Indications for intensive care unit treatment among neonates born to mothers with thyroid disease: A population-based cohort study.

INTRODUCTION: Thyroid diseases in pregnancy are relatively common and are associated with adverse pregnancy and perinatal outcomes, increasing a neonate's risk of admission to the neonatal intensive care unit (NICU). The aim of this study was to evaluate the indications for increased risk of NICU admission among the neonates of hypothyroid and hyperthyroid mothers. MATERIAL AND METHODS: The study data consisted of all singleton deliveries (n = 734 773) between 2004 and 2016 in Finland collected from the Finnish Medical Birth Register. The odds of NICU admission (with 95% confidence intervals) were compared between the neonates of hypothyroid or hyperthyroid mothers and of mothers without any thyroid diseases by specified neonatal characteristics and morbidities using logistic regression analysis. The studied neonatal characteristics were preterm birth (<37+0 gestational weeks), low birthweight (<2500 g), the rate of small- and large-for-gestational age infants, and eight disease-specific neonatal outcomes: asphyxia, respiratory distress syndrome, meconium aspiration syndrome, pneumothorax, cardiovascular problems, infections, jaundice and hypoglycemia. RESULTS: The most common indications for NICU care were principally the same in the neonates of the mothers with and without thyroid disease: respiratory distress syndrome, infections, preterm birth, low birthweight and neonatal hypoglycemia. The preterm neonates, neonates with low birthweight, and large-for-gestational-age infants had increased odds of NICU admission if their mother had hypothyroidism. Also neonates with cardiovascular problems, jaundice or hypoglycemia associated with maternal diabetes had increased odds of NICU admissions if their mother had hypothyroidism. Further, the preterm neonates, large-for-gestational-age infants, and term infants with jaundice had increased odds of NICU admission if their mother had hyperthyroidism. CONCLUSIONS: The most common indications for NICU care were similar for the neonates of the mothers with and without thyroid disease. However, the neonates of the mothers with thyroid diseases were more likely to need NICU care. The neonates of the mothers with thyroid diseases had higher odds of NICU treatment in cases of preterm birth, large for gestational age, and hypoglycemia.

Management Practices During Perinatal Respiratory Transition of Very Premature Infants.

The present review considers some controversial management practices during extremely premature perinatal transition. We focus on perinatal prevention and treatment of respiratory distress syndrome (RDS) in immature infants. New concerns regarding antenatal corticosteroid management have been raised. Many fetuses are only exposed to potential adverse effects of the drug. Hence, the formulation and the dosage may need to be modified. Another challenge is to increase the fraction of the high-risk fetuses that benefit from the drug and to minimize the harmful effects of the drug. On the other hand, boosting anti-inflammatory and anti-microbial properties of surfactant requires further attention. Techniques of prophylactic surfactant administration to extremely immature infants at birth may be further refined. Also, new findings suggest that prophylactic treatment of patent ductus arteriosus (PDA) of a high-risk population rather than later selective closure of PDA may be preferred. The TREOCAPA trial (Prophylactic treatment of the ductus arteriosus in preterm infants by acetaminophen) evaluates, whether early intravenous paracetamol decreases the serious cardiorespiratory consequences following extremely premature birth. Lastly, is inhaled nitric oxide (iNO) used in excess? According to current evidence, iNO treatment of uncomplicated RDS is not indicated. Considerably less than 10% of all very premature infants are affected by early persistence of pulmonary hypertension (PPHN). According to observational studies, effective ventilation combined with early iNO treatment are effective in management of this previously fatal disease. PPHN is associated with prolonged rupture of fetal membranes and birth asphyxia. The lipopolysaccharide (LPS)-induced immunotolerance and hypoxia-reperfusion-induced oxidant stress may inactivate NO-synthetases in pulmonary arterioles and terminal airways. Prospective trials on iNO in the management of PPHN are indicated. Other pulmonary vasodilators may be considered as comparison drugs or adjunctive drugs. The multidisciplinary challenge is to understand the regulation of pregnancy duration and the factors participating the onset of extremely premature preterm deliveries and respiratory adaptation. Basic research aims to identify deficiencies in maternal and fetal tissues that predispose to very preterm births and deteriorate the respiratory adaptation of immature infants. Better understanding on causes and prevention of extremely preterm births would eventually provide effective antenatal and neonatal management practices required for the intact survival.

