In this retrospective cohort from 2002 through 2007, 104,003 singleton live births in Hillsborough County, Florida were analyzed to elucidate the relationship between feto-infant morbidity outcomes and prenatal exposure to six criteria air pollutants. This study is based on three linked databases: The Florida Hospital Discharge database; The vital statistics records of singleton live births; Air Pollution meteorological data from the Environmental Protection Agency. There are six common air pollutants, particulate matter 2.5 (PM2.5), particulate matter 10 (PM10), ground-level ozone (O3), carbon monoxide (CO), nitrogen (NOx), and lead (Pb). These pollutants are harmful to human health and the environment. The primary outcomes of interest were low birth weight (LBW), preterm births, and small for gestational age (SGA). The intent of this project is to address these issues of air pollution effects and the methodology surrounding the study of air pollution. Using modeling, exposure values of the six criteria air pollutants were assigned to mothers over their period of pregnancy. To address these methodological concerns, this study utilizes the structural equation modeling, quartile groupings with dose response, and trimester groupings to evaluate the relationship between air pollution and birth outcomes of pregnant residents. Using structural equation modeling a significant B value of 0.35 indicated that exposure to the six criteria pollutant in pregnancy may have a significant relationship to all five birth outcomes if they are broken down into latent variables. Quartile data demonstrated that NOx seemed to have most significant associations with all outcomes with a dose response for SGA. PM10 and PM2.5 had some association to LBW and VLBW at high levels. PM10 demonstrated significance in the higher doses for SGA. However, the only dose response relationship that was demonstrated for PM10 and PM2.5 was in VLBW. PM10 also demonstrated a dose response with very preterm. If sub-divided into trimester data, PM10 demonstrated a significant relationship between exposures in all trimesters and LBW, VLBW, and SGA. PM2.5 demonstrated a significant relationship between exposures in all trimesters and VLBW. CO demonstrated a significant relationship in the 2nd trimester for LBW as well as for SGA. Mothers and their babies are a vulnerable population who are more susceptible to lower levels of pollution. These air pollutants can possibly have long-term effect on their children. Implantation of laws and regulations, warning system, or more strict EPA standards may be needed to adequately control the cost to our society.

Many parents experience high levels of stress after the birth of a premature infant admitted to a neonatal intensive care unit (NICU) given the often fragile status of their infant and the numerous medical interventions necessary to stabilize the infant. Previous research has found that parents of very preterm (VPT; <32 weeks‟ gestation) infants often experience high levels of stress, particularly in relation to feelings of having lost their parental role. Of particular concern are findings which suggest that such symptoms may last beyond the immediate hospitalization period to have an adverse effect on the parental ability to provide quality infant care-giving at home. However, little is known about the paternal NICU stress response, the role of stressors external to the NICU environment and the perceptions of NICU staff. Against this background, aims of this thesis were: 1) to describe and compare sources of NICU stress for mothers and fathers of VPT infants, 2) to identify key predictors of parental NICU stress, 3) to describe staff perceptions of parental NICU stress, and 4) to identify parental stressors external to the NICU. Two cohorts of parents of VPT infants were studied: 11 mothers and 10 fathers of VPT infants (<32 weeks' gestation) admitted to a level III NICU, Christchurch Women's Hospital; and 68 mothers and 68 fathers of VPT infants (<30 weeks' gestation) who participated in the Victorian Infant Brain Studies, admitted to the Royal Women‟s Hospital NICU, Melbourne. Twenty-three NICU nurses from Christchurch Women‟s Hospital, level III NICU were also interviewed. The Parental Stressors Scale: NICU (PSS: NICU) determined sources of stress among parents. NICU nurses completed an adapted version of the PSS: NICU that measured nursing staffs‟ perceptions of parental NICU stress. Parents also completed the Life Events Scale on upsetting life events from the previous 12 months. An external stressors scale which measured stress relating to finances, transport and childcare was developed and completed by parents and staff. Familial demographic and infant clinical information was collected from birth records and hospital databases. Results showed across both cohorts studied that mothers reported significantly higher levels of NICU stress than fathers on the “sights and sounds”, “infant appearance”, and “loss of parental role” subscales on the PSS: NICU (p < .05). The number of upsetting life events (B = .33, p = .01)) and paternal level of NICU stress predicted maternal NICU stress (B = .23, p = .03). Maternal NICU stress also predicted paternal NICU stress (B = .37, p = .01). Staff consistently overestimated parental stress levels (p < .05). The most stressful item on the external stressors scale reported by parents and staff was “fitting in everything else I have to do”. Findings emphasize the need for increased awareness of NICU-specific and NICU-external factors contributing to parental stress. Research into the extent to which staff perceptions of parent experiences may affect the quality of staff-parent relations in the NICU is also warranted. These findings contribute to our understanding of the parental experience of having a preterm infant in the NICU and implications for practice and future research are discussed.

