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

Relative uteroplacental insufficiency of labor (RUPI‐L) is a clinical condition that refers to alterations in the fetal oxygen "demand–supply" equation caused by the onset of regular uterine activity. The term RUPI‐L indicates a condition of "relative" uteroplacental insufficiency which is relative to a specific stressful circumstance, such as the onset of regular uterine activity. RUPI‐L may be more prevalent in fetuses in which the ratio between the fetal oxygen supply and demand is already slightly reduced, such as in cases of subclinical placental insufficiency, post‐term pregnancies, gestational diabetes, and other similar conditions. Prior to the onset of regular uterine activity, fetuses with a RUPI‐L may present with normal features on the cardiotocography. However, with the onset of uterine contractions, these fetuses start to manifest abnormal fetal heart rate patterns which reflect the attempt to maintain adequate perfusion to essential central organs during episodes of transient reduction in oxygenation. If labor is allowed to continue without an appropriate intervention, progressively more frequent, and stronger uterine contractions may result in a rapid deterioration of the fetal oxygenation leading to hypoxia and acidosis. In this Commentary, we introduce the term relative uteroplacental insufficiency of labor and highlight the pathophysiology, as well as the common features observed in the fetal heart rate tracing and clinical implications. [ABSTRACT FROM AUTHOR]

Introduction: The IMPACT BCN trial—a parallel‐group randomized clinical trial where 1221 pregnant women at high risk for small‐for‐gestational age (SGA) newborns were randomly allocated at 19‐ to 23‐week gestation into three groups: Mediterranean diet, Mindfulness‐based Stress reduction or non‐intervention—has demonstrated a positive effect of Mediterranean diet and Stress reduction in the prevention of SGA. However, the mechanism of action of these interventions remains still unclear. The aim of this study is to investigate the effect of Mediterranean diet and Stress reduction on placental volume and perfusion. Material and Methods: Participants in the Mediterranean diet group received monthly individual and group educational sessions, and free provision of extra‐virgin olive oil and walnuts. Women in the Stress reduction group underwent an 8‐week Stress reduction program adapted for pregnancy, consisting of weekly 2.5‐h and one full‐day sessions. Non‐intervention group was based on usual care. Placental volume and perfusion were assessed in a subgroup of randomly selected women (n = 165) using magnetic resonance (MR) at 36‐week gestation. Small placental volume was defined as MR estimated volume <10th centile. Perfusion was assessed by intravoxel incoherent motion. Results: While mean MR placental volume was similar among the study groups, both interventions were associated with a lower prevalence of small placental volume (3.9% Mediterranean diet and 5% stress reduction vs. 17% non‐intervention; p = 0.03 and p = 0.04, respectively). Logistic regression showed that small placental volume was significantly associated with higher risk of SGA in both study groups (OR 7.48 [1.99–28.09] in Mediterranean diet and 20.44 [5.13–81.4] in Stress reduction). Mediation analysis showed that the effect of Mediterranean diet on SGA can be decomposed by a direct effect and an indirect effect (56.6%) mediated by a small placental volume. Similarly, the effect of Stress reduction on SGA is partially mediated (45.3%) by a small placental volume. Results on placental intravoxel incoherent motion perfusion fraction and diffusion coefficient were similar among the study groups. Conclusions: Structured interventions during pregnancy based on Mediterranean diet or Stress reduction are associated with a lower proportion of small placentas, which is consistent with the previously observed beneficial effects of these interventions on fetal growth. [ABSTRACT FROM AUTHOR]

