Effects Of Preterm Birth Research Articles

Effect of preterm birth on growth and cardiovascular disease risk at school age.

Low birthweight is associated with increased risk for cardiovascular disease (CVD) in later life, but whether premature birth is also a risk factor for CVD has not been fully determined. The aim of this study was to investigate the relationship between gestational age and risk factors for CVD at school age. Using medical check-up data of school children, the relationship between gestational age and height, weight, body mass index, blood pressure, and lipid profiles at ages 9 and 12 years were investigated in children born preterm and admitted to neonatal intensive care unit at birth (n = 182; 115 boys and 67 girls). These data were also compared between preterm small for gestational age (SGA) children and preterm appropriate for gestational age (AGA) children. Gestational age was positively associated with height, and inversely associated with systolic blood pressure at school age. Preterm SGA children were significantly shorter and lighter at 9 and 12 years of age compared with preterm AGA children, but there were no significant differences in any CVD risk factors between the groups. In preterm infants, a shorter duration of gestation is associated with higher systolic blood pressure at school age.

Acquisition du langage chez l’enfant prématuré durant la première année de vie

Previous studies have shown that preterm children are at a higher risk for cognitive and language delays than full-term children. Most of these studies have concentrated on the effects of prematurity during the preschool or school years, while the effect of preterm birth on the early development of language, much of which occurs during the first year of life, remains very little explored. This article focuses on this crucial period and reviews the studies that have explored early phonological and lexical development in preterm infants. The results of these studies show uneven proficiency in different language subdomains in preterm infants. This raises the possibility that different constraints apply to the acquisition of different linguistic subcomponents in this population, in part as a result of a complex interaction between maturation, experience, and language subdomains.

Perinatal infections and cerebral palsy

There are many causes of cerebral palsy (CP) apart from hypoxic events during the perinatal period. Perinatal infections and systemic inflammatory response syndrome of the mother and infant can affect the development of CP significantly. The majority of premature infants are vulnerable to CP and the association between intraamniotic infections, preterm rupture of fetal membranes and the effect of preterm birth predispose the infant to CP. Incidence of intraventricular hemorrhage, white matter disease and periventricular leukomalacia has increased after preterm labor resulting from intraamniotic infections. Bacterial vaginosis, fever, periodontal disease of the mother, as well as bacterial, viral, protozoan and fungal infections of the newborn infant are effective during the development of CP. The balance between proinflammatory and anti-inflammatory cytokines and the combined effects of genetic predisposition, hypoxia, cytokines and bacterial products may initiate the unfavorable process. Treatments directed towards cytokines and bacterial products have not been effective until now. Fetuses and neonates should be protected from perinatal infections as much as possible and all infections should be treated promptly in order to prevent short-term and long-term adverse outcomes.

How do you think she feels? Vulnerability in empathy and the role of attention in school-aged children born extremely preterm.

The aim of this study was to examine empathic competence in children born extremely preterm (EP, <28weeks) given vulnerabilities in social relationships. Empathy in typically developing children is mediated by executive functions. Executive functioning is also impaired in preterm children. Of particular interest in this study are the attentional components of executive functioning as mediators of empathic development. Thirty-two 7-year-old EP children and 40 age-matched term children participated in the Project K.I.D.S program and completed the Kids Empathy Development Scale (KEDS), Wechsler Intelligence Scale for Children (WISC-IV), and Test of Everyday Attention for Children (TEA-Ch). Children born extremely preterm exhibited poorer performance on all measures. The mediating role of attention in empathy competence was not supported by mediation modelling when FSIQ was controlled. As predicted, the EP group showed weaker empathic development relative to typically developing children. They also showed poorer attentional abilities. However, the effect of preterm birth on empathy was not mediated by executive-level attention. The cognitive mechanisms underpinning poor empathy competence in EP children remain unclear. Future research needs to examine the role of inhibition, social-emotional recognition, and regulation.

