Made available in DSpace on 2014-12-17T14:13:32Z (GMT). No. of bitstreams: 1 NilbaLS_Tese.pdf: 636235 bytes, checksum: 871e98d076a82a24e17c822a9ea7198e (MD5) Previous issue date: 2009-12-18 / Hypertensive syndromes in pregnancy (HSP) are configured as one of the major complications in the pregnancy and postpartum period and can lead premature newborn and subsequent hospitalization of the newborn to the Neonatal Intensive Care Unit (NICU). This study aimed to analyze the perceptions, meanings and feelings of mothers on the hypertensive syndromes in pregnancy and premature obstetric labor. The research was qualitative and has a theoretical methodological the Social Representations Theory(SRT) in the approach to the Central Nucleus Theory. The study included 70 women, mean age 29 years, predominantly school to high school, most of them married or in consensual union, primiparous and prevalence of cesarean delivery occurred between 32 and 37 weeks of pregnancy.The data were collected from may to december 2008 in the Maternity School Janu?rio Cicco in Natal , and obtained through the following instruments for data collection: questionnaire including questions about socio-demographic status; the Free Words Association Test (FWAT) and and verbalized mental image construction used three stimuli: such as pregnancy with high blood pressure, preterm birth and NICU, and interview with the following guiding question: what it meant for you to have a pregnancy with high blood pressure and consequently the birth of a premature baby? Data analysis was performed using multi-method obtained from the data processing by EVOC (Ensemble Programmes Permettant L 'Analyze des ?vocations) and ALCESTE (Analyse Lexicale par Contexte d'un Ensemble de Segment de Texte) and thematic analysis in categories. The results will be presented in four thematic units under the following representative universes: HSP, prematurity as a result of HSP, NICU and the social representations of mothers on the hypertensive disorder of pregnancy sequenced premature birth and hospitalization of the child in the NICU. The results obtained by multimethod analyses showed similar constructions and point to death as the central nucleus and negative aspects, coping strategies, need of care, knowledge about the disease, fragility and meanings of the NICU as peripheral elements. It is considered that the perceptions, meanings and feelings of puerperal women in relation to HSPs and to premature delivery are a negative social representation, with representational elements that may have influenced the adverse effects on the disease and its consequences. We suggest action on the peripheral elements of this representation, with adequate orientation, early diagnosis, effective conduct, receptive attitude on the part of the team, health promotion measures and effective public policies, in order to improve the care provided to puerperal women, making them feel welcome and minimizing their suffering / As s?ndromes hipertensivas da gravidez (SHG) s?o complica??es do per?odo grav?dico puerperal e podem levar ? prematuridade neonatal e consequente hospitaliza??o do rec?m-nascido em Unidade de Terapia Intensiva Neonatal (UTIN). O estudo objetivou compreender percep??es, significados e sentimentos de pu?rperas relativos ?s SHGs que tiveram como consequ?ncia o parto prematuro e a hospitaliza??o do filho na UTIN. ? um estudo qualitativo que teve como referencial te?rico metodol?gico a Teoria das Representa??es Sociais (TRS), na abordagem complementar da Teoria do N?cleo Central. Participaram do estudo 70 mulheres ; com idade m?dia de 29 anos; a maioria com n?vel m?dio de escolaridade; em uni?o consensual; prim?paras e com parto ces?rio ocorrido entre 32 e 37 semanas de gesta??o. Os dados foram coletados de maio a dezembro de 2008, na Maternidade Escola Janu?rio Cicco, em Natal/RN, por meio de: question?rio para caracteriza??o sociodemogr?fica das participantes; t?cnica de associa??o livre de palavras (TALP); constru??o verbalizada de imagens mentais; e entrevista, com a seguinte quest?o norteadora: O que significou para voc? ter uma gravidez com press?o alta e, como consequ?ncia, o nascimento de um filho prematuro? A an?lise de dados foi realizada por meio de multim?todos, a partir do processamento de dados pelos software EVOC (Ensemble de programmes permettant L analyse des evocations) e ALCESTE (An?lise lexical por contexto em um conjunto de segmentos de texto), e an?lise tem?tica categorial. Os resultados foram apresentados em quatro unidades tem?ticas, no ?mbito dos seguintes universos representativos: SHG; prematuridade como consequ?ncia das SHGs; UTIN; e as representa??es sociais de pu?rperas sobre as SHGs seguidas do nascimento prematuro e hospitaliza??o do filho na UTIN. Os resultados obtidos por meio dos multim?todos de an?lise apresentaram constru??es semelhantes entre si e apontam a morte como n?cleo perif?rico, aspectos negativos, estrat?gias de enfrentamento, necessidades de cuidados, conhecimento sobre a doen?a, fragilidade e significados da UTIN. Considera-se que as percep??es, significados e sentimentos de pu?rperas relativas ?s SHGs e ao parto prematuro constituem uma representa??o social negativa, com elementos representacionais que podem ter influenciado os efeitos adversos sobre a doen?a e suas consequ?ncias. Sugere-se atua??o sobre os elementos perif?ricos dessa representa??o, com orienta??es adequadas, diagn?stico precoce, condutas efetivas, postura acolhedora da equipe, atitudes de promo??o ? sa?de e pol?ticas p?blicas eficazes, de forma a melhorar a assist?ncia ?s mulheres/pu?rperas, acolhendo-as adequadamente e minimizando seus sofrimentos

