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La naissance prématurée (PTB), soit une naissance se produisant avant la 37e semaine de grossesse chez l’humain, est encore à ce jour l’une des principales causes de mortalité et de morbidité néonatales. En accord avec les études actuelles, la gravité des issues à la naissance est fortement liée à une perte de la fine régulation physiologique de facteurs inflammatoires durant la grossesse. Notamment, plusieurs données ont identifié qu’une fluctuation à la hausse des taux d'interleukine(IL)-6 dans les tissus gestationnels, liquide amniotique et le sang fœtal augmentait grandement le pronostic de naissance prématurée et de ses comorbidités associées. En plus de créer un environnement inflammatoire défavorable durant la gestation, IL-6 augmente aussi les protéines d’activation utérine (UAP), ayant pour effet de diminuer le temps de gestation. À ce jour, les traitements disponibles consistent principalement à arrêter les contractions à l’aide de tocolytiques. Conséquemment, ils ne s'attaquent pas directement à l'inflammation maternelle en amont sur le développement du fœtus. C’est dans cette optique que notre laboratoire a développé un peptidomimétique, nommé HSJ633 (633), inhibant sélectivement le récepteur d’IL-6 (IL-6R). Brièvement, la liaison d’IL-6 à IL-6R permet l’activation de la protéine accessoire du récepteur, gp130, générant la phosphorylation des protéines STAT3, Akt et de Erk1/2. En se liant de manière allostérique, 633 a l’avantage d’inhiber sélectivement la voie de STAT3, celle-ci affectant principalement la production de protéines de la phase aiguë. Ainsi, nous émettons l'hypothèse qu’IL-6 peut causer des dommages aux tissus fœtaux et que l'inhibition d’IL-6R à l'aide de 633 améliorera les conditions à la naissance tout en maintenant l'intégrité du tissu fœtal. Durant tout ce travail, nous avons confirmé notre hypothèse en utilisant un modèle d’inflammation anténatal en administrant du lipopolysaccharide (LPS) sur des souris gestantes vers la fin de leur période de gestation. Les résultats ont montré que le LPS raccourcissait le temps de gestation, réduisaient le poids à la naissance et la survie des souriceaux. Nous avons confirmé qu’IL-6 est un acteur important dans l’induction de la PTB et que son inhibition sélective est suffisante pour diminuer les effets délétères de l’inflammation. De plus, nous avons caractérisé l’effet protecteur de 633 en analysant la transcription de gènes et la synthèse de protéines clés dans les tissus maternels et gestationnels. Nous avons poursuivi davantage la caractérisation en révélant la présence de 633 au niveau du placenta, mais pas dans le fœtus. Ces résultats permettent de clarifier que 633 diminue l’inflammation directement au niveau placentaire et qu’il empêche les dommages subséquents de se répercuter dans le fœtus. En outre, nous avons établi que 633 réduit la morphologie anormale des poumons et des intestins de la progéniture induite par l'inflammation. Ensemble, nos données montrent que 633 a rétabli avec succès les issues à la naissance en augmentant le temps de gestation, la survie à la naissance et en préservant l'intégrité des organes du fœtus dans un modèle de PTB induite par le LPS. Ces découvertes soulignent l’importance d’IL-6 et révèlent l’efficacité́ pharmacologique in vivo d’un nouveau modulateur de l’IL-6R. Le 633 est un nouveau prototype thérapeutique prometteur pour la prévention de la PTB chez l’humain. / Preterm birth (PTB), which occurs before the 37th week of pregnancy in humans, is still one of the leading causes of neonatal mortality and morbidity. In agreement with current studies, the severity of birth outcomes is strongly associated with the loss of fine physiological regulation of inflammatory factors during pregnancy. Notably, several data have identified that upward fluctuation of interleukin (IL)-6 levels in gestational tissue, amniotic fluid, and fetal blood greatly increase the prognosis of preterm birth and its comorbidities. In addition to creating an adverse inflammatory environment during gestation, IL-6 also increases uterine activating protein (UAP), which results in decreased gestation time. To date, available treatments mainly consist of attempts to stop contractions with tocolytics. Consequently, they do not directly address the upstream maternal inflammation on the development of the fetus. To that end, our laboratory has developed a peptidomimetic, named HSJ633 (633), that selectively inhibits the IL-6 receptor (IL-6R). Briefly, binding of IL-6 to IL-6R allows activation of the receptor accessory protein, gp130, resulting in phosphorylation of STAT3, Akt and Erk1/2. By binding allosterically, 633 has the advantage of selectively inhibiting the STAT3 pathway, the latter mainly affecting the production of acute phase proteins. Thus, we hypothesize that IL-6 can cause fetal tissue damage and that inhibition of IL-6R with 633 will improve birth outcomes while also preserving the integritý of fetal tissue. Throughout this work, we confirmed our hypothesis using a model of antenatal inflammation by injecting lipopolysaccharide (LPS) into pregnant mice towards the end of their gestation period. The results showed that LPS shortened gestation time and reduced pup weight and survival. We confirmed that IL-6 is an important player in the induction of PTB and that its selective inhibition is sufficient to decrease the deleterious effects of inflammation. In addition, we characterized the protective effect of 633 by investigating gene transcription and key protein synthesis in maternal and gestational tissues. We further characterized the effect by revealing the presence of 633 in the placenta, but not in the fetus. These results clarify that 633 decrease inflammation directly in the placenta and prevents subsequent injury in the fetus. In addition, we found that 633 reduces inflammation-induced abnormal morphology of the lungs and intestines of the offspring. Taken together, our data show that 633 successfully restored birth outcomes by increasing gestation time, survival at birth, and preserving fetal organ integrity in an LPS-induced PTB model. These findings underscore the importance of IL-6 and unveil the in vivo pharmacological efficacy of a novel modulator of IL-6R. 633 is a promising new therapeutic prototype for the prevention of PTB in humans.

