Introdução: A restrição de crescimento fetal (RCF) é a condição na qual o peso fetal encontra-se abaixo do percentil 10 para a idade gestacional. Essa condição caracteriza a gestação como de alto risco e constitui causa de morbidade e mortalidade perinatal. Além de fatores biológicos fetais, maternos e placentários, a RCF é influenciada por fatores psicossociais como depressão e estresse. Esse estudo tem como objetivo comparar gestantes com suspeita de RCF e gestantes sem intercorrências clínicas em relação à depressão, estresse, apoio social e autoestima. Método: Estudo transversal realizado com 79 gestantes com suspeita de RCF, atendidas no Ambulatório de Baixo Peso Fetal da Clínica Obstétrica do HC-FMUSP e 92 gestantes do Pré-Natal de baixo risco, com fetos de crescimento normal. O PRIME-MD foi utilizado para avaliar depressão e a PPP para avaliação de estresse, apoio social e autoestima. Análise quantitativa foi realizada por meio do teste t ou teste não paramétrico de Mann-Whitney e para comparação de mais de dois grupos foi considerado o teste não paramétrico de Kruskal-Wallis. O teste de Dunn com correção dos valores p foi utilizado para comparações 2 a 2. Os testes qui-quadrado de Pearson ou teste exato de Fisher foram utilizados para análise das variáveis qualitativas. Resultados: Neste estudo, as gestantes com suspeita de RCF apresentaram média de idade de 25,89(DP=6,11), média de idade gestacional de 33,33(DP=3,36) e média de números de gestação de 1,92(DP=1,22). As gestantes sem intercorrências clínicas apresentaram médias 27,27(DP=5,90), 32,55(DP=4,01) e 1,83(DP=0,93), respectivamente. Constatou-se diagnóstico de depressão entre 17,7% das gestantes com suspeita de RCF e 16,3% das gestantes sem intercorrências clínicas. Quanto ao estresse, apoio do companheiro, apoio de outras pessoas e autoestima, entre as gestantes com suspeita de RCF, foram constatados os escores médios de 18,27(DP=5,50), 55,15(DP=13,76), 53,77(DP=13,27) e 32,70(DP=4,60). Já entre as gestantes sem intercorrências clínicas, os escores médios foram 19,72(DP=5,16), 55,70(DP=11,37), 51,33(DP=13,26) e 34,22(DP=4,85), respectivamente. Na associação entre os grupos com suspeita de RCF e depressão(RCF+D) e com suspeita RCF sem depressão(RCF-D) foi verificada significância estatística entre estresse (p < 0,01) e autoestima (p < 0,01). Entre os grupos sem intercorrências e com depressão(BR+D) e sem intercorrências e sem depressão(BR-D) foi verificada significância estatística entre estresse (p=0,04) e autoestima (p < 0,01). Entre os grupos RCF+D e BR-D foi constatada significância estatística entre autoestima (p < 0,01). Entre os grupos BR+D e RCF-D foi encontrada significância estatística entre autoestima (p=0,03). Não foram verificadas diferenças estatísticas quanto ao estresse entre os grupos RCF+D e BR+D, RCF-D e BR-D, e BR-D e RCF+D e quanto à autoestima entre os grupos RCF+D e BR+D, e RCF-D e BR-D. Nenhum dos grupos estudados apresentou diferença estatística quanto aos escores de apoio do companheiro e de outras pessoas. Conclusão: Neste estudo, a presença de depressão durante a gestação mostrou-se associada à maior escore de estresse e menor escore de autoestima, tanto entre gestantes com suspeita de RCF como entre aquelas sem intercorrências clínicas / Evaluation of depression, stress, social support and self-esteem in pregnant woman with suspected fetal growth restriction [Dissertation]. São Paulo: Faculdade de Medicina, Universidade de São Paulo; 2017. Introduction: Fetal Growth Restriction (FGR) is the condition in which fetal weight is below the 10th percentile for gestational age. This condition characterizes a high-risk pregnancy and is an important cause of perinatal morbidity and mortality. In addition to biological fetal, maternal and placental factors, the FGR is influenced by psychosocial factors such as depression and stress. This study aims to compare pregnant woman with suspected FGR and pregnant woman without clinical intercurrences in relation to depression, stress, social support and self-esteem. Methods: Cross-sectional study with 79 pregnant women with suspected FGR, met at the Low Fetal Weight Clinic of the PRIME-MD