Pulmonary hypertension (PH) is associated with poor outcomes among preterm infants with bronchopulmonary dysplasia (BPD), but whether early signs of pulmonary vascular disease are associated with the ...subsequent development of BPD or PH at 36 weeks post-menstrual age (PMA) is unknown.
To prospectively evaluate the relationship of early echocardiogram signs of pulmonary vascular disease in preterm infants to the subsequent development of BPD and late PH (at 36 wk PMA).
Prospectively enrolled preterm infants with birthweights 500-1,250 g underwent echocardiogram evaluations at 7 days of age (early) and 36 weeks PMA (late). Clinical and echocardiographic data were analyzed to identify early risk factors for BPD and late PH.
A total of 277 preterm infants completed echocardiogram and BPD assessments at 36 weeks PMA. The median gestational age at birth and birthweight of the infants were 27 weeks and 909 g, respectively. Early PH was identified in 42% of infants, and 14% were diagnosed with late PH. Early PH was a risk factor for increased BPD severity (relative risk, 1.12; 95% confidence interval, 1.03-1.23) and late PH (relative risk, 2.85; 95% confidence interval, 1.28-6.33). Infants with late PH had greater duration of oxygen therapy and increased mortality in the first year of life (P < 0.05).
Early pulmonary vascular disease is associated with the development of BPD and with late PH in preterm infants. Echocardiograms at 7 days of age may be a useful tool to identify infants at high risk for BPD and PH.
Mechanisms contributing to chronic lung disease after preterm birth are incompletely understood.
To identify antenatal risk factors associated with increased risk for bronchopulmonary dysplasia (BPD) ...and respiratory disease during early childhood after preterm birth, we performed a prospective, longitudinal study of 587 preterm infants with gestational age less than 34 weeks and birth weights between 500 and 1,250 g.
Data collected included perinatal information and assessments during the neonatal intensive care unit admission and longitudinal follow-up by questionnaire until 2 years of age.
After adjusting for covariates, we found that maternal smoking prior to preterm birth increased the odds of having an infant with BPD by twofold (P = 0.02). Maternal smoking was associated with prolonged mechanical ventilation and respiratory support during the neonatal intensive care unit admission. Preexisting hypertension was associated with a twofold (P = 0.04) increase in odds for BPD. Lower gestational age and birth weight z-scores were associated with BPD. Preterm infants who were exposed to maternal smoking had higher rates of late respiratory disease during childhood. Twenty-two percent of infants diagnosed with BPD and 34% of preterm infants without BPD had no clinical signs of late respiratory disease during early childhood.
We conclude that maternal smoking and hypertension increase the odds for developing BPD after preterm birth, and that maternal smoking is strongly associated with increased odds for late respiratory morbidities during early childhood. These findings suggest that in addition to the BPD diagnosis at 36 weeks, other factors modulate late respiratory outcomes during childhood. We speculate that measures to reduce maternal smoking not only will lower the risk for preterm birth but also will improve late respiratory morbidities after preterm birth.
Childhood obesity is a growing problem worldwide. Recent research suggests that the gut microbiota may play an important and potentially causal role in the development of obesity and may be one ...mechanism that explains the transgenerational transmission of obesity risk. Here we examine the early-life gut microbiota at days 4, 10, 30, 120, 365, and 730 and the association with body mass index (BMI) z-scores at age 12 in a Norwegian prospective cohort (
= 165), and evaluate how these BMI-associated taxa relate to maternal overweight/obesity (Ow/Ob) and excessive gestational weight gain (GWG). We performed 16S rRNA gene sequencing on the gut microbiota samples. Taxonomic phylogeny at days 10 and 730 was significantly associated with childhood BMI, and the gut microbiota taxa at two years of age explained over 50% of the variation in childhood BMI in this cohort. The subset of the early-life taxa within the gut microbiota that best predicted later childhood BMI showed substantial overlap with the maternal taxa most strongly associated with maternal Ow/Ob and excessive GWG. Our results show an association between the infant gut microbiota and later BMI, and they offer preliminary evidence that the infant gut microbiota, particularly at 2 years of age, may have potential to help identify children at risk for obesity.
Understanding the role of the early-life gut microbiota in obesity is important because there may be opportunities for preventive strategies. We examined the relationships between infant gut microbiota at six times during the first two years of life and BMI at age 12 in a birth cohort of 165 children and their mothers. We found that the gut microbiota from early life to two years shows an increasingly strong association with childhood BMI. This study provides preliminary evidence that the gut microbiome at 2 years of age may offer useful information to help to identify youth who are at risk for obesity, which could facilitate more-targeted early prevention efforts.