Die vorzeitige Reifung der Zervix steht im engen Zusammenhang mit den komplexen Mechanismen der Frühgeburtlichkeit. Die transvaginalsonographische Evaluation der Zervix ermöglicht im Gegensatz zur digitalen Tastuntersuchung eine objektive Dokumentation des Befundes nach Visualisierung der Zervix. Dies gilt insbesondere für die exakte Messung der Zervixlänge und die Beurteilung des Os internum. Veränderungen wie eine Trichterbildung, ein Fruchtblasenprolaps oder eine (a)-symptomatische vorzeitige Zervixreifung können sichtbar gemacht und im Trend beurteilt werden. Die transvaginalsonographische Befunderhebung ist leicht erlernbar, objektiv und gut reproduzierbar. In ersten Teil der vorliegenden Arbeit wurde untersucht, in wieweit bei einem low-Risk Kollektiv vorzeitige Reifungszeichen der Zervix vor anderen Frühgeburtsmarkern zu beobachten sind. Die Zervixbeurteilung mit 22 oder 32 SSW konnte nicht als valider Frühgeburtsmarker für ein Screening im strikten low-Risk Kollektiv festgesetzt werden. Auch die rechtzeitige und sichere Diagnose einer drohenden Frühgeburt bei symptomatischen oder asymptomatischen Schwangeren mit vorzeitiger Zervixreifung ist bislang nicht verlässlich möglich. Im zweiten Teil dieser Arbeit wurde bei einem high-Risk Kollektiv von Patientinnen mit vorzeitigen Wehen und Zervixreifung die Aussagekraft der transvaginalsonographische Zervixbiometrie untersucht. Die Zervixbiometrie begründet sich auf der Tatsache, dass die Reifezeichen der Zervix, wie Verkürzung der Zervixlänge, Öffnung des inneren Muttermundes und Dilatation des Zervikalkanals, bei nahenden Geburtswehen unabhängig von der Schwangerschaftsdauer zunehmen. Nach diesen Ergebnissen kann der Einsatz der TVS zur frühzeitigen Erkennung einer drohenden Frühgeburt empfohlen werden. Ihr Nutzen liegt in der Identifizierung von symptomatischen und asymptomatischen Patientinnen mit hohem Frühgeburtsrisiko. Ihnen sollte eine Maximaltherapie angeboten werden. Auf der anderen Seite können Patientinnen erkannt werden, deren Frühgeburtsrisiko gering ist. Sie können ambulant betreut und engmaschig kontrolliert werden. Insbesondere bei Patientinnen mit blandem sonographischen Zervixbefund, die bereits ein höheres Gestationsalter erreicht haben, rechtfertigen die guten negativ prädiktiven Werte eine großzügigere ambulante und abwartetende Betreuung. Damit können die Ergebnisse der Studie zu allgemeingültigen Standards zur besseren Risikobeurteilung der symptomatischen Patientinnen beitragen. / The premature cervical ripening has a close connection with the complex mechanism of premature delivery. The transvaginal sonographic evaluation of the cervix enables, unlike the digital examination, an objective documentation of the evidence after visualisation of the cervix. This goes especially for the exact measurement of cervical length and the assessment of the internal os. Changes like funneling, prolapse of the amniotic sac or an (a-)symptomatic premature cervical ripening can be visualised and assessed. The transvaginal sonographic evaluation is easily learned, objective and well reproducible. In the first part of the paper it was examined how far in a low risk group premature ripening signs of the cervix can be observed before other premature delivery markers. The cervix assessment with 22 or 32 weeks of gestation could not be fixed as valid premature delivery marker for a screening in the strict low risk group. Also the timely and sure diagnosis of an imminent premature delivery in symptomatic and asymptomatic pregnant women with premature cervix ripening is not reliably possible until now. In the second part of this paper the meaningfulness of the transvaginal sonographic cervix biometry was examined in a high risk group of patients with premature labour pains and cervix ripening. The cervix biometry is based on the fact that the signs of cervix ripening as shortening of cervix length, opening of the internal os and dilatation of the cervix canal increase when delivery pains are approaching, regardless of the duration of pregnancy. According to these results the use of transvaginal sonography for the early detection of an imminent premature delivery can be recommended. Its benefit lies in the identification of symptomatic and asymptomatic patients with a high risk of premature delivery. A maximum therapy should be offered them. On the other side, patients with a low premature delivery risk can be recognized. They can be treated as an outpatient and controlled closely. Especially in patients with a moderate sonographic cervix result, who have already reached a higher gestational age the good negative predictive values justify a more generous ambulant and expectant care. Because of that, the results of the study can contribute to generally applicable standards for a better risk assessment of symptomatic patients.

L’asthme est l’une des pathologies chroniques les plus fréquemment rencontrées durant la grossesse, affectant environ 8% des femmes enceintes. Les lignes directrices pour le traitement de l’asthme affirment que le risque d’un développement non optimal du fœtus dû à un asthme mal maîtrisé est supérieur au risque associé à la prise de médicaments pour le traitement de l’asthme durant la grossesse. Des questions persistent par contre sur l’innocuité des hautes doses de corticostéroïdes inhalés (CSI) et très peu de données sont publiées pour les bêta2-agonistes à longue action (BALA). Un programme de recherche en deux volets a été développé afin de répondre à certaines de ces questions. Dans un premier volet, une cohorte de femmes asthmatiques accouchant au Québec de 1998 à 2008 a été assemblée à partir des bases de données de la Régie de l’assurance maladie du Québec et de MED-ÉCHO afin d’évaluer l’impact de la prise de CSI ou de BALA sur la prévalence de faible poids à la naissance (FPN), de prématurité et de bébé petit pour l’âge gestationnel (PAG). La cohorte était composée de 7376 grossesses dont 56,9% étaient exposées aux CSI et 8,8% aux BALA. Dans cette cohorte, l’utilisation de BALA n’était pas associée à des prévalences plus élevées de FPN (OR=0,81, IC95%:0,58–1,12), prématurité (OR=0,84, IC95%:0,61–1,15) ou PAG (OR=0,92, IC95%:0,70–1,20). Lors de la comparaison des BALA (salmétérol comparé au formotérol comme référence) la différence la plus importante était pour le PAG (OR=1,16, IC95%:0,67–2,02). Pour les CSI, une tendance à une augmentation de FPN, prématurité et PAG a été observée avec l’augmentation des doses. Le OR le plus élevé était pour une dose > 500 ug/jour (équivalent fluticasone) pour le FPN: (OR=1,57, IC95%:0,86–2,87). La comparaison des CSI les plus utilisés (fluticasone comparé au budésonide comme référence) montre des différences non statistiquement significatives avec la différence maximale observée pour le PAG (OR=1,10, IC95%:0,85–1,44). Dans un second volet, une sous-cohorte de femmes asthmatiques avec visites médicales pour exacerbation d’asthme au Centre hospitalier universitaire de Sherbrooke (CHUS) a été constituée pour comparer le traitement des exacerbations durant et hors grossesse. Les résultats montrent que le traitement par CS était moins fréquent et différé pour les femmes enceintes comparées aux femmes non-enceintes. Le traitement de maîtrise de l’asthme (CSI et/ou BALA) dans l’année précédant l’exacerbation était sous-optimal. Les résultats présentés dans cette thèse démontrent l’innocuité des BALA et des doses faibles à modérées de CSI pendant la grossesse pour les issues de FPN, prématurité et PAG alors que des études supplémentaires sont nécessaires afin d’évaluer l’innocuité des hautes doses de CSI. Une innocuité comparable entre les CSI (budésonide, fluticasone) et les BALA étudiés (formotérol, salmétérol) a également été démontrée. Les résultats montrent également un recours moindre aux CS pour le traitement des exacerbations d’asthme durant la grossesse comparativement à hors grossesse. Ces résultats sont un ajout important aux évidences permettant aux cliniciens et aux femmes enceintes asthmatiques de faire les meilleurs choix pour optimiser le traitement pharmacologique durant la grossesse. / Asthma is one of the most common chronic medical conditions encountered during pregnancy, affecting approximately 8% of pregnant women. Current asthma treatment guidelines emphasize the importance and safety of the use of asthma medications during pregnancy compared to the risk of poorly controlled asthma for the fetus. In the evaluation of the safety of asthma medications during pregnancy, the literature review shows that questions persist, amongst others, on the safety of high inhaled corticosteroids (ICSs) doses and that there is a paucity of data on the safety of long-acting beta2-agonists (LABAs). A two components research program was developed to answers some of these questions. In the first component, a cohort of asthmatic women giving birth from 1998 to 2008 was constructed from the Régie de l’assurance maladie du Québec (RAMQ) et de MED-ÉCHO databases to assess the impact of the use of long-acting β2-agonists (LABAs) and the dose of inhaled corticosteroids (ICSs) during pregnancy on the prevalence of low birth weight (LBW), preterm birth (PB), and small for gestational age (SGA). The cohort included 7,376 pregnancies: 8.8% exposed to LABAs and 56.9% exposed to ICSs. LABA use was not found to be associated with increased prevalence of LBW (OR=0.81; 95%CI: 0.58–1.12), PB (OR=0.84; 95%CI: 0.61–1.15), or SGA (OR=0.92; 95%CI: 0.70–1.20). In the LABAs comparison (salmeterol compared to formoterol as reference), the most important difference was observed for PAG (OR=1.16, 95%CI: 0.67–2.02). For the ICSs, increasing doses were associated with a trend of increased LBW, PB, and SGA. The maximal observed OR was for a dose > 500 ug/day (fluticasone-equivalent) for LBW: (OR=1.57, 95%CI: 0.86–2.87). The comparison of the most frequently used ICSs (fluticasone compared to budesonide as reference) revealed non-statistically significant differences with a maximal difference observed for SGA (OR=1.10, 95%CI: 0.85–1.44). In the second component, a sub-cohort of asthmatic women with medical visits for asthma exacerbations was constructed to compare the treatment of exacerbations during and outside of pregnancy. The results show a reduced and delayed use of systemic corticosteroids for the treatment of asthma exacerbations in women when pregnant than when non-pregnant. The preventive treatment of asthma (ICSs and/or BALAs) could also be optimized. The results presented in this thesis support the safety of the use during pregnancy of LABAs and low to moderate doses of ICSs for the outcomes of LBW, PB and SGA and point to the need for additional data on the safety of high ICS doses. A comparable safety between studied ICSs (budesonide and fluticasone) and BALAs (formoterol and salmeterol) was also demonstrated. We also observed a reduced and delayed use of systemic corticosteroids for the treatment of asthma exacerbations in women when pregnant than when non-pregnant.

L’objectif de cette thèse est l’étude du développement de l’attention auditive et des capacités de discrimination langagière chez l’enfant né prématurément ou à terme. Les derniers mois de grossesse sont particulièrement importants pour le développement cérébral de l’enfant et les conséquences d’une naissance prématurée sur le développement peuvent être considérables. Les enfants nés prématurément sont plus à risque de développer une variété de troubles neurodéveloppementaux que les enfants nés à terme. Même en l’absence de dommages cérébraux visibles, de nombreux enfants nés avant terme sont à risque de présenter des troubles tels que des retards langagiers ou des difficultés attentionnelles. Dans cette thèse, nous proposons donc une méthode d’investigation des processus préattentionnels auditifs et de discrimination langagière, à l’aide de l’électrophysiologie à haute densité et des potentiels évoqués auditifs (PEAs). Deux études ont été réalisées. La première visait à mettre sur pied un protocole d’évaluation de l’attention auditive et de la discrimination langagière chez l’enfant en santé, couvrant différents stades de développement (3 à 7 ans, 8 à 13 ans, adultes ; N = 40). Pour ce faire, nous avons analysé la composante de Mismatch Negativity (MMN) évoquée par la présentation de sons verbaux (syllabes /Ba/ et /Da/) et non verbaux (tons synthétisés, Ba : 1578 Hz/2800 Hz ; Da : 1788 Hz/2932 Hz). Les résultats ont révélé des patrons d’activation distincts en fonction de l’âge et du type de stimulus présenté. Chez tous les groupes d’âge, la présentation des stimuli non verbaux a évoqué une MMN de plus grande amplitude et de latence plus rapide que la présentation des stimuli verbaux. De plus, en réponse aux stimuli verbaux, les deux groupes d’enfants (3 à 7 ans, 8 à 13 ans) ont démontré une MMN de latence plus tardive que celle mesurée dans le groupe d’adultes. En revanche, en réponse aux stimuli non verbaux, seulement le groupe d’enfants de 3 à 7 ans a démontré une MMN de latence plus tardive que le groupe d’adulte. Les processus de discrimination verbaux semblent donc se développer plus tardivement dans l’enfance que les processus de discrimination non verbaux. Dans la deuxième étude, nous visions à d’identifier les marqueurs prédictifs de déficits attentionnels et langagiers pouvant découler d’une naissance prématurée à l’aide des PEAs et de la MMN. Nous avons utilisé le même protocole auprès de 74 enfants âgés de 3, 12 et 36 mois, nés prématurément (avant 34 semaines de gestation) ou nés à terme (au moins 37 semaines de gestation). Les résultats ont révélé que les enfants