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atresia in China: A case-control study
International Journal of Pediatric Otorhinolaryngology 115 (2018) 139–144
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International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Maternal risk factors for severe microtia/atresia in China: A case-control study
T
Qiang Liua, Xinmiao Fana, Shuang Liub, Li Wangc,∗∗, Yulin Jiangd, Xiaowei Chena,∗ a
Department of Otolaryngology, Peking Union Medical College Hospital, Beijing, 100730, China Institute of Clinical Medicine, Peking Union Medical College, Beijing, 100730, China c Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, 100730, China d Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Beijing, 100730, China b
A R T I C LE I N FO
A B S T R A C T
Keywords: Maternal risk factor Severe microtia/atresia China Case-control study
Objective: Microtia/atresia is a severe malformation of the external ear. Previous studies have reported the potential risk factors on microtia, whereas few focused on severe microtia/atresia. The aim of the study was to investigate the effects of maternal exposure to environmental risk factors in patients with severe microtia/atresia in China. Methods: A case-control study was conducted. Cases were patients with severe microtia/atresia who presented to PUMCH between January 2014 and October 2017. A total of 322 patients with severe microtia/atresia were enrolled and 322 normal controls matched 1:1 with the patients by sex, age and nationality were enrolled. The designed questionnaires were completed and data were gathered. Odds ratios were estimated with logistic regression models along with 95% confidence intervals in severe microtia/atresia. Results: Most cases were males(68.6%), and the cases were observed more common in unilateral(80.7%), rightsided (54.0%). Multivariate logistic regression analysis showed that threatened abortion (OR 4.066,95% CI = 2.360–7.007), NSAIDs (OR 2.576,95% CI = 1.079–6.148), virus infection (OR 1.933,95% CI = 1.148–3.256), anemia (OR 1.902,95% CI = 1.026–3.526), miscarriages (OR 1.804,95% CI = 1.425–2.285), maternal age (OR 1.079,95% CI = 1.015–1.148) and paternal age (OR 1.061,95% CI = 1.003–1.122) were associated with a higher risk of severe microtia/atresia. Conclusion: These results support that some maternal risk factors could be associated with severe microtia/ atresia.
1. Introduction Microtia/atresia is a congenital malformation of the external ear, often involving the pinna, tragus, lobe, and external auditory canal, and ranging in severity from minimally abnormal to the complete absence of the auricle [1]. The incidence of microtia/atresia in China has been estimated to range from 0.83 to 1.53 per 10,000 births [2]. Approximately 10% of patients with congenital microtia/atresia are affected bilaterally [3]. Microtia has been classified into four grades [4]: Grades I and II, minor or mild deformity with the auricle structures being fully or partially distinguishable; Grade III, severely malformed auricle with no definable structures; and Grade IV (anotia) [5], total absence of the
external ear. Microtia/atresia often presents as a rudimentary auricle, atresia of the auditory canal and middle ear abnormalities, resulting in conductive hearing loss [6]. Moreover, these patients experience higher rates of psychosocial burden and social stigma than the general population [7]. Although hereditary factors, such as chromosomal abnormalities and genetic mutations, have been reported to play an important role in the occurrence of microtia, environmental risk factors have also been associated with microtia. These risk factors may include prenatal exposure to maternal medications [8], maternal illness [9], advanced parental age [9–11], high parity [9–12], race/ethnicity [10,11,13], high altitude [14], urban area [15], low maternal education [13,16],
∗
Corresponding author. Department of Otolaryngology, Peking Union Medical College Hospital, #1 shuaifuyuan, Beijing, 100730, China. Corresponding author. Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China. E-mail addresses: [email protected] (Q. Liu), [email protected] (X. Fan), [email protected] (S. Liu), [email protected] (L. Wang), [email protected] (Y. Jiang), [email protected] (X. Chen). ∗∗
https://doi.org/10.1016/j.ijporl.2018.09.033 Received 10 June 2018; Received in revised form 29 September 2018; Accepted 30 September 2018 Available online 03 October 2018 0165-5876/ © 2018 Published by Elsevier B.V.
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abortion and preventive treatments, prenatal illness, medication history, alcohol consumption, smoking, and exposure to chemicals and ionizing radiation. For inclusion, the evaluated diseases must have been diagnosed by physicians during pregnancy. Women who had smoked at least one cigarette per day or were exposed to passive smoke during pregnancy were defined as having a history of smoking. Women who had consumed alcohol at least once per week during pregnancy were defined as having a history of alcohol consumption, with these women further subdivided into sporadic and regular alcohol drinkers according to their frequency of alcohol consumption. Women who had been frequently exposed during pregnancy to harmful chemicals, such as pesticides or formaldehyde, at home or at work, were defined as having a history of chemical exposure. Women who had received medical X-rays at least once or who worked at a computer for at least 10 h per day without protective measures during pregnancy were defined as having a history of ionizing radiation.
multiple births [10,13] and low birth weight [9,10,12]. Despite studies assessing the environmental risk factors for microtia in various populations, potential risk factors remain unclear. Although previous studies have examined patients with microtia with different levels of severity, little attention was given to describing malformations of the auricle and external auditory canal. However, a retrospective study found that maternal exposure to several factors was linked to a greater likelihood of severe microtia in infants [17], making it necessary to assess the association of severe malformation with environmental factors. In addition, factors evaluated in previous investigations of microtia, especially prenatal factors affecting embryonic development, have been limited and insufficient. To investigate the effects of exposure to environmental factors in patients with severe microtia/ atresia, we performed a case-control study to evaluate maternal risk factors for severe microtia/atresia in China. 2. Materials and methods
2.3. Statistical analysis 2.1. Study population All statistical analyses were performed using SPSS software, version 22.0 (IBM, USA). Quantitative variables were compared using Student's t-tests and categorical variables were compared using the Pearson chisquare and Fisher's exact tests. Univariable associations between proposed risk factors and microtia were estimated by calculating odds ratios (OR) and 95% confidence intervals (CIs) compared with matched controls, with variables having p-values less than 0.05 considered statistically significant. Variables found to be significant on univariate analysis were included in multivariate analysis by logistic regression. Cochran-Armitage tests for trend were performed to analyze ranked data in risk factors.