Survival analysis of a cohort of extremely preterm infants born in Finland during 2005-2013.

OBJECTIVE: This study aimed to analyze the mortality of extremely preterm infants (ELGA born alive before 28 weeks) until the postconceptional age of 42 weeks, death, or home discharge, whichever came first. It was focused especially on studying the relationship between antenatal risk factors, the time of death, and the postnatal morbidities associated with mortality. STUDY DESIGN: The original data obtained from the nationwide Finnish medical birth register of extremely preterm and low birthweight infants born during 2005-2013 were analyzed. The total population consisted of 1353 ELGA infants after the exclusion of 18 infants born with lethal congenital anomalies or genetic defects. Mortality risks were adjusted according to the length of gestation, the administration of antenatal steroids, and the delivery hospital. RESULTS: During the first 48 hours, extreme immaturity was seen to be the prominent cause of death, and intrauterine growth did not influence mortality. The ELGA population surviving for at least 48 hours (N = 1135) was submitted for mortality risk analysis. After the adjustments, small-for-gestational-age (SGA) (birth weight below -2 SD) was found to be the factor with the highest risk for demise [OR 6.2; 95% CI (3.9-10.0) p < .001]. Multiple deliveries were associated with increased risk for death [OR 1.5; 95% CI (1.0-2.1), p = .048] to a lesser extent. The main neonatal morbidities associated with the risk of mortality after 48 postnatal hours of life were severe intraventricular hemorrhage (IVH) [OR 4.4; 95% CI (3.0-6.7), p < .001], respiratory distress syndrome (RDS) [OR 2.6; 95% CI (1.3-5.0), p = .006], and necrotizing enterocolitis (NEC) [OR 2.3; 95% CI (1.5-3.4), p < .001]. The major morbidities associated with deaths among non-SGA infants were severe IVH (32.1% of all deaths), NEC (19.1%), and sepsis (8.4%). In SGA infants, severe respiratory disease (RDS, severe bronchopulmonary dysplasia, pulmonary hemorrhage, or pulmonary hypertension) was the main cause of death (60.9% of all deaths). Medical or surgical PDA treatment was not found to be associated with increased risk of death [OR 0.4; 95% CI (0.2-0.5), p < .001] compared to infants who had survived for more than 2 days. Severe preeclampsia was found to be associated with 42% of all ELGA-SGA births. After the adjustments, ELGA infants from pregnancies complicated by preeclampsia of the mother exhibited a significantly lower risk of severe IVH [OR 0.3; 95% CI (0.2-0.5), p < .001] compared to the non-preeclamptic mothers' infants. The low incidence of severe IVH was evident regardless of fetal growth in this patient group. CONCLUSIONS: SGA infants with less than 28 gestational weeks, who had survived for at least 2 days, had excessively high mortality due to severe pulmonary disease. Intrauterine growth had no influence on the risk of death, other than pulmonary causes. The infants of preeclamptic mothers exhibited an increased risk of intrauterine growth retardation; however, despite this serious complication, these infants exhibited a significant decrease in the risk for severe IVH.

Risk of spontaneous preterm birth and fetal growth associates with fetal SLIT2.

