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.
1
Introduction
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 , although 113 pregnant women affected with otitis media were recorded in the data set of the population-based Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA) .
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.
2
Materials and methods
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) 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, stillborn fetuses, electively terminated malformed fetuses in the second and third trimester of pregnancy) during the study period (1980–1996) , and about 90% of major CAs were notified to the HCAR .
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 , 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” (questionnaire, 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 nonrespondent and 600 respondent control mothers as part of 2 validation studies , 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 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 supplements, particularly folic acid and multivitamins .
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 χ 2 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 supplements 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 (<20 years vs 20–29 years vs ≥30 years), birth order (first delivery vs one or more previous deliveries), maternal employment status (professional-managerial-skilled worker vs semiskilled worker-unskilled worker-housewife vs others), other acute fever-related maternal diseases such as influenza and common cold with secondary complications, tonsillitis, drug treatments for OMP, and folic acid supplementation (as a dichotomous variable).
2
Materials and methods
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) 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, stillborn fetuses, electively terminated malformed fetuses in the second and third trimester of pregnancy) during the study period (1980–1996) , and about 90% of major CAs were notified to the HCAR .
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 , 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” (questionnaire, 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 nonrespondent and 600 respondent control mothers as part of 2 validation studies , 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 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 supplements, particularly folic acid and multivitamins .
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 χ 2 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 supplements 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 (<20 years vs 20–29 years vs ≥30 years), birth order (first delivery vs one or more previous deliveries), maternal employment status (professional-managerial-skilled worker vs semiskilled worker-unskilled worker-housewife vs others), other acute fever-related maternal diseases such as influenza and common cold with secondary complications, tonsillitis, drug treatments for OMP, and folic acid supplementation (as a dichotomous variable).
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