Rentabilidad de la ratio angiogénica en el seguimiento de gestantes de alto riesgo de preeclampsia precoz tratadas con ácido acetilsalicílico / Profitability of the angiogenic ratio in the follow-up of pregnant women at high risk of early preeclampsia treated with acetylsalicylic acid

Objetivo: Evaluar el valor predictivo negativo de la ratio antigénica y conocer su rentabilidad para descartar preeclampsia precoz en pacientes de alto riesgo de desarrollarla, con profilaxis de ácido acetilsalicílico. Métodos: Se realizó un estudio descriptivo transversal que recogió a las gestantes con cribado de preeclampsia precoz de alto riesgo (384 gestantes) en el Hospital Santa Lucía durante el año 2021, para lo que se usó test Elecsys® tabulado a un riesgo mayor a 1/150 en primer trimestre, y que tomaran ácido acetilsalicílico antes de la semana 16, quedando en 368 gestantes vistas en las semanas 20, 26, 31 y 36. Se realizó biometría, ratio angiogénica y doppler. Resultados: La incidencia de preeclampsia precoz en la población fue 4 casos (incidencia 1,08 %). Son significativos por su alto valor predictivo negativo del 100 % de preeclampsia precoz: la ratio angiogénica mayor a 38 en la semana 26 y el doppler de las uterinas en semana 20 y 26. Conclusión: En gestaciones con cribado de alto riesgo de preeclampsia que tomen ácido acetilsalicílico, una ratio angiogénica menor a 38 en la semana 26, además de un doppler uterino normal en semana 20 y 26 permite reducir el seguimiento gestacional(AU)

Objective: Our main objective was to evaluate the negative predictive value of the angiogenic ratio and to know its profitability to rule out early preeclampsia in patients at high risk of early preeclampsia with acetylsalicylic acid prophylaxis. Methods: A cross-sectional descriptive study was carried out that included pregnant women with high-risk early preeclampsia screening (384 pregnant women) at the Santa Lucía Hospital during the year 2021, for which the Elecsys® test tabulated at a risk >1/ was used. 150 in the first trimester, and who take acetylsalicylic acid before week 16, leaving 368 pregnant women seen in weeks 20, 26, 31 and 36, with biometry, angiogenic ratio and Doppler performed. Results: The incidence of early preeclampsia in the population was 4 cases (incidence 1.08%). They are significant due to their high negative predictive value of 100% of early preeclampsia: Angiogenic ratio > 38 in week 26, uterine Doppler in weeks 20 and 26. Conclusion: Pregnancies with high risk screening for preeclampsia who take acid acetylsalicylic acid, an angiogenic ratio < 38 at week 26 in addition to a normal uterine Doppler at weeks 20 and 26 allows for reduced gestational follow-up(AU)

Influencia de la NeuroEPO en el corazón fetal en un modelo de insuficiencia placentaria en ratas

Fundamento: la insuficiencia placentaria es la causa más común del retardo del crecimiento intrauterino, que puede provocar alteraciones cardiovasculares. Recientemente, se han desarrollado terapias con eritropoyetina que protegen los tejidos cardiacos con hipoxia. Objetivo: evaluar la influencia de la eritropoyetina recombinante humana con bajo contenido de ácido siálico (NeuroEPO) en el corazón fetal en un modelo de insuficiencia placentaria en ratas. Métodos: se utilizaron 14 ratas Wistar gestadas con ligadura unilateral de la arteria uterina derecha en el día 16 de la gestación. Ese mismo día, a siete ratas se le administró NeuroEPO (0,5 mg/kg/día subcutáneo por tres días) y al resto placebo. En el día 20 de la gestación los fetos se dividieron en cuatro grupos: un grupo control, un grupo con retardo del crecimiento intrauterino, un grupo control NeuroEPO y un grupo con retardo del crecimiento intrauterino y NeuroEPO. En los fetos se obtuvo el peso placentario, peso fetal y la eficacia placentaria. En el estudio histológico se cuantificó el número de cardiomiocitos, número de vasos sanguíneos y cantidad de las fibras de colágenos. Resultados: el grupo con retardo del crecimiento intrauterino presentó una disminución del peso fetal, del número de cardiomiocitos, del número de vasos sanguíneos y un aumento en la cantidad de fibras colágenas (p<0.05). Al tratar con NeuroEPO a los fetos con retardo en el crecimiento intrauterino, aumentó el peso fetal, aunque el peso no fue similar al control. El resto de las variables se comportaron semejantes al control. Conclusiones: la administración de esta molécula mejoró el peso fetal y permitió un equilibrio adecuado en el desarrollo del corazón fetal, quizás, debido a los efectos citoprotectores de esta molécula.

Foundation: placental insufficiency is the most common cause of intrauterine growth retardation, which can cause cardiovascular alterations. Recently, erythropoietin therapies have been developed that protect hypoxic cardiac tissues. Objective: To evaluate the influence of human recombinant erythropoietin with low sialic acid content (NeuroEPO) on the fetal heart in a rat model of placental insufficiency. Methods: 14 Wistar rats gestated with unilateral ligation of the right uterine artery on day 16 of gestation were used. That same day, seven rats were administered NeuroEPO (0.5 mg/kg/day subcutaneously for three days) and the rest received placebo. On day 20 of gestation, the fetuses were divided into four groups: a control group, a group with intrauterine growth retardation, a NeuroEPO control group, and a group with intrauterine growth retardation and NeuroEPO. In the fetuses, placental weight, fetal weight and placental efficiency were obtained. In the histological study, the number of cardiomyocytes, number of blood vessels and quantity of collagen fibers were quantified. Results: the group with intrauterine growth retardation presented a decrease in fetal weight, the number of cardiomyocytes, the number of blood vessels and an increase in the amount of collagen fibers (p<0.05). When fetuses with intrauterine growth retardation were treated with NeuroEPO, fetal weight increased, although the weight was not similar to the control. The rest of the variables behaved similar to the control. Conclusions: the administration of this molecule improved fetal weight and allowed an adequate balance in the development of the fetal heart, perhaps due to the cytoprotective effects of this molecule.