[Truncated abstract] Periodontal disease is a common and underdiagnosed disease in humans that may have adverse effects on pregnancy outcomes. The aim of this thesis was to investigate the effects of periodontal disease in pregnancy by means of two observational human studies and the development of animal models of fetal and uterine exposure to periodontopathic bacteria and lipopolysaccharide. I performed a prospective study examining the rates of preterm birth, small for gestational age neonates and neonatal inflammation in 277 women who had undergone a detailed antenatal periodontal examination and oral health questionnaire. Periodontal disease was associated with small for gestational age neonates, and increased CRP levels in umbilical cord blood, but no effect was seen on the rate of preterm birth. Maternal oral health symptoms predicted both periodontal disease and newborn biometry. In a retrospective case control study, I examined the role of periodontal disease in perinatal mortality. Participants included 53 women who had experienced a perinatal loss for which no cause could be found after thorough investigation, and 111 control women. Women who had experienced a perinatal loss were more than twice as likely as controls to have periodontal disease. The incidence of periodontal disease was even higher in women in whom the perinatal loss was due to extreme prematurity. In contrast to my prospective study, risks to the pregnancy could not be predicted by maternal oral health behaviours or oral health symptoms. In order to better understand the mechanisms regulating the associations described in the human studies, two animal models were developed; one to investigate acute exposure and the second to investigate long-term exposure to periodontal pathogens. The first study examined the effects of administration of a bolus of periodontopathic bacteria and lipopolysaccharide to the pregnant sheep. Injection of bacteria and lipopolysaccharide in the amniotic fluid of the pregnant preterm sheep caused a high rate of fetal lethality, disturbance of fetal acid base status and inflammation of the fetus and membranes. Given the circumstances of exposure to periodontopathic pathogens in human periodontal disease, a model investigating long-term exposure to periodontopathic lipopolysaccharide on pregnancy outcomes was developed. ... Overall, I have demonstrated that maternal periodontal disease is associated with adverse pregnancy outcomes including fetal growth restriction and possibly perinatal loss. Mechanisms regulating these effects are likely to be mediated by fetal adaptations to intrauterine inflammation resulting in altered fetal development, growth or survival. Randomised controlled trials that are currently in progress will provide further information on the effects of periodontal disease in human pregnancy, and the efficacy of treatment to reduce these adverse outcomes.

Abstract Increasing evidence suggests that early-life exposures influence the health and wellbeing in later life. Preterm birth (before 37 weeks of gestation) is associated with an increased risk of cardiometabolic disorders in later life. This risk may be partly mediated by nutrition along the course of life. As a part of the Helsinki Study of Very Low Birth Weight Adults, the aim of the present work was to investigate the association between energy and macronutrient intake during the first weeks after preterm birth at very low birth weight (VLBW, birthweight &#60; 1500g) and body composition and energy metabolism in adulthood (n=127). A further aim was to examine traits related to eating disorders and food and nutrient intake in young adults born early (&#60;34 weeks of gestational age, n=191) and late (34-&#60;37 weeks of gestational age, n=364) preterm and term-born controls (n=657) from the ESTER study and Arvo Ylppö Longitudinal study. Relatively low neonatal energy and nutrient intakes during the first weeks of life of infants born at VLBW predicted body composition and energy metabolism in adulthood. When adjusted for sex, age, gestational age and birth-weight SD score every 1g/kg/day greater early protein intake was associated with 10.4% (95% CI 2.4, 19.1) higher lean body mass (LBM) and 8.5% (0.2, 17.0) higher resting energy expenditure (REE). The ratio of REE/LBM however was 5.5% (0.8, 10.0) lower. In addition, higher protein and energy intakes predicted lower energy intake per unit of LBM in young adults. These associations were only partly mediated by early growth. Young women born early preterm reported on average healthier body image and fewer traits related to eating disorders when compared with term-born peers. However, their adherence to recommended eating