Search

Cervical length; Microbial diversity; Pessary Longitud cervical; Diversidad microbiana; Pesario Longitud cervical; Diversitat microbiana; Pessari Introduction Our objective was to compare the vaginal microbiome in low-risk and high-risk pregnant women and to explore a potential association between vaginal microbiome and preterm birth. Material and methods A pilot, consecutive, longitudinal, multicenter study was conducted in pregnant women at 18–22 weeks of gestation. Participants were assigned to one of three groups: control (normal cervix), pessary (cervical length ≤25 mm) and cerclage (cervical length ≤25 mm or history of preterm birth). Analysis and comparison of vaginal microbiota as a primary outcome was performed at inclusion and at 30 weeks of gestation, along with a follow-up of pregnancy and perinatal outcomes. We assessed the vaginal microbiome of pregnant women presenting a short cervix with that of pregnant women having a normal cervix, and compared the vaginal microbiome of women with a short cervix before and after placement of a cervical pessary or a cervical cerclage. Results The microbiome of our control cohort was dominated by Lactobacillus crispatus and inners. Five community state types were identified and microbiome diversity did not change significantly over 10 weeks in controls. On the other hand, a short cervix was associated with a lower microbial load and higher microbial richness, and was not correlated with Lactobacillus relative abundance. After intervention, the cerclage group (n = 19) had a significant increase in microbial richness and a shift towards community state types driven by various bacterial species, including Lactobacillus mulieris, unidentified Bifidobacterium or Enterococcus. These changes were not significantly observed in the pessary (n = 26) and control (n = 35) groups. The cerclage group had more threatened preterm labor episodes and poorer outcomes than the control and pessary groups. Conclusions These findings indicate that a short cervix is associated with an altered vaginal microbiome community structure. The use of a cerclage for preterm birth prevention, as compared with a pessary, was associated with a microbial community harboring a relatively low abundance of Lactobacillus, with more threatened preterm labor episodes, and with poorer clinical outcomes. This study was supported by the Instituto de Salud Carlos III/FEDER FIS PI15/02043; Beca Dexeus Mujer 2015. Francisca Yáñez was supported by a grant from ANID, BECAS Chile, N° 72190278. Zixuan Xie received a fellowship from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie Action, Innovative Training Network: FunHoMic; grant number 812969.

Background Fetal smallness affects 10% of pregnancies. Small fetuses are at a higher risk of adverse outcomes. Their management using estimated fetal weight and feto-maternal Doppler has a high sensitivity for adverse outcomes; however, more than 60% of fetuses are electively delivered at 37 to 38 weeks. On the other hand, classification using angiogenic factors seems to have a lower false-positive rate. Here, we present a protocol for the Fetal Growth Restriction at Term Managed by Angiogenic Factors Versus Feto-Maternal Doppler (GRAFD) trial, which compares the use of angiogenic factors and Doppler to manage small fetuses at term. Objective The primary objective is to demonstrate that classification based on angiogenic factors is not inferior to estimated fetal weight and Doppler at detecting fetuses at risk of adverse perinatal outcomes. Methods This is a multicenter, open-label, randomized controlled trial conducted in 20 hospitals across Spain. A total of 1030 singleton pregnancies with an estimated fetal weight ≤10th percentile at 36+0 to 37+6 weeks+days will be recruited and randomly allocated to either the control or the intervention group. In the control group, standard Doppler-based management will be used. In the intervention group, cases with a soluble fms-like tyrosine kinase to placental growth factor ratio ≥38 will be classified as having fetal growth restriction; otherwise, they will be classified as being small for gestational age. In both arms, the fetal growth restriction group will be delivered at ≥37 weeks and the small for gestational age group at ≥40 weeks. We will assess differences between the groups by calculating the relative risk, the absolute difference between incidences, and their 95% CIs. Results Recruitment for this study started on September 28, 2020. The study results are expected to be published in peer-reviewed journals and disseminated at international conferences in early 2023. Conclusions The angiogenic factor–based protocol may reduce the number of pregnancies classified as having fetal growth restriction without worsening perinatal outcomes. Moreover, reducing the number of unnecessary labor inductions would reduce costs and the risks derived from possible iatrogenic complications. Additionally, fewer inductions would lower the rate of early-term neonates, thus improving neonatal outcomes and potentially reducing long-term infant morbidities. Trial Registration ClinicalTrials.gov NCT04502823; https://clinicaltrials.gov/ct2/show/NCT04502823 International Registered Report Identifier (IRRID) DERR1-10.2196/37452

Cannabis consumption during pregnancy increases the risk of pregnancy and neonatal complications. Since the underlying mechanism is unknown, the purpose of this study is to evaluate the changes in maternal and fetal blood flow in pregnancies exposed to cannabis, Δ9-tetrahydrocannabinol (THC). A case-control study between 2013 and 2020, included women with continued cannabis exposure during the pregnancies, defined by qualitative detection of THC in urine (Cannabis Group), and low-risk pregnancy women divided into tobacco smokers (Tobacco Group), and non-tobacco smokers (Control Group). We evaluated the association between cannabis consumption and maternal and fetal blood flow parameters measured by Doppler ultrasound: uterine artery at 11-14, 20-22 and 33-35 weeks, umbilical artery and middle cerebral artery at 33-35 weeks. Cerebral-placental ratio was calculated. Overall, 275 participants were included, 60 in the Cannabis Group, 17 in the Tobacco Group and 198 in the Control Group. At 33-35 weeks, differences were found in the umbilical artery pulsatility index (PI) (1.05 ± 0.23, 1.06 ± 0.19, 0.93 ± 0.15, P < 0.01), middle cerebral artery PI (1.75 ± 0.35, 1.90 ± 0.45, 1.88 ± 0.34, P < 0.05), cerebral-placental ratio (1.69 ± 0.40, 1.85 ± 0.53, 2.07 ± 0.47, P < 0.05) and mean uterine artery PI (0.89 ± 0.26, 0.73 ± 0.19, 0.74 ± 0.20, P < 0.01), respectively. On logistic regression analysis, adjusted for maternal age, maternal body mass index, maternal weight and white ethnicity, both cannabis and tobacco were predictors for increased umbilical artery PI, but only cannabis was a predictor for a decreased cerebral-placental ratio and an increased uterine artery PI at 33-35 weeks. Data from a large cohort of continuous cannabis exposure pregnancies show that cannabis is associated with maternal and fetal blood flow changes. However, it is not possible to disentangle the association of the tobacco and cannabis. Continuous cannabis exposure pregnancies showed that cannabis is associated with maternal and fetal blood flow changes. Nevertheless, it is not possible to disentangle the association of the tobacco and cannabis

Maternal body mass index; Newborn weight; Obesity Índice de masa corporal materno; Peso del neonato; Obesidad Índex de massa corporal matern; Pes del nounat; Obesitat Background: Obesity and thinness are serious diseases, but cases with abnormal maternal weight have not been excluded from the calculations in the construction of customized fetal growth curves (CCs). Method: To determine if the new CCs, built excluding mothers with an abnormal weight, are better than standard CCs at identifying SGA. A total of 16,122 neonates were identified as SGA, LGA, or AGA, using the two models. Logistic regression and analysis of covariance were used to calculate the OR and CI for adverse outcomes by group. Gestational age was considered as a covariable. Results: The SGA rates by the new CCs and by the standard CCs were 11.8% and 9.7%, respectively. The SGA rate only by the new CCs was 18% and the SGA rate only by the standard CCs was 0.01%. Compared to AGA by both models, SGA by the new CCs had increased rates of cesarean section, (OR 1.53 (95% CI 1.19, 1.96)), prematurity (OR 2.84 (95% CI 2.09, 3.85)), NICU admission (OR 5.41 (95% CI 3.47, 8.43), and adverse outcomes (OR 1.76 (95% CI 1.06, 2.60). The strength of these associations decreased with gestational age. Conclusion: The use of the new CCs allowed for a more accurate identification of SGA at risk of adverse perinatal outcomes as compared to the standard CCs.