Our goal was to evaluate the potential utility of magnetic resonance imaging (MRI) placental volume as an assessment of placental insufficiency. Secondary analysis of a prospective cohort undergoing serial placental MRIs at two academic tertiary care centers. The population included 316 participants undergoing MRI up to three times throughout gestation. MRI was used to calculate placental volume in milliliters (ml). Placental-mediated adverse pregnancy outcome (cAPO) included preeclampsia with severe features, abnormal antenatal surveillance, and perinatal mortality. Serial measurements were grouped as time point 1 (TP1) <22 weeks, TP2 22 0/7–29 6/7 weeks, and TP3 ≥30 weeks. Mixed effects models compared change in placental volume across gestation between cAPO groups. Association between cAPO and placental volume was determined using logistic regression at each TP with discrimination evaluated using area under receiver operator curve (AUC). Placental volume was then added to known clinical predictive variables and evaluated with test characteristics and calibration. 59 (18.7 %) of 316 participants developed cAPO. Placental volume growth across gestation was slower in the cAPO group (p < 0.001). Placental volume was lower in the cAPO group at all time points, and alone was moderately predictive of cAPO at TP3 (AUC 0.756). Adding placental volume to clinical variables had moderate discrimination at all time points, with strongest test characteristics at TP3 (AUC 0.792) with sensitivity of 77.5 % and specificity of 75.3 % at a predicted probability cutoff of 15 %. MRI placental volume warrants further study for assessment of placental insufficiency, particularly later in gestation. • Placental volume grows more slowly in complicated pregnancies. • Placental volume measurement alone is associated with pregnancy complications. • Placental volume is most sensitive after 30 weeks for pregnancy complications. [ABSTRACT FROM AUTHOR]

Fetal growth restriction and underlying placental insufficiency are associated with increased oxidative stress. Current diagnostics fail to identify all growth restricted fetuses and newborns, due to focus on small size. This scoping review aims to summarize the available evidence on usefulness of cord blood oxidative stress biomarkers for identification of growth restricted newborns in need of monitoring and support because of associated health risks. MEDLINE and EMBASE were searched from inception to May 2024. Studies were included if oxidative stress biomarkers were measured in cord blood collected immediately after delivery in newborns suspected to be growth restricted. Biomarkers were categorized based on the origin and/or biological function and their interrelationships. Oxidative stress was determined for each individual biomarker and category. Literature search identified 78 studies on 39 different biomarkers, with a total of 2707 newborns with suspected growth restriction, and 4568 controls. Total oxidant/antioxidant status, catalase, glutathione, ischemia-modified albumin, and nucleated red blood cells were most consistently associated with suspected growth restriction. Reactive oxygen species/reactive nitrogen species, factors in their production, antioxidant enzymes, non-enzymatic antioxidants, and products of oxidative stress were not consistently associated. This review collates the evidence of associations between cord blood oxidative stress biomarkers and growth restriction. Total oxidant/antioxidant status, catalase, glutathione, ischemia-modified albumin, and nucleated red blood cells could potentially be candidates for developing a cord blood diagnostic tool for future clinical use. • Oxidative stress cord blood biomarkers useful to identify growth restricted newborns. • (Anti)oxidant status, CAT, GSH, IMA, NRBC most associated with growth restriction. • Offering possibilities for development of cord blood diagnostic tool for clinical use. [ABSTRACT FROM AUTHOR]

A high frequency of single nucleotide somatic mutations in the placenta has been recently described, but its relationship to placental dysfunction is unknown. We performed a pilot case-control study using paired fetal, maternal, and placental samples collected from healthy live birth controls (n = 10), live births with fetal growth restriction (FGR) due to placental insufficiency (n = 7), and stillbirths with FGR and placental insufficiency (n = 11). We quantified single nucleotide and structural somatic variants using bulk whole genome sequencing (30-60X coverage) in four biopsies from each placenta. We also assessed their association with clinical and histological evidence of placental dysfunction. Seventeen pregnancies had sufficiently high-quality placental, fetal, and maternal DNA for analysis. Each placenta had a median of 473 variants (range 111–870), with 95 % arising in just one biopsy within each placenta. In controls, live births with FGR, and stillbirths, the median variant counts per placenta were 514 (IQR 381–779), 582 (450–735), and 338 (245–441), respectively. After adjusting for depth of sequencing coverage and gestational age at birth, the somatic mutation burden was similar between groups (FGR live births vs. controls, adjusted diff. 59, 95 % CI -218 to +336; stillbirths vs controls, adjusted diff. −34, −351 to +419), and with no association with placental dysfunction (p = 0.7). We confirmed the high prevalence of somatic mutation in the human placenta and conclude that the placenta is highly clonal. We were not able to identify any relationship between somatic mutation burden and clinical or histologic placental insufficiency. • Somatic mutation is highly prevalent in the human placenta. • 95 % of comatic variants were present in just one of four biopsies in each placenta. • Somatic mutation estimates were driven by sequencing depth and gestational age. • Two variant calling algorithms yield very different somatic variation estimates. • We found no association between somatic variant burden and clinical outcome. [ABSTRACT FROM AUTHOR]