Fetal thymus in growth-restricted fetuses due to placental insufficiency

SUMMARY OBJECTIVE: The aim of this study was to assess fetal thymus size by ultrasound in growth-restricted fetuses due to placental insufficiency and compare to high-risk and low-risk pregnancy fetuses with normal placental function. METHODS: This is a nested case-control study of pregnant women followed up at a university hospital (July 2012 to July 2013). In all, 30 pregnant women presenting small fetuses for gestational age (estimated fetal weight <p10) due to placental insufficiency (umbilical artery Doppler >p95) were compared to 30 high-risk and 30 low-risk pregnancies presenting normal Doppler indices. The thymus transverse diameter and perimeter were converted into zeta score according to the normal values for gestational age. Head circumference and femur length were used to calculate ratios. RESULTS: Fetal thymus were significantly lower in pregnancies with placental insufficiency when compared to high-risk and low-risk pregnancies presenting, respectively, transverse diameter zeta score (-0.69±0.83 vs. 0.49±1.13 vs. 0.83±0.85, p<0.001) and P zeta score (-0.73±0.68 vs. 0.45±0.96 vs. 0.26±0.89, p<0.001). There was also a significant difference (p<0.05) in the ratios among the groups: pregnancies with placental insufficiency (TD/HC=0.10, P/FL=1.32, and P/HC=0.26), high-risk pregnancies (TD/HC=0.11, P/FL=1.40, and P/HC=0.30), and control group (DT/HC=0.11, P/FL=1.45, and P/HC=0.31). CONCLUSION: Fetal thymus size is reduced in growth-restricted fetuses due to placental insufficiency, suggesting fetal response as a consequence of the adverse environment.

Perinatal outcomes of two consecutive strategies for the management of fetal growth restriction: a before-after study.

PURPOSE: We aim to compare the perinatal outcomes of two consecutive management strategies for fetal growth restriction (FGR), with or without the inclusion of additional Doppler parameters. METHODS: A quasi-experimental before/after study was conducted in which we compared a composite perinatal outcome, prematurity rate, and neonatal complications between two management strategies in small fetuses. In the strategy 1 (S1), the management was based on fetal biometry and umbilical artery Doppler. The second strategy (S2) added the assessment of uterine and middle cerebral artery Doppler. We also compared outcomes between strategies according to early (≤ 32 weeks) and late (> 32 weeks) diagnosis subgroups. RESULTS: We included 396 patients, 163 in S1 and 233 in S2. There were no significant differences in the perinatal composite outcome (p 0.98), prematurity (p 0.19), or in the subgroup analysis. We found a significant reduction in respiratory distress syndrome (RDS) rate with S2 both globally (OR 0.50, p 0.02), and in the early diagnosis subgroup (OR 0.45, p 0.01). In addition, we observed a significant reduction in the incidence of sepsis with S2 both globally (OR 0.30, p 0.04) and in the early diagnosis subgroup (OR 0.25, p 0.02). We did not observe significant differences in necrotizing enterocolitis (p 0.41) and intraventricular hemorrhage (p 1.00). CONCLUSION: The expanded strategy for the management of FGR did not show significant differences in the primary composite outcome or prematurity. However, it was associated with a lower incidence of RDS and neonatal sepsis.

Prognostic factors and perinatal outcomes in early-onset intrauterine growth restriction due to placental insufficiency.

OBJECTIVE: To determine the principal prognostic factors and neonatal outcomes associated with perinatal death in cases of early-onset intrauterine growth restriction (IUGR) due to placental insufficiency and to define the cutoff point for the risk of perinatal death. METHODS: A retrospective cohort study conducted with 198 pregnant women with a diagnosis of early-onset IUGR (as detected before the 32nd week of gestational age). The association between the dependent variable (perinatal death) and the independent variables was investigated using a multivariate logistic regression model. The area under the receiver operating characteristic (ROC) curve was calculated to determine the sensitivity and specificity of the adjusted model. A significance level of 5% was established for the entire statistical analysis. RESULTS: Perinatal deaths occurred in 89 (44.9%) of the 198 fetuses with early-onset IUGR. Birthweight <800 grams (OR: 14.73; 95%CI: 4.13-52.54; p < .001), postnatal need for mechanical ventilation (OR: 24.56; 95%CI: 5.58-108.08; p < .001) and postnatal use of an oxygen hood (OR: 0.09; 95%CI: 0.02-0.39; p = .001) remained significantly associated with neonatal death in the multivariate model. The sensitivity, specificity, positive and negative predictive values for birthweight <800 grams and need for mechanical ventilation as predictors of death were, respectively, 84%, 91%, 88%, 88% and 93%, 71%, 60% and 96%, while the values for use of an oxygen hood were, respectively, 15%, 62%, 15% and 62%. CONCLUSION: The principal determinants of perinatal death in fetuses with early-onset IUGR were birthweight <800 grams, gestational age at delivery <30 weeks and postnatal need for mechanical ventilation as risk factors while postnatal use of an oxygen hood was found to constitute a protective factor.

Doppler Ultrasound of the Umbilical Artery: Clinical Application / Ultrassonografia Doppler da artéria umbilical: Aplicação clínica

Abstract Objective To provide a survey of relevant literature on umbilical artery Doppler ultrasound use in clinical practice, technical considerations and limitations, and future perspectives. Methods Literature searches were conducted in PubMed and Medline, restricted to articles written in English. Additionally, the references of all analyzed studies were searched to obtain necessary information. Results The use of this technique as a routine surveillance method is only recommended for high-risk pregnancies with impaired placentation. Meta-analyses of randomized trials have established that obstetric management guided by umbilical artery Doppler findings can improve perinatal mortality and morbidity. The values of the indices of Umbilical artery Doppler decrease with advancing gestational age; however, a lack of consensus on reference ranges prevails. Conclusion Important clinical decisions are based on the information obtained with umbilical artery Doppler ultrasound. Future efforts in research are imperative to overcome the current limitations of the technique.