Teachers' Knowledge About Consequences of Preterm Birth

Monitoring the development of school-age children born preterm is dependent on effective communication with school personnel. Researchers in the U.K. conducted a national survey of 585 primary and secondary school teachers and 212 educational psychologists to assess their knowledge about developmental, behavioral, and educational outcomes after preterm birth. On average, teachers answered 45% of …

The Effects of Preterm Birth on Cerebral Pressure‐Flow Dynamics

Altered cortical and neurodevelopmental outcomes have been described following very preterm birth and imparied blood pressure (BP) and cerebral blood flow regulation have been implicated as possible mechanisms. However, whether haemodynamic impairment persists into early childhood following preterm birth remains unclear. To test the hypothesis that cerebrovascular dysfunction persists in early childood (age 6.6 yrs ±0.8) following preterm brith, we recorded BP and middle cerebral blood velocity (MCAv) in 10 preterm children (5 males, mean gestastion age at birth =32.2 weeks ±2.7) and 10 children born at term (5 males, mean gestation age at birth =39.7 weeks ±1.0) under spontaneous baseline conditions. Cerebral BP-MCAv dynamics were assessed using linear transfer function analysis. Additionally, we applied Granger's causlity test to determine the direction and strength of BP-MCAv interactions using Vector Autoregressive Moving Average Models. Results showed that compared to term children, BP-MCAv coherence was higher in preterm females (0.35±0.079 vs. 0.58±0.086, p=0.08) but similar in males (0.41±0.072 vs. 0.049±0.10, p=0.53). The average directionality index was similar between term and preterm children but the standard deviation was greater in preterm children (-7.2±13.33 vs -7.8±32.25). Further, the directionality index was positively correlated to the transfer function coherence (r=48, p<0.05). These results indicate that preterm females may have impaired cerebrovacular regulation and that, as a group, preterm children are more likley to exhibit pressure-flow dynamics that are dominated by either BP or cerebral blood flow.

The long-term consequences of preterm birth: what do teachers know?

The knowledge and information needs of education professionals were assessed to determine how prepared they feel to support the growing number of preterm children entering schools today. In a national survey, 585 teachers and 212 educational psychologists completed the Preterm Birth-Knowledge Scale (PB-KS) to assess knowledge of outcomes following preterm birth. Total scores (range 0-33) were compared between groups and the impact of demographic characteristics on knowledge was analysed. Training and information needs were also assessed. Teaching staff (mean 14.7, SD 5.5) had significantly lower knowledge scores than educational psychologists (mean 17.1, SD 5.0; p<0.001); both had significantly lower scores than neonatal clinicians surveyed previously (mean 26.0, SD 3.6; p<0.001). Education professionals' poorest areas of knowledge related to the most frequent adverse outcomes following preterm birth. Only 16% of teaching staff had received training about preterm birth and more than 90% requested more information. Having a special educational needs role and being employed at least 16 years were associated with higher knowledge scores. Education professionals have poor knowledge of the needs of children born preterm and most feel ill-equipped to support them in school. As teachers have primary responsibility for providing long-term support for children born preterm, this is of significant public health and educational concern.

Preterm Birth: A Primary Etiological Factor for Delayed Oral Growth and Development.

ABSTRACTPreterm and low birthweight children comprise approximately 6% of all live births. It is now a well-known fact that premature children experience many oral complications associated with their preterm births. Prematurely born infants have a short prenatal development period and they are prone to many serious medical problems during the neonatal period, which may affect the development of oral tissues. Adverse perinatal factors, premature birth and exceptional early adaptation to extra-uterine life and functional activity may influence dental occlusal development and symmetry in the jaws. Thus, the goal of the present paper is to elucidate further the effect of preterm birth on the development of the dentition.How to cite this article: Zaidi I, Thayath MN, Singh S, Sinha A. Preterm Birth: A Primary Etiological Factor for Delayed Oral Growth and Development. Int J Clin Pediatr Dent 2015;8(3): 215-219.

Effect of preterm birth on exercise capacity: A systematic review and meta‐analysis

