Preterm Subjects Research Articles

Dose rationale and pharmacokinetics of dexmedetomidine in mechanically ventilated new-borns: impact of design optimisation

PurposeThere is a need for alternative analgosedatives such as dexmedetomidine in neonates. Given the ethical and practical difficulties, protocol design for clinical trials in neonates should be carefully considered before implementation. Our objective was to identify a protocol design suitable for subsequent evaluation of the dosing requirements for dexmedetomidine in mechanically ventilated neonates.MethodsA published paediatric pharmacokinetic model was used to derive the dosing regimen for dexmedetomidine in a first-in-neonate study. Optimality criteria were applied to optimise the blood sampling schedule. The impact of sampling schedule optimisation on model parameter estimation was assessed by simulation and re-estimation procedures for different simulation scenarios. The optimised schedule was then implemented in a neonatal pilot study.ResultsParameter estimates were more precise and similarly accurate in the optimised scenarios, as compared to empirical sampling (normalised root mean square error: 1673.1% vs. 13,229.4% and relative error: 46.4% vs. 9.1%). Most importantly, protocol deviations from the optimal design still allowed reasonable parameter estimation. Data analysis from the pilot group (n = 6) confirmed the adequacy of the optimised trial protocol. Dexmedetomidine pharmacokinetics in term neonates was scaled using allometry and maturation, but results showed a 20% higher clearance in this population compared to initial estimates obtained by extrapolation from a slightly older paediatric population. Clearance for a typical neonate, with a post-menstrual age (PMA) of 40 weeks and weight 3.4 kg, was 2.92 L/h. Extension of the study with 11 additional subjects showed a further increased clearance in pre-term subjects with lower PMA.ConclusionsThe use of optimal design in conjunction with simulation scenarios improved the accuracy and precision of the estimates of the parameters of interest, taking into account protocol deviations, which are often unavoidable in this event-prone population.

A New Efficient Algorithm for Prediction of Preterm Labor.

Electrohysterogram (EHG) signal represents electrical activity of uterine collected from abdominal surface of pregnant women. It has been proven that EHG analysis could be a suitable way to predict preterm labor and consequently to prevent it. The aim of this paper is to present an efficient low computational complexity algorithm to detect preterm labor using EHG signals. To this purpose, Empirical Mode Decomposition (EMD) has been applied for features extraction. Root mean square (RMS) of first two intrinsic mode function (IMF) of decomposed EHG signals were used as features and classification was performed by Support Vector Machine (SVM). In this experiment, the database consisted of 262 term delivery subjects (duration of pregnancy ≥37 weeks) and 38 preterm delivery subjects (duration of pregnancy <; 37 weeks). Each record contained 3 channels, therefore, various configurations of features and channels were applied. Among those configurations, classification based on RMS of the second IMF from channel one achieved best results with accuracy= 99.56%, sensitivity= 98.95% and specificity= 99.30%.

Association between elevated placental polycyclic aromatic hydrocarbons (PAHs) and PAH-DNA adducts from Superfund sites in Harris County, and increased risk of preterm birth (PTB)

The preterm birth (PTB) rate in Harris County, Texas, exceeds the U.S. rate (11.4% vs.9.6%), and there are 15 active Superfund sites in Harris County. Polycyclic aromatic hydrocarbons (PAHs) are contaminants of concern (COC) at Superfund sites across the nation. In this investigation, we tested the hypothesis that higher levels of exposure to PAHs and PAH-DNA adducts in placenta of women living near Superfund sites contribute to the increased rate of PTBs. Levels of benzo[a]pyene (BP), benzo[b]fluorene (BbF) and dibenz[a,h]anthracene (DBA), were higher in placentae from preterm deliveries compared with term deliveries in women living near Superfund sites, whereas this was not the case for women living in non-Superfund site areas. Among the PAHs, DBA levels were significantly higher than BP or BbF, and DBA levels were inversely correlated with gestational age at delivery and birth weight. Bulky PAH-DNA adducts are more prevalent in placental tissue from individuals residing near Superfund sites. Expression of Ah receptor (AHR) and NF-E2-related factor 2 (NRF2) was decreased in preterm deliveries in subjects residing near Superfund sites. Unbiased metabolomics revealed alterations in pathways involved in pentose phosphate, inositol phosphate and starch and sucrose metabolism in preterm subjects in Superfund site areas. In summary, this is the first report showing an association between PAH levels, DNA adducts, and modulation of endogenous metabolic pathways with PTBs in subjects residing near Superfund sites, and further studies could lead to novel strategies in the understanding of the mechanisms by which PAHs contribute to PTBs in women.

