Available online at www.sciencedirect.

com

American Journal of Otolaryngology–Head and Neck Medicine and Surgery 32 (2011) 203 – 209
www.elsevier.com/locate/amjoto

A possible association between maternal otitis media and ear

defect in their offspring
Nándor Ács, PhDa , Ferenc Bánhidy, PhDa , Erzsébet H. Puhó, PhDb , Andrew E. Czeizel, PhD, DScb,⁎
a
Second Department of Obstetrics and Gynecology, Semmelweis University, School of Medicine, Budapest, Hungary
b
Foundation for the Community Control of Hereditary Diseases, Budapest, Hungary
Received 19 October 2009

Abstract Background: The possible association between otitis media in pregnancy (OMP) and structural birth
defects, that is, congenital abnormalities (CAs), in their offspring has not been studied.
Methods: The data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities,
1980 and 1996, was evaluated.
Results: There were 58 (0.25%) and 55 (0.14%) of 22 843 cases and 38 151 controls with mothers
who had OMP, respectively. There was association of OMP and a higher risk of ear CA.
Conclusions: A possible explanation for the association of OMP with higher risk of ear CA may be
some morphological deviation of the inner ear.
© 2011 Elsevier Inc. All rights reserved.

1. Introduction 2. Materials and methods

There are well-known infectious diseases such as rubella,
varicella, influenza, or localized inflammatory diseases, for
example, urinary tact infections/diseases or vulvovaginitis,
that have been frequently studied regarding their maternal
and fetal effect during pregnancy. However, otitis media is
not presented in handbooks [1], although 113 pregnant
women affected with otitis media were recorded in the data
set of the population-based Hungarian Case-Control Sur-
veillance of Congenital Abnormalities (HCCSCA) [2].
Otitis media is the inflammatory disease of the inner ear in
general related to acute respiratory diseases and caused by
bacterial or viral infections. Otitis media is common in children
but may occur in adult persons including pregnant women. We
did not find reports of previous controlled epidemiological
studies regarding the possible associations between otitis
media in pregnancy (OMP) and adverse birth outcomes
particularly structural birth defects, that is, congenital
abnormalities (CAs); therefore, the objective of our study
was to evaluate these 113 pregnant women from this aspect.
⁎ Corresponding author. Foundation for the Community Control of
Hereditary Diseases, 1026 Budapest, Törökvész lejtő 32, Hungary. Tel.: +36
1 3944712; fax: +36 1 3944712.
E-mail address: czeizel@interware.hu (A.E. Czeizel).
0196-0709/$ – see front matter © 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.amjoto.2010.01.011
The protocol of the HCCSCA includes 5 steps.
The first step was the selection of cases with CA from the
Hungarian Congenital Abnormality Registry (HCAR) [3] for
the HCCSCA. Notification of cases with CAs is mandatory
for physicians from birth until the first birthday to the HCAR,
and most CAs are reported by obstetricians (in Hungary,
practically all deliveries take place in inpatient obstetric
clinics, and birth attendants are obstetricians) or pediatricians
(working at neonatal units of inpatient obstetric clinics as well
as of various general and special surgical, cardiologic,
orthopedic, and others, of inpatient and outpatient pediatric
clinics). Autopsy during the study period was obligatory for
all infant deaths and was usually performed in stillborn
fetuses. Pathologists sent a copy of the autopsy report to the
HCAR if defects were identified in stillborn fetuses or infant
deaths. Fetal defects diagnosed by prenatal diagnostic centers
with or without elective termination of pregnancy have also
been reported to the HCAR since 1984. Thus, malformed
fetuses diagnosed during the second and third trimester of
pregnancy and electively terminated are also included in the
data set of the HCAR. The recorded total (birth and fetal)
prevalence of cases with CA diagnosed from the second
trimester of pregnancy to the end of the first postnatal year
was 35 per 1000 informative offspring (live-born infants,
204 N. Ács et al. / American Journal of Otolaryngology–Head and Neck Medicine and Surgery 32 (2011) 203–209
stillborn fetuses, electively terminated malformed fetuses in
the second and third trimester of pregnancy) during the study
period (1980–1996) [3], and about 90% of major CAs were
notified to the HCAR [4].
However, there were 3 exclusion criteria at the selection
of cases with CA from the HCAR for the HCCSCA. First,
cases notified after 3 months of birth or elective termination
of pregnancy to the HCAR were not selected for the
HCCSCA. These cases comprised 33% of all cases with CAs
in the HCAR including mainly mild CAs [2], and the shorter
time between birth or elective pregnancy termination and
data collection increased the accuracy of information
