THESIS SUMMARY:BACKGROUND: Abnormal ductus venosus flow at 11-13 weeks has been associated to fetal chromosomal abnormalities and cardiac defects.The hypothesis of the studies is that flow through the ductus venosus can be assessed routinely at 11-13 weeks of gestation and that abnormal flow at this scan can help identify fetal chromosomal and structural defects as well as adverse pregnancy outcome.STUDIES:In the first study, ten sonographers received practical training in accurate assessment of the ductus venosus and performed 300 examinations each. The sonographers required an average of 80 examinations before they could successfully examine the ductus venosus flow. In the second study ductus venosus flow was assessed immediately before chorion villous sampling (CVS) in fetuses with nuchal translucency (NT) thickness of 3.5 mm or more. A fetal echocardiography was performed in euploid fetuses at 11-13 weeks and/or 18-22 weeks. Reverse or absent flow during atrial contraction was observed in 68.8% of the fetuses with cardiac defects and in 22.9% with no cardiac defects. In the third study screening by the combined test was performed in singleton pregnancies, including 19,614 with euploid fetuses, 122 with trisomy 21, 36 with trisomy 18, 20 with trisomy 13 and 8 with Turner syndrome. We examined the performance of two screening strategies: firstly, assessment of the a-wave in all patients and secondly, first-stage screening using the combined test in all patients followed by second-stage assessment of the a-wave only in those with an intermediate risk of 1 in 51 to 1 in 1,000 after the first-stage. Reversed a-wave was observed in 3.2% of the euploid fetuses and in 66.4%, 58.3%, 55.0% and 75.0% of fetuses with trisomies 21, 18 and 13 and Turner syndrome, respectively. Inclusion of ductus venosus flow in all pregnancies would detect 96%, 92%, 100% and 100% of trisomies 21, 18 and 13 and Turner syndrome, respectively, at a false positive rate of 3%. The same detection rates were achieved with the two-stage strategy at a false positive rate of 2.6%.In the fourth study the patients were subdivided into five groups: normal outcome (n=10,120), miscarriage or fetal death (n=185), abnormal karyotype (n=95), major cardiac (n=20) or non-cardiac defect (n=70). The prevalence of reversed a-wave was significantly higher in the groups with miscarriage or fetal death (10.8%), abnormal karyotype (62.1%) and fetal cardiac defect (25.0%) but not non-cardiac defect (4.3%) than in the normal outcome group (3.7%). The fifth study was a prospective study in 516 dichorionic and 179 monochorionic twin pregnancies. The prevalence of reversed a-wave in the fetal ductus venosus was compared between monochorionic and dichorionic pregnancies and between those with and without pregnancy complications. The prevalence of reversed a-wave in at least one of the fetuses was significantly higher in monochorionic than in dichorionic pregnancies (18.4% vs. 8.3%, p<0.001) and in pregnancies complicated by miscarriage (28.6%, p=0.005), fetal aneuploidy (70.0%, p<0.001) and twin-to-twin-transfusion syndrome (TTTS) (38.5%, p<0.001) compared to the pregnancies with two healthy live births (7.7%). Pregnancy outcome was normal in 76.7% dichorionic and in 42.4% monochorionic twins with reversed a-wave in at least one of the fetuses.CONCLUSIONS: After an extensive supervised training, ductus venosus flow assessment can be incorporated into the first trimester scan, where it improves the performance of screening for chromosomal defects and cardiac defects, and it helps to identify the fetuses with a higher risk of death. Similarly, in twin pregnancies ductus venosus assessment identifies the pregnancies with a higher risk of having a fetus with an aneuploidy, those with a higher risk of miscarriage, and those that will subsequently develop TTTS.KEY WORDS: Ductus venosus, First trimester, Chromosomal abnormality, Cardiac effect, Adverse outcome, Twin pregnancy

The present dissertation, which can be framed in the fields of behavioural and psychiatric genetics, was aimed to study how early environmental factors such as parental negativity and childhood adversity, directly or in interaction with genetic factors account for psychopathological variation (subclinical and clinical psychiatric symptoms) in general populatiol including childhood behavioural problems, adult psychotic, depressive and anxious symptoms and their neuroimaging correlates. Furthermore, from the different studies included in this dissertation, additional research questions were also explored. The studies included in the thesis were based in singletons and twins samples. We found evidence indicating that child behaviour problems, anxious and depressive symptoms and psychotic experiences (PEs) were present in our samples drawn from the general population which is in agreement with a dimensional approach to psychopathology. Furthermore, using neuroimaging techniques, we were able to find structural brain correlates of vulnerability for anxiety and depression in a MZ twin sample from the general population. Also, psychotic experiences were associated with brain activation to facial emotion in this MZ twin sample. In regard to the specific environmental factors studied (parental negativity and childhood maltreatment), experiences occurring early in life showed to be associated to adolescent behaviour problems and adult psychotic experiences highlighting the enduring effects of exposure to childhood adversity. These results highlight the relevance of early adversity in the understanding of psychopathological features. Finally, our findings provide evidence of different ways through genes, environment and their interplay can modulate the final expression of the phenotype. Thus, while there is no doubt regarding that genes and environmental factors can have a direct influence in the phenotype, there is a gene-environment interdependence that must be considered when studying the etiology of complex characters. / Esta tesis doctoral, que se puede enmarcar en las áreas de la genética de la conducta y psiquiatría genética, se centró en el estudio del papel que desarrollan los factores ambientales, tales como la negatividad parental y la adversidad infantil, de manera directa o en interacción con factores genéticos, en la expresión de características psicopatológicas subclínicas en población general. La variación psicopatológica subclínica estudiada incluyó problemas de conducta en la infancia y el desarrollo de experiencias psicóticas y síntomas ansiosos y depresivos en la etapa adulta. Además se exploraron posibles correlatos de neuroimagen de estos fenotipos subclínicos. En cuanto a los resultados, se hallaron evidencias que indicaban que los problemas de conducta infantil, los síntomas ansiosos y depresivos y las experiencias psicóticas se distribuyen de forma continua en la población general. Estos hallazgos están de acuerdo con el enfoque dimensional a la psicopatología. Por otra parte, mediante el uso de técnicas de neuroimagen, se encontraron correlatos cerebrales estructurales para la vulnerabilidad para el desarrollo de síntomas ansiosos y depresivos en una muestra de gemelos monozigóticos (MZ) de la población general. Además, las experiencias psicóticas se asociaron con la activación del cerebro en respuesta a la emoción facial en esta muestra de gemelos MZ. En referencia a los factores ambientales específicos estudiados (negatividad parental y maltrato en la infancia), las experiencias que acontecen durante los primeros años de vida se asociaron con el desarrollo de problemas de conducta adolescentes y el riesgo a desarrollar experiencias psicóticas en la etapa adulta. Estos hallazgos ponen de relevancia los efectos a largo de la exposición a la adversidad durante la infancia. Por último, nuestros resultados ponen de manifiesto la compleja interacción y diferentes tipos de efectos mediantes los cuales los factores genéticos y ambientales ejercen sus influencias en la variabilidad fenotípica. En este sentido, variación en algunas variantes genéticas como el gen del BDNF o el gen de la COMT proporcionaban mayor vulnerabilidad neurobiológica a algunos individuos que habían estado expuestos a maltrato infantil y/o consumo de cannabis, factores de riesgo ampliamente reconocidos en psicosis.