Search

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: 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.)

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.)

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.)

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.)

Introduction: In this study, we aimed at quantifying placental concentrations of 22 chemical elements in small fetuses (SGA) as compared with normally grown fetuses (AGA), and to assess the relationship with Doppler markers of placental function., Methods: Prospective cohort study, including 71 SGA fetuses (estimated fetal weight < 10th percentile) and 96 AGA fetuses (estimated fetal weight > 10th percentile), recruited in the third trimester of gestation. The placental concentration of 22 chemical elements was determined by inductively coupled plasma optical emission spectrophotometer (ICP-OES, ICAP 6500 Duo Thermo): aluminum (Al), beryllium (Be), bismuth (Bi), calcium (Ca), cadmium (Cd), cobalt (Co), chrome (Cr), copper (Cu), magnesium (Mg), manganese (Mn), molybdenum (Mo), nickel (Ni), phosphorus (P), lead (Pb), rubidium (Rb), sulfur (S), strontium (Sr), titanium (Ti), thallium (Tl), antimony (Sb), selenium (Se), and zinc (Zn). Placental function was assessed by measuring the following fetal-maternal parameters: Uterine artery Pulsatility Index (UtA PI), Umbilical artery Pulsatility Index (UA PI) and Middle Cerebral artery Pulsatility Index (MCA PI). The association between the chemical elements concentration and study group and the association with Doppler measures were evaluated., Results: SGA was associated with significantly (p < 0.05) lower concentrations of Al (AGA 21.14 vs SGA 0.51 mg/kg), Cr (AGA 0.17 vs SGA 0.12 mg/kg), Cu (AGA 0.89 vs SGA 0.81 mg/kg), Mg (AGA 0.007 vs SGA 0.006 g/100g), Mn (AGA 0.60 vs SGA 0.47 mg/kg), Rb (AGA 1.68 vs SGA 1.47 mg/kg), Se (AGA 0.02 vs SGA 0.01 mg/kg), Ti (AGA 0.75 vs SGA 0.05 mg/kg) and Zn (AGA 9.04 vs SGA 8.22 mg/kg). Lower placental concentrations of Al, Cr, Mn, Se, Ti were associated with abnormal UtA, UA and MCA Doppler., Discussion: Lower placental concentrations of Al, Cr, Cu, Mn, Rb, Se, Ti and Zn are associated with SGA fetuses and abnormal fetal-maternal Doppler results. Additional studies are required to further understand how chemical elements affect fetal growth and potentially find strategies to prevent SGA., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Brief hypercapnic challenge causes acute placental hypoperfusion with fetal brain sparing on BOLD-MRI. We hypothesize that this non-invasive imaging strategy can distinguish between normal pregnancy and chronic placental hypoperfusion (using the maternal hypoxia model)., Methods: Eighteen pregnant female ICR mice were randomized to three groups: normoxia, late-onset hypoxia (12%O 2 ;E13.5-17.5) and early-onset hypoxia (12%O 2 ;E10.5-17.5). On E17.5, animals were imaged in a 4.7-T Bruker-Biospec MRI scanner. Fast coronal True-FISP was performed to identify organs of interest (placenta and fetal heart, liver and brain). BOLD-MRI was performed at baseline and during a 4-min hypercapnic challenge (5%CO 2 ). %-change in placental and fetal signal was analyzed from T2*-weighted gradient echo MR images. Following MRI, fetuses and placentas were harvested, weighed and immuno-stained., Results: In normoxic mice, hypercapnia caused reduction in BOLD-MRI signal in placenta (-44% ± 7%; p < 0.0001), fetal liver (-32% ± 7%; p < 0.0001) and fetal heart (-54% ± 12%; p < 0.002), with relative fetal brain sparing (-12% ± 5%; p < 0.0001). These changes were markedly attenuated in both hypoxia groups. Baseline fetal brain/placenta SI ratio was highest in normoxic mice (1.14 ± 0.017) and reduced with increasing duration of hypoxia (late-onset hypoxia: 1.00 ± 0.026; early-onset hypoxia: 0.91 ± 0.016; p = 0.02). Both hypoxic groups exhibited fetal growth restriction with prominent placental glycogen-containing cells, particularly in early-onset hypoxia. There was increased fetal neuro- and intestinal-apoptosis in early-onset hypoxia only., Conclusions: BOLD-MRI with brief hypercapnic challenge distinguished between normoxia and both hypoxia groups, while fetal neuroapoptosis was only observed after early-onset hypoxia. This suggests that BOLD-MRI with hypercapnic challenge can identify chronic fetal asphyxia before the onset of irreversible brain injury., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Pregnancies with small-for-gestational-age fetuses are at increased risk of adverse maternal-fetal outcomes. Previous studies examining the relationship between maternal hemodynamics and fetal growth were mainly focused on high-risk pregnancies and those with fetuses with extreme birthweights, such as less than the 3rd or 10th percentile and assumed a similar growth pattern in fetuses above the 10th percentile throughout gestation., Objective: This study aimed to evaluate the trends in maternal cardiac function, fetal growth, and oxygenation with advancing gestational age in a routine obstetrical population and all ranges of birthweight percentiles., Study Design: This was a prospective, longitudinal study assessing maternal cardiac output and peripheral vascular resistance by bioreactance at 11 +0 to 13 +6 , 19 +0 to 24 +0 , 30 +0 to 34 +0 , and 35 +0 to 37 +0 weeks' gestation, sonographic estimated fetal weight in the last 3 visits and the ratio of the middle cerebral artery by umbilical artery pulsatility indices or cerebroplacental ratio in the last 2 visits. Women were divided into the following 5 groups according to birthweight percentile: group 1, <10th percentile (n=261); group 2, 10 to 19.9 percentile (n=180); group 3, 20 to 29.9 percentile (n=189); group 4, 30 to 69.9 percentile (n=651); and group 5, ≥70th percentile (n=508). The multilevel linear mixed-effects model was performed to compare the repeated measures of hemodynamic variables and z scores of the estimated fetal weight and cerebroplacental ratio., Results: In visit 2, compared with visit 1, in all groups, cardiac output increased, and peripheral vascular resistance decreased. At visit 3, groups 1, 2, and 3, compared with 4 and 5, demonstrated an abrupt decrease in cardiac output and increase in peripheral vascular resistance. From visit 2, group 1 had a constant decline in estimated fetal weight, coinciding with the steepest decline in maternal cardiac output and rise in peripheral vascular resistance. In contrast, in groups 4 and 5, the estimated fetal weight had a stable or accelerative pattern, coinciding with the greatest increase in cardiac output and lowest peripheral vascular resistance. Groups 2 and 3 showed a stable growth pattern with intermediate cardiac output and peripheral vascular resistance. Increasing birthweight was associated with higher cerebroplacental ratio. Groups 3, 4, and 5 had stable cerebroplacental ratio across visits 3 and 4, whereas groups 1 and 2 demonstrated a significant decline (P<.001)., Conclusion: In a general obstetrical population, maternal cardiac adaptation at 32 weeks' gestation parallels the pattern of fetal growth and oxygenation; babies with birthweight<20th percentile have progressive decline in fetal cerebroplacental ratio, decline in maternal cardiac output, and increase in peripheral vascular resistance., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

Introduction: Women with pregnancies complicated by IUGR are at increased risk for future cardiovascular disease. Nevertheless, it is unknown whether endothelial function of women with pregnancies complicated by IUGR is already impaired during pregnancy. Hence, we evaluated maternal endothelial function in pregnancies complicated by IUGR due to placental dysfunction., Methods: Prospective cohort study assessing systemic endothelial function of women with singleton pregnancies and estimated fetal weight (EFW) below 10th percentile and abnormal umbilical artery flow (n = 15). Control group included women with singleton pregnancies and normal EFW (n = 22). Endothelial function was assessed using EndoPAT™ device which evaluates the change in peripheral vascular tone in reaction to temporal ischemia, a process called reactive hyperemia. The ratio of the readings before and after ischemia is used to assess endothelial function and called reactive hyperemia index (RHI). Low RHI values indicate endothelial dysfunction., Results: The median gestational age at endoPAT examination was comparable between the IUGR and control groups (32; IQR 31,33; p = 0.18). The median RHI was significantly lower in the IUGR group compared to the control group (1.3 vs 1.5, p = 0.02). Median gestational age at delivery and mean neonatal birth weight were lower in the IUGR group compared to the control group (36.7 (35.6,37.2) vs 37.7 (35.3, 39.3), p = 0.04 and 1647 ± 414 g vs 2785 ± 587 g, p < 0.001)., Discussion: Pregnant women with IUGR due to placental dysfunction are characterized by impaired systemic endothelial function., (Copyright © 2021. Published by Elsevier Ltd.)