regarding the exposure data of the study pregnancy without
undue loss of power. Second, 3 mild isolated CAs such as
congenital dysplasia of the hip based on Ortolani click,
congenital inguinal hernia, and major hemangioma were
excluded from the HCCSCA. Third, CA syndromes caused
by major gene mutations or chromosomal aberrations (with
preconceptional and not teratogenic origin) were also not
included in the HCCSCA.
The second step was the identification and selection of
controls from the National Birth Registry of the Central
Statistical Office for the HCCSCA. Controls were defined as
newborn infants without CA, and in general, 2 controls were
matched with every case according to sex, birth week, and
district of parents' residence.
2.1. Exposure and confounder data
As the third step, the necessary exposure and confounder
data such as pregnancy complications, maternal disorders,
and related drug treatments were obtained from 3 sources
of information.
2.1.1. Medically recorded prospective data
Mothers were informed about the objectives and benefits
of the HCCSCA in a mailed explanatory letter, and they were
asked to send us the prenatal maternity logbook and other
medical records (mainly discharge summaries) regarding
their diseases and related treatments during the study
pregnancy and their child's CA. Prenatal care was mandatory
for pregnant women in Hungary (if somebody did not visit
prenatal care, she cannot get maternity grant and leave); thus,
nearly 100% of pregnant women visited prenatal care, on
average, 7 times. The first visit was between the 6th and 12th
gestational weeks. The task of licensed obstetricians was to
record all pregnancy complications, maternal diseases (such
as otitis media), and related drug prescriptions in the prenatal
maternity logbook. If pregnant women were hospitalized, in
general, the discharge summary was also available.
2.1.2. Retrospective maternal information
A structured questionnaire together with a list of diseases
and drugs and a printed informed consent were also mailed to
the mothers immediately after the selection of cases and
controls. To standardize the answers, mothers were asked to
read the enclosed list of diseases and medications as a
memory aid before replying. Mothers were asked to give a
signature for informed consent that authorized us to record
the name and address of their children in the HCCSCA.
The period between birth or elective termination of
pregnancy and return of “information package” (question-
naire, logbook, informed consent, and others) in our prepaid
envelop was 3.5 ± 1.2 and 5.2 ± 2.9 months for cases and
controls, respectively.
2.1.3. Supplementary data collection
Regional nurses were asked to visit and question all
nonrespondent mothers of cases, but only 200 nonrespon-
dent and 600 respondent control mothers as part of 2
validation studies [5, 6], as the ethics committee considered
that this follow-up would be disturbing to the parents of
healthy children. Regional nurses helped mothers to fill in
the same questionnaire, and they evaluated available medical
documents and obtained data regarding lifestyle (smoking,
drinking, drug use) through a personal interview of mothers
and their close relatives.
Finally, necessary data were collected for 96.3% of cases
(84.4% from reply, 11.9% from visit) and for 83.0% of
controls (81.7% from reply, 1.3% from visit). Informed
consent was signed and returned by 98.4% of mothers. The
name and address of children without signed informed
consent were deleted in the HCCSCA.
The procedure of data collection in the HCCSCA was
changed in 1997 such that regional nurses visited and
questioned all cases and controls; however, these data have
not been validated until now, thus, only the data set of 17
years between 1980 and 1996 is evaluated here.
2.2. Evaluation of OMP
The fourth step is the definition of maternal pathologic
condition studied, such as OMP, with its diagnostic criteria
and treatments in the protocol of the HCCSCA.
Otitis media in pregnancy was evaluated according to
6 aspects.
(a) Source of the diagnoses: (i) prospective and
medically recorded OMP in the prenatal maternity
logbook, (ii) maternal retrospective information in
the questionnaire, or (ii) both.
(b–c) Onset and duration of OMP to gestational month
during the study pregnancy.
(d) The gestational age was calculated from the first
day of the last menstrual period. Three time
intervals were considered: (i) first month of
gestation because it is before the organogenesis.
The first 2 weeks are before conception, whereas
the third and fourth weeks comprise the pre- and
implantation period of zygotes and blastocysts
including omnipotent stem cells. These facts
explain the “all-or-nothing effect” rule, that is,
total loss or normal further development; thus, the
first 14 postconceptional days are relatively
 N. Ács et al. / American Journal of Otolaryngology–Head and Neck Medicine and Surgery 32 (2011) 203–209 205

