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Preeclampsia (PE) is characterized by de novo hypertension (HTN) and is often associated with intrauterine growth restriction (IUGR). Hallmarks of PE are placental ischemia, decreased nitric oxide (NO) bioavailability, oxidative stress (OS), and organ damage in the kidneys and brain. This study aims to characterize a new model of PE using pregnant IUGR rats from hypertensive placental ischemic dams. It is hypothesized that pregnant IUGR rats from hypertensive placental ischemic dams will have elevated blood pressure (BP), OS, and organ damage. In this study, pregnant rats are divided into two groups: normal pregnant (NP) and hypertensive placental ischemic dams (RUPP). Offspring from NP and RUPP dams were mated at 10 weeks of age to generate pregnant IUGR (IUGR Preg) and pregnant control (CON Preg) rats. BP and other markers of PE were evaluated during late gestation. Pregnant IUGR rats had elevated BP and systemic OS. The maternal body weight of pregnant IUGR rats and their pups' weights were decreased, while the brains were enlarged with elevated OS. In summary, pregnant IUGR rats, born from hypertensive placental ischemic dams, have HTN and increased systemic and brain OS, with larger brain sizes and smaller pups. Furthermore, this study shows that pregnant IUGR rats exhibit a preeclamptic-like phenotype, suggesting a new epigenetic model of PE., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Objectives: In a cohort of patients with estimated fetal weights (EFWs) <10th centile, we aimed 1) to compare the prevalence of abnormalities of fetal 4-chamber view (4CV) cardiac size, shape, and ventricular contractility in fetal growth restricted (FGR) and small-for-gestational-age (SGA) fetuses and 2) to compare umbilical vein flow (UVF) measurements to standard Doppler surveillance in predicting abnormalities of cardiac function., Methods: Prospective observational cohort study of fetuses with EFW <10th percentile. Measurements of size and shape used were 4CV transverse width, 4CV cardiac area, 4CV global sphericity index, and right-to-left ventricular mid-chamber width ratio. Variables of contractility used were fractional shortening change at the mid-ventricle chamber, global longitudinal strain, fractional area change, and left ventricular cardiac output. The UVF and standard Doppler surveillance including umbilical artery (UA), middle cerebral artery, and cerebroplacental ratio (CPR) were collected. Control data were from previously published studies., Results: A total of 95 fetuses with EFWs <10th centile were included in the study. The rates of abnormalities of cardiac size and shape and ventricular contractility were all significantly elevated compared with normally grown control fetuses but similar between FGR and SGA fetuses. In a subset of 76 patients with UVF data, evaluation UVF identified more patients with any abnormality of contractility compared with UA (37.9 vs 17.2%, P = .02)., Conclusions: The addition of UVF doubled the detection rate of ventricular contractility abnormalities. The addition of UVF should be considered in the surveillance of FGR and SGA fetuses to further stratify the severity of hypoxemia and to identify those at greater risk for future cardiovascular dysfunction., (© 2024 American Institute of Ultrasound in Medicine.)

Background: Intrauterine fetal growth restriction (IUGR) affects up to 10% of all pregnancies. Severe IUGR is associated with impaired kidney development, reduced nephron endowment, and chronic kidney disease later in life. Currently, no early predictive biomarker exists for detecting altered kidney function in neonates with IUGR. Because nephrons produce key enzymes for the metabolism of arginine and methylarginine components, we quantified and compared the concentrations of arginine and methylarginine metabolites between IUGR and non-IUGR neonates to identify potential biomarkers for the early detection of altered kidney function in IUGR neonates., Methods: Seventy-one IUGR and 123 non IUGR neonates were examined. Serum and Urine samples were obtained between 30 h and 5 days of life and between 5 and 70 days of life. Serum concentrations of creatinine, urea, symmetric and asymmetric-dimethylarginine metabolites (SDGV, SDMA, ADGV, and ADMA), guanidino-2-oxo-caproic acid (GOCA), citrulline, homocitrulline, arginine, and homoarginine were quantified using LC-MS/MS and standard clinical laboratory methods. Datasets were compared by Mann-Whitney--Wilcoxon or Chi-square tests for continuous and discrete parameters. P values were corrected for multiple comparisons using the Bonferroni method., Results: After Bonferroni correction, we found that serum creatinine, urea, SDGV, ADGV, and GOCA levels were significantly lower in neonates with IUGR. Consequently, the ratios of SDGV/SDMA, ADGV/ADMA, and GOCA/homoarginine were significantly lower in IUGR neonates., Conclusion: Our study suggests that arginine and methylarginine are possible early biomarkers for detecting altered kidney function in IUGR neonates., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Fetal growth restriction (FGR) is associated with cardiovascular and respiratory complications after birth and beyond. Despite research showing a range of neurological changes following FGR, little is known about how FGR affects the brainstem cardiorespiratory control centres. The primary neurons that release serotonin reside in the brainstem cardiorespiratory control centres and may be affected by FGR. At two time points in the last trimester of sheep brain development, 110 and 127 days of gestation (0.74 and 0.86 of gestation), we assessed histopathological alterations in the brainstem cardiorespiratory control centres of the pons and medulla in early-onset FGR versus control fetal sheep. The FGR cohort were hypoxaemic and asymmetrically growth restricted. Compared to the controls, the brainstem of FGR fetuses exhibited signs of neuropathology, including elevated cell death and reduced cell proliferation, grey and white matter deficits, and evidence of oxidative stress and neuroinflammation. FGR brainstem pathology was predominantly observed in the medullary raphé nuclei, hypoglossal nucleus, nucleus ambiguous, solitary tract and nucleus of the solitary tract. The FGR groups showed imbalanced brainstem serotonin and serotonin 1A receptor abundance in the medullary raphé nuclei, despite evidence of increased serotonin staining within vascular regions of placentomes collected from FGR fetuses. Our findings demonstrate both early and adaptive brainstem neuropathology in response to placental insufficiency. KEY POINTS: Early-onset fetal growth restriction (FGR) was induced in fetal sheep, resulting in chronic fetal hypoxaemia. Growth-restricted fetuses exhibit persistent neuropathology in brainstem nuclei, characterised by disrupted cell proliferation and reduced neuronal cell number within critical centres responsible for the regulation of cardiovascular and respiratory functions. Elevated brainstem inflammation and oxidative stress suggest potential mechanisms contributing to the observed neuropathological changes. Both placental and brainstem levels of 5-HT were found to be impaired following FGR., (© 2023 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Background: The great obstetrical syndromes of fetal growth restriction and hypertensive disorders of pregnancy can occur individually or be interrelated. Placental pathologic findings often overlap between these conditions, regardless of whether 1 or both diagnoses are present. Quantification of placental villous structures in each of these settings may identify distinct differences in developmental pathways., Objective: This study aimed to determine how the quantity and surface area of placental villi and vessels differ between severe, early-onset fetal growth restriction with absent or reversed umbilical artery Doppler indices and hypertensive disorders of pregnancy or the 2 conditions combined among subjects with disease severity that warrant early preterm delivery. We hypothesized that the trajectories of placental morphogenesis diverge after a common initiating insult of deep defective placentation. Specifically, we postulated that only villi are affected in pregnancy-related hypertension, whereas both villous and vascular structures are proportionally diminished in severe fetal growth restriction with no additional effect when hypertension is concomitantly present., Study Design: In this retrospective cohort study, paraffin-embedded placental tissue was obtained from 4 groups, namely (1) patients with severe fetal growth restriction with absent or reversed umbilical artery end-diastolic velocities and hypertensive disorders of pregnancy, (2) patients with severe fetal growth restriction with absent or reversed umbilical artery Doppler indices and no hypertension, (3) gestational age-matched, appropriately grown pregnancies with hypertensive disease, and (4) gestational age-matched, appropriately grown pregnancies without hypertension. Dual immunohistochemistry for cytokeratin-7 (trophoblast) and CD34 (endothelial cells) was performed, followed by artificial intelligence-driven morphometric analyses. The number of villi, total villous area, number of fetoplacental vessels, and total vascular area across villi within a uniform region of interest were quantified. Quantitative analyses of placental structures were modeled using linear regression., Results: Placentas from pregnancies complicated by hypertensive disorders of pregnancy exhibited significantly fewer stem villi (-282 stem villi; 95% confidence interval, -467 to -98; P<.01), a smaller stem villous area (-4.3 mm 2 ; 95% confidence interval, -7.3 to -1.2; P<.01), and fewer stem villous vessels (-4967 stem villous vessels; 95% confidence interval, -8501 to -1433; P<.01) with no difference in the total vascular area. In contrast, placental abnormalities in cases with severe growth restriction were limited to terminal villi with global decreases in the number of villi (-873 terminal villi; 95% confidence interval, -1501 to -246; P<.01), the villous area (-1.5 mm 2 ; 95% confidence interval, -2.7 to -0.4; P<.01), the number of blood vessels (-5165 terminal villous vessels; 95% confidence interval, -8201 to -2128; P<.01), and the vascular area (-0.6 mm 2 ; 95% confidence interval, -1.1 to -0.1; P=.02). The combination of hypertension and growth restriction had no additional effect beyond the individual impact of each state., Conclusion: Pregnancies complicated by hypertensive disorders of pregnancy exhibited defects in the stem villi only, whereas placental abnormalities in severely growth restricted pregnancies with absent or reversed umbilical artery end-diastolic velocities were limited to the terminal villi. There were no significant statistical interactions in the combination of growth restriction and hypertension, suggesting that distinct pathophysiological pathways downstream of the initial insult of defective placentation are involved in each entity and do not synergize to lead to more severe pathologic consequences. Delineating mechanisms that underly the divergence in placental development after a common inciting event of defective deep placentation may shed light on new targets for prevention or treatment., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Routine Doppler study is a common tool for early diagnosis of Fetal Growth Restriction (FGR) and Small for Gestational Age (SGA) patients. It aimed to determine the role of the Foramen Ovale Pulsatility Index (FOPI) study beside routine Doppler study among patients with FGR and SGA fetuses., Methods: This prospective study was conducted on 35 FGR, 32 SGA, and 33 Appropriate for Gestational Age (AGA) fetuses. Demographic data, amniotic fluid index, neonatal outcome, and Doppler velocimetry, including Umbilical Artery Pulsatility Index (UMAPI), Uterine Artery Pulsatility Index (UTAPI), Middle Cerebral Artery Pulsatility Index (MCAPI), Ductus Venosus Pulsatility Index (DVPI), and FOPI were documented. Kolmogorov-Smirnov normality test, one-way ANOVA, Mann-Whitney U, Kruskal-Wallis, non-parametric pairwise comparisons adjusted for Bonferroni correction, Pearson correlation test, Chi square, Fisher's exact test, and Receiver Operating Characteristic Curve (ROC) analysis with Youden's Index (sensitivity+specificity-1) to estimate cut-off point were used to analyze the data at significance level <0.05 for all tests., Results: FOPI cut-off points were 2.24 (sensitivity=77%, specificity=94%) and 1.15 (sensitivity=90%, specificity=20%) to predict FGR and SGA, respectively. FOPI showed a positive correlation with UMAPI and UTAPI (r=0.52 and r=0.30, P<0.001 and P=0.006, respectively), but not with MCAPI and DVPI (r=0.08 and r=0.12, P=0.50 and P=0.30, respectively). Besides, UMAPI, UTAPI, and FOPI were altered among patients with stages I and II FGR. Umbilical cord potential hydrogen (umbilical cord pH), 1- and 5-min Apgar score significantly increased by Birth weight centile; however, UMAPI, FOPI, and UTAPI significantly decreased., Conclusion: UMAPI is recommended to predict short-term neonatal morbidities and demonstrate the early or late onset FGR. Besides, FOPI is suggested as the first-line Doppler study to detect abnormal growth velocity. More studies are warranted, especially considering long-term neonatal morbidities., Competing Interests: None declared., (Copyright: © Iranian Journal of Medical Sciences.)

