing Loss (HL), Sensorineural Hearing Loss (SNHL)
2.4
2.6
2.8
3
Variable CDP
1.63 [1.01, 2.52]
Hyperbilirubinemia
1.85 [1.18, 2.84]
Perinatal Asphyxia
1.90 [1.06, 3.16]
Preterm Birth
0.96 [0.81, 1.15]
NRDS
0.93 [0.56, 1.51]
Sepsis
1.28 [0.86, 1.85]
CHD
1.21 [1.07, 1.37]
0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 2.2 2.4 2.6 2.8 3 3.2 OR (95% CI)
Abbreviations: Children of Diabetic Pregnancies (CDP), Congenital Heart Disease (CHD), Neonatal Respiratory Distress Syndrome (NRDS)
S0165-5876(20)30068-9
DOI:
https://doi.org/10.1016/j.ijporl.2020.109925
Reference:
PEDOT 109925
To appear in:
International Journal of Pediatric Otorhinolaryngology
Received Date: 13 November 2019 Revised Date:
30 January 2020
Accepted Date: 30 January 2020
Please cite this article as: J.A. Lee, C.H. Mehta, S.A. Nguyen, T.A. Meyer, Hearing Outcomes in Children of Diabetic Pregnancies, International Journal of Pediatric Otorhinolaryngology, https:// doi.org/10.1016/j.ijporl.2020.109925. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Elsevier B.V. All rights reserved.
Hearing Outcomes in Children of Diabetic Pregnancies Joshua A. Lee BAa, Charmee H. Mehta MDa, Shaun A. Nguyen, MD FAPCRa, Ted A. Meyer MD PhDa Running Title: Hearing Loss in Children of Diabetic Pregnancies a
Department of Otolaryngology – Head and Neck Surgery, Medical University of South Carolina,
Charleston, SC Conflicts of Interest: none
Corresponding Author Joshua A. Lee [email protected] 135 Rutledge Ave, MSC 550, Charleston, SC 29425 Phone: (843) 876-0112 Fax: (843) 792-0553
Abstract Objective: Children of diabetic pregnancies (CDPs) face numerous risk factors for hearing loss (HL). The objective of this study was to investigate the hearing outcomes of CDPs on a population scale. Methods: Using the Audiological and Genetic Database, the prevalence, severity, and progression of HL in CDPs was compared against children of non-diabetic pregnancies (CNDPs) who served as controls. Results: Among 311 CDPs, 71.1% demonstrated evidence of HL compared to 45.5% in CNDPs (p<0.001). The mean age at which CDPs received audiograms was 3.6 years compared to 5.4 years for CNDPs (p<0.001). Compared to CNDPs, CDPs were similarly affected by common otologic conditions such as acute otitis media (25.7%), chronic otitis media (38.3%), and Eustachian tube dysfunction (41.8%) (all p>0.05). CDPs were more likely to have bilateral HL (81%) and sensorineural hearing loss (SNHL) (8%) relative to CNDPs (p<0.001 and p=0.004, respectively). Rates of conductive HL and mixed HL were not significantly different between groups (p=0.952 and p=0.058, respectively). CDPs were at significant risk for the development of HL (aOR 1.66 [1.28–2.17], SNHL (aOR 1.63 [1.01–2.52], and high-frequency HL (aOR 1.32 [1.03-1.68]). Of the comorbidities evaluated, CDPs with hyperbilirubinemia (aOR 1.85 [1.182.84]), perinatal asphyxia (aOR 1.90 [1.06-3.16]), or congenital heart disease (aOR 1.21 [1.071.37]) demonstrated higher risk of SNHL. Conclusion: Children of diabetic pregnancies face increased risks of developing HL, particularly bilateral and sensorineural hearing loss. Given these findings, we recommend close audiologic follow-up for these children, especially those with complicated birth histories or additional medical problems.
