ISSN
1916-694X

2010;
Volume 1 (Number 2): Pages 58-61

ORIGINAL RESEARCH

No association between inadvertent exposure
to ribostamycin during early pregnancy and fetal ototoxicity

Si Won LEEa,b,
Jung Yeol HANa,b,*, Hyun Jung LEEa,b, June Seek CHOIa,b,
Hyun Kyong AHN a,b, Min Hyoung KIMb , Hyun Mee RYUb,
Alejandro A. NAVA-OCAMPOc,d,e, Gideon KORENc

aThe
Korean Motherisk Program, bDepartment of Obstetrics and Gynecology,
Cheil General Hospital & Women’s Healthcare Center, Kwandong University
College of Medicine, Seoul, South Korea; cThe Motherisk Program,
Hospital for Sick Children, dDepartment of Pharmacology &
Toxicology, University of Toronto, and ePharmaReasons, Toronto,
Canada

*Corresponding author:
[email-masked]

ABSTRACT

Objective: Our goal was to evaluate a potential association between exposure
to ribostamycin in early pregnancy and ototoxicity in the offspring. Methods: In a prospective cohort study,
85 women inadvertently exposed to ribostamycin during the first trimester of
pregnancy and 170 age- and gravidity-matched control women, were voluntarily
enrolled. Newborns were clinically examined at birth by a neonatologist and by
imaging studies if any suspicious abnormalities were noted. Hearing was
assessed directly by auditory brainstem response. Results: No newborn had neonatal ototoxicity in the exposed group
(0/70) whereas 1/160 (0.6%) had evidence of ototoxicity in the control group (P
=0.5). Conclusions: Exposure to
ribostamycin during the first-trimester of pregnancy does not appear to be
associated with ototoxicity in the offspring. Although exposure occurred at
very early stages of fetal development, when the inner ear was not yet
developed, our findings may be valuable when counseling women inadvertently
exposed to this aminoglycoside in early pregnancy.

Key
words

Aminoglycosides;
Maternal exposure; Transplacental exposure

RÉSUMÉ

Objectif: Notre but était d’évaluer l’association
potentielle entre une exposition à la ribostamycine en début de grossesse et la
présence d’une ototoxicité à la naissance.
Méthodes: Etude Une cohorte
prospective de 85 femmes accidentellement exposées à la ribostamycine au cours
du premier trimestre et 170 femmes témoins de même âge et de statut gravidique
ont été incluses dans cette étude. Les nouveau-nés ont été examinés à la
naissance par un néonatalogiste et par imagerie de toute anomalie suspectée.
L’audition a été évaluée par la réponse auditive au niveau du tronc cérébral. Résultats: Aucun nouveau-né dans le
groupe exposé ne présentait d’ototoxicité (0/70) contre 1/160 (0,6 %) dans
le groupe témoin (P =0,5). Conclusions:
L’exposition à la ribostamycine au cours du premier trimestre de la grossesse
ne semble pas être associée à une ototoxicité à la naissance. Quoique
l’exposition ait eu lieu à un stade très précoce du développement fœtal,
lorsque l’oreille interne n’est pas encore formée, nos résultats peuvent aider
à conseiller les femmes exposées accidentellement à cet aminoside en début de
grossesse.

Mots
clés

Aminosides;
Exposition maternelle; Exposition transplacentaire

RESUMEN

Objetivo: Evaluar la asociación entre exposición a
ribostamicina en etapas tempranas del embarazo y ototoxicidad en el producto. Métodos: 85 mujeres que estuvieron
expuestas en forma inadvertida a ribostamicina durante el primer trimestre del
embarazo y 170 mujeres control de edades y número de embarazos similares fueron
voluntariamente incluidas en el estudio de cohorte prospectiva. Los recién
nacidos fueron examinados clínicamente al nacimiento por un neonatólogo y
mediante estudios de imagen en caso de que alguna posible anormalidad fuera
identificada. La capacidad auditiva fue evaluada mediante la respuesta auditiva
del tallo cerebral. Resultados:
Ninguno de los bebés nacidos en el grupo expuesto presentó ototoxicidad
neonatal (0/70) mientras que en el grupo control hubo un caso (1/160; 0.6%) (P
=0.5). Conclusiones: La exposición a
ribostamicina durante el primer trimestre del embarazo no parece estar asociada
con ototoxicidad neonatal. Aunque la exposición ocurrió a muy tempranas etapas
del desarrollo fetal, cuando el oído interno aún no estaba desarrollado,
nuestros hallazgos pueden ser útiles para dar el consejo adecuado a mujeres
expuestas en forma inadvertida a este aminoglucósido en etapas tempranas del
embarazo.