• Angiogenic biomarkers are important tools for the early prediction and diagnosis of preeclampsia. • Data from intervention trials do not support using angiogenic biomarkers for monitoring progressing of preeclampsia or deciding the timing of delivery. • There is insufficient evidence to recommend angiogenic biomarkers as an alternative to Doppler for surveillance and timing of delivery in fetal growth restriction. • Angiogenic biomarkers may have help differentiate between hypertension in chronic kidney disease from superimposed preeclampsia in pregnant women. Monitoring and timing of delivery in preterm preeclampsia and fetal growth restriction is one of the biggest challenges in Obstetrics. Finding the optimal time of delivery of these fetuses usually involves a trade-off between the severity of the disease and prematurity. So far, most clinical guidelines recommend the use of a combination between clinical, laboratory and ultrasound markers to guide the time of delivery. Angiogenic biomarkers, especially placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1), have gained significant attention in recent years for their potential role in the prediction and diagnosis of placenta-related disorders including preeclampsia and fetal growth restriction. Another potential clinical application of the angiogenic biomarkers is for the differential diagnosis of patients with chronic kidney disease, as this condition shares similar clinical features with preeclampsia. Consequently, angiogenic biomarkers have been advocated as tools for monitoring and deciding the optimal time of the delivery of fetuses affected by placental dysfunction. In this clinical opinion, we critically review the available literature on PlGF and sFlt-1 for the surveillance and time of the delivery in fetuses affected by preterm preeclampsia and fetal growth restriction. Moreover, we explore the use of angiogenic biomarkers for the differentiation between chronic kidney disease and superimposed preeclampsia. [ABSTRACT FROM AUTHOR]

Objective: To present the morphological features of placentas in pregnancies with hypertension and fetal growth restriction syndrome (FGRS) Methods: Eighty-six placentas in pregnancies with FGRS on the background of arterial hypertension are examined. Among them, there were 34 placentas from patients with chronic arterial hypertension (CAH), 24 placentas from patients with preeclampsia (PE), and 28 placentas from patients with PE in combination with CAH. All pregnant women underwent a Doppler ultrasound investigation. FGRS was diagnosed if uteroplacental-fetal circulatory disorders were combined with small for gestational age fetal size. Various types of hypertensive disorders were diagnosed in accordance with WHO recommendations. A comprehensive assessment of structural changes in the placentas included macroscopic examination, organometry and histological evaluation complemented by morphometry. Results: Placental hypoplasia, dominating magistral pattern of chorionic blood vessels, infarction foci, thrombosis of the intervillous space, and compensatory angiomatosis of the chorionic villi are the typical features of the placentas in pregnanсies with FGRS and the background hypertension. Histological signs of chorionic villi ischemia indicate placentation disorders and a decreased intensity of angiogenesis in the uteroplacental circulation. Conclusion: Hypertensive disorders during pregnancy associated with endothelial dysfunction lead to placental insufficiency (PI), causing FGRS.

Abstract Background Small-for-gestational-age (SGA), commonly caused by poor placentation, is a major contributor to global perinatal mortality and morbidity. Maternal serum levels of placental protein and angiogenic factors are changed in SGA. Using data from a population-based pregnancy cohort, we estimated the relationships between levels of second-trimester pregnancy-associated plasma protein-A (PAPP-A), placental growth factor (PlGF), and serum soluble fms-like tyrosine kinase-1 (sFlt-1) with SGA. Methods Three thousand pregnant women were enrolled. Trained health workers prospectively collected data at home visits. Maternal blood samples were collected, serum aliquots were prepared and stored at -80℃. Included in the analysis were 1,718 women who delivered a singleton live birth baby and provided a blood sample at 24–28 weeks of gestation. We used Mann-Whitney U test to examine differences of the median biomarker concentrations between SGA (