nés prématurément de tous les âges démontraient un délai significatif dans la latence de la réponse MMN et de la P150 par rapport aux enfants nés à terme lors de la présentation des sons verbaux. De plus, les latences plus tardives de la MMN et de la P150 étaient également corrélées à des performances langagières plus faibles lors d’une évaluation neurodéveloppementale. Toutefois, aucune différence n’a été observée entre les enfants nés à terme ou prématurément lors de la discrimination des stimuli non verbaux, suggérant des capacités préattentionnelles auditives préservées chez les enfants prématurés. Dans l’ensemble, les résultats de cette thèse indiquent que les processus préattentionnels auditifs se développent plus tôt dans l'enfance que ceux associés à la discrimination langagière. Les réseaux neuronaux impliqués dans la discrimination verbale sont encore immatures à la fin de l'enfance. De plus, ceux-ci semblent être particulièrement vulnérables aux impacts physiologiques liés à la prématurité. L’utilisation des PEAs et de la MMN en réponse aux stimuli verbaux en bas âge peut fournir des marqueurs prédictifs des difficultés langagières fréquemment observées chez l’enfant prématuré. / The aim of this thesis is to investigate early auditory attention and language development in full-term and preterm children. The last months of pregnancy are particularly important for the child’s cerebral development, and the impacts of a premature birth on his/her neurodevelopment can be substantial. Prematurely born children are at higher risk of developing a variety of neurodevelopmental disorders compared to full-terms. Even without visible brain injury, many premature children are at risk of presenting disorders such as language delays and attentional difficulties. In this thesis, we suggest an approach to investigate pre-attentional processes and early language discrimination abilities in infants using high-density electrophysiology and auditory event-related potentials (AERPs). We conducted two studies. The first one aimed at establishing a paradigm to evaluate auditory attention and language discrimination development in healthy full-term children, over different developmental stages (3 to 7 years, 8 to 13 years, adults; N = 40). To do so, we analyzed the Mismatch Negativity (MMN) component in response to speech (spoken syllables /Ba/ and /Da/) and non-speech stimuli (frequency-synthesized tones, Ba: 1578 Hz/2800 Hz; Da: 1788 Hz/2932 Hz). Distinct patterns of activation were revealed according to stimulus type and age. In all groups, non-speech stimuli elicited an MMN of larger amplitude and earlier latency than did the presentation of speech stimuli. Moreover, in response to speech stimuli, both children groups (3 to 7 years, 8 to 13 years) showed a significantly delayed MMN response compared to the adults group. In contrast, in response to non-speech stimuli, only the youngest group (3 to 7 years) showed a significantly delayed MMN compared to the adults. Age-related differences for tone discrimination therefore appear to occur earlier in children’s development than do the discriminative processes for speech sounds. In the second study, we aimed at identifying the electrophysiological markers of auditory attention and language deficits often incurred by a premature birth. We thus presented this paradigm to 74 infants born preterm (before 34 gestational weeks) or full-term (at least 37 gestational weeks), aged 3, 12 and 36 months old. Our results indicated that preterm children of all age groups showed a significantly delayed MMN and P150 responses to speech stimuli compared to full-terms. Moreover, significant correlations were found between the delayed MMN and P150 responses to speech sounds and lower language scores on a neurodevelopmental assessment. However, no significant differences were found between full-term and preterm children for the MMN in response to non-speech stimuli, suggesting preserved pre-attentional auditory discrimination abilities in these children. Altogether, the findings from this thesis indicate that the neurodevelopmental processes associated with auditory pre-attentional skills occur earlier in childhood compared to language discrimination processes. Cerebral networks involved in speech discrimination are still immature in late childhood. Furthermore, neural networks involved in speech discrimination and language development also appear to be particularly vulnerable to the impacts of prematurity. The use of AERPs and the MMN response to speech stimuli in infancy can thus provide predictive markers of language difficulties commonly seen in premature infants.

Para investigar o impacto em resultados pós-natais do uso de ciclo único de betametasona para maturação pulmonar em gestações (únicas, sem malformações fetais ou neonatais) com diástole zero ou diástole reversa à dopplervelocimetria das artérias umbilicais, foi conduzido estudo de coorte histórico com 62 recém-nascidos entre 26 e 34 semanas. Desses, 31 tinham uso antenatal do corticóide (nascidos entre maio de 2004 e julho de 2006) e 31 controles sem o uso da droga (nascidos entre janeiro de 2000 a março de 2004), pareados individualmente segundo índice de pulsatilidade para veias do ducto venoso (até 1,0 ou entre 1,01 e 1,50), idade gestacional ao nascimento (variação máxima de seis dias) e peso ao nascimento (variação máxima de 10%). Avaliaram-se: índice de Apgar de primeiro e quinto minutos, internação em unidade de terapia intensiva, uso de suporte respiratório (intubação orotraqueal, pressão positiva contínua nas vias aéreas, suplemento de oxigênio), tempo de internação, sobrevida, ocorrência de óbito (e causa principal), além da ocorrência de complicações (doença das membranas hialinas, displasia broncopulmonar, hemorragia intracraniana, retinopatia da prematuridade, persistência de canal arterial, enterocolite necrosante, sepse precoce e tardia). Fez-se análise estatística para os pares de recém-nascidos dos dois grupos, baseada na razão de pares discordantes e utilizaram-se os testes: t de Student para amostras pareadas, qui-quadrado de McNemar, de simetria assintótica, de Wilcoxon, de log-rank. No caso dos desfechos em que o uso de betametasona apresentou associação com ocorrência significativamente menor de complicações, foi calculado o número necessário para tratar para evitar o desfecho em um recém-nascido. Adotou-se significância de 5%. A média de idade gestacional foi de 29,4 semanas e, de peso, 794,2gramas. Os recém-nascidos cujas mães receberam betametasona apresentaram melhores índices de Apgar de primeiro minuto (p<0,001), uso de menos doses de surfactante exógeno (p=0,007), redução da freqüência de displasia broncopulmonar (p=0,02), persistência do canal arterial (p=0,002) e óbitos (p=0,008). As causas principais de óbito