Biliary atresia, a severe liver disease of childhood with an estimated prevalence of 5 to 10 per 100,000 births, is the leading indication for pediatric liver transplantation worldwide.1
Biliary atresia is characterized by obstruction of the bile duct system. As a result, bile cannot leave the liver and enter the intestines to help digest fats. Instead, bile is retained in the liver, leading to liver injury, progressive liver fibrosis, and, if untreated, end-stage liver disease by the first year of life.2
Despite the significant morbidity of biliary atresia, its key etiologic aspects, including when the disease begins, remain unknown. One possibility is that bile duct atresia is acquired after birth, which is consistent with babies typically appearing healthy as newborns, with discordance in identical twins and no recurrence in families.3 However, other lines of evidence Significant evidence argues that biliary atresia begins in utero. For example, infants with biliary atresia have elevated laboratory markers of biliary retention at birth, indicating that the disease may already be present.4 Additionally, abnormalities in fetal ultrasound and amniotic fluid analysis have been reported, which suggests that defects in biliary development occur as early as the 15th week of gestation.5
Approximately 10%-30% of patients with biliary atresia also have malformations of other organs, indicating broader problems during embryonic development.6,7 In this study, the novel hypothesis was proposed that if biliary atresia Bile duct begins in utero, then it would be associated with key early epidemiological factors relevant to fetal development. To explore this hypothesis, we leveraged data from a large birth defect registry.
| Methods |
This study was approved by the Institutional Review Boards of the Texas Department of State Health Services and Baylor College of Medicine. All patients were part of the Texas Birth Defects Registry (RDNT), one of the largest active birth defects surveillance centers managed by the Birth Defects Surveillance and Epidemiology Branch of the Texas Department of State Health Services.
RDNT members routinely visit all maternity hospitals, general hospitals, children’s hospitals, and midwifery facilities in Texas, and examine recorded discharge diagnosis codes for birth defects in all infants under 1 year of age. Diagnostic codes used are 6-digit entries based on the British Pediatric Association (BPA) Classification of Diseases and the World Health Organization’s International Classification of Diseases, Ninth Revision, with modifications made by the Centers for Disease Control and Prevention. Disease Prevention (the codes are called "APB codes" in this document).
The study population included infants born in Texas between January 1, 1999 and December 31, 2014. Infants were considered to have biliary atresia when they met 3 criteria:
(1) at least 1 medical record less than 1 year old of life with the APB code for biliary atresia (751.60);
(2) records manually reviewed by RDNT staff to ensure that the clinical course was consistent with biliary atresia;
(3) RDNT records reviewed again by a pediatric hepatologist to exclude patients who likely had another condition. As in other studies using RDNT data, patients in Texas Public Health Region 5/6 were excluded from this analysis due to differences in surveillance and case ascertainment strategies.8-10
| Data collection |
Early epidemiological factors relevant to fetal development were obtained from vital records. Infant variables included sex, gestational age, time of conception, and plurality. Gestational age was divided into >37 weeks (term), 32-37 weeks (moderate to late preterm), and <32 weeks (very to extremely preterm), and the time of conception was classified as spring (March-May), summer (June-August), autumn (September-November), and winter (December-February) based on the estimated date of the mother’s last menstruation.
Maternal variables included race/ethnicity (as classified by the RDNT), age, previous pregnancies that resulted in a live birth, previous pregnancies that did not result in a live birth, diabetes, body mass index, education, and residence near the border. Texas-Mexico during pregnancy. The body mass index was divided into categories of underweight (<18.5 kg/m2), normal weight (18.5-<25.0 kg/m2), overweight (25.0-<30.0 kg/m2 ), and obesity (≥30 kg/m2). Paternal factors included race/ethnicity, age, and education.
Children with biliary atresia were also assessed for the presence of concurrent malformations.7
Patients with isolated biliary atresia (subgroup 1) did not have major birth defects.
Patients with biliary atresia and birth defects without laterality (subgroup 2) had at least one other major malformation unrelated to organ malposition.
Patients with biliary atresia and laterality of congenital anomalies (subgroup 3) had at least one major malformation related to organ malposition.