OR17-6 Parenteral Cephalosporins and Glucose During the Neonatal Period Are Associated with Pediatric Type 1 Diabetes Development

Background: The incidence of both the survival of premature infants and type 1 diabetes (T1D) is rising worldwide. The pathophysiology of T1D depends on the differentiation of cellular and humoral immune systems recognition of the self, which occurs during the neonatal period and is influenced by environmental exposures. Aim: To assess the association between nutritional, antibiotic and parenteral exposures during the neonatal period and the development of pediatric T1D. Methods: a multicenter, paired case-control study. Preterm subjects who were born between 1990-2013, and developed T1D before the age of 18 years (T1D group), were paired with subjects who didn't develop TID (Control group) at a ratio of 1:3 by: gender, gestational age (GA), month of birth and birth medical center . This preterm population is a model of a neonatal population with strictly meticulous follow up data available in all medical centers in Israel. Data retrieved from charts included maternal history, delivery method, ethnic origin, weight for GA, NICU length of hospitalization, medications, parenteral fluid types, feeding modes and their timing. Univariate and multivariate analysis via Generalized Estimating Equations (GEE) using a binary logistic regression model were performed to evaluate the association between T1D and the assessed exposures. Results: T1D group included 52 subjects, 26 males, median GA 35 (26-36), mean BW 2307.6±534.5. Control group included 133 subjects, 69 males. median GA 35 (27-36), mean BW 2094.5±484.1. In univariate analysis, the odds ratio (OR) for T1D increased with each extra 100 grams in BW (OR 1.13, 95%CI 1.057-1.206, p < 0.001), later day of parenteral glucose initiation (OR 1.61, 95%CI 1.05-2.48, p 0.03), and parenteral cephalosporines initiated beyond the first week of life (OR 3.25, 95%CI 1.504-7.04, p 0.003). Treatment with narrow spectrum beta-lactam antibiotics during the first week of life was associated with lower risk for T1D development (OR 0.23, 95%CI 0.12-0.47, p < 0.001). Multivariate analysis revealed significant association between both treatment with cephalosporins beyond the first week of life and later day of parenteral glucose initiation and the development of pediatric T1D (OR 6.49, 95%CI 1.54-27.44, p 0.011 and OR 1.61, 95%CI 1.05-2.48, p 0.002, respectively). No association with feeding modality (oral/nasogastric), timing and type of feeding (breast or bottle) was found. Conclusions: This is the first report indicating a significant association between parenteral exposure and timing of variable antibiotic treatments and glucose solution administration during the neonatal period with development of T1D. This report indicates the need for a larger study to conclude clinical implications of management and exposure to these substances during the neonatal period and its relevance to the neonatal microbiome.

Early Pulmonary Vascular Disease in Young Adults Born Preterm.

Rationale: Premature birth affects 10% of live births in the United States and is associated with alveolar simplification and altered pulmonary microvascular development. However, little is known about the long-term impact prematurity has on the pulmonary vasculature.Objectives: Determine the long-term effects of prematurity on right ventricular and pulmonary vascular hemodynamics.Methods: Preterm subjects (n = 11) were recruited from the Newborn Lung Project, a prospectively followed cohort at the University of Wisconsin-Madison, born preterm with very low birth weight (≤1,500 g; average gestational age, 28 wk) between 1988 and 1991. Control subjects (n = 10) from the same birth years were recruited from the general population. All subjects had no known adult cardiopulmonary disease. Right heart catheterization was performed to assess right ventricular and pulmonary vascular hemodynamics at rest and during hypoxic and exercise stress.Measurements and Main Results: Preterm subjects had higher mean pulmonary arterial pressures (mPAPs), with 27% (3 of 11) meeting criteria for borderline pulmonary hypertension (mPAP, 19-24 mm Hg) and 18% (2 of 11) meeting criteria for overt pulmonary hypertension (mPAP ≥ 25 mm Hg). Pulmonary vascular resistance and elastance were higher at rest and during exercise, suggesting a stiffer vascular bed. Preterm subjects were significantly less able to augment cardiac index or right ventricular stroke work during exercise. Among neonatal characteristics, total ventilatory support days was the strongest predictor of adult pulmonary pressure.Conclusions: Young adults born preterm demonstrate early pulmonary vascular disease, characterized by elevated pulmonary pressures, a stiffer pulmonary vascular bed, and right ventricular dysfunction, consistent with an increased risk of developing pulmonary hypertension.