mais freqüentes foram hemorragia pulmonar e sepse, responsáveis por 64,5% do total dos óbitos. O número necessário para tratar relacionado à displasia broncopulmonar foi 3,2; à persistência do canal arterial, 2,4 e, ao óbito, de 2,8. O risco de óbito dos RN com uso antenatal de betametasona foi 60% menor do que aqueles sem essa terapia. A corticoterapia antenatal relacionou-se, de forma significativa, a melhores condições ao nascimento (com redução da freqüência de índices de Apgar de primeiro minuto inferiores a três); menos morbidade pós-natal (com uso de menor número de doses de surfactante exógeno, redução da ocorrência de displasia broncopulmonar e de persistência do canal arterial) e menor mortalidade. / A retrospective cohort study of 62 pregnancies with absent or reversed end-diastolic flow in the umbilical arteries was conducted in order to investigate the impact on postnatal outcome of a single course of antenatal betamethasone therapy for the acceleration of fetal lung maturation. Sixty-two singleton pregnancies, without fetal or neonatal anomalies, delivered during the period of January 2000 and July 2006 with a gestational age ranging from 26 to 34 weeks were included. The study included 31 newborns with the antenatal corticosteroid therapy and 31 nontreated, matched individually according to gestational age (within about six days), birth weight (within about 10%) and value of pulsatility index for veins in the ductus venosus (maximum of 1,0 or between 1,01 and 1,50). The outcomes assessed were: 1- and 5-minute Apgar scores, referral to the neonatal intensive care unit, need of tracheal intubation, use of continuous positive airway pressure, use of oxygen therapy, length of hospital stay, survival, in-hospital mortality (and main cause), use of surfactant, number of surfactant doses, and the occurrence of hyaline membrane disease, bronchopulmonary dysplasia, intracranial hemorrhage, retinopathy of prematurity, patent ductus arteriosus, necrotizing enterocolitis, early-onset and late-onset neonatal sepsis. Data from each matched-pair of infants were analyzed in terms of its discordance by the use of these tests: Student\'s t test for matched-pairs, McNemar´s chi-square test, symmetry test, Wilcoxon matched-pairs signed-ranks test, log-hank test. Numbers needed to treat in the case of beneficial effect were calculated for each outcome. A significance level of 5% was adopted for all tests. Mean of gestational age and birth weight were 29,4 weeks and 794,4grams. Infants whose mothers received antenatal betamethasone therapy had better 1-minute Apgar scores (p<0,001), use of fewer surfactant doses (p=0,007), reduction of the occurrence of bronchopulmonary dysplasia (p=0,02), patent ductus arteriosus (p=0,002) and in-hospital deaths (p=0,008). Pulmonary hemorrhage and sepsis were the two main causes of deaths (64,5% of the total of deaths). Number needed to treat related to bronchopulmonary dysplasia was 3,2; to patent ductus arteriosus was 2,4 and to in-hospital death was 2,8. The risk of death decreased of 60% by the use of antenatal steroid. Antenatal betamethasone therapy was significantly related to better birth conditions (reduction of 1-minute Apgar scores < 3), less morbidity (fewer surfactant doses and reduction on the occurrence of bronchopulmonary dysplasia and patent ductus arteriosus) and lower in-hospital mortality.

Para investigar o impacto em resultados pós-natais do uso de ciclo único de betametasona para maturação pulmonar em gestações (únicas, sem malformações fetais ou neonatais) com diástole zero ou diástole reversa à dopplervelocimetria das artérias umbilicais, foi conduzido estudo de coorte histórico com 62 recém-nascidos entre 26 e 34 semanas. Desses, 31 tinham uso antenatal do corticóide (nascidos entre maio de 2004 e julho de 2006) e 31 controles sem o uso da droga (nascidos entre janeiro de 2000 a março de 2004), pareados individualmente segundo índice de pulsatilidade para veias do ducto venoso (até 1,0 ou entre 1,01 e 1,50), idade gestacional ao nascimento (variação máxima de seis dias) e peso ao nascimento (variação máxima de 10%). Avaliaram-se: índice de Apgar de primeiro e quinto minutos, internação em unidade de terapia intensiva, uso de suporte respiratório (intubação orotraqueal, pressão positiva contínua nas vias aéreas, suplemento de oxigênio), tempo de internação, sobrevida, ocorrência de óbito (e causa principal), além da ocorrência de complicações (doença das membranas hialinas, displasia broncopulmonar, hemorragia intracraniana, retinopatia da prematuridade, persistência de canal arterial, enterocolite necrosante, sepse precoce e tardia). Fez-se análise estatística para os pares de recém-nascidos dos dois grupos, baseada na razão de pares discordantes e utilizaram-se os testes: t de Student para amostras pareadas, qui-quadrado de McNemar, de simetria assintótica, de Wilcoxon, de log-rank. No caso dos desfechos em que o uso de betametasona apresentou associação com ocorrência significativamente menor de complicações, foi calculado o número necessário para tratar para evitar o desfecho em um recém-nascido. Adotou-se significância de 5%. A média de idade gestacional foi de 29,4 semanas e, de peso, 794,2gramas. Os recém-nascidos cujas mães receberam betametasona apresentaram melhores índices de Apgar de primeiro minuto (p<0,001), uso de menos doses de surfactante exógeno (p=0,007), redução da freqüência de displasia broncopulmonar (p=0,02), persistência do canal arterial (p=0,002) e óbitos (p=0,008). As causas principais de óbito mais freqüentes foram hemorragia pulmonar e sepse, responsáveis por 64,5% do total dos óbitos. O número necessário para tratar relacionado à displasia broncopulmonar foi 3,2; à persistência do canal arterial, 2,4 e, ao óbito, de 2,8. O risco de óbito dos RN com uso antenatal de betametasona foi 60% menor do que aqueles sem essa terapia. A corticoterapia antenatal relacionou-se, de forma significativa, a melhores condições ao nascimento (com redução da freqüência de índices de Apgar de primeiro minuto inferiores a três); menos morbidade pós-natal (com uso de menor número de doses de surfactante exógeno, redução da ocorrência de displasia broncopulmonar e de persistência do canal arterial) e menor mortalidade. / A retrospective cohort study of 62 pregnancies with absent or reversed end-diastolic flow in the umbilical arteries was conducted in order to investigate the impact on postnatal outcome of a single course of antenatal betamethasone therapy for the acceleration of fetal lung maturation. Sixty-two singleton pregnancies, without fetal or neonatal anomalies, delivered during the period of January 2000 and July 2006 with a gestational age ranging from 26 to 34 weeks were included. The study included 31 newborns with the antenatal corticosteroid therapy