Purpose: We aimed to evaluate several quantitative methods to describe the diastolic notch (DN) and compare their performance in the prediction of fetal growth restriction., Materials and Methods: Patients who underwent a placental scan at 16-26 weeks of gestation and delivered between Jan 2016 and Dec 2020 were included. The uterine artery pulsatility index was measured for all of the patients. In patients with a DN, it was quantified using the notch index and notch depth index. Odds ratios for small for gestational age neonates (defined as birth weight <10th and <5th percentile) were calculated. Predictive values of uterine artery pulsatility, notch, and notch depth index for fetal growth restriction were calculated., Results: Overall, 514 patients were included, with 69 (13.4%) of them delivering a small for gestational age neonate (birth weight<10th percentile). Of these, 20 (20.9%) had a mean uterine artery pulsatility index >95th percentile, 13 (18.8%) had a unilateral notch, and 11 (15.9%) had a bilateral notch. 16 patients (23.2%) had both a high uterine artery pulsatility index (>95th percentile) and a diastolic notch. Comparison of the performance between uterine artery pulsatility, notch, and notch depth index using receiver operating characteristic curves to predict fetal growth restriction <10th percentile found area under the curve values of 0.659, 0.679, and 0.704, respectively, with overlapping confidence intervals., Conclusion: Quantifying the diastolic notch at 16-26 weeks of gestation did not provide any added benefit in terms of prediction of neonatal birth weight below the 10th or 5th percentile for gestational age, compared with uterine artery pulsatility index., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Objective: To compare maternal vascular indices and hemodynamic parameters at 35-37 weeks' gestation in pregnancies complicated by delivery of a small-for-gestational-age (SGA) or growth-restricted (FGR) neonate., Methods: This was a prospective observational study of women with a singleton pregnancy attending for a routine hospital visit at 35 + 0 to 36 + 6 weeks' gestation. The visit included recording of maternal demographic characteristics, medical history, vascular indices and hemodynamic parameters, which were obtained using a non-invasive operator-independent device and included pulse-wave velocity, augmentation index, cardiac output, stroke volume, central systolic and diastolic blood pressure, total peripheral resistance and heart rate. Women with hypertensive disorders of pregnancy were excluded. SGA was diagnosed if birth weight was < 10 th percentile. FGR was diagnosed if, in addition to birth weight < 10 th percentile, at the 35-37-week scan, uterine artery or umbilical artery pulsatility index (PI) was > 95 th percentile or fetal middle cerebral artery PI was < 5 th percentile., Results: Among the 6413 women included in the study, there were 605 (9.4%) cases of SGA, 133 (2.1%) cases of FGR and 5675 (88.5%) cases that were unaffected by SGA or FGR. Women with SGA or FGR, compared to unaffected pregnancies, had increased peripheral vascular resistance and reduced cardiac output. Central systolic and diastolic blood pressure were increased in the FGR group compared with the unaffected group. Aortic stiffness, as assessed by pulse-wave velocity, and augmentation index did not differ between affected and unaffected pregnancies. In the FGR group, compared with the SGA group, central systolic and diastolic blood pressure were higher, whereas heart rate was lower., Conclusions: SGA and FGR pregnancies exhibit deranged maternal hemodynamic responses compared with unaffected pregnancies. Pregnancies with FGR have higher central blood pressure compared to those with SGA, but it remains unclear whether these differences are driven by the size of the fetus or pathological fetal growth. © 2024 International Society of Ultrasound in Obstetrics and Gynecology., (© 2024 International Society of Ultrasound in Obstetrics and Gynecology.)

Purpose: Fetal growth restriction (FGR) is a common pregnancy complication that can be associated with several adverse perinatal outcomes. One of these negative outcomes is ductus arteriosus, especially in preterm babies. In this study, intrauterine heart function and ductus diameter were evaluated in babies with FGR., Methods: Thirty-seven fetuses with FGR were compared with 37 normal-weight fetuses at the same gestational week. In our study, ventricular diameters, aorta, pulmonary artery, ductus arteriosus (DA), aortic arch diameter, and flow traces were examined. In addition, the aorta and aortic isthmus diameters were proportioned to the ductus diameter, and the left ventricular myocardial performance index (MPI) [(ICT + IRT)/ET] was evaluated., Results: There was no difference in DA diameters between the patient and control groups. The intragroup comparison of the cases with early- and late-onset FGR revealed no statistically significant difference between DA diameters. However, the ratios of the aortic annulus diameter/ductus diameter (AOD/DAD) and aortic isthmus diameter/ductus diameter (AID/DAD) were significantly lower in early-onset FGR because the diameter of the DA was greater. In addition, the mod-MPI values were higher in the patient group., Conclusions: In our study, although the ductal diameters did not change significantly in the patient group, the ductal diameter was greater in the early-onset intrauterine growth restriction (FGR) group compared with other cardiac measurements. The mod-MPI value, a cardiac function indicator, was higher in fetuses with FGR. These findings may be useful for evaluating postnatal cardiac functions in FGR., (© 2024 Wiley Periodicals LLC.)

The study conducted retrospective analysis design, aiming to explore the use of Microvascular Imaging Technique (MVFI) to assess fetal cerebral microcirculation and analyze the relationship between Microvascular Index (MVI) and fetal growth and development. 100 pregnant women who met the criteria for fetal growth restriction (FGR) provided in the Expert Consensus on Fetal Growth Restriction (2019 Edition) and underwent routine prenatal examinations at the Obstetrics and Gynecology Department of Peking University Third Hospital from January 2021 to June 2023 were selected as the study subjects. A normal fetus with a fetal weight less than 10 % can be classified as FGR, Pregnant women with fetal umbilical artery (UA) systolic and diastolic (S/D) values ≥3 were included in the observation group, while 200 pregnant women with normal fetuses were selected as the control group during the same period. The fetuses' change in both groups were measured using color Doppler ultrasound, including bi-parietal diameter (BPD), head circumference (HC), abdominal circumference (AC), and femur length (FL). The cerebral microcirculation of the fetuses in both groups was evaluated using MVFI, and the MVI values were compared. The clinical characteristics of FGR fetuses with umbilical artery S/D ratio ≥ 3 were summarized, and the correlation between fetal cerebral microvascular status and fetal growth and development was analyzed using Pearson correlation analysis. The outcomes told that the BPD, HC, AC, and FL values of the fetuses in the control group were lower the other's value (P < 0.05), and the MVI and peak systolic velocity of the middle cerebral artery (MCA-PSV) values were also lower in the control group (P < 0.05). Pearson correlation analysis revealed a positive correlation between fetal growth and development and MVI and MCA-PSV values in FGR fetuses. In conclusion, MVFI can monitor and quantitatively analyze fetal intracranial microcirculation, visualize slow blood flow in microvascular structures, and this study provides preliminary evidence of the close relationship between fetal cerebral microcirculation and intrauterine growth and development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Dexamethasone is frequently prescribed for preterm infants to wean from respiratory support and/or to facilitate extubation. This pre-/postintervention prospective study ascertained the impact on clinical (respiratory support) and echocardiographic parameters after dexamethasone therapy in preterm fetal growth restriction (FGR) infants compared with appropriate for gestational age (AGA) infants. Echocardiography was performed within 24 h before the start and after completion of 10-day therapy. Parameters assessed included those reflecting pulmonary vascular resistance and right ventricular output. Seventeen FGR infants (birth gestation and birth weight, 25.2 ± 1.1 wk and 497 ± 92 g, respectively) were compared with 22 AGA infants (gestation and birth weight, 24.5 ± 0.8 and 663 ± 100 g, respectively). Baseline respiratory severity score (mean airway pressure × fractional inspired oxygen) was comparable between the groups, (median [interquartile range] FGR, 10 [6, 13] vs. AGA, 8 ± 2.8, P = 0.08). Pre-dexamethasone parameters of pulmonary vascular resistance (FGR, 0.19 ± 0.03 vs. AGA, 0.2 ± 0.03, P = 0.16) and right ventricular output (FGR, 171 ± 20 vs. 174 ± 17 mL/kg/min, P = 0.6) were statistically comparable. At post-dexamethasone assessments, the decrease in the respiratory severity score was significantly greater in AGA infants (median [interquartile range] FGR, 10 [6, 13] to 9 [2.6, 13.5], P = 0.009 vs. AGA, 8 ± 2.8 to 3 ± 1, P < 0.0001). Improvement in measures of pulmonary vascular resistance (ratio of time to peak velocity to right ventricular ejection time) was greater in AGA infants (FGR, 0.19 ± 0.03 to 0.2 ± 0.03, P = 0.13 vs. AGA 0.2 ± 0.03 to 0.25 ± 0.03, P < 0.0001). The improvement in right ventricular output was significantly greater in AGA infants (171 ± 20 to 190 ± 21, P = 0.014 vs. 174 ± 17 to 203 ± 22, P < 0.0001). This highlights differential cardiorespiratory responsiveness to dexamethasone in extremely preterm FGR infants, which may reflect the in utero maladaptive state. NEW & NOTEWORTHY Dexamethasone (DEX) is frequently used in preterm infants dependent on ventilator support. Differences in vascular structure and function that may have developed prenatally arising from the chronic intrauterine hypoxemia in FGR infants may adversely affect responsiveness. The clinical efficacy of DEX was significantly less in FGR (birth weight < 10th centile) infants, compared with appropriate for gestational age (AGA) infants. Echocardiography showed significantly less improvement in pulmonary vascular resistance in FGR, compared with AGA infants.

