Mitochondrial mutation m.1555A>G as a risk factor for failed newborn hearing screening in a large cohort of preterm infants

Abstract

BackgroundThe mitochondrial m.1555A>G mutation is associated with a high rate of permanent hearing loss, if aminoglycosides are given. Preterm infants have an increased risk of permanent hearing loss and are frequently treated with aminoglycoside antibiotics.MethodsWe genotyped preterm infants with a birth weight below 1500 grams who were prospectively enrolled in a large cohort study for the m.1555A>G mutation. Treatment with aminoglycoside antibiotics in combination with mitochondrial m.1555A>G mutation was tested as a predictor for failed hearing screening at discharge in a multivariate logistic regression analysis.Results7056 infants were genotyped and analysed. Low birth weight was the most significant predictor of failed hearing screening (p = 7.3 × 10-10). 12 infants (0.2%) had the m.1555A>G-mutation. In a multivariable logistic regression analysis, the combination of aminoglycoside treatment with m.1555A>G-carrier status was associated with failed hearing screening (p = 0.0058). However, only 3 out of 10 preterm m.1555A>G-carriers who were exposed to aminoglycosides failed hearing screening. The m.1555A>G-mutation was detected in all mothers of m.1555A>G-positive children, but in none of 2993 maternal DNA-samples of m.1555A>G-negative infants.ConclusionAntenatal screening for the m.1555A>G mutation by maternal genotyping of pregnant women with preterm labour might be a reasonable approach to identify infants who are at increased risk for permanent hearing loss. Additional studies are needed to estimate the relevance of cofactors like aminoglycoside plasma levels and birth weight and the amount of preterm m.1555A>G-carriers with permanent hearing loss.

Gentamicin Exposure and Sensorineural Hearing Loss in Preterm Infants

“…Mitochondrial DNA mutations have been linked to sensitivity to aminoglycosides and have also been associated with hearing loss in the absence of exposure to aminoglycosides [ 48 ]. Screening for genetic variants associated with hearing loss could identify patients at risk, but the opportunity for prevention may be limited as gentamicin is often prescribed on the first day of life for suspected early-onset sepsis [ 37 , 49 , 50 ]. We did not determine the prevalence of mutations predisposing for aminoglycoside toxicity.…”

“…However, since the early 1990s, a number of clinical studies have suggested that gentamicin administered in controlled therapeutic doses is not associated with ototoxicity in newborn infants [ 18 , 21 , 31 – 36 ]. Yet, controversies persist [ 17 , 20 , 23 , 29 , 37 ], and the dose, duration of treatment and circulating concentrations of gentamicin associated with the development of SNHL in VLBW infants have not been clearly determined.…”

PharmGKB summary

“…found 10 preterm infants out of a cohort of 7056 who carried the 1555G allele and received aminoglycoside treatment, though only three of these infants failed the hearing screening. However, the combination of aminoglycoside treatment and the 1555G allele was still a significant predictor of failed newborn hearing screening, with an odds ratio of approximately 1.3 (low birth weight was the most significant predictor of a failed newborn hearing screening) [47]. Most infants who fail a newborn hearing screen do not have permanent hearing loss [47], therefore this may not be the best metric for gauging the effect of the 1555G allele on aminoglycoside-induced hearing loss.…”

“…and Göpel et al . note that aminoglycoside-related sensorineural hearing loss may not appear until well after the time period in which their hearing screening was performed [42, 47], a caveat that may explain the results seen in the Johnson et al . study; as mentioned earlier, previous studies have shown great variability in the length of time between aminoglycoside treatment and development of hearing loss in those with the 1555G allele.…”

“…This may also apply to the 1494C>T variant, though few studies have provided information about the time between treatment and development of hearing loss. Aminoglycoside-related sensorineural hearing loss may not appear until much later than the time period in which newborn hearing screening is typically performed [42, 47]. …”