Survivors of preterm-birth have increased prevalence of respiratory, cardiovascular, and neurological diseases in later life however, the overall impact of prematurity on cardiorespiratory exercise capacity is unclear. We, therefore, systematically reviewed the literature on cardiorespiratory exercise capacity in survivors of preterm birth. Relevant studies up to March 2013 were searched using eight electronic health databases. Studies reporting exercise capacity in participants born preterm (<37 weeks) were included. The main outcome of interest was oxygen uptake (V˙O2max⁡) at maximal exercise. Data were categorized into four groups: (i) preterm-born subjects including those with or without bronchopulmonary dysplasia (BPD) but excluding study groups biased towards BPD; (ii) preterm-born subjects (BPD excluded); (iii) preterm-born subjects who had BPD28 (defined as oxygen dependency at 28 days of life) in infancy; (iv) preterm born subjects with BPD36 (oxygen dependency at 36 weeks post menstrual age) in infancy. From 9,341 abstracts, 22 included publications reported V˙O2max⁡ in ml/kg/min from 685 preterm and 680 term-born subjects. Overall 20 studies reported results for preterm-born subjects including BPD; 14 studies for the preterm group excluding BPD; 10 studies for the BPD28 group; and 8 studies for BPD36 group. The mean differences (95% CI) for the four groups were -2.20 (-3.70, -0.70) ml/kg/min; -2.26 (-4.44, -0.07 ml/kg/min; -3.04 (-5.48, -0.61) ml/kg/min, and -3.05 (-5.93, -0.18) ml/kg/min, respectively. Despite marked deficits in spirometry, preterm-born children have a marginally decreased V˙O2max⁡, which is unlikely to be of great clinical significance. Pediatr Pulmonol. 2015; 50:293-301. © 2014 Wiley Periodicals, Inc.

PS-169 Early Delay Gratification Abilities Mediate Effects Of Preterm Birth On Attention Regulation And Academic Achievement At Age 8 Years

Background and aims Preterm birth and delay gratification abilities both predict long-term achievement. The aim was to test if adverse effects of preterm birth on attention regulation and academic achievement are mediated by children’s early delay gratification abilities. Methods 558 children ranging from 26 to 41 weeks gestational age (GA) at birth were studied as part of a prospective geographically defined longitudinal investigation in South Germany. At corrected age 20 months, children’s delay gratification abilities were observed with an adapted version of the ‘marshmallow test’. At age 8 years, children’s attention regulation was assessed by paediatricians, psychologists, and mothers while academic achievement was measured with standardised mathematics, reading, and writing/spelling tests. Results Structural equation modelling showed that preterm birth was directly associated with low attention regulation and academic achievement at 8 years. In addition, very preterm children ( s = -.23, 95% CI[-.33,-.14]) compared with full term controls (39–41 weeks GA). Ability to delay gratification predicted attention regulation ( s = 0.21, 95% CI[.06,.32]) and academic achievement ( s = 0.15, 95% CI[.07,.24])). Analyses were controlled for child sex and family socio-economic status ( CMIN/DF = 1.83; p = 0.005; CFI = 0.981; RMSEA = 0.039). Conclusions Adverse effects of preterm birth on later attention regulation and academic achievement are partially mediated by children’s early abilities to delay instant gratification. These findings provide new information about the mechanisms linking preterm birth with long-term attention difficulties and academic underachievement. Practical implications include the use of this easy tool in routine follow-up assessments after preterm birth and possible new pathways to intervention.

Effects of preterm birth and gender on temperament and behavior in children

The aim of the present study was to assess the direct and interactive effects of premature birth and gender on temperament and behavioral problems in 80 children aged 18–36 months. The sample was composed of children born preterm (PT; n=44) and children born full-term (FT; n=36). The children's mothers completed temperament (ECBQ) and behavioral problem (CBCL 1.5–5) assessments. Analyses of variance (ANOVA 2×2) were performed. With regard to temperament, PT children exhibited significantly higher scores on high-intensity pleasure and perceptual sensitivity and lower scores on discomfort, cuddliness, and Attentional Focusing compared with FT children. Girls scored higher on fear and discomfort compared with boys. With concern to behavioral problems, PT children scored higher on attention problems compared with FT children. No interactive effect of premature birth and gender on temperament or behavioral problems was found.

Advances in prenatal diagnostics.

Advances in prenatal diagnostics.