insensitive to environmentally induced CAs. (ii)
The second and third months of gestation, as the
most sensitive, the so-called critical period for
most major CAs. (iii) The fourth through ninth
months of gestation, that is, pregnancy after the
organ-forming period.
(e) Medication (drugs and pregnancy supplements)
used during the study pregnancy including
administrative route (oral, parenteral, topical),
dose, and duration of treatment.
(f) Confounding factors, such as maternal age, birth
order, marital, and employment status as indicator of
socioeconomic status because it correlated well with
the level of education and income, other maternal
diseases, and use of drugs and pregnancy supple-
ments, particularly folic acid and multivitamins [7].
2.3. Statistical analysis
The fifth step of the HCCSCA's protocol was the
statistical analyses of data using the software package SAS
version 8.02 (SAS Institute Inc, Cary, NC). First, frequency
tables were made for the main maternal variables to describe
the total and affected study groups. Second, the birth
characteristics of cases and controls born to mothers with or
without OMP were compared using Student t test for
quantitative and χ2 statistics or odds ratios (ORs) with 95%
confidence interval (CI) for categorical variables. Pregnant
women without OMP were used as reference sample.
Gestational age and rate of preterm births were adjusted
for maternal diseases, related drug treatment, and folic acid
supplementation, whereas birth weight and rate of low birth
weight newborns for these maternal variables plus gestation
age. Third, the incidence of other acute and the prevalence of
chronic maternal diseases, drugs, and pregnancy supple-
ments used during pregnancy were compared between the
case and control groups, and crude OR with 95% CI were
evaluated. Fourth, the prevalence of OMP in mothers who
had cases with different CA groups was compared with the
frequency of these diseases in the mothers of all matched
controls, and adjusted OR with 95% CI were evaluated in a
conditional logistic regression model. The latter ORs were
adjusted for maternal age (b20 years vs 20–29 years vs ≥30
years), birth order (first delivery vs one or more previous
deliveries), maternal employment status (professional-man-
agerial-skilled worker vs semiskilled worker-unskilled
worker-housewife vs others), other acute fever-related
maternal diseases such as influenza and common cold with

