Fetal neurosonography at 31-35 weeks reveals altered cortical development in pre-eclampsia with and without small-for-gestational-age fetus.

OBJECTIVE: To explore the pattern of fetal cortical development in pregnancies complicated by pre-eclampsia (PE), with and without a small-for-gestational-age (SGA) fetus, compared to uncomplicated pregnancies. METHODS: This was a prospective observational study including singleton pregnancies complicated by normotensive SGA (birth weight < 10th centile) (n = 77), PE with an appropriate-for-gestational-age (AGA) fetus (n = 76) or PE with a SGA fetus (n = 67), and 128 uncomplicated pregnancies (normotensive AGA) matched by gestational age at ultrasound. All pregnancies underwent detailed neurosonography, using a transabdominal and transvaginal approach, at 31-35 weeks' gestation to assess the depth of the insula, Sylvian fissure, parieto-occipital sulcus, cingulate sulcus and calcarine sulcus. All measurements were adjusted for biparietal diameter (BPD). In addition, a grading score of cortical development was assigned to each brain structure, ranging from Grade 0 (no development) to Grade 5 (maximum development). Univariate and multiple regression analyses were conducted. RESULTS: Similar to findings in previous studies, normotensive pregnancies with a SGA fetus showed significant differences in cortical development compared with controls, with reduced Sylvian fissure depth adjusted for BPD (14.5 ± 2.4 vs 16.6 ± 2.3; P < 0.001) and increased insula depth adjusted for BPD (33.2 ± 2.0 vs 31.8 ± 2.0; P < 0.001). Interestingly, a similar cortical development pattern was observed in PE pregnancies with a SGA fetus and in PE pregnancies with an AGA fetus, manifested by reduced Sylvian fissure depth adjusted for BPD (14.2 ± 2.3 and 14.3 ± 2.3 vs 16.6 ± 2.3; P < 0.001 for both) and greater insula depth adjusted for BPD (33.2 ± 2.1 and 32.8 ± 1.7 vs 31.8 ± 2.0; P < 0.001 for both) compared with controls. No significant differences were observed in parieto-occipital, cingulate sulcus or calcarine sulcus depth across the study groups. The Sylvian fissure was scored as Grade 4 in significantly more (93.2% vs 59.5%) and as Grade 5 in significantly fewer (2.7% vs 37.3%) PE pregnancies with an AGA fetus compared with controls (P < 0.05 for both). These differences remained significant even after statistical adjustment for potential confounders, including ethnicity, low socioeconomic status, nulliparity, chronic hypertension, pregestational diabetes, assisted reproductive technologies, smoking and fetal gender, with the application of Benjamini-Hochberg procedure for multiple comparisons. CONCLUSIONS: PE with or without SGA is associated with a differential fetal cortical development pattern which is similar to that described previously in small fetuses. Future research is warranted to elucidate better the mechanism(s) underlying these changes. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Clinical phenotypes for risk stratification in small-for-gestational-age fetuses.

OBJECTIVE: To evaluate whether clinical phenotypes of small-for-gestational-age (SGA) fetuses can be identified and used for adverse perinatal outcome risk stratification to facilitate clinical decision-making. METHODS: This was a multicenter observational cohort study conducted in two tertiary care university hospitals. SGA fetuses were classified according to maternal, fetal and placental conditions using a two-step cluster algorithm, in which fetuses with more than one condition were assigned to the cluster associated with the highest mortality risk. Delivery and perinatal outcomes were compared using chi-square test among SGA clusters, and the associations between outcomes and each cluster were evaluated by calculating odds ratios (OR), adjusted for gestational age. RESULTS: The study included 17 631 consecutive singleton pregnancies, of which 1274 (7.2%) were defined as SGA at birth according to INTERGROWTH-21st standards. Nine SGA clinical phenotypes were identified using a predefined conceptual framework. All delivery and perinatal outcomes analyzed were significantly different among the nine phenotypes. The whole SGA cohort had a three-times higher risk of perinatal mortality compared with non-SGA fetuses (1.4% vs 0.4%; P < 0.001). SGA clinical phenotypes exhibited three patterns of perinatal mortality risk: the highest risk was associated with congenital anomaly (8.3%; OR, 17.17 (95% CI, 2.17-136.12)) and second- or third-trimester hemorrhage (8.3%; OR, 9.94 (95% CI, 1.23-80.02)) clusters; medium risk was associated with gestational diabetes (3.8%; OR, 9.59 (95% CI, 1.27-72.57)), preterm birth (3.2%; OR, 4.65 (95% CI, 0.62-35.01)) and intrauterine growth restriction (3.1%; OR, 5.93 (95% CI, 3.21-10.95)) clusters; and the lowest risk was associated with the remaining clusters. Perinatal mortality rate did not differ between SGA fetuses without other clinical conditions (54.1% of SGA fetuses) and appropriate-for-gestational-age fetuses (0.1% vs 0.4%; OR, 0.41 (95% CI, 0.06-2.94); P = 0.27). SGA combined with other obstetric pathologies increased significantly the risk of perinatal mortality, as demonstrated by the increased odds of perinatal death in SGA cases with gestational diabetes compared to non-SGA cases with the same condition (OR, 24.40 (95% CI, 1.31-453.91)). CONCLUSIONS: We identified nine SGA clinical phenotypes associated with different patterns of risk for adverse perinatal outcome. Our findings suggest that considering clinical characteristics in addition to ultrasound findings could improve risk stratification and decision-making for management of SGA fetuses. Future clinical trials investigating management of fetuses with SGA should take into account clinical information in addition to Doppler parameters and estimated fetal weight. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Fetal neurosonography detects differences in cortical development and corpus callosum in late-onset small fetuses.

