1.
An integrated model with classification criteria to predict small‐for‐gestational‐age fetuses at risk of adverse perinatal outcome
Figueras, F.; Savchev, S.; Triunfo, S. ...
Ultrasound in obstetrics & gynecology,
March 2015, Volume:
45, Issue:
3
Journal Article
Objective
To develop an integrated model with the best performing criteria for predicting adverse outcome in small‐for‐gestational‐age (SGA) pregnancies.
Methods
A cohort of 509 pregnancies with a ...
suspected SGA fetus, eligible for trial of labor, was recruited prospectively and data on perinatal outcome were recorded. A predictive model for emergency Cesarean delivery because of non‐reassuring fetal status or neonatal acidosis was constructed using a decision tree analysis algorithm, with predictors: maternal age, body mass index, smoking, nulliparity, gestational age at delivery, onset of labor (induced vs spontaneous), estimated fetal weight (EFW), umbilical artery pulsatility index (PI), mean uterine artery (UtA) PI, fetal middle cerebral artery PI and cerebroplacental ratio (CPR).
Results
An adverse outcome occurred in 134 (26.3%) cases. The best performing predictors for defining a high risk for adverse outcome in SGA fetuses was the presence of a CPR < 10th centile, a mean UtA‐PI > 95th centile or an EFW < 3rd centile. The algorithm showed a sensitivity, specificity and positive and negative predictive values for adverse outcome of 82.8% (95% CI, 75.1–88.6%), 47.7% (95% CI, 42.6–52.9%), 36.2% (95% CI, 30.8–41.8%) and 88.6% (95% CI, 83.2–92.5%), respectively. Positive and negative likelihood ratios were 1.58 and 0.36.
Conclusions
Our model could be used as a diagnostic tool for discriminating SGA pregnancies at risk of adverse perinatal outcome. Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
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2.
Placental findings in late-onset SGA births without Doppler signs of placental insufficiency
Parra-Saavedra, M; Crovetto, F; Triunfo, S ...
Placenta (Eastbourne),
12/2013, Volume:
34, Issue:
12
Journal Article
Abstract Objectives To describe placental pathological findings in late-onset small-for-gestational age (SGA) births for which Doppler signs of placental insufficiency are lacking. Methods A series ...
of placentas were evaluated from singleton pregnancies of SGA births (birth weight below the 10th percentile) delivered after 34 weeks with normal umbilical artery Doppler (pulsatility index below the 95th percentile), that were matched by gestational age with adequate-for-gestational age (AGA) controls. Using a hierarchical and standardized system, placental lesions were classified histologically as consequence of maternal underperfusion, fetal underperfusion or inflammation. Results A total of 284 placentas were evaluated (142 SGA and 142 AGA). In the SGA group, 54.2% (77/142) of the placentas had weights below the 3rd percentile for GA while it was a 9.9% (14/142) in the AGA group ( p < 0.001). Only 21.8% (31/142) of SGA placentas were free of histological abnormalities, while it was 74.6% (106/142) in the AGA group ( p < 0.001). In the abnormal SGA placentas (111/142) there were a total of 161 lesions, attributable to MUP in 64% (103/161), FUP in 15.5% (25/161), and inflammation in 20.5% (33/161). Discussion In most placentas of term SGA neonates with normal UA Doppler histological abnormalities secondary to maternal underperfusion prevail, reflecting latent insufficiency in uteroplacental blood supply. This is consistent with the higher risk of adverse perinatal outcome reported in this population and underscores a need for new markers of placental disease. Conclusions A significant proportion of late-onset SGA births with normal umbilical artery Doppler may still be explained by placental insufficiency.
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3.
First‐trimester screening with specific algorithms for early‐ and late‐onset fetal growth restriction
Crovetto, F.; Triunfo, S.; Crispi, F. ...
Ultrasound in obstetrics & gynecology,
September 2016, 2016-Sep, 20160901, Volume:
48, Issue:
3
Journal Article
ABSTRACT
Objective
To develop optimal first‐trimester algorithms for the prediction of early and late fetal growth restriction (FGR).
