Respiratory Distress Syndrome In Premature Infants

Description

The main cause of respiratory distress syndrome (RDS) in premature infants is a developmental deficiency of pulmonary surfactant. The frequency of RDS is inversely proportional to gestational age. However, not all infants born prematurely develop RDS, suggesting that there may be susceptibility factors. Because multiple factors can contribute to the pathogenesis of RDS specifically in premature infants, the etiology is considered to be multifactorial (summaries by Ramet et al., 2000; Clark and Clark, 2005).

Pathogenic germline mutations in several genes involved in surfactant metabolism, including SFTPB (178640) and SFTPC (178620), can cause clinical features of respiratory distress syndrome in term neonates, children, and adults, disorders referred to as 'surfactant metabolism dysfunction' (see, e.g., SMDP1, 265120). Susceptibility to the development of RDS in premature infants may be associated with polymorphisms in surfactant genes, such as surfactant protein A1 (SFTPA1; 178630), SFTPB, and SFTPC (see MOLECULAR GENETICS).

Clinical Features

Clinically, RDS is characterized by deficient gas exchange that is caused by diffuse atelectasis and high-permeability lung edema and that results in fibrin-rich alveolar deposits called 'hyaline membranes.' In addition, the risk of bronchopulmonary dysplasia increases with the severity of RDS (summaries by Ramet et al., 2000; Clark and Clark, 2005).

Pathogenesis

Among 61 premature newborn infants (24 to 29 weeks' gestational age), Hallman et al. (1991) found that the levels of surfactant A in lung epithelial lining fluid were significantly decreased in the 54 infants with RDS compared to those without RDS. Premature infants with RDS also had higher levels of free amino acids in the alveolar space compared to those without RDS, and some of these free amino acids were shown to inhibit the surface activity of surfactant. Regression analysis showed a correlation between the severity of respiratory failure and decreased surfactant protein A (SPA)/saturated phosphatidylcholine (SPC) ratio and increased protein in the epithelial lining fluid.

Moya et al. (1994) found about 90% lower levels of SPA in tracheal fluid samples from 37 preterm neonates with RDS compared to 16 preterm neonates without lung disease. A subset of patients tested indicated lesser posttranslational modification of SPA in patients with RDS compared to patients without RDS. The SPA levels correlated inversely with the severity of RDS. The findings suggested that preterm neonates with RDS have immature SPA metabolism that persists for several days after birth. However, even patients with RDS showed a relatively rapid increase in SPA in the days after birth.

Molecular Genetics

Associations Pending Confirmation

Using a candidate gene approach, Ramet et al. (2000) studied the association between the surfactant protein A1 gene (SFTPA1; 178630) and RDS in Finland. They matched 88 infants with RDS and 88 control infants for degree of prematurity, prenatal glucocorticoid therapy, and sex. They found that certain SFTPA1 alleles, 6A(2) and 6A(3), and a particular SFTPA1/SFTPA2 (178642) haplotype, 6A(2)/1A(0), were associated with RDS.

Haataja et al. (2000) genotyped 684 prematurely born neonates, of whom 184 developed RDS, at polymorphic sites in the SFTPA1 and SFTPB (178640) proteins. Two SFTPB polymorphisms were studied: an ile131-to-thr (I131T) variation, which affects a putative N-terminal, N-linked glycosylation site of proSFB; and the length variation of intron 4, which had previously been suggested to associate with RDS. Neither of the SFTPB polymorphisms associated directly with RDS or with prematurity. However, the previously identified association between SFTPA1 alleles and RDS was dependent on the SFTPB I131T genotype. On the basis of chi square and logistic regression analyses, the SFTPA1 allele, haplotype, and genotype distributions differed significantly between the RDS infants and controls only when the SFTPB genotype was thr/thr. Among the infants born before 32 weeks' gestation and having the SFTPB genotype thr/thr, the SFTPA1 allele 6A2 was overrepresented in the RDS group compared with controls. In the same comparison, the SFTPA1 allele 6A3 was underrepresented in RDS. The authors proposed that the SFTPB I131T polymorphism is a determinant for certain SFTPA1 alleles as factors causing genetic susceptibility to RDS (6A2, 1A0) or protection against it (6A3, 1A2).

Marttila et al. (2003) studied 100 same-sex twin pairs who had RDS in at least 1 twin. The concordance rates of RDS were 54% and 44% in the monozygotic and dizygotic pairs, respectively. The concordance difference of 10% was not significant, suggesting a low hereditary impact. The authors found that the SFTPB 131thr allele was associated with RDS. The association was particularly apparent in first-born male infants. Marttila et al. (2003) stated that the traditional twin concordance study appeared insufficient to evaluate genetic predisposition to RDS or other disorders that are confounded by birth order or multiple pregnancy.

Lahti et al. (2004) analyzed the frequencies of polymorphisms in the SFTPC gene (178620) in 245 preterm (less than 34 weeks' gestation) Finnish newborns and 158 healthy term infants, and studied their association with respiratory distress syndrome. They found an association between the asn138 and asn186 alleles and premature male infants with RDS (p = 0.018 and 0.045, respectively). Logistic regression analysis showed both alleles to be independent risk factors for RDS (asn138, p = 0.022; asn186, p = 0.036), as well as the haplotype asn138-asn186 (p = 0.020). Lahti et al. (2004) proposed that these SFTPC alleles influence susceptibility to RDS in premature infants.