Table 1
Characteristics of mothers with or without OMP (the latter as reference)
Variables Case mothers Case mothers
Without With Without With
OMP OMP
n = 22 785 n = 58 n = 38 096 n = 55
Quantitative
Maternal age, y n % n % n % n %
19 or less 2501 11.0 5 8.6 3273 8.6 4 7.3
20–29 15 549 68.2 44 75.9 27 560 72.3 42 76.4
30 or more 4735 20.8 9 15.5 7263 19.1 9 16.4
Mean ± SD 25.5 ± 5.3 25.0 ± 4.2 25.5 ± 4.9 25.3 ± 4.2
Birth order
1 10 677 46.9 31 53.4 18 188 47.7 21 38.2
2 or more 12 108 53.1 27 46.6 19 908 52.3 34 61.8
Mean ± SD 1.9 ± 1.1 1.7 ± 0.9 1.7 ± 0.9 1.8 ± 0.8
Categorical
Unmarried 1265 5.6 4 6.9 1469 3.9 3 5.5
Employment status
Professional 1967 8.6 10 17.2 4420 11.6 3 5.5
Managerial 5084 22.3 13 22.4 10 248 26.9 17 30.9
Skilled worker 6482 28.4 19 32.8 11 889 31.2 19 34.5
Semiskilled worker 4191 18.4 6 10.3 6149 16.1 12 21.8
Unskilled worker 1772 7.8 4 6.9 2185 5.7 2 3.6
Housewife 2400 10.5 6 10.3 2353 6.2 1 1.8
Others 889 3.9 0 0.0 852 2.2 1 1.8
Iron 14 706 64.5 36 62.1 26 736 70.2 35 63.6
Calcium 1797 7.9 6 10.3 3577 9.4 6 10.9
Folic acid 11 251 49.4 28 48.3 20 750 54.5 25 45.5
Vitamin B6 2005 8.8 8 13.8 4079 10.7 7 12.7
Vitamin D 6085 26.7 16 27.6 10 139 26.6 11 20.0
Vitamin C 907 4.0 5 8.6 1680 4.4 5 9.1
Vitamin E 1417 6.2 1 1.7 2283 6.0 4 7.3
Multivitamins 1325 5.8 5 8.6 2507 6.6 2 3.6
206 N. Ács et al. / American Journal of Otolaryngology–Head and Neck Medicine and Surgery 32 (2011) 203–209

Table 2 onset of OMP during the first trimester. The usual

Occurrence of acute and chronic diseases in women with or without OMP duration of OMP was 3 weeks; thus, all OMP with the
Diseases Case mothers Control mothers onset in the first gestational month continued during the
Without With Without With second month.
OMP OMP
Table 1 summarizes the most important maternal
variables. Mean maternal age was somewhat lower in
n = 22 785 n = 58 n = 38 096 n = 55
women with OMP, but it was reflected in the mean birth
Acute disease groups order only in case mothers. The rate of unmarried women
Influenza—common cold 4876 21.4 12 20.7 6996 18.4 10 18.2
was similar among the study groups, in addition, the
Respiratory system 2095 9.2 36 62.1 3441 9.0 36 65.5
Urinary tract 1583 6.9 5 8.6 2295 6.0 4 7.3 distribution of maternal employment status did not show
Genital organs 1584 7.0 5 8.6 2802 7.4 3 5.5 characteristic pattern. The use of folic acid during pregnancy
Others 1116 4.9 7 12.1 1877 4.9 4 7.3 was somewhat lower in women with OMP, particularly in
Chronic diseases control mothers with OMP.
Diabetes mellitus 156 0.7 0 0.0 228 0.6 1 1.8
Of 2640 case mothers visited at home, 8 (0.30%) had OMP
Migraine 563 2.5 1 1.7 708 1.9 0 0.0
Essential hypertension 1606 7.0 6 10.3 2677 7.0 3 5.5 and 6 (75.0%) smoked during pregnancy, whereas of 2632
Hypotension 538 2.4 2 3.4 1264 3.3 1 1.8 mothers without OMP, 569 (21.6%). Of 800 control mothers
Hemorrhoids 796 3.5 2 3.4 1622 4.3 2 3.6 visited at home, 152 (19.0%) smoked during the study
pregnancy, but only 2 case mothers were affected with OMP
and 1 smoked during the study pregnancy.
secondary complications, tonsillitis, drug treatments for The evaluation of other acute diseases showed a much
OMP, and folic acid supplementation (as a dichotomous higher incidence of acute respiratory diseases in mothers with
variable). OMP (Table 2). The prevalence of chronic maternal diseases
did not show significant difference among the study groups.
Pregnancy complications such as threatened abortion and
3. Results preterm delivery, severe nausea and vomiting, preeclampsia,
and others did not show significant differences between
Of 22 843 cases with CA, 58 (0.25%) had mothers with women with or without OMP.
the diagnosis of OMP, whereas of 38 151 controls, 55 Antimicrobial drugs such as ampicillin (67.3% vs 7.0%),
(0.14%) were born to pregnant women affected with OMP. penamecillin (32.7% vs 6.3%), parenteral benzylpenicillin
These pregnant women were affected with OMP prospec- (7.1% vs 0.3%), and oxytetracycline (6.2% vs 0.6%) were
tively and medically recorded in the prenatal maternity used much more frequently in 113 women with OMP than in
logbook because they were treated due to this acute disease. 60 854 mothers without OMP. Thus, all pregnant women
In addition, other 33 case mothers and 31 control mothers were treated with one or more of the above drugs. However,
reported on their otitis media in the questionnaire but without at the comparison of the rate of these drugs between case
the necessary information (onset and type of OMP, mothers and control mother with OMP, only oxytetracycline
treatment, and others); thus, these pregnant women were was used more frequently by 5 case mothers (8.6%)
excluded from the study. compared to 2 control mothers (3.6%).
There was no characteristic onset of OMP according Table 3 shows the birth outcomes of controls. (CA in
to gestational months. Of 58 case mothers, 26 (44.8%), cases may have a more drastic effect for gestational age and
and whereas of 55 control mothers, 14 (25.5%) had the birth weight than OMP.) The mean gestational age at