Resumo Objetivo Compilar informação relevante proveniente da literatura atual sobre a ultrassonografia Doppler das artérias umbilicais (AUs) na prática clínica, considerações e limitações técnicas e perspectivas futuras. Métodos A pesquisa bibliográfica foi realizada nos bancos de dados PubMed e Medline e restringiu-se a artigos escritos na língua inglesa. Recorreu-se também à bibliografia dos artigos selecionados, quando necessário, para obter informação relevante. Resultados A utilização desta técnica como método de vigilância de rotina está apenas recomendada emgravidezes de alto risco comdisfunção placentar.Metanálises de estudos randomizados mostraram que o seguimento obstétrico baseado nos achados do Doppler da artéria umbilical pode melhorar a mortalidade e a morbilidade perinatal. É consensual que os valores dos índices Doppler da AU decrescem com o avanço da idade gestacional. No entanto, há ainda muita incerteza quanto aos valores de referência. Conclusão As informações obtidas através da AU Doppler US são a base para muitas decisões clínicas importantes. Trabalhos de investigação nesta área são essenciais para tentar colmatar atuais limitações da técnica.

Doppler de arteria umbilical en fetos con síndrome de Down / Umbilical artery Doppler in fetuses with Down syndrome

INTRODUCCIÓN: La aneuploidía más común entre los recién nacidos vivos es el síndrome de Down (SD). En estos niños el crecimiento está disminuido, con una frecuencia del 25% de restricción del crecimiento intrauterino, pero no se ha establecido el papel de la insuficiencia placentaria. El objetivo es estudiar la resistencia placentaria a través del Doppler de arteria umbilical con índice de pulsatilidad (IP) y el tiempo medio de desaceleración (t/2), y el posible efecto de la insuficiencia placentaria en fetos con SD. MÉTODO: Se realizó Doppler en la arteria umbilical en 78 fetos con SD, se midieron el IP y el t/2, y se compararon los resultados con los pesos de nacimiento. RESULTADOS: Se estudiaron 78 fetos con SD con 214 mediciones Doppler. El t/2 y el IP estaban alterados en el 71,5% y el 65% de las mediciones, respectivamente. La incidencia de t/2 alterado aumenta con la edad gestacional desde un 28,6% a las 15-20 semanas hasta un 89,3% sobre las 36 semanas (p < 0,01); cifras similares se observan para el IP. La clasificación de los pesos fue: 64% adecuados, 12% grandes y 24% pequeños para la edad gestacional. La última medición de t/2 antes del parto era normal en el 17% y estaba alterada en el 83%. En el caso del IP, los valores fueron normales en el 27% y anormales en el 73%. El peso de nacimiento, la edad gestacional y el porcentaje de niños adecuados para la edad gestacional eran significativamente mayores en el grupo con Doppler normal que en el grupo con Doppler alterado. El z-score del t/2 estaba marcadamente alterado (−2.23), pero el del peso de nacimiento solo estaba algo disminuido (−0,39). La mortalidad perinatal fue del 10%, significativamente mayor cuando el flujo diastólico era ausente o reverso. CONCLUSIONES: El estudio demuestra que los fetos con SD tienen una alta incidencia de alteración del Doppler umbilical para el IP y el t/2, lo cual sugiere una insuficiencia placentaria grave. Este deterioro parece iniciarse hacia el final del segundo trimestre y aumenta con la edad gestacional. Sin embargo, en estos fetos, la insuficiencia placentaria produce una ligera caída en el crecimiento fetal. Como hipótesis general pensamos que en los fetos con SD hay datos claros de insuficiencia placentaria, pero habría algún factor que les protegería de una restricción grave del crecimiento.

INTRODUCTION: The most common aneuploidy in live newborns is Down syndrome (DS), in these children growth is decreased, with a frequency of 25-36% of fetal growth restriction (FGR); however, it is not established the role of placental insufficiency. The objective is to study the Doppler of the umbilical artery with pulsatility index (PI) and half peak systolic velocity (hPSV) deceleration time and the possible role of placental insufficiency in fetuses with DS. METHOD: Doppler was performed in fetuses with DS, the umbilical artery and IP and hPSV were measured, and the results were compared with birth weights. RESULTS: 78 fetuses with DS were studied with 214 Doppler measurements. hPSV and the IP were altered in 71.5% and 65% of the measurements; the incidence of abnormal hPSV increases with gestational age from 28.6% between 15 to 20 weeks, to 89.3% over 36 weeks (p < 0.01), similar figures are observed with respect to the PI. The weight classification was: 24% of FGR, 12% of great for age and 64% of adequate for gestational age (AGA). The last measurement of hPSV before delivery was normal in 17% of the fetuses and was abnormal in 83%, in the case of PI the normal and abnormal values were 27 and 73%, respectively. Birth weight, gestational age, and the percentage of AGA children were significantly higher in the normal Doppler group than in the abnormal Doppler group. The hPSV z-score was markedly altered (−2.23), but the birth weight z-score is slightly decreased (−0.39). Perinatal mortality is 10% and is significantly higher when diastolic flow is absent or reverse. CONCLUSIONS: The study shows that DS fetuses have a high incidence of abnormal umbilical Doppler measured with IP and hPSV, which suggests severe placental insufficiency, this deterioration seems to start towards the end of the second trimester and increases with gestational age. However, in these fetuses, placental insufficiency causes a discrete drop in fetal growth. As a general hypothesis, we think that there is clear evidence of placental insufficiency in fetuses with DS, but there would be some factor that would protect these fetuses from severe growth restriction.