Spontaneous preterm birth (SPTB) is the leading cause of neonatal death and morbidity worldwide. Both maternal and fetal genetic factors likely contribute to SPTB. We performed a genome-wide association study (GWAS) on a population of Finnish origin that included 247 infants with SPTB (gestational age [GA] < 36 weeks) and 419 term controls (GA 38-41 weeks). The strongest signal came within the gene encoding slit guidance ligand 2 (SLIT2; rs116461311, minor allele frequency 0.05, p = 1.6×10-6). Pathway analysis revealed the top-ranking pathway was axon guidance, which includes SLIT2. In 172 very preterm-born infants (GA <32 weeks), rs116461311 was clearly overrepresented (odds ratio 4.06, p = 1.55×10-7). SLIT2 variants were associated with SPTB in another European population that comprised 260 very preterm infants and 9,630 controls. To gain functional insight, we used immunohistochemistry to visualize SLIT2 and its receptor ROBO1 in placentas from spontaneous preterm and term births. Both SLIT2 and ROBO1 were located in villous and decidual trophoblasts of embryonic origin. Based on qRT-PCR, the mRNA levels of SLIT2 and ROBO1 were higher in the basal plate of SPTB placentas compared to those from term or elective preterm deliveries. In addition, in spontaneous term and preterm births, placental SLIT2 expression was correlated with variations in fetal growth. Knockdown of ROBO1 in trophoblast-derived HTR8/SVneo cells by siRNA indicated that it regulate expression of several pregnancy-specific beta-1-glycoprotein (PSG) genes and genes involved in inflammation. Our results show that the fetal SLIT2 variant and both SLIT2 and ROBO1 expression in placenta and trophoblast cells may be correlated with susceptibility to SPTB. SLIT2-ROBO1 signaling was linked with regulation of genes involved in inflammation, PSG genes, decidualization and fetal growth. We propose that this receptor-ligand couple is a component of the signaling network that promotes SPTB.

Morbidities associated with patent ductus arteriosus in preterm infants. Nationwide cohort study.

PURPOSE: To evaluate the predictive factors for the development of haemodynamically significant patent ductus arteriosus (PDA) in preterm infants and to study the morbidities associated with the treatment of PDA during the first hospitalization. MATERIALS AND METHODS: Data were collected from the Finnish national register of preterm infants (<32 gestational weeks) born in 2005-2013. In total, 3668 infants were included. Morbidities during the first hospitalization were analysed and compared between infants who received treatments for the closure of PDA (n = 1132) and infants who received no treatment for PDA (n = 2536). The results were adjusted for the duration of pregnancy, intrauterine growth pattern, antenatal steroids, delivery hospital and respiratory distress syndrome (RDS). RESULTS: RDS and mechanical ventilation were independently associated with an increased risk of PDA requiring treatment. Medical and surgical treatments were associated with the risk of severe bronchopulmonary dysplasia (BPD). Primary surgical ligation was associated with an increased risk of severe intraventricular haemorrhage (IVH) and necrotizing enterocolitis (NEC). Medical treatment itself and also followed by surgical ligation was associated with lower mortality. CONCLUSION: The severity of lung disease rather than prematurity per se was associated with the development of PDA requiring therapy. Both medical and surgical therapies for PDA were associated with severe BPD, and primary surgical ligation was associated with NEC and severe IVH.

Genome-wide association study of bronchopulmonary dysplasia: a potential role for variants near the CRP gene.

Bronchopulmonary dysplasia (BPD), the main consequence of prematurity, has a significant heritability, but little is known about predisposing genes. The aim of this study was to identify gene loci predisposing infants to BPD. The initial genome-wide association study (GWAS) included 174 Finnish preterm infants of gestational age 24-30 weeks. Thereafter, the most promising single-nucleotide polymorphisms (SNPs) associated with BPD were genotyped in both Finnish (n = 555) and non-Finnish (n = 388) replication cohorts. Finally, plasma CRP levels from the first week of life and the risk of BPD were assessed. SNP rs11265269, flanking the CRP gene, showed the strongest signal in GWAS (odds ratio [OR] 3.2, p = 3.4 × 10-6). This association was nominally replicated in Finnish and French African populations. A number of other SNPs in the CRP region, including rs3093059, had nominal associations with BPD. During the first week of life the elevated plasma levels of CRP predicted the risk of BPD (OR 3.4, p = 2.9 × 10-4) and the SNP rs3093059 associated nominally with plasma CRP levels. Finally, SNP rs11265269 was identified as a risk factor of BPD (OR 1.8, p = 5.3 × 10-5), independently of the robust antenatal risk factors. As such, in BPD, a potential role for variants near CRP gene is proposed.

School-age children enjoyed good respiratory health and fewer allergies despite having lung disease after preterm birth.