Abstract Each year in Finland, approximately 5.7% of infants are born preterm, i.e., before 37 completed weeks of gestation. Preterm birth is a major cause of mortality and several neonatal morbidities, especially the respiratory diseases. Infants born very preterm (<32 wk) are at higher risk of developing a chronic lung disease called bronchopulmonary dysplasia (BPD). The genetic factors predisposing to spontaneous preterm birth (SPTB) and BPD are incompletely known. The aims of this thesis project were to identify genetic factors that affect susceptibility to SPTB and BPD. Genetic case-control association studies were performed in mothers and infants of northern Finnish origin (SPTB study), or in multiple populations of very preterm infants of Finnish or European origin (BPD study). The candidate genes were selected based on their proposed roles in inflammation which is involved in both SPTB and BPD susceptibility. Additionally, the aim was to study the possible functional role of polymorphisms in the gene encoding surfactant protein B (SP-B) that have been shown previously to associate with pulmonary function. An association between Met31Thr polymorphisms in the gene encoding SP-D (SFTPD) and SPTB infants was found. The other collectin genes that were studied, encoding SP-A and mannose-binding lectin, did not associate with SPTB in mothers or infants. An intronic polymorphism in the gene encoding Kit ligand (KITLG) was associated with the risk of BPD in the northern Finnish and in the combined population that originated from Finland, Canada and Hungary. The role of KITLG in BPD was further supported by biomarker data, which showed higher concentrations of Kit ligand at the time of birth in infants that later developed BPD. The genes encoding interleukin 6 (IL-6), its receptors, IL-10, tumor necrosis factor alpha or glucocorticoid receptor did not associate with BPD susceptibility. Finally, a genetic variant 131Thr in the gene encoding SP-B (SFTPB) was associated with lower SP-B levels in vivo and delayed secretion in vitro. To date, there is no effective method to prevent SPTB, and especially the extremely preterm infants are at an increased risk of developing serious respiratory diseases. Better understanding of the mechanisms underlying both SPTB and BPD could help in the successful prediction of risk groups as well as in the design of new preventive and treatment strategies. / Tiivistelmä Noin 5,7 % lapsista syntyy Suomessa ennenaikaisesti, eli ennen kuin raskaus on kestänyt täydet 37 viikkoa. Ennenaikainen syntymä altistaa vastasyntyneen lapsen vakaville pitkäaikaissairauksille. Erityisesti hyvin pienillä keskosilla, jotka ovat syntyneet ennen 32. raskausviikkoa, on suurempi riski sairastua vakavaan hengitysvaikeuteen eli bronkopulmonaaliseen dysplasiaan, joka tunnetaan myös nimellä BPD-tauti. Perinnölliset tekijät vaikuttavat niin spontaanin ennenaikaisen syntymän (SEAS) kuin BPD-taudinkin taustalla, mutta nämä tekijät tunnetaan huonosti. Tässä väitöskirjatyössä pyrittiin tunnistamaan perinnöllisiä tekijöitä, jotka vaikuttavat SEAS:in ja BPD-taudin taustalla. Perinnöllisen taustan selvittämisessä ehdokasgeenien sisältämien muuntelevien kohtien esiintyvyyttä verrattiin terveiden verrokkien ja tautitapausten välillä. SEAS-tutkimuksessa tutkimusväestö koostui suomalaisista äideistä ja heidän lapsistaan. BPD-tutkimuksessa oli mukana hyvin ennenaikaisesti syntyneitä lapsia Suomesta, Kanadasta ja Unkarista. Tämän lisäksi kokeellisten tutkimusten avulla tutkittiin aiemmin keuhkosairauksiin liittyneen geenin muuntelevien kohtien osuutta sen koodaaman surfaktanttiproteiini (SP) B:n toiminnassa. Tutkimuksissa havaittiin SP-D:tä koodaavan geenin Met31Thr-polymorfismin olevan mahdollinen riskitekijä SEAS:lle lapsilla, mutta se ei selittänyt SEAS-riskiä äideissä. SP-A:ta ja mannoosia sitovaa lektiiniä koodaavilla geeneillä ei ollut yhteyttä SEAS-riskiin. Kit-ligandia koodaavan geenin intronissa sijaitseva polymorfismi selitti BPD-tautiriskiä pohjoissuomalaisessa sekä yhdistetyssä tutkimusväestössä. Lisäksi lapsilla, jotka myöhemmin sairastuivat BPD-tautiin, havaittiin suurempia Kit-ligandipitoisuuksia syntymähetkellä. Interleukiini 6:ta (IL-6), sen reseptoreita, IL-10:ta, tuumorinekroosifaktori-alfaa tai glukokortikoidireseptoria koodaavien geenien polymorfismien ja BPD-taudin välillä ei ollut yhteyttä. SP-B:tä koodaavan geenin Ile131Thr-polymorfismin Thr-variaatio liittyi alhaisempaan SP-B:n pitoisuuteen lapsivedessä sekä hidastuneeseen proteiinin tuottoon kokeellisessa solumallissa. Tulokset antavat uutta tietoa SEAS:n ja BPD-taudin perinnöllisestä taustasta. Tämä tieto voi auttaa synnytyksen käynnistymiseen sekä BPD-alttiuteen johtavien biologisten mekanismien selvittämisessä ja uusien hoitokeinojen kehittämisessä.