Objective: To evaluate the association between intrauterine growth restriction (IUGR) and the incidence of fetuses with patent ductus arteriosus (PDA) and Hemodynamically significant PDA (Hs-PDA) in dichorionic twins (DC) with selective IUGR., Materials and Methods: This is an observational cohort study and retrospective case assessment, involved twins born at Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan between 2013 and 2018. DC twins with selective IUGR (sIUGR) were defined as the presence of a birth weight discordance of >25% and a smaller twin with a birth weight below the tenth percentile. PDA was diagnosed using echocardiography between postnatal day 3 and 7. Hs-PDA was defined as PDA plus increased pulmonary circulation, poor systemic perfusion, cardiomegaly, pulmonary edema, or hypotension requiring pharmacotherapeutic intervention., Result: A total of 1187 twins were delivered during the study period, and 53 DC twins with selective IUGR were included in this study. DC twins with PDA have higher rate of preterm birth, lower gestational age of delivery, and lower mean birth weight of both twins compared with DC twins without PDA. In a comparison of the sIUGR twin with the appropriate for gestational age co-twin, both the incidences of PDA (28.30% vs. 7.55%, respectively; P = 0.003) and Hs-PDA (24.53% vs. 5.66%, respectively; P = 0.002) were higher in sIUGR fetuses than in the appropriate for gestational age co-twins. Small gestational age of delivery was the only variable to predict PDA and Hs-PDA [p = 0.002, Odds ratio = 0.57 (0.39-0.82), p = 0.009, Odds ratio = 0.71 (0.55-0.92), respectively]., Conclusion: An analysis of dichorionic twins with sIUGR indicated that IUGR increased the risk of PDA and hemodynamically significant PDA., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2021. Published by Elsevier B.V.)

Introduction: Impaired placental development is a major cause of fetal growth restriction (FGR) and early detection will therefore improve antenatal care and birth outcomes. Here we aim to investigate serial first-trimester ultrasound markers of utero-placental (vascular) development in association with embryonic and fetal growth., Methods: In a prospective cohort, we periconceptionally included 214 pregnant women. Three-dimensional power Doppler ultrasonography at 7, 9 and 11 weeks gestational age (GA) was used to measure placental volumes (PV) and basal plate surface area by Virtual Organ Computer-aided AnaLysis™, and utero-placental vascular volume (uPVV), crown-rump length (CRL) and embryonic volume (EV) by a V-scope volume rendering application. Estimated fetal weight (EFW) was measured by ultrasound at 22 and 32 weeks GA and birth weight percentile (BW) was recorded. Linear mixed models and regression analyses were applied and appropriately adjusted. All analyses were stratified for fetal sex., Results: PV trajectories were positively associated with CRL (β adj  = 0.416, 95%CI:0.255; 0.576, p < 0.001), EV (β adj  = 0.220, 95%CI:0.058; 0.381, p = 0.008) and EFW (β adj  = 0.182, 95%CI:0.012; 0.352, p = 0.037). uPVV trajectories were positively associated with CRL (β adj  = 0.203, 95%CI 0.021; 0.384, p = 0.029). In girls, PV trajectories were positively associated with CRL (p < 0.001), EV (p = 0.018), EFW (p = 0.026), and uPVV trajectories were positively associated with BW (p = 0.040). In boys, positive associations were shown between PV trajectories and CRL (p = 0.002), and between uPVV trajectories and CRL (p = 0.046)., Discussion: First-trimester utero-placental (vascular) development is associated with embryonic and fetal growth, with fetal sex specific modifications. This underlines the opportunity to monitor first-trimester placental development and supports the associations with embryonic and fetal growth., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The birth rates among women of advanced maternal age (AMA) have risen over the last two decades; yet, pregnancies with AMA are considered high-risk and are associated with a significant increase in pregnancy complications. Although the mechanisms leading to pregnancy complications in women with AMA are not fully understood, it has been well established in the literature that offspring exposed to unfavorable environmental conditions in utero, such as gestational diabetes, preeclampsia, and/or intrauterine growth restriction during the early stages of development are subject to long-term health consequences. Additionally, angiogenic growth mediators, which drive vascular development of the placenta, are imbalanced in pregnancies with AMA. These same imbalances also occur in pregnancies complicated by preeclampsia, gestational diabetes, and obesity. This review discusses the impact of AMA on pregnancy and offspring health, and the potential mechanistic role of placental angiogenic growth mediators in the development of pregnancy complications at AMA., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Intrauterine growth restriction (IUGR) is a pathological condition of pregnancy with high perinatal mortality and morbidity, characterized by inadequate fetal growth associated to altered maternal hemodynamics with impaired uteroplacental blood flow and placental insufficiency. To date, iatrogenic premature delivery remains the elective therapeutic strategy. However, in recent years the possibility of a therapeutic approach with vasodilators and myorelaxants, such as nitric oxide (NO) donors, has gained interest. NO controls many endothelial cell functions, including angiogenesis and vascular permeability, by regulating the expression of angiogenic factors, such as Vascular Endothelial Growth Factor. In the present study, we investigated if treatment of pregnancies complicated by IUGR with NO donors affects the expression of Epidermal Growth Factor-Like Domain 7 (EGFL7), a secreted endothelial factor, previously demonstrated to be expressed by both endothelial and trophoblast cells and involved in proper placental development. NO donor treatment induced placental levels of EGFL7 and, in association with oral fluids, significantly improved fetal growth. Ex vivo experiments confirmed that NO donors increased expression and secretion of EGFL7 by villous explants. To specifically investigate the potential response of trophoblast cells to NO, we treated HTR8-sVneo cells with NO donors and observed induction of EGFL7 expression. Altogether, our findings indicate that NO induces endothelial and trophoblast expression of EGFL7 in the placenta and improves fetal growth, suggesting a correlation between placental levels of EGFL7 and pregnancy outcome., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The diagnostic criteria for preeclampsia have evolved from the traditional definition of de novo hypertension and proteinuria to a broader definition of hypertension with evidence of end-organ dysfunction. Although this change is endorsed by various societies such as the International Society for the Study of Hypertension in Pregnancy and the American College of Obstetricians and Gynecologists, there remains controversy with regard to the implementation of broader definitions and the most appropriate definition of end-organ dysfunction., Objective: This study aimed to assess the impact of different diagnostic criteria for preeclampsia on rates of disease diagnosis, disease severity, and adverse outcomes and to identify associations between each component of the different diagnostic criteria and adverse pregnancy outcomes., Study Design: We performed a retrospective cohort study of singleton pregnancies at Monash Health between January 1, 2016 and July 31, 2018. Within this population, all cases of gestational hypertension and preeclampsia were reclassified according to the International Society for the Study of Hypertension in Pregnancy 2001, American College of Obstetricians and Gynecologists 2018, and International Society for the Study of Hypertension in Pregnancy 2018 criteria. Differences in incidence of preeclampsia and maternal and perinatal outcomes were compared between the International Society for the Study of Hypertension in Pregnancy 2001 group and the extra cases identified by American College of Obstetricians and Gynecologists 2018 and International Society for the Study of Hypertension in Pregnancy 2018. Outcomes assessed included biochemical markers of preeclampsia, a composite of adverse maternal outcomes, and a composite of adverse perinatal outcomes. Multiple logistic regression analysis was also performed to assess each component of the American College of Obstetricians and Gynecologists 2018 and International Society for the Study of Hypertension in Pregnancy 2018 criteria and their associations with adverse maternal and perinatal outcomes., Results: Of 22,094 pregnancies, 751 (3.4%) women had preeclampsia as defined by any of the 3 criteria. Compared with International Society for the Study of Hypertension in Pregnancy 2001, the American College of Obstetricians and Gynecologists 2018 criteria identified an extra 42 women (n=654 vs n=696, 6.4% relative increase) with preeclampsia, and International Society for the Study of Hypertension in Pregnancy 2018 identified an extra 97 women (n=654 vs n=751, 14.8% relative increase). The additional women identified by International Society for the Study of Hypertension in Pregnancy 2018 exhibited a milder form of disease with lower rates of severe hypertension (62.4% vs 44.3%; P<.01) and magnesium sulfate use (11.9% vs 4.1%; P<.05) and a trend toward lower rates of adverse maternal outcomes (9.8% vs 4.1%). These women also delivered at a later gestation, and their babies had a lower number of neonatal intensive care unit admissions and adverse perinatal outcomes. Objective features such as fetal growth restriction, thrombocytopenia, renal and liver impairment, and proteinuria were associated with an increased risk of adverse maternal and perinatal outcomes, whereas subjective neurologic features demonstrated poorer associations., Conclusion: Implementation of broader definitions of preeclampsia will result in an increased incidence of disease diagnosis. However, because women who exclusively fulfill the new criteria have a milder phenotype of the disease, it remains uncertain whether this will translate to improved outcomes., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: To investigate differences in the pregnancy outcomes and placental characteristics of selective intrauterine growth restriction (sIUGR) with or without twin anemia polythemia sequence (TAPS)., Methods: sIUGR patients were assigned into two groups based on the occurrence of TAPS. The pregnancy outcomes and placental characteristics were compared. A diameter of ≥2 mm was defined as thick anastomosis., Results: The prevalence of artery-to-artery (AA) (45.5% vs 88.6%, P = 0.002) and thick AA (0% vs 53.5%) in TAPS group were lower than non-TAPS group. The overall diameter of AA (0.5 (0.4-1.3) vs 2.5 (0.3-7.1) mm, P = 0.001) in TAPS group was smaller than non-TAPS group. The prevalence of thick artery-to-vein (AV) (0% vs 36.0%) in TAPS group was lower than non-TAPS group. Also, the overall diameter of AV (0.9 (0.6-2.1) vs 4.8 (0.3-17.8) mm, P < 0.001) in TAPS group was smaller than non-TAPS group. The total quantity (2 (1-6) vs 6 (1-16), P = 0.001), and the overall diameter of anastomoses (1.1 (0.6-4.7) vs 7.5 (0.5-22.4) mm, P < 0.001) were smaller in TAPS group than non-TAPS group. The placental territory discordance ratio of TAPS group was smaller than non-TAPS group (0.39 (0.13-0.56) vs 0.56 (0.01-0.88), P = 0.008). The umbilical cord insertion distance ratio in TAPS group was higher than non-TAPS group (0.81 ± 0.12 vs 0.57 ± 0.20, P < 0.001)., Discussion: The placental anastomoses of sIUGR with TAPS were small. sIUGR with TAPS had smaller differences in placental share and larger distances between umbilical cord insertions., (Copyright © 2020. Published by Elsevier Ltd.)