Marcadores morfológicos de hipoxia en el riñón fetal con insuficiencia placentaria tratado con neuro-EPO: estudio en ratas / Morphological markers of hypoxia in the fetal kidney with placental insufficiency treated with neuro-EPO: study in rats

RESUMEN Fundamento: la restricción del crecimiento intrauterino constituye una complicación del embarazo. Los recién nacidos con esta condición están expuestos a un mayor riesgo de morbimortalidad perinatal y postnatal. Objetivo: evaluar marcadores morfológicos de hipoxia en el desarrollo fetal y en el riñón, utilizando un modelo de insuficiencia placentaria tratado con eritropoyetina humana con bajo contenido de ácido siálico (neuro-Epo) en ratas. Métodos: se utilizaron tres grupos de ratas gestadas de la línea Wistar. Un grupo control (grupo I) y dos grupos experimentales (grupos II y III) con seis ratas cada uno. A las ratas de los grupos II y III se les realizó ligaduras de arterias uterinas en el día 16 de la gestación (E 16). Al grupo III desde E16 hasta E19 se le administró una dosis de 0,5 mg/kg/día de neuro-Epo por vía subcutánea y al grupo II se les administró placebo. En el día 20 de la gestación se pesaron los fetos y sus placentas. En el feto se midió la talla y los diámetros cefálicos. Las características morfométricas e histológicas en el riñón fetal se estudiaron con tinción de hematoxilina-eosina y PAS. Se realizó un análisis cualitativo histopatológico de sus tipos celulares. Resultados: los fetos con restricción del crecimiento intrauterino no mejoraron los marcadores de crecimiento. Se encontraron lesiones por hipoxia en el riñón fetal del grupo RCIU no tratado que mejoraron al administrar neuro-Epo. Conclusiones: la administración de neuro-Epo solo mostró efectos reparadores y protectores sobre alteraciones histológicas provocadas por la hipoxia en el riñón fetal.

ABSTRACT Foundation: intrauterine growth restriction constitutes a complication of pregnancy. Newborns with this condition are exposed to an increased risk of perinatal and postnatal morbidity and mortality. Objective: to evaluate morphological markers of hypoxia in fetal and kidney development, using a model of placental insufficiency treated with human erythropoietin with low sialic acid content (neuro-Epo) in rats. Methods: three groups of gestated rats from the Wistar line were used. A control group (group I) and two experimental groups (groups II and III) with six rats each. Rats of groups II and III had uterine artery ligation on day 16 of pregnancy (E 16). Group III from E16 to E19 was administered a dose of 0.5 mg / kg / day of neuro-Epo subcutaneously and group II was administered placebo. On the 20th day of gestation the fetuses and their placentas were weighed. The fetuses' size and cephalic diameters were measured. Morphometric and histological features in the fetal kidney were studied with hematoxylin-eosin staining and PAS. A qualitative histopathological analysis of their cell types was performed. Results: fetuses with intrauterine growth restriction did not improve growth markers. Hypoxia lesions were found in the fetal kidney of the untreated RCIU group that improved by administering neuro-Epo. Conclusions: the administration of neuro-Epo only showed reparative and protective effects on histological alterations caused by hypoxia in the fetal kidney.

Umbilical artery pulsatility index and half-peak systolic velocity deceleration time in fetuses with trisomy 21.

Objective: To analyze placental vascular resistance and the role of placental insufficiency in the etiology of reduced fetal growth in fetuses with trisomy 21 as determined by umbilical artery (UA) Doppler velocimetry.Methods: Second- and third-trimester UA Doppler ultrasound studies were performed in fetuses with trisomy 21 at the time of clinically indicated obstetric ultrasound assessment. The UA pulsatility index (PI) and half-peak systolic velocity deceleration time (hPSV-DT) were measured and recorded. Perinatal outcome was reviewed and the results from UA Doppler velocimetry were compared with birthweight according to gestational age at the time of the delivery.Results: A total of 60 fetuses with trisomy 21 were studied and information from 147 UA Doppler studies was analyzed. Overall, at least one of the UA PI and hPSV-DT values was abnormal in 82% (n = 49) and 90% (n = 54) of the cases, respectively. The incidence of abnormal UA PI values increased with gestational age from 39% (7/18) before 21 weeks to 78% (18/23) after 35 weeks (p < .05). The increase was even more evident for UA hPSV-DT values from 28% (5/18) before 20 weeks to 91% (21/23) after 35 weeks (p < .01). After exclusion of four fetuses with hydrops or isolated hydrothorax/ascites, 16 (29%) were classified at birth as small for gestational age (SGA), 34 (61%) as adequate for gestational age, and six (11%) as large for gestational age, with a mean birthweight z-score of -0.36. When only considering the last Doppler ultrasound assessment prior to delivery, UA PI and hPSV-DT values were abnormal in 73% (41/56, mean z-score = +1.72) and 82% (46/56; mean z-score = -2.18) of the cases, respectively. Mean gestational age at delivery and birth weight were significantly lower in the group with abnormal compared to normal UA PI and hPSV-DT values. Similarly, the incidence of SGA fetuses was significantly higher in the group with abnormal compared to normal UA PI and hPSV-DT values, with 94 (n = 15) and 100% of the 16 SGA newborn infants having abnormal UA PI and hPSV-DT values prior to delivery, respectively.Conclusions: Trisomy 21 fetuses have a progressively higher incidence of abnormal UA impedance indices throughout pregnancy, which suggests developing placental vascular resistance as the pregnancy progresses. This alteration likely begins around the mid second trimester and increases with gestational age; however, increasing placental vascular resistance seems to produce a discrete decrease in fetal growth, despite severe alteration of the UA Doppler impedance indices. As a general hypothesis, we postulate that trisomy 21 fetuses have increasing placental vascular resistance but there may be some factors that protect these fetuses from severe fetal growth restriction.