Abstract Children born preterm are prone to acute brain insults related to subsequent neurodevelopmental impairments. However, the role of specific biomarkers and perinatal clinical factors in the pathogenesis of brain injury and neurodevelopmental sequelae has remained poorly understood. The present study evaluated whether specific immunoproteins at birth predict the risk of intraventricular hemorrhage (IVH) and whether their receptors are localized at the bleeding site. We further investigated whether children who went on to develop cerebral palsy (CP) could be identified on the basis of blood immunoproteins collected during the perinatal period. The association between single nucleotide polymorphisms in the chemokine CCL18 gene and susceptibility to CP was also studied. Finally, we investigated the association of pre- and postnatal factors with cognitive outcomes in very preterm-born schoolchildren without impairments. The present study revealed that a low concentration of CCL18 in cord blood was an independent risk factor of IVH in very preterm infants. The CCL18 receptor, CCR3, was detectable in the periventricular area and in the neurons of the hippocampus in preterm infants already at 23 weeks of gestation. We also identified a cluster of cord blood cytokines that was associated with the risk of CP. In addition, inflammatory cytokine levels were associated with CP risk on days 1 and 7 after birth. The genetic study showed that both IVH and the CCL18 polymorphism independently and additively had an influence on CP susceptibility. Our study further demonstrated that schoolchildren born very preterm without CP or cognitive impairment had poorer performance in visuospatial–sensorimotor skills and in attention–executive functions than term-born children. Fetal growth restriction was an independent risk factor of compromised neurocognitive outcome in very preterm children predicting difficulties in language, memory and learning. In conclusion, specific cytokines and cytokine clusters serve as biomarkers of different pathways involved in damage to the brain structures and in the pathogenesis of CP. In addition, genetic factors can affect these processes. Further, fetal growth restriction and prematurity play important roles in neurocognitive development later in life. / Tiivistelmä Hyvin ennenaikaisina syntyneet lapset ovat alttiita akuuteille aivovaurioille sekä myöhemmin ilmeneville kehityshäiriöille. Eri välittäjäaineiden sekä raskaudenaikaisten ja syntymänjälkeisten kliinisten tekijöiden vaikutusta aivojen vaurioherkkyyteen sekä neurologiseen ja neurokognitiiviseen kehitykseen ei kuitenkaan ole tutkittu riittävästi. Tässä tutkimuksessa tarkasteltiin, ennustaako jokin napaverestä tutkituista sytokiineista aivoverenvuotoa hyvin ennenaikaisesti syntyneillä vastasyntyneillä. Lisäksi selvitettiin, onko sytokiinin spesifinen reseptori osoitettavissa vuotoherkällä alueella aivoissa. Tutkimme myös, ennustaako jokin napaveren immunoproteiini-profiilin komponentti CP-vamman syntyä joko itsenäisesti tai yhdessä muiden perinataalisten riskitekijöiden kanssa sekä lisääkö tietyn sytokiinin (CCL18) geneettinen vaihtelu CP-vamman riskiä hyvin ennenaikaisesti syntyneillä lapsilla. Lisäksi selvitimme, vaikuttavatko raskaudenaikaiset tekijät ja vastasyntyneisyyskauden sairaudet neurokognitiiviseen kehitykseen kouluiässä. Tämän tutkimuksen mukaan napaveren matala CCL18-kemokiinipitoisuus oli itsenäinen aivoverenvuodon riskitekijä. CCR3-reseptori, johon CCL18 sitoutuu, oli osoitettavissa sekä vuotoherkällä alueella että hermosoluissa 23. raskausviikon iästä lähtien. Havaitsimme myös, että tietyt napaveren sytokiiniryppäät ja yksittäisten tulehdusvastevälittäjäaineiden pitoisuudet 1. ja 7. elinpäivänä olivat yhteydessä CP-riskiin. Lisäksi havaitsimme yhteyden CCL18-kemokiinin geneettisen vaihtelun ja aivoverenvuodon sekä CP-vamman kehittymisen välillä. Tutkimuksemme mukaan hyvin ennenaikaisesti syntyneet koululaiset, joilla ei ollut CP- tai kehitysvammaa, suoriutuivat täysiaikaisina syntyneitä verrokkeja heikommin visuaalista hahmotusta ja sensomotoriikkaa sekä tarkkaavuutta ja toiminnanohjausta mittaavissa testeissä. Lisäksi havaitsimme sikiöaikaisen kasvuhäiriön ennustavan itsenäisesti heikkoa suoritusta kieltä, muistia ja oppimista testaavissa tehtävissä ennenaikaisesti syntyneillä lapsilla. Tietyt sytokiinit ja sytokiiniryppäät ovat yhteydessä aivovauriomekanismeihin. Nämä mekanismit saattavat yhdessä perinnöllisen alttiuden kanssa vaikuttaa myös CP-vamman syntyyn. Sikiöaikainen kasvuhäiriö ja ennenaikaisuus vaikuttavat lapsen myöhempään neurokognitiiviseen kehitykseen.

Vid prematur födsel finns en ökad risk för kognitiva svårigheter och utmaningar i språkutvecklingen. Tidigare forskning har framhållit vikten av att erbjuda interventioner med fokus på språkutvecklingen redan i tidig ålder för att stödja barns utveckling. En intervention som syftar till att utveckla barns språkutveckling är interaktiv högläsning. Syftet med denna pilotstudie var att utvärdera om en 4-veckors intervention med interaktiv högläsning kunde förbättra kommunikationsfärdigheterna hos små barn födda prematurt. För att undersöka detta filmades och analyserades två föräldra-barn-par i en single-subject design med fyra baslinjetillfällen och nio interventionstillfällen. Resultaten från studien antyder att interventionen kan ha en positiv påverkan på kommunikationsfärdigheterna hos små barn födda prematurt. Ytterligare forskning för att fördjupa förståelsen för metoden och dess tillämpning erfordras. / At preterm birth, there is an increased risk of cognitive difficulties and challenges in language development. Previous research on preterm infants has emphasized the importance of providing interventions focusing on language development at an early age to support children's development. Interactive reading is a method aimed at fostering children's language skills. The aim of this pilot study was to evaluate whether a four-week intervention with interactive reading could improve the communication skills of preterm infants. To investigate this, two parent-child pairs were videotaped and analyzed using a single-subject design with four baseline sessions and nine intervention sessions. New instructions/techniques were provided to the parents during the intervention sessions. The results of this pilot study suggest that the intervention may have a positive impact on the communication skills of prematurely born children. Further research to deepen the understanding of the method and its application is warranted.