El part prematur pot sobrevenir per riscos del mateix embaràs o bé per la necessitat de realitzar algun tipus de cirurgia fetal. La probabilitat de donar a llum abans de la data estimada se situa entre 8% i el 12% als països desenvolupats. Aquest percentatge augmenta 5-6 vegades quan es tracta d'embarassos múltiples. En aquest article, investigadores de l'Hospital Universitari Vall d'Hebron fan un repàs sobre alguns dels factors de risc, i avaluen algunes tècniques de prevenció comparant els riscos que impliquen cadascuna. Les conclusions es basen en la seva pròpia experiència com a professionals, que ha estat publicada en revistes científiques d'impacte. El parto prematuro puede sobrevenir por riesgos del propio embarazo o bien por la necesidad de realizar algún tipo de cirugía fetal. La probabilidad de dar a luz antes de la fecha estimada se sitúa entre 8% y el 12% en los países desarrollados, y aumenta 5-6 veces cuando se trata de embarazos múltiples. En este artículo, investigadoras del Hospital Universitari Vall d'Hebron hacen un repaso sobre algunos de los factores de riesgo, y evalúan algunas técnicas de prevención comparando los riesgos que implican cada una. Las conclusiones se basan en su propia experiencia como profesionales, que ha sido publicada en revistas científicas de impacto. Preterm delivery can occur either due to the risks of pregnancy itself, or due to the need to perform some type of fetal surgery. There is an 8% to 12% chance of a baby being born prematurely in developed countries. A risk which increases from 5 to 6 times when it comes to multiple gestations. In this article, researchers from the Vall d'Hebron University Hospital review some of the risk factors, and evaluate a series of prevention techniques by comparing the risks involved in each one. The conclusions are based on their own experience as professionals, which has been published in scientific journals of impact.

Objectives To compare the ability of first‐trimester combined screening for pre‐eclampsia (PE) to predict early‐onset and preterm PE when pregnancy‐associated plasma protein‐A (PAPP‐A) and placental growth factor (PlGF) were assessed before vs after 11 weeks' gestation. Methods This was a secondary analysis of a prospective cohort study of singleton pregnancies undergoing routine first‐trimester screening conducted at Vall d'Hebron University Hospital, Barcelona, Spain, between October 2015 and September 2017. Demographic characteristics, obstetric history, maternal history and biophysical markers (mean uterine artery pulsatility index and mean arterial blood pressure (MAP)) were recorded at the first‐trimester scan (at 11 + 0 to 13 + 6 weeks' gestation). Maternal serum concentrations of PAPP‐A and PlGF were assessed from the routine first‐trimester blood test (at 8 + 0 to 13 + 6 weeks). Women were classified into two groups depending on whether serum biomarkers were assessed at 8 + 0 to 10 + 6 weeks or at 11 + 0 to 13 + 6 weeks. Probability scores for early‐onset and preterm PE were calculated by using two different algorithms: the multivariate Gaussian‐distribution model and The Fetal Medicine Foundation (FMF) competing‐risks model. Receiver‐operating‐characteristics (ROC) curves were produced and detection rates at fixed 5% and 10% false‐positive rates were computed to compare the performance of these algorithms when PAPP‐A and PlGF were assessed before vs after 11 weeks. Results Of the 2641 women included, serum biomarkers were assessed before 11 weeks in 1675 (63.4%) and at or after 11 weeks in 966 (36.6%). Of these, 90 (3.4%) women developed PE, including 11 (0.4%) cases of early‐onset PE and 30 (1.1%) of preterm PE. Five (45.5%) cases of early‐onset and 16 (53.3%) of preterm PE were identified in the group in which serum biomarkers were assessed at 8 + 0 to 10 + 6 weeks and six (54.5%) cases of early‐onset and 14 (46.7%) of preterm PE in the group in which serum biomarkers were assessed at 11 + 0 to 13 + 6 weeks. In the prediction of early‐onset and preterm PE using the Gaussian algorithm, no differences were observed between the areas under the ROC curves (AUCs) when PAPP‐A and PlGF were measured before or after 11 weeks. In the prediction of early‐onset and preterm PE using the FMF algorithm, no differences were observed between AUCs for any of the combinations used for risk calculation when the serum biomarkers were obtained before vs after 11 weeks, except for the combination of PAPP‐A and MAP, which showed a greater AUC for the prediction of early‐onset PE when PAPP‐A was measured at or after 11 weeks. Conclusions The prediction of early‐onset and preterm PE is similar when serum biomarkers are measured before or after 11 weeks. This allows the use of a two‐step approach for PE risk assessment that permits immediate risk calculation at the time of the first‐trimester scan. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Introduction: The analysis of patients&rsquo, satisfaction with healthcare is recognised as being useful in the evaluation of health outcomes and perceived quality of care. Little is known, however, about how the psychological status of women who experience perinatal complications may affect their perceived satisfaction with care. Methods: We assessed healthcare satisfaction in 52 women who had undergone intrauterine surgery during a complicated monochorionic twin pregnancy and examined the influence that fetal loss and sociodemographic, clinical, and psychological factors had on the degree of satisfaction. Data were gathered in an individual interview and through the administration of the Medical Patient Satisfaction Questionnaire, Beck Depression Inventory, and State&ndash, Trait Anxiety Inventory. Relationships between variables were analysed using a chi-square test, Spearman&rsquo, s rho, Student&rsquo, s t test, and the Mann&ndash, Whitney U test, in accordance with the metric nature of the variables and the assumptions fulfilled. Results: Age and level of education were not associated with the degree of healthcare satisfaction. Negative but non-significant correlations were observed between the level of satisfaction and symptoms of anxiety and depression. Satisfaction with healthcare was high in the sample as a whole, although it was significantly higher among women who had not experienced fetal loss. There were no differences in satisfaction with services involving direct contact with medical staff, whereas satisfaction with indirect services was lower among women who had experienced perinatal loss. Conclusions: Due to the unique characteristics of this population, specialised care teams of both professional healthcare and indirect services are needed. Although administrative aspects of healthcare are regarded as being of secondary importance, this may not be the case with more vulnerable populations.

Pessari Arabin; Coll uterí curt; Progesterona vaginal Pesario de Arabin; Cuello uterino corto; Progesterona vaginal Arabin pessary; Short cervix; Vaginal progesterone Objective To investigate whether the classification of a previous spontaneous preterm birth (sPTB) as preterm labor (PTL) with intact membranes (IM) or as preterm prelabor rupture of membranes (PPROM) impacts the efficacy of cervical pessary or vaginal progesterone for prevention of sPTB in pregnant women with short cervix on transvaginal ultrasound. Methods This was a retrospective cohort study of asymptomatic high‐risk singleton pregnancies with a short cervix and history of sPTB, treated using Arabin pessary or vaginal progesterone for primary PTB prevention, conducted at four European hospitals. A log‐rank test on Kaplan–Meier curves was used to assess the difference in performance of pessary and progesterone, according to history of PTL‐IM or PPROM. Linear regression analysis was used to evaluate significant predictors of gestational age at delivery. Results Between 2008 and 2015, 170 women were treated with a pessary and 88 with vaginal progesterone. In women treated with a pessary, rate of sPTB

BACKGROUND: Fetoscopic LASER coagulation of the placental anastomoses has changed the prognosis of twin-twin transfusion syndrome. However, the prematurity rate in this cohort remains very high. To date, strategies proposed to decrease the prematurity rate have shown inconclusive, if not unfavourable results. METHODS: This is a randomised controlled trial to investigate whether a prophylactic cervical pessary will lower the incidence of preterm delivery in cases of twin-twin transfusion syndrome requiring fetoscopic LASER coagulation. Women eligible for the study will be randomised after surgery and allocated to either pessary or expectant management. The pessary will be left in place until 37 completed weeks or earlier if delivery occurs. The primary outcome is delivery before 32 completed weeks. Secondary outcomes are a composite of adverse neonatal outcome, fetal and neonatal death, maternal complications, preterm rupture of membranes and hospitalisation for threatened preterm labour. 352 women will be included in order to decrease the rate of preterm delivery before 32 weeks' gestation from 40% to 26% with an alpha-error of 0.05 and 80% power. DISCUSSION: The trial aims at clarifying whether the cervical pessary prolongs the pregnancy in cases of twin-twin transfusion syndrome regardless of cervical length at the time of fetoscopy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01334489 . Registered 04 December 2011.

Virus del Zika; Obstetrícia; Pediatria Zika virus; Obstetrics; Pediatrics Obstetricia; Pediatría Aquest document dóna recomanacions d'actuació per a la prevenció, detecció i tractament del virus del Zika a Catalunya.

Objective. To examine the value of one-step uterine artery Doppler at 20 weeks of gestation in the prediction pre-eclampsia (PE) and/or intrauterine growth restriction (IUGR).Methods. A prospective multicentre study that included all women with singleton pregnancies at 19–22 weeks of gestation (w). The mean pulsatility index (mPI) of both uterine arteries was calculated. Receiver-operating characteristics curves (ROC) were drawn to compare uterine artery Doppler and maternal risk factors for the prediction of early-onset PE and/or IUGR (before 32 w) and late-onset PE and/or IUGR.Results. 6,586 women were included in the study. Complete outcome data was recorded for 6,035 of these women (91.6%). PE developed in 75 (1.2%) and IUGR in 69 (1.1%) cases. Uterine Doppler mPI was 0.99 and the 90th centile was 1.40. For 10% false-positive rate, uterine Doppler mPI identified 70.6% of pregnancies that subsequently developed early-onset PE and 73.3% of pregnancies that developed early-onset IUGR. The test had a lower detection rate for the late-onset forms of the disease (23.5% for PE and 30% for IUGR). Maternal history has a low sensitivity in the detection of early-onset cases, although it is better at detecting late-onset PE.Conclusion. Uterine artery Doppler and maternal risk factors seem to select two different populations - early and late-onset PE which might suggest a different pathogenesis.