Galectin-3 belongs to a family of soluble glycan-binding proteins, which are increasingly recognized as modulators of pregnancy-associated processes, including proper placental development. Gestational hypertension and preeclampsia are significant complications of pregnancy, affecting millions of women annually. Despite their prevalence, the underlying pathophysiological mechanisms remain poorly understood. Several theories have been proposed, including inflammation, placental insufficiency, disturbed placental invasion, and angiogenesis. The Scopus and PubMed/MEDLINE databases were utilized until the end of May 2024. In total, 11 articles with 1011 patients, with 558 in the control group and 453 in the preeclampsia group, were included. Seven articles investigated the expression of galectin-3 (Gal-3) in placental tissue samples, eight studies calculated the serum levels of Gal-3 in maternal blood samples, while one study referred to the possible correlation of galectin-3 levels in umbilical cord blood. The results were inconsistent in both the placental tissue and maternal serum; Gal-3 placental expression was found to be statistically increased in five studies compared to that in women without gestational hypertensive disorders, while two studies either mentioned decreased expression or no difference. Similarly, the Gal-3 maternal serum levels, compared to those in women without gestational hypertensive disorders, were found to be statistically increased in five studies, while three studies did not find any statistical difference. Gal-3 can play a crucial role in the pathogenesis of preeclampsia, and its expression is influenced by gestational age and placental insufficiency. A further investigation ought to be conducted to enlighten the correlation of Gal-3 with gestational hypertension and preeclampsia development. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to provide gestational age (GA) specific reference ranges for 2-dimensional (2D) placental biometry and 3-dimensional (3D) placental volume between 11 and 14 weeks of gestation. Methods: Placental biometry including 2D and 3D variables was calculated in 1142 first-trimester singleton pregnancies with non-complicated outcome between September 2016 and February 2020. Ultrasound datasets were obtained at the time of the first-trimester ultrasound, and 2D basal plate (BP), chorionic plate (CP), placental thickness (PT), and 3D placental volume (PV) were measured following a standardized methodology. Reference ranges for each variable were calculated according to GA and crown-rump-length (CRL). Results: A total of 1142 uncomplicated pregnancies were considered for analysis. All placental measurements increased significantly between 11 and 14 weeks, especially for PT (39.64%) and PV (64.4%). Reference ranges were constructed for each 2D and 3D first-trimester placental variable using the best-fit regression model for the predicted mean and SD as a function of GA and CRL. Conclusions: Reference ranges of 2D placental biometry and 3D placental volume between 11 and 14 weeks of gestation were constructed, generating reference values. Placental biometry showed a progressive increase during the first trimester. This highlights the importance of using reference range charts according to GA. [ABSTRACT FROM AUTHOR]

Objective: To assess the association of the umbilicocerebral ratio (UCR) with adverse perinatal outcome in late preterm small‐for‐gestational age (SGA) fetuses and to investigate the effect on perinatal outcomes of immediate delivery. Design: Multicentre cohort study with nested randomised controlled trial (RCT). Setting: Nineteen secondary and tertiary care centres. Population: Singleton SGA pregnancies (estimated fetal weight [EFW] or fetal abdominal circumference [FAC] <10th centile) from 32 to 36+6 weeks. Methods: Women were classified: (1) RCT‐eligible: abnormal UCR twice consecutive and EFW below the 3rd centile at/or below 35 weeks or below the 10th centile at 36 weeks; (2) abnormal UCR once or intermittent; (3) never abnormal UCR. Consenting RCT‐eligible patients were randomised for immediate delivery from 34 weeks or expectant management until 37 weeks. Main outcome measures: A composite adverse perinatal outcome (CAPO), defined as perinatal death, birth asphyxia or major neonatal morbidity. Results: The cohort consisted of 690 women. The study was halted prematurely for low RCT‐inclusion rates (n = 40). In the RCT‐eligible group, gestational age at delivery, birthweight and birthweight multiple of the median (MoM) (0.66, 95% confidence interval [CI] 0.59–0.72) were significantly lower and the CAPO (n = 50, 44%, p < 0.05) was more frequent. Among patients randomised for immediate delivery there was a near‐significant lower birthweight (p = 0.05) and higher CAPO (p = 0.07). EFW MoM, pre‐eclampsia, gestational hypertension and Doppler classification were independently associated with the CAPO (area under the curve 0.71, 95% CI 0.67–0.76). Conclusions: Perinatal risk was effectively identified by low EFW MoM and UCR. Early delivery of SGA fetuses with an abnormal UCR at 34–36 weeks should only be performed in the context of clinical trials. [ABSTRACT FROM AUTHOR]