Keywords: Diabetes Mellitus, Gestational; Health of Newborn Infants; Premature Infants; Congenital Heart Defect; Infant of Diabetic Mother; Hearing Loss
1. Introduction Diabetes in pregnancy is an increasingly prevalent condition worldwide. Gestational diabetes (GDM) underlies 99% of diabetic pregnancies and pre-GDM comprises the remaining [1, 2]. In North America, GDM occurs between 7-14% of pregnancies [3, 4]. First-line treatments such as careful glycemic control and lifestyle modifications have only provided moderate disease control [1]. Children of diabetic pregnancies (CDPs) suffer the consequences of suboptimal glycemic control during gestation. Progress in maternal glucose monitoring and diabetes treatments has been made, however birth defects remain elevated in CDPs compared to children of non-diabetic mothers [5]. Both pre-GDM and GDM can cause a range of well-documented anatomic and physiologic abnormalities in the neonate, including preterm birth, congenital malformations, and neonatal respiratory distress [6]. Despite our knowledge of these major complications, the impact of the hyperglycemic in-utero environment on hearing outcomes remains understudied. As such, large-scale studies of this population are needed. In the present investigation, we used the Audiological and Genetic Database (AudGenDB) to evaluate hearing outcomes in CDPs. The AudGenDB is particularly useful in comparing disease associations due to its large sample size and available audiometric data. As a pediatric hearing database however, AudGenDB represents a select cohort of children referred for audiologic evaluation and its data should be interpreted with caution. To our knowledge, the present study is the first of its kind and aims to detail the characteristics of HL and associated risk factors within this growing population of children of diabetic pregnancies.
2. Materials and Methods 2.1 Subjects This study was exempt from review by the Institutional Review Board. The AudGenDB stores audiological data of over 175,000 children from Children’s Hospital of Philadelphia, Boston Children’s Hospital, and Vanderbilt University Medical Center. Electronic medical records, radiology reports, audiological testing, and genetic assessments are thoroughly deidentified and compliant with HIPAA. Using International Classification of Diseases 9th and 10th revision (ICD-9 and ICD-10) diagnostic codes or corresponding search terms, we queried the database for patients possessing the diagnosis of infant of a diabetic mother and neonatal hypoglycemia, which hereafter we refer to collectively as CDPs. These selection criteria ensured that patients had clinically significant disease resulting from the diabetic pregnancy. We included only patients who had at least one complete audiogram. Patients who did not meet the above diagnostic criteria for CDP served as controls, hereafter referred to as children of non-diabetic pregnancies (CNDPs) Medical comorbidities were populated for both cohorts using similar search strategies outlined above. The following conditions were queried from the database: congenital heart defect, neural tube defect, fetal macrosomia, preterm delivery, neonatal respiratory distress syndrome (NRDS), mechanical ventilation, sepsis and meningitis within the first 6 months of life, perinatal asphyxia, and hyperbilirubinemia. Common otologic comorbidities were also evaluated, such as acute and chronic otitis media, cholesteatoma, and Eustachian tube dysfunction. The diagnosis of these otologic conditions and assignment of the corresponding ICD code was made in the best judgment of the physician.
2.2 Audiologic Evaluation The present study modified methods for analyzing audiograms and defining HL outcomes detailed in prior AudGenDB studies [7-10]. Pure-tone air- and bone-conduction audiometry as well as sound field testing were used to evaluate hearing outcomes. Throughout the text, the number of ears (n) is used in place of number of patients (N) for outcomes in which these values could differ significantly. When available, ear-specific air-conduction thresholds were collected at octave frequencies of 0.25-8.0 kHz and at interoctave frequencies of 3.0-6.0 kHz. Both masked and unmasked bone conduction thresholds were analyzed at octave frequencies of 0.25-4.0 kHz and an interoctave frequency of 3.0 kHz. The PTA was calculated for air conduction bilaterally using the frequencies 0.5, 1.0, 2.0, and 3.0 kHz, in keeping with the American Academy of Otolaryngology–Head and Neck Surgery guidelines [11]. Where 3.0 kHz was unavailable, hearing levels at 2.0 kHz and 4.0 kHz was averaged instead. In a few cases, a PTA3 based on 0.5, 1.0, and 2.0 kHz substituted for conventional PTA when four thresholds were unavailable. Incomplete audiograms where PTA could not be determined were excluded. HL was defined as a PTA >15 dB for pure-tone audiometry or 20 dB for sound field audiometry at any frequency, or >25 dB at any frequency for infants aged <1 year. Moderate-to-profound HL was defined as a PTA >40 dB [12]. Audiologic patterns were categorized by the presence of HL, type of HL, severity of HL, and laterality of HL (unilateral or bilateral).
