Abstract
Introduction:
Lung disease due to ABCA3 variants and resultant surfactant dysfunction is an autosomal recessive disease. However, monoallelic ABCA3 variants are overrepresented in term or late-preterm infants with non-fatal neonatal respiratory distress syndrome (RDS). The childhood respiratory outcomes of infants with monoallelic ABCA3 variants who present with neonatal RDS are unknown. In this study, we report the respiratory outcomes beyond neonatal hospitalization (median follow-up 1 year [range 1–9.4 years]) for infants with monoallelic ABCA3 variants and neonatal RDS.
Methods:
Participants with monoallelic ABCA3 variants classified as pathogenic, likely pathogenic, or of uncertain significance with neonatal RDS identified in 3 cohorts (ChILD Registry n = 9, disease-based cohort n = 19, and nested case-control n = 20) were included in this retrospective, descriptive study. The primary outcome was duration of supplemental oxygen use. Secondary outcomes included respiratory morbidities after NICU discharge.
Results:
Of 48 infants who met inclusion criteria, 8 (17%) were discharged home on supplemental oxygen, including two who required home invasive mechanical ventilation. The ABCA3 pathogenic variant p.Glu292Val was the most common variant identified in the infants who required oxygen beyond NICU discharge (6 of 8). Oxygen was discontinued by 10 months of age in 50% of infants discharged from birth hospitalization on oxygen. Respiratory morbidities, including hospitalizations (62% vs. 8%, p = 0.005) and emergency department (ED) visits (71% vs. 35%, p < 0.01), were more common among participants discharged home on oxygen compared to those discharged home without oxygen.
Conclusions:
These findings suggest that infants with monoallelic ABCA3 variants and neonatal RDS may require prolonged home oxygen or mechanical ventilation and experience increased risk for respiratory morbidities, including subsequent hospitalization and ED visits.
1 ∣. Introduction
The ATP-binding cassette transporter A3 (ABCA3) plays a critical role in pulmonary surfactant metabolism, and its expression is developmentally regulated. ABCA3 localizes to the outer membrane of lamellar bodies, which are specialized intracellular organelles in alveolar type II cells where surfactant is assembled and stored. ABCA3 utilizes ATP to transport phospholipids from the cytoplasm into the lamellar bodies, where they assemble with surfactant protein (SP)-B and SP-C to form surfactant [1-5]. Over 300 disease-associated ABCA3 variants have been identified, and the majority are missense and private, that is, unique to individuals and families [6, 7]. Fewer than 20% of ABCA3 disease-associated variants have been functionally characterized in cell-based systems [1-5, 8-18]. Neonates with biallelic loss-of-function (nonsense, frameshift) variants in ABCA3 exhibit clinical and radiographic findings of surfactant deficiency associated with progressive neonatal respiratory failure that is fatal by 1 year of age without lung transplantation [6, 7, 19-21]. Infants with biallelic ABCA3 variants, including missense variants that presumably allow for some function of the ABCA3 protein, have a broad range of clinical manifestations, including severe neonatal RDS resulting in death or lung transplantation, interstitial lung disease presenting in childhood, adolescence, or adulthood, or they may remain relatively asymptomatic [6, 10, 15, 19, 22, 23]. The reasons for this variability may be related to residual ABCA3 function or genetic, epigenetic, or environmental factors [6]. Although ABCA3 deficiency is an autosomal recessive disorder, having a monoallelic ABCA3 variant (i.e., carriers) contributes 10.9% of the attributable risk for neonatal RDS among term and late preterm infants [6, 7, 24-26]. Additionally, monoallelic ABCA3 variants have been identified among preterm infants with neonatal RDS or bronchopulmonary dysplasia that are more severe than predicted by gestational age [26].