was used to evaluate depression and PPP for stress assessment, social support and self-esteem. Quantitative analysis was performed using the t-test or non-parametric Mann-Whitney test and for comparison of more than two groups was considered the nonparametric Kruskal-Wallis test. The Dunn test, with corrected p values, was used for 2 on 2 comparisons. The Pearson\'s chi-square tests or Fisher\'s exact tests were used for qualitative data analysis. Results: In the present study, pregnant women with a suspicion of FGR had a mean age of 25.89 (SD=6.11), mean gestational age of 33.33 weeks (SD=3.36 weeks) and average gestation numbers of 1.92 (SD=1.22). The pregnant woman without clinical intercurrences presented averages 27,27 (SD=5.90), 32.55 (SD=4.01) and 1.83 (SD=0.93), respectively. A diagnosis of depression was found among 17.7% of pregnant women with suspected FGR and 16.3% of pregnant women without clinical intercurrences. As for stress, peer support, support from other people and self-esteem was found among pregnant women with suspected FGR mean scores of 18.27 (SD=5.50), 55.15 (SD=13.76), 53.77 (SD=13.27) and 32.70 (SD=4.60). Among the pregnant women without clinical intercurrences, the mean scores were 19.72 (SD=5.16), 55.70 (SD=11.37), 51.33 (SD = 13.26) and 34.22 (SD = 4.85), respectively. The statistical significance of stress (p < 0.01) and self-esteem (p < 0.01) were found in the association between the groups with suspected FGR and depression (RCF+D) and with suspected FGR without depression (RCF-D). Among the groups without intercurrences and with depression (BR+D) and without intercurrences and without depression (BR-D), statistical significance was observed between stress (p=0.04) and self-esteem (p < 0.01). Among the RCF+D and BR-D groups, statistical significance was found between self-esteem (p < 0.01). Among the BR + D and RCF-D groups, statistical significance was found between self-esteem (p=0.03). Statistical differences were not found for stress among the RCF+D and BR+D, RCF-D and BR-D, and BR-D and RCF+D groups, and for self-esteem between the RCF+D and BR+D groups, And RCF-D and BR-D. None of the groups studied presented statistical difference regarding the support scores of the companion and the support of other people. Conclusions: In this study, the presence of depression during pregnancy was associated with a higher stress score and lower self-esteem score both among pregnant women with FGR suspicion and among pregnant women without clinical intercurrences

OBJETIVOS: Descrever os resultados obstétricos e perinatais em três grupos de gestações gemelares monocoriônicas diamnióticas (MCDA) conduzidas de forma expectante: com diástole zero (DZ) e/ou reversa (DR) fixas na Dopplervelocimetria de artérias umbilicais (AU) e restrição de crescimento fetal seletiva (RCFs) (tipo II de Gratacós); com DZ e/ou DR intermitente e RCFs (tipo III de Gratacós) e com DZ e/ou DR intermitente sem RCFs (Sem RCFs). MÉTODOS: Estudo retrospectivo, realizado no período de abril de 2007 a abril de 2017. Foram incluídas todas as gestações MCDA no período com DZ e/ou DR no Doppler de AU com IG < 26 semanas e ausência de Síndrome de Transfusão feto-fetal (STFF) ou malformações fetais e das quais foi possível obtenção dos dados obstétricos, fetais e dos recém-nascidos (RNs) até a alta hospitalar. Todas as variáveis foram analisadas descritivamente. Além disso, para as variáveis qualitativas foram calculadas as frequências absolutas e relativas. RESULTADOS: 33 pacientes preencheram os critérios de inclusão; 6 no tipo II, 22 no tipo III e 5 no grupo Sem RCFs. A mediana da IG do diagnóstico foi semelhante em todos os grupos. As discordâncias entre os pesos dos fetos e RNs foram maiores no tipo II. Quando a DZ e/ou DR eram intermitentes (tipo III e Sem RCFs), a latência entre o diagnóstico e o óbito fetal (OF) foi superior. Quanto aos resultados obstétricos, a IG mediana do parto foi de 29; 32,71 e 30,78 semanas nos tipos II, III e Sem RCFs, respectivamente, e as indicações foram, em sua maioria, por deterioração dos parâmetros ultrassonográficos ou biofísicos fetais. A taxa de OF foi maior no tipo II (33,3%), ocorreu