This is a hospital-based case-control study. The present study involved patients with severe microtia/atresia who presented to the Otorhinolaryngology Department of Peking Union Medical College Hospital (PUMCH) in Beijing, China, between January 2014 and October 2017. Because syndromic microtia may have hereditary origins, only patients with non-syndromic microtia were included in this study. Since microtia is recognized as a minimal phenotype of hemifacial microsomia, patients with hemifacial microsomia were also included. Patients with a family history of microtia and those with other major malformations, such as cardiac, renal and limb defects were excluded. All patients with microtia enrolled in this study underwent detailed physical examinations performed by experienced clinicians. The grade of microtia was determined using the Marx classification [4]. Considering severe microtia was more likely to be affected by maternal factors than mild microtia [17], only patients with microtia grades III and IV accompanied by atresia were defined as having severe microtia/ atresia and included in this study. This study included 322 patients with severe microtia/atresia. The mother of each patient was subsequently asked to fill out a detailed questionnaire, either by interview in the hospital or on the telephone, under the guidance of a clinician. A total of 322 normal controls matched 1:1 with the patients by sex, age and nationality were enrolled by field investigation. All the controls were recruited from healthy children in schools nearby PUMCH and those who came to the hospital for other reasons. None of the controls and their parents had any birth defects, including pre-auricular fistula and tags. The study protocol was approved by the Institutional Review Board of PUMCH, and written informed consent was obtained from the parents of all patients.
3. Results 3.1. Demographic data A total of 322 patients with severe microtia/atresia were enrolled in this study. Of these 322 patients, 221 (68.6%) were boys and 101 (31.4%) were girls; 174 (54.0%) were affected on the right side, 86 (26.7%) on the left side, and 62(19.3%) on both sides. According to the Marx classification, 319 (99.1%) and three (0.9%) patients were categorized as having Grades IIII and IV microtia respectively(Table 1). 3.2. Univariate analysis Among mothers of children in the severe microtia/atresia group, 79(24.5%) experienced threatened abortion, which characterized by vaginal bleeding and intermittent uterine cramping while the cervix os is closed, 72(22.4%) had viral illnesses(including the common cold, Table 1 Characteristics of the patients with severe microtia/atresia.
2.2. Questionnaire survey
Severe microtia/atresia
After reviewing previous studies concerning risk factors for birth defects, including microtia, and evaluating responses of patients’ parents, potential environmental risk factors that may contribute to the occurrence of microtia by directly affecting embryonic development during pregnancy were selected. Because auricle development is usually completed by the twelfth week of gestation, potential environmental risk factors occurring during the first trimester of pregnancy were investigated. Thus, 21 questions related to selected environmental exposure were included in the questionnaire administered to patients and controls. The questionnaire consisted of five sections: demographic information, history of miscarriage, maternal health history, maternal habits and exposure to environmental factors during the first trimester of pregnancy. The detailed questions included name, sex, age, geographic region, living environment, history of miscarriage, threatened
Total Cases
III
IV(Anotia)
No.(%)
Gender Male Female Laterality Unilateral Left side Right side Bilaterala
218(67.7%) 101(31.4%)
3(0.9%) 0
221(68.6%) 101(31.4%)
257(79.8%) 85(26.4%) 172(53.4%) 62(19.3%)
3(0.9%) 1(0.3%) 2(0.6%) 0
260(80.7%) 86(26.7%) 174(54.0%) 62(19.3%)
Total Cases
319(99.1%) 3(0.9%)
322(100%)
*The severity of ears were evaluated according to Marx classification. a Bilateral patients were classified according to the more severe ears. 140
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4.1. Demographic characteristics
influenza, varicella, zoster and parotitis), and 47(14.6%) suffered from anemia during the first trimester of pregnancy. While in the control group, the number and incidence were 22(6.9%), 36(11.2%) and 19(5.9%) respectively. Univariate analysis showed that threatened abortion (OR 4.43, 95% CI = 2.68–7.32; p < 0.001), viral illness (OR 2.29, 95% CI = 1.48–3.53; p < 0.001) and anemia (OR 2.0,95% CI = 1.15–3.48; p < 0.001) were significantly associated with severe microtia/atresia. Taking progesterone (OR 2.71, 95% CI = 1.49–4.95; p < 0.05); traditional Chinese medicines, such as radix isatidis, pseudo-ginseng and goldthread root (OR 2.86, 95% CI = 1.36–6.00; p < 0.05); and NSAIDs (OR 3.21, 95% CI = 1.54–6.67; p < 0.05) were also significantly associated with severe microtia/atresia. By contrast, taking folic acid during the first trimester reduced the risk of severe microtia/ atresia (OR 0.89, 95% CI = 0.45–1.74), but the difference was not statistically significant (p > 0.05). The prevalence of severe microtia/atresia was almost eight-times higher in the children of mothers aged > 35 years than in those aged 21–25 years (OR 8.17, 95% CI = 3.78–17.6), and was six-times higher in the children of older fathers compared to younger fathers (OR 6.69, 95% CI = 3.64–12.29). In addition, the mean maternal and paternal ages of patients with severe microtia/atresia (29.5 ± 2.8 and 30.4 ± 5.7 years, respectively) were significantly higher than those in the control group (26.9 ± 4.30 and 27.6 ± 4.5 years, respectively; p < 0.001 each). The occurrence of severe microtia/atresia was about 5.5-times higher in the children