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.

SARS-CoV-2 immunochromatographic IgM/IgG rapid test in pregnancy: A false friend?

BACKGROUND: An increasing body of evidence has revealed that SARS-CoV-2 infection in pregnant women could increase the risk of adverse maternal and fetal outcomes. Careful monitoring of pregnancies with COVID-19 and measures to prevent neonatal infection are warranted. Therefore, rapid antibody tests have been suggested as an efficient screening tool during pregnancy. CASES: We analysed the clinical performance during pregnancy of a rapid, lateral-flow immunochromatographic assay for qualitative detection of SARS-CoV-2 IgG/IgM antibodies. We performed a universal screening including 169 patients during their last trimester of pregnancy. We present a series of 14 patients with positive SARS-CoV-2 immunochromatographic assay rapid test result. Immunochromatographic assay results were always confirmed by chemiluminescent microparticle immunoassays for quantitative detection of SARS-CoV-2 IgG and IgM+IgA antibodies as the gold standard. We observed a positive predictive value of 50% and a false positive rate of 50% in pregnant women, involving a significantly lower diagnostic performance than reported in non-pregnant patients. DISCUSSION: Our data suggest that although immunochromatographic assay rapid tests may be a fast and profitable screening tool for SARS-CoV-2 infection, they may have a high false positive rate and low positive predictive value in pregnant women. Therefore, immunochromatographic assay for qualitative detection of SARS-CoV-2 IgG/IgM antibodies must be verified by other test in pregnant patients.

Distinctive patterns of placental lesions in pre-eclampsia vs small-for-gestational age and their association with fetoplacental Doppler.

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.

Premature placental aging in term small-for-gestational-age and growth-restricted fetuses.

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.

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.

Altered gene expression in human placenta after suspected preterm labour.

INTRODUCTION: Suspected preterm labour occurs in around 9% of pregnancies. However, almost two-thirds of women admitted for threatened preterm labour ultimately deliver at term and are considered risk-free for fetal development. METHODS: We examined placental and umbilical cord blood samples from preterm or term deliveries after threatened preterm labour as well as term deliveries without threatened preterm labour. We quantitatively analysed the mRNA expression of inflammatory markers (IL6, IFNγ, and TNFα) and modulators of angiogenesis (FGF2, PGF, VEGFA, VEGFB, and VEGFR1). RESULTS: A total of 132 deliveries were analysed. Preterm delivery and term delivery after suspected preterm labour groups showed similar increases in TNFα expression compared with the term delivery control group in umbilical cord blood samples. Placental samples from preterm and term deliveries after suspected preterm labour exhibited significantly increased expression of TNFα and IL6 and decreased expression of IFNγ. Suspected preterm labour was also associated with altered expression of angiogenic factors, although not all differences reached statistical significance. DISCUSSION: We found gene expression patterns indicative of inflammation in human placentas after suspected preterm labour regardless of whether the deliveries occurred preterm or at term. Similarly, a trend towards altered expression of angiogeneic factors was not limited to preterm birth. These findings suggest that the biological mechanisms underlying threatened preterm labour affect pregnancies independently of gestational age at birth.

Selection of medical technology students in a hospital-based program.

This article describes a process for selection of medical technology students into a hospital-based program. The process uses a weighting method for selection criteria and numerical ranking of applicants by a point system. Tools developed by the selection committee are discussed: Pre-Interview Rating Form, Interview Rating Form, Interview Rating Form Score Sheet, and Interview Questions Sets. The structured selection interview is described in detail. The process might easily be adapted to other hospital-based allied health programs.