em 20% no Sem RCFs e 11,36% no tipo III. Em relação aos dados perinatais gerais, o pior resultado ocorreu no tipo II, em que nenhuma paciente levou 2 RNs vivos para casa, sendo que isso sucedeu em 72,7% no tipo III e 60% no Sem RCFs. No que concerne à morbidade neonatal, o peso de nascimento foi menor no tipo II. Já, a HIV mostrou-se mais comum no tipo III (30,3%), porém, no tipo II, a ocorrência foi similar (28,57%), não acometeu nenhum RN no grupo Sem RCFs. CONCLUSÃO: A prematuridade foi preponderante. O acompanhamento da vitalidade dos fetos é de suma importância, uma vez que a piora de seus parâmetros indica a resolução da gestação em considerável parcela desses casos. O tipo II foi o que apresentou os desfechos perinatais mais desfavoráveis, além da maior discordância de peso entre os fetos e os RNsAbsent and/or reversed end-diastolic flow in the umbilical arteries / OBJECTIVES: To describe obstetric and perinatal outcomes in three groups of monochorionic diamniotic (MCDA) twin pregnancies under expectant management: with absent and/or reversed end-diastolic Doppler flow (AREDF) in the umbilical arteries (UA) and selective intrauterine growth restriction (sIUGR) (Gratacós\' type II); with intermittent AREDF (iAREDF) and sIUGR (Gratacós\' type III) and with iAREDF without sIUGR (Without sIUGR). METHODS: This was a retrospective study, from April 2007 to April 2017. All the MCDA twin pregnancies presenting AREDF or iAREDF in the UA at less than 26 weeks of gestational age (GA), without signs of Twin to Twin Transfusion Syndrome (TTTS) or fetal anomalies and of whom it was possible to obtain obstetrical data and information of the fetuses and neonates until hospital discharge were included. All the variables were descriptively analysed. Furthermore, absolute and relative frequencies were calculated for the qualitative variables. RESULTS: 33 patients were included; 6 in type II, 22 in type III and 5 in the group Without sIUGR. Median GA at diagnosis was similar among the groups. Fetal and neonate\'s weight discordances were greater in type II. The groups with iAREDF (type III and Without sIUGR) had the longest latency between diagnosis and intrauterine fetal demise (IUFD). Regarding obstetric outcome, median GA at delivery were 29, 32.71 and 30.78 weeks for type II, III and Without sIUGR respectively and sonographic and biophysical parameters deterioration was the main reason to indicate deliveries. IUFD was also more frequent in type II (33,3%), occurred in 20% of type III and 11,36% in the group Without sIUGR. As far as general perinatal outcome is concerned, type II had the worst result, in which no patient took 2 neonates home; it happened in 72.7% in type III and 60% in the group Without sIUGR. In relation to perinatal morbidity, type II neonates presented the lowest weight at birth. Type III and II had the highest, but similar proportions of intraventricular hemorrhage (30.3% and 28.57% respectively), it didn\'t happen in the group Without sIUGR, though. CONCLUSION: Prematurity was preponderant. It is of the highest importance to monitor fetal wellbeing, since the great majority of deliveries were indicated by the deterioration of its parameters. Type II sIUGR showed the most unfavorable perinatal outcome and additionally, the greatest fetal and neonatal weight discordances

Introdução: A restrição de crescimento intrauterino (RCIU) é uma intercorrência obstétrica de prevalência relevante e altas taxas de morbimortalidade. A ultrassonografia (US) obstétrica ainda é limitada para diagnosticar comprometimento cerebral na RCIU. Por isso, com o intuito de aumentar a acurácia diagnóstica de lesões no encéfalo e comprometimento da criança acometida, surgiram alguns trabalhos utilizando a ressonância magnética (RM), mas com dificuldades técnicas. Sendo assim, são necessários estudos que avaliem o encéfalo de fetos com RCIU e que identifiquem biomarcadores simples de hipóxia crônica e/ou aguda. Objetivos: comparar parâmetros morfométricos mensurados por RM do crânio e encéfalo de fetos com crescimento normal e de fetos com RCIU. Métodos: trata-se de um estudo de coorte prospectivo que incluiu 13 fetos de gestações