Introduction: Abnormal levels of first trimester placental biomarkers are associated with the development of placental syndrome (PS). However, prediction performance is moderate, possibly explained by the clinical heterogeneity of PS. Aim of this study is to investigate the association between first trimester biomarkers and the presence of maternal vascular malperfusion (MVM), as a marker for placental insufficiency., Methods: This retrospective study included 195 women with available first trimester blood sample and placenta histological sections for examination at the Maastricht University Medical Centre. Women were divided into 4 groups, based on the presence of having MVM lesions and/or PS. Levels of PAPP-A, PlGF and sFlt-1 were measured and MVM lesions were classified according to the Amsterdam Placental Workshop Group Consensus Statement., Results: MVM occurrence was observed in 32% of the uncomplicated pregnancies. Women with MVM (regardless of the PS) had lower levels of PAPP-A (p = 0.038) and sFLt-1 (p = 0.006), and a non-significant trend for lower PlGF and sFlt-1/PlGF ratio compared to women without MVM. Low PAPP-A levels individually and in combination with the presence of PS was significantly associated with MVM lesions (aOR = 3.0 and 6.1, respectively), as did the combination of low PlGF levels and PS (aOR = 4.6). In women with PS, having MVM increased the incidence of fetal growth restriction, small for gestational age neonates, lower birthweight and adverse neonatal outcome., Discussion: Our findings suggest that MVM lesions were found to be associated with increased obstetric risks due to early placental dysfunction that can potentially be predicted by the use of first trimester biomarkers., Competing Interests: Declaration of competing interest There are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aims: Intrauterine growth restriction (IUGR) can increase the risk of hypertension and kidney disease at adulthood due to fetal programming. In our previous study, we found that supplementation with low concentration of ouabain during pregnancy could restore glomerulus numbers at birth, rescuing kidney development. However, the metabolic pattern of kidney in IUGR offspring and the effect of ouabain have not been evaluated., Main Methods: In this study, based on GC-MS and LC-MS platforms, we used the protein restriction rat model to explore the molecular mechanisms of kidney damage induced by IUGR and the protective effect of ouabain., Key Findings: The results showed that malnutrition could induce IUGR in rat offspring at the 20th gestational day but ouabain treatment could partially reverse the body and kidney weight loss. Ouabain treatment could upregulate arginine, N-acetylornithine and carbamoyl phosphate as well as adenine nucleotide and guanine nucleotide downregulated by low-protein diet. Moreover, six metabolites were identified to be significantly correlated with fetal kidney weight, with 3 metabolites involved in arginine metabolism (arginine, N-acetylornithine, urea) and UDP-glucuronate correlated positively, while lysine and anthranilate correlated negatively., Significance: The results suggested that the underlying mechanism of ouabain against renal maldevelopment involved the metabolic regulation, particularly the arginine metabolism, which played an important role in the development of fetal kidney., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest with respect to the research and/or publication of this study., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The placenta is essential for the efficient delivery of nutrients and oxygen from mother to fetus to maintain normal fetal growth. Dysfunctional placental development underpins many pregnancy complications, including fetal growth restriction (FGR) a condition in which the fetus does not reach its growth potential. The FGR placenta is smaller than normal placentae throughout gestation and displays maldevelopment of both the placental villi and the fetal vasculature within these villi. Specialized epithelial cells called trophoblasts exhibit abnormal function and development in FGR placentae. This includes an altered balance between proliferation and apoptotic death, premature cellular senescence, and reduced colonisation of the maternal decidual tissue. Thus, the placenta undergoes aberrant changes at the macroscopic to cellular level in FGR, which can limit exchange capacity and downstream fetal growth. This review aims to compile stereological, in vitro, and imaging data to create a holistic overview of the FGR placenta and its pathophysiology, with a focus on the contribution of trophoblasts., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Sow litter sizes have increased, subjecting more small piglets to intra-uterine growth restriction (IUGR). Research on the development and growth of IUGR pigs is limited. The objective of this study was to compare the body composition and organ development of IUGR pigs at weaning, and to estimate their growth performance from birth to 30 kg. A total of 142 IUGR and 142 normal piglets were classified at birth based on their head morphology. At weaning, 20 IUGR and 20 normal piglets were collected, a whole-body dual-energy x-ray absorption scan was performed, and the piglets were euthanized for organ measurements. Body weight (BW) was measured weekly from birth to 30 kg, rectal temperature and whole-blood glucose levels were measured weekly from birth to weaning, and blood samples were collected at days 7, 14 and 21 for IGF-1 analysis. Results showed that IUGR pigs have a similar percentage of adipose tissue (P > 0.05) compared to normal pigs at 24 days of age. Organs were smaller (P < 0.001) in IUGR pigs than in normal pigs, whereas brain, liver, lungs and adrenal glands were relatively larger (P < 0.05) in relation to the BW of IUGR pigs. Average birth weight (BiW) of normal pigs was greater (P < 0.001) compared with IUGR pigs (1.38 v. 0.75 kg), and the average daily gain (ADG) of IUGR pigs was reduced from day 0 to 14, day 0 to 28 (weaning) and from weaning to 30 kg compared to normal pigs. From birth to weaning at day 28, IUGR piglets had a 72.9 g/day greater fractional ADG (FADG) in relation to their BiW (P < 0.05), but FADG did not differ (P > 0.05) from weaning to 30 kg. Rectal temperature of IUGR piglets was greater (P < 0.05) on day 7 compared with normal piglets, and, even though blood glucose levels were decreased (P < 0.001) in IUGR piglets at day 0, neither glucose nor IGF-1 concentrations differed (P > 0.05) between IUGR and normal piglets. In conclusion, IUGR piglets exhibited some relatively larger organs at weaning compared to normal pigs, but body composition was similar between IUGR and normal pigs. In addition, IUGR pigs had a reduced ADG from birth to 30 kg, and, although they exhibited a greater FADG during nursing, IUGR pigs still require six additional days to reach a BW of 30 kg in comparison to normal pigs.