Purpose: Fetal cardiotocography is the most common method to assess fetal well-being during labor. Nevertheless, its predictive ability for acidemia is limited, both in low-risk and high-risk pregnancies (Nelson et al. in N Engl J Med 334: 613-9, 1996; Rinciples P et al. in Health and Human Development Workshop Report on Electronic Fetal Monitoring : Update on Definitions. no. 2007, 510-515, 2008), especially in high-risk pregnancies, such as those complicated by growth restriction. In this study we aim examine the association between deceleration and acceleration areas and other measure of fetal heart rate in intrapartum fetal monitoring and neonatal arterial cord blood pH in pregnancies complicated by growth restriction., Materials and Methods: A retrospective cohort study of 100 deliveries complicated by growth restriction, delivered during 2018, was conducted. Known major fetal anomalies, non-vertex presentation and elective cesarean deliveries were excluded. Total deceleration and acceleration areas were calculated as the sum of the areas within the deceleration and acceleration, respectively., Results: In deliveries complicated by growth restriction, cord blood pH is significantly associated with total deceleration area (p = 0.05) and correlates with cumulative duration of the decelerations (Spearman's rank -0.363, p < 0.05), and total acceleration area (-0.358, p < 0.05). By comparing the cord blood pH in deliveries with a total deceleration area that was above and below the median total deceleration area, we demonstrated a significant difference between the categories., Conclusions: Cord blood pH significantly correlates with total deceleration area and other fetal monitoring characteristics in neonates with growth restriction. Future studies using real-time, machine-learning based techniques of fetal heart rate monitoring, may provide population specific threshold values that will support bedside clinical decision making and perhaps achieve better outcomes., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Intrauterine growth restriction (IUGR) affects a large proportion of infants, particularly in underdeveloped countries. Among the main causes of IUGR, maternal endocrine-metabolic dysfunction is highlighted, either due to its high incidence or due to the severity of the immediate and mediated changes that these dysfunctions cause in the fetus and the mother. Although the effects of endocrine and metabolic disorders have been widely researched, there are still no reviews that bring together and summarize the effects of these conditions on bone development in cases of IUGR. Therefore, the present literature review was conducted with the aim of discussing bone changes observed in fetuses with IUGR caused by maternal endocrine-metabolic dysfunction. The main endocrine dysfunctions that occur with IUGR include maternal hyperthyroidism, hypothyroidism, and hypoparathyroidism. Diabetes mellitus, hypertensive disorders, and obesity are the most important maternal metabolic dysfunctions that compromise fetal growth. The bone changes reported in the fetus are, for the most part, due to damage to cell proliferation and differentiation, as well as failures in the synthesis and mineralization of the extracellular matrix, which results in shortening and fragility of the bones. Some maternal dysfunctions, such as hyperthyroidism, have been widely studied, whereas conditions such as hypoparathyroidism and gestational hypertensive disorders require further study regarding the mechanisms underlying the development of bone changes. Similarly, there is a gap in the literature regarding changes related to intramembranous ossification, as most published articles only describe changes in endochondral bone formation associated with IUGR. Furthermore, there is a need for more research aimed at elucidating the late postnatal changes that occur in the skeletons of individuals affected by IUGR and their possible relationships with adult diseases, such as osteoarthritis and osteoporosis., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: To evaluate cardiac structural and functional changes in neonates with fetal growth restriction (FGR) compared to appropriate-for-gestational-age (AGA) neonates using conventional echocardiography, tissue Doppler imaging (TDI), and speckle tracking echocardiography., Method: This case-control study included 85 FGR neonates and 75 non-FGR, weight adequate for gestational age neonates. Among these, 37 were symmetric FGR and 48 were asymmetric FGR. All the biophysical profiles of these newborns were assessed. An echocardiographic test was performed to evaluate cardiac dimension, Left ventricular ejection fraction (LV EF), Mitral valve Doppler flow velocities, myocardial performance index, tissue annular velocities, and LV global longitudinal strain (GLS)., Results: Although LVEF was found to be within the normal range, mean EF was reduced among neonates with FGR than non-FGR controls (EF: 66.14 ± 3.85% vs 69.46 ± 3.58%; p  < 0.001, in FGR and non-FGR, respectively). Furthermore, LV E/E' a measure of LV diastolic function was altered among both types of FGR neonates. Similarly, LV GLS was reduced among FGR neonates (LV GLS: -20.69 ± 2.7% vs -19.06 ± 2.9%; p  < 0.001 in non-FGR and FGR, respectively)., Conclusion: FGR neonates exhibit significant alterations in cardiac geometry compared to AGA controls. FGR neonates also demonstrated a significant reduction in LV EF, FS, and LV global longitudinal strain, depicting failure to adapt to the increased cardiac workload after birth.

Background: Uteroplacental insufficiency in fetuses with growth restriction (FGR) leads to chronic hypoxia and stress, predominantly affecting the adrenal glands. However, the mechanisms of impact remain unclear. Objectives: This study is aimed at comparing the Doppler indices of the adrenal artery and the adrenal gland sizes between FGR and those with normal growth. Materials and Methods: A multicenter, cross-sectional study was conducted from February to December 2023. We compared 34 FGR to 34 with normal growth in terms of inferior adrenal artery (IAA) Doppler indices and adrenal gland volumes. Results: The IAA peak systolic velocity (PSV) in the FGR group was 14.9 ± 2.9 cm/s compared to 13.5 ± 2.0 cm/s in the normal group, with a mean difference of 1.4 cm/s (95% confidence interval [CI]: 0.27-2.65; p value = 0.017). There were no significant differences between groups in terms of IAA pulsatility index (PI), resistance index (RI), or systolic/diastolic (S/D), with p values of 0.438, 0.441, and 0.658, respectively. The volumes of the corrected whole adrenal gland and the corrected neocortex were significantly larger in the FGR group, with p values of 0.031 and 0.020, respectively. Conclusion: Both increased IAA PSV and enlarged volumes of the corrected whole adrenal gland and neocortex were found in fetuses with FGR, suggesting significant adrenal gland adaptation in response to chronic intrauterine stress., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Suphawan Pattamathamakul et al.)

Fetal growth restriction (FGR) is a common outcome in human suboptimal gestation and is related to prenatal origins of cardiovascular dysfunction in offspring. Despite this, therapy of human translational potential has not been identified. Using human umbilical and placental vessels and the chicken embryo model, we combined cellular, molecular, and functional studies to determine whether N-acetylcysteine (NAC) and hydrogen sulphide (H 2 S) protect cardiovascular function in growth-restricted unborn offspring. In human umbilical and placental arteries from control or FGR pregnancy and in vessels from near-term chicken embryos incubated under normoxic or hypoxic conditions, we determined the expression of the H 2 S gene CTH (i.e. cystathionine γ-lyase) (via quantitative PCR), the production of H 2 S (enzymatic activity), the DNA methylation profile (pyrosequencing) and vasodilator reactivity (wire myography) in the presence and absence of NAC treatment. The data show that FGR and hypoxia increased CTH expression in the embryonic/fetal vasculature in both species. NAC treatment increased aortic CTH expression and H 2 S production and enhanced third-order femoral artery dilator responses to the H 2 S donor sodium hydrosulphide in chicken embryos. NAC treatment also restored impaired endothelial relaxation in human third-to-fourth order chorionic arteries from FGR pregnancies and in third-order femoral arteries from hypoxic chicken embryos. This NAC-induced protection against endothelial dysfunction in hypoxic chicken embryos was mediated via nitric oxide independent mechanisms. Both developmental hypoxia and NAC promoted vascular changes in CTH DNA and NOS3 methylation patterns in chicken embryos. Combined, therefore, the data support that the effects of NAC and H 2 S offer a powerful mechanism of human translational potential against fetal cardiovascular dysfunction in complicated pregnancy. KEY POINTS: Gestation complicated by chronic fetal hypoxia and fetal growth restriction (FGR) increases a prenatal origin of cardiovascular disease in offspring, increasing interest in antenatal therapy to prevent against a fetal origin of cardiovascular dysfunction. We investigated the effects between N-acetylcysteine (NAC) and hydrogen sulphide (H 2 S) in the vasculature in FGR human pregnancy and in chronically hypoxic chicken embryos. Combining cellular, molecular, epigenetic and functional studies, we show that the vascular expression and synthesis of H 2 S is enhanced in hypoxic and FGR unborn offspring in both species and this acts to protect their vasculature. Therefore, the NAC/H 2 S pathway offers a powerful therapeutic mechanism of human translational potential against fetal cardiovascular dysfunction in complicated pregnancy., (© 2024 The Author(s). The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Fetal growth restriction (FGR) occurs in 8% of human pregnancies, and the growth restricted newborn is at a greater risk of developing heart disease in later adult life. In sheep, experimental restriction of placental growth (PR) from conception results in FGR, a decrease in cardiomyocyte endowment and an upregulation of pathological hypertrophic signalling in the fetal heart in late gestation. However, there is no change in the expression of markers of cellular proliferation nor in the level of cardiomyocyte apoptosis in the heart of the PR fetus in late gestation. This suggests that FGR arises early in gestation and programs a decrease in cardiomyocyte endowment in early, rather than late, gestation. Here, control and PR fetal sheep were humanely killed at 55 days' gestation (term, 150 days). Fetal body and heart weight were lower in PR compared with control fetuses and there was evidence of sparing of fetal brain growth. While there was no change in the proportion of cardiomyocytes that were proliferating in the early gestation PR heart, there was an increase in measures of apoptosis, and markers of autophagy and pathological hypertrophy in the PR fetal heart. These changes in early gestation highlight that FGR is associated with evidence of early cell death and compensatory hypertrophic responses of cardiomyocytes in the fetal heart. The data suggest that early placental restriction results in a decrease in the pool of proliferative cardiomyocytes in early gestation, which would limit cardiomyocyte endowment in the heart of the PR fetus in late gestation. KEY POINTS: Placental restriction leading to fetal growth restriction (FGR) and chronic fetal hypoxaemia in sheep results in a decrease in cardiomyocyte endowment in late gestation. FGR did not change cardiomyocyte proliferation during early gestation but did result in increased apoptosis and markers of autophagy in the fetal heart, which may result in the decreased endowment of cardiomyocytes observed in late gestation. FGR in early gestation also results in increased hypoxia inducible factor signalling in the fetal heart, which in turn may result in the altered expression of epigenetic regulators, increased expression of insulin-like growth factor 2 and cardiomyocyte hypertrophy during late gestation and after birth., (© 2024 The Author(s). The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Objectives: Fetuses with late-onset growth restriction (FGR) have a higher risk of suboptimal neurocognitive performance after birth. Previous studies have reported that impaired brain and cortical development can start in utero. The primary aim of this study was to report midline structure growth and cortical development in fetuses with late-onset FGR according to its severity; the secondary aim was to elucidate whether the severity of FGR, as defined by the presence of abnormal Doppler findings, plays a role in affecting brain growth and maturation., Methods: This was a prospective observational study that included fetuses with late-onset FGR (defined according to the Delphi FGR criteria) undergoing neurosonography between 32 and 34 weeks' gestation. Midline structure (corpus callosum (CC) and cerebellar vermis (CV)) length and cortical development, including the depth of the Sylvian (SF), parieto-occipital (POF) and calcarine (CF) fissures, were compared between late-onset FGR, small-for-gestational-age (SGA) and appropriate-for-gestational-age (AGA) fetuses. Subgroup analysis according to the severity of FGR (normal vs abnormal fetal Doppler) was also performed. Univariate analysis was used to analyze the data., Results: A total of 52 late-onset FGR fetuses with normal Doppler findings, 60 late-onset FGR fetuses with abnormal Doppler findings, 64 SGA fetuses and 100 AGA fetuses were included in the analysis. When comparing AGA controls with SGA fetuses, late-onset FGR fetuses with normal Doppler findings and late-onset FGR fetuses with abnormal Doppler findings, there was a progressive and significant reduction in the absolute values of the following parameters: CC length (median (interquartile range (IQR)), 43.5 (28.9-56.1) mm vs 41.9 (27.8-51.8) mm vs 38.5 (29.1-50.5) mm vs 31.7 (23.8-40.2) mm; K = 26.68; P < 0.0001), SF depth (median (IQR), 14.5 (10.7-16.8) mm vs 12.7 (9.8-15.1) mm vs 11.9 (9.1-13.4) mm vs 8.3 (6.7-10.3) mm; K = 75.82; P < 0.0001), POF depth (median (IQR), 8.6 (6.3-11.1) mm vs 8.1 (5.6-10.4) mm vs 7.8 (6.1-9.3) mm vs 6.6 (4.2-8.0) mm; K = 45.06; P < 0.0001) and CF depth (median (IQR), 9.3 (6.7-11.5) mm vs 8.2 (5.7-10.7) mm vs 7.7 (5.2-9.4) mm vs 6.3 (4.5-7.2) mm; K = 46.14; P < 0.0001). Absolute CV length was significantly higher in AGA fetuses compared with all other groups, although the same progressive pattern was not noted (median (IQR), 24.9 (17.6-29.2) mm vs 21.6 (15.2-26.1) mm vs 19.1 (13.8-25.9) mm vs 21.0 (13.5-25.8) mm; K = 16.72; P = 0.0008). When the neurosonographic variables were corrected for fetal head circumference, a significant difference in the CC length and SF, POF and CF depths, but not CV length, was observed only in late-onset FGR fetuses with abnormal Doppler findings when compared with AGA and SGA fetuses., Conclusions: Fetuses with late-onset FGR had shorter CC length and delayed cortical development when compared with AGA fetuses. After controlling for fetal head circumference, these differences remained significant only in late-onset FGR fetuses with abnormal Doppler. These findings support the existence of a link between brain development and impaired placental function. © 2024 International Society of Ultrasound in Obstetrics and Gynecology., (© 2024 International Society of Ultrasound in Obstetrics and Gynecology.)