of mothers who had miscarried more than three times than in those with no history of miscarriage(OR 6.49, 95% CI = 2.16–19.53). The mean numbers of miscarriages in mothers of patients with severe microtia/atresia (1.0 ± 1.1) were also significantly higher than those in the control group (0.3 ± 0.6; p < 0.001 each). Thirteen women (4.0%) were exposed to chemicals, such as formaldehyde, pesticides and organic solvents, during the first trimester of pregnancy, an exposure associated with a significantly higher risk of having a child with severe microtia/atresia (OR 4.6, 95% CI = 0.99–21.46; p < 0.05). Women who had smoked or were exposed to secondhand smoke ((OR 1.11, 95% CI = 0.66–1.85), consumed alcohol (OR 2.36, 95% CI = 0.61–9.22), and were exposed to ionizing radiation, including medical X-rays (OR 1.50, 95% CI = 0.25–9.07) and daily computer work (OR 1.52, 95% CI = 0.97–2.38) during pregnancy were also at higher risk of bearing children with severe microtia/ atresia, but these factors were not statistically significant (p > 0.05). (Fig s.s. 1–4).
The male predominance in this Chinese population (68.6%) was greater than that in studies evaluating populations in Hungary (54.0%) [20], Texas (56.7%) [21], and Finland (58%) [8]. However, greater male predominance has also been observed in other East Asian studies, which may be due not only to ethnic differences, but to Confucian cultures that prefer sons over daughters [15]. Of the 322 patients with severe microtia/atresia in our study, 80.7% were affected unilaterally, 54.0% on the right side and 26.7% on the left side, and only 19.3% were affected bilaterally. These findings are similar to those of previous studies, reporting both unilateral and rightsided predominance [18,20,21]. In contrast, one study reported that only 49.1% of patients were affected unilaterally, with equal prevalence on both sides [22]. The latter study, however, used a different criterion for bilaterality, making comparisons difficult. 4.2. Maternal diseases and medications Higher rates of disease and medication during pregnancy were considered to be associated with an elevated risk of microtia. Our study found that several of these factors were significantly associated with severe microtia/atresia. In the current study, nearly 24% of mothers of patients with severe microtia/atresia had a history of threatened abortion during the first trimester of pregnancy, significantly higher than in the control group (11.7%). Our study found that threatened abortion was highly associated with severe microtia/atresia (OR 4.066, 95% CI = 2.360–7.007), which is consistent with the results of previous studies [15,17]. However, maternal factors that play an important role in the etiology of threatened abortion include maternal infection, chronic illness, maternal lifestyle and illicit drug use. Thus the results of this study may have been influenced by these confounders. This study also found that viral infection (OR 1.933, 95% CI = 1.148–3.256) and anemia (OR 1.902, 95% CI = 1.026–3.526) during the first trimester of pregnancy were associated with severe microtia/atresia. The most frequent viral infections in the present study were the common cold and influenza. In comparison, a previous study reported that mothers who had measles during the first trimester of pregnancy were at higher risk of delivering infants with microtia [23]. These findings suggest that viruses may act as teratogens, affecting the development of the first and second pharyngeal arches and leading to congenital deformities during weeks 5–8 of gestation [8]. Anemia during the gestational period was also found to be associated with congenital microtia [24]. In the present study, 14.6% of mothers who delivered children with severe microtia/atresia had anemia during pregnancy, suggesting that anemia may have some effect on the development of the embryonic ear. Medication use during pregnancy have also been reported to be an increased risk factor for microtia. We found that 9.3% mothers who had children with severe microtia/atresia had taken NSAIDs for cold-like symptoms, especially fever, during pregnancy and that these women were at higher risk of having a child with severe microtia/atresia than matched controls (OR 2.576, 95% CI = 1.079–6.148). A previous study, however, reported no association between NSAID use and microtia [25]. The discrepancy between these studies may be related to the time of maternal interview, which could have led to recall bias. Use of specific medications during pregnancy, including retinoids, mycophenolate mofetil and cyclophosphamide, was found to be strongly associated with microtia [26–28]. None of the mothers in the present study, however, reported using these medications.
3.3. Multivariate analysis Multivariate logistic regression analysis showed that threatened abortion (OR 4.066, 95% CI = 2.360–7.007), taking NSAIDs (OR 2.576, 95% CI = 1.079–6.148), viral infection (OR 1.933,95% CI = 1.148–3.256), anemia (OR 1.902,95% CI = 1.026–3.526), history of miscarriages (OR 1.804, 95% CI = 1.425–2.285), maternal age (OR 1.079, 95% CI = 1.015–1.148) and paternal age (OR 1.061, 95% CI = 1.003–1.122) were risk factors for severe microtia/atresia (Table 2). 4. Discussion Although various environmental risk factors have been reported to be associated with microtia, this study focused on patients with severe microtia/atresia and maternal risk factors that may affect embryonic development. In addition, compared with two previous case-control studies [18,19] in Chinese populations, this study assessed a greater number of patients with severe microtia/atresia patients and evaluated a larger number of environmental factors, including maternal habits and exposure to radiation. Because microtia may have a multifactorial etiology, multivariate analysis was performed in the present study.