Pulmonary Vein Flow Impedance: An Early Predictor of Cardiac Dysfunction in Intrauterine Growth Restriction.

INTRODUCTION: In intrauterine growth restriction (IUGR), increased uteroplacental vascular impedance contributes to preferential flow to left ventricle (LV), with consequent alteration of its compliance and increased left atrial (LA) pressure. Pulmonary vein pulsatility index (PVPI) reflects the increased impedance to LA filling and could be used as a cardiac monitoring parameter in IUGR. MATERIAL AND METHODS: A total of 27 IUGR fetuses (group 1), 28 fetuses with appropriate growth for gestational age from hypertensive mothers (group 2), and 28 controls (group 3) were studied. Pulsatility indices (PIs) of pulmonary veins and ductus venosus were calculated by Doppler echocardiography. Obstetric ultrasound was used to assess the PIs of uterine, umbilical, and middle cerebral arteries. Statistical analysis used analysis of variance, post-hoc Tukey, and Pearson's tests. RESULTS: Mean PVPI was higher in IUGR group (1.27 ± 0.39) when compared to groups 2 (1.02 ± 0.37; p = 0.01) and 3 (0.75 ± 0.12; p < 0.001). In group 2, moderate correlation between PVPI and ductus venosus pulsatility index (DVPI) was found but not between PVPI and cerebroplacental ratio (CPR). DISCUSSION: Higher PVPI in IUGR reflects decreased LV compliance and altered LA dynamics. As LV dysfunction precedes right ventricle, our results suggest that PVPI could be an early echocardiographic parameter of fetal diastolic function in IUGR.

As consequências da restrição de crescimento intrauterino na estrutura e fluxo sanguíneo cerebral: uma revisão da literatura / The consequences of fetal growth restriction on brain structure and blood flow: a review

A Restrição de Crescimento Fetal (RCF) é definida como uma incapacidade do feto em alcançar seu potencial de crescimento, afeta 5-10% das gestações e está associada à alta morbimortalidade fetal e neonatal, principalmente a danos neurológicos. O objetivo dessa revisão foi levantar os estudos sobre a alteração cerebral nos fetos com RCF que possam estar relacionados aos danos neurológicos pós-natais já estabelecidos. Nesses fetos, há um crescimento desigual das estruturas cerebrais e reconhece-se que, na dependência de hipoxemia crônica e privação de nutrientes provocados pela insuficiência placentária, o feto tende a preferenciar o fluxo sanguíneo para o cérebro em detrimento de outros órgãos. Os resultados dessa revisão sugerem que o efeito protetor do aumento da perfusão sanguínea cerebral é diferente em cada estágio de deterioração fetal, propondo uma ordem hierárquica na proteção das diferentes funções/áreas cerebrais, e quanto mais severo esse acometimento, maiores mudanças estruturais cerebrais o feto apresentará.(AU)

Fetal growth restriction is defined as an inability of the fetus to reach its growth potential, affects 5-10% of pregnancies and is associated with high fetal and neonatal morbidity and mortality, mainly neurological damage. The aim of this review was to investigate brain alterations in fetus with fetal growth restriction that may be related to the already established postnatal neurological damage. In these fetus there is an uneven growth of the brain structures and it is recognized that in dependence on chronic hypoxemia and nutrient deprivation caused by placental insufficiency, the fetus tends to prefer the blood flow to the brain in detriment of other organs. The results of this review suggest that the protective effect of increased cerebral blood perfusion is different at each stage of fetal deterioration, proposing a hierarchical order in the protection of the different brain functions / areas and more severe this involvement, bigger structural changes the fetus will present.(AU)

Analysis of the performance of 11 formulae for fetal weight estimation in preterm fetuses with abnormal doppler velocimetry - A retrospective multicenter study / Análise do desempenho de 11 fórmulas de estimativa de peso fetal em conceptos prematuros com Dopplervelocimetria alterada - um estudo retrospectivo multicêntrico

Abstract Objective To assess 11 formulae commonly used to estimate fetal weight in a population of premature fetuses who had abnormal Doppler velocimetry due to early-onset placental insufficiency. The performance of each formula was evaluated in subgroups of fetuses with expected growth and intrauterine growth restriction. Methods Data were collected fromfetuses andmothers who delivered at three Brazilian hospitals between November 2002 and December 2013.We used the following formulae: Campbell; Hadlock I, II, III, IV and V; Shepard; Warsof; Weiner I and II; and Woo III. Results We analyzed 194 fetuses. Of these, 116 (59.8%) were considered appropriate for gestational age (AGA), and 103 (53.1%) were male. The amniotic fluid volume was reduced in 87 (44.8%) fetuses, and the umbilical artery Doppler revealed absence or inversion of diastolic flow in 122 (62.9%) cases, and the analysis of the ductus venosus revealed abnormal flow in 60 (34.8%) fetuses. The Hadlock formulae using three or four fetal biometric parameters had low absolute percentage error in the estimated fetal weight among preterm fetuses with abnormal Doppler studies who were born within 5 days of the ultrasound evaluation. The results were not influenced by the clinical and ultrasound parameters often found in early-onset placental insufficiency. Conclusion In this study, the formulae with the best performance for fetal weight estimation in the analyzed population were Hadlock I and IV, which use four and three fetal biometric parameters respectively to estimate the weight of preterm fetuses with abnormal Doppler studies.