únicas, com crescimento adequado e 13 fetos de gestações únicas com RCIU, na relação 1 caso:1 controle, de 26 a 38 semanas de idade gestacional (IG) que foram submetidos à avaliação ultrassonográfica para determinação da biometria, volume de líquido amniótico e Dopplervelocimetria fetal e à RM para avaliação de medidas encefálicas e cranianas. Variáveis relacionadas ao tipo de parto, condições do nascimento e resultados perinatais adversos foram obtidas de prontuários médicos. Para análise estatística foram empregados os testes de Wilcoxon e Chi-quadrado. Resultados: as medidas do diâmetro biparietal (DBP) ósseo e cerebral e do diâmetro occipitofrontal (DOF) ósseo de fetos restritos foram menores que as de controles, assim como os percentis desses diâmetros, da circunferência craniana e do DOF cerebral. Observou-se também que a mediana da relação DBP cerebral/cerebelo da população de fetos restritos tendeu a ser menor que a de controles. Além disso, as medidas do líquor cerebroespinhal (LCE) extracerebral e seus percentis também foram menores nos fetos restritos. Também há diferenças nas relações DOF ósseo/LCE, DOF cerebral/LCE, DBP ósseo/LCE e DBP cerebral/LCE entre os grupos de fetos estudados. Além disso, as medidas das distâncias interoperculares axiais direita e esquerda foram significativamente menores nos fetos restritos. Conclusões: podemos concluir que fetos com RCIU possuem medidas cranianas e encefálicas menores que fetos com crescimento adequado, além de haver redução do LCE extracerebral. Estudos de RM fetal com casuística maior, que permitam análise com regressão logística multivariada e aqueles que avaliem comprometimento neurológico das crianças acometidas são necessários. / Introduction: intrauterine growth restriction (IUGR) is an obstetric intercurrence of relevant prevalence and high morbidity and mortality rates. Obstetrical ultrasonography is still limited to diagnose brain impairment in IUGR. Therefore, in order to increase the diagnostic accuracy of brain lesions and impairment of the affected child, some studies using magnetic resonance imaging (MRI) have emerged, but with technical difficulties. Hence, studies that evaluate the brain of fetuses with IUGR and that identify simple biomarkers of chronic and/or acute hypoxia are needed. Objectives: to compare morphometric parameters measured by MRI of the skull and brain of fetuses with normal growth and fetuses with IUGR. Methods: this was a prospective cohort study that included 13 fetuses with normal growth and 13 fetuses with IUGR from singleton pregnancies, in the ratio 1 case: 1 control, from 26 to 38 weeks of gestational age (GI) who underwent ultrasound evaluation to determine the biometry, amniotic fluid volume and fetal Doppler velocimetry and MRI for evaluation of brain and cranial measurements. Variables related to the type of delivery, birth conditions and adverse perinatal outcomes were obtained from medical records. Wilcoxon and Chi-square tests were used for statistical analysis. Results: the measurements of skull and brain biparietal diameter (BPD) and skull occipitofrontal diameter (OFD) of IUGR fetuses were lower than those of controls, as well as the percentiles of these diameters, head circumference and the brain OFD. It has also been observed that the median of the brain BPD/cerebellar diameter ratio of the IUGR fetuses tended to be lower than that of the controls. In addition, measurements of the extracerebral cerebrospinal fluid (CSF) and their percentiles were also lower in IUGR fetuses. There are also differences in the skull OFD/ CSF, brain OFD/ CSF, skull BPD/ CSF and brain BPD/ CSF and extracerebral CSF ratios between the groups of fetuses studied. In addition, measurements of right and left axial interopercular distances were significantly lower in the IUGR fetuses. Conclusions: we can conclude that IUGR fetuses have smaller cranial and brain measures than fetuses with normal growth, besides having reduction of extracerebral CSF. Fetal MRI studies with larger number of subjects, allowing analysis with multivariate logistic regression and those which assess neurological impairment of affected children are needed.