4.3. Miscarriage and parental age A history of miscarriage was also considered to be associated with microtia. The present study found that mothers with a history of miscarriage were at higher risk of having a baby with severe microtia/ 141
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Fig. 1. Odds Ratio for the Association between Severe Microtia/atresia and Selected Risk Factors during the first trimester of Pregnancy.
Fig. 2. Comparision of Maternal age in Severe Microtia/atresia(29.5 ± 2.8) and Controls(26.9 ± 4.3).
Fig. 3. Comparision of Paternal age in Severe Microtia/atresia(30.4 ± 5.7) and Controls(27.6 ± 4.5).
atresia (OR 1.804, 95% CI = 1.425–2.285), with the risks increasing with the number of miscarriages. Abortion may injure the uterus, especially induced abortion, affecting the development of future fetuses and leading to the occurrence of congenital anomalies [15]. Several studies have shown that the incidence of microtia tends to increase with increasing maternal age [11,21], whereas other studies have observed no clear relationship between microtia and maternal age
[13,16]. A study in South America reported that increased paternal age was associated with a higher incidence of microtia [29]. The present study found that severe microtia/atresia was weakly associated with both maternal (OR 1.079, 95% CI = 1.015–1.148) and paternal (OR 1.061, 95% CI = 1.003–1.122) age. However, there were some links among these factors; for example, older women were more likely to have had more miscarriages. Thus, the effects of one factor may have 142
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4.5. Strength and limitation This study presented the investigation of maternal risk factors of severe microtia/atresia in China. Strengths of this study include accurate classification of microtia cases based on an experienced doctor, and controls were randomly selected adjusted by age and sex, which could diminish the recall bias regarding maternal self-reported information and the effect of confounders. The limitation is that it was a retrospective review and the data were collected from the parents’ memories which can be subjective, so referral bias was inevitable. 5. Conclusion In conclusion, the results of this case-control study suggested that maternal age, paternal age, history of miscarriages, threatened abortion, viral infection, anemia and NSAIDs taken during the first trimester of pregnancy were considered to be associated with severe microtia/ atresia. These results provide additional evidence that several factors are likely implicated in the causes of sporadic microtia. Clinicians should explain the risk of exposure to environmental factors to their patients and make people aware of these risk factors for microtia.
Fig. 4. Comparision of miscarriage in severe Microtia/atresia(1.0 ± 1.1) and Controls(0.3 ± 0.6). Table 2 Results of Severe microtia/atresia in multivariate analysis by Logistic regression. Variables
βa
S.Eb
Waldχ2
OR(95%CI)c
P
Maternal age Paternal age Miscarriages Threatened abortion Virus infection Anemia NSAIDsd
0.076 0.059 0.59 1.403 0.659 0.643 0.946
0.031 0.029 0.12 0.278 0.266 0.315 0.444
5.913 4.256 24.043 25.528 6.141 4.166 4.545
1.079(1.015–1.148) 1.061(1.003–1.122) 1.804(1.425–2.285) 4.066(2.360–7.007) 1.933(1.148–3.256) 1.902(1.026–3.526) 2.576(1.079–6.148)
0.015 0.039 0.0001 0.0001 0.013 0.041 0.033
a b c d
Declaration of interest statement The authors report no conflicts of interest and have received no payment for the preparation of this manuscript. The authors alone are responsible for the content and writing of this paper. Authors' contributions
Regression coefficient. Standard error. OR: Odds Ratio; CI: confidence intervals. NSAIDs: Non-Steroidal Antiinflammatory Drugs.
XWC conceived and designed the experiments. QL designed the questionnaire. XMF and SL interviewed the patients’ mothers and collected the data. QL analyzed the data and wrote the paper. LW and YLJ revised the paper critically for important intellectual content. All authors read and approved the final manuscript.
been influenced by the effects of the other two confounders.
Funding 4.4. Maternal habits and exposure history
This work was supported by a grant to Xiaowei Chen from the General Programs of National Natural Science Foundation of China (grant number: 81271053) and the National Key Research and Development Program of China (grant number: 2016YFC0901501).
Smoking and alcohol use during pregnancy have been reported to be associated with microtia [30]. Nicotine is believed to cause oxidative stress, which could lead to neural crest disturbance, and alcohol is thought to be involved in impaired neural crest cell migration, resulting in structural defects [31]. However, the present study, found that smoking, including exposure to second-hand smoke, and alcohol were not associated with severe microtia/atresia. Because most women in China do not smoke or drink alcohol during pregnancy, these results can likely be explained by the small number of exposed individuals. Exposure to chemicals is considered another risk factor for human deformities [18,19]. These chemicals may be associated with epigenetic changes, such as methylation or microRNA changes. The present study found that 2.8% of mothers of children with severe microtia/atresia had been exposed to chemicals, such as hair dye, rubber, pesticides, formaldehyde and gasoline. However, multivariate analysis showed no significant association between exposure and severe microtia/atresia. A study evaluating the relationship between maternal occupations with potential exposure to ionizing radiation and birth defects found that the risk was elevated in mothers of infants with microtia [32]. These findings may have been due to damage to DNA in the ovum before conception or cell damage during early pregnancy [33]. In our study, 16.5% of mothers of children with severe microtia/atresia were engaged in occupations requiring prolonged computer work every day, such as programmer, software engineer, and network administrator. However, we observed no association between these occupations and severe microtia/atresia.