2.3 Type of Hearing Loss We classified HL as 1. Conductive (CHL), with an air conduction threshold of >15 dB HL and an air-bone gap of ≥10 dB at any recorded frequency, 2. Sensorineural (SNHL), with an
air-conduction threshold of >15 dB HL and an air-bone gap of <10 dB at any recorded frequency; 3. Mixed, with the presence of both CHL and SNHL at the same or different frequencies; or 4. Undefined, when the type of HL could not be determined due to inadequate data (e.g., audiograms without bone conduction testing or non–ear-specific sound field audiograms). High-frequency HL was defined as loss >20 dB at 4.0, 6.0, or 8.0 KHz.
2.4 Progression of Hearing Loss Initial severity of HL was calculated using the PTA of the earliest and most complete audiogram demonstrating HL. Final severity of HL was calculated using the PTA of the last available complete audiogram. Progression of HL was measured by calculating the difference between the initial PTA showing HL and the final PTA.
2.5 Statistical Analysis Statistical analyses were performed with R version 3.5.2 (R Institute for Statistical Computing, Vienna, Austria). Categorical variables were summarized by frequency and percentage. Continuous variables were summarized by mean ± standard deviation or median and interquartile range (IQR: 75th and 25th) where appropriate. All continuous variables were assessed for normality using the Shapiro-Wilk test. Comparisons of patient characteristics and outcomes (categorical variables) were performed using a Fisher’s exact test or Pearson’s Chisquare test. For continuous variables, an independent t-test or Mann-Whitney test was used to compare the two groups. A correlation model was used to determine the relationships among all outcome variables. All independent variables that showed a significant correlation at an α level of < 0.10 with dependent variables were placed in a multivariate regression analysis. Adjusted
odds ratio (aOR) and its confidence interval [95%CI] were obtained from the final model as a measure of the association between the independent predictors (age of first audiogram, sex, race, ethnicity, comorbidities, and common otolaryngologic conditions) and the dependent responses (different hearing patterns, SNHL). Cohen’s effect sizes (ES) estimates with 95% confidence intervals (CI) were calculated using contingency tables of outcome data for comorbid variables. Effect size is represented by standardized mean difference (SMD), a unitless numerical value also known as Cohen’s d, which assesses the magnitude and certainty of benefit [13, 14]. Positive values indicate a positive effect on outcome interpretation being suggested by Cohen: 0.25 small effect, 0.55 medium effect, and 0.85 large effect [13]. A P value <.05 was considered to indicate a statistically significant difference for all statistical tests.