Table 3
Birth outcomes of control newborns without CA
Birth outcomes Controls born to mothers Comparison
Without With
OMP
n = 38 096 n = 55 Unadjusted Adjusted
Quantitative Mean SD Mean SD t P t P
Gestational age (wk)⁎ 39.4 2.1 39.6 1.9 0.9 .35 0.9 .37
Birth weight (g)† 3275 511 3370 376 1.9 .07 1.1 .26

Categorical n % n % OR (95% CI) OR (95% CI)

Preterm births⁎ 3492 9.2 4 7.3 0.8 (0.3–2.1) 0.8 (0.3–2.2)
Low birth weight† 2165 5.7 2 3.6 0.6 (0.2–2.6) 0.8 (0.2–3.6)
⁎ Adjusted for maternal age, birth order, and maternal socioeconomic status.
†
Adjusted for maternal age, birth order, maternal socioeconomic status, and gestational age.
 N. Ács et al. / American Journal of Otolaryngology–Head and Neck Medicine and Surgery 32 (2011) 203–209 207

Table 4
Estimation of risk of different CAs in case mothers with OMP compared to the control mothers with OMP
Study groups Grand total (N) Entire pregnancy 2–3 mo
n % OR 95% CI n % OR 95% CI
Controls 38 151 55 0.1 Reference 14 0.04 Reference
CAs of ears 354 4 1.1 5.5 1.6–20.4 3 0.85 16.0 3.6–71.3
Cardiovascular CAs 4479 12 0.3 3.5 1.3–9.7 4 0.09 6.6 0.7–63.3
Hypospadias 3038 6 0.2 0.7 0.3–1.8 4 0.13 1.5 0.4–6.1
Poly/syndactyly 1744 6 0.3 1.9 0.5–6.7 3 0.17 3.1 0.3–30.1
Clubfoot 2424 6 0.3 1.7 0.7–5.1 2 0.08 3.6 0.3–40.0
Other CAs 10 804 24⁎ 0.2 1.9 1.1–3.5 10 0.09 2.6 0.9–7.2
Total 22 843 58 0.3 1.8 1.2–2.6 25 0.11 2.8 1.4–5.6
⁎ Congenital hydrocephaly, 2; congenital pyloric stenosis, 2; undescended testis, 2; limb deficiencies, 2; torticollis, 2; anencephaly, 1; spina bifida, 1; cleft
lip, 1; cleft lip + cleft palate, 1; cleft palate, 1; rectal stenosis, 1; renal agenesis, 1; cystic kidney disease, 1; omphalocele, 1; congenital genu varum, 1; vaginal
atresia, 1; indeterminate sex, 1; CA of spine, 1; and multiple CA, 2.