guidelines was on average lower. According to the results of present work, energy balance is partly programmed by relatively small variations in the amount of protein in the diet in infancy. Among young adults born preterm, focusing on primary prevention, such as dietary counseling, is suggested. / Tiivistelmä Elämän varhaisvaiheet muokkaavat terveyttä ja hyvinvointia pitkällä aikavälillä. Ennenaikaisesti (ennen 37. raskausviikkoa) syntyneillä aikuisilla on todettu olevan suurempi riski sairastua sydän- ja verisuonitauteihin verrattuna täysiaikaisina syntyneisiin ikätovereihin. Ravitsemuksella, läpi elämänkaaren, on keskeinen rooli tuon riskin muokkaajana. Tämän väitöskirjatutkimuksen tavoitteena oli selvittää osana Pikku-k-tutkimusta (n=127), miten pienipainoisina (syntymäpaino &#60;1500g) syntyneiden keskosten elämän ensimmäisten viikkojen energian ja ravintoaineiden saanti ennustaa kehonkoostumusta ja energiankulutusta sekä energian saantia aikuisiässä. Lisäksi tavoitteena oli tutkia ESTER- tai AYLS-kohorttitutkimuksiin osallistuneiden, hyvin (&#60;34 raskausviikolla syntyneiden, n=191) ja lievästi (34-37, n=364) keskosena syntyneiden ja täysiaikaisena syntyneiden (n=657) nuorten aikuisten syömishäiriöpiirteitä, kehonkuvaa sekä ruoan käyttöä ja ravintoaineiden saantia. Suhteellisen matala elämän ensimmäisten viikkojen aikainen energian ja ravintoaineiden saanti ennusti kehonkoostumusta ja energia-aineenvaihduntaa aikuisiässä. 1g/kg/päivä korkeampi proteiininsaanti oli yhteydessä 10,4 % (95% luottamusväli 2,4; 19,1) suurempaan rasvattomaan painoon sekä 8,5 % (0,2; 17,0) korkeampaan lepoenergiankulutukseen aikuisiässä. Lepoenergiankulutus rasvatonta painoyksikköä kohden oli kuitenkin 5,5 % (0,8; 10,0) matalampi enemmän proteiinia saaneilla keskosilla. Lisäksi korkeampi energian ja proteiininsaanti elämän ensimmäisten viikkojen aikana ennusti matalampaa energiansaantia painoyksikköä kohden aikuisiässä. Varhaisella kasvulla oli vain pieni rooli tämän yhteyden välittäjänä. Nuorilla, hyvin ennenaikaisena (ennen 34. raskausviikkoa) syntyneillä, naisilla oli vähemmän syömishäiriöihin liittyviä piirteitä ja terveellisempi kehonkuva verrattaessa heitä täysiaikaisena syntyneisiin ikätovereihin. Arvioitaessa heidän ruokavaliotaan, todettiin kuitenkin heidän syövän hieman epäterveellisemmin ikätovereihin verrattuna. Tämän väitöskirjatutkimuksen tulosten valossa varhainen puuttuminen keskosena syntyneiden lisääntyneeseen sydän- ja verisuonitautien riskiin on mahdollista kiinnittämällä huomiota varhaiseen ravitsemukseen ja varhaisen aikuisiän elintapaohjaukseen, etenkin ravitsemukseen liittyen.

No description available.

A prematuridade é um dos grandes problemas de saúde pública, contribuindo com elevados números para a morbi-mortalidade infantil, principalmente em países em desenvolvimento como o Brasil. Conceitua-se o nascido prematuro ou pré-termo como aquele que nasce com menos de 37 semanas de gestação. Os fatores de risco individuais associados à incidência da prematuridade são conhecidos. No entanto, os fatores contextuais que podem influenciar na sua incidência têm sido pouco estudados. Sabe-se que a prematuridade é variável conforme a raça, as condições socioeconômicas, ambientais e culturais em que as mães estão inseridas. Assim, a presente tese teve por objetivo analisar o padrão da distribuição geográfica do risco relativo da prematuridade infantil em diferentes escalas: no estado de São Paulo, na Região Metropolitana de São Paulo e na esfera intra-urbana do município de São Paulo, durante o período de 2002 a 2007 (estado de SP), 2000 a 2010 (RMSP) e 2002 a 2013 (MSP) por meio da análise espacial exploratória. Investigamos como o contexto geográfico tem afetado o risco relativo de nascimentos pré-termo, através de testes de associação espacial global e local (I Moran e LISA) para estado de SP e para RMSP. Pela regressão multivariada global (OLS) e regressão geograficamente ponderada (GWS), estudamos quais variáveis explanatórias tiveram melhor capacidade explicativa para compreender espacialmente os riscos de nascimentos pré-termo no estados de SP (variável dependente). As variáveis explanatórias (independentes) foram representadas: pelas condições socioeconômicas das mães e foram mensuradas pelo índice de privação sociomaterial (IP), assim como pelo acesso ao sistema de saúde materna e do recém-nascido, representados pela porcentagem de cesáreas, pelo número de consultas pré-natal acima de 7 e pelo número de UTIs neonatais por 1000 nascidos vivos. Para isso, utilizamos dados de saúde do Sistema de Nascidos Vivos (SINASC) do Ministério da Saúde (DATASUS), dados socioeconômicos da Fundação SEADE, e dados de acesso da saúde materna e do recém-nascido do