Trends in the Prevalences of Selected Birth Defects in Korea (2008–2014)

Little information is available on the prevalences of birth defects in Korea. The aims of this study were to estimate recent prevalences of selected birth defects and to analyze the prevalence trends of these defects during the period from 2008 to 2014. Prevalences were calculated for 69 major birth defects using health insurance claim data obtained from the Korea National Health Insurance Service (NHIS). Prevalence rate ratios were calculated using Poisson regression to analyze trends over the 7-year study period. The overall prevalence of a major birth defect was 446.3 per 10,000 births (95% CI: 444.0–448.6); 470.9 per 10,000 births (95% CI: 467.6–474.2) for males and 420.2 per 10,000 births (95% CI: 417–423.4) for females. The prevalence rates of the most common birth defects over the study period were; septal defect (138.2 per 10,000; 95% CI: 136.9–139.5), congenital hip dislocation (652 per 10,000; 95% CI: 64.1–65.9), and ventricular septal defect (62.62 per 10,000; 95% CI: 61.7–63.5). During the study period, a significant increase in the prevalence of a major birth defect was observed with a prevalence rate ratio (PRR) of 1.091. The strongest trend was observed for renal dysplasia, which had a PRR of 1.275 (95% CI: 1.211–1.343), and upward trends were observed for urogenital anomalies, such as, renal agenesis (PRR 1.102, 95% CI: 1.067–1.138), undescended testis (PRR 1.082, 95% CI: 1.072–1.093) and hypospadias (PRR 1.067, 95% CI: 1.044–1.090). This study shows an overall increase in the prevalences of birth defects, including hypospadias and undescended testis, which are known to be associated with endocrine factors. In the future, standardized birth defect registries should be established to enable these trends to be monitored.


Introduction
Worldwide, about 3-6% of infants are born with a major defect [1], and 11.3% of infant mortalities occurring within four weeks of birth are due to congenital malformations [2]. The European Surveillance of Congenital Anomalies (EUROCAT) reported that the prevalence of major congenital anomalies in 2003-2007 was 239 per 10,000 births, of which 80% were delivered, 17.6% were terminated by induced abortion, 2.5% died after birth, and 2% were stillbirths [3]. During the period 1978-2005, the prevalence of major birth defects was estimated at 3% in Atlanta, GA, USA [4]. In Korea, the prevalence of 27 selected birth defects in 2002 was 57.8 per 10,000 live births and 750.6 per 10,000 stillbirths [5]. The prevalence of 69 major specific birth defects, as monitored by the National Birth Defects Prevention Network (NBDPN), the International Clearinghouse of Birth Defects Surveillance and Research (ICBDSR), and EUROCAT in 2005-2006 were 186.1 and 215.2, respectively [6]. Based on data obtained from 5 hospitals in Seoul and Gyeonggi Province in 2009-2010, the prevalence of the 76 specific birth defects considered by EUROCAT was 348.7 per 10,000 [7].

Congenital Anomalies of the Central Nervous System
The most common birth defects were spina bifida (8.1 per 10,000; 95% CI: 7.6-8.5), microcephaly (3.2 per 10,000; 95% CI: 3.0-3.4), and congenital hydrocephalus (2.9 per 10,000; 95% CI: 2.7-3.0) ( Table 1). The prevalence trends of congenital anomalies of the central nervous system are provided in Figure 1. The prevalences of spina bifida (PRR 1.10, 1.08-1.12) and microcephaly (PRR 1.03, 1.00-1.06) increased significantly over the study period, whereas the prevalence of holoprosencephaly decreased significantly. Other birth defects revealed no significant trends. significantly over the study period, whereas the prevalence of holoprosencephaly decreased significantly. Other birth defects revealed no significant trends.

Congenital Anomalies of the Urogenital System
The most common anomalies of the urogenital system were undescended testis (60. 8