Abstract 17209: Impaired Ventricular-Vascular Coupling in Young Adults Born Preterm

Background: Preterm birth affects 10% of live births in the United States, often requiring mechanical ventilation and oxygen supplementation. Although a known risk factor for neonatal and childhood pulmonary vascular disease, little is known regarding the long-term impact on the right ventricle (RV). Here, we utilize novel techniques to investigate RV afterload, contractility, and ventricular-vascular coupling (VVC) in young adults born preterm. Methods: Adults born premature (n=7; 4; current age 26.7±0.4 years; gestational age 28.6±1.1 weeks) born with very low birth weight (≤1500g) were recruited from the Newborn Lung Project. Control subjects (n=7; 2) from the same birth years were recruited from the general population. All subjects had no known cardiopulmonary disease. Right heart catheterization (RHC) and magnetic resonance imaging (MRI) were performed to assess right ventricular hemodynamics. Asynchronously acquired pressure and volume data (from RHC and MRI, respectively) were used to compute effective arterial elastance (Ea), end-systolic elastance (Ees), and VVC as: [ESP/SV], [(P max -ESP)/SV], and [Ees/Ea], respectively, where ESP is the end-systolic pressure, SV is the stroke volume, and P max is the maximum isovolumetric pressure estimated from a novel single-beat approach. Results were analyzed via two-sample t-test; p&lt;0.05 was considered significant. Results: Preterm subjects had significantly increased Ea, a measure of RV afterload (Figure 1A). No difference Ees, a measure of RV contractility, was evident (Figure 1B), resulting in significantly impaired VVC in preterm subjects (Figure 1C). Conclusion: Otherwise healthy young adults born preterm have high resistance-low compliance pulmonary vascular beds with no RV adaptation, resulting in impaired right ventricular-pulmonary vascular coupling. These findings add to the growing literature that preterm birth has profound lifelong consequences that warrant further study.

Preterm Birth: Long Term Cardiovascular and Renal Consequences.

Background: Cardiovascular and chronic kidney diseases are a part of non-communicable chronic diseases, the leading causes of premature death worldwide. They are recognized as having early origins through altered developmental programming, due to adverse environmental conditions during development. Preterm birth is such an adverse factor. Rates of preterm birth increased in the last decades, however, with the improvement in perinatal and neonatal care, a growing number of preterm born subjects has now entered adulthood. Clinical and experimental evidence suggests that preterm birth is associated with impaired or arrested structural or functional development of key or-gans/systems making preterm infants vulnerable to cardiovascular and chronic renal diseases at adult-hood. This review analyzes the evidence of such cardiovascular and renal changes, the role of perina-tal and neonatal factors such as antenatal steroids and potential pathogenic mechanisms, including de-velopmental programming and epigenetic alterations.Conclusion: Preterm born subjects are exposed to a significantly increased risk for altered cardio-vascular and renal functions at young adulthood. Adequate, specific follow-up measures remain to be determined. While antenatal steroids have considerably improved preterm birth outcomes, repeated therapy should be considered with caution, as antenatal steroids induce long-term cardio-vascular and metabolic alterations in animals’ models and their involvement in the accelerated cellular senescence observed in human studies cannot be excluded.

Exome sequencing identifies gene variants and networks associated with extreme respiratory outcomes following preterm birth

BackgroundPrevious studies have identified genetic variants associated with bronchopulmonary dysplasia (BPD) in extremely preterm infants. However, findings with genome-wide significance have been rare, and not replicated. We hypothesized that whole exome sequencing (WES) of premature subjects with extremely divergent phenotypic outcomes could facilitate the identification of genetic variants or gene networks contributing disease risk.ResultsThe Prematurity and Respiratory Outcomes Program (PROP) recruited a cohort of > 765 extremely preterm infants for the identification of markers of respiratory morbidity. We completed WES on 146 PROP subjects (85 affected, 61 unaffected) representing extreme phenotypes of early respiratory morbidity. We tested for association between disease status and individual common variants, screened for rare variants exclusive to either affected or unaffected subjects, and tested the combined association of variants across gene loci. Pathway analysis was performed and disease-related expression patterns were assessed. Marginal association with BPD was observed for numerous common and rare variants. We identified 345 genes with variants unique to BPD-affected preterm subjects, and 292 genes with variants unique to our unaffected preterm subjects. Of these unique variants, 28 (19 in the affected cohort and 9 in unaffected cohort) replicate a prior WES study of BPD-associated variants. Pathway analysis of sets of variants, informed by disease-related gene expression, implicated protein kinase A, MAPK and Neuregulin/epidermal growth factor receptor signaling.ConclusionsWe identified novel genes and associated pathways that may play an important role in susceptibility/resilience for the development of lung disease in preterm infants.