Cadastro Nacional de Estabelecimentos de Saúde (CNEs). Tanto os riscos relativos de nascimentos pré-termo como as variáveis socioeconômicas apresentaram autocorrelação espacial global significativa. Houve associação espacial local significativa entre os riscos relativos de nascidos prematuros com todas as variáveis socioeconômicas testadas para o estado de SP e para RMSP. As distribuições geográficas destas associações ocorreram de maneira não aleatória e heterogênea pelo estado de SP e pela RMSP, demonstrando a forte e complexa relação entre indicadores de saúde dos recém-nascidos com as condições socioeconômicas em que mães estão inseridas. Apenas o número de UTIs neonatais foi a única variável estatisticamente significativa do modelo global OLS, que melhor explicou a distribuição geográfica dos riscos relativos de nascimentos pré-termo no estado de SP. O modelo GWR ajudou a identificar separadamente e localmente quais os munícipios do território paulista que apresentaram riscos mais altos de nascimentos pré-termo pela privação sócio-material, pela porcentagem de cesáreas, pela porcentagem de consultas pré-natal acima de 7 e pelo número de UTIs neonatais por 1000 nascidos vivos. / Prematurity is a serious public health issue, increasing significantly the child morbidity and mortality cases, especially in developing countries such as Brazil. A premature or preterm birth is defined when the birth occurs with less than 37 gestational weeks. While the individual risk factors associated with the incidence of prematurity are known, contextual factors able to impact it have not been given the same attention. It is known that prematurity is influenced by the ethnic group and socio-economic, environmental and cultural conditions experienced by the mother. In this context, the present thesis aimed to analyze the spatial distribution patterns of the relative risk of premature birth, through exploratory spatial data analysis, in three different spatial scales: the state of São Paulo (SP), the São Paulo Metropolitan Area (SPMA), and in the intra-urban scale of the municipality of São Paulo (SPM). The time period studied ranged from 2002 to 2007 (SP), 2000 to 2010 (SPMA) and 2002 to 2013 (SPM). We investigated how the geographical context has affected the relative risk of preterm birth through global and local spatial association tests (Morans I and LISA) for the state of SP and the SPMA. Using the global multivariate regression (OLS) and the geographically weighted regression (GWR), we studied which explanatory variables best explained, spatially, the risk of preterm birth in the state of SP (dependent variable). The explanatory variables (independent) were represented by the socioeconomic conditions of the mothers and were measured by the sociospatial deprivation index (DPi), as well as the health system access by the mothers and premature infants, represented by the number of caesarian deliveries, number of prenatal testings above 7 and number of newborn emergency entries by 1000 live births. For that, we used data from the national Live Birth System (SINASC) from the Ministry of Health (DATASUS), socioeconomic data from the SEADE foundation, and newborn and maternal health access data from the National Registry of Health Facilities (CNEs) from Brazil. Both the preterm birth relative risks and the socioeconomic variables presented significant global spatial autocorrelation. There was significant spatial local association between the premature birth relative risks with all socioeconomic variables tested for the state of SP and for the SPMA. The geographical distribution of such associations occurred in a non-random pattern, and heterogeneously distributed through the territory of the state of SP and the SPMA, revealing the strong and complex relation between the newborn health indicators and the socioeconomic conditions to which their mothers are subject. The number of emergency entries was the statistically significant variable form the global model that best explained the geographical distribution of the preterm birth relative risks in the state of SP. The GWR helped to identify locally which municipalities of the state presented higher risks of preterm birth due to the sociospatial deprivation index, the number of caesarian deliveries, number of prenatal testings above 7 and number of newborn emergency entries by 1000 live births.