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Maternal risk factors for severe microtia/atresia in China: A case-control study
T
Qiang Liua, Xinmiao Fana, Shuang Liub, Li Wangc,∗∗, Yulin Jiangd, Xiaowei Chena,∗ a
Department of Otolaryngology, Peking Union Medical College Hospital, Beijing, 100730, China Institute of Clinical Medicine, Peking Union Medical College, Beijing, 100730, China c Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, 100730, China d Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Beijing, 100730, China b
A R T I C LE I N FO
A B S T R A C T
Keywords: Maternal risk factor Severe microtia/atresia China Case-control study
Objective: Microtia/atresia is a severe malformation of the external ear. Previous studies have reported the potential risk factors on microtia, whereas few focused on severe microtia/atresia. The aim of the study was to investigate the effects of maternal exposure to environmental risk factors in patients with severe microtia/atresia in China. Methods: A case-control study was conducted. Cases were patients with severe microtia/atresia who presented to PUMCH between January 2014 and October 2017. A total of 322 patients with severe microtia/atresia were enrolled and 322 normal controls matched 1:1 with the patients by sex, age and nationality were enrolled. The designed questionnaires were completed and data were gathered. Odds ratios were estimated with logistic regression models along with 95% confidence intervals in severe microtia/atresia. Results: Most cases were males(68.6%), and the cases were observed more common in unilateral(80.7%), rightsided (54.0%). Multivariate logistic regression analysis showed that threatened abortion (OR 4.066,95% CI = 2.360–7.007), NSAIDs (OR 2.576,95% CI = 1.079–6.148), virus infection (OR 1.933,95% CI = 1.148–3.256), anemia (OR 1.902,95% CI = 1.026–3.526), miscarriages (OR 1.804,95% CI = 1.425–2.285), maternal age (OR 1.079,95% CI = 1.015–1.148) and paternal age (OR 1.061,95% CI = 1.003–1.122) were associated with a higher risk of severe microtia/atresia. Conclusion: These results support that some maternal risk factors could be associated with severe microtia/ atresia.
1. Introduction Microtia/atresia is a congenital malformation of the external ear, often involving the pinna, tragus, lobe, and external auditory canal, and ranging in severity from minimally abnormal to the complete absence of the auricle [1]. The incidence of microtia/atresia in China has been estimated to range from 0.83 to 1.53 per 10,000 births [2]. Approximately 10% of patients with congenital microtia/atresia are affected bilaterally [3]. Microtia has been classified into four grades [4]: Grades I and II, minor or mild deformity with the auricle structures being fully or partially distinguishable; Grade III, severely malformed auricle with no definable structures; and Grade IV (anotia) [5], total absence of the
external ear. Microtia/atresia often presents as a rudimentary auricle, atresia of the auditory canal and middle ear abnormalities, resulting in conductive hearing loss [6]. Moreover, these patients experience higher rates of psychosocial burden and social stigma than the general population [7]. Although hereditary factors, such as chromosomal abnormalities and genetic mutations, have been reported to play an important role in the occurrence of microtia, environmental risk factors have also been associated with microtia. These risk factors may include prenatal exposure to maternal medications [8], maternal illness [9], advanced parental age [9–11], high parity [9–12], race/ethnicity [10,11,13], high altitude [14], urban area [15], low maternal education [13,16],
∗
Corresponding author. Department of Otolaryngology, Peking Union Medical College Hospital, #1 shuaifuyuan, Beijing, 100730, China. Corresponding author. Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China. E-mail addresses: [email protected] (Q. Liu), [email protected] (X. Fan), [email protected] (S. Liu), [email protected] (L. Wang), [email protected] (Y. Jiang), [email protected] (X. Chen). ∗∗
https://doi.org/10.1016/j.ijporl.2018.09.033 Received 10 June 2018; Received in revised form 29 September 2018; Accepted 30 September 2018 Available online 03 October 2018 0165-5876/ © 2018 Published by Elsevier B.V.
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abortion and preventive treatments, prenatal illness, medication history, alcohol consumption, smoking, and exposure to chemicals and ionizing radiation. For inclusion, the evaluated diseases must have been diagnosed by physicians during pregnancy. Women who had smoked at least one cigarette per day or were exposed to passive smoke during pregnancy were defined as having a history of smoking. Women who had consumed alcohol at least once per week during pregnancy were defined as having a history of alcohol consumption, with these women further subdivided into sporadic and regular alcohol drinkers according to their frequency of alcohol consumption. Women who had been frequently exposed during pregnancy to harmful chemicals, such as pesticides or formaldehyde, at home or at work, were defined as having a history of chemical exposure. Women who had received medical X-rays at least once or who worked at a computer for at least 10 h per day without protective measures during pregnancy were defined as having a history of ionizing radiation.
multiple births [10,13] and low birth weight [9,10,12]. Despite studies assessing the environmental risk factors for microtia in various populations, potential risk factors remain unclear. Although previous studies have examined patients with microtia with different levels of severity, little attention was given to describing malformations of the auricle and external auditory canal. However, a retrospective study found that maternal exposure to several factors was linked to a greater likelihood of severe microtia in infants [17], making it necessary to assess the association of severe malformation with environmental factors. In addition, factors evaluated in previous investigations of microtia, especially prenatal factors affecting embryonic development, have been limited and insufficient. To investigate the effects of exposure to environmental factors in patients with severe microtia/ atresia, we performed a case-control study to evaluate maternal risk factors for severe microtia/atresia in China. 2. Materials and methods
2.3. Statistical analysis 2.1. Study population All statistical analyses were performed using SPSS software, version 22.0 (IBM, USA). Quantitative variables were compared using Student's t-tests and categorical variables were compared using the Pearson chisquare and Fisher's exact tests. Univariable associations between proposed risk factors and microtia were estimated by calculating odds ratios (OR) and 95% confidence intervals (CIs) compared with matched controls, with variables having p-values less than 0.05 considered statistically significant. Variables found to be significant on univariate analysis were included in multivariate analysis by logistic regression. Cochran-Armitage tests for trend were performed to analyze ranked data in risk factors.