3. Results 3.1 Patient Demographics Our search strategy of the AudGenDB yielded 311 CDPs as well as 102,995 CNDP patients who served as our control group. African Americans comprised a greater proportion of CDPs (19.6%, p=0.035) as did children with Hispanic ethnicity (11.3%, p=0.025) compared to CNDPs. The male to female ratio did not differ significantly between CDPs and the control group (p=0.160). Compared to controls, CDPs were significantly more likely to have a history of congenital heart anomalies (40.5% vs. 4.9%), preterm delivery (53.4% vs. 4.3%), NRDS (27.3% vs. 0.4%), perinatal asphyxia (7.1% vs. 0.2%), and hyperbilirubinemia (34.4% vs 0.4%) (p<0.001 for all comparisons). Sepsis (37.6%) and meningitis (4.8%) within the first 6 months of life affected CDPs at a tremendously higher rate compared to CNDPs (0.5% and 0.1%, p<0.001). While CDPs had an increased prevalence of fetal macrosomia (1.0%) and neural tube defects
(1.3%) relative to controls (both p<0.001), the event rate was small and not included in subsequent multivariable analysis. Common otolaryngologic conditions associated with HL, such as acute otitis media, chronic otitis media, cholesteatoma, and Eustachian tube dysfunction, affected both cohorts similarly (p=0.492, p=0.364, p=0.408, p=0.458, respectively). Table 1 summarizes patient demographics.
3.2 Prevalence and Laterality of Hearing Loss Among the 311 CDPs, 71.1% children demonstrated evidence of HL whereas 45.5% CNDPs had HL (p<0.001). CDPs were also more likely to have bilateral HL (81% ears) compared to CNDPs (68.5% ears) (p<0.001). CDPs also had higher odds of having HL on multivariable analysis (aOR 1.66 [1.28-2.17]) (Figure 1).
3.3 Patterns of Hearing Loss High-frequency HL affected a greater proportion of CDPs compared to controls (44.1% vs. 33.2%, p<0.001). Similarly, a greater prevalence of moderate-to-profound HL was found in CDPs relative to CNDPs (20.9% vs 12.6%, p<0.001). Concerning the type of HL (CHL, SNHL, or mixed HL), only SNHL affected CDPs at a significantly higher rate compared to controls (8% vs. 4.5%, p=0.004). On multivariable analysis, CDPs were independently associated with having high-frequency HL (aOR 1.32, [1.03-1.68]) and SNHL (aOR 1.63 [1.01-2.52]) (Figure 1). Comorbidities such as congenital heart disease (aOR 1.21 [1.07-1.37]), perinatal asphyxia (aOR 1.90 [1.67, 3.16]), and hyperbilirubinemia (aOR 1.85 [1.18, 2.84]) were significantly associated with SNHL on multivariable analysis (Figure 2).
3.4 Progression of Hearing Loss CDPs obtained their first complete audiogram at an earlier mean age of 3.6 years (range 0.08-14.9) as compared to CNDPs at 5.4 years (0.0-18.0) (p<0.001). Among ears of children with hearing loss, initial PTAs were extracted based on the first audiograms demonstrating any HL. In our cohorts of interest, initial median PTA was 21.3 dB (IQR 18.8-36.3) for CDPs and 25.0 dB (IQR 19.4-37.5) for CNDPs (p<0.004). Follow-up data were available for 137 CDPs and 31,091 CNDPs, with a median follow-up duration of 1.0 year (IQR 0.2 – 3.4). In both groups, for individual ears, hearing improved approximately 5dB at their last complete audiogram (p=0.1002). Among the 10 children with SNHL and follow-up data, one experienced worsened hearing while the remaining 9 did not demonstrate any change in hearing. Table 3 summarizes patient details by type of HL.
4. Discussion Diabetes in pregnancy remains an increasingly prevalent medical condition worldwide and in the United States [1, 3, 4]. While major associated fetal abnormalities have been well documented, the effect of maternal diabetes on childhood hearing remains understudied. Existing literature has shown little consensus on the association of hearing loss in CDPs. Studies comparing audiometric testing from CDP versus CNDPs show conflicting results [15-18]. On the other hand, reports have demonstrated the association of maternal diabetes with failure on newborn hearing screening [19] as well as with craniofacial conditions affecting hearing [20-24]. Thus, hearing outcomes of CDPs deserve further investigation.
