Antenatal inflammation and brain pathology in preterm infants

Chorioamnionitis is known to be an important risk factor underlying preterm delivery, and it has also been suggested to associate with brain lesions and deviant neurological development in both preterm and term infants. Cytokines are believed to be the link causing the deleterious effects of inflammation to the nervous system. Their genetic regulation has also been suggested to play a role, as interleukin (IL)-6 -174 and -572 genotypes, which partly regulate IL-6 synthesis responses, have been connected with deviant neurological development in preterm infants. We evaluated the association of histological chorioamnionitis with brain lesions, regional brain volumes, and the functioning of the auditory pathway in very low birth weight/very low gestational age (VLBW/VLGA) infants. In addition, we investigated the association between IL-6 -174 and -572 genotypes and histological chorioamnionitis, neonatal infections, and brain lesions and regional brain volumes in VLBW/VLGA infants. This study is a part of a larger multidisciplinary project PIPARI (Development and Functioning of Very Low Birth Weight Infants from Infancy to School Age), in which the survivors of a 6-year cohort of VLBW/VLGA infants (n=274) are being followed until school age in Turku University Central Hospital, Finland. Placental samples were collected in the delivery room, and were analyzed for histological inflammatory findings. Blood samples from the infants were collected and DNA was genotyped for IL-6-174 and -572 polymorphisms (GG/GC/CC). Brain ultrasound examinations were performed repeatedly in the neonatal intensive care unit and at term age, and were analysed for structural brain lesions. Brain magnetic resonance imaging was performed at term age, and was analysed for regional brain volumes. In addition, diffusion tensor imaging was performed at term, and was used to analyse fractional anisotrophy and the apparent diffusion coefficient of inferior colliculus. The brainstem auditory evoked potential recordings were carried out according to the routine clinical procedure at median age of 30 days after term age. In our study, we found that histological chorioamnionitis was not an independent risk factor for brain lesions, reduced regional brain volumes or abnormal functioning of the auditory pathway in VLBW/VLGA infants. In addition, we found that IL-6 -174 GG and -572 GC genotypes were associated with a higher incidence of histological chorioamnionitis, and that -174 CC genotype associated with higher incidence of septicaemia. The analysed IL-6 genotypes were not associated with other brain lesions, but a reduced volume of basal ganglia and thalami was associated with IL-6 -174 CC and -572 GG genotypes. In conclusion, our findings suggest that histological chorioamnionitis is not an independent risk factor for the brain development of VLBW/VLGA infants, or that the risk caused by inflammation does not exceed the risks attributed to other underlying pathologies behind preterm deliveries. In addition, our findings give reason to propose that IL-6 promoter genotypes have a role in the defence against serious infections and in the brain development of VLBW/VLGA infants.

The effect of the birth hospital and the time of birth on the outcome of Finnish very preterm infants