This is a hospital-based case-control study. The present study involved patients with severe microtia/atresia who presented to the Otorhinolaryngology Department of Peking Union Medical College Hospital (PUMCH) in Beijing, China, between January 2014 and October 2017. Because syndromic microtia may have hereditary origins, only patients with non-syndromic microtia were included in this study. Since microtia is recognized as a minimal phenotype of hemifacial microsomia, patients with hemifacial microsomia were also included. Patients with a family history of microtia and those with other major malformations, such as cardiac, renal and limb defects were excluded. All patients with microtia enrolled in this study underwent detailed physical examinations performed by experienced clinicians. The grade of microtia was determined using the Marx classification [4]. Considering severe microtia was more likely to be affected by maternal factors than mild microtia [17], only patients with microtia grades III and IV accompanied by atresia were defined as having severe microtia/ atresia and included in this study. This study included 322 patients with severe microtia/atresia. The mother of each patient was subsequently asked to fill out a detailed questionnaire, either by interview in the hospital or on the telephone, under the guidance of a clinician. A total of 322 normal controls matched 1:1 with the patients by sex, age and nationality were enrolled by field investigation. All the controls were recruited from healthy children in schools nearby PUMCH and those who came to the hospital for other reasons. None of the controls and their parents had any birth defects, including pre-auricular fistula and tags. The study protocol was approved by the Institutional Review Board of PUMCH, and written informed consent was obtained from the parents of all patients.
3. Results 3.1. Demographic data A total of 322 patients with severe microtia/atresia were enrolled in this study. Of these 322 patients, 221 (68.6%) were boys and 101 (31.4%) were girls; 174 (54.0%) were affected on the right side, 86 (26.7%) on the left side, and 62(19.3%) on both sides. According to the Marx classification, 319 (99.1%) and three (0.9%) patients were categorized as having Grades IIII and IV microtia respectively(Table 1). 3.2. Univariate analysis Among mothers of children in the severe microtia/atresia group, 79(24.5%) experienced threatened abortion, which characterized by vaginal bleeding and intermittent uterine cramping while the cervix os is closed, 72(22.4%) had viral illnesses(including the common cold, Table 1 Characteristics of the patients with severe microtia/atresia.
2.2. Questionnaire survey
Severe microtia/atresia
After reviewing previous studies concerning risk factors for birth defects, including microtia, and evaluating responses of patients’ parents, potential environmental risk factors that may contribute to the occurrence of microtia by directly affecting embryonic development during pregnancy were selected. Because auricle development is usually completed by the twelfth week of gestation, potential environmental risk factors occurring during the first trimester of pregnancy were investigated. Thus, 21 questions related to selected environmental exposure were included in the questionnaire administered to patients and controls. The questionnaire consisted of five sections: demographic information, history of miscarriage, maternal health history, maternal habits and exposure to environmental factors during the first trimester of pregnancy. The detailed questions included name, sex, age, geographic region, living environment, history of miscarriage, threatened
Total Cases
III
IV(Anotia)
No.(%)
Gender Male Female Laterality Unilateral Left side Right side Bilaterala
218(67.7%) 101(31.4%)
3(0.9%) 0
221(68.6%) 101(31.4%)
257(79.8%) 85(26.4%) 172(53.4%) 62(19.3%)
3(0.9%) 1(0.3%) 2(0.6%) 0
260(80.7%) 86(26.7%) 174(54.0%) 62(19.3%)
Total Cases
319(99.1%) 3(0.9%)
322(100%)
*The severity of ears were evaluated according to Marx classification. a Bilateral patients were classified according to the more severe ears. 140
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4.1. Demographic characteristics
influenza, varicella, zoster and parotitis), and 47(14.6%) suffered from anemia during the first trimester of pregnancy. While in the control group, the number and incidence were 22(6.9%), 36(11.2%) and 19(5.9%) respectively. Univariate analysis showed that threatened abortion (OR 4.43, 95% CI = 2.68–7.32; p < 0.001), viral illness (OR 2.29, 95% CI = 1.48–3.53; p < 0.001) and anemia (OR 2.0,95% CI = 1.15–3.48; p < 0.001) were significantly associated with severe microtia/atresia. Taking progesterone (OR 2.71, 95% CI = 1.49–4.95; p < 0.05); traditional Chinese medicines, such as radix isatidis, pseudo-ginseng and goldthread root (OR 2.86, 95% CI = 1.36–6.00; p < 0.05); and NSAIDs (OR 3.21, 95% CI = 1.54–6.67; p < 0.05) were also significantly associated with severe microtia/atresia. By contrast, taking folic acid during the first trimester reduced the risk of severe microtia/ atresia (OR 0.89, 95% CI = 0.45–1.74), but the difference was not statistically significant (p > 0.05). The prevalence of severe microtia/atresia was almost eight-times higher in the children of mothers aged > 35 years than in those aged 21–25 years (OR 8.17, 95% CI = 3.78–17.6), and was six-times higher in the children of older fathers compared to younger fathers (OR 6.69, 95% CI = 3.64–12.29). In addition, the mean maternal and paternal ages of patients with severe microtia/atresia (29.5 ± 2.8 and 30.4 ± 5.7 years, respectively) were significantly higher than those in the control group (26.9 ± 4.30 and 27.6 ± 4.5 years, respectively; p < 0.001 each). The occurrence of severe microtia/atresia was about 5.5-times higher in the children of mothers who had miscarried more than three times than in those with no history of miscarriage(OR 6.49, 95% CI = 2.16–19.53). The mean numbers of miscarriages in mothers of patients with severe microtia/atresia (1.0 ± 1.1) were also significantly higher than those in the control group (0.3 ± 0.6; p < 0.001 each). Thirteen women (4.0%) were exposed to chemicals, such as formaldehyde, pesticides and organic solvents, during the first trimester of pregnancy, an exposure associated with a significantly higher risk of having a child with severe microtia/atresia (OR 4.6, 95% CI = 0.99–21.46; p < 0.05). Women who had smoked or were exposed to secondhand smoke ((OR 1.11, 95% CI = 0.66–1.85), consumed alcohol (OR 2.36, 95% CI = 0.61–9.22), and were exposed to ionizing radiation, including medical X-rays (OR 1.50, 95% CI = 0.25–9.07) and daily computer work (OR 1.52, 95% CI = 0.97–2.38) during pregnancy were also at higher risk of bearing children with severe microtia/ atresia, but these factors were not statistically significant (p > 0.05). (Fig s.s. 1–4).