Methods
This was a prospective cohort study of singleton ...
pregnancies undergoing first‐trimester screening. FGR was defined as an ultrasound estimated fetal weight < 10th percentile plus Doppler abnormalities or a birth weight < 3rd percentile. Logistic regression‐based predictive models were developed for predicting early and late FGR (cut‐off: delivery at 34 weeks). The model included the a‐priori risk (maternal characteristics), mean arterial pressure (MAP), uterine artery pulsatility index (UtA‐PI), placental growth factor (PlGF) and soluble fms‐like tyrosine kinase‐1 (sFlt‐1).
Results
Of the 9150 pregnancies included, 462 (5%) fetuses were growth restricted: 59 (0.6%) early and 403 (4.4%) late. Significant contributions to the prediction of early FGR were provided by black ethnicity, chronic hypertension, previous FGR, MAP, UtA‐PI, PlGF and sFlt‐1. The model achieved an overall detection rate (DR) of 86.4% for a 10% false‐positive rate (area under the receiver–operating characteristics curve (AUC): 0.93 (95% CI, 0.87–0.98)). The DR was 94.7% for FGR with pre‐eclampsia (PE) (64% of cases) and 71.4% for FGR without PE (36% of cases). For late FGR, significant contributions were provided by chronic hypertension, autoimmune disease, previous FGR, smoking status, nulliparity, MAP, UtA‐PI, PlGF and sFlt‐1. The model achieved a DR of 65.8% for a 10% false‐positive rate (AUC: 0.76 (95% CI, 0.73–0.80)). The DR was 70.2% for FGR with PE (12% of cases) and 63.5% for FGR without PE (88% of cases).
Conclusions
The optimal screening algorithm was different for early vs late FGR, supporting the concept that screening for FGR is better performed separately for the two clinical forms. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.
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4.
First‐trimester screening for early and late small‐for‐gestational‐age neonates using maternal serum biochemistry, blood pressure and uterine artery Doppler
Crovetto, F.; Crispi, F.; Scazzocchio, E. ...
Ultrasound in obstetrics & gynecology,
January 2014, Volume:
43, Issue:
1
Journal Article
ABSTRACT
OBJECTIVE
To assess the effectiveness of first‐trimester screening for early and late small‐for‐gestational‐age (SGA) neonates using maternal serum biochemistry, blood pressure and uterine ...
artery Doppler.
Methods
This was a prospective study of 4970 women with a singleton pregnancy who underwent routine first‐trimester screening between 2009 and 2011. A logistic regression‐based predictive model for SGA, defined as birth weight < 10th percentile, divided into early‐ or late‐onset based on gestational age at delivery before or after 34 weeks' gestation, was constructed. The model included maternal baseline characteristics: serum levels of pregnancy‐associated plasma protein‐A and free β‐human chorionic gonadotropin at 8–12 weeks and blood pressure and uterine artery Doppler at 11 + 0 to 13 + 6 weeks.
Results
The prevalence of early and late SGA was 0.6% and 7.9%, respectively. Association with pre‐eclampsia was 67% and 8%, respectively. At a false‐positive rate of 15%, the detection rate for early SGA was 73%; however it differed substantially for cases with and without pre‐eclampsia (90% vs 40%). For late SGA, at false‐positive rates of 15 and 50%, detection rates were 32% and 70%, respectively, and did not substantially differ between cases with and without pre‐eclampsia.
Conclusions
First‐trimester screening predicts early SGA mainly because of its strong association with pre‐eclampsia. Although prediction of late SGA was poorer, at a high false‐positive rate it might be considered as part of a first‐trimester strategy to select women requiring ultrasound assessment in the third trimester. Copyright © 2013 ISUOG. Published by John Wiley & Sons Ltd.
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5.