and 31 nontreated, matched individually according to gestational age (within about six days), birth weight (within about 10%) and value of pulsatility index for veins in the ductus venosus (maximum of 1,0 or between 1,01 and 1,50). The outcomes assessed were: 1- and 5-minute Apgar scores, referral to the neonatal intensive care unit, need of tracheal intubation, use of continuous positive airway pressure, use of oxygen therapy, length of hospital stay, survival, in-hospital mortality (and main cause), use of surfactant, number of surfactant doses, and the occurrence of hyaline membrane disease, bronchopulmonary dysplasia, intracranial hemorrhage, retinopathy of prematurity, patent ductus arteriosus, necrotizing enterocolitis, early-onset and late-onset neonatal sepsis. Data from each matched-pair of infants were analyzed in terms of its discordance by the use of these tests: Student\'s t test for matched-pairs, McNemar´s chi-square test, symmetry test, Wilcoxon matched-pairs signed-ranks test, log-hank test. Numbers needed to treat in the case of beneficial effect were calculated for each outcome. A significance level of 5% was adopted for all tests. Mean of gestational age and birth weight were 29,4 weeks and 794,4grams. Infants whose mothers received antenatal betamethasone therapy had better 1-minute Apgar scores (p<0,001), use of fewer surfactant doses (p=0,007), reduction of the occurrence of bronchopulmonary dysplasia (p=0,02), patent ductus arteriosus (p=0,002) and in-hospital deaths (p=0,008). Pulmonary hemorrhage and sepsis were the two main causes of deaths (64,5% of the total of deaths). Number needed to treat related to bronchopulmonary dysplasia was 3,2; to patent ductus arteriosus was 2,4 and to in-hospital death was 2,8. The risk of death decreased of 60% by the use of antenatal steroid. Antenatal betamethasone therapy was significantly related to better birth conditions (reduction of 1-minute Apgar scores < 3), less morbidity (fewer surfactant doses and reduction on the occurrence of bronchopulmonary dysplasia and patent ductus arteriosus) and lower in-hospital mortality.

一、研究目的 (1). 將針對世界各國相關規範下，早產兒之法律地位進行探討，以釐清現行我國規範對於早產兒法律地位所持之立場。 (2). 促進我國法界前輩更了解照顧早產兒，特別是極早期早產兒所遭遇的醫學倫理困境，能制定更清楚明確的有關極早期早產兒救治的相關法律或更貼切的法律實務判例或見解。 二、研究方法 (1). 文獻探討法，為了解分析照顧早產兒之醫學倫理困境，閱讀中外學者之研究報告、論著等文獻，加以探討。 (2). 歷史比較研究法，蒐集東西方歷史文獻嬰兒生命權利關係之演變資料加以分析；並且比較探討大陸法系及英美法系諸國對相關之早產兒生命權利相關醫學倫理規範及法律規定。 三、研究內容 (1). 早產兒倂發症、後遺症及存活率之情況 (2). 東西方嬰兒生命權利關係之演變史 (3). 照顧早產兒之醫護人員及早產兒家長的困境研究 (4). 國內生命權相關法律規定及醫療法規之分析 (5). 國內外極早期早產兒生命權相關醫學倫理規範及法律規定之分析比較 (6). 更適切之早產兒生命權利法律見解之提出 四、研究結果 經由本研究，基本上理解各國對早產兒生命的尊嚴及生命決定權的醫學倫理規範、法律規定及理論構成，同時也希望藉由此研究能讓政府、社會、法界及醫界對於早產兒生命權利及所遭遇的醫學倫理困境更加重視，我國能制定更清楚明確的有關極早期早產兒救治的相關法律或更貼切的法律實務判例或見解。 / As article 3 of the Universal Declaration of Human Rights prescribes “Everyone has the right to life, liberty and security of person.”, the right to life is the most fundamental human right. However, extremely preterm infants (20 to 23 weeks of gestation) are infants of borderline viability. They are at greater risk for mortality and severe disability. Who can surrogate to make decisions about resuscitation with intensive care or palliative care for them in terms of their best interests? It is a dilemma. There is a potential conflict between palliative care and the general medical duty to save life. It presents complex medical, legal, ethical and social issues for their parents and the health professionals. Until now, it is still out ruled legally in Taiwan. This article focuses on the right to life of extreme prematurity. We will discuss different insights about the right to life of infant from history, culture, society and religion in the world, and analyze guidelines and legal regimes of different countries. Based on that, we can get objective solutions to the right to life of extreme prematurity in Taiwan, as an aid for parents in making ethical and legally based decisions.

Objectif: Cette étude vise à examiner l’issue de la grossesse des mères-nées haïtiennes pour la prématurité, la naissance de faible poids (NFP) et le retard-de-croissance intra-utérine (RCIU) et étudier leur tendance temporelle au Québec. Méthode: Étude populationnelle sur les naissances vivantes simples au Québec de 1981-2006 (N = 2 193 637). À l’aide des modèles de régression logistique, prenant comme référence les mères-nées canadiennes, les associations entre l’issue défavorable de grossesse et les mères-nées haïtiennes étaient étudiées. Résultats: Les proportions de prématurité, de NFP et du RCIU sont plus fréquentes chez les mères-nées haïtiennes (8,5%, 7,5% et 12,6% respectivement) que chez les Canadiennes (5,8%; 5,1% et 11,5% respectivement). Ajustés pour les variables de confusions potentielles (âge maternel, éducation, parité, statut matrimonial, sexe, période-de-naissance), les susceptibilités de prématurité, NFP et RCIU demeuraient plus élevés chez les mères-nées haïtiennes (RC 1,44 IC 95% [1,36-1,52] ; RC 1,40 IC 95% [1,32-148] ; RC 1,09 IC 95% [1,04-1,14] respectivement). Les susceptibilités de prématurité, de NFP et du RCIU augmentaient avec le temps chez les mères-nées haïtiennes. Conclusion : Les mères-nées haïtiennes ont une issue de grossesse défavorable pour la prématurité, NFP et RCUI comparée aux mères-nées canadiennes. Des recherches sur les facteurs responsables de ces associations et des interventions pour améliorer la santé périnatale des immigrants haïtiens, diminuer les inégalités de santé sont nécessaires au Québec. / Objective: This study aimed to examine birth outcomes among Haitian-born mothers specifically prematurity, low birth weight (LBW) and small for gestational age (SGA) births and their trends over time in Quebec. Method: Analysing for a 25 years period a cohort of 2 193 637 singleton live births from the Quebec birth file. Multiple logistic regression models were used to examine adverse birth outcomes for Haitian-born relative to Canadian-born mothers. Results: Haitian-born mothers had higher proportions of preterm birth, LBW and SGA (8.5%, 7.5% and 12.6% respectively) outcomes than Canadian-born mothers (5.8%, 5.1% and 11.5% respectively). In models accounting for maternal age, education, marital status, gravidity, infant sex and period, Haitian-born had a greater odds of premature births, LBW and SGA (OR 1.44 CI 95% [1,36-1,52]; OR 1.40 95% [1,32-148]; OR 1.09 95% [1,04-1,14] respectively) relative to Canadian-born mothers. When examined over time the odds of premature birth, LBW and SGA increased with time among Haitian-born mothers in Québec. Conclusion: Haitian-born mothers have a greater likelihood of adverse birth outcomes relative to Canadian-born mothers. Research on the factors underlying these associations and interventions to improve prenatal health and reduce health disparity among Haitian-born minority are needed in Quebec.