The most common cause of intrauterine growth restriction (IUGR) in the developed world is placental insufficiency, a concept often used synonymously with reduced utero-placental and umbilical blood flows. However, placental insufficiency and IUGR are associated with complex, coordinated and highly regulated changes in placental signaling and nutrient transport including inhibition of insulin and mTOR signaling and down-regulation of specific amino acid transporters, Na + /K + -ATPase, the Na +/ H + -exchanger, folate and lactate transporters. In contrast, placental glucose transport capacity is unaltered and Ca 2+ -ATPase activity and the expression of proteins involved in placental lipid transport are increased in IUGR. These findings are not entirely consistent with the traditional view that the placenta is dysfunctional in IUGR, but rather suggest that the placenta adapts to reduce fetal growth in response to an inability of the mother to allocate resources to the fetus. This new model has implications for the understanding of the mechanisms underpinning IUGR and for the development of intervention strategies., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background and Aims: Intrauterine growth restriction (IUGR) is a state of slower fetal growth usually followed by a catch-up growth. Postnatal catch-up growth in IUGR models increases the incidence of pulmonary arterial hypertension in adulthood. Here, we hypothesize that the adverse pulmonary vascular consequences of IUGR may be improved by slowing down postnatal growth velocity. Meanwhile, cognitive function was also studied., Methods and Results: We established an IUGR rat model by restricting maternal food throughout gestation. After birth, pups were fed a regular or restricted diet during lactation by changing litter size. Thus, there were three experimental groups according to the dam/offspring diet: C/C (gold standard), IUGR with catch-up growth (R/C) and IUGR with delayed growth (R/D). In adulthood (14 weeks of age), we assessed pulmonary vascular development by hemodynamic measurement and immunohistochemistry. Our results showed that adult R/C offspring developed an elevated mean pulmonary arterial pressure (mPAP) and pulmonary arteriolar remodeling accompanied with decreased eNOS mRNA and protein expressions compared to C/C or R/D offspring. This suggested that delayed postnatal growth improved pulmonary circulation compared to postnatal catch-up growth. Conversely, adult R/D offspring performed poorly in cognition. Behavior test and electrophysiology results exhibited a reduced synaptic plasticity. Furthermore, decreased mRNA expression levels of the memory-related gene zif268 and transcription factor recruitment factor p300 in the hippocampus region were also observed in R/D group., Conclusion: These findings indicate that delayed postnatal growth results in cognitive impairment, but it reverses elevations in mPAP induced by postnatal catch-up growth following IUGR., (Copyright © 2019 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Purpose: To evaluate the effect of maternal hyperoxygenation on placental perfusion in normal and Fetal Growth Restricted (FGR) pregnancies using Intravoxel Incoherent Motion (IVIM)., Methods: Ten FGR pregnancies and twenty-five normal pregnancies underwent IVIM examinations before and after maternal hyperoxygenation (95% O 2 , 5% CO 2 ) using a 1.5T MR scanner. The IVIM parameters (f p , D t , D p ) were determined for the placentas of both groups. The IVIM parameters within and between groups and their correlations with Doppler findings were statistically analyzed. ROC analysis was performed to evaluate the diagnostic power of IVIM derived parameters., Results: Before maternal hyperoxygenation, the perfusion fraction f p was significantly lower in the FGR group than that in the normal group (22.88±10.29 (%) vs. 36.28±9.70 (%), p = 0.000). After maternal hyperoxygenation, f p decreased significantly in the normal group (36.28±9.70 (%) vs. 29.93±10.25 (%), p = 0.032), whereas it remained relatively stable in the FGR group (22.88±10.29 (%) vs. 24.38±13.67 (%), p = 0.508). An increase of D t was found only for the normal group and D p did not changed significantly after maternal hyperoxygenation. There existed a negative correlation between f ppre and umbilical artery pulsatility index (PI) (r = -0.385, p < 0.05) as well as D tpost and PI (r = -0.574, p < 0.01). The f ppre displayed a best diagnostic power of all parameters with the area under curve (AUC) of 0.912., Conclusion: The perfusion fraction, f p , is able to distinguish FGR from normal pregnancies by its value pre and by its change (or lack thereof) post maternal hyperoxygenation. IVIM may potentially help improve the diagnosis of placenta function as it relates to disease., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: To determine whether abnormal global, transverse, and longitudinal ventricular contractility of the heart in fetuses with an estimated fetal weight <10th centile is present, irrespective of Doppler studies of the umbilical artery and cerebroplacental ratio., Study Design: This was a retrospective study of 50 fetuses with an estimated fetal weight <10th centile that were classified based on Doppler results from the pulsatility indices of the umbilical artery and middle cerebral artery, and the calculated cerebroplacental ratio (pulsatility indices of the umbilical artery/middle cerebral artery). Right and left ventricular measurements were categorized into 3 groups: (1) global ventricular contractility (fractional area change), (2) transverse ventricular contractility (24-segment transverse fractional shortening), and (3) basal-apical longitudinal contractility (longitudinal strain, longitudinal displacement fractional shortening, and basal lateral and septal wall annular plane systolic excursion). Z scores for the above measurements were computed for fetuses with an estimated fetal weight <10th centile using the mean and standard deviation derived from normal controls. Ventricular contractility measurements were considered abnormal if their Z score values were <5th centile (z score <-1.65) or >95th centile (Z score >1.65), depending on the specific ventricular measurement., Results: The average gestational age at the time of the examination was 32 weeks 4 days (standard deviation 3 weeks 4 days). None of the 50 study fetuses demonstrated absent or reverse flow of the umbilical artery Doppler waveform. Eighty-eight percent (44/50) of fetuses had one or more abnormal measurements of cardiac contractility of 1 or both ventricles. Analysis of right ventricular contractility demonstrated 78% (39/50) to have 1 or more abnormal measurements, which were grouped as follows: global contractility 38% (19/50), transverse contractility 66% (33/50); and longitudinal contractility 48% (24/50). Analysis of left ventricular contractility demonstrated 1 or more abnormal measurements in 58% (29/50) that were grouped as follows: global contractility 38% (19/50); transverse contractility 40% (20/50); and longitudinal contractility 40% (20/50). Of the 50 study fetuses, 25 had normal pulsatility index of the umbilical artery and cerebroplacental ratios, 80% of whom had 1 or more abnormalities of right ventricular contractility and 56% of whom had 1 or more abnormalities of left ventricular contractility. Abnormal ventricular contractility for these fetuses was present in all 3 groups of measurements; global, transverse, and longitudinal. Those with an isolated abnormal pulsatility index of the umbilical artery (n=11) had abnormalities of transverse contractility of the right ventricular and global contractility in the left ventricle. When an isolated cerebroplacental ratio abnormality was present, the right ventricle demonstrated abnormal global, transverse, and longitudinal contractility, with the left ventricle only demonstrating abnormalities in transverse contractility. When both the pulsatility index of the umbilical artery and cerebroplacental ratio were abnormal (3/50), transverse and longitudinal contractility measurements were abnormal for both ventricles, as well as abnormal global contractility of the left ventricle., Conclusions: High rates of abnormal ventricular contractility were present in fetuses with an estimated fetal weight <10th centile, irrespective of the Doppler findings of the pulsatility index of the umbilical artery, and/or cerebroplacental ratio. Abnormalities of ventricular contractility were more prevalent in transverse measurements than global or longitudinal measurements. Abnormal transverse contractility was more common in the right than the left ventricle. Fetuses with estimated fetal weight less than the 10th centile may be considered to undergo assessment of ventricular contractility, even when Doppler measurements of the pulsatility index of the umbilical artery, and cerebroplacental ratio are normal., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The Polyvagal theory argues that behavioral modulation is a fundamental neurodevelopmental process that depends on autonomic regulation., Objective: The present study aimed to assess sleep architecture in newborns with fetal growth restriction (FGR) using polysomnography as an indicator of Polyvagal theory., Methods: We studied polysomnography recordings from 68 preterm infants, 34 with FGR and 34 born with appropriate growth for gestational age (AGA), who were matched according to the corrected age for prematurity (CA). Total sleep time, arousals, the percentage of quiet sleep, active sleep, indeterminate sleep, and heart rate were compared between the groups. Linear multiple regression analyses were used to evaluate polysomnography data for the FGR and AGA groups., Results: Average heart rate was significantly lower in most FGR groups compared with AGA groups, and small to large effect sizes were observed in several sleep responses when comparing these groups. In the lineal regression model the CA explains significantly the differences in heart rate, controlled by FGR (p = .012). Additionally, there was evidence that sleeping states show similar trends, that is, increases in quiet and indeterminate sleep, as well as decreases in active sleep when CA was controlled by FGR., Conclusion: FGR probably intensifies the unfavorable effect of preterm birth in the responses evaluated by polysomnography. It seems that FGR is associated with alteration in sleep regulation and with differences in heart rate modulation, which may serve as a strategy to preserve energy and such differences likely underlie neurodevelopmental impairments in affected newborns., (Copyright © 2019 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Background: Fetal growth restriction accounts for a significant proportion of perinatal morbidity and death. The cerebroplacental ratio is gaining much interest as a useful tool in differentiating the "at-risk" fetus in both fetal growth restriction and appropriate-for-gestational-age pregnancies. The Prospective Observational Trial to Optimize Pediatric Health in Fetal Growth Restriction group has demonstrated previously that the presence of this "brain-sparing" effect is associated significantly with adverse perinatal outcomes in the fetal growth restriction cohort. However, data about neurodevelopment in children from pregnancies that are complicated by fetal growth restriction are sparse and conflicting., Objective: The aim of the Prospective Observational Trial to Optimize Pediatric Health in Fetal Growth Restriction NeuroDevelopmental Assessment Study was to determine whether children born after fetal growth-restricted pregnancies are at additional risk of adverse early childhood developmental outcomes compared with children born small for gestational age. The objective of this secondary analysis was to describe the role of cerebroplacental ratio in the prediction of adverse early childhood neurodevelopmental outcome., Study Design: Participants were recruited prospectively from the Perinatal Ireland multicenter observational Prospective Observational Trial to Optimize Pediatric Health in Fetal Growth Restriction study cohort. Fetal growth restriction was defined as birthweight <10th percentile with abnormal antenatal umbilical artery Doppler indices. Small for gestational age was defined similarly in the absence of abnormal Doppler indices. Cerebroplacental ratio was calculated with the pulsatility indices of the middle cerebral artery and divided by umbilical artery with an abnormal value <1. Children (n=375) were assessed at 3 years with the use of the Ages and Stages Questionnaire and the Bayley Scales of Infant and Toddler Development, 3rd edition. Small-for-gestational-age pregnancies with normal Doppler indices were compared with (1) fetal growth-restricted cases with abnormal umbilical artery Doppler and normal cerebroplacental ratio or (2) fetal growth restriction cases with both abnormal umbilical artery and cerebroplacental ratio. Statistical analysis was performed with statistical software via 2-sample t-test with Bonferroni adjustment, and a probability value of .00625 was considered significant., Results: Assessments were performed on 198 small-for-gestational-age children, 136 fetal growth-restricted children with abnormal umbilical artery Doppler images and normal cerebroplacental ratio, and 41 fetal growth-restricted children with both abnormal umbilical artery Doppler and cerebroplacental ratio. At 3 years of age, although there were no differences in head circumference, children who also had an abnormal cerebroplacental ratio had persistently shorter stature (P=.005) and lower weight (P=.18). Children from fetal growth restriction-affected pregnancies demonstrated poorer neurodevelopmental outcome than their small-for-gestational-age counterparts. Fetal growth-restricted pregnancies with an abnormal cerebroplacental ratio had significantly poorer neurologic outcome at 3 years of age across all measured variables., Conclusion: We have demonstrated that growth-restricted pregnancies with a cerebroplacental ratio <1 have a significantly increased risk of delayed neurodevelopment at 3 years of age when compared with pregnancies with abnormal umbilical artery Doppler evidence alone. This study further substantiates the benefit of routine assessment of cerebroplacental ratio in fetal growth-restricted pregnancies and for counseling parents regarding the long-term outcome of affected infants., (Copyright © 2019. Published by Elsevier Inc.)