Vaccine safety surveillance in pregnancy in low- and middle-income countries using GAIA case definitions: A feasibility assessment

BackgroundGlobal efforts to adequately monitor safety of new vaccines for pregnant women in low and middle-income countries (LMICs) are needed. The Global Alignment of Immunization Safety Assessment in pregnancy (GAIA) project recently published case definitions based on levels of diagnostic certainty for pregnancy- and neonatal outcomes and maternal vaccination. As a preliminary step to assessing the applicability of these definitions in LMICs, WHO selected sites and conducted a feasibility assessment to evaluate their ability to identify and classify selected outcomes (preterm birth, neonatal death, neonatal invasive bloodstream infection (NI-BSI), stillbirth) and maternal vaccination. MethodsCandidate sites were initially screened using a questionnaire. For each outcome, eligible sites were asked to retrospectively identify and collect information for three individuals born in 2016. Subsequently, outcomes were classified by level of diagnostic certainty. ResultsFifty-one sites (15 countries) were screened; 32 of them (9 countries) participated in the assessment and identified 315 subjects with the outcomes of interest. Twenty-four sites (8 countries) identified at least one subject per outcome and agreed to continue participating. The majority (80%) of preterm births, neonatal deaths, and NI-BSI subjects, but only 50% of stillbirths, could be assessed for diagnostic certainty. The main reasons for not classifying stillbirths were insufficient information to distinguish between antepartum and intrapartum stillbirth (29%); or that not all data for one subject fit into a single level of diagnostic certainty (35%). Forty-nine percent of mothers were considered vaccinated, 6% not-vaccinated, and vaccination status could not be assessed in 44% of them. DiscussionGAIA case definitions for four neonatal outcomes and maternal vaccination were successfully piloted in 24 sentinel sites across four WHO regions. Our assessment found that modification of the stillbirth definition could help avoid potential misclassification. Vaccine safety monitoring in LMICs will benefit from systematic recording of all vaccinations during pregnancy.

Population-based longitudinal study showed that children born small for gestational age faced a higher risk of hospitalisation during early childhood.

We examined the effects of being born small for gestational age (SGA) on the risk of being hospitalised for common diseases during childhood. This Japanese nationwide, population-based longitudinal survey followed babies born before 42weeks of gestation from 10 to 17 January and from 10 to 17 July 2001, using data from the Government's Longitudinal Survey of Babies in the 21st Century. Our study followed 41268 children until 5.5years of age: 39107 full term (8.7% SGA) and 2161 preterm (15.5% SGA). We evaluated the relationship between SGA status and hospitalisation using their history of hospitalisation for common diseases and comparing full-term or preterm births. Logistic regression analysis, adjusted for potential confounders, estimated the odds ratios (ORs) and 95% confidence intervals (CIs). The full-term and preterm children who were born SGA were more likely to be hospitalised during infancy and early childhood than those born non SGA. The ORs for hospitalisation from six months to 18months of age were 1.23 (95% CI: 1.10-1.37) for full-term and 1.67 (95% CI: 1.23-2.25) for preterm subjects. Higher risks of hospitalisation due to bronchitis, pneumonia, bronchial asthma and diarrhoea were also observed. Being born SGA was associated with all-cause and cause-specific hospitalisation in early childhood, particularly for term infants.

Altered functional network connectivity in preterm infants: antecedents of cognitive and motor impairments?

