In utero drug exposure and hearing impairment in 2-year-old children A case-control study using the EFEMERIS database

Abstract

Introduction

As the ear development extends from the 4th to the 30th week of pregnancy, in utero exposure to ototoxic drugs might lead to hearing impairment in the fetus. The main study objective was to assess the association between in utero drug exposure and the occurrence of hearing impairment in 2-year-old children.

Methods and materials

A case-control study was carried out using the EFEMERIS database, recording medications dispensed during pregnancy and the compulsory health certificates for child at 8 days, 9 and 24 months. Cases were defined as children with an abnormal hearing examination recorded on the 24-month certificate and controls as children with a normal hearing examination.

Exposure was defined as at least one prescription and dispensation to the mother of drugs grouped at the 3rd level of the Anatomical Therapeutic and Chemical Classification level, compared to no exposure. Univariate logistic regressions were carried out. If the 95% confidence interval (95% CI) of the odds ratio (OR) was significant, a multivariable logistic regression was performed, adjusted on confounders.

Results

A total of 1,245 cases with abnormal hearing evaluation and 28,046 controls were selected for analysis. Case and control mothers were comparable in terms of age, education and congenital infection. Cases and controls were comparable in terms of prematurity, asphyxia and weight at birth. However, among cases (versus controls), there were more ear deformities (0.6% vs 0.0% p≤0.001), and more recurring otitis (11.3% vs 5.3% p≤0.0001).

When adjusted on confounders, the following drugs remained significant versus no exposure: acetylsalicylic acid at low dosage (OR 95% CI 1.61 [1.09-2.37]), valproic acid or valpromide (OR 95% CI 5.20 [1.93-14.00]), systemic corticosteroids (OR 95% CI 0.75 [0.61-0.93]. In a sensitivity analysis which excluded children with recurrent otitis at 24 months, these three results remained significant.

Conclusions

This is the first study evaluating the risk of hearing disorders due to in utero exposure to drugs. Hearing loss was associated with valproic acid and low-dose acetylsalicylic acid exposure during pregnancy. Conversely, children with normal hearing were more likely to have been exposed in utero to corticosteroids than children with hearing loss.

Introduction

The ear is composed of three parts: the outer ear (pinna, ear canal), middle ear (tympanic cavity, three ossicles), and inner ear (cochlea containing the organ of Corti and hair cells). The inner ear is the first to develop. The cochlea starts to grow around the 5th pregnancy week and has completed two and a half turns at the 10th week. Ciliated sensory cells of the organ of Corti develop from the 12th to the 20th weeks. At the 22nd week, the inner ear has reached its adult size and shape. In the middle ear, the ossicles start to differentiate around the 8th week. The ossicles and the tympanic cavity have reached their full size at the 26th and 30^th week, respectively. In the outer ear, pinna development extends from the 5th to the 10th week, and ear cannel development ends around the 16th week [[1], [2], [3], [4], [5]]. Therefore, drug exposure might impair audition during all stages of fetal development.

In adults, drugs such as loop diuretics or aminoglycosides are known to induce hearing loss due to functional impairment and/or inner ear tissue damage [6]. In utero, ear development extends from the 4th to the 30^th week of pregnancy; after this, the fetus is able to react to external auditory stimuli [[2], [3], [4], [5], [6]]. Therefore, in utero exposure to ototoxic drugs could lead to hearing impairment.

In France, 0.13% of infants suffer from severe deafness [7]. Hearing loss in infants, even mild, negatively impacts language and speech development, and delays social-emotional development. Evidence tends to indicate that the earlier an intervention is performed (before 3 or 6 months-old), the more the language skills improve [8,9].

To early diagnose delayed-onset or progressive hearing loss in childhood, the Joint Committee on Infant Hearing (JCIH) released a list of risk indicators in 2007. In terms of drug induced-toxicity, only neonatal administration of aminoglycosides or loop diuretics was included. In utero drug exposure was not mentioned as an indicator for closed hearing monitoring. However, the JCIH invited research on pharmacologic factors that contribute to hearing loss, allowing for tailored prevention programs [10].

To our knowledge, literature is sparse regarding in utero drug exposure and hearing disorders. The EFEMERIS database currently records anonymous data on more than 115,000 pregnancy outcomes (with health data about children) and drug prescriptions during pregnancy in the Haute-Garonne region of France. We used this database to study hearing impairment and in utero drug exposure [11].

The main study objective was to assess the association between in utero drug exposure and the occurrence of hearing impairment in 2-year-old children, using the EFEMERIS database, between 2004 and 2015.