Aim: Long-term follow-up studies on children born with fetal growth restriction (FGR) have revealed a specific profile of neurocognitive difficulties, including problems with speech, language and literacy skills. We hypothesized that problems with communication skills, including language use and literacy skills of FGR children at primary school age are associated with prenatal circulatory changes., Methods: Ultrasonographic assessment of fetoplacental hemodynamics was performed prenatally in 77 fetuses. After a follow-up period of 8-10 years, assessment of reading and spelling skills using standardized tests and the Children's Communication Questionnaire (CCC-2) was performed to measure different language skills in 37 FGR children and 31 appropriately grown (AGA) controls, matched for gestational age., Results: Increased blood flow resistance in the umbilical artery (UA PI >2 SD) during fetal life showed odds ratios of 3.5-19.1 for poor literacy and communication skills and need for speech and language therapy. Furthermore, FGR children with prenatal cerebral vasodilatation (cerebroplacental ratio (CPR) < -2 SD) had significantly poorer literacy and communication skills, at primary school age compared to the AGA controls. Abnormal CPR demonstrated odds ratios of 4.2-28.1 for poor literacy and communication skills and need for speech and language therapy., Conclusion: Increased blood flow resistance in the umbilical artery and cerebral vasodilatation are associated with poor communication, language, and literacy skills at early school age in children born with FGR. These findings indicate the need for continuous follow-up of this group and timely targeted support to ensure optimal academic outcomes., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: Children born from pregnancies that were complicated by hypertensive disorders of pregnancy (HDP, i.e. pre-eclampsia or HELLP syndrome) are at risk for elevated systolic and diastolic blood pressure (SBP/DBP) in childhood., Aim: To examine which neonatal, life style, and family characteristics are associated with SBP/DBP., Methods: Study design: Prospective cohort., Subjects: 12-years-old preterm and growth restricted children born to women with severe early-onset HDP., Outcome Measures: SBP/DBP standard deviation scores (SDS), corrected for age, gender and height., Results: Ninety-two of the 174 mother-child pairs participated at age 12 years (mean gestational age 32 weeks, range 27 to 38 weeks, mean birth weight ratio (BWR) 0.68, range 0.33 to 0.99). Mean SBP SDS was 0.70 ± 0.81 and mean DBP SDS was 0.14 ± 0.78. SBP SDS was positively associated with very preterm birth (beta 0.53, p = .002), with child BMI SDS (beta 0.25, p = .035), and maternal BMI ≥ 25 kg/m 2 at 12 years (beta 0.49, p = .003), and not with pre-pregnancy maternal BMI ≥ 25 kg/m 2 . DBP SDS was positively associated with maternal BMI ≥ 25 kg/m 2 (beta 0.35, p 0.002). BWR was not associated with blood pressure., Conclusions: In 12-years old children born to women with HDP, higher systolic blood pressure values were associated with very preterm birth and child BMI. Higher blood pressure values were also associated with current maternal BMI ≥ 25 kg/m 2 . Life style adaptations may benefit long-term cardio vascular health in mother and child., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Infants born small for gestational age because of pathologic placenta-mediated fetal growth restriction can be difficult to distinguish from those who are constitutionally small. Additionally, even among fetal growth-restricted pregnancies with evident placental disease, considerable heterogeneity in clinical outcomes and long-term consequences has been observed. Gene expression studies of fetal growth-restricted placentas also have limited consistency in their findings, which is likely due to the presence of different molecular subtypes of disease. In our previous study on preeclampsia, another heterogeneous placenta-centric disorder of pregnancy, we found that, by clustering placentas based only on their gene expression profiles, multiple subtypes of preeclampsia, including several with co-occurring suspected fetal growth restriction, could be identified., Objective: The purpose of this study was to discover placental subtypes of normotensive small-for-gestational-age pregnancies with suspected fetal growth restriction through the use of unsupervised clustering of placental gene expression data and to investigate their relationships with hypertensive suspected fetal growth-restricted placental subtypes., Study Design: A new dataset of 20 placentas from normotensive small-for-gestational-age pregnancies (birthweight <10th percentile for gestational age and sex) with suspected fetal growth restriction (ultrasound features of placental insufficiency) underwent genome-wide messenger RNA expression assessment and blinded detailed histopathologic evaluation. These samples were then combined with a subset of samples from our previously published preeclampsia cohort (n=77) to form an aggregate fetal growth-focused cohort (n=97) of placentas from normotensive small-for-gestational-age, hypertensive (preeclampsia and chronic hypertensive) small-for-gestational-age, and normotensive average-for-gestational-age pregnancies. Gene expression data were subjected to unsupervised clustering, and clinical and histopathologic features were correlated to the identified sample clusters., Results: Clustering of the aggregate dataset revealed 3 transcriptional subtypes of placentas from normotensive small-for-gestational-age/suspected fetal growth-restricted pregnancies, with differential enrichment of clinical and histopathologic findings. The first subtype exhibited either no placental disease or mild maternal vascular malperfusion lesions, and, co-clustered with the healthy average-for-gestational-age control subjects; the second subtype showed more severe evidence of hypoxic damage and lesions of maternal vascular malperfusion, and the third subtype demonstrated an immune/inflammatory response and histologic features of a maternal-fetal interface disturbance. Furthermore, all 3 of these normotensive small-for-gestational-age subtypes co-clustered with a group of placentas from hypertensive small-for-gestational-age pregnancies with more severe clinical outcomes, but very comparable transcriptional and histologic placental profiles., Conclusion: Overall, this study provides evidence for at least 2 pathologic placental causes of normotensive small-for-gestational-age, likely representing true fetal growth restriction. These subtypes also show considerable similarity in gene expression and histopathology to our previously identified "canonical" and "immunologic" preeclampsia placental subtypes. Furthermore, we discovered a subtype of normotensive small-for-gestational-age (with suspected fetal growth restriction) with minimal placental disease that may represent both constitutionally small infants and mild fetal growth restriction, although these cannot be distinguished with the currently available data. Future work that focuses on the identification of etiology-driven biomarkers and therapeutic interventions for each subtype of fetal growth restriction is warranted., (Copyright © 2018. Published by Elsevier Inc.)