Made available in DSpace on 2016-03-15T19:39:47Z (GMT). No. of bitstreams: 1 Natalia Goncalves Albuquerque.pdf: 768903 bytes, checksum: 93c3caae46019ce7d673c0cb194dd653 (MD5) Previous issue date: 2011-08-16 / Prematurity has been identified as a risk factor for development of autism spectrum disorder (ASD). The aim of the present study was to perform a screening for autistic features in children with a history of preterm birth and to correlate with pregnancy, obstetric and neonatal complications. This study enrolled 37 infants, with gestational age < 34 weeks who had been admitted at Obstetric Center of Hospital do Servidor Público Estadual de São Paulo - Francisco Morato de Oliveira, from July 2005 to March 2007. Information of pregnancy, labor, delivery and neonatal complications were obtained from medical records at Neonatal Intensive Care Unit and the Office of Medical File (SAME). Follow-up assessment was performed when the children reached between 4 and 5 years of age, using Autism Behavior checklist (ABC). The gestational age at birth ranged from 24 to 34 weeks, and birth weight average was1655 + 613 g. The maternal age average was 33.5 + 8 years old. Approximately 56% and 100% of infants scored Apgar > 7 at one and five minutes, respectively. Birth conditions and perinatal complications show no differences between the sex groups, except that in favor of females, she were more likely to get higher Apgar scores at five minutes and body birth weight. Cyanosis and fetal distress were associated with increased risk of Apgar score <7 at one minute in preterm infants with birth weight <1500g. Immaturity was associated with increased risk for Apgar score <7 at one minute and bronchopulmonary dysplasia. Negative screening for autism spectrum disorder in this casuistic was primarily due to small sample size, limiting factor in this study, and secondly, the absence of certain characteristics in the casuistic. The literature assumes that maternal and neonatal morbidities, as gestational age < 26 weeks, very low birth weight infant, preeclampsia, being born small for gestational age, congenital malformations and low Agar score at five minutes and intracranial bleeding are strongly associated with autistic disorders in preterm birth. / A prematuridade tem sido associada com aumento de risco para desenvolvimento do transtorno do espectro do autismo (TEA). Este estudo teve como objetivo descrever as características de uma amostra de prematuros com idade gestacional < 34 semanas, rastrear sintomas de TEA em uma amostra de prematuros e correlacionar com as condições de nascimento, complicações obstétricas e neonatais. A casuística foi composta por 37 prematuros, com idade gestacional < 34 semanas que ingressaram no Centro Obstétrico do Hospital do Servidor Público Estadual de São Paulo - Francisco Morato de Oliveira, entre julho de 2005 a março de 2007. As variáveis maternas, obstétricas e neonatais foram obtidas nos prontuários da Unidade de Terapia Intensiva Neonatal e do Serviço de Arquivo Médico (SAME). O rastreamento dos sintomas dos transtornos do espectro do autismo foi realizado por meio de entrevistas com as mães aplicando-se o Inventário de Comportamentos Autísticos. A idade média materna foi de 33,5 + 8 anos, Ao nascimento, o peso médio dos prematuros foi 1655 + 613 g e a idade gestacional de 32 (intervalo de 24 a 34) semanas. Aproximadamente 56% e 100% dos prematuros obtiveram índice de Apgar > 7 no primeiro e no quinto minutos de vida, respectivamente. As condições de nascimento e as freqüências das complicações neonatais não foram diferentes entre os gêneros, exceto que, em favor do sexo feminino, observou-se maior índice de Apgar do quinto minuto e uma diferença marginal no peso ao nascimento. Condições neonatais como cianose e sofrimento fetal aumentaram a chance de Apgar de primeiro minuto <7 em prematuros com peso nascimento < 1500g. A imaturidade aumentou a chance de Apgar de primeiro minuto <7 e a broncodisplasia pulmonar. A triagem negativa para transtorno do espectro do autismo deveu-se primariamente a casuística reduzida, fator limitante deste estudo, e secundariamente, baseando-se em premissas da literatura, na ausência de certas características da amostra estudada.

Abstract Respiratory distress syndrome, RDS, is a multifactorial lung disease of premature infants. The main cause of RDS is a deficiency of pulmonary surfactant, a lipoprotein mixture required to reduce surface tension at the air-liquid interface and to prevent generalized atelectasis of the alveolar ducts and alveoli. Prematurity is the most important factor predisposing to RDS. During the past decade the number of multiple pregnancies has increased significantly as a result of diversified infertility treatments and advanced maternal age. Due to the considerably higher rate of preterm births of multiples compared to singletons, RDS is one of the major causes of morbidity among them. The objectives of the present research were to evaluate the incidence and risk factors of RDS in twins compared to