4.1 Characteristics of HL
Our evaluation of the AudGenDB revealed that HL affected significantly more CDPs compared to CNDPs. Of note, CDPs demonstrated increased risk of HL on multivariate analysis, suggesting that diabetes in pregnancy might represent a primary risk factor. CDPs with HL were more likely to present with bilateral loss, at high frequencies, and with moderate-to-profound severity than CNDPs. Sensorineural hearing loss occurred in a significantly greater proportion of CDPs compared to controls. Mixed HL also occurred in a greater proportion of CDPs compared to CNDPs, though this difference did not reach statistical significance. In contrast, CDPs showed similar rates of CHL relative to controls. This result was consistent with our finding that rates of otitis media, cholesteatoma, and Eustachian tube dysfunction were similar between CDPs and CNDPs. The literature also suggests potential mechanisms of the development of SNHL in CDPs. Authors have hypothesized that poor gestational glycemic control causes vascular damage in the developing inner ear [25, 26]. Other theories have suggested that increased glucose metabolism can disrupt organogenesis or produce reactive oxygen species resulting in improper gene expression [5]. Additionally, one study proposed that higher levels of insulin-like growth factor1 can alter cochlear morphogenesis [27]. Along with findings from the present study, these proposed mechanisms might indicate that diabetes in pregnancy impacts children globally and impairs sensorineural components of hearing.
4.2 Progression of Hearing Progression of hearing represents one of the most clinically relevant outcomes obtainable from a pediatric hearing database. However, we encountered some discrepancies in hearing
progression. For instance, despite having a greater proportion of HL, CDPs appeared to have less hearing loss (better initial PTA) and similarly better final PTA compared to controls. As reported in our study, initial PTA selects the first audiogram capturing any hearing loss. Because CDPs received their first audiogram at an earlier age, HL might have presented in a milder form compared to controls who were assessed at a later point. With respect to final PTA, poor followup might account for the similar performance between cohorts. In total, these limitations preclude our ability to draw informative conclusions on progression of hearing loss.
4.3 Medical Comorbidities Common fetal consequences of GDM include fetal macrosomia, congenital malformations, cardiomyopathies, preterm birth, and neonatal respiratory distress. Other disturbances include hypoglycemia, polycythemia, and hyperbilirubinemia [6]. While our study showed that CDPs were at increased risk of developing HL and SNHL, multiple evaluated comorbidities also contributed significantly to hearing outcomes (see Figure 2). The most prominent variables were congenital heart defects, perinatal asphyxia, hyperbilirubinemia, mechanical ventilation, and sepsis. Studies have validated the association between hyperbilirubinemia and SNHL as well as further exacerbations in hearing function after exchange transfusion [28, 29]. Mechanical ventilation and sepsis have been associated with failure on hearing screening tests, especially among preterm infants [30]. These factors are particularly relevant to our study as over half of CDPs were delivered prematurely. GDM has also been shown to increase rates of perinatal asphyxia [6], which can expose the cochlea and neural pathways of hearing to hypoxic injury [31].
40.5% of CDPs in our study possessed a congenital heart defect, which is not surprising given its high association with diabetes in pregnancy [32]. Children with congenital heart defects are also at risk of HL [33]. However, unifying explanations for the coexistence of both HL and cardiac anomalies due to maternal diabetes are lacking. A prior study of the AudGenDB examined rates of HL in children with velocardiofacial syndrome [10], whose association with maternal diabetes has been implicated [34, 35]. Interestingly, CHL represented the predominant type of HL (32.5%) which the authors attributed to recurrent middle ear infections in the setting of immunodeficiency. In contrast, the present study found that the study population was predisposed to SNHL. Altogether, these important comorbidities might present risks of HL to CDPs that is in addition to risks conferred by diabetic pregnancy.