Although the risk of neonatal RDS among infants with monoallelic ABCA3 variants is known, descriptions of respiratory outcomes after their birth hospitalizations are lacking. The objective of this study was to report respiratory morbidity, duration of supplemental oxygen use, and healthcare utilization in early childhood among children with monoallelic ABCA3 variants and neonatal RDS. This timeframe is particularly important, as it is the period during which alveolar growth occurs most rapidly [27].
2 ∣. Methods
2.1 ∣. Study Design and Population
We performed a retrospective, descriptive study using three sources of data: an ongoing observational multi-center prospective study [28] (US ChILD Registry Collaborative), previously collected prospective data from a neonatal RDS disease-based cohort [24], and data from a nested case-control study of the genetic epidemiology of RDS [29]. Inclusion criteria were (a) a history of neonatal RDS and (b) a monoallelic ABCA3 variant classified as pathogenic, likely pathogenic, variant of uncertain significance (VUS), or variants that have demonstrated impaired ABCA3 function in cell-based systems [1, 4, 5, 8-10, 15, 30]. Case definitions for neonatal RDS included the need for supplemental oxygen (fraction of inspired oxygen [FiO2] ≥ 0.3) along with a chest radiograph consistent with neonatal RDS and continuous positive airway pressure or mechanical ventilation requirement within the first 48 h of life, impairment in oxygenation with a chest radiograph consistent with RDS or surfactant administration, or a history of NICU admission for respiratory distress [24, 29]. Genotype exclusion criteria included the presence of biallelic variants (combination of pathogenic, likely pathogenic, or VUS) and the presence of monoallelic ABCA3 variants classified as benign or likely benign. Additional clinical exclusion criterion included the presence of alternate diagnoses that could explain the respiratory phenotype, including congenital heart disease, SFTPC variants, Noonan syndrome, or 22q11.2 deletion syndrome. Preterm infants were included. The classification of ABCA3 variants was updated in December 2024. This study was approved under the Institutional Review Boards of Children's Hospital of Philadelphia (CHOP) (coordinating center of the multi-center ChILD Registry), Washington University, and Kaiser Permanente Northern California. Birth characteristics of the neonatal RDS disease-based cohort [24] and the nested RDS genetic epidemiology case-control study [29] were previously published. However, both studies focused on identifying risks for neonatal RDS and therefore did not include details of respiratory support, subsequent respiratory course, or oxygen need [24, 29]. The data on the primary outcomes of the present study have not been previously published, but preliminary analyses of pooled data from the ChILD Registry and disease-based cohort were previously presented as an abstract [31]. The objectives of the present study were (a) to determine the duration of respiratory support following NICU discharge for infants with neonatal RDS and monoallelic ABCA3 variants, (b) to report the duration of respiratory support in preterm and term infants with monoallelic ABCA3 variants, and (c) to characterize the respiratory morbidities in infants with monoallelic ABCA3 variants measured by use of respiratory medications, hospitalizations, and emergency department (ED) visits due to acute respiratory illnesses in early childhood (median follow-up 1 year [range 1–9.4 years]). The primary outcome was the duration of supplemental oxygen use.
2.2 ∣. Data Collection
Participants with monoallelic ABCA3 variants and a history of neonatal RDS were identified from the US ChILD Registry Collaborative, a network of 23 sites at the time of this study that prospectively enroll infants and children with ILD [28]. The criteria for ChILD Registry enrollment include a clinical suspicion or diagnosis of interstitial and diffuse lung disease in childhood, age 0–21 years, subject/parental/guardian permission (informed consent), and child assent when appropriate. ABCA3 variants were reviewed for the above study inclusion criteria (Figure 1). Electronic questionnaires were distributed to individual site investigators, pediatric pulmonologists, and neonatologists to obtain additional clinical data regarding respiratory morbidities, medication use, and hospitalizations. Study data were collected and managed using REDCap (Research Electronic Data Capture) electronic data capture tools hosted at CHOP [32, 33]. Genetic testing for participants from the ChILD Registry was performed based on clinical indication prior to the start of this study. Data were pooled with previously collected data in the neonatal RDS disease-based cohort [24] and the nested case-control study of the genetic epidemiology of RDS. Informed consent was obtained from parents or legal guardians of all participants [24, 28, 29].