INTRODUÇÃO: O antecedente de parto prematuro espontâneo em gestação anterior é considerado o principal e mais importante fator de risco clínico para prematuridade, principal causa de morbidade e mortalidade neonatal. Cerca de 25% das pacientes que tiveram parto prematuro apresentarão recorrência. A prevenção secundária consiste na pesquisa de marcadores de maior risco, com o intuito de instituir medidas terapêuticas apropriadas e de evitar tratamentos desnecessários. A hipótese do presente estudo é a de que existe correlação entre os resultados da avaliação do colo uterino e do teste para proteína-1 fosforilada ligada ao fator de crescimento insulina-símile (phIGFBP-1) e que a utilização de ambos em associação possa predizer a ocorrência de parto prematuro com maior sensibilidade. OBJETIVOS: Averiguar a utilidade da medida do comprimento do colo uterino e do teste para phIGFBP-1 na predição do parto prematuro antes de 37 e de 34 semanas, a existência de relação dos testes entre si, o melhor valor de corte da medida do colo em diferentes idades gestacionais e a melhor época de realização de cada um dos exames. MÉTODO: Foram compilados e submetidos a análise secundária os dados de 101 gestantes com antecedente de parto prematuro atendidas no Setor de Baixo Peso Fetal da Clínica Obstétrica do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, entre 2003 e 2008. A medida do comprimento cervical e o teste para phIGFBP-1 foram realizados a cada três semanas, entre 24 e 34 semanas de gestação, e comparados com o desfecho de parto prematuro e nascimento com 34 semanas ou menos, e o melhor valor de corte do colo uterino foi estabelecido por meio de curva de características operacionais. RESULTADOS: Das 101 gestações estudadas, 25 (24,8%) terminaram em parto prematuro, das quais 12 (11,9%) ocorreram com 34 semanas ou menos. As idades gestacionais médias de avaliação foram de 24, 27, 30 e 33 semanas, e os valores de corte do colo uterino foram de 22, 21, 20 e 16 mm, respectivamente. A medida do comprimento do colo apresentou maior sensibilidade (cerca de 70%) e foi capaz de predizer o parto prematuro em todas as avaliações. O teste para phIGFBP-1 não foi útil com 24 semanas, porém foi capaz de detectar de forma independente o risco de prematuridade com 27, com 30 e com 33 semanas. Houve associação estatística dos exames entre si, de forma que o comprimento cervical médio foi menor em gestantes com teste positivo para phIGFBP-1. A associação dos exames elevou a sensibilidade e o valor preditivo negativo de forma significativa. CONCLUSÕES: A medida do comprimento do colo pela ultrassonografia transvaginal constitui bom marcador de risco para parto prematuro com 24 semanas, e o teste para phIGFBP-1 é útil após 27 semanas. A associação dos dois exames possui alta sensibilidade e alto valor preditivo negativo em gestantes de alto risco para prematuridade espontânea, e a realização do primeiro com 24 semanas e do segundo com 27 semanas constitui bom modelo preditivo para o parto prematuro / INTRODUCTION: The history of spontaneous preterm birth in a previous pregnancy is considered the main and most important clinical risk factor for preterm birth, the leading cause of neonatal morbidity and mortality. About 25% of these patients will deliver prematurely again. Secondary prevention consists in the search for markers of increased risk, in order to institute appropriate therapeutic actions and to avoid unnecessary treatments. The hypothesis of this study is that there is a correlation between the results of the evaluation of the cervix and the test for phosphorylated insulin-like growth factor binding protein-1 (phIGFBP-1) and that the use of both in combination can predict the occurrence of preterm delivery with higher sensitivity. OBJECTIVES: To investigate the usefulness of the measurement of the cervical length and phIGFBP-1 rapid test in the prediction of preterm birth before 37 and 34 weeks, the existence of a relationship between the tests themselves, the best cutoff value of cervical length measurement at different gestational ages and the best time to carry out each of the exams. METHODS: Data of 101 women with previous preterm birth assisted at the Obstetrical Clinic of the Hospital das Clínicas, Faculty of Medicine, University of São Paulo between 2003 and 2008 were collected and subjected to secondary analysis. The measurement of cervical length and the phIGFBP-1 test were performed every three weeks, between 24 and 34 weeks gestation, and compared with the outcome of premature birth before 37 and 34 weeks, and the best cutoff value of the cervix was determined by receiver operator characteristic curves. RESULTS: Of the 101 pregnancies studied, 25 (24.8%) ended in preterm birth, of which 12 (11.9%) occurred at 34 weeks or less. The mean gestational age in each evaluation was 24, 27, 30 and 33 weeks, and the cutoff of the cervix were 22, 21, 20 and 16 millimeters, respectively. The measurement of cervical length showed the highest sensitivity (approximately 70%) and was able to predict preterm birth in all evaluations. The phIGFBP-1 test was not useful at 24 weeks, but was able to independently detect the risk of prematurity at 27, 30 and 33 weeks. Statistical association between the exams was observed, so that the mean cervical length was lower in pregnant women testing positive for phIGFBP-1. The combination of both tests significantly increased the sensitivity and negative predictive value. CONCLUSIONS: The measurement of cervical length by transvaginal ultrasound is a good marker of risk for preterm delivery at 24 weeks, and the test for phIGFBP-1 is useful after 27 weeks. The association of the two tests is valuable and shows high sensitivity and high negative predictive value in women at high risk for spontaneous preterm birth, when the first is preformed with 24 weeks, and the second with 27 weeks