The purpose of this study was to evaluate the effect of the birth hospital and the time of birth on mortality and the long-term outcome of Finnish very low birth weight (VLBW) or very low gestational age (VLGA) infants. This study included all Finnish VLBW/VLGA infants born at <32 gestational weeks or with a birth weight of ≤1500g, and controls born full-term and healthy. In the first part of the study, the mortality of VLBW/VLGA infants born in 2000–2003 was studied. The second part of the study consisted of a five-year follow-up of VLBW/VLGA infants born in 2001–2002. The study was performed using data from parental questionnaires and several registers. The one-year mortality rate was 11% for live-born VLBW/VLGA infants, 22% for live-born and stillborn VLBW/VLGA infants, and 0% for the controls. In live-born and in all (including stillbirths) VLBW/VLGA infants, the adjusted mortality was lower among those born in level III hospitals compared with level II hospitals. Mortality rates of live-born VLBW/VLGA infants differed according to the university hospital district where the birth hospital was located, but there were no differences in mortality between the districts when stillborn infants were included. There was a trend towards lower mortality rates in VLBW/VLGA infants born during office hours compared with those born outside office hours (night time, weekends, and public holidays). When stillborn infants were included, this difference according to the time of birth was significant. Among five-year-old VLBW/VLGA children, morbidity, use of health care resources, and problems in behaviour and development were more common in comparison with the controls. The health-related quality of life of the surviving VLBW/VLGA children was good but, statistically, it was significantly lower than among the controls. The median and the mean number of quality-adjusted life-years were 4.6 and 3.6 out of a maximum five years for all VLBW/VLGA children. For the controls, the median was 4.8 and the mean was 4.9. Morbidity rates, the use of health care resources, and the mean quality-adjusted life-years differed for VLBW/VLGA children according to the university hospital district of birth. However, the time of birth, the birth hospital level or university hospital district were not associated with the health-related quality of life, nor with behavioural and developmental scores of the survivors at the age of five years. In conclusion, the decreased mortality in level III hospitals was not gained at the expense of long-term problems. The results indicate that VLBW/VLGA deliveries should be centralized to level III hospitals and the regional differences in the treatment practices should further be clarified. A long-term follow-up on the outcome of VLBW/VLGA infants is important in order to recognize the critical periods of care and to optimise the care. In the future, quality-adjusted life-years can be used as a uniform measure for comparing the effectiveness of care between VLBW/VLGA infants and different patient groups

Probiotic interventions in infancy: Benefit and Safety Assessment of Extended Applications

Immaturity of the gut barrier system in the newborn has been seen to underlie a number of chronic diseases originating in infancy and manifesting later in life. The gut microbiota and breast milk provide the most important maturing signals for the gut-related immune system and reinforcement of the gut mucosal barrier function. Recently, the composition of the gut microbiota has been proposed to be instrumental in control of host body weight and metabolism as well as the inflammatory state characterizing overweight and obesity. On this basis, inflammatory Western lifestyle diseases, including overweight development, may represent a potential target for probiotic interventions beyond the well documented clinical applications. The purpose of the present undertaking was to study the efficacy and safety of perinatal probiotic intervention. The material comprised two ongoing, prospective, double-blind NAMI (Nutrition, Allergy, Mucosal immunology and Intestinal microbiota) probiotic interventions. In the mother-infant nutrition and probiotic study altogether 256 women were randomized at their first trimester of pregnancy into a dietary intervention and a control group. The intervention group received intensive dietary counselling provided by a nutritionist, and were further randomized at baseline, double-blind, to receive probiotics (Lactobacillus rhamnosus GG and Bifidobacterium lactis) or placebo. The intervention period extended from the first trimester of pregnancy to the end of exclusive breastfeeding. In the allergy prevention study altogether 159 women were randomized, double-blind, to receive probiotics (Lactobacillus rhamnosus GG) or placebo 4 weeks before expected delivery, the intervention extending for 6 months postnatally. Additionally, patient data on all premature infants with very low birth weight (VLBW) treated in the Department of Paediatrics, Turku University Hospital, during the years 1997 - 2008 were utilized. The perinatal probiotic intervention reduced the risk of gestational diabetes mellitus (GDM) in the mothers and perinatal dietary counselling reduced that of fetal overgrowth in GDM-affected pregnancies. Early gut microbiota modulation with probiotics modified the growth pattern of the child by restraining excessive weight gain during the first years of life. The colostrum adiponectin concentration was demonstrated to be dependent on maternal diet and nutritional status during pregnancy. It was also higher in the colostrum received by normal-weight compared to overweight children at the age of 10 years. The early perinatal probiotic intervention and the postnatal probiotic intervention in VLBW infants were shown to be safe. To conclude, the findings in this study provided clinical evidence supporting the involvement of the initial microbial and nutritional environment in metabolic programming of the child. The manipulation of early gut microbial communities with probiotics might offer an applicable strategy to impact individual energy homeostasis and thus to prevent excessive body-weight gain. The results add weight to the hypothesis that interventions aiming to prevent obesity and its metabolic consequences later in life should be initiated as early as during the perinatal period.