FIGURE 1 ∣.
Flow diagram of included participants illustrating recruitment in the study across the three independent sources. Figure 1. (A) Forty participants in the ChILD registry were identified to have a case classification of disease related to ABCA3 variants. There was no genotype in 3 of them, 16 had biallelic ABCA3 variants, and 21 had monoallelic variants. Twelve of them were excluded due to lack of clinical data, 7 due to variants being classified as benign, 6 of them were excluded due to the presence of other genetic diagnoses, and 2 did not have a history of neonatal RDS [28]. For the 12 participants excluded various criteria were applicable to more than one participant. (B) Nineteen participants with ABCA3 variants were ascertained in the neonatal RDS disease-based cohort [24]. (C) Twenty-one participants with neonatal RDS and monoallelic ABCA3 variants were identified from the nested case-control.
2.3 ∣. Statistical Analysis
The participants were classified into two groups based on the respiratory support status at the time of discharge from birth hospitalization: “oxygen group” and “no oxygen group.” Descriptive statistics were used to report median, mean, and ranges for continuous variables, and frequencies and percentages for categorical variables. Fisher's exact test and the Wilcoxon rank-sum test were performed for continuous and categorical variables, respectively, using Stata 15.0 (StataCorp. 2017. Stata Statistical Software: Release 15. College Station, TX: StataCorp LLC).
3 ∣. Results
Of the 48 participants who met inclusion criteria (ChILD Registry n = 9, disease-based cohort n = 19, nested case-control n = 20), all had only a monoallelic (heterozygous) ABCA3 variant identified; none had benign or likely benign variants on the other allele. The median age at data collection in the overall study population was 1 year [range 1–9.4 years]. Eight infants (17%) required respiratory support after discharge from birth hospitalization and comprised the study group designated as the “oxygen group.” Forty (83%) infants were discharged without respiratory support and comprised the reference group or “no oxygen group.”
Perinatal demographic characteristics are summarized in Table 1. All participants in the oxygen group were born via cesarean delivery, compared with 49% of those in the no oxygen group (p < 0.01). The distributions of estimated gestational ages and birth weights were similar in both study groups. Infants in the oxygen group were more likely to receive treatment with diuretics (43% vs. 5%, p = 0.019) and systemic corticosteroids (62% vs. 7%, p = 0.002) during NICU hospitalization. The rates of surfactant administration and mechanical ventilation during NICU hospitalization were similar between the two groups.
TABLE 1 ∣.
Respiratory morbidity and perinatal characteristics by supplemental oxygen status at hospital discharge.