Le retard de croissance intra-utérin (RCIU) est une complication responsable d’une importante mortalité et morbidité périnatales. Son dépistage représente un enjeu important de la surveillance prénatale. Les objectifs de la thèse étaient d’évaluer la performance du dépistage anténatal du RCIU, d’identifier ses déterminants et de mesurer son impact sur les issues périnatales. Dans une première partie, nous avons utilisé les données de l’Enquête Nationale Périnatale de 2010 (N=14 100 enfants uniques) : 21,7% des enfants de poids <10ème percentile étaient suspectés avec un RCIU en anténatal tandis que la moitié des enfants suspectés avait un poids normal à la naissance (faux positifs). Le risque de naissance induite était élevé en cas de suspicion, indépendamment de l’existence d’un faible poids, suggérant des interventions iatrogènes. Les issues néonatales n’étaient pas différentes selon la suspicion. Dans une seconde partie, nous avons utilisé les données d’une cohorte nationale d’enfants nés avant 32 SA en 2011, EPIPAGE 2 (N=3698 enfants uniques sans anomalie congénitale). La prise en charge active pour indication fœtale en cas de RCIU était initiée à partir de 26 SA. Pour 14% des enfants, il existait une discordance entre la suspicion d’un RCIU en anténatal et un faible poids à la naissance. En cas de discordance, le poids de naissance était le paramètre le plus important pour évaluer le pronostic néonatal. Nos travaux soulèvent des questions sur l’efficacité du dépistage du RCIU en France. Ils montrent la nécessité de développer de nouvelles stratégies de dépistage et de poursuivre les recherches pour mesurer leur impact sur les décisions médicales et sur la santé. / Fetal growth restriction (FGR) is a pregnancy complication that is responsible for significant perinatal mortality and morbidity. Screening for FGR is a key component of prenatal care. The objectives of this thesis were to evaluate the performance of prenatal screening for FGR, to identify the determinants of antenatal suspicion of FGR and to measure its impact on perinatal outcomes. For the first part of the thesis, we used data from the nationally representative French National Perinatal Survey of births (N=14,100 singleton pregnancies): 21.7% of infants with a low birthweight <10th percentile were suspected with FGR during pregnancy and half of infants suspected with FGR had a normal birthweight (false positives). The risk of indicated delivery was higher when FGR was suspected, regardless of the existence of low birthweight, suggesting possible iatrogenic effects. Outcomes were not different for suspected versus unsuspected low birthweight infants. In the second part of the thesis, we used data from the EPIPAGE 2 national cohort of children born before 32 weeks of GA in 2011 (N=3698 singleton non-anomalous infants). Active management for fetal indications in cases of suspected FGR was initiated at 26 weeks. Antenatal and postnatal assessments of FGR were discordant for 14% of infants. When assessments were discordant, birthweight was a better predictor of adverse neonatal outcome. Our results raise questions about the effectiveness of screening strategies for FGR in France. New strategies for the detection of FGR are needed as well as research to measure the impact of screening on medical decisions and health.