Discussion
In the current study, a significant increase in the prevalence of 69 major birth defects with a prevalence rate ratio (PRR) of 1.091 was observed during the study period (2008)(2009)(2010)(2011)(2012)(2013)(2014) in Korea, which means that the overall prevalence of birth defects increased by 9.1% per year on average. We identified apparent upward trends in the prevalences of urogenital anomalies, particularly, renal dysplasia, renal agenesis, undescended testis, and hypospadias. In Korea, previous studies have reported increases in the prevalence of some urogenital anomalies [13,14]. Kim et al. indicated that the incidence of cryptorchidism and hypospadias increased in Korea from 2000 to 2005 (5.01 to 17.43 per 10,000 and 1.40 to 3.28 per 10,000 births, respectively). Lamichhane et al. also reported that the prevalence of some urogenital birth defects increased from 14.1 to 6.2 times between 1993-1994 and 2009-2010. Hence, our study suggests that urogenital birth defects persist at high levels in Korea.
Urinary malformations are caused by complex interactions between genetic and non-genetic factors, some of which have been identified [31]. Some studies have suggested that maternal diabetes, kidney disease, smoking during pregnancy, and drinking influence urinary anomalies [32,33], whereas others have suggested environmental pollution is an important factor. Studies on environmental pollution indicate the risks of renal dysplasia and obstructive genitourinary defect are higher in regions with a dioxin-emitting incinerator [26,27], and suggest an association between the chlorination disinfection byproduct in drinking water and urinary anomalies [34]. Abbott et al. concluded that TCDD (2,3,7,8-tetracholrodibenzo-p-dioxin) induces hydronephrosis in mice [35], and others have suggested an association between congenital renal defects and low birth weight (LBW) in animal models and human [36,37]. Chevalier et al. suggested genetic defects in hormone synthesis and receptors related to testicular descent, endocrine disrupting chemicals (EDCs), smoking, and drinking were causes of undescended testis [37]. Koskenniemi et al. suggested that exposure to dioxin increased the risk of undescended testis [23], whereas others suggested that exposure to EDCs and organic solvents increased the risk of hypospadias [24,25].
The present study shows that the most common birth defects of the circulatory system were atrial septal defect (138.2 per 10,000; 95% CI: 136.9-139.5), congenital hip dislocation (65.2 per 10,000; 95% CI: 64.1-65.9), and ventricular septal defect (62.62 per 10,000; 95% CI: 61.7-63.5). This finding is consistent with those of previous studies that showed atrial septal defect and ventricular septal defect are the most common defects in Korea [14,38]. Congenital heart defect (CHD) had the highest prevalence in the present study, and reportedly is the most common anomalies in other countries [12,39]. EUROCAT (2011EUROCAT ( -2015 reported that among congenital anomalies ventricular septal defect had the highest prevalence, followed by hypospadias and atrial septal defect [40]. In the US, the common defects were hypospadias, atrial septal defect, and ventricular septal defect during 2008-2012 [41]. Although these rates differ from those obtained in the current study, CHD proportions were similar. Furthermore, the current study shows the prevalence of some CHD subtypes increased at 3.4-14.3% per year during the study period (2008)(2009)(2010)(2011)(2012)(2013)(2014). A meta-analysis indicated that the increase in total CHD worldwide showed a steep increase from the late 1970s until 1995, and stabilized from 1995 [12]. The authors suggested that these increases may have been due to improvements in diagnostic techniques, such as, ultrasound, and screening methods. Cavadino et al. reported decreasing trends in the prevalences of atrial septal defect and pulmonary valve stenosis, but no significant trend for ventricular septal defect in EUROCAT (2003-2012) [42]. The authors suggested that trend differences might be due to different case definitions used in the EUROCAT study. In a Norwegian study (1994)(1995)(1996)(1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008)(2009)), CHDs showed a significant increase until around 2005 and a subsequent decrease. The authors suggested that increased consumption of folic acid may have explained this decreasing trend [43]. In addition, the following have been reported to be risk factors of CHDs; genetic abnormalities, maternal illnesses, and maternal factors, such as, maternal diabetes, rubella, febrile illnesses and obesity, drug exposure, smoking, drinking alcohol, environmental exposure, and maternal sociodemographic characteristics [44]. Recently, the number of environmental epidemiological papers published on CHDs has increased. Some studies have shown relations between CHDs and environmental pollution, such as, air pollution and chemicals [18,19,22]. Tanner et al. reported a positive relationship between exposure to PM 2.5 and increased CHD prevalence in Florida in a retrospective cohort study [17], and Zhang et al. suggested the risk of ventricular septal defect increased 1.11-1.17 per 10 µm/m 3 change in PM 2.5 during the 7th to 10th weeks of pregnancy [45]. Others have suggested that phthalate exposure is associated with the risk of CHDs, such as, ventricular septal defect and atrial septal defect [46,47], and Gilboa et al. found that occupational exposure to chlorinated organic solvents was related to ventricular septal defect [48].
In the present study, the overall prevalence of omphalocele was 4.2 per 10,000 births per annum, which is higher than that reported in the US (1995)(1996)(1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004)(2005) [49], and was the second highest increasing trend (26.6% increase per annum) observed in the present study. Congenital hip dislocation was found to be a common defect (65 per 10,000 births), and also showed a considerable increasing trend (18.5% increase per year). Prevalences of congenital hip dislocation vary by country from 1.5 to 4.9% [50]. Its causes have been suggested to be breech presentation, oligohydramnios, skeletal malformations due to teratogenic agents, and neuromuscular disease [51].
The strength of the present study is that it had substantial statistical power because it was conducted using nationally representative data from the NHIS. The national health insurance system in Korea covers almost all of the population, and thus, the use of NHIS data minimizes selection-associated risks and related potential bias. In addition, the dataset analyzed provided sufficient power to analyze trends. However, there were several limitations to this study. First, the prevalences were likely to be underestimated due to using the data that did not include stillbirth, miscarriage, and abortion. Second, the present study is subject to limitations associated with the use of insurance claims data, particularly with respect to coding, diagnostic criteria and the timings for follow-up of patients, which differ between hospitals. Furthermore, it was difficult to validate accuracies of diagnoses using claim data due to a lack of detailed records. Finally, it was difficult to adjust for maternal characteristics (e.g., maternal age) affecting the trends in the prevalence because the NHIS data could not be merged with the birth and maternal data due to the privacy protection.

Conclusions
The current study shows the prevalence of major birth defects increased significantly in Korea from 2008 to 2014. In particular, apparent upward trends in the prevalences of hormone-mediated urogenital anomalies, such as, undescended testis and hypospadias, may suggest the involvement of environmental factors. Furthermore, congenital heart defects also showed increasing trends over the study period, possibly due to the development of diagnostic techniques and more frequent prenatal diagnosis. However, increasing trends were not consistent across all categories of birth defects, as significant decreases were observed in the prevalences of holoprosencephaly, Hirschsprung's disease and club foot-talipes equinovarus. In future, it is needed to establish a nationwide surveillance system for birth defects to evaluate the risk factors for congenital anomalies and prevention efforts.