| Oxygen group n = 8 | No oxygen n = 40 | p value** | |
|---|---|---|---|
| Age at data collection, months median [range] | 42 (12–92.7) | 12 (12–113.8) | 0.150 |
| A. Perinatal characteristics | |||
| Maternal diabetes n (%) | 2 (29)1 | 1 (6)2 | 0.194 |
| Antenatal steroids n (%) | 1 (12) | 5 (14)3 | 0.703 |
| Gestational age-weeks, median [range] | 35.5 [25–39] | 36 [25–40] | 0.569 |
| Cesarean delivery n (%) | 8 (100) | 19 (49) | 0.006 |
| Birth weight-kg median [range] | 2.6 [0.66–3.89] | 2.8 [0.72–3.94] | 0.558 |
| B. NICU respiratory morbidity | |||
| Surfactant n (%) | 8 (100) | 33 (82) | 0.583 |
| NICU diuretics n (%) | 3 (43)1 | 2 (5) | 0.019 |
| Systemic corticosteroids n (%) | 5 (62) | 3 (7) | 0.002 |
| Maximum respiratory support | 0.070 | ||
| ECMO n (%) | 1 (12) | 0 | |
| Intubation and mechanical ventilation n (%) | 6 (75) | 31 (77) | |
| NIPPV n (%) | 1 (12) | 9 (23) | |
| Prolonged rupture of membranes (PROM) | 01 | 5 (23)4 | 0.030 |
| +GBS | 01 | 2 (9)4 | 0.611 |
| Chorioamnionitis, +Blood culture | 01 | 04 | — |
| C. Respiratory morbidity after NICU discharge | |||
| Supplemental oxygen duration in months median [range] | 10.5 [1–28] | — | — |
| Amount of supplemental oxygen in LPM median [range] | 0.3 [0.1–0.6]1 | — | — |
| Chronic mechanical ventilation n (%) | 2 (25) | — | — |
| ≥ 2 courses of oral corticosteroids n (%) | 3 (43)1 | 3 (14)4 | 0.110 |
| Number of courses median [range] | 2 [1–5] | 2 [1–15] | |
| Inhaled corticosteroids n (%) | 4 (57)1 | 3 (75)5 | 1.000 |
| Hospitalizations n (%) | 5 (62) | 2 (8)6 | 0.005 |
| Number of hospitalizations median [range] | 1 [1–3] | 1 | |
| ED visit n (%) | 5 (71)1 | 8 (35)7 | 0.003 |
| Number of ED visits median [range] | 1 [1–2] | 1.5 [1–3] | |
| Tube feeds | 5 (71)1 | 2 (10)8 | 0.004 |
Note:
Data not available for the full study group
n = 7
n = 17
n = 36
n = 22
n = 4
n = 24
n = 23
n = 21.
p values obtained using Fisher's exact test and Chi-Square for categorical variants, and Wilcoxon Rank-Sum Test for continuous variables without correction for multiple comparisons.
Abbreviations: LPM = liters per minute.
The median age at data collection among participants in the oxygen and the reference groups did not differ statistically, but those in the oxygen group were older at the time of data collection (3.5 years, range 1–7.7 years) versus 1 year (range 1–9.5 years), respectively (Table 1). For the primary outcome, the median duration of supplemental oxygen therapy was 10.5 months with a range of 1–28 months (Table 1). Oxygen flow at discharge ranged from 0.125 to 0.6 liters per minute. Two of the infants discharged on supplemental oxygen also required a tracheostomy and home mechanical ventilation, while the other six infants were discharged on supplemental oxygen exclusively. Datum on oxygen flow was missing for one of the infants, who was discharged on invasive mechanical ventilation with a FiO2 of 0.64. The two infants who required home mechanical ventilation were born extremely preterm (25 weeks and 28 weeks, respectively) (Tables 1 and 3).
TABLE 3 ∣.
Duration of supplemental oxygen use, gestational age, and ABCA3 variants among infants in the oxygen group.
| Age at discontinuation (month) |
EGA at birth (weeks) |
ABCA3 variant |
|---|---|---|
| 1 | 34 | p.Glu292Val |
| 4.2 | 39 | p.Glu292Val |
| 6 | 36 | p.Glu292Val |
| 10 | 35 | p.Glu292Val |
| 11 | 37 | p.Glu292Val |
| 20 | 38 | p.Glu292Val |
| 27 | 28* | p.Ala2Asp |
| 28 | 25* | p.Arg638His |
Note:
infant discharged on home mechanical ventilation
In terms of respiratory morbidities, infants who were discharged on oxygen were more likely to be hospitalized (62% vs. 8%, p = 0.005) or to be evaluated in the ED for respiratory symptoms (71% vs 35%, p < 0.01). Hospitalizations ranged from 1 to 3 admissions (mean 1) in the age range of 0 to 53 months of age. There was no difference between the two groups in the rates of treatment with ≥2 courses of oral corticosteroids for acute illness after discharge from birth hospitalization. The infants who were discharged on oxygen were more likely to receive tube feedings (71% vs. 10%, p < 0.01) after discharge (Table 1). Mechanical ventilation was discontinued at 28 and 33 months in the two preterm infants, respectively. No deaths were reported in either study group within the follow-up period.