singletons, and to assess the role of SP-A and SP-B gene variations and gene-environment interactions in the susceptibility to the disease in a population of preterm twins and higher order multiples. This research showed that during the past fifteen years the gestational age-specific incidence of RDS has declined. Twin infants do not have increased risk of RDS except when born very immaturely at a very early gestational age. The presenting twin is less susceptible to RDS than the non-presenting twin or singleton infant after 28 weeks of gestation until term. Additionally the SP-B Ile131Thr polymorphism was shown to affect the susceptibility specifically in the presenting twin. The role of SP-A polymorphisms in the risk of RDS in twins turned out to be different from that in singletons. The major allele and genotype of SP-A1 were associated with a decreased risk of RDS in near-term twin infants. The threonine allele in SP-B Ile131Thr appeared interactively with SP-A1 to associate with the risk of RDS both in twins and in singletons: associating with a lower risk of RDS in singletons at very early gestation, but surprisingly associating with a protection in twins and multiples from RDS near term. The risk of RDS, defined by the interaction of SP-A and SP-B alleles, was additionally associated with the fetal mass. Thus, the difference in the susceptibility to RDS in premature singletons and multiples may depend on the size of the conceptus. In an evaluation of the genetic risk factors for RDS, the classical twin study method comparing the concordance of a disease between MZ and DZ twins underestimates the extent of heredity. Several predominant intrauterine and perinatal environmental factors contribute to disease susceptibility regardless of zygosity and are suspected to override the hereditary components of RDS. Twin gestation was shown to be an effect modifier in the genetic susceptibility to RDS. / Tiivistelmä Vastasyntyneen hengitysvaikeusoireyhtymä, RDS-tauti, on hyvin monitekijäinen ennenaikaisena syntyneiden lasten sairaus. Taudin tärkein syy on keuhkojen pintajännitystä alentavan aineen, surfaktantin, puute ennenaikaisessa synnytyksessä. Surfaktantti on rasva-proteiiniseos, joka alentaa keuhkorakkuloiden pintajännitystä ja estää rakkuloiden kasaan painumisen hengityksen aikana. Epäkypsyys on tärkein RDS-taudin kehittymiselle altistava tekijä. Viimeisen vuosikymmenen aikana monisikiöiset raskaudet ovat lisääntyneet merkittävästi keinohedelmöitysten ja synnyttäjien kohonneen iän seurauksena. RDS-tauti on monisikiösynnytyksissä tärkeä sairastavuutta aiheuttava tekijä, koska monisikiöraskaudet päättyvät huomattavasti useammin ennenaikaisesti kuin yksösraskaudet. Tämän tutkimuksen tarkoituksena oli selvittää RDS-taudin ilmaantuvuutta ja riskitekijöitä kaksosilla verrattuna yksösiin, tutkia surfaktanttiproteiinien A ja B geenivaihtelua sekä geenien ja ympäristötekijöiden vuorovaikutusta kaksosten ja monisikiöisistä raskauksista syntyneiden lasten RDS-taudissa. Tutkimus osoitti, että viimeisten viidentoista vuoden aikana RDS-taudin raskausikäkohtainen ilmaantuvuus on vähentynyt. Vain hyvin epäkypsillä, ennenaikaisilla kaksosilla on lisääntynyt riski sairastua RDS-tautiin verrattuna yksösiin. 28 raskausviikon jälkeen ensimmäisenä syntyvällä kaksosella on pienempi riski saada RDS-tauti kuin toisena syntyvällä tai yksösellä. Lisäksi surfaktanttiproteiini B:n (SP-B) geenin eksonin 4 monimuotoisuus osoittautui vaikuttavan RDS-taudin alttiuteen erityisesti ensin syntyvällä kaksosella. Surfaktanttiproteiini A:n (SP-A) geenin yhteys RDS-taudin riskiin osoittautui olevan erilainen kaksosilla verrattuna yksösiin. Lähes täysiaikaisilla kaksosilla SP-A1 geenin valta-alleeli ja genotyyppi liittyivät RDS-taudin vähentyneeseen riskiin. SP-B geenin eksonin 4 treoniini alleeli osoittautui liittyvän yhdessä SP-A1 valtagenotyypin kanssa RDS-taudin riskiin sekä yksösillä että kaksosilla: hyvin ennenaikaisilla yksösillä geenien yhteisvaikutus lisäsi riskiä, kun taas lähes täysiaikaisilla kaksosilla sama geenien yhteisvaikutus yllättäen suojeli RDS-taudilta. SP-A ja SP-B geenien vuorovaikutuksen kautta välittyvä RDS-taudin riski oli lisäksi yhteydessä sikiön kokoon. Siten ennenaikaisena syntyneiden yksösten ja monisikiöisten RDS-taudin alttiuden ero voi olla riippuvainen sikiön koosta. Klassinen kaksostutkimusmenetelmä, jossa verrataan identtisten ja ei-identtisten kaksosten sairastuvuutta, aliarvioi perimän määräämien tekijöiden osuutta RDS-taudin synnyssä. Useat hallitsevat kohdunsisäiset ja synnytykseen liittyvät ympäristötekijät vaikuttavat RDS-taudin syntyyn ja kumoavat perimän osuutta. Kaksosuus osoittautui olevan periytymisen vaikutusta muokkaava tekijä RDS-taudissa.