AIM: This study explored the under-researched area of whether preterm birth or bronchopulmonary dysplasia (BPD) affected hospitalisation rates, allergies or health-related quality of life (HRQoL). METHODS: We studied 88 schoolchildren born preterm at a mean gestational age of 28.8 weeks (range 24.1-31.9) and matched term-born controls at the mean age of 11 years (range 8-14). Hospitalisations after the first discharge were recorded, skin prick allergy tests were performed and HRQoL was assessed with a parental questionnaire. RESULTS: Preterm children were hospitalised more than controls (64% versus 39%, p = 0.001), mostly before two years of age. The adjusted odds ratios (OR) for two-year-old preterm-born children being hospitalised for wheezing was 8.2 (95% CI 2.0-34.1). BPD affected 56% of the preterm children, but did not influence hospitalisations, and the positive skin prick rate was similar between the preterm and term-born children (35% versus 48%, p = 0.126). Preterm BPD children had fewer positive skin prick tests than those without BPD. HRQoL was lower in preterm than term children (81.25 ± 10.84 versus 86.80 ± 9.60, p = 0.001). CONCLUSION: Most health problems experienced by preterm-born schoolchildren occurred before two years of age and were mainly wheezing disorders. BPD decreased atopy but had no influence on hospitalisation rates.

Intrafamily and Interfamilial Phenotype Variation and Immature Immunity in Patients With Netherton Syndrome and Finnish SPINK5 Founder Mutation.

IMPORTANCE: Netherton syndrome (NS) is a rare and severe genodermatosis caused by SPINK5 mutations leading to the loss of lymphoepithelial Kazal-type-related inhibitor (LEKTI). Netherton syndrome is characterized by neonatal scaling erythroderma, a bamboolike hair defect, a substantial skin barrier defect, and a profound atopic diathesis. Netherton syndrome has been proposed to be a primary immunodeficiency syndrome because of the high frequency of infections. The precise mechanisms underlying the disease are not fully understood. OBJECTIVE: To study the association of the SPINK5 mutation with the NS phenotype and the extent of immunologic deficiencies in NS. DESIGN, SETTING, AND PARTICIPANTS: Relevant tissue samples and follow-up data from 11 patients with NS from 7 families, including 3 multiplex families, were collected, constituting all known patients with NS in Finland. Another patient with NS from a neighboring country was included. Data were collected from August 10, 2011, to February 20, 2015. SPINK5 mutations were sequenced, and thorough clinical evaluation and histopathologic and immunohistochemical evaluations of skin samples were performed. The function of natural killer cells, lymphocyte phenotype, and serum immunoglobulin subclass levels were evaluated. Data analysis was conducted from October 19, 2011, to February 20, 2015. MAIN OUTCOMES AND MEASURES: The nature of SPINK5 mutations and their correlation with phenotypes in Finnish patients with NS, intrafamilial phenotype variations, and the type of immunologic defects in NS were evaluated. RESULTS: Among the 11 Finnish patients with NS (8 male [73%]; 3 female [27%]; mean [SD] age, 30.1 [9.1] years), a Finnish founder mutation c.652C>T (p.Arg218*) in SPINK5 was identified in 10 patients from 6 families who all originated from the same region. Eight patients were homozygotes for this mutation and 2 siblings were compound heterozygotes with a splice site mutation c.1220 + 1G>C (IVS13 + 1 G>C). Phenotypes were comparable, but some intrafamilial and interfamilial variations were noted. Compound heterozygous patients had a milder phenotype and showed residual LEKTI expression. A previously unreported c.1772delT (p.Leu591Glnfs124*) mutation was found in 1 patient with a phenotype similar to the patients homozygous for the founder mutation. The patient from the neighboring country had a distinct phenotype and different mutations. Immunologically, natural killer cells had an immature phenotype and impaired cytotoxicity and degranulation, levels of memory B cells were reduced, and serum IgG4 levels were elevated. Intravenous immunoglobulin treatment has been beneficial in 1 patient with NS. CONCLUSIONS AND RELEVANCE: This report discloses a prevalent SPINK5 founder mutation in Finland and illustrates NS phenotype variability. Our results also point to a possible role of immature immunity in the frequent infections seen in NS.