The list of ABCA3 variants identified among participants in both groups is outlined in Table 2, along with variant pathogenicity classification. The p.Glu292Val pathogenic variant (c.875 A > T, reference sequence NM_001089.3, minor allele frequency (MAF) 0.00453 in the genome aggregation database gnomAD v.4.1.0) [34] was the most frequently identified variant (n = 16, 33%). Six term and late-preterm infants in the oxygen group carried the p.Glu292Val ABCA3 variant. The two preterm infants who required home mechanical ventilation each carried an ABCA3 VUS: p.Arg638His (MAF 0.000322) and p.Ala2Asp (MAF 0.000163), respectively (Table 3). No differences were found in the perinatal or respiratory morbidities when comparing infants with and without home oxygen and who carried the p.Glu292Val.
TABLE 2 ∣.
ABCA3 variants in the study group and gnomAD allele frequency.
| ABCA3 Variants in the study group and gnomAD allele frequency | |||||
|---|---|---|---|---|---|
| Oxygen group |
No oxygen |
||||
| Variant | Number of infants n = 8 |
gnomAD allele frequency |
Variant | Number of infants n = 40 |
gnomAD allele frequency |
| p.Glu292Val (P) | 6 (0.75) | 4.53 e-3 | p.Glu292Val (P) | 10 (0.2) | 4.53 e-3 |
| p.Arg638His (VUS) | 1 (0.125) | 3.22e-4 | p.Arg288Lys (VUS) | 7 (0.15) | 7.03e-3 |
| p.Ala2Asp (VUS) | 1 (0.125) | 1.63e-4 | p.Ser1516Asn (VUS) | 1 (0.02) | 1.37e-6 |
| P = Pathogenic | c.3863-98 C > T (P) | 1 (0.02) | N.L. | ||
| LP = Likely Pathogenic | p.Thr575Ile (VUS) | 1 (0.02) | 1.05e-5 | ||
| VUS = Variant of Uncertain Significance | p.Ala132Thr (VUS) | 1 (0.02) | 1.31e-5 | ||
| N.L. = not listed | p.Arg1474Trp (VUS) | 2 (0.04) | 3.69e-3 | ||
| p.Ala90Thr (VUS) | 1 (0.02) | 1.86e-6 | |||
| p.Pro186Leu (LP) | 1 (0.02) | 3.72e-6 | |||
| p.Leu1159Met (VUS) | 1 (0.02) | N.L. | |||
| p.Arg671Cys (VUS) | 1 (0.02) | 2.17e-5 | |||
| c.2700+1 G > A (LP) | 1 (0.02) | 1.90e-6 | |||
| p.Ser1262Gly (VUS) | 4 (0.08) | 1.98e-3 | |||
| p.Phe478Leu (VUS) | 2 (0.04) | 4.71e-5 | |||
| p.Leu457Met (VUS) | 1 (0.02) | N.L. | |||
| p.Gly1443Arg (VUS) | 1 (0.02) | 3.78e-5 | |||
| p.Thr761Met (VUS) | 1 (0.02) | 3.16e-5 | |||
| p.Ile1586Met (VUS) | 1 (0.02) | 8.06e-6 | |||
| p.Ile561Phe (VUS) | 1 (0.02) | 8.55e-5 | |||
| p.Lys816Lys (VUS) | 1 (0.02) | 6.20e-6 | |||
4 ∣. Discussion
This study describes the early-life respiratory outcomes of 48 symptomatic neonates with monoallelic ABCA3 variants. The majority of infants with neonatal RDS and monoallelic ABCA3 variants did not require respiratory support after discharge from birth hospitalization, despite requiring non-invasive or invasive ventilation in the NICU. Increased respiratory morbidities, including hospitalizations and ED visits, were identified among infants with monoallelic ABCA3 variants who were discharged home on oxygen from the NICU. These infants were also more likely to require tube feedings after NICU discharge. We did not assess the association between gestational age and the need for home respiratory support due to the statistical power provided by our cohort size. Notably, all participants were alive at the time of follow-up. All infants discharged on supplemental oxygen therapy were born via cesarean delivery. Operative delivery could be further studied as an additional risk factor for prolonged oxygen supplementation. Usage of diuretics and systemic corticosteroids during the neonatal hospitalization was more common in the oxygen group, likely reflecting a more severe neonatal RDS phenotype. None of the study participants were discharged from birth hospitalization on diuretics or systemic corticosteroids.