This included incorrect vessel locations (aorta anomalies, pulmonary artery anomalies, partially anomalous pulmonary veins, persistent left superior vena cava, bilateral superior vena cava, or anomalous portal vein termination), thoracic organs (dextrocardia), and/or or abdominal organs (displacement or transposition of the stomach, malrotation of the cecum/colon, malrotation of the small intestine, annular pancreas, asplenia, polysplenia, right-sided spleen or situs inversus).
| Statistic analysis |
To identify associations between biliary atresia and factors that could influence fetal development, unadjusted prevalence proportions (PP) with 95% CIs were first calculated using Poisson regression analysis with data from all live births as the denominator.
Variables were considered significantly associated with biliary atresia when the 95% CI excluded 1.00. Adjusted PPs and 95% CIs were then calculated by evaluating all significant variables in a multivariable adjusted Poisson regression model.
For adjusted models, paternal race/ethnicity was excluded due to a high percentage of missing responses (14.5%). Additionally, repeated analyzes were performed for subgroups of cases based on the presence of concurrent malformations as described above. All calculations were performed using Stata 14.0 (StataCorp).
| Results |
There were 4,689,920 births during the study period, including 341 infants with a diagnostic code for biliary atresia in the RDNT. Of these, 21 patients were excluded because they were considered to have a liver disease other than biliary atresia after manual review of their case descriptors, and 15 patients were excluded because they had chromosomal abnormalities or other Mendelian disorders.
The remaining 305 patients were considered to have biliary atresia without other known genetic syndromes, resulting in a birth prevalence of 6.5 per 100,000 births. Year after year, the prevalence varied from 0.49 to 0.78 per 10,000 births without any recognizable temporal trend.
Next, the impact of early epidemiological factors relevant to fetal development on the prevalence of biliary atresia at birth was evaluated. Childhood factors that were positively associated with biliary atresia included female sex (adjusted PP, 1.68; 95% CI, 1.33-2.12), gestational age of 32-37 weeks (adjusted PP, 1.64; 95%, 1.18-2.29), and gestational age <32 weeks (adjusted PP, 3.85; 95% CI, 2.38-6.22). A childhood factor inversely associated with biliary atresia was the season of conception in the fall relative to the spring (adjusted PP, 0.62; 95% CI, 0.45-0.86).
Maternal factors that were significantly more common in cases of bile duct atresia included non-Hispanic black race/ethnicity relative to non-Hispanic white race/ethnicity (adjusted PP, 1.54; 95% CI, 1.06-2 .24) and maternal diabetes (adjusted PP, 2.34; 95% CI, 1.57-3.48). The association with maternal diabetes was significant for pregestational diabetes (adjusted PP, 4.94; 95% CI, 2.32-10.54) but not for gestational diabetes. Parental factors were excluded from the adjusted model due to a high percentage of missing responses.
When cases of biliary atresia were divided into subgroups according to the presence of concurrent malformations, there were 212 cases in subgroup 1 (69.5%) with isolated biliary atresia, 66 cases in subgroup 2 (21.6%) with birth defects without laterality most commonly affecting the cardiovascular and genitourinary systems, and 27 cases in subgroup 3 (8.9%), with congenital defects with laterality most commonly affecting the cardiovascular and digestive systems.
Overall, the impact of early epidemiologic factors relevant to fetal development was consistent across biliary atresia subgroups, especially for those with isolated biliary atresia. Examples of exceptions included no association with female sex in subgroup 3 or with maternal diabetes in subgroup 2; however, estimates in these groups were limited by sample size.
| Discussion |
These findings suggest that factors related to fetal development appear to predispose infants to biliary atresia.
Specifically, biliary atresia was found to be significantly more common among infants who were female, premature, conceived in seasons other than fall, born to non-Hispanic black mothers, or born to mothers with pregestational diabetes.
Importantly, these associations were also observed in infants with isolated biliary atresia, who do not have other major malformations or signs of disrupted fetal development. These results raise the possibility that early life events influence the occurrence of bile duct atresia and support the hypothesis that biliary atresia begins in utero.