INTRODUÇÃO: O antecedente de parto prematuro espontâneo em gestação anterior é considerado o principal e mais importante fator de risco clínico para prematuridade, principal causa de morbidade e mortalidade neonatal. Cerca de 25% das pacientes que tiveram parto prematuro apresentarão recorrência. A prevenção secundária consiste na pesquisa de marcadores de maior risco, com o intuito de instituir medidas terapêuticas apropriadas e de evitar tratamentos desnecessários. A hipótese do presente estudo é a de que existe correlação entre os resultados da avaliação do colo uterino e do teste para proteína-1 fosforilada ligada ao fator de crescimento insulina-símile (phIGFBP-1) e que a utilização de ambos em associação possa predizer a ocorrência de parto prematuro com maior sensibilidade. OBJETIVOS: Averiguar a utilidade da medida do comprimento do colo uterino e do teste para phIGFBP-1 na predição do parto prematuro antes de 37 e de 34 semanas, a existência de relação dos testes entre si, o melhor valor de corte da medida do colo em diferentes idades gestacionais e a melhor época de realização de cada um dos exames. MÉTODO: Foram compilados e submetidos a análise secundária os dados de 101 gestantes com antecedente de parto prematuro atendidas no Setor de Baixo Peso Fetal da Clínica Obstétrica do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, entre 2003 e 2008. A medida do comprimento cervical e o teste para phIGFBP-1 foram realizados a cada três semanas, entre 24 e 34 semanas de gestação, e comparados com o desfecho de parto prematuro e nascimento com 34 semanas ou menos, e o melhor valor de corte do colo uterino foi estabelecido por meio de curva de características operacionais. RESULTADOS: Das 101 gestações estudadas, 25 (24,8%) terminaram em parto prematuro, das quais 12 (11,9%) ocorreram com 34 semanas ou menos. As idades gestacionais médias de avaliação foram de 24, 27, 30 e 33 semanas, e os valores de corte do colo uterino foram de 22, 21, 20 e 16 mm, respectivamente. A medida do comprimento do colo apresentou maior sensibilidade (cerca de 70%) e foi capaz de predizer o parto prematuro em todas as avaliações. O teste para phIGFBP-1 não foi útil com 24 semanas, porém foi capaz de detectar de forma independente o risco de prematuridade com 27, com 30 e com 33 semanas. Houve associação estatística dos exames entre si, de forma que o comprimento cervical médio foi menor em gestantes com teste positivo para phIGFBP-1. A associação dos exames elevou a sensibilidade e o valor preditivo negativo de forma significativa. CONCLUSÕES: A medida do comprimento do colo pela ultrassonografia transvaginal constitui bom marcador de risco para parto prematuro com 24 semanas, e o teste para phIGFBP-1 é útil após 27 semanas. A associação dos dois exames possui alta sensibilidade e alto valor preditivo negativo em gestantes de alto risco para prematuridade espontânea, e a realização do primeiro com 24 semanas e do segundo com 27 semanas constitui bom modelo preditivo para o parto prematuro / INTRODUCTION: The history of spontaneous preterm birth in a previous pregnancy is considered the main and most important clinical risk factor for preterm birth, the leading cause of neonatal morbidity and mortality. About 25% of these patients will deliver prematurely again. Secondary prevention consists in the search for markers of increased risk, in order to institute appropriate therapeutic actions and to avoid unnecessary treatments. The hypothesis of this study is that there is a correlation between the results of the evaluation of the cervix and the test for phosphorylated insulin-like growth factor binding protein-1 (phIGFBP-1) and that the use of both in combination can predict the occurrence of preterm delivery with higher sensitivity. OBJECTIVES: To investigate the usefulness of the measurement of the cervical length and phIGFBP-1 rapid test in the prediction of preterm birth before 37 and 34 weeks, the existence of a relationship between the tests themselves, the best cutoff value of cervical length measurement at different gestational ages and the best time to carry out each of the exams. METHODS: Data of 101 women with previous preterm birth assisted at the Obstetrical Clinic of the Hospital das Clínicas, Faculty of Medicine, University of São Paulo between 2003 and 2008 were collected and subjected to secondary analysis. The measurement of cervical length and the phIGFBP-1 test were performed every three weeks, between 24 and 34 weeks gestation, and compared with the outcome of premature birth before 37 and 34 weeks, and the best cutoff value of the cervix was determined by receiver operator characteristic curves. RESULTS: Of the 101 pregnancies studied, 25 (24.8%) ended in preterm birth, of which 12 (11.9%) occurred at 34 weeks or less. The mean gestational age in each evaluation was 24, 27, 30 and 33 weeks, and the cutoff of the cervix were 22, 21, 20 and 16 millimeters, respectively. The measurement of cervical length showed the highest sensitivity (approximately 70%) and was able to predict preterm birth in all evaluations. The phIGFBP-1 test was not useful at 24 weeks, but was able to independently detect the risk of prematurity at 27, 30 and 33 weeks. Statistical association between the exams was observed, so that the mean cervical length was lower in pregnant women testing positive for phIGFBP-1. The combination of both tests significantly increased the sensitivity and negative predictive value. CONCLUSIONS: The measurement of cervical length by transvaginal ultrasound is a good marker of risk for preterm delivery at 24 weeks, and the test for phIGFBP-1 is useful after 27 weeks. The association of the two tests is valuable and shows high sensitivity and high negative predictive value in women at high risk for spontaneous preterm birth, when the first is preformed with 24 weeks, and the second with 27 weeks