The findings of this study suggest that infants with neonatal RDS and monoallelic ABCA3 variants are likely to survive to hospital discharge. However, some require prolonged home oxygen or mechanical ventilation and experience respiratory morbidities, including subsequent hospitalizations and ED visits. With increasing availability and access to genetic testing in the NICU [35, 36], we anticipate an increase in the detection of neonates with monoallelic ABCA3 variants. The results of this study may impact the anticipatory guidance provided to families of infants with neonatal RDS and monoallelic ABCA3 variants, in terms of short-term respiratory outcomes and need for pulmonary follow-up. The finding of improved respiratory disease in 71% of participants requiring oxygen at hospital discharge will help with management and family counseling. The risk for neonatal RDS requiring positive pressure ventilation may also help guide decisions on the location of delivery for subsequent pregnancies. In our cohort, the p.Glu292Val ABCA3 variant emerged as the most common, with nearly 40% of affected infants requiring supplemental oxygen at discharge.
The p.Glu292Val variant is a missense variant and is present in 0.45% of adults in gnomAD, with an increased frequency among adults of European descent [34]. Several in vitro studies and a mouse model suggest that the p.Glu292Val variant partially disrupts ATP-mediated phospholipid transport into lamellar bodies [8, 10, 37]. Other loss-of-function (frameshift, nonsense) ABCA3 variants are present in 0.05% of adults in gnomAD. The combined allele frequencies of loss-of-function variants and the most common pathogenic variant p.Glu292Val is 0.5% (1 in 200 alleles), which indicates a carrier frequency of at least 1 in 100 individuals. Thus, for ABCA3 deficiency, an autosomal recessive disorder, the estimated disease incidence is approximately 1 per 40,000 births. Of note, this disease incidence is likely an underestimate as many pathogenic ABCA3 variants are missense and private, and many missense variants in gnomAD may be pathogenic [6]. Therefore, this disease incidence is likely an underestimate. The p.Glu292Val variant is most commonly associated with chILD phenotypes rather than fatal or severe neonatal RDS [6], and symptomatic adults without neonatal symptoms have been identified with homozygous or compound heterozygous p.Glu292Val variants later in life [22, 38]. Furthermore, a report described different neonatal phenotypes in two siblings homozygous for p.Glu292Val, one of the siblings presented with neonatal respiratory symptoms while the other had an asymptomatic neonatal course [39]. Among the participants in this study, the majority discharged on respiratory support (6 out of 8) carried the p.Glu292Val variant. While this highlights the clinical significance of the p.Glu292Val variant, many infants discharged without oxygen also carried this variant. Further, there was no difference in the range of gestational ages between infants with p.Glu292Val needing prolonged respiratory support compared to those who did not, suggesting other factors may contribute to the prolonged need for oxygen supplementation, including gestational age, maternal diabetes, delivery route, as well as genetic, epigenetic, or environmental factors. Finally, two participants in the oxygen group had variants classified as VUS (p.Ala2Asp and p.Ar-g638His). However, these two infants were also born preterm at 25 weeks and 28 weeks respectively (Tables 1 and 3), and it is not possible to exclude the role of prematurity in the supplemental oxygen and mechanical ventilation requirements for these infants.