Fetal growth and development are dependent on adequate placental nutrient transfer. The surface area of the placental villous network is a key determinant of nutrient exchange, which is regulated by vasculogenic and angiogenic factors. These factors are altered by intrauterine growth restriction (IUGR) and maternal obesity in both the first (F1) and second (F2) generations. We investigated the impact of endurance exercise in IUGR dams fed a High-fat diet on placental vasculogenesis and angiogenesis. Uteroplacental insufficiency (Restricted) or sham (Control) surgery was induced on embryonic day (E) 18 in Wistar-Kyoto rats. F1 offspring were fed a Chow or High-fat diet from weaning, and at 16 weeks were further allocated an exercise protocol; Sedentary, Exercised prior to and during pregnancy (Exercise), or Exercised during pregnancy only (PregEx). Females were mated (20 weeks) and F2 placentae collected at E20. Maternal Restriction, High-fat feeding and Exercise had a minimal impact on placental regulators of vasculogenesis and angiogenesis. However, Restriction increased placental labyrinth tissue area in Chow-fed dams. PregEx induced overt adaptations, including increased VEGFA and decreased PLGF protein expression, and reduced blood space area. These alterations were sex-dependent and associated with alterations in miRNA27a, a known regulator of VEGF translation. These data highlight that maternal exercise initiated during pregnancy (PregEx) causes alterations in placental vasculogenesis and angiogenesis in a sex-dependent manner, with minimal Restriction and maternal diet effects. However, further investigation is required to determine if these adaptations are beneficial or harmful for maternal and fetoplacental outcomes., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background and Aims: Intrauterine growth restriction (IUGR) is a major risk factor for perinatal morbidity and mortality, leading to long-term adverse cardiovascular outcomes. The present study aimed to investigate the potential mechanisms in IUGR-associated vascular endothelial dysfunction., Methods and Results: Human umbilical vein endothelial cells (HUVECs) were derived from IUGR or normal newborns. We found that the proliferation of IUGR-derived HUVECs was accelerated compared to those from normal subjects. Gene profiles related to vascular function including vasomotion, oxidative stress, and angiogenesis were dysregulated in IUGR-HUVECs. Compared with HUVECs from normal newborns, nitric oxide (NO) production was reduced, with imbalance between endothelial nitric oxide synthase (eNOS) and arginase-2 (Arg-2) in IUGR. Meanwhile, intracellular asymmetric dimethylarginine (ADMA) level was elevated with diminished dimethylarginine dimethylaminohydrolase 1 (DDAH1) expression in IUGR-HUVECs. Furthermore, endothelin-1 (ET-1) and hypoxia-inducible factor 1α (HIF-1α) expression were increased, and endothelin receptor type-B (ET B R) was reduced in the IUGR group. IUGR-HUVECs exposed to hypoxia increased the ratio of ADMA to l-arginine, HIF-1α and protein arginine methyltransferase 1 (PRMT1) expression compared to controls., Conclusions: The present study demonstrated that the reduction of NO bioavailability and release results from elevated Arg-2, accumulation of intracellular ADMA, and imbalance of ET-1 and ET B R, further leading to IUGR-associated vascular endothelial dysfunction. Our study provides novel evidence on the mechanism underlying fetal programming associated with IUGR, which will serve as potential therapeutic targets in the prevention of adverse cardiovascular consequences in adulthood., (Copyright © 2018 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Objective: The current study aims to assess the efficacy of fetal middle cerebral artery/umbilical artery pulsatility index ratio (cerebroplacental ratio CPR) in predicting the occurrence of adverse perinatal outcomes in pregnancies complicated with severe pre-eclampsia., Materials and Methods: This cohort study included 100 pregnant women between 34 and 40 weeks of gestation attended the labor ward and diagnosed with severe pre-eclampsia. Doppler evaluation was carried out to measure the CPR. Apgar score and fetal umbilical artery pH were assessed within 5 min of delivery. The rate of neonatal intensive care unit (NICU) admission was obtained., Results: Apgar score at 5 min >7 was in 82 cases (82%) and 12 cases (12%) scored < 7. Fetal blood PH was >7.2 in 67% of cases while 33% of cases had PH <7.2. As regard the NICU admission; 66% of neonates did not need admission while 34% of neonates were admitted to the NICU. There was a significant association between CPR and low Apgar score at 5 min (P < 0.001). The sensitivity of CPR in detection of Apgar score <7 was 50%, and specificity 88.1%. CPR had a poor predictive value of the low umbilical artery PH <7.2 (P = 0.318) with 43.75% sensitivity and 69.05% specificity. There was a significant association between CPR and NICU admission (P = 0.009)., Conclusions: Adding CPR ratio to routine antepartum fetal surveillance from 34 weeks gestation may help with patient counseling regarding adverse neonatal outcomes for women with severe pre-eclampsia as there is a strong correlation between it and adverse neonatal outcomes., (Copyright © 2018 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Objective: Fetuses with fetal growth restrictions have higher perinatal mortality rates than fetuses without fetal growth restrictions. Vascularization of the fetal kidney is crucial to fetal growth. Hence, we assessed blood flow and vascularization of fetal kidneys in non-growth-restricted as well as growth-restricted fetuses using quantitative three-dimensional power Doppler ultrasound., Materials and Methods: We undertook a prospective study to evaluate the vascular indices of fetal kidneys; i.e., the vascularization index, flow index and vascularization-flow index, in growth-restricted and non-growth-restricted fetuses using three-dimensional power Doppler ultrasound and quantitative three-dimensional histogram analysis. All fetuses from 20 to 40 weeks of gestation were singletons with a normal pregnancy and were followed up to delivery., Results: In total, 209 fetuses without fetal growth restriction and 50 fetuses with fetal growth restriction were included. Our results showed the fetal renal vascularization index, flow index, and vascularization-flow index evaluated by three-dimensional power Doppler ultrasound can differentiate fetuses with fetal growth restriction from fetuses without fetal growth restriction., Conclusion: The fetal renal vascularization index, flow index, and vascularization-flow index measured by three-dimensional power Doppler ultrasound can be applied to prenatally detect fetal growth restriction. Our data support assessment of the fetal renal vascularization index, flow index, and vascularization-flow index using three-dimensional power Doppler ultrasound as a useful test for detecting fetuses with fetal growth restriction., (Copyright © 2018. Published by Elsevier B.V.)

We explored whether there was a relationship between the sFlt-1/PlGF ratio in early-late and late-onset SGA patients and whether it is associated with neonatal birth weight., Material/methods: 110 patients who were diagnosed with a fetal weight below the 10th percentile for gestational age and who at the same time delivered neonates with a birth weight below the 10th percentile for gestational age. For each of the patients sFlt-1, PlGF and the sFlt-1/PlGF ratio were studied and uterine artery (UtA) and umbilical artery (UA) Doppler were performed., Results: sFlt-1/PlGF ratios and neonatal birth weight which showed significant negative correlation across the entire population studied (R = -0.46, p < 0.001). In late-onset SGA patients this negative correlation was observed, as well (R = -0.54, p < 0.001) In the group of patients with pregnancies older than 34 weeks and an sFlt-1/PlGF ratio ≥38, we observed a significantly lower neonatal birth weight when compared to the same gestational age group with an sFlt-1/PlGF ratio <38 (2045 g vs 2405 g, p < 0.001)., Conclusion: Late-onset SGA syndromes are characterized by lower sFlt-1/PlGF ratios, which indicates a lower degree of placental function impairment. The sFlt-1/PlGF ratio can be a predictor of more significant growth disorders and a lower neonatal birth weight. The sFlt-1/PlGF ratio can be helpful in distinguishing between disordered angiogenesis-dependent and other causes of late-onset SGA cases., (Copyright © 2018 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Objective: Intrauterine growth restriction (IUGR) is one of the most serious complications of pregnancy. Up to date, there is no evidence of achieving antenatal treatment of IUGR with abnormal placentation. Although, Sildenafil citrate has shown promising results, there are no firm conclusion till now. The aim of our study is to evaluate the use of Sildenafil citrate in the treatment of IUGR cases associated with impaired placental circulation., Materials and Methods: This was a prospective non-randomized study conducted at Mansoura university hospitals starting from March 2016 till October 2017. The studied population included singleton pregnancy and suffering from IUGR associated with impaired placental circulation., Results: This study included 50 pregnant women. Cases were divided into two groups. The first group received sildenafil citrate and the second control group did not receive sildenafil citrate. After 4 weeks after the 1st dose of Sildenafil significant decrease in umbilical artery Doppler indices. There was a statistically significant difference in the mean birth weight at delivery and neonatal admission to the newborn nursery in sildenafil group., Conclusion: sildenafil citrate treatment may present a new hope towards better perinatal outcomes for pregnancies complicated by IUGR and impaired placental circulation that may help to decrease neonatal admission to the newborn nursery., (Copyright © 2018. Published by Elsevier B.V.)