Very preterm infants (≤ 31weeks gestational age) are at high risk for brain injury and delayed development. Applying functional connectivity and graph theory methods to resting state MRI data (fcMRI), we tested the hypothesis that preterm infants would demonstrate alterations in connectivity measures both globally and in specific networks related to motor, language and cognitive function, even when there is no anatomical imaging evidence of injury. Fifty-one healthy full-term controls and 24 very preterm infants without significant neonatal brain injury, were evaluated at term-equivalent age with fcMRI. Preterm subjects showed lower functional connectivity from regions associated with motor, cognitive, language and executive function, than term controls. Examining brain networks using graph theory measures of functional connectivity, very preterm infants also exhibited lower rich-club coefficient and assortativity but higher small-worldness and no significant difference in modularity when compared to term infants. The findings provide evidence that functional connectivity exhibits deficits soon after birth in very preterm infants in key brain networks responsible for motor, language and executive functions, even in the absence of anatomical lesions. These functional network measures could serve as prognostic biomarkers for later developmental disabilities and guide decisions about early interventions.

Fecal elastase-1 in healthy children up to 2 years of age: a cross-sectional study.

BackgroundFecal elastase-1 (E-1) levels in infants and young children may be expected to differ from those in adults and older children because of the immaturity of the gastrointestinal tract and the specificity of their diet. Despite the availability of data describing E-1 levels in the stools of preterm infants, older children, adults and subjects with malabsorption, there is still a lack of data regarding E-1 in healthy infants and toddlers.The aim of this cross-sectional study was to evaluate fecal E-1 concentrations in infants and children from 1 up to 24 months of age.Material and methodsE-1 was measured in 160 healthy subjects aged 1-24 months (8 groups of 20: aged 1-3, 4-6 months, etc.) using an enzyme-linked immunosorbent assay (ELISA).ResultsFecal E-1 concentrations ranged from 200 to 1695 μg/g of feces. No child had a fecal E-1 level below 200 μg/g of feces. Fecal E-1 concentrations did not significantly differ between age groups. However, fecal E-1 levels in the first 3 months were lower than in the second year of life (1-3 months vs 13-24 months, p=0.0230). A statistically significant correlation between the E-1 concentration and age was found (p=0.0007, r=0.2639; however, it does not affect the cut-off level of the reference values). The trend was rather exponential. Fecal E-1 values reached a plateau around the age of 6-10 months.ConclusionsOur study has shown that the fecal E-1 test can be reliably applied in infants and toddlers to confirm normal exocrine pancreatic function. However, within the first months of life fecal E-1 concentrations may be lower than later in life.

Apnea in Preterm and Term Infants After Deep Sedation and General Anesthesia.

Determine the incidence of apnea in preterm and term infants after deep sedation (DS) compared with general anesthesia (GA). A retrospective chart review was performed on infants who underwent elective DS or GA from January 2008 to December 2013, were <60 weeks postmenstrual age if preterm or <50 weeks postmenstrual age if term, and were monitored for apnea as inpatients after DS or GA. Gestational age, postmenstrual age, chronologic age, anesthetic and sedative medications, procedure indication, and postsedation events were collected. There were 61 DS encounters (24 preterm and 37 term) and 175 GA encounters (120 preterm and 55 term) that met inclusion criteria. No recorded apneic events in either preterm or term infants were recorded after DS. After GA, 1.7% of infants had apneic events (2.5% preterm and 0 term; P = .57 versus DS). All events occurred within 2 hours of monitoring in recovery. None of the infants had apnea after DS. Rates from the literature would suggest that 2 to 6 of the preterm DS subjects should have experienced postsedation apnea. Sampled GA subjects had a rate of 2.5% in preterm infants exhibiting apnea after GA. Although the post-DS apnea rate is lower than what has been previously published, the small sample size and limitations of a retrospective design prevent us from directing a change in postsedation monitoring recommendations. However, we do support the need for prospective studies with strict monitoring criteria to reveal the true risk of post-DS apnea.

Carotid body size measured by computed tomographic angiography in individuals born prematurely