Newborn screening (NBS) aims to achieve early identification and treatment of affected infants prior to onset of symptoms. The timely completion of each step (i.e., specimen collection, transport, ...testing, result reporting), is critical for early diagnosis. Goals developed by the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC) for NBS timeliness were adopted (time-critical results reported by five days of life, and non-time-critical results reported by day seven), and implemented into a multi-year quality improvement initiative (NewSTEPS 360) aimed to decrease the time to result reporting and intervention.
The NBS system from specimen collection through reporting of results was assessed (bloodspot specimen collection, specimen shipping, sample testing, and result reporting). Annual data from 25 participating NBS programs were analyzed; the medians (and interquartile range, IQR) of state-specific percent of specimens that met the goal are presented.
The percent of specimens collected before 48 hours of life increased from 95% (88-97%) in 2016 to 97% (IQR 92-98%) in 2018 for the 25 states, with 20 (80%) of programs collecting more than 90% of the specimens within 48 hours of birth. Approximately 41% (IQR 29-57%) of specimens were transported within one day of collection. Time-critical result reporting in the first five days of life improved from 49% (IQR 26-74%) in 2016 to 64% (42%-71%) in 2018, and for non-time critical results from 64% (IQR 58%-78%) in 2016 to 81% (IQR 68-91%) in 2018. Laboratories open seven days a week in 2018 reported 95% of time-critical results within five days, compared to those open six days (62%), and five days (45%).
NBS programs that participated in NewSTEPs 360 made great strides in improving timeliness; however, ongoing quality improvement efforts are needed in order to ensure all infants receive a timely diagnosis.
Preterm birth exposes the developing lung to an environment with direct exposure to bacteria, often facilitated by endotracheal intubation. Despite evidence linking bacterial infections to the ...pathogenesis of bronchopulmonary dysplasia (BPD), systematic studies of airway microbiota are limited. The objective was to identify specific patterns of the early respiratory tract microbiome from tracheal aspirates of mechanically ventilated preterm infants that are associated with the development and severity of BPD. Infants with gestational age ≤34 weeks, and birth weight 500-1250g were prospectively enrolled. Mechanically ventilated infants had tracheal aspirate samples collected at enrollment, 7, 14, and 21 days of age. BPD was determined by modified NIH criteria with oxygen reduction tests; infants without BPD were excluded due to low numbers. Aspirates were processed for bacterial identification by 16S rRNA sequencing, and bacterial load by qPCR. Cross-sectional analysis was performed using 7 day samples and longitudinal analysis was performed from subjects with at least 2 aspirates. Microbiome analysis was performed on tracheal aspirates from 152 infants (51, 49, and 52 with mild, moderate, and severe BPD, respectively). Seventy-nine of the infants were included in the cross-sectional analysis and 94 in the longitudinal. Shannon Diversity, bacterial load, and relative abundance of individual taxa were not strongly associated with BPD status. Longitudinal analysis revealed that preterm infants who eventually developed severe BPD exhibited greater bacterial community turnover with age, acquired less Staphylococcus in the first days after birth, and had higher initial relative abundance of Ureaplasma. In conclusion, longitudinal changes in the airway microbial communities of mechanically ventilated preterm infants may be associated with BPD severity, whereas cross-sectional analysis of airway ecology at 7 days of age did not reveal an association with BPD severity. Further evaluation is necessary to determine whether the observed longitudinal changes are causal or in response to clinical management or other factors that lead to BPD.
Recent evidence supports that the maternal gut microbiota impacts the initial infant gut microbiota. Since the gut microbiota may play a causal role in the development of obesity, it is important to ...understand how pre-pregnancy weight and gestational weight gain (GWG) impact the gut microbiota of mothers at the time of delivery and their infants in early life. In this study, we performed 16S rRNA gene sequencing on gut microbiota samples from 169 women 4 days after delivery and from the 844 samples of their infants at six timepoints during the first 2 years of life. We categorized the women (1) according to pre-pregnancy body mass index into overweight/obese (OW/OB, BMI ≥ 25) or non-overweight/obese (BMI < 25) and (2) into excessive and non-excessive GWG in the subset of mothers of full-term singleton infants (N = 116). We compared alpha diversity and taxonomic composition of the maternal and infant samples by exposure groups. We also compared taxonomic similarity between maternal and infant gut microbiota.