Cervical pessary; Fetoscopic LASER coagulation, Twin-to-twin transfusion syndrome Pessari cervical; Coagulació làser fetoscòpica; Síndrome de transfusió bessó a bessó Pesario cervical; Coagulación láser fetoscópica; Síndrome de transfusión de gemelo a gemelo Background Fetoscopic LASER coagulation of the placental anastomoses has changed the prognosis of twin-twin transfusion syndrome. However, the prematurity rate in this cohort remains very high. To date, strategies proposed to decrease the prematurity rate have shown inconclusive, if not unfavourable results. Methods This is a randomised controlled trial to investigate whether a prophylactic cervical pessary will lower the incidence of preterm delivery in cases of twin-twin transfusion syndrome requiring fetoscopic LASER coagulation. Women eligible for the study will be randomised after surgery and allocated to either pessary or expectant management. The pessary will be left in place until 37 completed weeks or earlier if delivery occurs. The primary outcome is delivery before 32 completed weeks. Secondary outcomes are a composite of adverse neonatal outcome, fetal and neonatal death, maternal complications, preterm rupture of membranes and hospitalisation for threatened preterm labour. 352 women will be included in order to decrease the rate of preterm delivery before 32 weeks’ gestation from 40% to 26% with an alpha-error of 0.05 and 80% power. Discussion The trial aims at clarifying whether the cervical pessary prolongs the pregnancy in cases of twin-twin transfusion syndrome regardless of cervical length at the time of fetoscopy.

Acompanyament al naixement; Voluntats de la dona; Atenció al nadó Birth support; Women's wills; Newborn care Acompañamiento en el nacimiento; Voluntades de la mujer; Atención al recién nacido L’Organització Mundial de la Salut, l’any 2018 va proposar una sèrie d’actuacions per a l’atenció al moment del part, que tenen per lema ‘Atenció per a una experiència positiva en el naixement’. En aquest document s’actualitza el ‘Protocol del part, puerperi i atenció al nadó’, document elaborat pel Departament de Salut, publicat l’any 2003 i actualitzat l’any 2019 com a ‘Protocol d’atenció i acompanyament al naixement’, seguint les recomanacions de l’OMS, així com totes aquelles basades en l’evidència científica, amb el màxim respecte a les opinions i voluntats de les dones gestants i amb l’objectiu d’ajudar-les a elles i a les seves famílies a tenir una experiència positiva en el part. Les activitats de promoció de la salut i prevenció de la malaltia són l’eix vertebrador d’aquest protocol i de tots els que es coordinen des del Servei de Salut Maternoinfantil de la Sub-direcció de Promoció de la Salut de l’Agència de Salut Pública de Catalunya del Departament de Salut. En aquest sentit, cal ressaltar la seva relació amb el Protocol del seguiment de l’embaràs a Catalunya (3a. edició) que es va presentar el 2018, amb el qual comparteix principis i enfocament. El protocol s’estructura en tres capítols en relació a les etapes (prepart, part i puerperi), recollint en el tercer, l’atenció la nadó. Cada capítol té diversos apartats en les activitats a realitzar, la informació a donar i el registre, entre d’altres. Es recull, després, la bibliografia i una sèrie de annexos amb eines pràctiques.