Abstract Advances over the past few decades in ante- and neonatal care have led to the survival of a growing number of premature infants of extremely low gestational age. However, the occurrence of serious diseases, particularly those affecting the most immature infants, remains high. Bronchopulmonary dysplasia (BPD), a chronic lung disease of premature infants, is one such disease. Our current understanding of the molecular pathogenesis of BPD is incomplete; consequently, there are few preventive and therapeutic options for BPD. Moreover, it is challenging to predict the risk of BPD. Previous studies of BPD in twins revealed that the heritability of BPD is quite high. However, the individual genes that predispose premature infants to BPD are largely unknown. The aim of this study was to identify and study genes associated with BPD in order to investigate its pathogenesis. An additional aim was to add to knowledge of the risk of BPD in newborn premature infants, with an emphasis on twins. A candidate gene study found no consistent association between common polymorphisms of vascular endothelial growth factor receptor 2 and BPD. A second candidate gene study noted an association between the gene encoding Kit ligand and BPD. A genome-wide association study found a suggestive association between a locus close to the gene encoding C-reactive protein (CRP) and BPD, and in subsequent analyses, plasma levels of CRP during the first week of life predicted BPD. Finally, a nationwide register study found that the risk of BPD was lower in twins than in singletons. The results of this study add to what is known of the genetics and pathogenesis of BPD. They also provide new data on the risk of BPD, which may be used to improve early identification of infants for whom the risk of developing BPD is high. / Tiivistelmä Ennenaikaisen syntymän ja keskoslasten hoidon kehittymisen myötä yhä useammat huomattavan epäkypsinä syntyneet lapset jäävät henkiin. Samalla erityisesti juuri näitä lapsia uhkaavien sairauksien esiintyvyys on pysynyt korkeana. Bronkopulmonaalinen dysplasia (BPD, keskosen krooninen keuhkosairaus) on yksi näistä sairauksista. BPD:n molekyylitasoinen tautimekanismi on vielä osin tuntematon, eikä BPD:tä tehokkaasti estävää tai siitä parantavaa hoitoa ole. Myös BPD riskin arvioiminen vastasyntyneen keskoslapsen kohdalla on vaikeaa. BPD on huomattavan perinnöllinen tauti. BPD:lle altistavista geeneistä on kuitenkin vasta vähän tietoa. Tämän tutkimuksen tavoitteena oli lisätä tietoa BPD:n tautimekanismista tutkimalla BPD:lle altistavia geenejä. Lisäksi tutkimuksessa tarkasteltiin BPD:n esiintyvyyttä ja syntymää edeltäviä riskitekijöitä erityisesti kaksosten osalta. Ehdokasgeenitutkimuksessa verisuonten endoteelikasvutekijää koodaava geeni ei assosioitunut toistuvasti BPD:hen. Kit ligandia koodaava geeni sen sijaan assosioitui. Koko genomin assosiaatiotutkimuksessa C-reaktiivista proteiinia (CRP) koodaavan geenin lähistöltä löydettiin BPD:hen mahdollisesti assosioituva alue. Lisäksi ensimmäisen viikon CRP-arvojen osoitettiin ennakoivan myöhemmin kehittyvää BPD:tä. BPD-riskin todettiin olevan matalampi kaksi- kuin yksisikiöisistä raskauksista syntyneillä lapsilla. Tutkimuksen tulokset lisäävät tietoa BPD:n perinnöllisyydestä ja sitä kautta BPD:n tautimekanismista. Tutkimus toi myös uutta tietoa BPD:n riskitekijöistä parantaen vastasyntyneen keskoslapsen BPD-riskin arviota.

Abstract Advances in perinatal treatment practices—such as antenatal corticosteroids, surfactant replacement therapy, and gentler ventilator modalities—have improved the survival of infants born preterm. Consequently, later morbidity and pulmonary outcome for survivors has attracted increasing interest. The incidence of bronchopulmonary dysplasia (BPD) remains high and the condition is manifesting in infants born at earlier gestational weeks than before. This so-called new BPD results from the arrest of alveolar development and is associated with less structural airway injury and interstitial fibrosis than previously. Long-term follow-up data on lung function, lung structure and respiratory morbidity of children treated with modern methods is insufficiently known. We performed a follow-up study of 88 preterm-born children and 88 matched term-born controls at school age. Children born preterm had lower values in lung function measurements than term-born peers. Reductions were most marked in those with a history of BPD. In accordance with the foetal origins hypothesis, children with intrauterine growth restriction (IUGR) had lower lung function than gestation-controls. This indicates that poor growth in utero is an additional burden on pulmonary health. Both IUGR and BPD predicted lower lung function independently. High-resolution computed tomography of the lung was obtained from 21 children with a history of BPD. Structural abnormalities were common, children with severe BPD being most affected. Preterm children were hospitalised more often than controls, mainly because of wheezing disorders. However, BPD did not influence the