Resumo Objetivo Avaliar o desempenho de 11 fórmulas comumente utilizadas para estimativa de peso fetal em uma população de fetos prematuros com dopplervelocimetria alterada devido a insuficiência placentária de início precoce. O desempenho de cada fórmula foi avaliado em subgrupos de fetos com crescimento adequado e com crescimento intrauterino restrito. Métodos Foram coletados os dados de mães e fetos cujos partos foram acompanhados em 3 instituições brasileiras entre novembro de 2002 e dezembro de 2013. As fórmulas selecionadas para análise foram: Campbell; Hadlock I, II, III, IV e V; Shepard; Warsof; Weiner I e II; e Woo III. Resultados Foram analisados os pesos de 194 fetos, dos quais 116 (59,8%) foram considerados adequados para a idade gestacional, 103 (53,1%) eram do sexo masculino, em 87 (44,8%) havia redução do volume de líquido amniótico, em 122 (62,9%) o Doppler de artéria umbilical demonstrou ausência ou inversão do fluxo na diástole, e em 60 (34,8%) a análise do duto venoso indicou fluxo anormal. A média do erro percentual absoluto (EPA) demonstrou que as fórmulas de Hadlock que utilizam 3 ou 4 parâmetros biométricos fetais apresentaram o melhor desempenho. Os resultados obtidos para essas fórmulas não sofreram influência dos parâmetros clínicos e ultrassonográficos frequentemente encontrados na insuficiência placentária de início precoce. Conclusão O presente estudo demonstrou o melhor desempenho das fórmulas de Hadlock que contêm 3 ou 4 parâmetros da biometria para estimativa de peso de fetos prematuros com anormalidades ao mapeamento Doppler.

Impact of thermal stress on placental function and fetal physiology.

In ruminants, prolonged exposure to high ambient temperatures negatively affects placental development and function. The pursuing limitations in placental oxygen and nutrient supply between the mother and fetus slow fetal growth lowering birth weights and postnatal performance. The pregnant ewe is a long-standing animal model for the study of maternal- fetal interactions and is susceptible to naturally occurring heat stress, which causes fetal growth restriction. In the pregnant ewe, studies show that the fetus adapts to hyperthermia-induced placental insufficiency to preserve placental transport capacity of oxygen and nutrients. These adaptive responses are at the expense of normal fetal development and growth. Enlarged transplacental gradient for oxygen and glucose facilitates diffusion across the placenta, but develops by lowering fetal blood oxygen and glucose concentrations. Fetal hypoxemia and hypoglycemia slow growth and alter their metabolic and endocrine profiles. Deficits in amino acids transport across the placenta are present but are overcome by reduced fetal clearance rates, likely due to fetal hypoxemia or endocrine responses to hypoxic stress. Here, we provide an overview of the performance limitations observed in ruminants exposed to heat stress during pregnancy, but we focus our presentation on the sheep fetus in pregnancies complicated by hyperthermia-induced placental insufficiency. We define the characteristics of placental dysfunction observed in the fetus of heat stressed ewes during pregnancy and present developmental adaptations in organogenesis, metabolism, and endocrinology that are proposed to establish maladaptive situations reaching far beyond the perinatal period.

Impact of thermal stress on placental function and fetal physiology

In ruminants, prolonged exposure to high ambient temperatures negatively affects placental development and function. The pursuing limitations in placental oxygen and nutrient supply between the mother and fetus slow fetal growth lowering birth weights and postnatal performance. The pregnant ewe is a long-standing animal model for the study of maternalfetal interactions and is susceptible to naturally occurring heat stress, which causes fetal growth restriction. In the pregnant ewe, studies show that the fetus adapts to hyperthermia-induced placental insufficiency to preserve placental transport capacity of oxygen and nutrients. These adaptive responses are at the expense of normal fetal development and growth. Enlarged transplacental gradient for oxygen and glucose facilitates diffusion across the placenta, but develops by lowering fetal blood oxygen and glucose concentrations. Fetal hypoxemia and hypoglycemia slow growth and alter their metabolic and endocrine profiles. Deficits in amino acids transport across the placenta are present but are overcome by reduced fetal clearance rates, likely due to fetal hypoxemia or endocrine responses to hypoxic stress. Here, we provide an overview of the performance limitations observed in ruminants exposed to heat stress during pregnancy, but we focus our presentation on the sheep fetus in pregnancies complicated by hyperthermia-induced placental insufficiency. We define the characteristics of placental dysfunction observed in the fetus of heat stressed ewes during pregnancy and present developmental adaptations in organogenesis, metabolism, and endocrinology that are proposed to establish maladaptive situations reaching far beyond the perinatal period.

Impact of thermal stress on placental function and fetal physiology

In ruminants, prolonged exposure to high ambient temperatures negatively affects placental development and function. The pursuing limitations in placental oxygen and nutrient supply between the mother and fetus slow fetal growth lowering birth weights and postnatal performance. The pregnant ewe is a long-standing animal model for the study of maternalfetal interactions and is susceptible to naturally occurring heat stress, which causes fetal growth restriction. In the pregnant ewe, studies show that the fetus adapts to hyperthermia-induced placental insufficiency to preserve placental transport capacity of oxygen and nutrients. These adaptive responses are at the expense of normal fetal development and growth. Enlarged transplacental gradient for oxygen and glucose facilitates diffusion across the placenta, but develops by lowering fetal blood oxygen and glucose concentrations. Fetal hypoxemia and hypoglycemia slow growth and alter their metabolic and endocrine profiles. Deficits in amino acids transport across the placenta are present but are overcome by reduced fetal clearance rates, likely due to fetal hypoxemia or endocrine responses to hypoxic stress. Here, we provide an overview of the performance limitations observed in ruminants exposed to heat stress during pregnancy, but we focus our presentation on the sheep fetus in pregnancies complicated by hyperthermia-induced placental insufficiency. We define the characteristics of placental dysfunction observed in the fetus of heat stressed ewes during pregnancy and present developmental adaptations in organogenesis, metabolism, and endocrinology that are proposed to establish maladaptive situations reaching far beyond the perinatal period.(AU)

¿Se relaciona la obesidad en el embarazo con muerte fetal por insuficiencia placentaria? / Is obesity in pregnancy related to fetal death due to placental insufficiency?