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

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Intrauterine growth-restricted (IUGR) fetuses exhibit systemic inflammation that contributes to programmed deficits in myoblast function and muscle growth. Thus, we sought to determine if targeting fetal inflammation improves muscle growth outcomes. Heat stress-induced IUGR fetal lambs were infused with eicosapentaenoic acid (IUGR+EPA; n = 9) or saline (IUGR; n = 8) for 5 days during late gestation and compared to saline-infused controls (n = 11). Circulating eicosapentaenoic acid was 42% less (p < 0.05) for IUGR fetuses but was recovered in IUGR+EPA fetuses. The infusion did not improve placental function or fetal O2 but resolved the 67% greater (p < 0.05) circulating TNFα observed in IUGR fetuses. This improved myoblast function and muscle growth, as the 23% reduction (p < 0.05) in the ex vivo differentiation of IUGR myoblasts was resolved in IUGR+EPA myoblasts. Semitendinosus, longissimus dorsi, and flexor digitorum superficialis muscles were 24–39% lighter (p < 0.05) for IUGR but not for IUGR+EPA fetuses. Elevated (p < 0.05) IL6R and reduced (p < 0.05) β2 adrenoceptor content in IUGR muscle indicated enhanced inflammatory sensitivity and diminished β2 adrenergic sensitivity. Although IL6R remained elevated, β2 adrenoceptor deficits were resolved in IUGR+EPA muscle, demonstrating a unique underlying mechanism for muscle dysregulation. These findings show that fetal inflammation contributes to IUGR muscle growth deficits and thus may be an effective target for intervention. [ABSTRACT FROM AUTHOR]

To achieve the purpose of the study, based on developed clinical and laboratory criteria, a prospective study of the course of pregnancy and its outcomes was conducted in 62 pregnant women aged 18 to 39 years (average age 27.98±5.3) for the period from 2019 to 2022. with undif- ferentiated connective tissue dysplasia (UCTD), which formed a high-risk group for the development of pathol- ogy of the fetoplacental system. All pregnant women were divided into 2 groups: main (n = 36), comparison (n = 32). The first group of the study (main) consisted of 36 pregnant women with UCTD, carriers of cytomegalovi- rus infection, the second group (comparison) 32 pregnant women with UCTD, without carriage of cytomegalovirus infection. The control group consisted of 24 pregnant women without the presence of UCTD and cytomegalo- virus infection at the time of the study. The conducted studies found that disturbances in the cellular immune system in women with UCTD increased the frequency of the infectious process. In the third trimester, women in the main group were more likely to have threatened labor (15 women (41.7±8.2% in the main group and 6 women (18.8±6.9%) in the comparison group); oligohydramnios (9 women (25 .0±7.2%) and 3 women (9.4±5.1%); intrauterine growth retardation syndrome (28 women (77.8±6.9% and 19 women (59.4±8.6 %). This was re- flected in the high concentration of IgM and an increase in the relative number of CD16+ and CD20+ lympho- cytes in pregnant women of the main group. Histological examination confirmed a higher frequency of infection of the ovum in pregnant women with UCTD, carriers of cy- tomegalovirus, which was limited to the placenta and was not accompanied by intrauterine infection of the fetus. The presence of UCTD in pregnant women with persis- tent infection of the herpesvirus family increases the risk of unfavorable implementation of the infectious process, and this should be taken into account when making a prognosis for the development of obstetric and perinatal complications and justifies the advisability of carrying out treatment and preventive measures during pregnancy and in the postpartum period.