Inhibition of the renin-angiotensin system in early postnatal life is a potential therapeutic approach to prevent long-term cardiovascular and kidney diseases in individuals born small. We determined the long-term effects of juvenile losartan treatment on cardiovascular and kidney function in control male rat offspring and those exposed to uteroplacental insufficiency and born small. Bilateral uterine vessel ligation (Restricted) or sham (Control) surgery was performed in late gestation in Wistar Kyoto rats. At weaning, male offspring were randomly assigned to receive losartan in their drinking water or drinking water alone from 5 to 8 weeks of age, and followed to 26 weeks of age. Systolic blood pressure and kidney function were assessed throughout the study. Pressure myography was used to assess passive mechanical wall properties in mesenteric and femoral arteries from 26-week-old offspring. Losartan treatment for three weeks lowered systolic blood pressure in both Control and Restricted groups but this difference was not sustained after the cessation of treatment. Losartan, irrespective of birth weight, mildly increased renal tubulointerstitial fibrosis when assessed at 26 weeks of age. Mesenteric artery stiffness was increased by the early losartan treatment, and was associated with increased collagen and decreased elastin content. Losartan also exerted long-term increases in fat mass and decreases in skeletal muscle mass. In this study, untreated Restricted offspring did not develop hypertension, vascular dysfunction or kidney changes as anticipated. Regardless, we demonstrate that short-term losartan treatment in the juvenile period negatively affects postnatal growth, and kidney and vascular parameters in adulthood, irrespective of birth weight. The long-term effects of early-life losartan treatment warrant further consideration in settings where the potential benefits may outweigh the risks; i.e. when programmed adulthood diseases are apparent and in childhood cardiovascular and kidney diseases., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The objective of this study was to investigate soluble epidermal growth factor receptor (sEGFR), soluble vascular endothelial growth factor receptor 1 (sFlt-1), soluble endoglin (sEndoglin) and placenta growth factor (PLGF) concentrations in normotensive, preterm and term preeclamptic pregnancies' serum and thus to specify the clinical utility of these biochemical markers in monitoring severity and intrauterine growth retardation of preterm preeclampsia. 172 pregnant women were divided into the following groups: preterm preeclampsia, preterm control, term preeclampsia and term control. Preterm preeclampsia patients were stratified with severe feature (n = 50) and without severe feature (n = 22). sEGFR, sEndoglin and PLGF were assessed using Luminex multiplex immunoassay, whilesFlt-1 was assessed using ELISA. sEGFR was significantly lower in preterm preeclampsia than matched control (p < 0.001) and mildly lower in term preeclampsia than matched control (p < 0.01). On contrary, sFlt-1 was significantly higher in preterm preeclampsia than matched control (p < 0.001) and mildly higher in term preeclampsia than matched control (p < 0.01). sFlt-1, sFlt-1/sEGFR and sFlt-1/PLGF were positively correlated with the severity of preterm preeclampsia (P < 0.001, R value ≥ 0.6), especially sFlt-1/sEGFR had the highest R value (R value = 0.711) among them. Furthermore, sEndoglin and the ratio of sEndoglin/sEGFR were associated with neonatal birth weight small for gestational age (SGA, n = 25) in preterm preeclampsia group., Conclusions: The ratio of sFlt-1/sEGFR could be used as a novel candidate biochemical marker in monitoring the severity of preterm preeclampsia. sEndoglin and sEGFR may be involved in the pathogenesis of SGA in preterm preelampsia., (Copyright © 2018 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Objective: To analyze the usefulness of a clinical protocol for early detection of preeclampsia and/or fetal growth restriction (PE/FGR) using, in previously selected pregnancies, the measurement of the sFlt-1/PlGF ratio at 24-28 weeks of gestation., Study Design: Prospective observational cohort study carried out in a single tertiary hospital in Spain. 5601 consecutive singleton pregnancies with complete follow-up were included. High-risk women for PE/FGR were selected by combining data from maternal history and second trimester uterine artery Doppler. Subsequently these patients underwent intensive monitoring, including the measurement of the sFlt-1/PlGF ratio at 24-28 weeks to predict PE/FGR., Main Outcome Measures: Early, intermediate and late PE/FGR (delivery <32 + 0, 32 + 0 - <36 + 0 and ≥36 + 0 weeks, respectively)., Results: Overall incidence of early, intermediate and late PE/FGR was 0.3%, 0.7% and 3.2%, respectively, being higher in the 4.3% of women selected for intensive monitoring: 5.8%, 8.7% and 15.4%, respectively (all p < 0.001). The area under the curve (AUC) with 95%CI of the sFlt-1/PlGF ratio for detecting early PE/FGR was 0.98 (0.97-1.00), and the sFlt-1/PlGF ratio >95th centile showed a sensitivity (%) of 100 (95%CI, 78.5-100) and specificity (%) of 80.6 (95%CI, 75.0-85.2). The AUC of the sFlt-1/PlGF ratio for detecting intermediate and late PE/FGR was of 0.87 (95%CI, 0.77-0.97) and 0.68 (95%CI, 0.58-0.79), respectively., Conclusion: A contingent strategy of measuring the sFlt-1/PlGF ratio at 24-28 weeks in women previously selected by clinical factors and uterine artery Doppler enables an accurate prediction of PE/FGR. This performance is optimal to predict PE/FGR requiring delivery before 32 weeks., (Copyright © 2018 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Objectives: The objective of this study was the analysis of B-Cell Activating Factor (BAFF) levels in pregnancies affected by PE, and in pregnancies affected by fetal growth restriction without Hypertensive disorders and its possible correlation with pulse wave velocity and cardiac output., Study Design: Prospective study of 69 women at 24-40 weeks gestation. Haemodynamic function was assessed in those with Pre-eclampsia (PE, n = 19), fetal growth restriction (FGR, n = 10) and healthy pregnancies (n = 40). Maternal venous BAFF levels at recruitment were measured using ELISA. We analysed the relationship between BAFF and cardiac output (CO), and BAFF and PWV (pulse wave velocity); the gold standard for assessing arterial stiffness. PWV was measured with an oscillometric device and CO using inert gas rebreathing technique. PWV and CO were converted to gestation adjusted indices (z scores)., Main Outcome Measures: The association between BAFF levels in PE and FGR, and the relationship of BAFF with PWV and CO., Results: BAFF was higher in PE (p = 0.03) but not in FGR (p = 0.83) when compared to healthy pregnancies. There was a positive correlation between BAFF levels and z score PWV (r = 0.25, p = 0.04), but not CO (r = -0.01, p = 0.91). BAFF levels did not change with gestational age. (r = 0.012, p = 0.925)., Conclusions: These findings provide evidence of a possible contribution of BAFF to both maternal inflammation and arterial dysfunction associated with PE. Though no relationship was found with another disorder of placentation: normotensive FGR, this condition is not thought to be associated with maternal inflammation., (Copyright © 2018. Published by Elsevier B.V.)

Background: Preeclampsia and fetal growth restriction are considered to be placentally mediated disorders. The clinical manifestations are widely held to relate to gestation age at onset with early- and late-onset preeclampsia considered to be phenotypically distinct. Recent studies have reported conflicting findings in relation to cardiovascular function, and in particular cardiac output, in preeclampsia and fetal growth restriction., Objective: We conducted this study to examine the possible relation between cardiac output and peripheral vascular resistance in preeclampsia and fetal growth restriction., Study Design: We investigated maternal cardiovascular function in relation to clinical subtype in 45 pathological pregnancies (14 preeclampsia only, 16 fetal growth restriction only, 15 preeclampsia and fetal growth restriction) and compared these with 107 healthy person observations. Cardiac output was the primary outcome measure and was assessed using an inert gas-rebreathing method (Innocor), from which peripheral vascular resistance was derived; arterial function was assessed by Vicorder, a cuff-based oscillometric device. Cardiovascular parameters were normalized for gestational age in relation to healthy pregnancies using Z scores, thus allowing for comparison across the gestational range of 24-40 weeks., Results: Compared with healthy control pregnancies, women with preeclampsia had higher cardiac output Z scores (1.87 ± 1.35; P = .0001) and lower peripheral vascular resistance Z scores (-0.76 ± 0.89; P = .025); those with fetal growth restriction had higher peripheral vascular resistance Z scores (0.57 ± 1.18; P = .04) and those with both preeclampsia and fetal growth restriction had lower cardiac output Z scores (-0.80 ± 1.3 P = .007) and higher peripheral vascular resistance Z scores (2.16 ± 1.96; P = .0001). These changes were not related to gestational age of onset. All those affected by preeclampsia and/or fetal growth restriction had abnormally raised augmentation index and pulse wave velocity. Furthermore, in preeclampsia, low cardiac output was associated with low birthweight and high cardiac output with high birthweight (r = 0.42, P = .03)., Conclusion: Preeclampsia is associated with high cardiac output, but if preeclampsia presents with fetal growth restriction, the opposite is true; both conditions are nevertheless defined by hypertension. Fetal growth restriction without preeclampsia is associated with high peripheral vascular resistance. Although early and late gestation preeclampsias are considered to be different diseases, we show that the hemodynamic characteristics of preeclampsia were unrelated to gestational age at onset but were strongly associated with the presence or absence of fetal growth restriction. Fetal growth restriction more commonly coexists with preeclampsia at early gestation, thus explaining the conflicting results of previous studies. Furthermore, antihypertensive agents act by reducing cardiac output or peripheral vascular resistance and are administered without reference to cardiovascular function in preeclampsia. The underlying pathology (preeclampsia, fetal growth restriction, preeclampsia and fetal growth restriction) defines cardiovascular phenotype, providing a rational basis for choice of therapy in which high or low cardiac output or peripheral vascular resistance is the predominant feature., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: Stress during pregnancy is known to have negative effects on fetal outcome. The purpose of this exploratory study was to examine placental perfusion alterations after stress challenge during pregnancy in a mouse model., Material and Methods: Seven Tesla MRI was performed on pregnant mice at embrionic day (ED) 14.5 and 16.5. Twenty dams were exposed to an established acoustic stress challenge model while twenty non-exposed dams served as controls. Placental perfusion was analyzed in dynamic contrast-enhanced (DCE) MRI using the steepest slope model. The two functional placental compartments, the highly vascularized labyrinth and the endocrine junctional zone, were assessed separately., Results: Statistical analysis revealed decreased perfusion levels in the stress group at ED 14.5 compared to controls in both placenta compartments. On ED 16.5, the perfusion level increased significantly in the stress group while placenta perfusion in controls remained similar or even slightly decreased leading to an overall increased perfusion in the stress group on ED 16.5 compared to controls., Conclusion: MR imaging allows noninvasive placenta perfusion assessment in this fetal stress mimicking animal model. In this exploratory study, we demonstrated that stress challenge during pregnancy leads to an initial reduction followed by an increase of placenta perfusion., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The growth-restricted fetus in utero is exposed to a hostile environment and suffers undernutrition and hypoxia. To cope with the stress, the fetus changes its physiological functions. These adaptive changes aid intrauterine survival; however, they can lead to permanent functional and structural changes that can contribute to the development of serious chronic diseases later in life. Epigenetic mechanisms are an important part of the pathophysiological processes behind this "developmental origin of adult diseases." The dominant cardiovascular adaptive change is the redistribution of blood flow in hypoxic fetuses, with preferential supply of blood to the fetal brain, myocardium, and adrenal glands. The proportion of blood from the umbilical vein to the ductus venosus and foramen ovale increases, which increases the cardiac output of the left heart ventricle. The increased perfusion of fetal brain can be followed with Doppler ultrasound as increased diastolic velocities and decreased pulsatility index in the middle cerebral artery., (Copyright © 2018. Published by Elsevier Ltd.)