Made available in DSpace on 2016-06-02T20:44:09Z (GMT). No. of bitstreams: 1 4166.pdf: 640336 bytes, checksum: 80394a2355787e24b01541f7afc91b93 (MD5) Previous issue date: 2012-02-17 / Financiadora de Estudos e Projetos / The birth of a child preterm and with low birth weight is considered one of the main risk factors that can lead to changes and delays in neuro-psychomotor development. Among these changes are the difficulties in motor, learning, and visual-motor integration areas, as well as sensory and perceptive problems that alone or in combination, ultimately will impact the child's social participation, especially in carrying out activities of daily living, school and play. Considering playing as the main activity for children, this study aimed to investigate possible correlations between the performance of the ludic behavior of children with a history of preterm birth and their neuro-psychomotor development. We tried to understand this phenomenon in the pre-school period, in order to produce knowledge in a preventive perspective in relation to schooling. This study was approved by the Ethics Committee of Universidad Federal de São Carlos. It is a descriptive and correlational study involving 52 children divided into three groups: Study group GI (consisting of 12 children with a history of prematurity and low birth weight at risk of developmental delay detected), Study group GII (consisting for 14 children with a history of prematurity and low birth weight without developmental delay detected) and the comparison group GIII (without the mentioned history and with 26 children from the same socioeconomic class according to the classification made by the Criteria Questionnaire Brazil). Three methods were used to perform the evaluations: TSDD-II (Screening Test Denver II), the EPP-DP (teacher s perception scale on student s performance and participation in the school environment), and ELPK-rb (Knox s Pre-school Ludic Scale - Revised). The first test was used to compose samples, the second to raise the awareness of teachers of the development of children, and the latter to the specific assessment of ludic behavior. The data were analyzed quantitatively in order to verify the presence of significant differences in ludic behavior in the three groups. To verify the significance of possible associations between groups of preterm and term infants, with the results obtained from the TSDD-II, we chose Fisher s Exact Test. After verifying the association between the variables of interest, we used the Kruskal-Wallis Test in order to ascertain whether or not differences exist between the scores obtained by the classes of variables in the ELPK-rb participation fields. The results of this study revealed that from a detailed analysis of the play behavior of children, that is, the way the play you can identify the presence of changes in global development, as well as in more specific areas of human development. Regarding the performance of children with a history of prematurity ande risk for developmental delay 8% had unsatisfactory results and 17% were assessed as having a partially satisfactory performance, something that was not repeted in the other groups analyzed, which had in most cases very satisfactory performances. A similar picture was observed when analyzing the performance of children in fine motor activities, where children with a history of prematurity had inferior performances to those of children born at term, principally when comparing the results obtained from children of group GI with those obtained from children in group GIII. Regarding the results obtained in evaluating the ELPK-rb participation field, lmost all children from groups GI, GII and GIII presented co-operative play behavior, or would rather play only with other children. Another factor that draws our attention when observing the results of participation fields, was the presence of a greater difficulty for children with a history of prematurity and risk for developmental delay in playing games with simple rules (being that 17% did not show the expected behavior and 25% played tentatively). Still with respect to the participation field, when analyzing the results related to the language area it was observed, again, a lower performance among children with a history of prematurity, especially among children in group GI, when compared to children born at term. Regarding the children s performance in the ELPK-rb field of make believe/symbolic games, it was noted that children of the group GI obtained results lower tah those of children from GII and GIII, especially in sub-items interprets more complex emotions and demonstrates function in the games for or with others . By establishing the association between the results obtained by the groups in ELPK-rb, with those presented in TSDD-II, it was observed that there are changes in play behavior of children with a history of prematurity, due to possible delays in neuro-psychomotor development, once working with all comparisons involved, the results presented by children in strata 1 (with a history of prematurity and risk for developmental delay) differed from the children in strata 4 (born at term and with the presence of caution ). However, we cannot say that the presence of risk for developmental delay detected by TSDD-II, as well as changes in play behavior of children are unique conseqyuences of prematurity, but that they results from multiple factors that add up and influence, concomitantly, the development of motor, cognitive, psychological, and social skills of children. It is confirmed then, that pratical education, health, and social skills of children. It is confirmed then, that pratical education, health, and the promoting of development occur in conjunction, contributing to the detection of risk factors and promoting the quality of interactions and the environment in which children are placed. In this sense, it is necessary to invest in the training of educators/caregivers/pages, since they can provide protective factors in children s development, minimizing/offsetting the negative effects arising from the presence of social and biological risk factors through play, as this constitutes one of the main activities performed by children in preschool, and whose primary essence is the promotion of cognitive and bio-psychomotor development in the subjects. To give children opportunities to play is to give them much more than the act itself, because it provides to each of them a better perspective of life and natural and healthy development. / O nascimento da criança pré-termo é considerado um dos principais fatores de risco que pode levar às alterações e atrasos no desenvolvimento neuropsicomotor. Dentre estas alterações estão as dificuldades nas áreas motoras, de aprendizagem, da integração visomotora, problemas sensoriais e perceptivos que isolados ou de forma