PurposeWe tested the hypothesis that the carotid bodies would be smaller in individuals born prematurely or exposed to perinatal oxygen therapy when compared individuals born full term that did not receive oxygen therapy. MethodsA retrospective chart review was conducted on patients who underwent head/neck computed tomography angiography (CTA) at the Mayo Clinic between 10 and 40 years of age (n = 2503). Patients were identified as premature ( < 38 weeks) or receiving perinatal oxygen therapy by physician completion or billing codes (n = 16 premature and n = 7 receiving oxygen). Widest axial measurements of the carotid body images captured during the CTA were performed. ResultsCarotid body visualization was possible in 43% of patients and 52% of age, sex, and body mass index (BMI)-matched controls but only 17% of juvenile preterm subjects (p = .07). Of the carotid bodies that could be visualized, widest axial measurements of the carotid bodies in individuals born prematurely (n = 7, 34 ± 4 weeks gestation, birth weight: 2460 ± 454 g; average size: 2.5 ± 0.2 cm) or individuals exposed to perinatal oxygen therapy (n = 3, 38 ± 2 weeks gestation, Average size: 2.2 ± 0.1 cm) were not different when compared to controls (2.3 ± 0.2 cm and 2.3 ± 0.2 cm, respectively, p > 0.05). ConclusionsCarotid body size, as measured using CTA, is not smaller in adults born prematurely or exposed to perinatal oxygen therapy when compared to sex, age, and BMI-matched controls. However, carotid body visualization was lower in juvenile premature patients. The decreased ability to visualize the carotid bodies in these individuals may be a result of their prematurity.

Adults born preterm exhibit bi‐ventricular hypercontractility and inefficiency

IntroductionIn the US, prematurity accounts for approximately 10% of all live births. Infants born preterm are at an increased risk of cardiopulmonary disease. Until recently, little was known about the long‐term sequelae in the myocardium in adult survivors of prematurity. One study demonstrated that adults born preterm had larger left (LV) and right ventricular (RV) masses, and lower RV ejection fraction compared to term born controls. To date, there is a paucity of information on the potential mechanism of altered ventricular mechanics in adult survivors of prematurity. Therefore, we hypothesized that preterm subjects would display reduced RV and LV strain.MethodsPreterm subjects were recruited from a prospectively followed cohort at UW‐Madison. Gestational ages for the preterm subjects were 28.2 ± 0.84 weeks and they weighed &lt; 1500 grams. Term‐born subjects were recruited from the general public. Cardiac magnetic resonance imaging (MRI) was used to determine myocardial strain and stroke volume (SV) in adults born preterm (n = 10, age = 26.9 ± 0.3 years) and age‐matched term born controls (n = 12, age = 25.8 ± 0.2 years). Three slices from the RV and LV (apex, mid and base) short‐axis cine MR images were used to analyze RV and LV circumferential and LV radial dimensions (mean peak strain, systolic and diastolic strain rate). SV was obtained from the main pulmonary artery (MPA) and aorta (Ao) 2‐D phase contrast images. SV was normalized to body surface area (SVI) and was divided by peak RV and LV circumferential strain to obtain RV and LV efficiency. All MRI analysis was performed using Segment (http://segment.heiberg.se). A Mann‐Whitney test was performed to test differences between groups (p &lt; 0.05).ResultsPreterm subjects demonstrated increased peak RV circumferential (−11.36 % ± 1.90 vs. −8.83 % ± 1.95; p = 0.003) and LV circumferential (−20.15 % ± 2.29 vs. −17.96 % ± 1.96; p = 0.025) strain compared to controls, respectively. Additionally, RV circumferential systolic strain rate, LV circumferential systolic and diastolic strain rate, and LV radial diastolic strain rate were greater (p &lt; 0.05) in preterm adults as compared to controls. SVI as measured from the MPA and Ao flow was not different between groups. Preterm subjects exhibited reduced (p &lt; 0.05) RV and LV (p = 0.06) efficiency as compared to controls.DiscussionWe used MRI to measure RV and LV strain, which is a measure of ventricular displacement during the cardiac cycle. Contrary to our hypothesis, these results demonstrate that adults born preterm exhibit a hypercontractile myocardium (increased strain) under resting conditions. The increased bi‐ventricular strain in the circumferential dimension in preterm born adults occurred despite no differences in SVI between groups. This results in reduced RV and LV efficiency in preterm subjects compared to controls, suggesting increased cardiac work may be required in adults born preterm for the same SVI. The implications for life‐time cardiovascular risk merit further study.Support or Funding InformationProject supported by funding from the National Institutes of Health: 1RO1 HL086897 (MWE) and RO1 HL38149 (MWE). Kara Goss is supported by the University of Wisconsin Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS), grant NIH UL1TR000427 (PI Drezner; 4KL2TR000428‐‐10).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Blood Pressure and Stroke Volume Response to Exercise in Adolescent Children Born Very Preterm