The male predominance in this Chinese population (68.6%) was greater than that in studies evaluating populations in Hungary (54.0%) [20], Texas (56.7%) [21], and Finland (58%) [8]. However, greater male predominance has also been observed in other East Asian studies, which may be due not only to ethnic differences, but to Confucian cultures that prefer sons over daughters [15]. Of the 322 patients with severe microtia/atresia in our study, 80.7% were affected unilaterally, 54.0% on the right side and 26.7% on the left side, and only 19.3% were affected bilaterally. These findings are similar to those of previous studies, reporting both unilateral and rightsided predominance [18,20,21]. In contrast, one study reported that only 49.1% of patients were affected unilaterally, with equal prevalence on both sides [22]. The latter study, however, used a different criterion for bilaterality, making comparisons difficult. 4.2. Maternal diseases and medications Higher rates of disease and medication during pregnancy were considered to be associated with an elevated risk of microtia. Our study found that several of these factors were significantly associated with severe microtia/atresia. In the current study, nearly 24% of mothers of patients with severe microtia/atresia had a history of threatened abortion during the first trimester of pregnancy, significantly higher than in the control group (11.7%). Our study found that threatened abortion was highly associated with severe microtia/atresia (OR 4.066, 95% CI = 2.360–7.007), which is consistent with the results of previous studies [15,17]. However, maternal factors that play an important role in the etiology of threatened abortion include maternal infection, chronic illness, maternal lifestyle and illicit drug use. Thus the results of this study may have been influenced by these confounders. This study also found that viral infection (OR 1.933, 95% CI = 1.148–3.256) and anemia (OR 1.902, 95% CI = 1.026–3.526) during the first trimester of pregnancy were associated with severe microtia/atresia. The most frequent viral infections in the present study were the common cold and influenza. In comparison, a previous study reported that mothers who had measles during the first trimester of pregnancy were at higher risk of delivering infants with microtia [23]. These findings suggest that viruses may act as teratogens, affecting the development of the first and second pharyngeal arches and leading to congenital deformities during weeks 5–8 of gestation [8]. Anemia during the gestational period was also found to be associated with congenital microtia [24]. In the present study, 14.6% of mothers who delivered children with severe microtia/atresia had anemia during pregnancy, suggesting that anemia may have some effect on the development of the embryonic ear. Medication use during pregnancy have also been reported to be an increased risk factor for microtia. We found that 9.3% mothers who had children with severe microtia/atresia had taken NSAIDs for cold-like symptoms, especially fever, during pregnancy and that these women were at higher risk of having a child with severe microtia/atresia than matched controls (OR 2.576, 95% CI = 1.079–6.148). A previous study, however, reported no association between NSAID use and microtia [25]. The discrepancy between these studies may be related to the time of maternal interview, which could have led to recall bias. Use of specific medications during pregnancy, including retinoids, mycophenolate mofetil and cyclophosphamide, was found to be strongly associated with microtia [26–28]. None of the mothers in the present study, however, reported using these medications.
3.3. Multivariate analysis Multivariate logistic regression analysis showed that threatened abortion (OR 4.066, 95% CI = 2.360–7.007), taking NSAIDs (OR 2.576, 95% CI = 1.079–6.148), viral infection (OR 1.933,95% CI = 1.148–3.256), anemia (OR 1.902,95% CI = 1.026–3.526), history of miscarriages (OR 1.804, 95% CI = 1.425–2.285), maternal age (OR 1.079, 95% CI = 1.015–1.148) and paternal age (OR 1.061, 95% CI = 1.003–1.122) were risk factors for severe microtia/atresia (Table 2). 4. Discussion Although various environmental risk factors have been reported to be associated with microtia, this study focused on patients with severe microtia/atresia and maternal risk factors that may affect embryonic development. In addition, compared with two previous case-control studies [18,19] in Chinese populations, this study assessed a greater number of patients with severe microtia/atresia patients and evaluated a larger number of environmental factors, including maternal habits and exposure to radiation. Because microtia may have a multifactorial etiology, multivariate analysis was performed in the present study.