combinada, acabam por repercutir na participação social da criança, especialmente na realização das atividades da vida diária, escolar e no brincar. Considerando-se o brincar como uma das principais atividades infantis, o presente estudo teve por objetivo investigar possíveis associações entre o desempenho do comportamento lúdico de crianças com histórico de prematuridade ao nascimento e seu desenvolvimento neuropsicomotor. Buscou-se compreender este fenômeno na etapa pré-escolar, ou seja, no momento exato em que antecede a escolaridade formal (ingresso no ensino fundamental) a fim de se produzir conhecimentos numa perspectiva preventiva em relação à escolarização. A presente pesquisa fora aprovada pelo Comitê de Ética da Universidade Federal de São Carlos. Trata-se de um estudo analítico, observacional, e de coorte retrospectivo, composto por 52 crianças distribuídas em três grupos: Grupo de estudo GI (constituído por 12 crianças com histórico de prematuridade e baixo peso ao nascimento com risco para atraso no desenvolvimento detectado); Grupo de estudo GII (constituído por 14 crianças com histórico de prematuridade e baixo peso ao nascimento sem atraso no desenvolvimento detectado) e o Grupo Comparado-GIII (sem o referido histórico) composto por 26 crianças pertencentes a mesma classe socioeconômica de acordo com a classificação realizada por meio do Questionário Critério Brasil). Para realização das avaliações foram utilizados três instrumentos: TSDD-II (Teste de Triagem Denver II), a EPPDP (Escala de percepção dos professores sobre o desempenho e participação do aluno no ambiente escolar), e a ELPK-rb (Escala Lúdica Pré-escolar de Knox-Revisada). O primeiro instrumento foi utilizado para definir a composição das amostras, o segundo com o objetivo de aferir a percepção dos professores frente ao desenvolvimento das crianças, e o último para realizar a avaliação específica do comportamento lúdico. Os dados coletados foram analisados de forma quantitativa, no intuito de se verificar a presença de diferenças significativas no comportamento lúdico em relação aos três grupos. Para verificar a significância de possíveis associações entre os grupos de prematuros e crianças nascidas a termo, com os resultados obtidos a partir do TSDD-II, optou-se pelo Teste Exato de Fisher. Depois de verificada a associação entre as variáveis de interesse, foi empregado o teste de Kruskal-Wallis no intuito de verificar a existência, ou não, de diferenças entre os escores obtidos pelas classes de variáveis analisadas, nos domínios da ELPK-rb. Os resultados deste estudo revelaram que a partir de uma análise detalhada do comportamento lúdico das crianças, ou seja da maneira como elas brincam, é possível identificar a presença de alterações no desenvolvimento global, como também em áreas mais específicas do desenvolvimento humano. Em relação ao desempenho das crianças nas atividades que envolvem a coordenação motora global, observou-se que entre as crianças com histórico de prematuridade e risco para atraso no desenvolvimento 8% obtiveram resultados insatisfatórios e 17% foram avaliadas como tendo um desempenho parcialmente satisfatório, o que não se repetiu nos demais grupos analisados, os quais obtiveram na maioria dos casos rendimento muito satisfatórios. Um quadro semelhante foi observado ao se analisar o desempenho das crianças nas atividades motoras finas, onde as crianças com histórico de prematuridade apresentaram um desempenho inferior aos das crianças nascidas a termo, principalmente ao se comparar os resultados obtidos pelas crianças do grupo GI com os obtidos pelas crianças do grupo GIII. Em relação aos resultados obtidos na avaliação do domínio da participação da ELPK-rb, a quase totalidade das crianças dos grupos GI, GII e GIII apresentaram um brincar cooperativo, ou seja, preferiam brincar com outras crianças do que só. Outro fator que nos chama a atenção ao observar os resultados referentes ao domínio da participação, foi a presença de uma maior dificuldade das crianças com histórico de prematuridade e risco para atraso no desenvolvimento em participar de jogos com regras simples (uma vez que 17% não apresentaram o comportamento esperado e 25% o realizaram de forma hesitante). Ainda com relação ao domínio da participação, ao se analisar os resultados referentes à área da linguagem observou-se, novamente, um desempenho inferior entre as crianças com histórico de prematuridade, principalmente entre as crianças do grupo GI, quando comparadas às crianças nascidas a termo. Sobre o desempenho das crianças no domínio do faz-de-conta/jogo simbólico da ELPK-rb, notou-se que as crianças do grupo GI obtiveram resultados inferiores aos das crianças dos grupos GII e GIII, principalmente nos subitens interpreta emoções mais complexas e desempenha função nas brincadeiras para/ou com os outros . Ao realizar a associação entre os resultados obtidos pelos grupos na ELPK-rb, com os apresentados no TSDD-II, observou-se que há alterações no comportamento lúdico das crianças com histórico de prematuridade, decorrentes de possíveis atrasos no desenvolvimento neuropsicomotor, uma vez em todas as comparações realizadas, os resultados apresentados pelas crianças do estrato 1 (com histórico de prematuridade e risco para atraso no desenvolvimento) diferiram das crianças do estrato 4 (nascidas a termo e com presença de cautelas ). No entanto, não é possível afirmar que a presença de risco para atraso no desenvolvimento detectado pelo TSDD-II, bem como as alterações no comportamento lúdico das crianças sejam conseqüências exclusivas da prematuridade, mas sim que são decorrentes de múltiplos fatores que se somam e influenciam, concomitantemente, no processo de desenvolvimento das habilidades motoras, cognitivas, psicológicas, e sociais das crianças. Confirma-se, então, a necessidade das práticas de educação, saúde e promoção do desenvolvimento ocorrer em conjunto, contribuindo para a detecção de fatores de risco e para a promoção da qualidade das interações e do ambiente em que as crianças encontram-se inseridas. Neste sentindo, é necessário realizar investimentos na capacitação de educadores/cuidadores/pajens, uma vez que estes podem constituir-se em fatores protetivos ao desenvolvimento das crianças, minimizando/anulando os efeitos negativos advindos da presença de fatores de riscos sociais e biológicos mediante a estimulação das habilidades que englobam o desenvolvimento infantil, principalmente através do brincar, já que este se constitui como uma das principais atividades realizadas pelas crianças em idade pré-escolar, e cuja essência primordial é a promoção do desenvolvimento biopsicomotor e cognitivo dos sujeitos. Ao oferecer às crianças a possibilidades de brincar, dá-se a estas muito mais que o ato em si mesmo, pois proporciona-se a cada uma delas uma perspectiva melhor de vida e um desenvolver de forma natural e saudável.