Distinctive patterns of placental lesions in pre‐eclampsia vs small‐for‐gestational age and their association with fetoplacental Doppler
Paules, C.; Youssef, L.; Rovira, C. ...
Ultrasound in obstetrics & gynecology,
November 2019, 2019-Nov, 2019-11-00, 20191101, Volume:
54, Issue:
5
Journal Article
ABSTRACT
Objectives
To describe placental histopathological findings in a large cohort of pregnancies complicated by pre‐eclampsia (PE) and/or small‐for‐gestational age (SGA), and to investigate ...
their association with fetoplacental Doppler parameters.
Methods
This was a prospective observational study of normotensive pregnancies with SGA (defined as birth weight < 10th centile) (n = 184), PE pregnancies with a normally grown fetus (n = 102), pregnancies with both PE and SGA (n = 120) and uncomplicated pregnancies (n = 202). Uterine (UtA), umbilical (UA) and fetal middle cerebral (MCA) artery pulsatility indices (PI) were assessed. The cerebroplacental ratio (CPR) was calculated by dividing MCA‐PI by UA‐PI. Doppler parameters were considered abnormal when UtA‐PI or UA‐PI was > 95th centile or MCA‐PI or CPR was < 5th centile. Placental lesions were categorized as vascular (maternal or fetal side), immunoinflammatory or other, according to the 2014 Amsterdam Placental Workshop Group Consensus Statement. Comparison between the study groups was performed using univariate and multiple regression analysis, and logistic regression was used to determine the relationship between abnormal Doppler parameters and placental lesions.
Results
Maternal‐side vascular lesions were significantly more common in PE pregnancies with SGA than in the other groups (PE + SGA, 73% vs PE, 46% vs SGA, 38% vs controls, 31%; P = 0.01) and included mainly two types of lesion: developmental (PE + SGA, 13% vs PE, 5% vs SGA, 3% vs controls, 1.5%; P < 0.001) and malperfusion (PE + SGA, 70% vs PE, 39% vs SGA, 32% vs controls, 25%; P = 0.001). In contrast, the incidence of fetal‐side developmental lesions was significantly higher in normotensive SGA pregnancies than in controls and PE pregnancies (PE + SGA, 0% vs PE, 3% vs SGA, 8% vs controls, 2%; P = 0.001). All cases displayed a lower prevalence of infectious lesions than did controls, with the highest prevalence of immune lesions observed in pregnancies with both PE and SGA (PE + SGA, 18% vs PE, 8% vs SGA, 10% vs controls, 9%; P = 0.001). All fetoplacental Doppler parameters evaluated were associated with maternal‐side vascular lesions, mainly malperfusion (mean UtA‐PI: odds ratio (OR), 2.45 (95% CI, 1.51–3.97); UA‐PI: OR, 2.05 (95% CI, 1.02–4.47); MCA‐PI: OR, 2.75 (95% CI, 1.40–5.42); CPR: OR, 1.75 (95% CI, 1.04–2.95)). This association was evident mainly in the normotensive SGA group, being
non‐significant in controls or PE pregnancies without SGA. No significant associations were observed between fetoplacental Doppler parameters and other placental lesions in any of the study groups.
Conclusions
PE and SGA are associated with different patterns of placental histopathological lesions in accordance with the clinical manifestation of the placental disorder (maternal vs fetal). Fetoplacental Doppler findings show an association with placental malperfusion lesions on the maternal side, supporting the use of abnormal Doppler as a surrogate for placental insufficiency. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.
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6.
Premature placental aging in term small‐for‐gestational‐age and growth‐restricted fetuses
Paules, C.; Dantas, A. P.; Miranda, J. ...
Ultrasound in obstetrics & gynecology,
20/May , Volume:
53, Issue:
5
Journal Article
ABSTRACT
Objective
To perform a comprehensive assessment of the placental aging process in small term fetuses classified as being small‐for‐gestational age (SGA) or having fetal growth restriction ...
(FGR) through analysis of senescence and apoptosis markers.