Abstract Despite improvements in peri- and neonatal care and an increase in the overall survival of very preterm infants, the incidence of neurologic sequelae has remained high. The pathogenesis of many brain imaging findings, such as white matter damage, WMD, is poorly understood. The factors predisposing to brain damage differ between term and preterm infants. More detailed information is needed of how brain imaging correlates with neurodevelopmental impairment after the neonatal period. The present study investigated the pre- and perinatal factors leading to brain damage and their effects on neurologic and neurodevelopmental outcome in very preterm children. We also analyzed the differences in umbilical cord serum cytokines in term and preterm children with cerebral palsy, CP. Furthermore, the correlations between the findings on diffusion-weighted imaging, DWI, measurements in brainstem auditory evoked potentials, and neurodevelopmental outcome were assessed. We demonstrated that pregnancies complicated by combined histologic chorioamnionitis and placental insufficiency independently predicted abnormal neurologic outcome at 2 years of corrected age. WMD additively predicted poor outcome. Isolated fetal inflammatory response, umbilical cord serum acute phase cytokines (IL-1α, IL-1β, IL-6, IL-8, TNF-α), did not associate with neurologic outcome in either term or preterm children. Instead, a cluster of cytokines different from acute phase cytokines were related to CP, and the protein profile differed between term and preterm children. Disturbed hemodynamics during the pre- and perinatal period affected outcome in very preterm infants. In severe placental insufficiency, fetal cardiac compromise associated with suboptimal neurodevelopmental outcome at 1 year of corrected age. In addition, several clinical factors characterising cardiorespiratory status after birth associated with abnormal neurologic outcome at 2 years of corrected age. We found the apparent diffusion coefficient, ADC, a quantitative measurement of water diffusion, in pons to correlate with the conduction rate of impulses travelling through the auditory tract. We also demonstrated a high value of ADC in corona radiata to associate with poor outcome in gross motor and eye-hand coordination skills at 2 years of corrected age. Both pre- and perinatal factors associate with later outcome in very preterm infants. An isolated fetal inflammatory response does not predict neurologic outcome. Findings on DWI in specific brain regions predict abnormal neurodevelopmental outcome. / Tiivistelmä Huolimatta vastasyntyneisyyskauden parantuneista hoitotuloksista ja että yhä useampi hyvin ennenaikaisena syntynyt lapsi jää eloon, heidän neurologisen vammautuneisuuden ilmaantuvuus on edelleen korkea. Monien aivojen kuvantamislöydösten, kuten valkean aineen vaurion, syntymekanismit tunnetaan huonosti. Aivojen vaurioitumiselle altistavat tekijät eroavat täysiaikaisena ja ennenaikaisena syntyneillä lapsilla. Tarvitaan myös aiempaa yksityiskohtaisempaa tietoa aivojen kuvantamislöydösten merkityksestä lasten vastasyntyneisyyskauden jälkeiseen kehitykseen. Tässä tutkimuksessa selvitettiin raskauden- ja syntymänaikaisia tekijöitä, jotka vaikuttavat aivojen vaurioitumiseen hyvin ennenaikaisena syntyneillä lapsilla sekä näiden tekijöiden merkitystä lasten neurologiseen kehitykseen. Tarkastelimme myös napaveren seerumin välittäjäaineiden, sytokiinien, eroavuuksia täysiaikaisena ja ennenaikaisena syntyneillä CP-lapsilla. Lisäksi selvitimme diffuusiomagneettitutkimus- ja aivorunkoherätevastelöydösten sekä neurologisen kehityksen välisiä yhteyksiä. Tämän tutkimuksen mukaan kohdunsisäinen tulehdus ja istukan vajaatoiminta yhtä aikaa esiintyessään ovat poikkeavan neurologisen kehityksen itsenäisiä riskitekijöitä lapsilla 2 vuoden korjatussa iässä tutkittuna. Valkoisen aivoaineen vaurio edelleen lisäsi näiden lasten huonon neurologisen kehityksen ennustetta. Raskauden kestosta riippumatta, sikiön tulehdusvastetta kuvaavat napaveren akuutin vaiheen tulehdusvälittäjäaineet (IL-1α, IL-1β, IL-6, IL-8, TNF- α) eivät vaikuttaneet lapsen neurologiseen kehitykseen. Sen sijaan, CP-lasten napaverestä löytyi erityinen joukko ei-akuutin vaiheen välittäjäaineita. Nämä valkuaisaineet erosivat toisistaan täysiaikaisena ja ennenaikaisena syntyneillä CP-lapsilla. Raskauden- ja syntymänaikaiset verenkierron häiriöt vaikuttivat hyvin ennenaikaisena syntyneiden lasten myöhempään kehitykseen. Vaikeassa istukan vajaatoiminassa sikiön sydämen toiminnan heikkeneminen liittyi lapsen suboptimaaliin neurologiseen kehitykseen 1 vuoden korjatussa iässä tutkittuna. Lisäksi useat syntymänjälkeiset keuhkojen ja verenkierron tilaa kuvaavat kliiniset tekijät liittyivät lapsen poikkeavaan neurologiseen kehitykseen 2 vuoden korjatussa iässä tutkittuna. Tutkimuksemme mukaan, veden diffuusiota määrällisesti kuvaava diffuusiokerroin, ADC, aivosillasta mitattuna, liittyi impulssien johtumisnopeutueen kuuloradastossa. Lisäksi korkea ADC-arvo aivojen sepelviuhkassa liittyi karkean motoriikan ja silmä-käsi-yhteistyötaitojen huonoon kehitykseen 2 vuoden korjatussa iässä tutkittuna. Sekä raskauden- että syntymänaikaiset tekijät vaikuttavat hyvin ennenaikaisena syntyneiden lasten myöhempään kehitykseen. Yksittäinen sikiön tulehdusvaste ei ennakoi lapsen neurologista kehitystä. Tiettyjen aivoalueiden diffuusiokuvantamislöydökset ennustavat lapsen poikkeavaa neurologista kehitystä.