The Vulnerable Brain and Very Preterm Infants - Findings from the PIPARI-Study

Preterm birth is a risk for normal brain development. Brain maturation that normally happens in the uterus is in very preterm infants a developmental challenge during their stay in a neonatal intensive care unit (NICU). Typical brain injuries of preterm infants include ischemic injuries, brain haemorrhages, ventricular dilatation (VD), and reduced brain volumes. Brain injury is a serious complication of prematurity leading to possible long term consequences for the neurodevelopment of the very low birth weight (VLBW) infant, such as cerebral palsy (CP), hearing impairments, vision problems, and delay in cognitive development.There is a need for further studies to ascertain the potential risk factors and their causal relationships to brain vulnerability, growth and development in the increasing number of surviving VLBW infants. This thesis consists of four studies evaluating the definitions, causes and consequences of brain lesions in VLBW(<1500g) or very low gestationalage (VLGA) (gestational age <32 gestational weeks) infants. We showed that the redistribution of fetal blood flow is a risk factor for smaller brain volumes at term. In addition,we showed that brain lesions related to prematurity are not associated with increased spontaneous crying behaviour or circadian rhythm development in infancy. However, the preterm infants began to fuss more often and were held more than term infants at five months of age. Furthermore, we showed that VD is associated with brain lesions and smaller brain volumes. Therefore, brain magneticresonance imaging can be recommended for infants with VD. VD together with other brain pathology is a risk factor for the onset of developmental impairments in VLBW/VLGA infants at two years of age.

Cognitive Development of Very Low Birth Weight Children from Infancy to Pre-school Age

The survival of preterm born infants has increased but the prevalence of long-term morbidities has still remained high. Preterm born children are at an increased risk for various developmental impairments including both severe neurological deficits as well as deficits in cognitive development. According to the literature the developmental outcome perspective differs between countries, centers, and eras. Definitions of preterm infant vary between studies, and the follow-up has been carried out with diverse methods making the comparison less reliable. It is essential to offer parents upto-date information about the outcome of preterm infants born in the same area. A centralized follow-up of children at risk makes it possible to monitor the consequences of changes in the treatment practices of hospitals on developmental outcome. This thesis is part of a larger regional, prospective multidisciplinary follow-up project entitled “Development and Functioning of Very Low Birth Weight Infants from Infancy to School Age” (PIeniPAinoisten RIskilasten käyttäytyminen ja toimintakyky imeväisiästä kouluikään, PIPARI). The thesis consists of four original studies that present data of very low birth weight (VLBW) infants born between 2001 and 2006, who are followed up from the neonatal period until the age of five years. The main outcome measure was cognitive development and secondary outcomes were significant neurological deficits (cerebral palsy, CP, deafness, and blindness). In Study I, the early crying and fussing behavior of preterm infants was studied using parental diaries, and the relation of crying behavior and cognitive and motor development at the age of two years was assessed. In Study II, the developmental outcome (cognitive, CP, deafness, and blindness) at the age of two years was studied in relation to demographic, antenatal, neonatal, and brain imaging data. Development was studied in relationship to a full-term born control group born in the same hospital. In Study III, the stability of cognitive development was studied in VLBW and full-term groups by comparing the outcomes at the ages of two and five years. Finally, in Study IV the precursors of reading skills (phonological processing, rapid automatized naming, and letter knowledge) were assessed for VLBW and full-term children at the age of five years. Pre-reading skills were studied in relation to demographic, antenatal, neonatal, and brain imaging data. The main findings of the thesis were that VLBW infants who fussed or cried more in the infancy were not at greater risk for problems in their cognitive development. However, crying was associated with poorer motor development. The developmental outcome of the present population was better that has been reported earlier and this improvement covered also cognitive development. However, the difference to fullterm born peers was still significant. Major brain pathology and intestinal perforation were independent significant risk factors for adverse outcome, also when several individual risk factors were controlled for. Cognitive development at the age of two years was strongly related with development at the age of five years, stressing the importance of the early assessment, and the possibility for early interventions. Finally, VLBW children had poorer pre-reading skills compared with their full-term born peers, but the IQ was an important mediator even when children with mental retardation were excluded from the analysis. The findings suggest that counseling parents about the developmental perspectives of their preterm infant should be based on data covering the same birth hospital. Neonatal brain imaging data and neonatal morbidity are important predictors for developmental outcome. The findings of the present study stress the importance of both short-term (two years) and long-term (five years) follow-ups for the individual, and for improving the quality of care.