INTRODUCCIÓ El pronòstic vital dels pacients amb cardiopaties congènites (CC) ha millorat significativament en els darrers anys, fet que ha focalitzat als professionals en la morbiditat associada. Estudis de neuroimatge han demostrat que els nens amb CC tenen una incidència incrementada de lesions cerebrals i retràs maduratiu que podrien originar-se durant la vida intra-uterina. Per altra banda, es coneix que fins a un 50% dels nens amb una cardiopatia congènita presentaran al llarg de la infància dèficits en alguna de les àrees del desenvolupament neurològic. Existeix evidència que relaciona l’origen de l’afectació materna i fetal en la preeclàmpsia amb l’alteració de la invasió trofoblàstica i la posterior hipòxia tissular placentària. En aquest context augmenten els factors antiangiogènics com sFlt i disminueixen els proangiogènics com PlGF. Diversos estudis relacionen les cardiopaties congènites amb complicacions pròpies de l’embaràs en un entorn d’insuficiència placentària. Es coneix que els fetus amb CC tenen una incidència de baix pes al néixer corregit per gènere i setmanes de gestació superior als fetus sans. OBJECTIUS L’objectiu d’aquesta tesis doctoral és establir la presència d’alteracions neurològiques prenatals mitjançant tècniques d’imatge i determinar la implicació de la funció placentària en el desenvolupament neurològic en nens amb diferents tipus de CC. MÈTODES Es tracta d’un estudi prospectiu multicèntric. Les dades obtingudes es van comparar entre nens sans i afectes de CC així com entre grups de cardiopatia. Per a la classificació dels subgrups es va decidir classificar els tipus de cardiopatia segons els sis diagnòstics més freqüents del tipus moderat-sever: Transposició de Grans Vasos (TGV), Tetralogia de Fallot, Hipoplasia de Cavitats Esquerres (HCE), Defectes septals (DS), Obstruccions aòrtiques (OA) i un últim grup de cardiopaties diverses (Altres). Es van separar també els casos segons una classificació funcional utilitzada prèviament en estudis del nostre grup: cardiopaties valvulars, conotruncals i obstrucció del tracte de sortida esquerre. Al grup cas, 179 mares embarassades de fetus amb CC moderades o severes. Paral·lelament es van reclutar 138 gestants control portadores de fetus sans. RESULTATS Es va registrar un augment significatiu de les complicacions de l’embaràs d’origen placentari en el conjunt de casos amb CC comparats amb els controls. Els resultats de l’estudi de les mesures cefàliques i cerebrals entre cardiopaties i controls a través de RM eren congruents amb la literatura en que la mida cefàlica dels nascuts amb CC és inferior a la dels nens sans en el conjunt de CC10. El grup de HCE tenia les biometries més petites. En sang materna, es van trobar nivells de PlGF inferiors en el grup de CC. Entre ells, els afectats per Fallot presentava el nivell més baix, en canvi, el ràtio de factors angiogènics sFlt-1/PlGF era significativament superior als casos que als controls i el grup Fallot presentava de nou el ràtio més alt. En l’estudi de correlacions, el valor de sFlt-1 i del ràtio sFlt-1/PlGF en sang materna era inversament proporcional al pes al néixer i al perímetre cefàlic. Els resultats del nostre estudi mostren que el desenvolupament neuroconductual dels nens amb CC valorat als dos anys de vida mitjançant l’escala de Bayley-III és similar a la mitjana poblacional. No hi ha diferències entre grups de cardiopaties. CONCLUSIONS Existeixen diferències en les proves d’imatge prenatals en CC comparades amb controls així com en l’embaràs amb CC s’observa un augment dels factors antiangiogènics en sang materna i una disminució dels proangiogènics. En la nostra cohort, no podem relacionar aquests canvis amb un pitjor neurodesenvolupament postnatal. INTRODUCCIÓN El pronóstico vital de los pacientes con cardiopatía congénita (CC) ha mejorado significativamente en los últimos años, lo que ha centrado a los profesionales su morbilidad asociada. Los estudios de neuroimagen han demostrado que los niños con CC tienen una mayor incidencia de lesiones cerebrales y retraso de maduración que podrían originarse durante la vida intrauterina. Por otro lado, se sabe que hasta el 50% de los niños con cardiopatía congénita presentarán déficits a lo largo la infancia en alguna de las áreas del neurodesarrollo. Hay evidencia que relaciona el orígen de la afectación materna y fetal en la preeclampsia con una alteración de la invasión trofoblástica y una posterior hipoxia del tejido placentario. En ese contexto, aumentan los factores antiangiogénicos como el sFlt y disminuyen factores proangiogénicos como el PlGF. Otros estudios relacionan la enfermedad cardíaca congénita con complicaciones típicas del embarazo en un ambiente de insuficiencia placentaria. Como ejemplo, se sabe que los fetos con CC tienen incidencia aumentada de bajo peso al nacer, corregido por sexo y semanas de gestación, comparados con los niños sanos. OBJETIVOS El objetivo de esta tesis doctoral es establecer la presencia de alteraciones neurológicas prenatales utilizando técnicas de diagnóstico por imagen y determinar la implicación de la función placentaria en el desarrollo neurológico de los niños con CC. MÉTODOS Se trata de un estudio prospectivo multicéntrico. Los datos obtenidos se compararon entre niños sanos y afectados por CC así como entre grupos de enfermedades cardíacas. Para la clasificación en subgrupos se decidió dividir según los seis diagnósticos más frecuentes del tipo moderado-severo: Transposición de Grandes Vasos (TGV), Tetralogía Fallot, Hipoplasia de Cavidades Izquierdas (HCE), Defecto Septales (DS), Obstrucción Aórtica (OA) y un último grupo con cardiopatías diversas (Otras). Los casos también se separaron de acuerdo con una clasificación funcional utilizada previamente en estudios de nuestro grupo: cardiopatías valvulares, conotruncales y obstrucción del tracto de salida izquierdo. En el grupo caso 179 madres embarazadas de fetos con CC moderada o grave. Al mismo tiempo se reclutaron 138 gestantes portadores de fetos sanos. RESULTADOS Se registró un aumento significativo de las complicaciones del embarazo de origen placentario en el grupo caso en comparación con los controles. Los resultados del estudio de las medidas cefálicas y cerebrales entre las cardiopatías y los controles a través de la RMN fueron congruentes con la literatura mostrando que el tamaño cefálico de los nacidos con CC es menor que el de los niños sanos en el conjunto de CC. El grupo de HCE tenía las biometrías más pequeñas. En sangre materna, se encontraron niveles más bajos de PlGF en el grupo de CC. Entre ellos, los afectados por Fallot tuvieron el nivel más bajo. El valor del ratio de factores angiogénicos sFlt-1/PlGF fue significativamente mayor que en los casos en que en los controles y el grupo Fallot de nuevo tenía el ratio más elevado. En el estudio de correlaciones, el valor de sFlt-1 y la relación sFlt-1/PlGF en la sangre materna fueron inversamente proporcionales al peso al nacer y al perímetro cefálico. Los resultados de nuestro estudio muestran que el desarrollo neuroconductual de los niños con CC evaluado a los dos años de vida mediante la escala Bayley-III es similar al promedio de la población. No hay diferencias entre los grupos de enfermedades cardíacas. CONCLUSIONES Existen diferencias en las pruebas de diagnóstico por imágen prenatales en CC comparadas con fetos sanos, así como en el embarazo con CC hay un aumento de los factores antiangiogénicos en sangre materna y una disminución de la proangiogenicos. En nuestra cohorte, no podemos relacionar estos cambios. INTRODUCTION Survival prognosis of patients affected by congenital heart disease (CHD) has significantly improved these last years and has turned focus on associated morbidity. Neuroimaging studies have shown children with CHD have an increased incidence of brain injury and maturing delay that could have its origin during prenatal life. On the other hand, it is known that up to 50% of children with congenital heart disease will present some type of neurological deficit throughout childhood. Evidence suggests an alteration of trophoblastic invasion and subsequent placental tissue hypoxia as the origin of maternal and fetal symptoms in preeclampsia. In this environenent, an increase of antiangiogenic factors such as sFlt and decrease proangiogenic factors such as PlGF is often found. Other studies have related CHD pregnancy to complications typical of pregnancy in an environment of placental failure. It is known that fetuses with CHD have a low incidence at birth corrected by gender and weeks of gestation higher than healthy fetuses. OBJECTIVES The aims of this PhD studies are to establish the presence of prenatal neurological alterations using imaging techniques and to assess the implication of placental function in neurological development in children with different types of CHD. METHODS This is a multicenter prospective study. The data obtained were compared between healthy children and CHD fetuses, as well as among groups of cardiac malformations. We decided to classify the types of heart disease according to the six most frequent diagnoses of the moderate-severe type: Transposition of Great Vessels (TGV), Tetralogy of Fallot, Hypoplastic Left Heart Syndrome (HLHS), Septal Defects (SD), Aortic Obstruction (AO) and a group with other heart diseases (Others). Cases were also separated according to a functional classification previously used in studies of our group: valvular heart disease, conotruncal malformations and left exit ventricular outflow track obstruction (LVOTO). Case group consisted in 179 pregnant women carrying fetuses with a moderate or severe CHD. 138 patients pregnant with a healthy fetus were recruited for control group. RESULTS A significant increase in placenta-related pregnancy complications was recorded in patients with CHD compared to controls. Cephalic and cerebral measures between heart disease and controls through MRI were consistent with previous literature: cephalic size of those born with CHD is lower than that of healthy children. HLHS group had the smallest biometrics once compared with others. In maternal blood, lower PlGF levels were found in the CHD group. Among them, those affected by Fallot had the lowest level. The ratio of angiogenic factors sFlt-1/PlGF was significantly higher in case group compared to controls and this time again, Fallot group had the highest ratio. Levels of sFlt-1 and sFlt-1/PlGF ratio in maternal blood were inversely proportional to the weight at birth and the cephalic perimeter. The results of our study show that the neuroconductive development in children with CHD rated at two years of life using Bayley-III test is no different to the average population. We also did not find any differences between CHD groups. CONCLUSIONS There are differences in prenatal imaging tests in CHD compared to controls as well as in an increase of antiangiogenic factors in maternal blood and a decrease in proangiogenics factors can be found in CHD pregnancies. In our study, we could not relate these changes to a worse neuro development at two years of age. Universitat Autònoma de Barcelona. Programa de Doctorat en Pediatria, Obstetrícia i Ginecologia

La prematuritat representa la principal causa de morbimortalitat perinatal tant en països desenvolupats com en aquells en vies de desenvolupament, sent actualment la primera causa de mortalitat en els infants per sota de 5 anys. Tot i que disposem, cada vegada més, de mètodes més precisos per a la detecció d’aquelles pacients de major risc i d’eines terapèutiques específiques per a cada context clínic, la taxa de prematuritat està lluny de disminuir. En aquesta tesi doctoral farem una revisió dels principals conceptes relatius a la prematuritat d’una manera global per acabar descrivint el cas concret de la insuficiència cervical, entitat sobre la qual es basa l’estudi CEPEIC. La taxa de la insuficiència cervical (IC) s’estima del 0.15% - 1%, s’associa a una gran prematuritat i, conseqüentment, a una important morbimortalitat neonatal. El cerclatge cervical és la tècnica clàssicament establerta per evitar les pèrdues gestacionals o parts preterme en aquelles dones amb IC. Tot i que múltiples estudis avalen la seva eficàcia, no deixa de ser un mètode amb un grau considerat de dificultat en la seva col·locació i no està exempt de riscos i efectes secundaris per a la pacient. Els últims estudis sobre el pessari cervical han demostrat uns resultats més que optimistes en quant al seu paper en la prevenció de la prematuritat. La seva curta corba d’aprenentatge, la seva bona relació cost – efectivitat i les escasses implicacions per a la dona en quant a la seva col·locació i efectes secundaris, fan del pessari una eina amb gran potencial. A l’estudi CEPEIC ens plantegem si el pessari cervical és útil per les dones amb un cèrvix insuficient per a la prevenció de pèrdues gestacionals o parts preterme recurrents, de manera que puguem ampliar, o no, el ventall de situacions clíniques on aquesta eina és efectiva. La prematuridad representa la principal causa de morbimortalidad perinatal tanto en paises desarrollados como en aquellos en vías de desarrollo, siendo actualmente la primera causa de mortalidad en los niños por debajo de 5 años. A pesar de que disponemos cada vez más de métodos más precisos para la detección de aquellas pacientes de mayor riesgo y de instrumentos terapéuticos específicos para cada contexto clínico, la tasa de prematuridad está lejos de disminuir. En esta tesis doctoral realizamos una revisión de los principales conceptos relativos a la prematuridad de una manera global para terminar describiendo el caso concreto de la insuficiencia cervical, entidad sobre la cual se basa el estudio CEPEIC. La tasa de la insuficiencia cervical (IC) se estima del 0.15% - 1%, se associa a una gran prematuridad y, consecuentmente, a una importante morbimortalidad neonatal. El cerclaje cervical es la técnica clásicamente establecida para evitar pérdidas gestacionales o partos pretérmino en aquellas mujeres con IC. A pesar de que múltiples estudios avalan su eficacia, no deja de ser un método con un grado considerable de dificultad en su colocación y no está libre de riesgos y efectos secundarios para la paciente. Los últimos estudios sobre el pesario cervical han demostrado unos resultados más que optimistas en su papel en la prevención de la prematuridad. Su corta curva de aprenendizaje, su buena relación coste - efectividad y sus escasas implicaciones para la mujer en cuanto a su colocación y efectos secundarios, hacen del pesario una herramienta con un gran potencial. En el estudio CEPEIC nos planteamos si el pesario cervical es útil en mujeres con un cérvix insuficiente para la prevención de pérdidas gestacionales o partos pretérmino recurrentes, de manera que podamos ampliar, o no, las situaciones clínicas donde esta herramienta es efectiva. Cervical Insufficiency is used to describe painless cervical dilation leading to recurrent pregnancy losses in the second trimester or preterm births in otherwise normal pregnancies. This doctoral thesis describes the general concept of prematurity and ends describing the particular case of cervical insufficiency. Cervical pessary and cervical cerclage are both considered preventive treatments in women at risk for preterm birth. The CEPEIC trial aims to assess the feasibility of conducting a future randomised controlled trial focused on evaluating the potential effectiveness of the cervical pessary compared with cerclage in pregnant women with cervical insufficiency. Universitat Autònoma de Barcelona. Programa de Doctorat en Pediatria, Obstetrícia i Ginecologia