Abstract Pulmonary surfactant is a lipid-protein mixture that lines the inner surface of the lung. The main function of surfactant is to reduce surface tension at the air-liquid interface, thus preventing alveolar collapse at the end of expiration. Lack of surfactant is the main cause of respiratory distress syndrome (RDS) in preterm infants. Very preterm babies are at risk of developing a lung disease called bronchopulmonary dysplasia (BPD). The surfactant proteins SP-A, -B, -C and -D have important functions in surfactant structure, homeostasis and innate immunity of the lung. The genes of these proteins have been studied as candidates for several multifactorial lung diseases both in adults and in children. The aim of the present study was to examine the genetic variation in SP genes and to evaluate the role of SP gene polymorphism in the etiology of severe pulmonary infantile diseases, including RDS, BPD and severe respiratory syncytial virus (RSV) infection among the Finnish population. Conventional allelic association methods in combination with multiparameter analysis and family-based transmission disequilibrium test (TDT) were used. The SP-D Met11 allele was associated with a risk for severe RSV bronchiolitis in a matched case-control setting of 84 infants with severe RSV infection and 93 control infants. The variants of the SP-C gene had no detectable association with BPD. However, a modest association of SP-C Asn138 and Asn186 alleles with RDS was found. A length variation in the SP-B gene was associated with BPD among very preterm infants born before 32 weeks of gestation. The SP-B intron 4 deletion variant allele increased the risk for BPD especially in very low birth weight infants. The association was confounded by birth order, being evident only among presenting infants, who are more prone to ascending infections during a preterm birth process. The present study provides new evidence about the significance of SP gene polymorphisms in the etiology of complex infantile pulmonary diseases, including RDS, BPD and severe RSV bronchiolitis. The results help us to understand the molecular mechanisms underlying these diseases and may, in the long run, enable better treatment of these life-threatening diseases. / Tiivistelmä Keuhkosurfaktantti on keuhkon sisäpintaa peittävä kalvomainen rasva-proteiinikompleksi, jonka tärkein ominaisuus on pintajännityksen vähentäminen keuhkorakkuloissa. Surfaktantin puutos ennenaikaisesti syntyneillä lapsilla aiheuttaa hengitysvaikeusoireyhtymän, RDS-taudin (respiratory distress syndrome). Alle 30 raskausviikon iässä syntyneistä, useimmiten RDS-taudin saaneista keskosista n. 30 % sairastuu vakavaan krooniseen keuhkotautiin, BPD-tautiin (bronchopulmonary dysplasia). Surfaktanttiproteiineilla SP-A, -B, -C ja -D on osoitettu olevan tärkeä tehtävä surfaktantin toiminnassa ja keuhkon synnynnäisessä immuniteetissa. Tämän tutkimuksen tavoitteena oli selvittää surfaktanttiproteiineissa esiintyvän geneettisen muuntelun määrää ja merkitystä keskosten RDS- ja BPD-taudeissa sekä pienten lasten vakavassa respiratory syncytial -viruksen (RSV) aiheuttamassa keuhkotulehduksessa. Tutkimuksen laajin osa keskittyi tutkimaan keskosten BPD-tautia ja surfaktanttiproteiinien geenien osuutta siinä. Geneettisen muuntelun merkitystä tarkasteltiin populaatiogeneettisin keinoin tapaus-verrokkiasetelmissa ja perheaineistojen avulla. Yhteensä analysoitiin noin tuhannen lapsen ja yli kahdensadan vanhemman DNA-näytteet. Tutkimuksessa havaittiin SP-D-geenissä olevan metioniini11-geenimuodon liittyvän pienten lasten vakavaan RSV-infektioon. Lisäksi saatiin uutta tietoa SP-C-geenin populaatiotason yleisestä muuntelusta ja todettiin SP-C:n asparagiini138 ja asparagiini186 -geenimuotojen yhteys keskosten RDS-taudin esiintymiseen. Merkittävin löydös oli SP-B-geenissä olevan deleetiovariantin kytkeytyminen alle 32-viikkoisina syntyneiden keskosten BPD-tautiin. Geneettisen altistuksen lisäksi BPD-tautiin sairastumiseen vaikuttivat lukuisat keskosuudelle ominaiset seikat, kuten alhainen syntymäpaino, RDS-tauti ja syntymähetkellä todettu hapenpuute. Geneettisen tekijän vaikutus oli voimakkain erittäin pienipainoisilla keskosilla. Tutkimuksen tulokset ovat tuoneet arvokasta lisätietoa surfaktanttiproteiinien geenien osuudesta keskosten RDS- ja BPD-taudeissa sekä pienten lasten vakavassa RSV-infektiossa. Ne auttavat ymmärtämään näiden molekyylibiologisia syntymekanismeja ja voivat ajan mittaan olla edistämässä uusien hoitomuotojen kehittämistä.