Placental insufficiency is one of the major causes of fetal growth restriction (FGR), a significant pregnancy disorder in which the fetus fails to achieve its full growth potential in utero. As well as the acute consequences of being born too small, affected offspring are at increased risk of cardiovascular disease, diabetes and other chronic diseases in later life. The placenta and heart develop concurrently, therefore placental maldevelopment and function in FGR may have profound effect on the growth and differentiation of many organ systems, including the heart. Hence, understanding the key molecular players that are synergistically linked in the development of the placenta and heart is critical. This review highlights the key growth factors, angiogenic molecules and transcription factors that are common causes of defective placental and cardiovascular development., (© 2024 The Author(s).)

The reduced uterine perfusion pressure (RUPP) model is frequently used to study preeclampsia and fetal growth restriction. An improved understanding of influential factors might improve reproducibility and reduce animal use considering the variability in RUPP phenotype. We performed a systematic review and meta-analysis by searching Medline and Embase (until 28 March, 2023) for RUPP studies in murine. Primary outcomes included maternal blood pressure (BP) or proteinuria, fetal weight or crown-rump length, fetal reabsorptions, or antiangiogenic factors. We aimed to identify influential factors by meta-regression analysis. We included 155 studies. Our meta-analysis showed that the RUPP procedure results in significantly higher BP (MD = 24.1 mmHg; [22.6; 25.7]; n = 148), proteinuria (SMD = 2.3; [0.9; 3.8]; n = 28), fetal reabsorptions (MD = 50.4%; [45.5; 55.2]; n = 42), circulating soluble FMS-like tyrosine kinase-1 (sFlt-1) (SMD = 2.6; [1.7; 3.4]; n = 34), and lower fetal weight (MD = -0.4 g; [-0.47; -0.34]; n = 113. The heterogeneity (variability between studies) in primary outcomes appeared ≥90%. Our meta-regression identified influential factors in the method and time point of BP measurement, randomization in fetal weight, and type of control group in sFlt-1. The RUPP is a robust model considering the evident differences in maternal and fetal outcomes. The high heterogeneity reflects the observed variability in phenotype. Because of underreporting, we observed reporting bias and a high risk of bias. We recommend standardizing study design by optimal time point and method chosen for readout measures to limit the variability. This contributes to improved reproducibility and thereby eventually improves the translational value of the RUPP model.

Background: Assessing the umbilical artery pulsatility index via Doppler measurements plays a crucial role in evaluating fetal growth impairment., Objective: This study aimed to investigate perinatal outcomes associated with discordant pulsatility indices of umbilical arteries in fetuses with growth restriction., Study Design: In this retrospective cohort study, all singleton pregnancies were included if their estimated fetal weight and/or abdominal circumference fell below the 10th percentile for gestational age (2017-2022). Eligible cases included singleton pregnancies with concurrent sampling of both umbilical arteries within 14 days of birth at the ultrasound evaluation closest to delivery. The exclusion criteria included births before 22 weeks of gestation, evidence of absent or reverse end-diastolic flow in either umbilical artery, and known fetal genetic or structural anomalies. The study compared cases with discordant umbilical artery pulsatility index values (defined as 1 umbilical artery pulsatility index at ≤95th percentile and the other umbilical artery pulsatility index at >95th percentile for gestational age) to pregnancies where both umbilical artery pulsatility indices had normal pulsatility index values and those with both umbilical arteries displaying abnormal pulsatility index values. The primary outcome assessed was the occurrence of composite adverse neonatal outcomes. Multivariable logistic regressions were performed, adjusting for relevant covariates., Results: The study encompassed 1014 patients, including 194 patients (19.1%) with discordant umbilical artery pulsatility index values among those who had both umbilical arteries sampled close to delivery, 671 patients (66.2%) with both umbilical arteries having normal pulsatility index values, and 149 patients (14.7%) with both umbilical arteries exhibiting abnormal values. Pregnancies with discordant umbilical artery pulsatility index values displayed compromised sonographic parameters compared with those with both umbilical arteries showing normal pulsatility index values. Similarly, the number of abnormal umbilical artery pulsatility index values was associated with adverse perinatal outcomes in a dose-response manner. Cases with 1 abnormal (discordant) umbilical artery pulsatility index value showed favorable sonographic parameters and perinatal outcomes compared with cases with both abnormal umbilical artery pulsatility index values, and cases with both abnormal umbilical artery pulsatility index values showed worse sonographic parameters and perinatal outcomes compared with cases with discordant UA PI values. Multivariate analysis revealed that discordant umbilical artery pulsatility indices were significantly and independently associated with composite adverse perinatal outcomes, with an adjusted odds ratio of 1.75 (95% confidence interval, 1.24-2.47; P = .002)., Conclusion: Evaluating the resistance indices of both umbilical arteries may provide useful data and assist in assessing adverse perinatal outcomes among fetuses with growth restriction., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Intrauterine growth restriction (IUGR) is a common complication of pregnancy. We previously demonstrated that IUGR is associated with an impaired nitric oxide (NO)-induced relaxation in the human umbilical vein (HUV) of growth-restricted females compared to appropriate for gestational age (AGA) newborns. We found that phosphodiesterase (PDE) inhibition improved NO-induced relaxation in HUV, suggesting that PDEs could represent promising targets for therapeutic intervention. This study aimed to investigate the effects of PDE inhibition on human umbilical arteries (HUAs) compared to HUV. Umbilical vessels were collected in IUGR and AGA term newborns. NO-induced relaxation was studied using isolated vessel tension experiments in the presence or absence of the nonspecific PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX). PDE1B, PDE1C, PDE3A, PDE4B, and PDE5A were investigated by Western blot. NO-induced vasodilation was similar between IUGR and AGA HUAs. In HUAs precontracted with serotonin, IBMX enhanced NO-induced relaxation only in IUGR females, whereas in HUV IBMX increased NO-induced relaxation in all groups except IUGR males. In umbilical vessels preconstricted with the thromboxane A2 analog U46619, IBMX improved NO-induced relaxation in all groups to a greater extent in HUV than HUAs. However, the PDE protein content was higher in HUAs than HUV in all study groups. Therefore, the effects of PDE inhibition depend on the presence of IUGR, fetal sex, vessel type, and vasoconstrictors implicated. Despite a higher PDE protein content, HUAs are less sensitive to IBMX than HUV, which could lead to adverse effects of PDE inhibition in vivo by impairment of the fetoplacental hemodynamics. NEW & NOTEWORTHY The effects of phosphodiesterase inhibition on the umbilical circulation depend on the presence of intrauterine growth restriction, the fetal sex, vessel type, and vasoconstrictors implicated. The human umbilical vascular tone regulation is complex and depends on the amount and activity of specific proteins but also probably on the subcellular organization mediating protein interactions. Therefore, therapeutic interventions using phosphodiesterase inhibitors to improve the placental-fetal circulation should consider fetal sex and both umbilical vein and artery reactivity.