Methods
This was a prospective nested case–control study of singleton pregnancies delivered at term, including 21 control pregnancies with normally grown fetuses and 36 with a small fetus classified as SGA (birth weight between the 3rd and 9th percentiles and normal fetoplacental Doppler; n = 18) or FGR (birth weight < 3rd percentile and/or abnormal cerebroplacental ratio and/or uterine artery Doppler; n = 18). Telomerase activity, telomere length (quantified by comparing the amount of amplification product for the telomere sequence (T) to that of a single copy of the gene 36B4 (S)) and RNA expression of senescence (Sirtuins 1, 3 and 6) and apoptosis (p53, p21, BAX and Caspases 3 and 9) markers (analyzed using the 2–ΔΔCt method) were determined in placental samples collected at birth and compared between the three groups.
Results
Compared to pregnancies with a normally grown fetus, both SGA and FGR pregnancies presented signs of accelerated placental aging, including lower telomerase activity (mean ± SD, 12.8 ± 6.6% in controls vs 7.98 ± 4.2% in SGA vs 7.79 ± 4.6% in FGR; P = 0.008), shorter telomeres (mean ± SD T/S ratio, 1.20 ± 0.6 in controls vs 1.08 ± 0.9 in SGA vs 0.66 ± 0.5 in FGR; P = 0.047) and reduced Sirtuin‐1 RNA expression (mean ± SD 2–ΔΔCt, 1.55 ± 0.8 in controls vs 0.91 ± 0.8 in SGA vs 0.63 ± 0.5 in FGR; P = 0.001) together with increased p53 RNA expression (median (interquartile range) 2–ΔΔCt, 1.07 (0.3–3.3) in controls vs 5.39 (0.6–15) in SGA vs 3.75 (0.9–7.8) in FGR; P = 0.040). FGR cases presented signs of apoptosis, with increased Caspase‐3 RNA levels (median (interquartile range) 2–ΔΔCt, 0.94 (0.7–1.7) in controls vs 3.98 (0.9–31) in FGR; P = 0.031) and Caspase‐9 RNA levels (median (interquartile range) 2–ΔΔCt, 1.21 (0.6–4.0) in controls vs 3.87 (1.5–9.0) in FGR; P = 0.037) compared with controls. In addition, Sirtuin‐1 RNA expression, telomerase activity, telomere length and Caspase‐3 activity showed significant linear trends across groups as severity of the condition increased.
Conclusions
Accelerated placental aging was observed in both clinical forms of late‐onset fetal smallness (SGA and FGR), supporting a common pathophysiology and challenging the concept of SGA fetuses being constitutionally small. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.
RESUMEN
Envejecimiento prematuro de la placenta en fetos pequeños para la edad gestacional y con restricción del crecimiento
Objetivo
Realizar una evaluación integral del proceso de envejecimiento de la placenta en fetos a término clasificados como pequeños para la edad gestacional (PEG) o con restricción del crecimiento fetal (RCF) mediante el análisis de los marcadores de senescencia y apoptosis.
Métodos
Este fue un estudio prospectivo de casos y controles anidados de embarazos únicos a término, que incluyó 21 embarazos de control con fetos de crecimiento normal y 36 con un feto clasificado como PEG (peso al nacer entre los percentiles 3o y 9o y Doppler fetoplacentario normal; n=18) o con RCF (peso al nacer menor del percentil 3o y/o relación cerebroplacentaria anómala y/o Doppler de la arteria uterina; n=18). La actividad de la telomerasa, la longitud de los telómeros (cuantificada comparando la cantidad de producto de amplificación para la secuencia de telómeros (T) con la de una sola copia del gen 36B4 (S)) y la expresión del ARN de la senescencia (Sirtuinas 1, 3 y 6) y los marcadores de apoptosis (p53, p21, BAX y Caspasas 3 y 9) (analizados usando el método 2–∆∆Ct) se determinaron en muestras de placenta obtenidas en el momento del nacimiento y se compararon entre los tres grupos.