Some associations identified in this study are consistent with previous reports, although how these might contribute to the pathogenesis of biliary atresia remains unclear. For example, many, but not all, studies have reported a higher rate of biliary atresia in women.11-16 However, to date, no female-specific factors have been found that may contribute to problems in duct development. biliary. Likewise, multiple studies have reported a higher incidence in premature newborns.14-17
One possibility is that an early biliary event may cause fetal distress and preterm birth. Alternatively, babies born prematurely may be prone to bile duct damage when outside the intrauterine environment. Possible associations with season of conception/birth and maternal race/ethnicity have also been reported.12-14,18-23
A study in French Polynesia identified a higher incidence of biliary atresia with births in drier seasons, while different studies on race/ethnicity suggested that biliary atresia occurs uniformly in the population or more often in children of non-Hispanic black mothers .18-20,22
Maternal diabetes was strongly associated with isolated cases of biliary atresia.
Previous studies have reported associations with biliary atresia with laterality defects, including one study that examined gestational diabetes specifically.7,24 The additional observation in isolated biliary atresia raises the possibility that fetal hyperglycemia may influence the development of the bile ducts in isolation, without affecting the development of other organs.
Second, in the authors’ sensitivity analysis of cases between 2005 and 2014 when diabetes onset was also recorded, pregestational diabetes rather than gestational diabetes had a significant association with bile duct atresia. A similar observation was reported with data from the National Birth Defects Prevention Study.25
The findings indicate that biliary atresia begins early in development, before 24 weeks of gestation, preceding the onset of hyperglycemia of gestational diabetes.26 This potential early onset is consistent with other studies of biliary atresia showing morphologic abnormalities of the gallbladder from 15 weeks of gestation or low levels of gamma-glutamyl transferase in the amniotic fluid (which would indicate biliary obstruction) at 18-19 weeks of gestation.5
This study also identified factors not associated with biliary atresia that provide potential clues to the pathogenesis of the disease. For example, maternal age was not significantly associated with biliary atresia, suggesting that chromosomal aberrations that arise as gametes age do not promote the development of this pathology. Furthermore, birth order was not associated with the prevalence of biliary atresia. If biliary atresia were an alloimmune disease, early pregnancies would probably be less affected while later pregnancies would be more susceptible.27
Finally, babies born to mothers who lived near the Texas-Mexico border were no more likely to have biliary atresia. Living near the Texas-Mexico border is an independent risk factor for the development of other birth defects.28
An important limitation of this study is the way in which cases of biliary atresia were confirmed. Although the RDNT has unprecedented coverage throughout Texas and has been validated in previous birth defect studies, there are scenarios in which cases could be misclassified. For example, a patient who was born in Texas but then moved to another state before biliary atresia was diagnosed would have been overlooked.
Additionally, a patient without biliary atresia could have been included if the data in the RDNT database were not complete enough to exclude infants with an incorrect diagnosis of biliary atresia. However, it is assumed that the RDNT accurately captured biliary atresia, because the birth prevalence matches the birth prevalence in other studies.1 Furthermore, the proportion of each subgroup approached previously reported rates of 67%-84. % for isolated biliary atresia, 6% for biliary atresia and non-laterality defects, and 10% for biliary atresia and laterality defects.7
In conclusion, the authors identified factors relevant to fetal development that are more common in infants with bile duct atresia compared to the general population. These factors include female sex, preterm birth, and maternal pregestational diabetes. Associations are also present in isolated cases of biliary atresia that do not have other malformations. These results are consistent with early life events influencing the pathogenesis of biliary atresia and warrant additional studies investigating in utero events.
| Comment |
Biliary atresia is a serious childhood disease characterized by obstruction of the bile duct system leading to liver injury, progressive fibrosis, and, if untreated, end-stage liver disease by the first year of life.
Despite its significant morbidity, its key etiological aspects, including when the disease begins, remain unknown.
The present study suggests that certain factors related to fetal development could predispose infants to biliary atresia.
Specifically, biliary atresia was found to be significantly more common in infants who were female, premature, conceived outside of the fall, born to non-Hispanic black mothers, or to mothers with pregestational diabetes; These associations were also observed in children with isolated biliary atresia, without other major malformations or signs of disrupted fetal development. These results raise the possibility that early life events influence the onset of this condition and support the hypothesis that biliary atresia could begin in utero. New studies investigating these events are warranted.