The hippocampus is a vital brain structure deep in the medial temporal lobe that mediates a range of functions encompassing emotional regulation, learning, memory, and cognition. Hippocampal development is exquisitely sensitive to perturbations and adverse conditions during pregnancy and at birth, including preterm birth, fetal growth restriction (FGR), acute hypoxic-ischaemic encephalopathy (HIE), and intrauterine inflammation. Disruptions to hippocampal development due to these conditions can have long-lasting functional impacts. Here, we discuss a range of preclinical models of prematurity and FGR and conditions that induce hypoxia and inflammation, which have been critical in elucidating the underlying mechanisms and cellular and subcellular structures implicated in hippocampal dysfunction. Finally, we discuss potential therapeutic targets to reduce the burden of these perinatal insults on the developing hippocampus. IMPACT: The review explores the preclinical literature examining the association between pregnancy and birth complications, and hippocampal form and function. The developmental processes and cellular mechanisms that are disrupted within the hippocampus following perinatal compromise are described, and potential therapeutic targets are discussed., (© 2024. The Author(s).)

Introduction: To evaluate the maternal and fetal hemodynamic effects of treatment with a nitric oxide donor and oral fluid in pregnancies complicated by fetal growth restriction., Methods: 30 normotensive participants with early fetal growth restriction were enrolled. 15 participants were treated until delivery with transdermal glyceryl trinitrate and oral fluid intake (Treated group), and 15 comprised the untreated group. All women underwent non-invasive assessment of fetal and maternal hemodynamics and repeat evaluation 2 weeks later., Results: In the treated group, maternal hemodynamics improved significantly after two weeks of therapy compared to untreated participants. Fetal hemodynamics in the treated group showed an increase in umbilical vein diameter by 18.87 % (p < 0.01), in umbilical vein blood flow by 48.16 % (p < 0.01) and in umbilical vein blood flow corrected for estimated fetal weight by 30.03 % (p < 0.01). In the untreated group, the characteristics of the umbilical vein were unchanged compared to baseline. At the same time, the cerebro-placental ratio increased in the treated group, while it was reduced in the untreated group, compared to baseline values. The treated group showed a higher birthweight centile (p = 0.03) and a lower preeclampsia rate (p = 0.04) compared to the untreated group., Discussion: The combined therapeutic approach with nitric oxide donor and oral fluid intake in fetal growth restriction improves maternal hemodynamics, which becomes more hyperdynamic (volume-dominant). At the same time, in the fetal circuit, umbilical vein flow increased and fetal brain sparing improved. Although a modest sample size, there was less preeclampsia and a higher birthweight suggesting beneficial maternal and fetal characteristics of treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Fetal growth restriction (FGR) increases cardiovascular risk by cardiac remodeling and programming. This systematic review and meta-analysis across species examines the use of echocardiography in FGR offspring at different ages. PubMed and Embase.com were searched for animal and human studies reporting on echocardiographic parameters in placental insufficiency-induced FGR offspring. We included six animal and 49 human studies. Although unable to perform a meta-analysis of animal studies because of insufficient number of studies per individual outcome, all studies showed left ventricular dysfunction. Our meta-analyses of human studies revealed a reduced left ventricular mass, interventricular septum thickness, mitral annular peak velocity, and mitral lateral early diastolic velocity at neonatal age. No echocardiographic differences during childhood were observed, although the small age range and number of studies limited these analyses. Only two studies at adult age were performed. Meta-regression on other influential factors was not possible due to underreporting. The few studies on myocardial strain analysis showed small changes in global longitudinal strain in FGR offspring. The quality of the human studies was considered low and the risk of bias in animal studies was mostly unclear. Echocardiography may offer a noninvasive tool to detect early signs of cardiovascular predisposition following FGR. Clinical implementation yet faces multiple challenges including identification of the most optimal timing and the exact relation to long-term cardiovascular function in which echocardiography alone might be limited to reflect a child's vascular status. Future research should focus on myocardial strain analysis and the combination of other (non)imaging techniques for an improved risk estimation. NEW & NOTEWORTHY Our meta-analysis revealed echocardiographic differences between fetal growth-restricted and control offspring in humans during the neonatal period: a reduced left ventricular mass and interventricular septum thickness, reduced mitral annular peak velocity, and mitral lateral early diastolic velocity. We were unable to pool echocardiographic parameters in animal studies and human adults because of an insufficient number of studies per individual outcome. The few studies on myocardial strain analysis showed small preclinical changes in FGR offspring.

Objectives: This systematic review explores cardiac adaptation in monochorionic (MC) twins with twin-twin transfusion syndrome (TTTS) or selective fetal growth restriction (sFGR) and assesses the risk of congenital heart defects (CHDs)., Methods: Adhering to PRISMA guidelines, 63 studies were reviewed (49 on cardiac adaptation, 13 on CHD, one on both). A narrative synthesis of cardiac adaptation patterns was performed. Additionally, a meta-analysis compared the livebirth prevalence of CHD in TTTS and sFGR against uncomplicated MC twins., Results: In TTTS recipients, cardiac function may be impaired for diastolic, systolic, as well as global functions, while in donors, cardiac function is generally preserved. In sFGR, large twins may show hypertrophic cardiomyopathy, and small twins may show impaired systolic function. Co-occurrence of TTTS and sFGR magnifies cardiac impact but is often underreported. Meta-analysis for CHD prevalence revealed a relative risk ratio of 3.5 (95% CI: 2.5-4.9) for TTTS and 2.2 (95%CI: 1.3-3.5) for sFGR compared with uncomplicated MC twins., Conclusions: This study highlights the well-documented cardiac adaptation in TTTS, contrasting with limited understanding in sFGR. Elevated CHD risks were observed in both conditions. Enhanced cardiovascular surveillance is warranted in complicated MC twin pregnancies. Future research should explore cardiac adaptation in sFGR and its long-term consequences., (© 2024 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) in pregnancy are associated with the development of preeclampsia and fetal growth restriction (FGR). Recently, preeclampsia was linked to impaired maternal hemodynamic function. This retrospective study evaluated singleton pregnancies with COVID-19 during pregnancy and healthy pregnant controls matched for gestational age from November 2020 to March 2022. Non-invasive assessment of maternal hemodynamics by continuous wave Doppler ultrasound measurements (USCOM-1A ® Monitor) and oscillometric arterial stiffness (Arteriograph) was performed. Overall, 69 pregnant women were included-23 women after COVID-19 during pregnancy and 46 healthy controls. While two women (8.7%) were admitted to the hospital due to COVID-19-related symptoms, none required intensive care unit admission or non-invasive/invasive ventilation. There were no statistically significant differences in the majority of hemodynamic parameters between the two cohorts. The prevalence of FGR was significantly higher in the COVID-19 during pregnancy group (9.5% vs. healthy controls: 0.0%; p = 0.036), especially in nulliparous women. No difference in angiogenic markers and neonatal outcomes were observed between pregnant women after COVID-19 and healthy controls. In conclusion, no significant differences in hemodynamic parameters or neonatal outcome were observed in women with COVID-19 during pregnancy. However, an increased prevalence of FGR could be described.

Objectives: Monochorionic twins (MC) have higher risk of perinatal morbi-mortality compared to singletons and dichorionic twins (DC). Selective fetal growth restriction (sFGR) increases the chances of adverse outcome. Hepatic arterial buffer response (HABR) is an important mechanism for maintaining liver perfusion. We hypothesised that HABR is active in monochorionic diamniotic twins (MCDA) with sFGR where restricted fetus may have liver hypoperfusion. The objective of this study is to test whether the HAV-ratio is diminished in pregnancies affected by selective fetal growth restriction pointing to activation of HABR in the growth-restricted fetus., Methods: sFGR was defined according to a consensus definition. Hepatic artery (HA) peak systolic velocity (PSV) was measured and its correlation with fetal Dopplers and pregnancy characteristics were determined. A ratio using HA-PSV (HAV-ratio) was calculated and its association with sFGR was established. Further analysis of HA-PSV was performed comparing z-scores between normal and growth restricted fetuses., Results: We included 202 MCDA pregnancies, 160 (79 %) normal and 42 (21 %) with sFGR. HAV-ratio was significant different between groups. The mean HAV-ratio was 1.01 (±0.20) for normal twins and 0.77 (±0.25) for sFGR. Furthermore, HA-PSV z-scores was significant increased in in growth-restricted fetus (0.94±1.45), while in normal fetuses was -0.16 (±0.97)., Conclusions: Our findings demonstrate that, in pregnancies with sFGR, HAV-ratio is significantly lower than in normal MCDA pregnancies. The lower HAV-ratio is due to an increase in HA PSV in the growth restricted fetus. This observation indicates an activation of HABR in the small fetus., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Fetal growth restriction is a hallmark of Fetal Alcohol Syndrome (FAS) and is accompanied by maternal uterine circulatory maladaptation. FAS is the most severe form of Fetal Alcohol Spectrum Disorder (FASD), a term for the range of conditions that can develop in a fetus when their pregnant mother consumes alcohol. Alcohol exerts specific direct effects on lipids that control fundamental developmental processes. We previously demonstrated that direct in vitro application of phosphatidic acid (PA, the simplest phospholipid and a direct target of alcohol exposure) to excised uterine arteries from alcohol-exposed rats improved vascular function, but it is unknown if PA can rescue end organ phenotypes in our FASD animal model. Pregnant Sprague-Dawley rats ( n = 40 total dams) were gavaged daily from gestational day (GD) 5 to GD 19 with alcohol or maltose dextrin, with and without PA supplementation, for a total of four unique groups. To translate and assess the beneficial effects of PA, we hypothesized that in vivo administration of PA concomitant with chronic binge alcohol would reverse uterine artery dysfunction and fetal growth deficits in our FASD model. Mean fetal weights and placental efficiency were significantly lower in the binge alcohol group compared with those in the control ( p < 0.05). However, these differences between the alcohol and the control groups were completely abolished by auxiliary in vivo PA administration with alcohol, indicating a reversal of the classic FAS growth restriction phenotype. Acetylcholine (ACh)-induced uterine artery relaxation was significantly impaired in the uterine arteries of chronic in vivo binge alcohol-administered rats compared to the controls ( p < 0.05). Supplementation of PA in vivo throughout pregnancy reversed the alcohol-induced vasodilatory deficit; no differences were detected following in vivo PA administration between the pair-fed control and PA alcohol groups. Maximal ACh-induced vasodilation was significantly lower in the alcohol group compared to all the other treatments, including control, control PA, and alcohol PA groups ( p < 0.05). When analyzing excitatory vasodilatory p1177-eNOS, alcohol-induced downregulation of p1177-eNOS was completely reversed following in vivo PA supplementation. In summary, these novel data utilize a specific alcohol target pathway (PA) to demonstrate a lipid-based preventive strategy and provide critical insights important for the development of translatable interventions.