Intrauterine growth restriction predicts lower lung function at school age in children born very preterm.

OBJECTIVE: Children born preterm have lower lung function compared with term-born children. Intrauterine growth restriction (IUGR) may predispose individuals to chronic obstructive pulmonary disease. The purpose of this observational study was to investigate the role of IUGR as predictor of lung function at school age in children born very preterm. We further studied the difference in lung function between term-born and preterm-born children with distinct morbidities. DESIGN: Preterm-born children and age-matched and sex-matched term-born comparison groups (88 of each) were studied at the mean age of 11 years. Spirometry and diffusing capacity of the lung for carbon monoxide (DLCO) were recorded. All preterm-born subjects with IUGR (n=23), defined as birth weight less than -2 SD, were compared with preterm-born subjects without IUGR (n=65). RESULTS: In the preterm-born children exposed to IUGR, the forced expiratory volume in 1 s (FEV1) was 5.7 (95% CI -10.2 to -1.3) and DLCO 9.2 percentage points lower (95% CI -15.7 to -2.7) than in the preterm-born children with appropriate in utero growth (expressed as percentage of predicted values). The effect of IUGR in decreasing FEV1 and DLCO remained significant after adjustment for bronchopulmonary dysplasia (BPD). Further study indicated that after adjustment with IUGR and BPD, prematurity explained reduction in FEV1 but not in DLCO. CONCLUSIONS: In children born very preterm, IUGR is an independent risk factor for a lower lung function in school age. We propose that IUGR and BPD are the major early factors predisposing the children born very preterm to lower lung function.

Cerebral Palsy and Polymorphism of the Chemokine CCL18 in Very Preterm Children.

BACKGROUND: Prematurity and hereditary factors predispose to cerebral palsy (CP). Previously, low cord blood levels of the anti-inflammatory chemokine CCL18 have been found to be associated with risk of CP in preterm children. OBJECTIVES: To investigate the association between single nucleotide polymorphisms (SNPs) in CCL18 and susceptibility to CP, as well as the association between the SNPs and cord blood levels of CCL18. METHODS: The original population comprised very-low-gestational-age (VLGA; <32 weeks) children from northern and central Finland (25 cases, 195 controls). Five CCL18 SNPs were genotyped and examined for associations with CP and cord blood CCL18. The replication population comprised Caucasian VLGA children from southern Finland and Canada (23 cases, 248 controls). RESULTS: In the original population, SNP rs2735835 was associated with CP; the minor allele A was underrepresented in cases compared to controls (OR = 0.42, 95% CI: 0.21-0.83, p = 0.01). This association remained significant after adjustment for multiple testing and risk factors of CP, and after combining the original and replication populations (OR = 0.52, 95% CI: 0.33-0.83, p = 0.005). Intraventricular hemorrhage (IVH) additively predicted CP. The Rs2015086 genotype was modestly associated with CCL18 concentration. CONCLUSIONS: A common CCL18 polymorphism together with IVH had an additive influence on CP susceptibility. Developmentally regulated CCL18, confined to primates, may be involved in the complex sequence of events leading to brain injury and predisposition to CP phenotype.