4.4 Limitations This study was limited by the biases inherent in a retrospective study, including the demonstration of association without causation. Our results might also overestimate the prevalence of HL as AudGenDB collects data from children referred for audiologic examination. Additionally, the reason for referral cannot be determined. Confounding interventions and comorbid variables without an ICD-9 or ICD-10 code could not be assessed in this study, including the use of ototoxic antibiotics [36]. Despite these limitations, we succeeded in obtaining a valid internal control group against which CDPs could be compared. Importantly, our study draws attention to an understudied subject and identifies further areas of investigation.
5. Conclusion
Diabetes mellitus and gestational diabetes remain an increasingly prevalent public health concern. Children of diabetic pregnancies face significant risk of developing HL, particularly SNHL. Along with providing preventive measures and prenatal counseling to mothers, close audiologic follow-up in CDPs, especially in those with complicated birth histories, might reduce the risk of HL and provide opportunity for early intervention.
Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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Figure Captions Figure 1. Patterns of Hearing Loss Associated with Children of Diabetic Pregnancies Figure 2. Variables Associated with Sensorineural Hearing Loss
Table 1. Patient Characteristics CDP, N (%)
CNDP, N (%)
p-value†
311
102,995
-
195 (62.7)
60363 (58.6)
Race White African American Other
152 (63.7) 61 (19.6) 52 (16.7)
66200 (64.3) 15476 (15.0) 21319 (20.7)
Ethnicity Hispanic Non-Hispanic Other§
35 (11.3) 210 (67.5) 66 (21.2)
7625 (7.4) 74574 (72.4) 20796 (20.2)
Comorbidities Congenital Heart Defect Neural Tube Defect Fetal Macrosomia Preterm Delivery NRDS Mechanical Ventilation Sepsis Meningitis Perinatal Asphyxia Hyperbilirubinemia
126 (40.5) <10‡ <10‡ 166 (53.4) 85 (27.3) <10‡ 117 (37.6) 15 (4.8) 22 (7.1) 107 (34.4)
5038 (4.9) 292 (0.3) 37 (0.0) 4406 (4.3) 361 (0.4) 79 (0.1) 519 (0.5) 137 (0.1) 177 (0.2) 387 (0.4)
Demographic Variable Total children Sex Male Female
Effect Size [95% CI]
0.160
0.09 [-0.03 – 0.22]
0.035
-0.20 [-0.32 - -0.08]
0.025
-0.06 [-0.17 – 0.06]
<0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
1.42 [1.30 – 1.55] 0.84 [0.29 – 1.39] 1.82 [1.17 – 2.47] 1.79 [1.66 – 1.91] 2.58 [2.43 – 2.72] 1.69 [1.18 – 2.19] 2.64 [2.50 – 2.77] 2.01 [ 1.71 – 2.31] 2.09 [1.84 – 2.34] 2.72 [2.58 - 2.86]
Otologic Comorbidities Acute otitis media 80 (25.7) 28459 (27.6) 0.492 -0.05 [-0.19 – 0.09] Chronic otitis media 119 (38.3) 42189 (41.0) 0.364 -0.06 [0.19 – 0.06] Cholesteatoma <10‡ 2189 (2.1) 0.408 -0.28 [-0.82 – 0.26] Eustachian tube 130 (41.8) 40765 (39.6) 0.458 0.05 [-0.07 – 0.18] dysfunction Abbreviations: Children of Diabetic Pregnancies (CDP), Children of Non-diabetic Pregnancies (CNDP), Neonatal Respiratory Distress Syndrome (NRDS) † P-value for univariate chi-square tests. Any outcomes significant at p<0.10 were further assessed on multivariable analysis § Ethnicity is unknown, missing, or not revealed ‡ Exact value of less than 10 is censored per AudGenDB policy to protect patient identity.