Objective: To investigate the relationship of umbilical vein flow (UVF) measured close to term with abnormal fetal growth and adverse perinatal outcome in a cohort of pregnancies at low risk of placental insufficiency., Methods: This was a prospective multicenter observational study conducted across two tertiary maternity units. Patients with a singleton appropriate-for-gestational-age fetus between 35 and 38 weeks' gestation were included. Pregnancies at higher risk of placental insufficiency or with fetal anomalies were excluded. At ultrasound examination, the abdominal circumference (AC), umbilical vein diameter and peak velocity of the umbilical vein were measured, and, using these variables, a new variable, UVF/AC, was calculated. The primary outcome was the occurrence of severely stunted fetal growth, defined as a greater than 40-percentile drop between estimated fetal weight at the third-trimester ultrasound and birth weight. The occurrence of adverse perinatal outcome (defined as one of the following: neonatal acidosis (umbilical artery pH < 7.15 and/or base excess > 12 mmol/L) at birth, 5-min Apgar score < 7, neonatal resuscitation or neonatal intensive care unit admission) was analyzed as a secondary outcome., Results: Between April 2021 and March 2023, 365 women were included in the study. The mean UVF/AC at enrolment was 6.4 ± 2.6 mL/min/cm, and 35 (9.6%) cases were affected by severely stunted fetal growth. Severely stunted fetal growth was associated with a lower mean UVF/AC (5.4 ± 2.6 vs 6.5 ± 2.6 mL/min/cm; P = 0.02) and a higher frequency of UVF/AC < 10 th percentile (8/35 (22.9%) vs 28/330 (8.5%); P = 0.01). Moreover, UVF/AC showed an area under the receiver-operating-characteristics curve (AUC) of 0.65 (95% CI, 0.55-0.75; P = 0.004) in predicting the occurrence of severely stunted fetal growth, and the optimal cut-off value of UVF/AC for discriminating between normal and severely stunted fetal growth was 7.2 mL/min/cm. This value was associated with a sensitivity and specificity of 0.77 (95% CI, 0.60-0.90) and 0.33 (95% CI, 0.28-0.39), and positive and negative predictive values of 0.11 (95% CI, 0.07-0.15) and 0.93 (95% CI, 0.87-0.97), respectively. Regarding the occurrence of adverse perinatal outcome, this was associated independently with maternal age (adjusted odds ratio (aOR), 0.93 (95% CI, 0.87-0.99); P = 0.04), UVF/AC Z-score (aOR, 0.53 (95% CI, 0.30-0.87); P = 0.01) and augmentation of labor (aOR, 2.69 (95% CI, 1.28-5.69); P = 0.009). UVF/AC showed an AUC of 0.65 (95% CI, 0.56-0.73; P = 0.005) in predicting the occurrence of adverse perinatal outcome, and the optimal cut-off value of UVF/AC for discriminating between normal and adverse perinatal outcome was 6.7 mL/min/cm. This value was associated with a sensitivity and specificity of 0.70 (95% CI, 0.54-0.83) and 0.40 (95% CI, 0.34-0.45), and positive and negative predictive values of 0.14 (95% CI, 0.09-0.19) and 0.91 (95% CI, 0.85-0.95), respectively., Conclusions: Our data demonstrate an association between reduced UVF close to term, severely stunted fetal growth and adverse perinatal outcome in a cohort of low-risk pregnant women, with a moderate ability to rule out and a poor ability to rule in either outcome. Further studies are needed to establish whether the assessment of UVF can improve the identification of fetuses at risk of subclinical placental insufficiency and adverse perinatal outcome. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Objectives: To investigate the clinical outcomes and Doppler patterns changes in monochorionic diamniotic (MCDA) twins with selective fetal growth restriction (sFGR)., Methods: We retrospectively analyzed 362 sFGR cases from January 2010 to May 2016 at a single tertiary referral center. The Doppler waveforms of umbilical artery end-diastolic flow were collected, and all neonates were subjected to an early neonatal brain scan., Results: A total of 66/100 (66 %) type I cases were stable, whereas 25/100 (25 %) cases changed to type II and 9/100 (9 %) changed to sFGR complicated twin-twin transfusion syndrome (TTTS). A total of 48.9 % (22/45) sFGR cases were complicated with polyhydramnios and 30.4 % (7/23) sFGR cases were complicated with oligohydramnios, both of which were progressed to sFGR with TTTS. Mild cerebral injury was significantly associated with Doppler flow abnormalities, earlier gestational age at delivery and type of sFGR diagnosis. Severe cerebral injury was significantly associated with gestational age at delivery (31.6 vs. 34.1, p=0.002) and larger birthweight discordance (43.9 vs. 29.3 %, p=0.011)., Conclusions: Doppler patterns in sFGR can gradually change, with important consequences with regard to management and outcomes. Along with abnormal Doppler findings, earlier occurrence of sFGR and delivery are associated with subsequent neonatal cerebral injury., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Objectives: To investigate midbrain growth, including corpus callusum (CC) and cerebellar vermis (CV) and cortical development in late fetal growth restricted (FGR) subclassified according to the umbilical vein blood flow (UVBF) values., Methods: This was a prospective study on singleton fetuses late FGR with abnormal placental cerebral ratio (PCR). FGR fetuses were further subdivided into normal (≥fifth centile) and abnormal (

Introduction: Growth-restricted fetuses may have changes in their neuroanatomical structures that can be detected in prenatal imaging. We aim to compare corpus callosal length (CCL) and cerebellar vermian height (CVH) measurements between fetal growth restriction (FGR) and control fetuses and to correlate them with cerebral Doppler velocimetry in growth-restricted fetuses., Methods: This was a prospective cohort of FGR after 20 weeks of gestation with ultrasound measurements of CCL and CVH. Control cohort was assembled from fetuses without FGR who had growth ultrasound after 20 weeks of gestation. We compared differences of CCL or CVH between FGR and controls. We also tested for the correlations of CCL and CVH with middle cerebral artery (MCA) pulsatility index (PI) and vertebral artery (VA) PI in the FGR group. CCL and CVH measurements were adjusted by head circumference (HC)., Results: CCL and CVH were obtained in 68 and 55 fetuses, respectively. CCL/HC was smaller in FGR fetuses when compared to control fetuses (difference = 0.03, 95% CI: [0.02, 0.04], p &lt; 0.001). CVH/HC was larger in FGR fetuses compared to NG fetuses (difference = 0.1, 95% CI: [-0.01, 0.02], p = &lt; 0.001). VA PI multiples of the median were inversely correlated with CVH/HC (rho = -0.53, p = 0.007), while CCL/HC was not correlated with VA PI. Neither CCL/HC nor CVH/HC was correlated with MCA PI., Conclusions: CCL/HC and CVH/HC measurements show differences in growth-restricted fetuses compared to a control cohort. We also found an inverse relationship between VA PI and CVH/HC. The potential use of neurosonography assessment in FGR assessment requires continued explorations., (© 2024 S. Karger AG, Basel.)

Introduction: The aim of the study was to identify predictors of poor outcomes in monochorionic diamniotic twin (MCDA) pregnancies with selective fetal growth restriction (sFGR), irrespective of the umbilical artery (UA) Doppler abnormalities., Methods: Single-center retrospective analysis of MCDA twins diagnosed with sFGR that opted for expectant management between 2010 and 2021. The presence of any of the following variables in the growth-restricted fetus: low amniotic fluid volume (DVP ≤2 cm), lack of a cycling bladder, absent or reversed flow in the ductus venosus (DV) with atrial contraction, and elevated middle cerebral artery peak systolic velocity (MCA-PSV) defined as ≥1.50 multiples of the median was categorized as complicated. sFGR cases were classified as simple in the absence of the above-mentioned variables., Results: Overall, 63.3% of cases qualified as simple, and 36.7% were complicated. Intertwin EFW discordance was higher in the complicated category (26 vs. 33%, p = 0.0002). The median gestational age at delivery was earlier (33 weeks vs. 30.5 weeks, p = 0.002), and the likelihood of survival was lower in the complicated category (p &lt; 0.0001). The likelihood of two survivors to discharge was lower in type I complicated cases (70% in complicated type I vs. 97.1% in simple type I, p = 0.0003). On logistic regression analysis, an increase in the "complicated" score negatively correlated with two survivors to discharge (p &lt; 0.0001). An ROC curve was created, and the AUC was 0.79. Increasing intertwin EFW discordance also decreased the probability of two survivors to discharge., Conclusion: The presence of oligohydramnios, lack of a cycling bladder, abnormal DV Doppler, and elevated MCA-PSV in the growth restricted fetus is associated with poor perinatal outcomes and a lower likelihood of having two survivors to discharge. The addition of intertwin EFW discordance to these variables helped improve the survival predictability., (© 2024 S. Karger AG, Basel.)

Introduction: Intravoxel Incoherent Motion (IVIM) imaging has been used to assess placental microcirculatory flows. We proposed a joint analysis of flow-compensated (FC) and non-compensated (NC) diffusion MRI to estimate the fraction and velocity of ballistic microcirculatory flow (f b and v b ), and evaluated the diagnostic performance of the new markers in maternal and fetal disorders., Methods: Gestational diabetes mellitus (GDM, n = 15) pregnancies and fetal growth restriction (FGR, n = 12), along with gestational age matched normal controls (n = 19 for GDM and 15 for FGR) underwent FC and NC-encoded IVIM scans at 1.5 T. f b and v b obtained from a FC-NC joint model, along with the conventional IVIM indices, were compared between patient groups for whole-placenta and maternal/fetal sides of the placenta. A linear support vector machine (SVM) was used to classify the GDM, FGR and controls., Results: v b of whole-placenta were significantly lower in both GDM (p = 0.017) and FGR (p = 0.043), compared with their controls, and the differences were more evident in the fetal side (p = 0.010 for GDM and p = 0.042 for FGR). f b and f FC showed group differences in the fetal side and D FC showed differences in whole-placenta for GDM patients. In the classification task, v b showed the highest diagnostic accuracy of 70.6% for GDM and 63.0% for FGR, and the combination of f b and v b further improved the detection accuracy to 73.5% and 66.7% for GDM and FGR, respectively., Discussion: v b showed superior performance in the diagnosis of GDM and FGR, indicating the potential of the joint FC-NC IVIM method for placenta examinations., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: To investigate the association of the maternal serum albumin (MAlb) level with fetal growth and fetal growth restriction (FGR) risk in term-born singletons., Design: Prospective cohort study., Setting: Four hospital maternity units of the Tongji Maternal and Child Health Cohort study initiated from September 2013 to April 2016 at Wuhan City, in central China., Patient(s): A total of 3,065 mother-offspring pairs., Intervention(s): None., Main Outcome Measure(s): Fetal growth was evaluated by birth weight (BW) and birth length. Fetal growth restriction was defined as BW below the 10th percentile., Result(s): All MAlb levels were within the upper limit of normal. After adjustment for liver function parameters, inflammatory indicators, and others, a reverse U-shaped relationship between MAlb and fetal growth was observed. Specifically, BW increased significantly with an increasing MAlb level when the MAlb level was <36.1 g/L (per g/L: β = 36.8; 95% CI, 0.8, 72.7) but decreased with increasing the MAlb level when the MAlb level was >36.1 g/L (per g/L: β = -15.1; 95% CI, -21.2, -8.9). There was a similar association between MAlb and birth length. Furthermore, the adjusted odd ratios of FGR across increasing tertiles of the MAlb levels were 1.0 (reference), 1.1 (0.7, 1.8), and 1.7 (1.0, 2.6)., Conclusion(s): There was a reverse U-shaped association between MAlb and fetal growth. A higher MAlb level was associated with an increased risk of FGR., Clinical Trial Registration Number: NCT03099837., (Copyright © 2021. Published by Elsevier Inc.)