delivery of mothers with OMP was longer by 0.2 week, and
it was reflected in the somewhat lower rate of preterm births.
The mean birth weight was larger by 95 g in newborns
delivered by mothers with OMP, and it associated with a
somewhat lower rate of low birth-weight newborns.
However, these differences did not reach the level of
significance, but the observed general pattern seems to
reflect better birth outcomes than expected.
The evaluation of possible association between OMP and
CAs (including at least 3 cases) is shown in Table 4. There
was a higher risk of total CA groups explained mainly by ear
CAs, cardiovascular CA, and other isolated CAs. The latter
group included heterogeneous types of isolated CAs. In the
next step, only the critical period of most major CAs, that is,
the second and/or third gestational months was evaluated.
The higher risk was confirmed in the total CA group and
among different CA groups, only in ear CAs, but the
previous higher risk of cardiovascular CAs disappeared.
The detailed data of cases with ear CAs and cardiovas-
cular CA are shown in Table 5. Ear CAs showed severe
defect of auditory canal and middle ear, and there was no
other serious maternal diseases beyond OMP in their
mothers. Of 13 cardiovascular CAs, 5 belong to the very
severe defect (transposition of great vessel, 3; endocardial
cushion defect, 2) and 4 affected infants died. However, the
critical period of these CAs is in the second gestational
month, and only one mother had OMP in this time window.
4. Discussion
As far as we know, this is the first controlled
epidemiological study to evaluate the possible association
between maternal OMP and CAs of their offspring, and our
population-based case-control study showed a higher risk of
total CAs and ear CAs in the offspring of women with OMP.

Table 5
Data of cases with ear CAs and cardiovascular CA
Ear CA Otitis media Others diseases Drug treatments
(gestational month)
Atresia of auditory canal with fusion of ear ossicles II–III – –
Atresia of auditory canal with microtia III–IV Preeclampsia Dipyrone (III–IV)
Atresia of auditory canal with the absent of membranous III–IV Tonsillitis (IV) Xylometazoline (IV–VI)
labyrinth in the middle ear and organ Corti penamecillin (IV–VI)
Fusion of ear ossicles VI–VII Tonsillitis (V–VI) Xylometazoline (VI–VII)