Hipòtesi L’ecografia transvaginal pot identificar els canvis que el pesari exerceix sobre el cèrvix uterí i aquests canvis es podrien correlacionar amb el risc de part prematur (PP)

La espina bífida representa el defecto congénito del tubo neural más grave compatible con la vida. Su forma más frecuente es el mielomeningocele, caracterizado por la falta de cierre del arco posterior vertebral en las semanas 3ª-4ª del desarrollo embrionario, momento en el cual la placa neural no completaría su desarrollo provocando un canal espinal abierto, con exposición al líquido amniótico de las meninges y otros elementos neurales durante el resto de la gestación. Los beneficios de la cirugía prenatal de los defectos del tubo neural y, concretamente del mielomeningocele, han sido ampliamente demostrados, proporcionando un cierre del defecto para proteger los elementos neurológicos desprovistos del mismo, prevenir la fuga de líquido cefalorraquídeo y disminuir el riesgo de infección, con la menor morbilidad materno-fetal posible. En la unidad de Medicina Materno-fetal del Hospital Vall d´Hebron se ofrece a las gestantes la posibilidad de cirugía intrauterina de los defectos del tubo neural. El abordaje quirúrgico de la cirugía intrauterina se puede realizar mediante cirugía fetoscópica o mediante cirugía fetal abierta, siendo el objetivo general de este estudio el análisis del manejo anestésico en estos dos tipos de cirugía. Creemos que la monitorización continua del binomio materno-fetal permitiría anticiparnos y adaptar de manera individualizada las dosis de fármacos vasoactivos y fluidos, minimizando los episodios de hipotensión materna y, por consiguiente, de hipoperfusión placentaria, así como disminuir las complicaciones respiratorias en el periodo perioperatorio. Además, consideramos que la cirugía fetoscópica para la corrección intrauterina de los defectos del tubo neural estaría asociada a menos cambios hemodinámicos maternos que la cirugía abierta, con el consiguiente efecto sobre la disminución de los requerimientos de fármacos vasoactivos y sobre la morbimortalidad materno-fetal asociada. Para ello, hemos realizado un estudio descriptivo retrospectivo en el Hospital Universitario Vall d´Hebron de Barcelona, durante el periodo comprendido entre los años 2011-2016, siendo nuestras principales conclusiones: -En la corrección intrauterina del mielomeningocele fetal mediante cirugía abierta o fetoscópica, no se encontraron diferencias en las dosis maternas de mórficos ni de relajantes musculares entre los dos tipos de cirugía. Sí hubo diferencias en la dosis requerida de halogenados y de nitroglicerina, siendo mayor en la cirugía abierta. -La fluidoterapia con cristaloides no difirió entre los dos grupos, mientras que el volumen administrado de coloides fue inferior en las gestantes del grupo de cirugía fetoscópica. El consumo de vasoconstrictores estuvo directamente relacionado con el tiempo de exposición uterina, sin encontrarse diferencias entre ambos grupos. -La tensión arterial media de las pacientes sometidas a cirugía abierta fue menor que en grupo de la fetoscópica y este grupo de pacientes experimentó más episodios de hipotensión arterial. Las tensiones arteriales sistólicas, diastólicas y medias disminuyeron en ambos grupos durante la exteriorización uterina y este descenso fue mayor en el grupo de cirugía abierta. -No se encontraron diferencias en los parámetros gasométricos maternos durante la insuflación con CO2 en la cirugía fetoscópica. -La tasa de rotura prematura de membranas fue similar en ambos grupos. La tasa de oligoamnios y la necesidad de tocolíticos en el postoperatorio fue superior en el grupo de cirugía abierta. -La frecuencia cardiaca fetal permaneció estable en los dos tipos de cirugía. La tasa de prematuridad fue superior en el grupo de la cirugía abierta., Spina bifida represents the most serious congenital neural tube deffect compatible with life. Its most frequent form is myelomeningocele, which is caracterized by the lack of closure of the posterior vertebral arch during third-fourth embrionary development weeks, moment in which the neural plate wouldn't complete its development causing an open spinal canal, with exposure to the amniotic fluid of the meninges and other neural elements during the rest of the pregnancy. The benefits of the prenatal surgery of the neural tube deffects and, specifically of the myelomeningocele, have been widely demostrated, providing a closure of the deffect to protect the neurological elements devoid of it, to prevent the leak of cerebrospinal fluid and to decrease the risk of infection, with the minimal possible maternal-fetal morbidity. In the Materno-fetal Unit of Vall d'Hebron Hospital it is offered to pregnant women the possibility of intrauterine surgery of the neural tube deffects. The surgical approach of intrauterine surgery can be performed through fetoscopic surgery or open fetal surgery, being the general objective of this study the analysis of the anesthetic management in these two types of surgery. We believe that continous monitoring of maternal-fetal binomial would allow us to anticipate and adapt in an individualized way the doses of vaoactive drugs and fluids, minimizing episodes of maternal hypotension and therefore, of placental hypoperfusion, as well as decrease respiratory complications during the perioperative period. We also consider that fetoscopic surgery for the intrauterine correction of neural tube deffects would be associated with fewer hemodynamic maternal changes than open surgery, with the consequent effect about the decrease of the requirements of vasoactive drugs and about maternal-fetal associated morbimortality. Therefore, we have carried out a retrospective descriptive study in Vall d'Hebron Hospital, Barcelona, during the period between years 2011-2016, being our main conclusions: - In the intrauterine fetal myelomeningocele correction through open surgery or fetoscopic, no differences were found in the maternal morphic doses neither muscle relaxants between two types of surgery. There were differences between the required dose of halogenated and nytroglicerin, being higher in open surgery. - Fluidotherapy with crystalloids wasn't different between groups, while the administered volum of colloids was lower in the pregnant women of the fetoscopic surgery group. The consumption of vasoconstrictors was directly related to the uterine exposure time, without finding differences between both groups. - The mean arterial blood pressure of the patients urdergoing open surgery was lower than in the fetoscopic group, and this group of patients experienced more episodes of arterial hypotension. The arterial tensions systolics, diastolics and mean decreased in both groups during the uterine exteriorization and this decrease was higher in the open surgery group. - No differences were found in gasometric maternal parameters during the CO2 insufflation in fetoscopic surgery. - The rate of premature rupture of membranes was similar in both groups. The rate of olighydramnios and the need for tocolytics in the postoperative period was higher in the open surgery group. - The fetal heart rate remained stable in both types of surgery. The prematurity rate was higher in the open surgery group.