Objective: To determine whether the presence of brain sparing in fetal growth restricted (FGR) fetuses involves elevation of the cerebral injury biomarker S100B in maternal circulation., Methods: We included 63 women with suspected small for gestational age (SGA) fetuses between 24 and 35 +6/7 weeks of gestation. Maternal plasma angiogenic factors measurements and sonographic evaluation were performed at recruitment. Next, we subdivided our SGA cohort into three groups: SGA fetuses, FGR fetuses without brain-sparing, and FGR fetuses with brain-sparing (FGR-BS). Serum S100B concentration was calculated as S100B µg/L, S100B MoM, and the ratio S100B/ estimated fetal weight (EFW). We also report one case of S100B concentration surge in maternal serum following the diagnosis of fetal intraventricular hemorrhage (IVH)., Results: The FGR-BS group had higher maternal S100B µg/L (p < 0.01, p < 0.05, respectively), S100B MoM (p < 0.001, p < 0.001, respectively), and S100B/EFW (p < 0.001, p < 0.01, respectively), compared to the SGA and FGR groups. In the case report, maternal serum S100B concentrations were 0.0346 µg/L before, and 0.0874 µg/L after IVH occurrence., Conclusions: S100B concentration in maternal serum increased in pregnancies complicated by FGR and brain sparing. These results may substantiate in-utero cerebral injury and may explain the adverse neurocognitive outcomes reported for this group., (© 2021 John Wiley & Sons Ltd.)

49,XXXXY is an X and Y chromosome variation that occurs in 1:85,000 to 1:100,000 live male births. Previous case studies have described boys with this disorder to be shorter than average when compared with boys with only one extra chromosome and with the mean stature in a small cohort reported to range from the seventh to 33rd percentile. The origin behind the possible differences in height between boys with 47,XXY and 49,XXXXY is currently unknown, however one study hypothesized that it was due to a difference in the expression of the SHOX gene. This study reports on the anthropometric measurements of 84 boys with 49,XXXXY. Forty-five percent of children with 49,XXXXY were found to be below the third percentile in height at the time of evaluation. In addition, 7.14% of the cohort were diagnosed and given treatment for growth hormone deficiency (GHD). The analysis of this cohort demonstrates that the below average heights seen throughout childhood in this population potentially begins prenatally and suggests that boys with 49,XXXXY may be at a higher risk for intrauterine growth restriction (IUGR) and GHD. Future research is needed to investigate the etiology of the poor growth in boys with 49,XXXXY and evaluate the incidence of GHD and IUGR in this population., (© 2020 Wiley Periodicals LLC.)

Intrauterine growth restriction (IUGR) due to uteroplacental insufficiency results in a placenta that is unable to provide adequate nutrients and oxygen to the fetus. These growth-restricted babies have an increased risk of hypertension and chronic kidney disease later in life. In rats, both male and female growth-restricted offspring have nephron deficits but only males develop kidney dysfunction and high blood pressure. In addition, there is transgenerational transmission of nephron deficits and hypertension risk. Therefore, epigenetic mechanisms may explain the sex-specific programming and multigenerational transmission of IUGR-related phenotypes. Expression of DNA methyltransferases (Dnmt1and Dnmt3a) and imprinted genes (Peg3, Snrpn, Kcnq1, and Cdkn1c) were investigated in kidney tissues of sham and IUGR rats in F1 (embryonic day 20 (E20) and postnatal day 1 (PN1)) and F2 (6 and 12 months of age, paternal and maternal lines) generations (n = 6-13/group). In comparison to sham offspring, F1 IUGR rats had a 19% decrease in Dnmt3a expression at E20 (P < 0.05), with decreased Cdkn1c (19%, P < 0.05) and increased Kcnq1 (1.6-fold, P < 0.01) at PN1. There was a sex-specific difference in Cdkn1c and Snrpn expression at E20, with 29% and 34% higher expression in IUGR males compared to females, respectively (P < 0.05). Peg3 sex-specific expression was lost in the F2 IUGR offspring, only in the maternal line. These findings suggest that epigenetic mechanisms may be altered in renal embryonic and/or fetal development in growth-restricted offspring, which could alter kidney function, predisposing these offspring to kidney disease later in life.

Objective: We have shown previously that third-trimester growth in small fetuses (estimated fetal weight (EFW) < 10 th percentile) with birth weight (BW) < 10 th percentile is heterogeneous using individualized growth assessment (IGA). We aimed to test our hypothesis that individual growth patterns in small fetuses with BW > 10 th percentile are also variable but in different ways., Methods: This was a study of 191 cases with EFW < 10 th percentile and BW > 10 th percentile (appropriate-for-gestational-age (AGA) cohort), derived from the PORTO study. Composite size parameters were used to quantify growth pathology at individual third-trimester timepoints (individual composite prenatal growth assessment score (-icPGAS)). The fetal growth pathology score 1 (-FGPS1), calculated cumulatively from serial -icPGAS values, was used to characterize third-trimester growth patterns. Vascular-system evaluation included umbilical artery (UA) and middle cerebral artery (MCA) Doppler velocimetry. Outcome variables were birth age (preterm/term delivery) and BW (expressed as growth potential realization index for weight (GPRI WT ) and percentile). The findings from the AGA cohort were compared with those from small fetuses (EFW < 10 th percentile) with BW < 10 th percentile (small-for-gestational-age (SGA) cohort)., Results: The AGA cohort was found to have 134 fetuses (70%) with normal growth pattern and 57 (30%) with growth restriction based on IGA criteria. Seven growth-restriction -FGPS1 patterns were observed, including the previously defined progressive, late, adaptive and recovering types. The recovering type was the most common growth pattern in the AGA cohort (50.9%). About one-third of fetuses without any evidence of growth restriction had significant unexplained abnormalities in the UA (34%) and MCA (31%) and elevated mean GPRI WT values (113 ± 12.5%). Comparison of the AGA and SGA cohorts indicated a significant difference in the distribution of -FGPS1 growth patterns (P = 0.0001). Compared with the SGA cohort, the AGA cohort had more fetuses with a normal growth pattern (70% vs 38%) and fewer cases with growth restriction (30% vs 62%). While the recovering type was the most common growth-restriction pattern in the AGA cohort (51%), the progressive type was the primary growth-restriction pattern in the SGA cohort (44%). No difference in the incidence of MCA or UA abnormality was found between the SGA and AGA cohorts when comparing subgroups of more than 10 fetuses., Conclusions: Both normal-growth and growth-restriction patterns were observed in the AGA cohort using IGA, as seen previously in the SGA cohort. The seven types of growth restriction defined in the SGA cohort were also identified in AGA cases, but their distribution was significantly different. In one-third of cases without evidence of growth pathology in the AGA cohort, Doppler abnormalities in the UA and MCA were seen. This heterogeneity underscores the difficulty of accurate classification of fetal and neonatal growth status using conventional population-based methods. © 2021 International Society of Ultrasound in Obstetrics and Gynecology., (© 2021 International Society of Ultrasound in Obstetrics and Gynecology.)

Fetal growth restriction (FGR) increases the risk for impaired cognitive function later in life. However, the precise mechanisms remain elusive. Using dexamethasone-induced FGR and protein restriction-influenced FGR mouse models, we observe learning and memory deficits in adult FGR offspring. FGR induces decreased hippocampal neurogenesis from the early post-natal period to adulthood by reducing the proliferation of neural stem cells (NSCs). We further find a persistent decrease of Tet1 expression in hippocampal NSCs of FGR mice. Mechanistically, Tet1 downregulation results in hypermethylation of the Dll3 and Notch1 promoters and inhibition of Notch signaling, leading to reduced NSC proliferation. Overexpression of Tet1 activates Notch signaling, offsets the decline in neurogenesis, and enhances learning and memory abilities in FGR offspring. Our data indicate that a long-term decrease in Tet1/Notch signaling in hippocampal NSCs contributes to impaired neurogenesis following FGR and could serve as potential targets for the intervention of FGR-related cognitive disorders., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Evaluate survival in twin twin transfusion syndrome (TTTS) with and without selective fetal growth restriction (sFGR) after fetoscopic laser surgery (FLS)., Methods: Retrospective study of monochorionic diamniotic twins undergoing FLS. The cohort was classified as TTTS and TTTS with sFGR. Baseline, intra-operative and postoperative variables were analyzed. Mann-Whitney U, Pearson chi-square, Fisher's exact, t-test and receiver operating characteristic (ROC) curve analysis were performed., Results: Four hundred and ninety-two pregnancies were included, 304 (61.78%) TTTS and 188 (38.22%) TTTS with sFGR. No difference in donor outcomes. TTTS group had higher donor estimated fetal weight (EFW%) percentile (19.7 ± 18.8 vs. 2.2 ± 2.1, p < 0.001). Significant predictors for demise at 30 days were 37% intertwin weight discordance (IWD) with donor EFW% < first (area under ROC curve [AUC] = 0.85, p = 0.001) or IWD >25% and intertwin umbilical artery pulsatility index discordance (DUAPI) ≥0.4 (AUC = 0.71, p = 0.001)., Conclusion: Combination of IWD of 37% and donor EFW%

Objective: To clarify the relationships between placental characteristics and birthweight discordance in three types of selective intrauterine growth restriction (sIUGR) in monochorionic diamniotic twins., Methods: A retrospective cohort study was conducted between april 2013 and april 2020. Associations between placental characteristics and birthweight discordance were evaluated through multiple linear regression analyses with two models for each sIUGR type. Model A was adjusted for gestational age, Model B additionally adjusted for the impact of placental characteristics interacted., Results: In cases of type I sIUGR, birthweight discordance ratio was positively associated with placental territory discordance ratio [(β = 0.181,95%CI(0.072,0.290), p < 0.05), (β = 0.239,95%CI(0.125, 0.353), p < 0.05)] under both Model A and Model B. In-type II sIUGR [(β = -0.012,95%CI(-0.020, -0.004), p < 0.05) (β = -0.010,95%CI (-0.018, -0.002), p < 0.05)] and type III sIUGR [(β = -0.011,95%CI (-0.021, -0.001), p < 0.05), (β = -0.012,95%CI(-0.022, -0.003), p < 0.05)], birthweight discordance ratio was negatively associated with the total diameter of all the anastomoses as calculated with both Model A and Model B., Conclusion: Birthweight discordance is primarily related to placental territory discordance in type I sIUGR, whereas vascular anastomoses play important roles for growth-restricted fetal compensation in type II and III sIUGR., (© 2021 John Wiley & Sons Ltd.)