hospitalisations. According to the meta-analysis of the contemporary data available, the respiratory outcome of children who had only mild BPD may have improved in comparison to old follow-up data, whereas the results for those without BPD or moderate-to-severe BPD have remained remarkably stable despite progress in treatment practices during early life. In conclusion, preterm children had subtle impairments in lung function at school age. Although they were fairly asymptomatic, concern about the possible long-term effects of preterm birth on pulmonary health is justified. It has been proposed that BPD may predispose individuals to an early COPD-like disorder. Preterm children must be protected from any additional burden on respiratory health and should be monitored appropriately for early detection of lung disease. / Tiivistelmä Keskosten tehohoito on kehittynyt viime vuosikymmeninä merkittävästi, ja yhä epäkypsempänä syntyvät keskoset selviävät hengissä syntymän jälkeen. Keskosten pitkäaikainen keuhkosairaus, bronkopulmonaalinen dysplasia (BPD), on perinteisesti johtunut hengityskonehoidon ja happikaasun aiheuttamasta keuhkovauriosta ja johtanut keuhkokudoksen arpeutumiseen. Aiempaa ennenaikaisemmilla keskosilla esiintyy kuitenkin nykyään niin sanottua uutta BPD:tä, jonka ajatellaan johtuvan enemmän keuhkorakkuloiden kehityshäiriöstä kuin hoitojen aiheuttamasta keuhkovauriosta. Selvitimme, miten nykyaikaisilla menetelmillä hoidettujen keskosten keuhkojen rakenne ja toiminta kehittyvät kouluikään mennessä. Seurantatutkimukseemme osallistui 88 ennenaikaisena syntynyttä, kouluikään ehtinyttä lasta ja 88 täysiaikaisena syntynyttä, kaltaistettua verrokkia. Keskosena syntyneiden lasten keuhkofunktio oli kouluiässä huonompi kuin täysiaikaisena syntyneiden verrokkien. Alhaisin keuhkofunktio oli niillä keskosena syntyneillä lapsilla, jotka olivat sairastaneet vastasyntyneenä BPD:n. Myös kohdunsisäiseen kasvuhäiriöön (intrauterine growth restriction, IUGR) liittyi alentunut keuhkofunktio. BPD ja IUGR ennustivat alentunutta keuhkofunktiota toisistaan riippumatta. Tutkimuksessa tehtiin myös keuhkojen ohutleiketietokonekuvaus 21 keskoselle, jotka olivat sairastaneet BPD:n. Lähes kaikilla havaittiin poikkeavia löydöksiä – eniten niillä, joilla oli ollut vastasyntyneenä BPD:n vaikea tautimuoto. Keskosina syntyneet joutuivat kahden ensimmäisen vuoden aikana verrokkeja useammin sairaalahoitoon. Yleisimpiä syitä olivat hengityksen vinkumista aiheuttavat taudit kuten ilmatiehyttulehdus, ahtauttava keuhkoputkitulehdus tai akuutti astmakohtaus. Vastasyntyneenä sairastettu BPD ei kuitenkaan lisännyt todennäköisyyttä joutua sairaalahoitoon. Tutkimuksessa tehtiin myös meta-analyysi nykyaikaisilla menetelmillä hoidettujen keskosten keuhkofunktiosta: lievää BPD:tä sairastavien tulokset näyttävät parantuneen, kun taas keskivaikeaa tai vaikeaa tautimuotoa sairastavien ja ilman BPD:tä selvinneiden keuhkofunktio ei ole muuttunut uusien hoitojen myötä. Yhteenvetona voidaan todeta, että keskosten keuhkojen toimintakyky on jonkin verran alentunut täysiaikaisiin verrattuna. Lievästi alentunut keuhkofunktio ei kuitenkaan yleensä aiheuttanut koululaisille oireita. Keskosena syntyneiden lasten hengityselinten toimintaa on syytä seurata, sillä niin sanotun uuden BPD:n pitkäaikaisesta ennusteesta ei ole vielä tietoa.

Abstract Approximately 5.5% of all infants are born preterm (before 37 completed weeks of gestation) in Finland. Preterm birth is the cause of several life-threatening neonatal diseases and long-term morbidity. The most important risk factor for preterm birth is intrauterine infection and inflammation. Approximately 70% of preterm births have a spontaneous onset. Evidence suggests that genetic factors are involved in spontaneous preterm birth (SPTB), but knowledge about the actual genes conferring genetic predisposition is limited. The major aim of this work was to identify genetic factors that predispose to SPTB. Genome-wide linkage analysis was performed to identify genomic regions associating with SPTB in large northern Finnish families recurrently affected by SPTB. Genes near regions with linkage signals were subsequently analyzed in a Finnish case-control population of mothers and infants. Due to their roles in innate immunity, the genes encoding surfactant protein A (SP-A), SP-C, SP-D and mannose-binding lectin (MBL) were also investigated as candidates for SPTB in this population. In addition, expression of SP-C in human and mouse gestational tissues was examined. Linkage signals were detected on chromosome loci 15q26.3, Xq13.1 and Xq21.1 with the phenotype of being born preterm. In subsequent association analyses, the genes encoding the insulin-like growth factor 1 receptor (IGF1R) located within locus 15q26.3 and the androgen receptor (AR) located near locus Xq13.1 were identified as potential novel fetal SPTB susceptibility genes. These genes did not associate with SPTB in the mothers. An association was found between the Met31Thr polymorphism of the SFTPD gene encoding SP-D and SPTB in the infants. There was no association in the mothers. Polymorphisms of the genes encoding SP-A or MBL did not associate with SPTB. The Thr138Asn polymorphism of the SFTPC gene encoding SP-C did not associate with SPTB. However, this polymorphism associated strongly with the interval between preterm premature rupture of membranes and SPTB in the fetuses. Expression of SP-C was detected in human and mouse fetal membranes and placenta, and in mouse pregnant uterus. Currently, there is no effective method to prevent SPTB. The results of this study may help to clarify