Resultados
En comparación con los embarazos con un feto de crecimiento normal, tanto los embarazos PEG y con RCF presentaron signos de envejecimiento placentario acelerado, como una menor actividad de la telomerasa (media ± SD, 12,8 ± 6,6% en los controles frente a 7,98 ± 4,2% en PEG frente a 7,79 ± 4,6% en RCF; P=0,008), telómeros más cortos (media ± SD razón T/S, 1,20 ± 0,6 en los controles frente a 1,08 ± 0,9 en PEG frente a 0,66 ± 0,5 en RCF; P=0,047) y expresión reducida de la Sirtuina 1 en el ARN (media ± SD 2–∆∆Ct, 1,55 ± 0,8 en los controles frente a 0,91 ± 0,8 en PEG frente a 0,63 ± 0,5 en RCF; P=0,001), junto con una mayor expresión del p53 en el ARN (mediana (rango intercuartil) 2–∆∆Ct, 1,07 (0,3‐3,3) en los controles frente a 5,39 (0,6–15) en PEG frente a 3,75 (0,9–7,8) en RCF; P=0,040). Los casos de RCF presentaron signos de apoptosis, con un aumento de los niveles en ARN de la Caspasa 3 (mediana (rango intercuartil) 2–∆∆Ct, 0,94 (0,7–1,7) en los controles frente a 3,98 (0,9–31) en RCF; P=0,031) y Caspasa 9 (mediana (rango intercuartil) 2–∆∆Ct, 1,21 (0,6‐4,0) en los controles frente a 3,87 (1,5–9,0) en RCF; P=0,037) en comparación con los controles. Además, la expresión de la Sirtuina 1 en el ARN, la actividad de la telomerasa, la longitud de los telómeros y la actividad de la Caspasa 3 mostraron tendencias lineales significativas entre los grupos en función del aumento de la severidad de la anomalía.
Conclusiones
Se observó un envejecimiento acelerado de la placenta en ambas formas clínicas de tamaño pequeño del feto de inicio tardío (PEG y RCF), lo que apoya una fisiopatología común y pone en tela de juicio el concepto de que los fetos PEG son en pequeños por su propia condición.
摘要
足月小于胎龄儿和生长受限胎儿胎盘过早老化
目的
通过衰老和细胞凋亡标志物分析，对足月小于胎龄儿(SGA)或生长受限(FGR)胎儿的胎盘老化过程进行综合评估。
方法
这是一项对足月分娩的单胎妊娠进行的前瞻性巢式病例对照研究，研究纳入21例胎儿正常发育的对照组妊娠和36例小胎儿:SGA(出生体重介于3%和9%之间，胎儿胎盘多普勒正常；n=18)或FGR(出生体重<3%和/或脑胎盘比值异常和/或子宫动脉多普勒异常；n=18)。出生时采集胎盘标本，分别检测端粒酶活性、端粒长度(通过将端粒序列(T)的扩增产物数量与基因36B4(S)的单一拷贝扩增产物数量进行比较来量化)及衰老的RNA表达(Sirtuins 1、3、6)和细胞凋亡(p53、p21、BAX、Caspases 3、9)标志物(利用2–∆∆Ct法分析)，并在三组中进行比较。
结果
与正常发育的胎儿相比，SGA和FGR妊娠均表现出胎盘老化加速的迹象，包括降低的端粒酶活性(均数 ± 标准差，对照组12.8 ± 6.6% vs SGA组7.98 ± 4.2% vs FGR组7.79 ± 4.6%；P=0.008)、缩短的端粒(均数 ± 标准差 T/S 比值，对照组1.20 ± 0.6 vs SGA组1.08 ± 0.9 vs FGR组0.66 ± 0.5； P=0.047)及Sirtuin‐1 RNA表达减弱(均数 ± 标准差2–∆∆Ct；对照组1.55 ± 0.8 vs SGA组0.91 ± 0.8 vs FGR组0.63 ± 0.5；P=0.001)和P53 RNA表达增强(中位数(四分位数间距)2–∆∆Ct，对照组1.07(0.3–3.3) vs SGA组5.39(0.6–15)vs FGR组3.75(0.9–7.8)； P=0.040)。与对照相相比，FGR病例出现细胞凋亡迹象，并伴随caspase‐3 RNA水平升高(中位数(四分位数间距)2–∆∆Ct,，对照组0.94(0.7–1.7)vs FGR组3.98(0.9–31)；P=0.031)及caspase‐9 RNA水平升高(中位数(四分位数间距)2–∆∆Ct，对照组1.21(0.6–4.0)vs FGR组3.87(1.5–9.0)；P=0.037)。此外，随着病情的加重，Sirtuin‐1 RNA的表达、端粒酶活性、端粒长度和Caspase‐3活性在各组间呈明显的线性趋势。
结论
两种临床形式的迟发性胎小症(SGA和FGR)均出现胎盘加速老化的现象，支持共同的病理生理机制，并对SGA胎儿天生小的概念提出质疑。
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Fetal neurosonography detects differences in cortical development and corpus callosum in late‐onset small fetuses