Fetal growth restriction (FGR) is a complication diagnosed in about 10% of pregnancies and is associated with significant perinatal mortality and morbidity. Both the diagnosis and the correct management of cases of intrauterine growth restriction remain a challenge of modern obstetrics. A normal placental development is essential for a proper intrauterine physical and neurological growth of the fetus throughout pregnancy. Various pathophysiological situations may reflect in abnormal placental development linked with severe pregnancy disorders. In this paper we aim to exemplify sonographic aspects in various placental pathology associated with FGR along with the recommended management. Placental insufficiency is the most common risk factor for FGR and it cannot be directly measured and objectified, remaining a diagnostic of exclusion. The risk for perinatal adverse outcomes in placenta accreta spectrum cases is increased through the pathological implantation especially in depth. In pregnancies complicated with placental insufficiency, secondary macroscopic lesions can be noted, as parabasal and intervillous thrombosis, hematomas, extensive fibrin deposits and infarcts areas. Even if, over time, multiple studies have targeted methods of preventing intrauterine growth restriction through actions on the mother, the effectiveness of no treatment has been demonstrated.

Background: Fetal Growth Restriction (FGR), often due to placental insufficiency, poses significant risks to perinatal outcomes. This review evaluates the efficacy of pentaerythritol tetranitrate (PETN), a nitric oxide donor, in preventing FGR. Methods: A systematic review and meta-analysis was conducted by searching PubMed, Embase, and CENTRAL up to July 2024. The inclusion criteria focused on randomized controlled trials comparing PETN to placebo in FGR prevention. Key outcomes were incidences of FGR, perinatal mortality, neonatal mortality, and intrauterine fetal demise (IUFD). Other outcomes were classified as maternal, fetal, neonatal and safety outcomes. We used Cochrane RoB 2.0 tool to assess risk of bias, and GRADE criteria for evidence quality. Results: Two eligible studies encompassing 417 pregnant women at risk of FGR were included. PETN did not significantly reduce incidence of FGR (RR 0.83, 95 % CI 0.66–1.04, 2 trials, 417 participants, low certainty) or perinatal mortality (RR 0.64, 95 % CI 0.26–1.58, 2 trials, 417 participants, very low certainty) compared to placebo. None of the studies reported neonatal mortality or IUFD. However, PETN treatment was associated with a reduction in preterm birth (RR 0.74, 95 % CI 0.58–0.93, 2 trials, 417 participants, moderate certainty). Other outcomes were similar between the groups. Conclusion: While PETN does not significantly impact FGR rates or perinatal mortality, it is associated with a reduction in preterm birth, suggesting potential benefits in high-risk pregnancies. Larger trials are necessary to substantiate these findings and clarify the role of PETN in FGR prevention.

Objective Delta-like homolog 1 (DLK1) is a growth factor that is reduced in maternal sera in pregnancies with small for gestational age neonates. We sought to determine if DLK1 is associated with stillbirth (SB), with and without placental insufficiency. Study Design A nested case-control study was performed using maternal sera from a multicenter case-control study of SB and live birth (LB). SB and LB were stratified as placental insufficiency cases (small for gestational age <5% or circulatory lesions on placental histopathology) or normal placenta controls (appropriate for gestational age and no circulatory lesions). Enzyme-linked immunosorbent assay (ELISA) was used to measure DLK1. The mean difference in DLK1 was compared on the log scale in an adjusted linear regression model with pairwise differences, stratified by term/preterm deliveries among DLK1 results in the quantifiable range. In exploratory analysis, geometric means were compared among all data and the proportion of "low DLK1" (less than the median value for gestational age) was compared between groups and modeled using linear and logistic regression, respectively. Results Overall, 234 SB and 234 LB were analyzed; 246 DLK1 values were quantifiable within the standard curve. Pairwise comparisons of case and control DLK1 geometric means showed no significant differences between groups. In exploratory analysis of all data, adjusted analysis revealed a significant difference for the LB comparison only (SB: 71.9 vs. 99.1 pg/mL, p = 0.097; LB: 37.6 vs. 98.1 pg/mL, p = 0.005). In exploratory analysis of "low DLK1," there was a significant difference between the odds ratio of having "low DLK1" between preterm cases and controls for both SB and LB. There were no significant differences in geometric means nor "low DLK1" between SB and LB. Conclusion In exploratory analysis, more placental insufficiency cases in preterm SB and LB had "low DLK1." However, low DLK1 levels were not associated with SB. Key Points Maternally circulating DLK1 is correlated with placental insufficiency. Maternally circulating DLK1 is not correlated with SB. DLK1 is a promising marker for placental insufficiency. [ABSTRACT FROM AUTHOR]