Palabras clave

Aminoglucósidos;
Exposición materna; Exposición transplacentaria

INTRODUCTION

Ribostamycin is an aminoglycoside antibiotic
used to treat infections caused by gram-negative organisms such as Neisseria
gonorrhoeae, Escherichia coli, Klebsiella spp., and Proteus spp. [1]. It has similar efficacy and reduced ototoxicity when
compared to other major aminoglycosides [2]. It is primarily used to treat infections such as
pelvic inflammatory disease (PID), cystitis, and severe upper respiratory tract
infections (URTI), and is administered intramuscularly, once a day, at doses of
500-1,000 mg [3].

Approximately four decades ago, a study in
17 children between the age of 6 and 13 years whose mothers had received
streptomycin during pregnancy reported that although there was no apparent
deafness at speech frequencies, 8 children had minor abnormalities of
eighth-nerve function on caloric test or audiograms [4]. In addition, two cases of congenital deafness after in utero exposure to gentamicin 80 mg
three times daily for two days and to 100 mg three times a day for a single
day, respectively, have been reported elsewhere [5] [6]. In contrast, a recent study in 40 infants who were
exposed in utero to gentamicin
documented no case of hearing loss [7].

The present study was conducted to
investigate a potential association between inadvertent exposure to
ribostamycin in early pregnancy with adverse fetal outcomes and ototoxicity in
the offspring. The first part of the study assessing major and minor
malformations of babies born to exposed women was submitted for publication
elsewhere [8]; the current paper assessed the potential ototoxicity
in the offspring.

METHODS

The protocol was approved by the
Institutional Review Board at Cheil General Hospital and Women’s Healthcare
Center, Seoul, Korea; the study was performed between January 1999 and February
2008 at the Korean Motherisk Program.

Subjects

Pregnant women who were inadvertently
exposed to ribostamycin were invited to participate into the study; 85 women
were enrolled. Pregnancy was confirmed by transvaginal ultrasound examination.
In all cases, fetal age was estimated according to the somatometric results of
the transvaginal ultrasound examination, and the time of exposure to
ribostamycin was calculated accordingly. In addition, a large group of pregnant
women who were not exposed to any aminoglycoside or to any known or potential
human teratogen were followed-up prospectively as potential controls. From this
group, two consenting controls were enrolled for each case, after matching for
age (± 2 years that of
the control) and gravidity.

Study outcomes

As a marker of ototoxicity, hearing was
assessed in the newborns with the automated auditory brainstem response (AABR)
method ALGO 1 (Natus Medical Inc., San Carlos CA, USA) [9]. The system delivered thousands of soft ‘click’
sounds at 35 dB within a normal hearing level (normal acoustic frequency
spectrum: 70 to 5,000 Hz) through disposable earphones in order to evoke a
series of identifiable brain waves from auditory brainstem. All infants with
abnormal AABR results were reexamined 1-2 days later. Infants with repeated
abnormal test results were referred to a tertiary care center for further
evaluation.

Statistical
analysis

Continuous variables including gestational
age at birth (weeks) and birth weight (grams), were compared between groups by
a Student t test. The rate of babies with altered hearing test ototoxicity was
compared between groups by means of a Fisher’s exact test. A P <0.05 was considered
as statistically significant.

RESULTS

We recruited 85 pregnant women who were
inadvertently exposed to ribostamycin at the 3.9 ± 1.5 (mean ± SD) weeks of
gestation (median: 4.1 weeks) at a dose ranging from 250 mg to 1 g per

day (mean duration of exposure: 2.4 days) (Table 1). In the exposed group, there were 85 births
(83.3%), 6 spontaneous abortions (5.9%), 8 voluntary abortions (7.8%), 1
ongoing pregnancy (1.0%) and 2 cases were lost to follow-up (2.0%).