Se presentan 4 casos de muerte fetal en pacientes obesas con embarazos de término, con hallazgos placentarios variados, que sugieren insuficiencia placentaria, que podrían estar asociados a la obesidad. Esta afirmación se basa en evidencias recientes que demuestran que la obesidad por intermedio de la disminución de los mediadores como apelina, leptina, reguladores del tono vascular placentario y de otros reguladores de la angiogénesis, alteran la función placentaria especialmente en embarazos de término y podrían estar implicados con inadecuado crecimiento fetal y con resultados adversos asociados con la obesidad. Comunicamos un mecanismo inusualmente descrito relacionado posiblemente con la obesidad y con resultado desfavorable del embarazo.

We present 4 cases of fetal death in obese pregnant women with term pregnancies, with several placental findings suggesting placental insufficiency, that could be associated with obesity. According to recent evidence obesity could be associated with inadequate fetal growth and adverse outcomes especially at term pregnancies, through the decrease of mediators such as apelin, leptin, regulators of placental vascular tone and other regulators of angiogenesis altering placental function. We report a rarely described mechanism possibly related to obesity and unfavorable outcome of pregnancy.

Revealed versus concealed criteria for placental insufficiency in an unselected obstetric population in late pregnancy (RATIO37): randomised controlled trial study protocol.

INTRODUCTION: Fetal growth restriction (FGR) affects 5%-10% of all pregnancies, contributing to 30%-50% of stillbirths. Unfortunately, growth restriction often is not detected antenatally. The last weeks of pregnancy are critical for preventing stillbirth among babies with FGR because there is a pronounced increase in stillbirths among growth-restricted fetuses after 37 weeks of pregnancy. Here we present a protocol (V.1, 23 May 2016) for the RATIO37 trial, which evaluates an integrated strategy for accurately selecting at-risk fetuses for delivery at term. The protocol is based on the combination of fetal biometry and cerebroplacental ratio (CPR). The primary objective is to reduce stillbirth rates. The secondary aims are to detect low birth weights and adverse perinatal outcomes. METHODS AND ANALYSIS: The study is designed as multicentre (Spain, Chile, Mexico,Czech Republic and Israel), open-label, randomised trial with parallel groups. Singleton pregnancies will be invited to participate after routine second-trimester ultrasound scan (19+0-22+6 weeks of gestation), and participants will be randomly allocated to receive revealed or concealed CPR evaluation. Then, a routine ultrasound and Doppler scan will be performed at 36+0-37+6 weeks. Sociodemographic and clinical data will be collected at enrolment. Ultrasound and Doppler variables will be recorded at 36+0-37+6 weeks of pregnancy. Perinatal outcomes will be recorded after delivery. Univariate (with estimated effect size and its 95% CI) and multivariate (mixed-effects logistic regression) comparisons between groups will be performed. ETHICS AND DISSEMINATION: The study will be conducted in accordance with the principles of Good Clinical Practice. This study was accepted by the Clinical Research Ethics Committee of Hospital Clinic Barcelona on 23May 2016. Subsequent approval by individual ethical committees and competent authorities was granted. The study results will be published in peer-reviewed journals and disseminated at international conferences. TRIAL REGISTRATION NUMBER: NCT02907242; pre-results.

Defective trophoblast invasion underlies fetal growth restriction and preeclampsia-like symptoms in the stroke-prone spontaneously hypertensive rat.

STUDY QUESTION: What is the impact of chronic hypertension on placental development, fetal growth and maternal outcome in the stroke-prone spontaneously hypertensive rat (SHRSP)? SUMMARY ANSWER: SHRSP showed an impaired remodeling of the spiral arteries and abnormal pattern of trophoblast invasion during placentation, which were associated with subsequent maternal glomerular injury and increased baseline hypertension as well as placental insufficiency and asymmetric fetal growth restriction (FGR). WHAT IS KNOWN ALREADY: A hallmark in the pathogenesis of preeclampsia (PE) is abnormal placentation with defective remodeling of the spiral arteries preceding the onset of the maternal syndrome. Pregnancies affected by chronic hypertension display an increased risk for PE, often associated with poor maternal and fetal outcomes. However, the impact of chronic hypertension on the placentation process as well as the nature of the factors promoting the development of PE in pregnant hypertensive women remain elusive. STUDY DESIGN, SIZE, DURATION: Timed pregnancies [n = 5] were established by mating 10-12-week-old SHRSP and Wistar Kyoto (WKY, normotensive controls) females with congenic males. Maternal systolic blood pressures (SBPs) were recorded pre-mating, throughout pregnancy (GD1-19) and post-partum by the tail-cuff method. On selected dates, 24 h urine- and blood samples were collected, and animals were euthanized for isolation of implantation sites and kidneys for morphometrical analyses. PARTICIPANTS/MATERIALS, SETTING, METHODS: The 24 h proteinuria and the albumin:creatinine ratio were used for evaluation of maternal renal function. Renal injury was assessed on periodic acid Schiff, Masson's trichrome and Sirius red stainings. Placental and fetal weights were recorded on gestation day (GD)18 and GD20, followed by determination of fetal cephalization indexes and developmental stage, according to the Witschi scale. Morphometric analyses of placental development were conducted on hematoxylin-eosin stained tissue sections collected on GD14 and GD18, and complemented with immunohistochemical evaluation of isolectin B4 binding for assessment of placental vascularization. Analyses of vascular wall alpha actin content, perforin-positive natural killer (NK) cells and cytokeratin expression by immunohistochemistry were used for evaluation of spiral artery remodeling and trophoblast invasion. MAIN RESULTS AND THE ROLE OF CHANCE: SHRSP females presented significantly increased SBP records from GD13 to GD17 (SBPGD13 = 183.9 ± 3.9 mmHg, P < 0.005 versus baseline) and increased proteinuria at GD18 (P < 0.01 versus WKY). Histological examination of GD18 kidneys revealed glomerular enlargement and mesangial matrix expansion, which were not evident in pregnant WKY or age-matched virgin SHRSP. At GD20, SHRSP displayed a significant reduction of placental mass (P < 0.01 versus WKY) and signs of placental insufficiency (i.e. hypertrophy and reduced branching morphogenesis of the labyrinth layer), associated with decreased offspring weights and increased cephalization index (both P < 0.001 versus WKY) indicating asymmetric FGR. Notably, SHRSP placentas displayed an incomplete remodeling of spiral arteries starting as early as GD14, with luminal narrowing and reduced densities of perivascular NK cells followed by decreased infiltration of endovascular trophoblasts at GD18. LARGE SCALE DATA: n/a. LIMITATIONS, REASONS FOR CAUTION: A pitfall of the present study is the differences in the blood pressure profiles between rats and humans (i.e. unlike pregnancies affected by PE, blood pressure in SHRSP and other hypertensive rat models decreases pre-delivery), which limits extrapolation of the results. WIDER IMPLICATIONS OF THE FINDINGS: Our findings provide new insights on the role of chronic hypertension as a risk factor for PE by interfering with early events during the placentation process. The SHRSP strain represents an attractive model for further studies aimed at addressing the relative contribution of intrinsic (i.e. placental) and extrinsic (i.e. decidual/vascular) factors to defective spiral artery remodeling in pregnancies affected by PE. STUDY FUNDING AND COMPETING INTEREST(S): This work was supported by research grants from Fundación Florencio Fiorini to G.B., from Charité Stiftung to S.M.B. and University of Buenos Aires (UBACyt) to J.T. The authors have no competing interests to declare.