Paules, C.; Miranda, J.; Policiano, C. ...
Ultrasound in obstetrics & gynecology,
July 2021, 2021-07-00, 20210701, Volume:
58, Issue:
1
Journal Article
ABSTRACT
Objective
To explore whether neurosonography can detect differences in cortical development and corpus callosal length in late‐onset small fetuses subclassified into small‐for‐gestational ...
age (SGA) or growth restricted (FGR).
Methods
This was a prospective cohort study in singleton pregnancies, including normally grown fetuses (birth weight between the 10th and 90th centiles) and late‐onset small fetuses (estimated fetal weight < 10th centile, diagnosed after 32 weeks of gestation and confirmed by birth weight < 10th centile). Small fetuses were subclassified into SGA (birth weight between the 3rd and 9th centiles and normal fetoplacental Doppler) and FGR (birth weight < 3rd centile and/or abnormal cerebroplacental ratio and/or abnormal uterine artery Doppler). Neurosonography was performed at 33 ± 1 weeks of gestation to assess the depth of the insula, Sylvian fissure and parieto‐occipital sulcus in the axial views and corpus callosal length in the midsagittal plane. Measurements were performed offline using Alma Workstation software and were adjusted by biparietal diameter or cephalic index. Linear regression analysis was used to assess the association between the neurosonographic variables and study group, adjusting for confounding factors such as gender, gestational age at neurosonography, nulliparity and pre‐eclampsia.
Results
In total, 318 fetuses were included, of which 97 were normally grown and 221 were late‐onset small fetuses that were further subdivided into late‐onset SGA (n = 67) or late‐onset FGR (n = 154). Compared to controls, both SGA and FGR cases showed significantly increased insular depth adjusted for biparietal diameter (median (interquartile range), controls 0.329 (0.312–0.342) vs SGA 0.339 (0.321–0.347) vs FGR 0.336 (0.325–0.349); P = 0.006). A linear tendency to reduced Sylvian fissure depth adjusted for biparietal diameter was also observed across the study groups (mean ± SD, controls 0.148 ± 0.021 vs SGA 0.142 ± 0.025 vs FGR 0.139 ± 0.022; P = 0.003). However, differences were significant only between the FGR and control groups. Corpus callosal length adjusted for cephalic index was significantly reduced in FGR cases compared with both controls and SGA cases, while there was no difference between SGA cases and controls (median (interquartile range), controls 0.500 (0.478–0.531) vs SGA 0.502 (0.487–0.526) vs FGR 0.475 (0.447–0.508); P = 0.005). No differences were found in parieto‐occipital sulcus depth between the three study groups.
Conclusion
Neurosonography seems to be a sensitive tool to detect subtle structural differences in brain development in late‐onset small fetuses. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.
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