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

Objective: Pregnancies with fetal growth restriction (FGR) are at increased risk for pre‐eclampsia. Angiogenic markers including soluble fms‐like tyrosine kinase‐1 (sFlt‐1) and placental growth factor (PlGF) are altered in pregnancies complicated by FGR, but their utility for predicting pre‐eclampsia in growth‐restricted pregnancies is uncertain. This study aimed to evaluate the prognostic value of angiogenic markers for predicting the development of pre‐eclampsia in pregnancies with FGR and suspected pre‐eclampsia. Methods: This was a retrospective study of singleton pregnancies with FGR, defined according to Delphi consensus criteria, which underwent sampling of sFlt‐1 and PlGF for suspicion of pre‐eclampsia at the Medical University of Vienna, Vienna, Austria, between 2013 and 2020. Women with an established diagnosis of pre‐eclampsia at sampling were excluded. Cox regression analysis and logistic regression analysis were performed to evaluate the association of angiogenic markers with the development of pre‐eclampsia at various timepoints. Results: In this cohort of 93 women, pre‐eclampsia was diagnosed in 14 (15.1%) women within 1 week after sampling, 21 (22.6%) within 2 weeks after sampling and 38 (40.9%) at any time after assessment. The sFlt‐1/PlGF ratio consistently showed a stronger association with the development of pre‐eclampsia compared to sFlt‐1 or PlGF alone (pre‐eclampsia within 1 week: area under the receiver‐operating‐characteristics curve, 0.87 vs 0.82 vs 0.72). Models including the sFlt‐1/PlGF ratio were associated more strongly with pre‐eclampsia hazard compared to models including sFlt‐1 or PlGF alone (concordance index, 0.790 vs 0.759 vs 0.755). The risk classification capability of the sFlt‐1/PlGF ratio decreased after the 2‐week timepoint. The established cut‐off value for the sFlt‐1/PlGF ratio of < 38 was effective for ruling out pre‐eclampsia within 2 weeks, with a negative predictive value of 0.933 and sensitivity of 0.952. Conclusions: Use of the sFlt‐1/PlGF ratio is preferrable to the use of PlGF alone for the prediction of pre‐eclampsia in pregnancies with FGR. Established cut‐offs for ruling out the development of pre‐eclampsia in the short term seem to be effective in these patients. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Fetal growth restriction (FGR) may affect placental transfer of key nutrients to the fetus, such as the fatty acid docosahexaenoic acid (DHA). Major facilitator superfamily domain containing 2A (MFSD2A) has been described as a specific DHA carrier in placenta, but its expression has not been studied in FGR. The aim of this study was to evaluate for the first time the placental MFSD2A levels in late-FGR pregnancies and the maternal and cord plasma DHA. 87 pregnant women from a tertial reference center were classified into late-FGR (N = 18) or control (N = 69). Fatty acid profile was determined in maternal and cord venous plasma, as well as placental levels of MFSD2A and of insulin mediators like phospho-protein kinase B (phospho-AKT) and phospho-extracellular regulated kinase (phospho-ERK). Maternal fatty acid profile did not differ between groups. Nevertheless, late-FGR cord vein presented higher content of saturated fatty acids than control, producing a concomitant decrease in the percentage of some unsaturated fatty acids. In the late-FGR group, a lower DHA fetal/maternal ratio was observed when using percentages, but not with concentrations. No alterations were found in the expression of MFSD2A in late-FGR placentas, nor in phospho-AKT or phospho-ERK. MFSD2A protein expression was not altered in late-FGR placentas, in line with no differences in cord DHA concentration between groups. The increase in the saturated fatty acid content of late-FGR cord might be a compensatory mechanism to ensure fetal energy supply, decreasing other fatty acids percentage. Future studies are warranted to elucidate if altered saturated fatty acid profile in late-FGR fetuses might predispose them to postnatal catch-up and to long-term health consequences. • First study about placental MFSD2A levels in fetal growth restriction. • Fetuses with late-FGR presented higher content of saturated fatty acids. • No alterations in placental MFSD2A or fetal DHA concentration in late-FGR. [ABSTRACT FROM AUTHOR]