Fetal growth restriction: current knowledge.

BACKGROUND: Fetal growth restriction (FGR) is a condition that affects 5-10% of pregnancies and is the second most common cause of perinatal mortality. This review presents the most recent knowledge on FGR and focuses on the etiology, classification, prediction, diagnosis, and management of the condition, as well as on its neurological complications. METHODS: The Pubmed, SCOPUS, and Embase databases were searched using the term "fetal growth restriction". RESULTS: Fetal growth restriction (FGR) may be classified as early or late depending on the time of diagnosis. Early FGR (<32 weeks) is associated with substantial alterations in placental implantation with elevated hypoxia, which requires cardiovascular adaptation. Perinatal morbidity and mortality rates are high. Late FGR (≥32 weeks) presents with slight deficiencies in placentation, which leads to mild hypoxia and requires little cardiovascular adaptation. Perinatal morbidity and mortality rates are lower. The diagnosis of FGR may be clinical; however, an arterial and venous Doppler ultrasound examination is essential for diagnosis and follow-up. There are currently no treatments to control FGR; the time at which pregnancy is interrupted is of vital importance for protecting both the mother and fetus. CONCLUSION: Early diagnosis of FGR is very important, because it enables the identification of the etiology of the condition and adequate monitoring of the fetal status, thereby minimizing risks of premature birth and intrauterine hypoxia.

Muertes fetales tardías en la provincia de Cienfuegos / Late Fetal Deaths in Cienfuegos Province

Fundamento: Entre las complicaciones más temidas del embarazo, se encuentra el óbito fetal, llamado también muerte fetal tardía, si ocurre entre las 28 semanas de gestación y el parto. La tasa de muerte fetal tardía es un indicador del avance científico y desarrollo social de un país. Objetivo: describir los factores asociados a la ocurrencia de muerte fetal tardía. Métodos: estudio descriptivo, de una serie de 221 casos de muertes fetales tardías ocurridas en la provincia Cienfuegos, en el período de enero de 2006 a diciembre del 2013. Algunas de las variables estudiadas fueron: momento y lugar de la muerte, causa de la muerte, edad materna, peso materno, número de embarazos enfermedades maternas, complicaciones durante el embarazo, edad gestacional y alteraciones en la placenta y el cordón umbilical. Resultados: la tasa de muerte fetal tardía fue 6,38. Predominaron las muertes fetales de causa desconocida, seguidas de las ocasionadas por enfermedad hipertensiva del embarazo y el crecimiento intrauterino retardado. El mayor número de muertes fetales ocurrieron anteparto, fuera del hospital, en gestantes obesas, pretérmino, con trastornos hipertensivos, diabéticas, y en fetos malformados. La insuficiencia placentaria y la angiopatía obliterante fueron las alteraciones placentarias más frecuentes. Conclusión: a pesar de los avances introducidos en Obstetricia, la tasa de muerte fetal tardía en la provincia de Cienfuegos se mantiene elevada, de forma similar a lo reflejado por otros estudios cubanos.

Background: stillbirth, also called late fetal death if it occurs between 28 weeks’ gestation and birth, is one of the most feared complications of pregnancy. The late fetal mortality rate is an indicator of scientific progress and social development of a country.Objective: to describe the factors associated with late fetal death. Methods: a study of a series of 221 cases of late fetal deaths was conducted in Cienfuegos province from January 2006 to December 2013. The variables studied included: time and place of death, cause of death, maternal age, maternal weight, number of pregnancies, maternal diseases, pregnancy complications, gestational age and placental and umbilical cord abnormalities. Results: late fetal death rate was 6.38. Fetal deaths from unknown cause predominated, followed by those associated with hypertensive disorders of pregnancy and intrauterine growth retardation. The largest number of fetal deaths occurred antepartum, before term, outside the hospital, in obese pregnant women, in women with hypertensive disorders and diabetes, and in malformed fetuses. Placental insufficiency and obliterating angiopathy were the most common placental abnormalities.Conclusion: despite the advances in obstetrics, the late fetal death rate in Cienfuegos province remains high, similar to what have been reflected in other Cuban studies.