Preeclampsia (PE), the leading cause of maternal and fetal morbidity and mortality, is associated with poor fetal growth, intrauterine growth restriction (IUGR) and low birth weight (LBW). Offspring of women who had PE are at increased risk for cardiovascular (CV) disease later in life. However, the exact etiology of PE is unknown. Moreover, there are no effective interventions to treat PE or alleviate IUGR and the developmental origins of chronic disease in the offspring. The placenta is critical to fetal growth and development. Epigenetic regulatory processes such as histone modifications, microRNAs and DNA methylation play an important role in placental development including contributions to the regulation of trophoblast invasion and remodeling of the spiral arteries. Epigenetic processes that lead to changes in placental gene expression in PE mediate downstream effects that contribute to the development of placenta dysfunction, a critical mediator in the onset of PE, impaired fetal growth and IUGR. Therefore, this review will focus on epigenetic processes that contribute to the pathogenesis of PE and IUGR. Understanding the epigenetic mechanisms that contribute to normal placental development and the initiating events in PE may lead to novel therapeutic targets in PE that improve fetal growth and mitigate increased CV risk in the offspring., (© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Background: The aims of this study were to evaluate the time intervals of flow velocity waveforms (FVW) of ductus venosus (DV) and cardiac cycles, as well as the pulsatility index of DV-FVW (DV-PI), in correlation with umbilical artery (UA) pH at birth in fetal growth restriction (FGR) complicated with placental insufficiency., Methods: Data were retrospectively retrieved from pregnancies complicated by FGR. FGR was defined as an estimated fetal weight below - 2.0 S.D. with an elevated UA-PI. Time interval assessments of DV-FVW were as follows: the duration of systolic wave was divided by the duration of diastolic wave and defined as DV-S/D. We also measured the following time intervals of ventricular inflow through tricuspid valve (TV) and mitral valve (MV): (iii), from the second peak of ventricular inflow caused by atrial contraction (A-wave) to the opening of atrio-ventricular valves and: (iv), from the opening of atrio-ventricular valves to the peak of A-wave. (iii)/(iv) was expressed as TV-S/D and MV-S/D, for TV and MV, respectively. The time interval data were transformed into z-scores., Results: Thirty-one FGR fetuses were included in this study. Both DV-PI and DV-S/D showed significant correlation with UA-pH (r = - 0.677, p = < 0.001 and r = 0.489, p = 0.005 for DV-PI and z-score of DV-S/D, respectively) and more significances were observed in FGR ≤ 28 + 6 gestational weeks (r = - 0.819, p < 0.001 and r = 0.726, p = 0.005, for DV-PI and z-score of DV-S/D, respectively) than in FGR > 28 + 6 gestational weeks (r = - 0.634, p = 0.007 and r = 0.635, p = 0.020, for DV-PI and z-score of DV-S/D, respectively). On the other hand, TV-S/D and MV-S/D showed no significant correlation with UA-pH, although these z-scores indicated significant decreases compared with normal references., Conclusions: Time interval analysis of DV-FVW might be a valuable parameter, as well as DV-PI, for the antenatal prediction of fetal acidemia in the management of FGR fetuses., (© 2021. The Author(s).)

Background: Intrauterine growth restriction (IUGR) leads to cardiac dysfunction and adverse remodeling of the fetal heart, as well as a higher risk of postnatal cardiovascular diseases. The rat model of IUGR, via uterine artery ligation, is a popular model but its cardiac sequelae is not well investigated. Here, we performed an echocardiographic evaluation of its cardiac function to determine how well it can represent the disease in humans., Methods: Unilateral uterine artery ligation was performed at embryonic day 17 (E17) and echocardiography was performed at E19 and E20., Results: Growth-restricted fetuses were significantly smaller and lighter, and had an higher placenta-to-fetus weight ratio. Growth-restricted fetal hearts had reduced wall thickness-to-diameter ratio, indicating left ventricular (LV) dilatation, and they had elevated trans-mitral and trans-tricuspid E/A ratios and reduced left and right ventricular fractional shortening (FS), suggesting systolic and diastolic dysfunction. These were similar to human IUGR fetuses. However, growth-restricted rat fetuses did not demonstrate head-sparing effect, displayed a lower LV myocardial performance index, and ventricular outflow velocities were not significantly reduced, which were dissimilar to human IUGR fetuses., Conclusions: Despite the differences, our results suggest that this IUGR model has significant cardiac dysfunction, and could be a suitable model for studying IUGR cardiovascular physiology., Impact: Animal models of IUGR are useful, but their fetal cardiac function is not well studied, and it is unclear if they can represent human IUGR fetuses. We performed an echocardiographic assessment of the heart function of a fetal rat model of IUGR, created via maternal uterine artery ligation. Similar to humans, the model displayed LV dilatation, elevated E/A ratios, and reduced FS. Different from humans, the model displayed reduced MPI, and no significant outflow velocity reduction. Despite differences with humans, this rat model still displayed cardiac dysfunction and is suitable for studying IUGR cardiovascular physiology., (© 2021. The Author(s).)

Infants born after intrauterine growth restriction (IUGR) are at risk of developing arterial hypertension at adulthood. The endothelium plays a major role in the pathogenesis of hypertension. Endothelial colony-forming cells (ECFCs), critical circulating components of the endothelium, are involved in vasculo-and angiogenesis and in endothelium repair. We previously described impaired functionality of ECFCs in cord blood of low-birth-weight newborns. However, whether early ECFC alterations persist thereafter and could be associated with hypertension in individuals born after IUGR remains unknown. A rat model of IUGR was induced by a maternal low-protein diet during gestation versus a control (CTRL) diet. In six-month-old offspring, only IUGR males have increased systolic blood pressure (tail-cuff plethysmography) and microvascular rarefaction (immunofluorescence). ECFCs isolated from bone marrow of IUGR versus CTRL males displayed a decreased proportion of CD31+ versus CD146+ staining on CD45- cells, CD34 expression (flow cytometry, immunofluorescence), reduced proliferation (BrdU incorporation), and an impaired capacity to form capillary-like structures (Matrigel test), associated with an impaired angiogenic profile (immunofluorescence). These dysfunctions were associated with oxidative stress (increased superoxide anion levels (fluorescent dye), decreased superoxide dismutase protein expression, increased DNA damage (immunofluorescence), and stress-induced premature senescence (SIPS; increased beta-galactosidase activity, increased p16 INK4a , and decreased sirtuin-1 protein expression). This study demonstrated an impaired functionality of ECFCs at adulthood associated with arterial hypertension in individuals born after IUGR.

Fetal growth restriction (FGR) is a complication of pregnancy that reduces birth weight, markedly increases infant mortality and morbidity and is associated with later-life cardiometabolic disease. No specific treatment is available for FGR. Placentas of human FGR infants have low abundance of sodium-coupled neutral amino acid transporter 2 (Slc38a2/SNAT2), which supplies the fetus with amino acids required for growth. We determined the mechanistic role of placental Slc38a2/SNAT2 deficiency in the development of restricted fetal growth, hypothesizing that placenta-specific Slc38a2 knockdown causes FGR in mice. Using lentiviral transduction of blastocysts with a small hairpin RNA (shRNA), we achieved 59% knockdown of placental Slc38a2, without altering fetal Slc38a2 expression. Placenta-specific Slc38a2 knockdown reduced near-term fetal and placental weight, fetal viability, trophoblast plasma membrane (TPM) SNAT2 protein abundance, and both absolute and weight-specific placental uptake of the amino acid transport System A tracer, 14C-methylaminoisobutyric acid (MeAIB). We also measured human placental SLC38A2 gene expression in a well-defined term clinical cohort and found that SLC38A2 expression was decreased in late-onset, but not early-onset FGR, compared with appropriate for gestational age (AGA) control placentas. The results demonstrate that low placental Slc38a2/SNAT2 causes FGR and could be a target for clinical therapies for late-onset FGR., (© 2021 The Author(s).)

The mechanical force of blood flow is a fundamental determinant of vascular homeostasis. This frictional stimulation of cells, fluid shear stress (FSS), is increasingly recognised as being essential to placental development and function. Here, we focus on the role of FSS in regulating fetoplacental circulatory flow, both in normal pregnancy and that affected by fetal growth restriction (FGR). The fetus is reliant on placental perfusion to meet its circulatory and metabolic demands. Failure of normal vascular adaptation and the mechanisms enabling responsive interaction between fetoplacental and maternal circulations can result in FGR. FSS generates vasodilatation at least partly through the release of endothelial nitric oxide, a process thought to be vital for adequate blood flow. Where FGR is caused by placental dysfunction, placental vascular anatomy is altered, alongside endothelial dysfunction and hypoxia, each impacting upon the complex balance of FSS forces. Identifying specific mechanical sensors and the mechanisms governing how FSS force is converted into biochemical signals is a fast-paced area of research. Here, we raise awareness of Piezo1 proteins, recently discovered to be FSS-sensitive in fetoplacental endothelium, and with emerging roles in NO generation, vascular tone and angiogenesis. We discuss the emerging concept that activating mechanosensors such as Piezo1 ultimately results in the orchestrated processes of placental vascular adaptation. Piecing together the mechanisms governing endothelial responses to FSS in placental insufficiency is an important step towards developing new treatments for FGR., (Copyright © 2021. Published by Elsevier Ltd.)