some of the biological mechanisms underlying SPTB and finally allow the development of specific treatment strategies for its prevention. / Tiivistelmä Suomessa syntyy noin 5,5 % lapsista ennenaikaisina eli raskauden kestettyä vähemmän kuin 37 täyttä viikkoa. Näillä lapsilla on alttius hengenvaarallisiin sairauksiin, ja osalle heistä jää pysyvä kehitysvamma. Noin 70 % ennenaikaisista syntymistä käynnistyy spontaanisti. Tärkein ennenaikaisen syntymän riskitekijä on kohdunsisäinen tulehdusreaktio. Myös perinnöllisten tekijöiden tiedetään vaikuttavan spontaanin ennenaikaisen syntymän (SEAS) käynnistymiseen, mutta alttiusgeenejä tunnetaan huonosti. Työssä pyrittiin tunnistamaan SEAS:lle altistavia perinnöllisiä tekijöitä. Perimänlaajuista kytkentäanalyysiä käyttäen etsittiin SEAS:ään liittyviä perimän kohtia tutkimalla toistuvasti ennenaikaisia syntymiä kokeneita isoja pohjoissuomalaisia perheitä. Kytkentäsignaalien lähellä olevia geenejä tutkittiin tutkimusaineistossa, joka koostui suomalaisista äideistä ja lapsista. Surfaktanttiproteiini A:ta (SP-A), SP-C:tä, SP-D:tä ja mannoosia sitovaa lektiiniä (MBL) koodaavia geenejä tutkittiin ehdokasgeeneinä SEAS:lle tässä populaatiossa, koska nämä proteiinit osallistuvat elimistön puolustukseen ja voivat siten vaikuttaa SEAS:ään liittyvään tulehdusreaktioon. Lisäksi tutkittiin SP-C:n ilmentymistä ihmisen ja hiiren sikiökalvoilla, istukassa ja kohdussa. Kytkentäsignaaleja havaittiin kromosomikohdissa 15q26.3, Xq13.1 ja Xq21.1, kun tutkittavana ilmiasuna oli ennenaikaisena syntyminen. Lisätutkimukset osoittivat, että sikiön insuliininkaltaisen kasvutekijän 1 reseptoria koodaava IGF1R-geeni (kohta 15q26.3) ja androgeenireseptorigeeni AR (lähellä kohtaa Xq13.1) ovat mahdollisia uusia SEAS:n alttiusgeenejä. Nämä geenit eivät selittäneet SEAS:ää äideissä. Sikiön SP-D:tä koodaavan geenin Met31Thr-polymorfismi tunnistettiin mahdolliseksi riskitekijäksi, mutta tämä polymorfismi ei selittänyt SEAS:ää äideissä. SP-A:ta ja MBL:ää koodaavat geenit eivät liittyneet SEAS:ään. SP-C:tä koodaavan geenin Thr138Asn-polymorfismi ei ollut yhteydessä SEAS:ään. Sikiön Thr138Asn-polymorfismi liittyi kuitenkin vahvasti sikiökalvojen puhkeamisen ja SEAS:n väliseen kestoon. SP-C:n havaittiin ilmentyvän ihmisen ja hiiren sikiökalvoilla ja istukassa sekä raskaana olevan hiiren kohdussa. Tulokset antavat uutta tietoa SEAS:n perinnöllisestä taustasta. Tämä tieto voi auttaa selvittämään sen käynnistymiseen johtavia biologisia mekanismeja ja johtaa lopulta uusiin hoitokeinoihin, joilla pystytään estämään spontaaneja ennenaikaisia syntymiä.

La naissance prématurée (<37 semaines de gestation) touche près de 10% de la population canadienne chaque année et induirait des altérations permanentes dans la structure et la fonction des organes. Nous avons démontré que de jeunes adultes nés ≤29 semaines de gestation présentent une capacité aérobie à l'effort réduite, un facteur prédictif de la qualité de vie et de la mortalité. Cette capacité dépend de l'intégrité des systèmes impliqués dans le transport et la consommation de l'oxygène, comme le système musculosquelettique. Cependant, l’oxygénation musculaire a été très peu étudiée chez les individus nés prématurément. Ainsi, nous postulons que les jeunes adultes nés très prématurément (PT) démontrent une oxygénation musculaire squelettique réduite et altérée par rapport aux jeunes adultes nés à terme (T). Cette étude pilote porte sur 16 jeunes adultes PT et 35 témoins T ayant entre 18 et 29 ans. L'oxygénation musculaire a été mesurée en continu par spectroscopie proche infrarouge (Artinis, Oxymon III, Leiden, Pays- Bas) sur le vastus lateralis et le gastrocnémien lors d’un test d’épreuve à l’effort. La comparaison entre les groupes a été fait par test-U Mann-Whitney pour données non paramétriques. Au niveau des mesures d’oxygénation musculaire, nous n’avons pas détecté de différences dans la variation relative d’hémoglobine oxygénée, désoxygénée et totale dans les deux muscles. Bien que la naissance prématurée pourrait affecter l’intégrité du muscle squelettique, nous n’avons pas décelé de différence dans l’oxygénation à l’effort chez les PT comparés aux T. / Premature birth (<37 weeks of gestation) affects about 10% of the Canadian population each year and induces permanent alterations in the structure and function of organ systems. We have shown that young adults born ≤29 weeks of gestation have a reduced aerobic exercise capacity, a strong predictor of quality of life and mortality. Aerobic capacity depends on the integrity of the systems involved in the transport and consumption of oxygen, such as skeletal muscles. However, muscle oxygenation has not yet been studied in individuals born prematrurely. Thus, we postulate that young adults born very prematurely (PT) have reduced and impaired skeletal muscle oxygenation compared to young adults born at term (T). This pilot study examined 16 young adults PT and 35 controls T between 18 and 29 years of age. Muscle oxygenation was measured continuously by near-infrared spectroscopy (Artinis, Oxymon III, Leiden, Pays-Bas) on the vastus lateralis and gastrocnemius during a cardiopulmonary exercise test. Comparison between both groups was accomplished by the Mann-Whitney U-test for non-parametric data. In terms of muscle oxygenation, we did not detect any differences in the relative variation of oxygenated, deoxygenated and total hemoglobin change in both muscles. Although premature birth would appear to affect the integrity of skeletal muscle, we did not find a difference in its oxygenation during exercise in PT compared with T young adults.