Genes Encoding Vascular Endothelial Growth Factor A (VEGF-A) and VEGF Receptor 2 (VEGFR-2) and Risk for Bronchopulmonary Dysplasia.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is one of the main consequences of prematurity, with notably high heritability. Vascular endothelial growth factor A (VEGF-A) and its main receptor, vascular endothelial growth factor receptor 2 (VEGFR-2), have been implicated in the pathogenesis of BPD. OBJECTIVE: To study whether common polymorphisms of the genes encoding VEGF-A and VEGFR-2 are associated with BPD. METHODS: In this association study, six tagging single nucleotide polymorphism (tSNPs) for VEGFA and 25 tSNPs for VEGFR2 were genotyped in a prospectively collected, genetically homogeneous discovery population of 160 infants (44 infants with grade 2-3 BPD) born before 30 completed gestational weeks. The replication population of 328 infants included 120 cases of BPD. RESULTS: VEGFR2 SNP rs4576072 was associated with BPD grade 2-3 with a minor allele frequency in 23.9% of the cases compared to 9.1% in controls (p = 0.0005, odds ratio 3.15, 95% CI: 1.62-6.12) in the discovery population. This association was not observed in the more heterogeneous replication population. CONCLUSIONS: In line with the results of recent large-scale genetic studies, our findings indicate that common polymorphisms of the genes encoding VEGF-A and VEGFR-2 are not consistently associated with BPD. This finding does not rule out the involvement of VEGFA and VEGFR2 in BPD pathogenesis since, in addition to common variations within the gene region, other mechanisms also play important roles in the regulation of gene function.

New BPD predicts lung function at school age: Follow-up study and meta-analysis.

New treatment practices have improved survival of preterm infants and decreased airway pathology in bronchopulmonary dysplasia (BPD). Our aim was to investigate whether preterm birth, BPD, and the severity of BPD predict lung function in school children that are born in surfactant era. We studied pulmonary function of 88 school-aged children born very preterm (gestational age <32 weeks) and paired them with 88 age- and sex-matched controls born at term. Spirometry and diffusion capacity were recorded. We also performed a meta-analysis covering the era of antenatal corticosteroid and surfactant treatment. BPD was defined as oxygen dependence for ≥ 28 days and it was severity-graded by oxygen requirement at 36 weeks postmenstrual age (mild, none; moderate, FiO2 = 0.22-0.29; severe, FiO2 ≥ 0.30). Preterm children had lower forced expiratory volume in 1 sec (FEV1 ) 86.4 ± 11.8 versus 94.9 ± 10.1 (mean % predicted ± SD; P < 0.001), and lower diffusion capacity (DLCO) 87.6 ± 13.9 versus 93.7 ± 12.0 (P = 0.005) compared with term controls. BPD group differed in both FEV1 (P = 0.037) and DLCO (P = 0.018) from those without BPD. For meta-analysis, search identified 210 articles. Together with present results, six articles met the inclusion criteria. FEV1 of no BPD, all BPD, and moderate to severe BPD groups differed from that in term controls by -7.4, -10.5, and -17.8%, respectively. According to meta-analysis and follow-up study, the adverse effects of prematurity on pulmonary function are still detectable in school-age. BPD was associated with reductions in both diffusion capacity and spirometry. New interventions are required to document a further decrease in the life-long consequences of prematurity.

Polymorphisms of the gene encoding Kit ligand are associated with bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is a chronic inflammatory lung disease that affects infants born preterm. Family studies indicate that BPD has a significant genetic component. RATIONALE: We assessed the gene encoding Kit ligand (KITLG) as a candidate for genetic predisposition to moderate-to-severe BPD (controls were infants with no or mild BPD). STUDY DESIGN: Eight KITLG-tagging single nucleotide polymorphisms (SNPs) were analyzed in cohorts of very preterm infants originating from northern Finland (56 cases and 197 controls), southern Finland (n = 59 + 52), and Canada (n = 58 + 68). Additional replication populations included infants born in Finland (n = 41 + 241) and Hungary (n = 29 + 40). All infants were of European origin. Results were controlled for risk factors of BPD. Kit ligand concentration in umbilical cord blood, collected from very preterm infants (n = 120), was studied. RESULTS: Six SNPs of KITLG and a haplotype including all eight genotyped SNPs were associated with moderate-to-severe BPD in the northern Finnish population. When all the populations were combined, SNP rs11104948 was significantly associated with BPD. Kit ligand concentration in umbilical cord blood of infants born very preterm was an independent risk factor of BPD. CONCLUSIONS: We show that KITLG polymorphisms are associated with susceptibility to moderate-to-severe BPD. In addition, higher Kit ligand concentrations were observed in infants that subsequently developed BPD. These results support the possibility that KITLG gene is involved in predisposition to BPD. Pediatr Pulmonol. 2015; 50:260-270. © 2014 Wiley Periodicals, Inc.