4.3. Miscarriage and parental age A history of miscarriage was also considered to be associated with microtia. The present study found that mothers with a history of miscarriage were at higher risk of having a baby with severe microtia/ 141
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Fig. 1. Odds Ratio for the Association between Severe Microtia/atresia and Selected Risk Factors during the first trimester of Pregnancy.
Fig. 2. Comparision of Maternal age in Severe Microtia/atresia(29.5 ± 2.8) and Controls(26.9 ± 4.3).
Fig. 3. Comparision of Paternal age in Severe Microtia/atresia(30.4 ± 5.7) and Controls(27.6 ± 4.5).
atresia (OR 1.804, 95% CI = 1.425–2.285), with the risks increasing with the number of miscarriages. Abortion may injure the uterus, especially induced abortion, affecting the development of future fetuses and leading to the occurrence of congenital anomalies [15]. Several studies have shown that the incidence of microtia tends to increase with increasing maternal age [11,21], whereas other studies have observed no clear relationship between microtia and maternal age
[13,16]. A study in South America reported that increased paternal age was associated with a higher incidence of microtia [29]. The present study found that severe microtia/atresia was weakly associated with both maternal (OR 1.079, 95% CI = 1.015–1.148) and paternal (OR 1.061, 95% CI = 1.003–1.122) age. However, there were some links among these factors; for example, older women were more likely to have had more miscarriages. Thus, the effects of one factor may have 142
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4.5. Strength and limitation This study presented the investigation of maternal risk factors of severe microtia/atresia in China. Strengths of this study include accurate classification of microtia cases based on an experienced doctor, and controls were randomly selected adjusted by age and sex, which could diminish the recall bias regarding maternal self-reported information and the effect of confounders. The limitation is that it was a retrospective review and the data were collected from the parents’ memories which can be subjective, so referral bias was inevitable. 5. Conclusion In conclusion, the results of this case-control study suggested that maternal age, paternal age, history of miscarriages, threatened abortion, viral infection, anemia and NSAIDs taken during the first trimester of pregnancy were considered to be associated with severe microtia/ atresia. These results provide additional evidence that several factors are likely implicated in the causes of sporadic microtia. Clinicians should explain the risk of exposure to environmental factors to their patients and make people aware of these risk factors for microtia.
Fig. 4. Comparision of miscarriage in severe Microtia/atresia(1.0 ± 1.1) and Controls(0.3 ± 0.6). Table 2 Results of Severe microtia/atresia in multivariate analysis by Logistic regression. Variables
βa
S.Eb
Waldχ2
OR(95%CI)c
P
Maternal age Paternal age Miscarriages Threatened abortion Virus infection Anemia NSAIDsd
0.076 0.059 0.59 1.403 0.659 0.643 0.946
0.031 0.029 0.12 0.278 0.266 0.315 0.444
5.913 4.256 24.043 25.528 6.141 4.166 4.545
1.079(1.015–1.148) 1.061(1.003–1.122) 1.804(1.425–2.285) 4.066(2.360–7.007) 1.933(1.148–3.256) 1.902(1.026–3.526) 2.576(1.079–6.148)
0.015 0.039 0.0001 0.0001 0.013 0.041 0.033
a b c d
Declaration of interest statement The authors report no conflicts of interest and have received no payment for the preparation of this manuscript. The authors alone are responsible for the content and writing of this paper. Authors' contributions
Regression coefficient. Standard error. OR: Odds Ratio; CI: confidence intervals. NSAIDs: Non-Steroidal Antiinflammatory Drugs.
XWC conceived and designed the experiments. QL designed the questionnaire. XMF and SL interviewed the patients’ mothers and collected the data. QL analyzed the data and wrote the paper. LW and YLJ revised the paper critically for important intellectual content. All authors read and approved the final manuscript.
been influenced by the effects of the other two confounders.
Funding 4.4. Maternal habits and exposure history
This work was supported by a grant to Xiaowei Chen from the General Programs of National Natural Science Foundation of China (grant number: 81271053) and the National Key Research and Development Program of China (grant number: 2016YFC0901501).
Smoking and alcohol use during pregnancy have been reported to be associated with microtia [30]. Nicotine is believed to cause oxidative stress, which could lead to neural crest disturbance, and alcohol is thought to be involved in impaired neural crest cell migration, resulting in structural defects [31]. However, the present study, found that smoking, including exposure to second-hand smoke, and alcohol were not associated with severe microtia/atresia. Because most women in China do not smoke or drink alcohol during pregnancy, these results can likely be explained by the small number of exposed individuals. Exposure to chemicals is considered another risk factor for human deformities [18,19]. These chemicals may be associated with epigenetic changes, such as methylation or microRNA changes. The present study found that 2.8% of mothers of children with severe microtia/atresia had been exposed to chemicals, such as hair dye, rubber, pesticides, formaldehyde and gasoline. However, multivariate analysis showed no significant association between exposure and severe microtia/atresia. A study evaluating the relationship between maternal occupations with potential exposure to ionizing radiation and birth defects found that the risk was elevated in mothers of infants with microtia [32]. These findings may have been due to damage to DNA in the ovum before conception or cell damage during early pregnancy [33]. In our study, 16.5% of mothers of children with severe microtia/atresia were engaged in occupations requiring prolonged computer work every day, such as programmer, software engineer, and network administrator. However, we observed no association between these occupations and severe microtia/atresia.
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