A uniform approach to management of fetal growth restriction (FGR) improves outcome, prevents stillbirth, and allows appropriately timed delivery. An estimated fetal weight below the tenth percentile with coexisting abnormal umbilical artery (UA), middle cerebral artery (MCA), or cerebroplacental ratio Doppler index best identifies the small fetus requiring surveillance. Placental perfusion defects are more common earlier in gestation; accordingly, early-onset (≤32 weeks of gestation) and late-onset (>32 weeks) FGR differ in clinical phenotype. In early-onset FGR, progression of UA Doppler abnormality determines clinical acceleration, while abnormal ductus venosus (DV) Doppler precedes deterioration of biophysical variables and stillbirth. Accordingly, late DV Doppler changes, abnormal biophysical variables, or an abnormal cCTG require delivery. In late-onset FGR, MCA Doppler abnormalities precede deterioration and stillbirth. However, from 34 to 38 weeks, randomized evidence on optimal delivery timing is lacking. From 38 weeks onward, the balance of neonatal versus fetal risks favors delivery., (Copyright © 2018. Published by Elsevier Ltd.)

Objectives: The aim of this study was to investigate, whether maternal serum levels of sFlt-1, PlGF and PAPP-A at third trimester of pregnancy are associated with late-onset PE and intrauterine growth retardation (IUGR) after 34 weeks of pregnancy., Methods: This was a prospective study measuring the maternal serum levels of soluble tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF) and pregnancy-associated plasma protein-A (PAPP-A) at 32-37 weeks of pregnancy: 730 patients were enrolled and 676 had neither intrauterine growth restriction (IUGR) nor preeclampsia (PE) or pregnancy induced hypertension (PIH) throughout the pregnancy. 22 patients developed IUGR, 32 PE and 24 PIH., Results: Linear regression analyses after adjusting for maternal age, gestational age at the blood sampling and maternal BMI showed associations between PE and serum sFlt-1 levels (Exp(ß) = 3.29; 95% CI: 2.69-4.04), serum PlGF levels (Exp(ß) = 0.18; 95% CI: 0.13-0.24), sFlt-1/PlGF ratio (Exp(ß) = 15.59; 95% CI: 10.64-22.84) and serum PAPP-A (Exp(ß) = 1.48; 95% CI 1.15-1.89). sFlt-1, PlGF and sFlt-1/PlGF-Ratio showed comparable area under the curve (AUC) estimates with a predictive ability to discriminate pregnancies developing PE and IUGR from controls. The predictive ability of PAPP-A for PE was only slightly better than chance., Conclusions: This study supported the ability of a single measurement of sFlt-1/PlGF ratio at third trimester to predict PE and IUGR occurring after 34 weeks of pregnancy. However, larger multicentre studies are needed to replicate our results., (Copyright © 2018 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Objectives: To investigate the risks of delivering small-for-gestational-age (SGA) and large-for-gestational-age (LGA) infants in women with early- (delivered before 34weeks of gestation) and late-onset (delivered at or after 34weeks of gestation) preeclampsia., Study Design: We conducted a retrospective cohort study of 29,494 singleton deliveries after 24weeks' gestation, excluding pregnancies complicated by fetal anomalies, stillbirths, and prepregnancy diabetes mellitus. Univariate and multivariate logistic analyses adjusted for potential confounding factors, including prepregnancy body mass index (BMI), gestational weight gain (GWG), and gestational diabetes mellitus (GDM), were performed., Results: Among women who delivered before 34weeks, significantly more women with preeclampsia delivered SGA infants than women without preeclampsia (50.6% vs. 7.0%; adjusted odds ratio [OR] 16.3; 95% confidence interval [CI] 8.1-32.9). Among women who delivered at or after 34weeks, women with preeclampsia had higher rates of delivering SGA (25.5% vs. 7.0%) and LGA (13.7% vs. 9.9%) infants than women without preeclampsia. After adjustment for confounding factors, preeclampsia remained a significant risk factor for delivering SGA infants (adjusted OR 5.7; 95% CI 4.6-7.1), but the association between preeclampsia and the delivery of LGA infants was diminished (adjusted OR 0.8; 95% CI 0.6-1.1)., Conclusions: Our results confirm that preeclampsia is associated with SGA and that the association is stronger with early-onset disease. Although women with late-onset preeclampsia had a higher rate of delivering LGA infants, the association between late-onset preeclampsia and LGA is due to confounding factors, such as high prepregnancy BMI, excessive GWG, and GDM, related to maternal metabolic abnormalities., (Copyright © 2017 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Objective: To examine maternal and neonatal outcomes of gestational proteinuria, and to identify maternal characteristics for progression to pre-eclampsia., Study Design: Retrospective cohort. Included all pregnant women who delivered between Jan 2014-Feb 2017 with new onset proteinuria in a single obstetric unit. Demographic, maternal and neonatal outcomes were compared., Results: Eighteen (25%) out of 73 women with new onset gestational proteinuria developed pre-eclampsia. The incidence of gestational proteinuria was 0.54%. Compared with women that remained normotensive, those that developed hypertension had delivery at earlier gestation (p = .02), increased risk of fetal growth restriction (p = .01) and lower newborn birthweight (p = .002). Maximal proteinuria and fetal growth restriction were independent factors associated with development of pre-eclampsia. In particular, high proteinuria level ≥ 2 g/d constitute a major predictor for progression (p = .03)., Conclusion: Increased vigilance for antenatal surveillance is important in women with gestational proteinuria as a substantial portion progress to pre-eclampsia. Serial growth scan and proteinuria assay are suggested to predict possible pre-eclampsia development., (Copyright © 2017 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Fetal growth restriction (FGR) continues to be a leading cause of preventable stillbirth and poor neurodevelopmental outcomes in offspring, and furthermore is strongly associated with the obstetrical complications of iatrogenic preterm birth and pre-eclampsia. The terms small for gestational age (SGA) and FGR have, for too long, been considered equivalent and therefore used interchangeably. However, the delivery of improved clinical outcomes requires that clinicians effectively distinguish fetuses that are pathologically growth-restricted from those that are constitutively small. A greater understanding of the multifactorial pathogenesis of both early- and late-onset FGR, especially the role of underlying placental pathologies, may offer insight into targeted treatment strategies that preserve placental function. The new maternal blood biomarker placenta growth factor offers much potential in this context. This review highlights new approaches to effective screening for FGR based on a comprehensive review of: etiology, diagnosis, antenatal surveillance and management. Recent advances in novel imaging methods provide the basis for stepwise multi-parametric testing that may deliver cost-effective screening within existing antenatal care systems., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Pulmonary function in former preterm infants may be compromised during childhood., Objectives: To assess pulmonary function in very-low-birth-weight preterm infants at 6-12 months of corrected age and analyze the factors associated with abnormal pulmonary function., Methods: Cross-sectional study with preterm infants at 6-12 months of corrected age with birth weight <1500 g. Children with malformations or affected by neuromuscular and respiratory diseases were excluded. Forced expiratory flows were assessed using the chest compression technique, and volumes were measured by total body plethysmography. Pulmonary function parameters in preterm infants were compared to a control group of same-aged children born at term., Results: We studied 51 preterm and 37 infants born at term. Preterm infants had: gestational age at birth (30.0 ± 2.5 weeks), birth weight (1179 ± 247 g), 27.5% had bronchopulmonary dysplasia, and 45% received mechanical ventilation. Preterm infants had lower median z-scores in comparison to term infants for the following parameters (p < 0.05): FVC (-0.3 vs. 0.7), FEV 0.5 (-0.5 vs. 0.9), FEV 0.5 /FVC (-0.6 vs. -0.5), FEF 50 (-0.4 vs. 0.9), FEF 75 (-0.3 vs. 0.8), FEF 85 (-0.1 vs. 0.6) and FEF 25-75 (-0.5 vs. 1.1). No term child had abnormal lung function, compared to 39.2% of preterm infants (p = 0.001). Factors associated with abnormal pulmonary function were lower gestational age at birth, small for gestational age, need for mechanical ventilation and presence of recurrent wheezing., Conclusions: Preterms had a high prevalence of abnormal pulmonary function and lower pulmonary function in comparison to term infants. Prematurity, intrauterine growth restriction, respiratory support and recurrent wheezing were associated with abnormal pulmonary function., (Copyright © 2018. Published by Elsevier Ltd.)