CONTEXT: El part prematur (PP) segueix éssent la causa principal de morbimortalitat neonatal. En la població general, la taxa de PP és del 8-12%; malgrat això, diversos subgrups de gestants configuren poblacions de risc elevat de PP, com les dones amb antecedents de PP, les gestacions múltiples, o les dones que, durant la gestació, presenten episodis d’amenaça de part prematur (APP). Una longitud cervical (LC) ecogràfica curta s’ha convertit en el principal factor predictor de PP en pacients assimptomàtiques al segon trimestre, tant en gestacions úniques com gemel.lars. La taxa de PP és 5-6 vegades més gran en bessons, arribant al 50%. Entorn un 15% de gestacions gemel-lars presenten un cèrvix curt al segon timestre; la progesterona vaginal ha demostrat eficàcia en la prevenció del PP en aquestes pacients, mentre que el cerclatge cervical sembla empitjorar-ne els resultats. Les gestants que presenten APP durant la gestació també conformen un grup d’alt risc de PP: fins un 45% presentaràn novament APP, i un 25-30% pariràn preterme. La LC és un factor de risc independent pel PP després d’una APP. Cap intervenció s’ha mostrat eficaç en reduïr la taxa de PP en aquestes pacients. En un estudi randomitzat (RCT) multicèntric conduït pel nostre grup, el pesari cervical va mostrar una reducció significativa de la taxa de PP en gestacions úniques assimptomàtiques amb cèrvix curt al segon trimestre. OBJECTIU I DISSENY: Vam voler avaluar la utilitat del pesari cervical en la disminució de la taxa de PP en dues poblacions d’alt risc: vam dissenyar dos RCT en gestants assimptomàtiques amb cèrvix curt: un en gestacions gemel.lars (PECEP-Twins Trial), i l’altre en gestacions úniques després d’una APP (PECEP-Retard). Ambdós han estat publicats a la literatura científica i composen aquesta tesi per comendi de publicacions. El PECEP-Twins Trial fou un RCT multicèntric. L’objectiu principal era la taxa de PP

Antecedents El virus Zika és un agent teratogènic amb tropisme predominant per al cervell fetal. S’ha demostrat que pot causar lesions neurològiques severes en fetus però es desconeix la incidència real de la infecció i la afectació fetal. Material i mètode Des del brot del virus del Zika a Brasil el novembre de 2015 es van estudiar de forma prospectiva totes les dones embarassades amb vincle epidemiològic a zona endèmica de virus Zika. Seguint el protocol de l’Agència Catalana de Salut Pública, es van utilitzar proves biològiques i serològiques per tal d’identificar les dones infectades. Es va fer un seguiment ecogràfic mensual amb ecografia i neurosonografia; i se'ls va oferir ressonància magnètica i amniocentesi. També es van obtenir mostres de placenta i teixits fetals i neonatals. Resultats Setanta-dues dones embarassades van ser positives per a la infecció per virus del Zika; deu van ser casos confirmats i 62 van ser casos probables. La taxa global de mal resultat perinatals en dones amb infecció confirmada i seguiment complet va ser del 33% (95% IC: 12,1 a 64,6%). Va haver-hi dos casos de síndrome congènita per virus del Zika i un cas d’avortament espontani, tots ells en dones amb infecció confirmada durant el primer trimestre. El 25% de les dones van referir símptomes durant l'embaràs, en general erupció cutània i febre. Totes les dones amb infecció confirmada tenien virèmies persistents de més de 14 dies (mitjana de 61.50 dies (IQR 35.50 - 80.75 dies)). Conclusió La taxa global de mal resultat perinatal en dones amb infecció pel virus Zika confirmada és del 33%. Les infeccions durant el primer trimestre s'associen a pitjor resultat en un país no endèmic. Background Zika virus is a teratogenic agent with predominant tropism for the fetal brain. The real incidence of fetal infection and affection is unknown, and severe disease has been demonstrated throughout pregnancy. Methods Since the Zika virus outbreak in Brazil in November 2015 all pregnant women with epidemiological link to an endemic area were prospectively screened for Zika virus in Catalonia, Spain. According to the Spanish protocol, serological and biological tests were used to identify infected pregnant women. They were followed-up in a monthly basis with ultrasound scans and neurosonograms; magnetic resonance and amniotic fluid testing were performed after signed informed consent. Samples of placenta and fetal and neonatal tissues were also obtained. Results Seventy-two pregnant women tested positive for Zika virus infection; ten were confirmed cases and 62 were probable cases. The overall rate of adverse perinatal outcome in women with confirmed Zika virus infection and complete follow-up was 33% (95%CI, 12.1-64.6%). Two cases of Zika virus congenital syndrome and one miscarriage, all of them born to women with confirmed infection in the first trimester. 25% of women reported symptoms during pregnancy, mostly rash and fever. All women with confirmed infection had persistent viremias beyond the expected time (median 61.50 days (IQR 35.50-80.75)). Conclusion The overall adverse outcome rate in women with confirmed Zika virus infection is 33%. First trimester infections of Zika virus are associated with worse outcomes in a non-endemic country.

Esta tesis es el resumen de tres trabajos realizados siguiendo una misma línea de trabajo en relación al papel de los factores angigogénicos en el neurodesarrollo de los fetos con cardiopatía congénita (CC). Estudio 1: Complicaciones derivadas de la insuficiencia placentaria en gestantes portadoras de fetos con CC. Introducción: Estudios recientes reportaron un desequilibrio angiogénico en la circulación materna y fetal en las gestaciones con CC sugiriendo una placentación alterada. Objetivos: Evaluar si las gestantes con fetos con CC tiene una mayor incidencia de complicaciones derivadas de la insuficiencia placentaria. Métodos: Se compararon los resultados perinatales de gestantes con CC y una población de bajo riesgo. Resultados: Se incluyeron 279 gestaciones con fetos con CC. Se observó una incidencia significativamente mayor de preeclampsia en el grupo con CC (5,7% frente a 1,2% p, This thesis is the summary of three studies carried out along the same line of work in relation to the role of angiogenic factors in the neurological development of foetuses with congenital heart diseases (CHD). Study 1: Placenta-related complications in women carrying a foetus with congenital heart disease Introduction: Recent studies pointed to an intrinsically angiogenic imbalance in CHD in the maternal and foetal circulation suggestive of impaired placentation. Objectives: To assess whether pregnant women with a CHD foetus are at greater risk of placenta-related complications. Methods: Perinatal results of women with a CDH foetus were compared with those of a nonselected population followed up at our centre. Results: 279 pregnancies with CHD foetuses were included. A significantly higher incidence of pre-eclampsia was observed in the CHD group compared with the normal population (5.7% vs 1.2% p< 0.0001). 9.7% of foetuses with CHD had < 3rd birth weight percentile compared with 3% for the normal population. A higher incidence of stillbirth was also observed in the CHD group compared with the normal population (2.5% vs 0.4%). Study 2: Longitudinal changes in fetal biometries and cerebroplacental haemodynamics in fetuses with congenital heart disease. Objectives: To determine the longitudinal behaviour of fetal biometries and cerebroplacental haemodynamics throughout gestation in fetuses with CHD. Methods: Fetal biometries and Doppler haemodynamic were serially measured in a cohort of consecutive fetuses diagnosed with CHD. Evaluations were made at various time points, from diagnosis (