Effect of preterm birth on motor development, behavior, and school performance of school-age children: a systematic review

Objectivesto examine and synthesize the available knowledge in the literature about the effects of preterm birth on the development of school-age children. Sourcesthis was a systematic review of studies published in the past ten years indexed in MEDLINE/Pubmed, MEDLINE/BVS; LILACS/BVS; IBECS/BVS; Cochrane/BVS, CINAHL, Web of Science, Scopus, and PsycNET in three languages (Portuguese, Spanish, and English). Observational and experimental studies that assessed motor development and/or behavior and/or academic performance and whose target-population consisted of preterm children aged 8 to 10 years were included. Article quality was assessed by the Strengthening the reporting of observational studies in epidemiology (STROBE) and Physiotherapy Evidence Database (PEDro) scales; articles that did not achieve a score of 80% or more were excluded. Summary of findingsof findings the electronic search identified 3,153 articles, of which 33 were included based on the eligibility criteria. Only four studies found no effect of prematurity on the outcomes (two articles on behavior, one on motor performance and one on academic performance). Among the outcomes of interest, behavior was the most searched (20 articles, 61%), followed by academic performance (16 articles, 48%) and motor impairment (11 articles, 33%). Conclusionpremature infants are more susceptible to motor development, behavior and academic performance impairment when compared to term infants. These types of impairments, whose effects are manifested in the long term, can be prevented through early parental guidance, monitoring by specialized professionals, and interventions.

Effect of preterm birth on motor development, behavior, and school performance of school‐age children: a systematic review

Objectivesto examine and synthesize the available knowledge in the literature about the effects of preterm birth on the development of school‐age children. Sourcesthis was a systematic review of studies published in the past ten years indexed in MEDLINE/Pubmed, MEDLINE/BVS; LILACS/BVS; IBECS/BVS; Cochrane/BVS, CINAHL, Web of Science, Scopus, and PsycNET in three languages (Portuguese, Spanish, and English). Observational and experimental studies that assessed motor development and/or behavior and/or academic performance and whose target‐population consisted of preterm children aged 8 to 10 years were included. Article quality was assessed by the Strengthening the reporting of observational studies in epidemiology (STROBE) and Physiotherapy Evidence Database (PEDro) scales; articles that did not achieve a score of 80% or more were excluded. Summary of findingsthe electronic search identified 3,153 articles, of which 33 were included based on the eligibility criteria. Only four studies found no effect of prematurity on the outcomes (two articles on behavior, one on motor performance and one on academic performance). Among the outcomes of interest, behavior was the most searched (20 articles, 61%), followed by academic performance (16 articles, 48%) and motor impairment (11 articles, 33%). Conclusionpremature infants are more susceptible to motor development, behavior and academic performance impairment when compared to term infants. These types of impairments, whose effects are manifested in the long term, can be prevented through early parental guidance, monitoring by specialized professionals, and interventions.

Preterm Birth and Hypertension Risk

The majority of epidemiological studies in developmental programming have explored the influence of low birth weight (irrespective of gestational age) on long-term chronic disease in individuals born during the first half of the 20th century.1,2 Low birth weight neonates may represent infants born at term with intrauterine growth restriction (IUGR) or born preterm with or without IUGR. As such, there is emerging interest in the effects of preterm birth alone (beyond birth weight and IUGR) on specific aspects of human development and long-term health. Approximately 10% of all births worldwide are preterm (before 37 completed weeks of gestation).3 Besides being of low birth weight, preterm neonates are suddenly and prematurely exposed to the extrauterine environment at a time when organogenesis is incomplete. Exposure postnatally to factors such as high oxygen concentrations,4 medications5 (including glucocorticoids),6 and inadequate nutrition7 likely adversely influence postnatal growth and ongoing organ development. In addition to possible genetic and epigenetic factors that may contribute to hypertension risk (including hypertension-related complications of pregnancy), a multitude of aspects related to both intrauterine and extrauterine growth, as well as the postnatal environment, may all play an important role in the programming of hypertension in individuals born preterm. In this review, we will highlight, in particular, the potential effect of oxidative stress associated with preterm birth on neonatal development and future disease risk. The survival of neonates born at low and very low gestational ages is recent in the history of medicine and has increased remarkably over the last few decades. The first generations of survivors of very preterm birth are currently just reaching adulthood and as such are providing emerging evidence of chronic health conditions, such as hypertension. The link between preterm birth and hypertension risk (independent of birth weight) has been …