IntroductionMultiple studies have shown that adolescents born preterm have exercise intolerance. The etiology of the intolerance remains controversial. It has been demonstrated that infants and young adults born preterm have higher blood pressure (BP) than term‐borns of the same age. Very little is known about the effects of premature birth on cardiovascular function in adolescent children. The purpose of this study was to investigate BP and stroke volume responses to exercise in children. We hypothesized that adolescent children born prematurely would have an augmented BP response with a lower stroke volume response to exercise compared to children born at term.MethodsSubjects were adolescent children born in 2003 and 2004. Preterm subjects were born &lt;33 weeks gestation, and term‐born subjects were born &gt;38 weeks gestation. 21 adolescent children born premature and 20 term‐born controls completed the study. Measurements of systolic BP (SBP) and diastolic BP (DBP) were recorded at rest and during supine submaximal exercise (70% of predetermined maximal wattage). BP data was obtained using a brachial artery cuff every 2 minutes during a 10 minute rest period, and during a 10 minute submaximal exercise period. Rest and exercise mean arterial BP (MABP), SBP and DBP were averaged for every subject. A 3T cardiac MRI was used to determine left ventricular stroke volume using aortic blood flow from a 2D flow cine sequence during rest and exercise using Segment post‐processing software. Stroke volume was calculated the average of aortic flow waveforms from one cardiac cycle. Unpaired t‐tests were used to compare results between controls and preterms.ResultsChildren born preterm had higher SBP (114.8±5.7 mmHg vs. 109.7±4.7 mmHg respectively: p = 0.006), DBP (65.8±4.7 mmHg vs. 60.0±5.3 mmHg respectively: p = 0.001) and MABP (82.2±3.7 mmHg vs. 76.6 ±4.0 mmHg respectively: p &lt; 0.001) compared to term born children at rest. Contrary to our hypothesis, there was no difference in BP response to exercise. There was no difference in SV at rest between preterm and term‐born adolescents (73.0±22.7 vs. 81.6±9.6 ml respectively: p = 0.30). SV during exercise was significantly lower in preterms than controls (66.3±9.0 vs. 99.1±15.6 ml respectively: p = 0.02), resulting in a blunted SV response to exercise in preterms compared to controls (ΔSV; 2.4±1.8 vs. 17.5±6.6 ml respectively: p = 0.02).DiscussionWe found that adolescent children born preterm have higher BP at rest than term‐born controls, with no significant difference during exercise. Elevated BP, while not considered hypertensive, was in the upper limits of what is considered normal for this age group. While we did not find a difference in SV between preterm and term‐born controls at rest, we found that there was a blunted SV response to exercise in preterms. The inability to augment SV appropriately to exercise is indicative of cardiovascular or autonomic dysfunction. In combination, the higher BP and blunted SV response to exercise suggests a need for further cardiovascular investigations in this population.Support or Funding InformationNIH‐NHLBI R01–HL115061This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Physiological Stress Elicits Impaired Left Ventricular Function in Preterm-Born Adults

BackgroundExperimental and clinical studies show that prematurity leads to altered left ventricular (LV) structure and function with preserved resting LV ejection fraction (EF). Large-scale epidemiological data now links prematurity to increased early heart failure risk. ObjectivesEchocardiography imaging was performed at prescribed exercise intensities to determine whether preterm-born adults have impaired LV functional response to physical exercise. MethodsA total of 101 normotensive young adults born preterm (n = 47; mean gestational age 32.8 ± 3.2 weeks) and term (n = 54) were recruited for detailed cardiovascular phenotyping. Full clinical resting and exercise stress echocardiograms were performed, with apical 4-chamber views collected while exercising at 40%, 60%, and 80% of peak exercise capacity, determined by maximal cardiopulmonary exercise testing. ResultsPreterm-born individuals had greater LV mass (p = 0.015) with lower peak systolic longitudinal strain (p = 0.038) and similar EF to term-born control subjects at rest (p = 0.62). However, by 60% exercise intensity, EF was 6.7% lower in preterm subjects (71.9 ± 8.7% vs 78.6 ± 5.4%; p = 0.004) and further declined to 7.3% below the term-born group at 80% exercise intensity (69.8 ± 6.4% vs 77.1 ± 6.3%; p = 0.004). Submaximal cardiac output reserve was 56% lower in preterm-born subjects versus term-born control subjects at 40% of peak exercise capacity (729 ± 1,162 ml/min/m2 vs. 1,669 ± 937 ml/min/m2; p = 0.021). LV length and resting peak systolic longitudinal strain predicted EF increase from rest to 60% exercise intensity in the preterm group (r = 0.68, p = 0.009 and r = 0.56, p = 0.031, respectively). ConclusionsPreterm-born young adults had impaired LV response to physiological stress when subjected to physical exercise, which suggested a reduced myocardial functional reserve that might help explain their increased risk of early heart failure. (Young Adult Cardiovascular Health sTudy [YACHT]; NCT02103231)

Impaired autonomic function in adolescents born preterm.