Smoking during pregnancy and fetal brain development

Background: Although the knowledge of adverse effects of smoking during pregnancy has increased in recent years, more research is needed to gain a better understanding of the effects of smoking during pregnancy. Smoking exposure is the most common preventable factor that causes adverse pregnancy outcomes. Aims and Methods: First, data on smoking habits during pregnancy from the Nordic Medical Birth Registers was used to study the national differences in trends of smoking during pregnancy. Second, the effects of prenatal smoking exposure on fetal brain development, assessed by brain MRI at term age, were studied by using data from the multidisciplinary PIPARI Study consisting of a 6-year cohort of VLBW/VLGA infants (n = 232, of which 18.1% were exposed to prenatal smoking) born in Turku University Hospital, Finland. Third, the effects of prenatal smoking exposure on psychiatric morbidity and use of psychotropic medication were studied in a cohort of children born from 1987–1989 in Finland (n = 175,869, of which 15.3% were exposed). The data used were obtained from population-based longitudinal registers from the National Institute of Health and Welfare, the Statistics Finland, and the Finnish Social Insurance Institution. Results: Smoking rates during pregnancy differed considerably between the countries. Smoking rates were highest among teenagers and women with lower socioeconomic positions. The smoking prevalence was found to be increasing among teenagers in both Finland and Norway. Prenatal smoking exposure was associated with smaller frontal lobe and cerebellar volumes in preterm infants. A clear association was found between prenatal smoking exposure and psychiatric morbidity treated with specialized hospital care and the use of various psychotropic medications. Conclusions: Prenatal smoking exposure had adverse effects on fetal brain development. These effects might explain part of the association found between smoking exposure and psychiatric problems in later life. Our study suggests that prenatal smoking exposure is linked with both mild and severe psychiatric problems. This study emphasizes the importance of efforts to reduce smoking during pregnancy.

Psychological well-being of the parents and child development, behavior, and quality of life in very low birth weight infants

The parents of premature infants, especially the mothers, are at increased risk for distress. Infants born prematurely are at risk for developmental problems. The aim of this study was to investigate whether the psychological well-being of both parents is associated with child development in very low birth weight (VLBW, ≤1500g) children. The burden of prematurity-related morbidity to the children and to the family was also assessed. A cohort of 201 VLBW infants born during 2001–2006 in the Turku University Hospital, Finland, and their parents were studied (I–IV). One study included a control group (n=166) of full-term infants (IV). The psychological well-being of the parents was evaluated by assessments of depressive symptoms, parenting stress, the sense of coherence and general family functioning. Cognitive, behavioral, and socio-emotional development, and the health-related quality of life (HRQoL) of the children were determined when the children were 2 to 8 years old. The psychological well-being of the parents was associated with the cognitive, behavioral and social development of the VLBW children. The VLBW infants with prematurity-related morbidities had a poorer HRQoL and the general functioning of the family was inferior compared to the control children and their families. 64.5% of the VLBW children survived without morbidities. Most of the VLBW children did not have significant behavior problems (93%), had normal social skills (63%), had no emotional problems (64%), and had no problems in executive functioning (62%). Only 3% of the surviving VLBW infants had significant cognitive delay. In conclusion, the depressive symptoms and stress of the parents can be risk factors for disadvantageous child development, while a strong sense of coherence can be protective. Parents of the premature children with developmental delays might also experience more depressive symptoms and stress than other parents. Prematurity-related morbidities were a burden to the VLBW child as well as to the family.