Authors' Reply: Preterm birth rise in Greece: time for action

It was with great interest that we read the letter sent to AOGS by Vlachadis et al. (1), where updated results of our work (2) were presented. We are grateful for their kind words and their valuable contribution in highlighting preterm birth as a major public health issue and, indeed, an epidemic. Their results are also interesting because they represent the first data on preterm birth in the financial crisis era. It seems that the trend for an increase in preterm birth persists regardless of the financial turmoil. The projected rate of preterm birth by the end of the current decade is extremely high and if proven accurate then the consequences will be severe. Could an increase in preterm birth rate be justified by a favorable impact on stillbirths and neonatal death counts? Recently published results show that the increase in preterm birth rate is associated with a lower stillbirth and neonatal death rate (3), but this finding is not supported by the results in our population. We concluded that, in our dataset, the factors contributing to the preterm birth rate rise are a combination of increased maternal age, increased use of assisted reproductive technology techniques and obstetric intervention. The impact of the financial crisis will most probably lead to a further increase in the maternal age (4) and further affect the rate. The aim of our study was to record the preterm birth rate in Greece so that action against its rise could be initiated. We believe that our esteemed colleagues think the same and we would like to invite them to join forces with us. In this context, we would like to announce from the platform of AOGS our next moves: We will forward the results of our study to the Greek authorities as well as to the relevant scientific societies, to officially inform them about our findings. We will urge for efforts to be put into identifying the exact causes of preterm birth in Greece and for guidelines to be implemented. The hypothesis that the altered obstetrical practice (and the concomitant increase in cesarean sections rate) plays a significant role needs to be investigated. Additionally, we will issue a press announcement explaining the main results of our study in lay language so that the Greek public may be aware of the sequelae of preterm birth (even after 34 weeks of gestation). We endeavor to raise the issue among the health practitioners and the people. We believe that in this way, academic results will disseminate in the community and may have an impact on the incidence of preterm birth. We believe that it is time to change course and re-evaluate our approach to preterm birth. The consequences of preterm birth have to be thoroughly understood. Increased use of assisted reproductive technology techniques and the ever-increasing maternal age are contributing factors that are not easy to intercept in a modern European society. Obstetric practice complying with already established international guidelines is the key to reduce the epidemic of preterm birth.

The effect of preterm birth and low birth weight on visual attention in adults

Preterm birth and low birth weight has been associated with an increased risk of cognitive, behavioral and psychiatric problems. In this study we examine how these problems are linked to specific attentional networks. Based on a sample from the Bavarian Longitudinal Study we compared a cohort of 121 survivors born very preterm (<32 weeks gestational age, GA) or very-low-birth-weight (VLBW <1500g) in 1985/86 (mean birth weight, 1323g; mean GA at birth, 30.3 weeks; 53% male) with 129 controls from the same population in Bavaria (mean birth weight, 3402g; mean GA at birth, 39.7 weeks; 47% male). Participants simply had to discriminate the orientation (left, right) of an arrow. The arrival of the arrow could be indicated by an alerting tone, its location (top, bottom) could be indicated by a spatial cue, and the arrow was always presented among other flanker arrows that were either congruent or incongruent. Each of these manipulation allowed to assess a separate component of attention: alerting, orienting and executive control (Fan et al., 2002, Journal of Cognitive Neuroscience). The RT index, representing efficiency for each attentional network (i.e., RT difference for tone present-absent, for cue valid-invalid, and for flanker congruent-incongruent) was calculated separately for each group. The VLBW group showed a large and highly significant deficit in the executive network and a smaller but significant deficit in the orienting network, but no deficit in the alerting network. Although RTs were generally longer for VLBW, the RT index result did not change when using RT ratio scores. Multiple regression analysis further showed that gender and IQ can to some degree – but not entirely account for this deficit in executive control. These results show that VLBW is linked to specific attentional deficiencies, especially those involving executive control.

Effects of Preterm Birth on Intrinsic Fluctuations in Neonatal Cerebral Activity Examined Using Optical Imaging

Medical advancements in neonatology have significantly increased the number of high-risk preterm survivors. However, recent long-term follow-up studies have suggested that preterm infants are at risk for behavioral, educational, and emotional problems. Although clear relationships have been demonstrated between preterm infants and developmental problems during childhood and adolescence, less is known about the early indications of these problems. Recently, numerous studies on resting-state functional connectivity (RSFC) have demonstrated temporal correlations of activity between spatially remote cortical regions not only in healthy adults but also in neuropathological disorders and early childhood development. In order to compare RSFC of the cerebral cortex between preterm infants at term-equivalent ages and full-term neonates without any anatomical abnormality risk during natural sleep, we used an optical topography system, which is a recently developed extension of near-infrared spectroscopy. We clarified the presence of RSFC in both preterm infants and full-term neonates and showed differences between these groups. The principal differences were that on comparison of RSFC between the bilateral temporal regions, and bilateral parietal regions, RSFC was enhanced in preterm infants compared with full-term neonates; whereas on comparison of RSFC between the left temporal and left parietal regions, RSFC was enhanced in full-term neonates compared with preterm infants. We also demonstrated a difference between the groups in developmental changes of RSFC related to postmenstrual age. Most importantly, these findings suggested that preterm infants and full-term neonates follow different developmental trajectories during the perinatal period because of differences in perinatal experiences and physiological and structural development.