El mielomeningocele (MMC) és una malformació congènita caracteritzada per l'extrusió de la medul·la com a conseqüència d'una falta de fusió d'arcs vertebrals que dóna lloc a una lesió neurològica. El pronòstic motor dels nadons afectes de MMC s’estableix després del naixement amb la determinació del nivell neurològic mitjançant l’exploració dels moviments de les extremitats inferiors. Proposem que, d’una manera similar a l’exploració postnatal, l’avaluació ecogràfica sistemàtica dels moviments de les extremitats inferiors en fetus amb MMC podria ser realitzada per explorar el nivell neurològic prenatal i proporcionar informació sobre el pronòstic de la futura capacitat de deambulació, abans del naixement. Objectius: Establir la correlació entre el nivell neurològic prenatal i el postnatal en casos sotmesos a la reparació intraúter del MMC, analitzar la reproductibilitat de la interpretació de la tècnica per l’avaluació ecogràfica del nivell neurològic prenatal, correlacionar el nivell neurològic prenatal amb el nivell anatòmic de la lesió, analitzar l’evolució del nivell neurològic en els casos que no es van operar prenatalment i descriure els casos de MMC valorats a l’Hospital Universitari Vall d’Hebron. Mètodes: Estudi prospectiu observacional que inclou fetus afectes de MMC operats prenatalment. Els patrons de moviments de les extremitats inferiors dels fetus afectes van ser avaluats sistemàticament per ecografia per un expert en medicina materno-fetal i un especialista en rehabilitació. D'acord amb la funció nerviosa coneguda associada a cada grup muscular, es va establir el nivell neurològic prenatal. Totes les exploracions ecogràfiques van ser gravades i, posteriorment, van ser analitzades per dos observadors amb nivells d’expertesa diferents, els quals van interpretar cada exploració gravada per assignar el nivell neurològic, en dues ocasions diferents i cegats pels resultats de l’altre. La concordança entre el nivell neurològic assignat amb la tècnica d’ecografia prenatal i el nivell neurològic assignat després del naixement amb l’exploració neurològica clàssica va ser avaluada mitjançant l’índex de Kappa ponderat (wk). El mateix índex va ser utilitzat per establir la concordança entre el nivell neurològic i el nivell anatòmic i per analitzar la reproductibilitat intra- i interobservador. Resultats: Es van valorar 93 fetus amb MMC. Després de l'assessorament, els pares decidien si desitjaven cirurgia prenatal (26 casos), interrupció de l’embaràs (48 casos) o cirurgia postnatal (2 casos). Cinc pacients no complien els criteris d'inclusió per a la cirurgia prenatal i tres van ser exclosos després del naixement. En els 18 fetus que es van sotmetre cirurgia i que es van analitzar, la concordança entre els nivells neurològics prenatals i postnatals assignats va ser del 91,7% per a l'extremitat dreta (wκ = 0,80) i 88,9% per l'esquerra (wκ = 0,73). La concordança entre el nivell anatòmic i el nivell neurològic va ser del 62,0% (wκ = 0,024). Vint-i.vuit exploracions van ser registrades i avaluades per l’estudi de reproductibilitat. L'acord entre els observadors i l’expert en medicina materno-fetal es va mantenir constant per a l'observador amb major grau d’experiència (wκ = 0,82) i va augmentar (wκ = 0,66 - wκ = 0,72), per l'altre observador. La variabilitat inter- i intraobservador per l’observador més experimentat va ser wκ = 0,72 i wκ = 0,94, respectivament. Conclusions: La correlació entre l’assignació prenatal i postnatal dels nivells neurològics obtinguda en aquest estudi mostra que l'avaluació del nivell neurològic és factible abans del naixement. La concordança per l’avaluació prenatal dels nivells neurològics va ser excel·lent per als observadors amb diferents graus d'experiència. Aquesta tècnica d'avaluació ecogràfica dels moviments de les extremitats inferiors té el potencial de proporcionar informació precisa i individualitzada sobre el pronòstic de deambulació en fetus amb MMC operats prenatalment., Myelomeningocele (MMC) is a congenital malformation characterized by the extrusion of the spinal cord as a result of a lack of fusion of vertebral arches leading to a neurological lesion. Motor prognosis of neonates affected by MMC is usually established after birth by the examination of lower limb movements to determine the neurological level of lesion. We propose that, in a similar manner, a systematic ultrasound evaluation of lower-limb movements in fetuses with MMC should be performed to explore the prenatal neurological level of lesion and provide the prognosis for future ambulation before birth. Objectives: To establish the correlation between the prenatal and postnatal neurological level in fetuses with MMC repaired in utero, to assess the reliability of the interpretation of the technique for the ultrasound evaluation of the prenatal neurological level, to correlate the prenatal neurological level with the anatomical level of lesion, to assess the evolution of the neurological level in cases not operated prenatally and to describe the MMC cases evaluated in Hospital Universitari Vall d’Hebron. Methods: prospective observational study including fetuses with MMC operated on prenatally. The patterns of movements in the affected fetuses’ lower limbs were evaluated systematically by ultrasound examination by a maternal-fetal medicine expert and a specialist in rehabilitation. According to the known nerve function associated with each muscle group, the segmental level of neurological lesion was established before birth. All ultrasound scans were recorded and, afterwards, were analyzed by two observers, with different levels of experience, who interpreted each recorded scan to assign the neurological level, two different times and blinded to each other’s results. The agreement for the neurological levels assigned, between the prenatal ultrasound technique and the classical neurological clinical examination after birth, was tested using the weighed kappa (wκ) index. The same index was used to establish the agreement between neurological level and anatomical level and to test the inter-observer and intra-observer reproducibility. Results: Ninety-three fetuses with MMC were evaluated. After counseling, the parents opted for prenatal surgery (26 cases), termination of pregnancy (48 cases) or postnatal repair (2 cases). Five patients did not fulfil the inclusion criteria for prenatal surgery and three were excluded after birth. In the 18 fetuses that underwent surgery and were analyzed, the agreement between prenatal and postnatal neurological levels assigned was 91.7% for the right limb (wκ=0.80) and 88.9% for the left limb (wκ = 0.73). The agreement between neurological level and anatomical level was 62.0% (wκ=0.024). Twenty-eight scans were recorded and evaluated to assess the reproducibility. The agreement between the observers and the expert in maternal-fetal medicine remained constant for the observer with greater experience (wκ=0.82) and increased (wκ=0.66 - wκ=0.72) for the other one. Inter-observer and intra-observer variability for the most experienced observer were wκ=0.72 and wκ=0.94, respectively. Conclusions: The agreement found between prenatal and postnatal assignment of neurological level of lesion in this study shows that the evaluation of neurological level is feasible before birth. The agreement for the prenatal evaluation of the neurological level was excellent for observers with different degrees of expertise. This technique of ultrasound evaluation of lower-limb movements has the potential to provide accurate individualized information about the ambulation prognosis of fetuses with MMC operated on prenatally.

INTRODUCCION El parto pretérmino es una de las principales causas de morbi-mortalidad neonatal. En el Hospital Civil de Guadalajara, en el año 2008 de un total de 8,896 nacimientos, se reporta un porcentaje de recién nacidos prematuros del 7.9% Los uteroinhibidores como un mecanismo para evitar los partos pretérmino han sido utilizados ampliamente en Obstetricia. Suelen tener una serie de efectos colaterales conocidos en la madre, sin embargo se ha estudiado poco el efecto de estos fármacos sobre el feto. El estudio Doppler pretende obtener más conocimientos sobre las repercusiones en ambos. Lamentablemente no se cuenta hasta hoy con valoración amplia sobre el uso de la Orciprenalina y Nifedipina y la respuesta en la flujometría Doppler de la arteria uterina, arteria umbilical, arteria cerebral media y en el índice cerebro-placentario, tema que genera un gran interés ya que de esta forma se valorarían mejor sus consecuencias durante el manejo de la amenaza del parto pretérmino, siendo que en nuestro medio estos fármacos son ampliamente utilizados para este fin. OBJETIVO PRINCIPAL Valorar la influencia de distintos fármacos útero-inhibidores sobre la circulación materna y fetal valorada mediante estudio Doppler. MATERIAL Y METODOS Se realizó un estudio tipo quasiexperimental, en la Unidad de Medicina Materno Fetal (UMMF) del Hospital Civil de Guadalajara UdeG México. A 27 pacientes se les aplico Orciprenalina y a otro grupo de 27 pacientes Nifedipina con embarazos de 28-34 semanas. Se utilizo el Protocolo de manejo de la UMMF. En ambos grupos se evaluaron los efectos hemodinámicos que pudieran presentarse en la madre y el feto ante su administración. RESULTADOS De un total de 54 pacientes se encontró que a mayor edad gestacional menor el índice de pulsatilidad (IP) cuando fue utilizada la Nifedipina y la Orciprenalina. Los cambios hemodinámicos en los diferentes vasos sanguíneos estudiados mediante la valoración de flujometría Doppler los índices de pulsatilidad (IP) sufrieron algunas variaciones mostrando valores estadísticamente significativos, pero sin salir de los percentiles de normalidad para cada edad gestacional y sin ninguna repercusión en la respuesta clínica materna o en el resultado perinatal. CONCLUSIONES La respuesta hemodinamica materno-fetal evaluada mediante flujometría Doppler en las arterias uterinas (Aut), arteria umbilical (AU), arteria cerebral media (ACM) y el índice cerebro-placentario (ICP) no fuueron afectadas por la utilización de Orciprenalina y Nifedipina durante la amenaza de parto pretérmino., INTRODUCTION Preterm birth is a major cause of neonatal morbidity and mortality. In the Civil Hospital of Guadalajara, in 2008 a total of 8.896 births, reported a percentage of premature infants of 7.9% The uteroinhibidores as a mechanism to prevent preterm births have been widely used in obstetrics. They usually have a number of known side effects in the mother, but has been little studied the effect of these drugs on the fetus. The Doppler study aims to gain more knowledge on the impact on both. Unfortunately there is no comprehensive assessment to date with the use of metaproterenol and Nifedipine and response Doppler flowmetry of the uterine artery, umbilical artery, middle cerebral artery and cerebro-placental index, a topic that generates a lot of interest and that in this way would be valued best consequences for the management of preterm labor threat, considering that in our midst these drugs are widely used for this purpose. OBJECTIVE To evaluate the influence of different drugs on the uterus-inhibiting maternal and fetal circulation assessed by Doppler study. MATERIAL AND METHODS A study quasiexperimental type in the Maternal Fetal Medicine Unit (UMMF) of the Civil Hospital of Guadalajara Mexico UdeG. A 27 patients received metaproterenol and another group of 27 patients with pregnancy Nifedipine 28-34 weeks. We used the Protocol UMMF management. Both groups evaluated the hemodynamic effects that may occur in the mother and fetus before its administration. RESULTS Of a total of 54 patients found that higher gestational age less pulsatility index (PI) was used as nifedipine and metaproterenol. Hemodynamic changes in different blood vessels studied by assessing Doppler flowmetry pulsatility indices (PI) were some variations showing statistical significance, but without leaving the normal percentiles for each gestational age and without any impact on clinical response maternal or perinatal outcome. CONCLUSIONS The maternal-fetal hemodynamic response assessed by Doppler flowmetry in the uterine arteries (Aut), umbilical artery (UA), middle cerebral artery (MCA) and cerebro-placental index (PCI) fuueron not affected by the use of metaproterenol and Nifedipine during preterm labor.