Cardiovascular CAs
Transposition of great vessels VI – Ampicillin (VI)
II–VIII – –
III–IV Influenza (VIII) –
Ventricular septal defect V–VI Laryngitis (V–IX) Ampicillin (V)
cefalexin (VI–VII)
VIII–IX – Phenazon + tetracain (VIII–IX)
VIII Vulvovaginitis (IV) –
Atrial septal defect, type II III Sinusitis (III) Penamecillin (III)
VI – –
Endocardial cushion defect VI Preeclampsia (VII) Penamecillin (VI)
VII Laryngitis (V) Benzylpenicillin (V)
Coarctation of aorta VI Influenza (VII) Penamecillin (VI)
Unspecified cardiovascular CA III – Dipyrone (III)
208 N. Ács et al. / American Journal of Otolaryngology–Head and Neck Medicine and Surgery 32 (2011) 203–209
Most OMP was preceded with acute infectious diseases of
respiratory system, mainly tonsillitis; thus, OMP was the
secondary complications of these maternal diseases. Unex-
pected results of the study were the detection of a somewhat
longer gestational age at delivery and lower rate of preterm
birth. Our hypothesis is that this relatively short inflammatory
disease during pregnancy was followed by a more conscious
prenatal care and healthier lifestyle, in addition, the drugs
used for the treatment of OMP were affective for the
undiagnosed and/or nonsymptomatic urogenital infections of
pregnant women that are the main causes of preterm births.
The strengths of the study are the following: (i)
population-based large data set of the HCCSCA including
113 pregnant women with prospectively and medically
recorded OMP in ethnically homogenous European (white)
people; (ii) the matching of cases and controls; (iii) the
knowledge of the onset and duration of these infectious
diseases; (iv) most confounders such as other maternal
diseases and related treatments are known; (iv) birth weight
and gestational age at delivery were also medically recorded
in the discharge summary of mothers after delivery; and (v) it
is worth mentioning the good validity of CA diagnoses due to
the medically reported cases to the HCAR that were checked
by a pediatrician and medical geneticist [3]. In addition, new
information from recent medical examinations and the
questionnaire was helpful to exclude cases with misdiag-
nosed CA or to correct the CA diagnosis in the HCCSCA [2].
However, our data set also has weaknesses. (i) The
diagnosis of OMP was based on the clinical symptoms
without the identification and/or reporting of microbial
agents. (ii) The occurrence of maternal smoking as
confounder was not known in the total data set. Our previous
study showed the low validity of retrospective maternal self-
reported information regarding smoking and alcohol drink-
ing during pregnancy [8]; therefore, these data were
collected only in a minor part of the data set of the HCCSCA
based on the cross interview of women and their family
members at the home visit and the so-called family
consensus was accepted. Of 800 controls, 152 (19.0%)
smoked during pregnancy, which corresponded well to the
figure of smoking among Hungarian pregnant women [9].
However, the possible smoking habit may be associated with
a higher risk for OMP but cannot explain the high risk of ear
CAs found in the study.
The objective of our study was to check the possible
association between OMP and adverse birth outcomes,
particularly CAs. An association was detected between OMP
and a higher risk of total CAs. However, teratogenic agents
induce specific CAs [10]. A higher risk of ear CAs was
found in the study, and this association was supported by 2
phenomena. On the one hand, there was an overlapping
between the critical period of these CAs and the exposure,
that is, OMP. On the other hand, these ear CAs belonged to
the severe defect of auditory canal and middle ear. However,
it is necessary to mention that this unexpected association
was based only on 3 cases.
Previously, a genetic susceptibility in the origin of otitis
media was suggested by racial variations because the
frequency of otitis media is unusually high in American
Indians and Australian aborigines and comparatively low in
blacks with African origin. This possible genetic predispo-
sition for otitis media was confirmed on the basis of
familial aggregation of otitis media, mastoid size, and
cholesteatoma [11]. Thus, the unusual anatomical config-
uration of middle ear and auditory canal may have a
predisposition or higher susceptibility for otitis media [12].
The question is whether this genetically determined
anatomical configuration may associate with a higher risk
for the developmental errors of ears.
We did not find any data regarding the possible
association between the microbial causes of OMP and ear
CAs [13]. High fever-related maternal diseases may associate
with a higher risk of some CA due to the teratogenic effect of
hyperthermia. Fever, sometimes high fever, may be the
symptom of otitis media; however, auditory canal and middle
ear CAs are not part of the high fever spectrum CAs [14].
Another plausible hypothesis for the explanation of this