Preterm birth temporarily disrupts autonomic nervous system (ANS) development, and the long‐term impacts of disrupted fetal development are unclear in children. Abnormal cardiac ANS function is associated with worse health outcomes, and has been identified as a risk factor for cardiovascular disease. We used heart rate variability (HRV) in the time domain (standard deviation of RR intervals, SDRR; and root means squared of successive differences, RMSSD) and frequency domain (high frequency, HF; and low frequency, LF) at rest, as well as heart rate recovery (HRR) following maximal exercise, to assess autonomic function in adolescent children born preterm. Adolescents born preterm (less than 36 weeks gestation at birth) in 2003 and 2004 and healthy age‐matched full‐term controls participated. Wilcoxon Rank Sum tests were used to compare variables between control and preterm groups. Twenty‐one adolescents born preterm and 20 term‐born controls enrolled in the study. Preterm‐born subjects had lower time‐domain HRV, including SDRR (69.1 ± 33.8 vs. 110.1 ± 33.0 msec, respectively, P = 0.008) and RMSSD (58.8 ± 38.2 vs. 101.5 ± 36.2 msec, respectively, P = 0.012), with higher LF variability in preterm subjects. HRR after maximal exercise was slower in preterm‐born subjects at 1 min (30 ± 12 vs. 39 ± 9 bpm, respectively, P = 0.013) and 2 min (52 ± 10 vs. 60 ± 10 bpm, respectively, P = 0.016). This study is the first report of autonomic dysfunction in adolescents born premature. Given prior association of impaired HRV with adult cardiovascular disease, additional investigations into the mechanisms of autonomic dysfunction in this population are warranted.

Differential expression and methylation of integrin subunit alpha 11 and thrombospondin in the amnion of preterm birth.

ObjectiveThis study aimed to investigate the association between preterm birth and epigenetic mechanisms in the amnion.MethodsWe examined the association between differentially methylated regions (DMRs) and differentially expressed genes (DEG) using a cytosine-phosphate-guanine methylation array and whole-transcriptome sequencing from the amnion (preterm birth, n=5; full term, n=5). We enrolled 35 participants for mRNA expression analysis and pyrosequencing: 16 full-term and 19 preterm subjects. We compared the association of integrin subunit alpha 11 (ITGA11) and thrombospondin 2 (THBS2) gene methylation status with mRNA expression in the amnion.ResultsIn the preterm birth group, methylation of ITGA11 and THBS2 genes was significantly lower (ITGA11 gene: 60.30% vs. 73.16%, P<0.05; THBS2 gene: 64.59% vs. 73.16%, P<0.05), and the expression of the genes was significantly higher than that in the full-term group (ITGA11 gene: 14.20 vs. 1.57, P<0.01; THBS2 gene: 1.18 vs. 10.34, P<0.05).ConclusionMethylation of the ITGA11 and THBS2 genes in the amnion was associated with preterm birth. Thus, ITGA11 and THBS2 gene methylation status in the amnion may be valuable in explaining the mechanism underlying preterm birth.

Cerebellar-dependent associative learning is impaired in very preterm born children and young adults

Preterm birth incorporates an increased risk for cerebellar developmental disorders likely contributing to motor and cognitive abnormalities. Experimental evidence of cerebellar dysfunction in preterm subjects, however, is sparse. In this study, classical eyeblink conditioning was used as a marker of cerebellar dysfunction. Standard delay conditioning was investigated in 20 adults and 32 preschool children born very preterm. Focal lesions were excluded based on structural magnetic resonance imaging. For comparison, an equal number of matched term born healthy peers were tested. Subgroups of children (12 preterm, 12 controls) were retested. Preterm subjects acquired significantly less conditioned responses (CR) compared to controls with slower learning rates. A likely explanation for these findings is that preterm birth impedes function of the cerebellum even in the absence of focal cerebellar lesions. The present findings are consistent with the assumption that prematurity results in long-term detrimental effects on the integrity of the cerebellum. It cannot be excluded, however, that extra-cerebellar pathology contributed to the present findings.