Previously published data by Wittmann et al. on long-term outcomes of nine participants with neonatal RDS who carried the p.Arg288Lys ABCA3 variant described heterogeneous clinical courses and restrictive lung disease patterns on pulmonary function tests [23]. While our study identified only one participant with the p.Arg288Lys variant who was discharged without oxygen, the findings of our study of infants with monoallelic ABCA3 variants, including the variable outcomes with respect to oxygen for participants with pathogenic p.Glu292Val variants, are nevertheless consistent with the heterogeneous clinical courses reported by Wittmann and colleagues.
While the short-term outcomes of our study appear to be favorable early in childhood, special attention to the characterization of disease evolution throughout the lifespan is needed. Development of interstitial lung disease later in life has been described in individuals with monoallelic ABCA3 variants [23, 40]. A decrease in the FEV1/FVC ratio has been reported among individuals identified with the p.Glu292Val variant in the United Kingdom Biobank cohort (n ~ 500,000 adults), suggesting that monoallelic ABCA3 variants may contribute to mild respiratory disease phenotypes in adults [40]. To fully understand the impact of monoallelic ABCA3 variants and their long-term respiratory outcomes, future studies should include extended follow-up into adulthood, universal genetic testing of infants with neonatal RDS, and comprehensive longitudinal assessments such as pulmonary function tests, imaging, and other clinical markers (i.e., respiratory support and symptoms).
Limitations of this study include the small sample size, especially for extremely preterm infants, and selection bias for disease severity. However, as ABCA3 deficiency is a rare disease, the sample size of 48 infants represents a relatively large cohort. Symptomatic infants underwent genetic testing at the discretion of the treating physician or as part of enrollment in research studies. Asymptomatic infants with monoallelic ABCA3 variants were thus not included in this study. The sequencing strategy (i.e., single gene vs. gene panel vs. exome sequencing) may have limited discovery of pathogenic variants in other genes or in non-coding regions. Comparisons between our study group and an unaffected group of neonates with a different neonatal RDS disease process were not feasible in this retrospective design. Because the need for testing was clinically determined for participants enrolled through the ChILD Registry, the clinical threshold and availability of genetic testing may vary between sites. Therefore, our sample may underrepresent the true prevalence of monoallelic ABCA3 variants among infants with neonatal RDS. Since clinical concern for chILD is required for enrollment in the US ChILD Registry, it could have led to the inclusion of infants with more severe pulmonary phenotypes. Similarly, recruiting infants from two neonatal RDS studies could have potentially added to the selection of cases with increased disease severity. The variables collected did not include the duration of NICU hospitalization, which could result in an underestimation of disease severity among the infants discharged without respiratory support. The difference in median age at data collection between the two groups could have also contributed to an underrepresentation of the respiratory morbidities among the infants discharged without respiratory support. Variations in the clinical practice for chronic home oxygen use among institutions are a reproducibility limitation that may be mitigated by the multi-center design. The inclusion of participants with monoallelic ABCA3 VUS also represents a limitation due to the unknown clinical and functional effects of these variants. Finally, while the primary outcome (duration of supplemental oxygen use) was pre-specified based on a priori knowledge, other secondary outcomes could be affected by type I error due to multiple comparisons.
The findings of this study emphasize the importance of strategies, such as a national registry, to enroll and follow infants with rare diseases over time from multiple centers, including infants with monoallelic ABCA3 variants. Additionally, it highlights the important collaboration between neonatologists and pediatric pulmonologists to identify infants at risk for monogenic lung disease and ensure pulmonary follow-up after NICU hospital discharge.
Funding
The authors have nothing to report.
Footnotes
Conflicts of Interest
The authors declare no conflicts of interest.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.