Effect of preterm birth and birth weight on eating behavior at 2 y of age

Preterm infants frequently present eating difficulties in early childhood. Determinants of these difficulties are not known. We assessed the influence of neonatal and maternal characteristics on eating behaviors at 2 y of age. The following 2 cohorts were compared: 234 preterm children born <33 wk of gestational age from the POLYmorphisme génétique, Nutrition et Comportement Alimentaire cohort and 245 term children from the Observation des Préférences ALImentaires du Nourrisson et de l'Enfant cohort. Eating behaviors were assessed by using the validated Children's Eating Difficulties Questionnaire, which assesses the following 2 dimensions: a low drive to eat and narrow food repertoire. Each dimension was graded from 2 to 10 with more severe difficulties reflected by a higher score. Children in the upper quintile were classified as having eating disorders. Compared with term children, preterm children had a worse drive-to-eat score (4.3 ± 1.6 compared with 3.6 ± 1.5, respectively; P = 0.001) and a marginally lower food-repertoire score (5.0 ± 1.5 compared with 4.8 ± 1.6, respectively; P = 0.05). In a multilevel logistic regression model, female sex [adjusted OR (aOR): 1.76; 95% CI: 1.08, 2.88; P = 0.025] and birth weight less than -1 z score (aOR: 2.88; 95% CI: 1.47, 5.67; P = 0.002) but not gestational age were associated with a worse drive to eat. A maternal level of education beyond high school was associated with lower risk of a poor food-repertoire score (aOR: 0.54; 95% CI: 0.32, 0.90; P = 0.02). Preterm children have more eating difficulties than term children do, but after adjustment for maternal and neonatal characteristics, gestational age is not associated with impaired eating behaviors at the age of 2 y. Female sex, a low maternal level of education, and less than -1 SD intrauterine growth are associated with eating difficulties at 2 y of age. This trial was registered at clinicaltrials.gov as NCT 00663572.

Effect of preterm birth on later FEV1: a systematic review and meta-analysis

Increasing evidence suggests that preterm birth affects later lung function. We systematically reviewed the literature to determine whether percentage predicted forced expiratory volume in 1 s (%FEV1) is lower in later life in preterm-born subjects, with or without bronchopulmonary dysplasia (BPD), compared with term-born controls. Studies reporting %FEV1, with or without a term-born control group, in later life for preterm-born subjects (<37 weeks gestation) were extracted from eight databases. Data were analysed using Review Manager and STATA. The quality of the studies was assessed. From 8839 titles, 1124 full articles were screened and 59 were included: 28 studied preterm-born children without BPD, 24 with BPD28 (supplemental oxygen dependency at 28 days), 15 with BPD36 (supplemental oxygen dependency 36 weeks postmenstrual age) and 34 born preterm. For the preterm-born group without BPD and for the BPD28 and BPD36 groups the mean differences (and 95% CIs) for %FEV1 compared with term-born controls were -7.2% (-8.7% to -5.6%), -16.2% (-19.9% to -12.4%) and -18.9% (-21.1% to -16.7%), respectively. Pooling all data on preterm-born subjects whether or not there was a control group gave a pooled %FEV1 estimate of 91.0% (88.8% to 93.1%) for the preterm-born cohort without BPD, 83.7% (80.2% to 87.2%) for BPD28 and 79.1% (76.9% to 81.3%) for BPD36. Interestingly, %FEV1 for BPD28 has improved over the years. %FEV1 is decreased in preterm-born survivors, even those who do not develop BPD. %FEV1 of survivors of BPD28 has improved over recent years. Long-term respiratory follow-up of preterm-born survivors is required as they may be at risk of developing chronic obstructive pulmonary disease.