Table 1

Maternal
characteristics, dose and duration of exposure to ribostamycin in pregnancy,
and fetal outcome

Exposed

(n=
85)

Control

(n=
170)

P
value

Age
(years)

30.6
± 3.0

31.0
± 3.2

0.4

Gestational
age at exposure (weeks)

3.9
± 1.5

(range:
0.5 - 8.0)

-

-

Dose
of ribostamycin (mg/day)

250
- 1,000

-

-

Duration
of exposure (days)

2.4
± 2.6

-

-

Ototoxicity
in neonates/infants

0/70

1/160
(0.6%)

0.5

The AABR test for hearing ability was
obtained in 70 infants in the exposed group and 160 infants in the control
group. The test was performed at postnatal age between one to five days. Only
one infant (0.6%) had an abnormal test in the control group compared to none in
the exposed group (Table 1). We were not able to assess
the AABR hearing test in 15 infants from the exposed group and 10 from the
control group.

DISCUSION

This appears to be the first prospective cohort
study to examine the hearing outcome of infants exposed to ribostamycin in
early pregnancy. The rate of hearing impairment in general population is
approximately 1 to 2 per 1,000 uncomplicated births [10]; however, in infants at risk, the prevalence of
neonatal hearing disorders may increase 10- to 50-fold. At the Cheil General
Hospital in Seoul, the calculated incidence of abnormal hearing tests is 4.5
per 1,000 healthy babies. Hearing loss is associated with exposure to other
ototoxic drugs (e.g. furosemide, indomethacin, or ibuprofen) [7] [10], genetic disorders such as Turner syndrome or
osteogenesis imperfecta [11], intrauterine infections such as rubella or
toxoplasmosis [10] [11], or exposure to alcohol or cocaine [11]. Prematurity, craniofacial malformations,
hyperbilirubinemia, hypoxia, bacterial infections, mumps, low Apgar scores, and
low birth weight can also be associated with hearing deficits [4] [10] [11] .

The AABR test has a sensitivity of 98% and
specificity of approximately 96% and have proved to be an effective screening
tool in evaluation of hearing in the newborns [9] [10] [12] [13] [14] [15]. According to the previous reports [16], aminoglycoside induced ototoxicity leads to
permanent bilaterally severe, high-frequency sensorineural hearing loss and
temporary vestibular hypofunction accompanied by degeneration of hair cells and
neurons in the cochlea of the internal ear. The onset of development of
otic placode occurs on 24th day of fetal development (38th gestational age, or
5th gestational week). However, the onset of otic invagination occurs on the
30th day of fetal development, while the onset of development of otic
vesicle is on the 34th day of gestation age [17]. The target of aminoglycoside toxicity is the hair
cells of cochlea which starts to develop after the 34th day of organogenesis,
i.e. after the 48th gestational day (at the end of 6th gestational week).

In our study, the mean gestational age at
exposure was approximately 4 weeks, at a time when the development of inner ear
has not yet started. Therefore, our results cannot be extrapolated to women
requiring anti-infective treatment at later stages of fetal development.
Treatment with other antimicrobials with proven safety and efficacy in
pregnancy should still be preferred over ribostamycin. However, our study is
relevant for counseling women who were inadvertently exposed to this drug at
early stages of pregnancy in order to avoid unnecessary pregnancy terminations
and to reduce the level of anxiety because of the exposure.

CONCLUSIONS

Exposure to ribostamycin during the
first-trimester of pregnancy does not appear to be associated with ototoxicity
in the offspring. Although exposure occurred at very early stages of fetal
development, when the inner ear was not yet developed, our findings may be
valuable when counseling women inadvertently exposed to this aminoglycoside in
early pregnancy.

AUTHORS’ PARTICIPATION

SW L, JY H, HJ L & JS C provided
teratogenic risk counseling and reviewed the literature. HK A, MH K, & HM R
did the medical and obstetrical follow-up of participants, JY H, AA N-O, &
G K designed the study. All the authors drafted the manuscript and discussed
findings.

ACKNOWLEDGEMENTS

None to declare.

CONFLICT OF INTERESTS/DISCLAIMERS

JY H, AA N-O, and G K are members of the
Editorial Board of the journal. The study was not supported in any form by any
pharmaceutical company.

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