association is the related drugs treatments of OMP.
However, the teratogenic potential of ampicillin [15],
penamecillin [16], parenteral benzylpenicillin [17], and
oxytetracycline [18] was checked. The teratogenic effect of
oxytetracycline was confirmed, but a higher risk of ear CA
was not found. Of 4 cases with ear CA, nobody had a mother
with oxytetracycline treatment. Ampicillin treatment showed
a weak association with cleft palate during the critical period
of this CA but did not have any association with ear CAs.
The teratogenic potential of penamecillin and parenteral
benzylpenicillin was excluded. Of 4 cases with ear CA, 2
mothers were treated with xylometazoline. On the one hand,
medicinal products in otic drops in general cannot reach a
concentration of maternal blood level that may be hazardous
for the fetus [10]. On the other hand, xylometazoline did not
associate with a higher risk of CAs [19]. One pregnant
woman was treated by dipyrone, but this drug has no
teratogenic effect [20]. Thus, the possible association of
OMP with higher risk of ear CAs cannot be explained by the
related drug treatment.
Of course, a large number of statistical tests result in a
significant difference (P b .05) in every 20th calculation due
to chance; thus, this possible explanation for this association
is a reasonable hypothesis.
In conclusion, a higher risk of adverse birth outcomes was
not found in the pregnancies of women with OMP; in fact,
the rate of preterm birth and low birth weight newborns was
somewhat lower. However, a higher risk of ear CAs was
found in mothers with OMP, and this association needs
confirmation or disproval.
Acknowledgment
This study was partly sponsored by a generous grant from
Richter Gedeon Pharmaceuticals Ltd, Budapest, Hungary.
 N. Ács et al. / American Journal of Otolaryngology–Head and Neck Medicine and Surgery 32 (2011) 203–209
References
[1] Creasy K, Resnik R, Iams JD, editors. Maternal-fetal medicine. 5th ed.
Philadelphia: Saunders; 2004.
[2] Czeizel AE, Rockenbauer M, Siffel CS, et al. Description and mission
evaluation of the Hungarian Case-Control Surveillance of Congenital
Abnormalities, 1980–1996. Teratology 2001;63:176-85.
[3] Czeizel AE. First 25 years of the Hungarian Congenital Abnormality
Registry. Teratology 1997;55:299-305.
[4] Czeizel AE, Intődy ZS, Modell B. What proportion of congenital
abnormalities can be prevented. Br Med J 1993;306:499-503.
[5] Czeizel AE, Petik D, Vargha P. Validation studies of drug exposures in
pregnant women. Pharmacoepid Drug Safety 2003;12:409-16.
[6] Czeizel AE, Vargha P. Periconceptional folic acid/multivitamin
supplementation and twin pregnancy. Am J Obstet Gynecol 2004;
191:790-4.
[7] Czeizel AE. Periconceptional folic acid and multivitamin supplemen-
tation for the prevention of neural tube defects and other congenital
abnormalities. Birth Defects Res (Part A) 2009;85:260-8.
[8] Czeizel AE, Petik D, Puho AE. Smoking and alcohol drinking during
pregnancy. The reliability of retrospective maternal self-reported
information. Cent Eur J Publ Health 2004;12:179-83.
[9] Czeizel AE, Kodaj I, Lenz WC. Smoking during pregnancy and
congenital limb deficiency. Brit Med J 1994;308:1473-6.
[10] Czeizel AE. The estimation of human teratogenic/fetotoxic risk of
exposures to drugs on the basis of Hungarian experience: a critical
evaluation of clinical and epidemiological models of human teratology.
Expert Opin Drug Saf 2009;8:283-303.
209
[11] Todd NV. Familial predisposition for otitis media in Apache Indians at
Canyon Day, Arizona. Genet Epidemiol 1987;4:25-31.
[12] Murphy V, Kennea NL. Antenatal infection/inflammation and fetal
tissue injury. Best Pract Res Clin Obstet Gynaecol 2007;21:
479-89.
[13] Shepard TH, Lemire RJ. Catalog of teratogenic agents. 11th ed.
Baltimore: Johns Hopkins Univ Press; 2004.
[14] Czeizel AE, Ács N, Bánhidy F, et al. Primary prevention of congenital
abnormalities due to high fever related maternal diseases by antifever
therapy and folic acid supplementation. Curr Womens Health Rev
2007;3:1-17.
[15] Czeizel AE, Rockenbauer M, Sorensen HT, et al. A population-based
case-control teratologic study of ampicillin treatment during pregnan-
cy. Am J Obstet Gynecol 2001;185:140-7.
[16] Czeizel AE, Rockenbauer M, Sorensen HT, et al. A population-based
case-control study of penicillin V: oral penamecillin treatment during
pregnancy. Cong Anom 1999;39:267-79.
[17] Czeizel AE, Rockenbauer M, Sorensen HT, et al. A population-based
case-control study of three parenteral penicillin G. Cong Anom 1999;
39:37-42.
[18] Czeizel AE, Rockenbauer M. A population-based case-control
teratologic study of oral oxytetracycline treatment during pregnancy.
Eur J Obstet Gynecol Reprod Biol 2000;88:27-33.
[19] Aselton PA, Jick H, Milunsky A, et al. First-trimester drug use and
congenital disorders. Obstet Gynecol 1985;65:451-5.
[20] Bánhidy F, Ács N, Puho E, et al. A population-based case-control
study of oral dipyrone treatment during pregnancy. Drug Safety 2006;
30:1-13.