Children descending from pregnancy complicated by gestational hypertension, preeclampsia or fetal growth restriction have a lifelong increased risk of development of cardiovascular disease. This study investigates the expression profile of 29 cardiovascular and cerebrovascular microRNAs in children at the age of 3 to 11 years. MicroRNAs are short non-coding RNA molecules affecting gene expression by posttranscriptional modifications of mRNA, which affects biological processes. Abnormal microRNA levels can lead to pathological conditions of the individual. This study explores the relationship between dysregulated microRNA levels in whole peripheral venous blood of children and the presence of complications during pregnancy. Furthermore, this study looks at expression profile specificities depending on the presence of pathology in the child's cardiovascular system, as found in a clinical examination consisting of BMI assessment and evaluation, blood pressure testing and ultrasound examination of the heart. Dysregulated profile was present in children with gestational hypertension in miR-1-3p, miR-17-5p, miR-20a-5p, miR-21-5p, miR-26a-5p, miR-29a-3p, miR-126-3p, miR-133a-3p, miR-181a-5p, miR-199a-5p, miR-342-3p and miR-499-5p. In children with preeclampsia, dysregulation was found with miR-1-3p and...

La prématurité et la restriction de croissance fœtale (RCF) sont deux pathologies néonatales fréquentes, qui ont en commun des difficultés d'adaptation à la naissance, avec le développement d'une tubulopathie chez le prématuré, et le développement d'une hypertension artérielle (HTA) a l'âge adulte. L’objectif de ce travail était d’évaluer l'implication des voies de signalisation corticostéroïdes rénales dans la survenue de ces complications dans un modèle murin de prématurité induite par des lipopolysaccharides, et un modèle de RCF par exposition périnatale a la dexaméthasone. Dans ce travail nous avons montré que ces deux pathologies programment la survenue d’une HTA à l’âge adulte chez les mâles, associée à des altérations franches de la signalisation corticostéroïde rénale en période périnatale et une augmentation de la sensibilité rénale aux glucocorticoïdes à l’âge adulte. Dans le modèle de prématurité, nous avons identifié la transmission transgénérationelle d’anomalies de régulation de la pression artérielle chez les mâles jusqu’à la 3ème génération de souris, associée à une hypométhylation du promoteur de GILZ et une augmentation d’expression de GILZ. Notre étude a permis l’identification de potentiels mécanismes moléculaires impliqués dans la programmation fœtale de l’HTA, sur plusieurs générations, ce qui pourrait aboutir à une meilleure prise en charge des patients nés prématurés ou avec une RCF, et de leurs descendants. / Preterm birth and fetal growth restriction (IUGR) are prevalent neonatal diseases, which both induce poor perinatal adaptation, including the development of tubulopathy in premature infants, and the development of high blood pressure in adults. The objective of this work was to evaluate the involvement of renal corticosteroid signaling pathways in the development of these complications in a lipopolysaccharide-induced mouse model of preterm birth, and a dexamethasone-induced model of IUGR. In this work, we have shown that these two pathologies program the development of hypertension in former preterm and IUGR male mice, associated with strong alterations of renal corticosteroid signaling in the perinatal period, and an increase in renal sensitivity to glucocorticoids in adulthood. Moreover, we have identified a transgenerational inheritance of altered blood pressure regulation induced by preterm birth, in males, up to the 3rd generation of mice, associated with GILZ promoter hypomethylation and increased GILZ expression.Our study has identified potential molecular mechanisms involved in the fetal programming of hypertension, over several generations. These findings could facilitate better management of patients born prematurely

The aim of this study was to investigate gene expression of cardiovascular miRNAs in peripheral blood of mothers after delivery. MiRNAs are small non-coding RNAs, which significantly modulate posttranscriptional adjustments of mRNA and thus regulate gene expression across biological processess. Dysregulation of miRNAs is associated with many pathological phenomena, thanks that we can use them for diagnosis and potentionaly we can treat these diseases by the manipulation of miRNA gene expression. We examined gene expression of circulating miRNAs associated with cardiovascular diseases, and we investigated, how the expression profile depends on pregnancy course and manifestation of pregnancy-related complications. For this purpose we examined material from 221 mothers 3-10 years after delivery. A group with identical pregnancy-related complication was always compared with a group of mothers after physiological pregnancy. Gene expression of 29 cardiovascular miRNAs in peripheral blood was studied using reverse transcription and quantitative real-time PCR. It was confirmed, that the expression profile of miRNAs differed between pregnancy-related complications and physiological controls. We also confirmed, that the profile of gene expression discovered at mothers 3-10 years after delivery was different...