Maternal OW/OB was associated with lower maternal alpha diversity. Maternal pre-pregnancy OW/OB and excessive GWG were associated with taxonomic differences in the maternal gut microbiota, including taxa from the highly heritable family Christensenellaceae, the genera Lachnospira, Parabacteroides, Bifidobacterium, and Blautia. These maternal characteristics were not associated with overall differences in the infant gut microbiota over the first 2 years of life. However, the presence of specific OTUs in maternal gut microbiota at the time of delivery did significantly increase the odds of presence in the infant gut at age 4-10 days for many taxa, and these included some lean-associated taxa.
Our results show differences in maternal gut microbiota composition at the time of delivery by pre-pregnancy weight and GWG, but these changes were only associated with limited compositional differences in the early life gut microbiota of their infants. Further work is needed to determine the degree to which these maternal microbiota differences at time of birth with OW/OB and GWG may affect the health of the infant over time and by what mechanism.
The identification of small molecules that target specific CFTR variants has ushered in a new era of treatment for cystic fibrosis (CF), yet optimal, individualized treatment of CF will require ...identification and targeting of disease modifiers. Here we use genome-wide association analysis to identify genetic modifiers of CF lung disease, the primary cause of mortality. Meta-analysis of 6,365 CF patients identifies five loci that display significant association with variation in lung disease. Regions on chr3q29 (MUC4/MUC20; P=3.3 × 10(-11)), chr5p15.3 (SLC9A3; P=6.8 × 10(-12)), chr6p21.3 (HLA Class II; P=1.2 × 10(-8)) and chrXq22-q23 (AGTR2/SLC6A14; P=1.8 × 10(-9)) contain genes of high biological relevance to CF pathophysiology. The fifth locus, on chr11p12-p13 (EHF/APIP; P=1.9 × 10(-10)), was previously shown to be associated with lung disease. These results provide new insights into potential targets for modulating lung disease severity in CF.
Bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, is associated with impaired vascular and alveolar growth. Antenatal factors contribute to the risk for developing BPD by ...unclear mechanisms. Endothelial progenitor cells, such as angiogenic circulating progenitor cells (CPCs) and late-outgrowth endothelial colony-forming cells (ECFCs), may contribute to angiogenesis in the developing lung. We hypothesise that cord blood angiogenic CPCs and ECFCs are decreased in preterm infants with moderate and severe BPD. We quantified ECFCs and the CPC/nonangiogenic-CPC ratio (CPC/non-CPC) in cord blood samples from 62 preterm infants and assessed their relationships to maternal and perinatal risk factors as well as BPD severity. The CPC/non-CPC ratio and ECFC number were compared between preterm infants with mild or no BPD and those with moderate or severe BPD. ECFC number (p<0.001) and CPC/non-CPC ratio (p<0.05) were significantly decreased in cord blood samples of preterm infants who subsequently developed moderate or severe BPD. Gestational age and birth weight were not associated with either angiogenic marker. Circulating vascular progenitor cells are decreased in the cord blood of preterm infants who develop moderate and severe BPD. These findings suggest that prenatal factors contribute to late respiratory outcomes in preterm infants.
Objective To determine the clinical course and outcomes of infants with chronic lung disease (CLD) and pulmonary hypertension (PH) who received prolonged sildenafil therapy. Study design We conducted ...a retrospective review of 25 patients <2 years of age with CLD in whom sildenafil was initiated for the treatment of PH while they were hospitalized from January 2004 to October 2007. Hemodynamic improvement was defined by a 20% decrease in the ratio of pulmonary to systemic systolic arterial pressure or improvement in the degree of ventricular septal flattening with serial echocardiograms. Results Chronic sildenafil therapy (dose range, 1.5-8.0 mg/kg/d) was initiated at a median of 171 days of age (range, 14-673 days of age) for a median duration of 241 days (range, 28-950 days). Twenty-two patients (88%) achieved hemodynamic improvement after a median treatment duration of 40 days (range, 6-600 days). Eleven of the 13 patients with interval estimates of systolic pulmonary artery pressure with echocardiogram showed clinically significant reductions in PH. Five patients (20%) died during the follow-up period. Adverse events leading to cessation or interruption of therapy occurred in 2 patients, 1 for recurrent erections, and the other had the medication held briefly because of intestinal pneumatosis. Conclusion These data suggest that chronic sildenafil therapy is well-tolerated, safe, and effective for infants with PH and CLD.
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