Con el objetivo de evaluar las modificaciones anatomopatológicas e inmunohistoquímicas en la hipoplasia pulmonar fetal, se ha realizado un estudio descriptivo observacional con materiales de autopsia fetal de pacientes sin patología pulmonar agrupados por grupos de edades gestacionales y pacientes con patología de hernia diafragmática congénita y displasia renal. Se realizó análisis comparativo bivariado de las mediciones en pulmones sanos y pulmones afectos por las condiciones hernia diafragmática y displasia renal. Las variables de morfometria pulmonar mas relevantes que describen las modificaciones estructurales de las unidades funcionales pulmonares corresponden a: relación peso pulmonar / peso fetal, recuento alveolar radial, densidad alveolar, densidad bronquial, grosor de la pared alveolar y estado madurativo pulmonar. Las evaluaciones inmunohistoquímicas comparativas entre grupos muestran expresiones diferenciadas en los componentes del tejido pulmonar: estroma, alveolo, mesénquima para captación de las señales de factores involucrados en el crecimiento pulmonar: factor de crecimiento epidérmico, factor de crecimiento derivado de las plaquetas y factor transformador de crecimiento beta. El presente estudio utiliza el material de autopsia fetal para mostrar las complejas interacciones relacionadas con el desarrollo pulmonar en fetos sanos y en fetos con patologías específicas y analiza las variables más relevantes en la morfometria e inmunohistoquímica pulmonar. Establece líneas de investigación para estimular el estudio del desarrollo pulmonar en fetos afectos de hipoplasia pulmonar., In order to evaluate the anatomopathological and immunohistochemical modifications in fetal pulmonary hypoplasia, a descriptive, observational study has been conducted with fetal autopsy material from patients with no pulmonary pathology grouped by gestational age, and patients with congenital diaphragmatic hernia and renal dysplasia pathology. A comparative bivariate analysis was conducted with measurements in healthy lungs and lungs subject to diaphragmatic hernia and renal dysplasia conditions. The most relevant pulmonary morphometric variables describing the structural modifications of pulmonary functional units are the following: lung weight / body weight (LW/BW) ratio, radial alveolar count, alveolar density, bronchial density, thickness of alveolar wall and pulmonary maturity status. Comparative immunohistochemical evaluations among groups show differentiated expressions within lung tissue components: stroma, alveoli, mesenchyme to get hold of signals of factors involved in pulmonary growth: epidermal growth factor (EGF), platelet-derived growth factor (PDGF) and transforming growth factor – beta (TGF-β). The present study uses fetal autopsy material to show the complex interactions connected with pulmonary development in healthy fetuses and fetuses with specific pathologies, and analyzes the most relevant pulmonary morphometric and immunohistochemistry. It sets research topics to encourage the study of pulmonary development in fetuses subject to pulmonary hypoplasia.

La presente Tesis Doctoral se ha estructurado siguiendo la Normativa Interna de la Universidad Autónoma de Barcelona para la presentación de tesis doctorales como un compendio de publicaciones, aprobada por la Comisión de Doctorado de la Facultad de Medicina. Los trabajos que forman parte de la memoria del proyecto de tesis doctoral pertenecen a la misma línea de investigación, enmarcada en la predicción y prevención del parto prematuro en las gestantes con cérvix corto, en particular, evaluando la utilidad del pesario cervical como herramienta de prevención del parto prematuro. Los resultados de estos trabajos han aportado información relevante e innovadora en este campo y se han recogido 3 artículos originales publicados en revistas de elevado factor de impacto., The present Doctoral Thesis has been structured following the Internal Regulation of the Autonomous University of Barcelona for the presentation of doctoral theses as a compendium of publications, approved by the Commission of Doctorate of the Faculty of Medicine. The works that form a part of the memory of the project of doctoral thesis belong to the same line of research, placed in the prediction and prevention of preterm birth in pregnant women with a short cervix, particularly, evaluating the usefulness of the cervical pessary as tool of prevention of preterm birth. The results of these works have contributed relevant and innovative information in this field and there have been gathered 3 original articles published in magazines of high impact factor.

Objetivos Objetivo principal: Desarrollar una herramienta para medir el flujo y perfusión fetales, mediante el uso de ecografía tridimensional en tiempo real por correlación espacio-tiempo (4D) y el uso de la señal power-Doppler. Objetivo secundario: evaluar y calibrar la herramienta diseñada en un modelo animal bien controlado (ovino). Métodos: Modelación matemática de un algoritmo de la velocidad de desplazamiento de color vectorial de la señal de color. Medida experimental del algoritmo al compararlo con los perfiles de flujo conocidos in vitro mediante el diseño de un modelo fantasma de flujo pulsátil e in vivo, mediante la comparación de los valores obtenidos con las mediciones reales obtenidas por métodos invasivos, desde el arco aórtico fetal en ocho ovejas gestantes plazo. La adquisición de bases de datos 4D de volumen en línea con el análisis de la señal de color mediante el índice de vascularización de flujo ya validado (VFI), ® y el Índice de Volumen de perfusión, diseñado por nuestro equipo (VPI). La comparación de ambos métodos en términos de replicabilidad y precisión, in vitro, así como in vivo. Resultados: Durante el ensayo in vitro, ambas técnicas mostraron una buena capacidad de repetición. Intra-observador coeficiente de correlación intraclase (ICC, IC 95%) fue similar para VPI (0,95; 0,91 a 0.99) y VFI (0,9; 0,88 a 0.92). Inter-observador CCI también fue igual para VPI (0,90; 0,87 a 0,99) y VFI (0,88; 0,84 a 0,91). Al trazar VPI contra la corriente real de cálculo Índice de correlación de Pearson (95% IC) fue de 0,88 (.58 a .97) para VPI y 0,34 (0,31-0,44) para la VFI. Cuando la prueba in vivo el VPI exhibió una Corte Penal Internacional intra-observador (95% IC) de 0.9 (0.88-0.99) y la VFI 0,79 (0,75 a 0,92), y una Corte Penal Inter-observador (955 CI) de 0,88 (0,87- 0,99) para VPI y 0.78 (0.74 a 0.91) para la VFI. La medición de flujo en el modelo animal se correlacionó significativamente mejor en VPI que en VFI con un índice de correlación de Pearson (95% IC) de 0.88 (0.58-0.97) vs -0,34 (-0,31 hasta 0,44). p, Primary aim: To develop a tool for measuring fetal flow and perfussion by Spatio- time correlation (4D) and power Doppler signal. Secondary aim: To test and calibrate the designed tool in a well controled animal (sheep) model Methods: Mathematical modelling of a vectorial velocity color signal displacement algorithm. Experimental measurement of the algorithm by comparing it to known flow profiles in vitro by designing a phantom model of pulsatile flow and in-vivo by comparing obtained values to actual measurements obtained, by invasive methods, from fetal aortic arch in eight term pregnant sheep. Acquisition of 4D volume datasets with offline analysis of color signal by using the already validated Vascularization Flow Index (VFI)® and the newly designed Volume Perfusion Index (VPI). Comparison of both methods in terms of repeatability and accuracy, in-vitro as well as in-vivo. Results: When tested in-vitro, both techniques showed a good repeatability. Intra-Observer Intraclass Correlation Coefficient (ICC; 95% CI) was similar for VPI (0.95; 0.91-0.99) and VFI (0.9; 0.88-0.92). Inter-Observer ICC was also alike for VPI (0.90; 0.87-0.99) and VFI (0.88; 0.84-0.91). When plotting VPI against actual flow calculation the Pearson’s correlation Index (95% CI) was 0.88 (0.58-0.97) for VPI and 0.34 (0.31-0.44) for VFI. When tested in-vivo the VPI exhibited an Intra-Observer ICC(95% CI) of 0.9(0.88-0.99) and the VFI 0.79(0.75-0.92); and an Inter-Observer ICC (955 CI) of 0.88 (0.87-0.99) for VPI and 0.78 (0.74-0.91) for VFI. The flow measurement in the animal model correlated significantly better in VPI than in VFI with a Perason’s Correlation Index (95% CI) of 0.88(0.58-0.97) Vs -0.34 (-0.31-0.44). p< 0.001 Conclusion The Volume Perfusion Index exhibits a more robust correlation with actual flow than the currently used Vazcularization Flow Index and further work and investment in this direction is clearly justified