[Netherton syndrome--a rare form of inherited ichtyosis]. / Nethertonin oireyhtymä--harvinainen periytyvän kalansuomutaudin muoto.

Netherton syndrome is a rare skin disease classified into ichtyoses. It has a recessive pattern of inheritance. It is associated with scaly erythrodermia, bamboo hair defect, immunological abnormalities of varying severity, IgE-mediated allergic reactions, infections and defective temperature regulation that often leads to retarded growth and development of a newborn. The phenotype of the disease varies from mild skin symptoms to lethal forms of the disease. We describe two Finnish families, whose children were diagnosed with this disease.

Toll-like receptor 4 Asp299Gly polymorphism in respiratory syncytial virus epidemics.

The respiratory syncytial virus (RSV) antigen serves as ligand for Toll-like receptor (TLR) 4 that is a transmembrane signaling receptor in macrophages and dendritic cells. According to current evidence single nucleotide polymorphism involving amino acid 299 influences the susceptibility to severe RSV infections. The Asp299Gly allele has been shown to influence the TLR4-mediated signaling causing conformational change in the extracellular domain that recognizes pathogen-associated molecular patterns. The aim was to study the association between the TLR4 Asp299Gly polymorphism and the susceptibility to severe RSV bronchiolitis in infants. Altogether 312 cases and 356 controls, selected on the basis place of residence, date of birth, gender, and gestation at birth, were studied. When adjusted for multiple dependent variables, no allele or genotype frequency difference was found between the cases and the controls. Post hoc analysis revealed that during the year 2000 epidemics, the Gly299Gly genotype associated with protection against severe RSV and during 2004 epidemics Gly299Gly genotype and 299Gly allele associated with severe RSV. To conclude, we could not confirm the association of the Gly299 allele with severe RSV. This is consistent with the evidence that the susceptibility to severe RSV infection is principally dependent on environmental and constitutional factors. We propose that the risk of severe RSV infection may additionally depend on the interaction between individual TLR4 genotype and the particular RSV group causing bronchiolitis.

Genes and environment in common neonatal lung disease.

Respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD) are common, serious lung diseases in preterm infants. Polymorphism of the genes involved in basic lung function and alveolar stability, lung differentiation and pulmonary host defense may influence the risk. Natural selection has refined the genes responsible for cardiopulmonary adaptation and resistance against pneumonia in term and near-term infants. Before the era of antibiotics, however, virtually all very preterm infants died of asphyxia, respiratory failure or infections. Today, the degree of prematurity plays a dominant role in susceptibility to serious lung disease. In addition, genetic polymorphism and constitution modulate the risk of RDS and BPD that have different, partly overlapping predisposition. According to twin studies, the genetic impact on the risk of RDS and BPD among preterm and very preterm infants is 35-65%. Individual disease genes generally have low penetrance. Large-scale genetic studies are required as part of neonatal and perinatal research in order to learn about the risk factors and to investigate pharmacogenetics. The aim in the future is to individualize therapies.

Randomized trial of a single repeat dose of prenatal betamethasone treatment in imminent preterm birth.

BACKGROUND: A single dose of prenatal betamethasone treatment decreases neonatal morbidity rates when administered within 7 days before preterm delivery. A single repeat dose or booster dose of betamethasone before delivery has been proposed to be effective, but its efficacy has not been subjected to a randomized, blinded trial. METHODS: Women with imminent delivery before 34.0 gestational weeks were eligible if they remained without delivery for >7 days after a single course of betamethasone. After stratification, a single repeat dose of betamethasone (12 mg) or placebo was administered. The primary outcome was survival without respiratory distress syndrome or severe intraventricular hemorrhage (grade 3 or 4). RESULTS: A total of 249 mothers had been enrolled by the time the study was discontinued. All of the 159 infants in the betamethasone group and 167 in the placebo group were born before 36 weeks of gestation. The intact survival rate was unaffected and was lower than anticipated, because the gestational age-adjusted incidence of respiratory distress syndrome was higher than the population incidence. The requirement for surfactant therapy in respiratory distress syndrome was increased in the betamethasone group. According to posthoc analysis of the data for 206 infants who were delivered within 1 to 24 hours, the betamethasone booster tended to increase the risk of respiratory distress syndrome and to decrease intact survival rates. CONCLUSIONS: According to this study, a single booster dose of betamethasone just before preterm birth may perturb respiratory adaptation. These results caution against uncontrolled use of a repeat dose of glucocorticoid in high-risk pregnancies.