Uterine NK (uNK) cells are a distinct subset of NK cells in the decidua of humans and rodents during pregnancy, which are essential for remodelling of the spiral arteries supplying the feto-placental unit. Similarly to peripheral NK cells, uNK cells express Natural Killer receptors (NKRs) that engage MHC class I molecules. Evidence from human genetic association studies suggests that, in the presence of allogeneic cognate paternal MHC class I ligands, inhibitory uterine NKRs are associated with disorders of pregnancy arising from impaired decidual vascular remodelling. Conversely, enhancement of human uNK cell activity through activating NKRs is associated with high birth weight. Evidence from mouse models corroborates that uNK cell activity is modulated by interactions between NKRs and MHC class I, but has largely focussed on the effect of paternal MHC. In this study, the contribution of maternal immunogenetic regulation of NK cell function to reproductive outcome was assessed independently of parental MHC disparity in mice. To evaluate the role of NKR genes in isolation, I used congenic B6.BALB-TC1 (TC1) mice that differ from C57BL/6 (B6) mice only within the region of chromosome six encoding NKRs that recognise MHC class I. Absence of a major inhibitory NKR for self-MHC, Ly49I, in TC1 mice causes a compensatory shift in the NKR repertoire expressed and preserves a majority subpopulation of educated NK cells. B6 and TC1 splenic and uterine NK cells are similarly functionally reactive and mature, and no significant differences could be detected in spiral arterial remodelling or fetal growth between these strains in MHC-syngeneic matings. This supports data from human immunogenetic studies showing that maternal uterine NKRs are not associated with differences in pregnancy outcome in the absence of novel paternal MHC class I ligands, and highlights the importance of maternal and paternal co-regulation of uNK cell activity during pregnancy. No mouse models of uNK cell activation are currently available with which to corroborate human immunogenetic associations between activating uterine NKRs and high birth weight. Male m157-transgenic (m157-Tg) mice, which ubiquitously express viral m157 glycoprotein ligands for the activating NKR Ly49H, were mated with B6 females. Exclusive expression of m157 glycoprotein by trophoblast improved placental efficiency, but did not enhance fetal growth. Some fertility clinics surmise that uNK cell activation initiates the pathogenesis of spontaneous abortion. It has been suggested that this may occur due to reduced expression by human uNK cells of miR-483-3p, which stimulates endogenous insulin-like growth factor (IGF)-1 production and uNK cell cytotoxicity in vitro. It is demonstrated here that neither miR-483-3p nor IGF-1 regulate murine NK cell development, maturation or function. No discernible reproductive phenotype is evident in miR-483 deficient females. It can be inferred that post-transcriptional control by miR-483 is not biologically relevant to murine NK cell function. Although m157-Tg mice may provide an interesting model to further study uNK cell-mediated placental adaptations, it remains important to identify a murine model of enhanced uNK cell function to corroborate human immunogenetic associations with high birth weight and to challenge the supposition that uNK cell activation is harmful to pregnancy.

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.

Pregnancy-related complications such as gestational hypertension, preeclampsia, fetal growth restriction, gestational diabetes mellitus, spontaneous preterm birth, and preterm premature rupture of membranes may have severe consequences for both the mother and the child. The development of reliable early screening methods for pregnancy-related complications has therefore been a long-term goal of obstetrics. New possibilities for prenatal diagnostics have opened with the discovery of circulating microRNAs in maternal plasma. MicroRNAs are short, noncoding, 21 to 23 nucleotides long, single-strand RNAs whose main function is to regulate gene expression. During pregnancy, both common and unique miRNAs are expressed by the placenta, amongst them the miRNAs of the C19MC cluster. Several C19MC miRNAs have been shown to display a different expression profile associated with certain pregnancy-related complications. This thesis identifies the plasma exosomal profiles of six C19MC miRNAs (miR-516-5p, miR-517-5p, miR-518b, miR-520a-5p, miR-520h, and miR-525-5p) in patients in their first trimester of gestation who later developed pregnancy-related complications, and compares them with profiles in patients with normal pregnancies.