Table 2. Hearing Outcomes in Children of Diabetic Pregnancies vs. Controls Hearing Outcome Mean age of audiogram (range)
†
CDP 3.6 (0.08-14.9)
CNDP 5.4 (0.0-18.0)
p-value <0.001
Effect Size [95% CI] 0.40 [0.28 – 0.51]
221 (71.1)
46879 (45.5)
< 0.001
0.59 [0.46 – 0.73]
Unilateral HL
42 (19.0)
14758 (31.5)
<0.001
-0.37 [-0.56 – 0.19]
Bilateral HL
179 (81.0)
32121 (68.5)
High-Frequency HL, N (%)
137 (44.1)
34210 (33.2)
<0.001
0.25 [0.13 – 3.77]
Prevalence of CHL, N (%)
60 (19.3)
19566 (19.0)
0.952
0.01 [-0.15 – 0.17]
Prevalence of SNHL, N (%)
25 (8.0)
4612 (4.5)
0.004
0.34 [0.12 - 0.57]
Prevalence of Mixed HL, N (%)
65 (20.9)
17226 (16.7)
0.058
0.15 [0.00 – 0.30]
Prevalence of Undefined HL, N (%)
71 (22.8)
5475 (5.3)
<0.001
0.92 [0.77 – 1.06]
Median initial PTA (IQR), dB
21.3 (18.8-36.3)
25.0 (19.437.5)
0.004
NR
Median final PTA (IQR), dB
20.0 (13.8-29.3)
0.066
NR
65 (20.9)
20.0 (11.926.5) 13004 (12.6)
<0.001
0.33 [0.18 – 0.48]
5.0 (0.6-10.6)
5.0 (0.0-13.1)
0.1002
NR
HL Prevalence, N (%) Laterality, N (%)
Severity
Moderate to profound HL, N (%) ‡
Progression Improvement in PTA (IQR), dB
Abbreviations: conductive hearing loss (CHL), hearing loss (HL), children of diabetic pregnancies (CDP), children of non-diabetic pregnancies (CNDP), interquartile range (IQR), not reportable (NR), number of children (N), number of ears (n), pure-tone audiometry (PTA), sensorineural hearing loss (SNHL). † P-value for univariate chi-square tests. Any outcomes significant at p<0.10 were further assessed on multivariable analysis ‡ HL improvement was calculated by ears (n) rather than by child (N) due to discrepancies in improvement between ears
Table 3. Patient Characteristics within Types of Hearing Loss CHL SNHL Median Age of CDP (IQR) 5.9 (4.4-8.5) 8.6 (5.5-12.7)
Mixed HL 7.8 (5.3-11.9)
Undefined HL 3.2 (1.8-5.4)
Children Included in Hearing Loss Progression Analysis (N) CDP 21 10 20 86 CNDP 9523 1142 6933 13493 Abbreviations: conductive hearing loss (CHL), hearing loss (HL), children of diabetic pregnancies (CDP), children of non-diabetic pregnancies (CNDP), interquartile range (IQR), number of children (N), sensorineural hearing loss (SNHL)
Pattern of HL
Any HL
1.66 [1.28, 2.17]
SNHL
1.63 [1.01, 2.52]
Moderate-toprofound HL
1.26 [0.93, 1.70]
High-Frequency HL
1.32 [1.03, 1.68]
0.8
1
1.2
1.4
1.6
1.8 2 2.2 OR (95% CI)
Abbreviations: Hearing Loss (HL), Sensorineural Hearing Loss (SNHL)
2.4
2.6
2.8
3
Variable CDP
1.63 [1.01, 2.52]
Hyperbilirubinemia
1.85 [1.18, 2.84]
Perinatal Asphyxia
1.90 [1.06, 3.16]
Preterm Birth
0.96 [0.81, 1.15]
NRDS
0.93 [0.56, 1.51]
Sepsis
1.28 [0.86, 1.85]
CHD
1.21 [1.07, 1.37]
0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 2.2 2.4 2.6 2.8 3 3.2 OR (95% CI)
Abbreviations: Children of Diabetic Pregnancies (CDP), Congenital Heart Disease (CHD), Neonatal Respiratory Distress Syndrome (NRDS)