G protein-coupled receptor for asthma susceptibility associates with respiratory distress syndrome.

BACKGROUND: Respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD) have some common features with asthma. AIM: To study whether G protein-coupled receptor for asthma susceptibility (GPRA) contributes to RDS or BPD. METHODS: A haplotype association study was performed in a case-control setting of 521 Finnish infants (including 176 preterm neonates with RDS and 37 with BPD). Immunoreactivity of GPRA isoforms A and B was determined in pulmonary samples of fetuses, term infants and preterm infants with RDS or BPD. GPRA mRNA expression was determined by quantitative real-time polymerase chain reaction (PCR) in samples from nasal respiratory epithelium of adults, term infants and preterm infants. RESULTS: In infants with RDS born at 32-35 weeks of gestation, GPRA haplotype H1 was significantly underrepresented in RDS, whereas haplotype H4/H5 was associated with an increased risk. As in asthma, GPRA B isoform was induced in bronchial smooth muscle cells in RDS and BPD. In nasal respiratory epithelium, relative GPRA mRNA expression was strong in adults, weak in preterm and slightly higher in term samples. CONCLUSIONS: The results suggest that near-term RDS and asthma share the same susceptibility and protective GPRA haplotypes. Altered GPRA expression may play a role in the pathogenesis of RDS and BPD in preterm infants.

Wheezing illness and re-hospitalization in the first two years of life after neonatal respiratory distress syndrome.

OBJECTIVES: To determine the impact of respiratory distress syndrome (RDS) on wheezing illnesses and re-hospitalizations in children as old as 2 years of age. STUDY DESIGN: We observed 2 geographically defined cohorts of children with RDS born after 26 weeks of gestation during 1990 to 1995 and 1996 to 1999 and gestationally paired control subjects. Recurrent wheezing illness and the re-hospitalizations caused by a respiratory condition were recorded. RESULTS: In the first year of life, 47 of 224 infants with RDS and 18 of 224 control subjects born in 1990 to 1995 had recurrent wheezing illness (P <.005) compared with 21 of 109 infants with RDS and 14 of 109 control subjects in the latter cohort (P=.27). A higher number of infants with RDS were readmitted to the hospital (25% versus 13%, P=.002) in the former period, and they spent more days in hospital during both periods. The frequencies of wheezing remained constant in the second year of life, but hospital admissions decreased. Siblings at home, male sex, and bronchopulmonary dysplasia were additional risk factors of wheezing illnesses. CONCLUSION: RDS increases the incidence of wheezing illnesses during the first 2 years of life. Changes in the management of RDS during the 1990s was associated with a decreased incidence of subsequent RDS-associated respiratory morbidity.

Respiratory distress syndrome in twin infants compared with singletons.

OBJECTIVE: The purpose of this study was to determine gestational age-specific incidence and risk factors of respiratory distress syndrome (RDS) in twins compared with singletons. STUDY DESIGN: An analysis of 850,406 singleton and 23,278 twin infants born alive in Finland between 1987 and 2000 was performed. A number of antenatal and perinatal/intranatal factors were evaluated. RESULTS: At less than 28 weeks of gestation, the incidence of RDS was higher in both first- and second-born twins compared with singletons. At more advanced gestation, first-born twins had a significantly lower incidence of RDS compared with the others. There was no difference in the concordance of RDS between same-sex and opposite-sex twin pairs. Vaginal delivery, female sex, being born first, and being the lighter of the twins protected from RDS. CONCLUSION: After taking into account gestation, twins are not at higher risk of RDS compared with singletons except at very early gestation. Environmental factors predominate over genetic ones in the predisposition to RDS in twins.