The objective: development of a method of prevention of great obstetrical syndromes (GOS) from the standpoint of a single genesis determined by morphofunctional disorders in the fetoplacental system (FPS) and evaluation of its clinical effectiveness. Materials and methods. 155 women of the high-risk group for the development of GOS were examined. I group – 32 pregnant women who had GOS prophylaxis with low doses of acetylsalicylic acid (ASA) 100–150 mg per os once a day from the 12th to the 36th week of pregnancy; II group – 31 pregnant women who from the 6th to the 16th week had prophylactically progesterone according to the scheme: 200 mg once a day per vaginally every day; III group – 36 pregnant women who received prophylactic monotherapy, consisting of the use of magnesium with a complex with vitamin B6 for three courses of 6 weeks each; IV group – 56 pregnant women who refused any preventive measures. To assess the effectiveness of preventive therapy a dynamic examination of the pregnant women of the study groups, their fetuses and newborns was carried out. Statistical processing of research results was carried out using standard Microsoft Excel 5.0 and Statistica 6.0 programs. Results. The analysis of obstetrical and perinatal outcomes in women of the high-risk group for the development of GOS showed that the development of placental insufficiency (PI) in the IV group was realized in 100% (56 cases), including severe forms in 51.8% (29 cases); the frequency of PI in I, II and III groups was 12.5% (4 cases), 29.0% (9 cases) and 36.6% (11 cases), respectively, and was significantly lower (p<0.05); premature births were in 3 cases each in I and III groups, which amounted to 9.3% and 8.3%, respectively (р<0.05), in II group – 2 cases (6.5%); p<0.05. In general, the realization of GOS (preeclampsia, fetal growth retardation syndrome, premature birth) in I group was 25.0% (8 cases), including severe form – 3.1% (1 case); in the II group – 29.0% (9 cases), severe forms – 2 cases (6.3%); in the III group – 30.6% (11 cases), severe forms – 3 cases (8.3%) versus 100.0% (56 cases) realization of all clinical manifestations of GOS in the IV group of the study (р<0.05).Conclusions. A promising direction for the prevention of vasculitis in the high-risk group for their development is the consistent, early gestational appointment of low doses of ASA according to the developed method, which demonstrates the greatest effectiveness: a significant reduction in the frequency of preeclampsia, placental insufficiency with fetal growth retardation, premature birth, severe forms of preeclampsia according to optimized by the standards of evidence-based medicine: the number of pregnant women who need prophylaxis is 1.4; 95% confidence interval (CI): 1.1–1.7; odds ratio 5.3; 95% CI: 4.7–5.8. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of low‐molecular‐weight heparin (LMWH) on placenta‐mediated fetal growth restriction (FGR). Methods: A cohort of 570 pregnant women diagnosed with placenta‐mediated FGR were enrolled from January 1, 2015 through to December 31, 2021. A birth database, including demographic data, antenatal complications, and detailed delivery and newborn data, was created to collect variables from the Hospital Information System (HIS) Database. The unique personal registration number, assigned to each patient on first registration with HIS in the West China Second University Hospital, was used to link these patients. LMWH use was defined as at least 1‐week prescription from diagnosis of placenta‐mediated FGR. Pregnant women received LMWH (Enoxaparin 4000 IU/day) by self‐administered subcutaneous injection only when they agreed and signed informed consent. Primary outcome was intrauterine fetal death after 20 weeks of pregnancy. Secondary outcomes included preterm birth (PB), Apgar score less than 7 at 1 min, admission to neonatal intensive care unit (NICU), and birth weight. Logistic regression analysis was conducted to compute adjusted odds ratio (aOR) with 95% confidence intervals (CI) for outcomes. Results: After controlling for confounders, LMWH use was associated with a decreased risk of intrauterine fetal death (aOR 2.49, 95% CI 1.35–4.57, P = 0.003), PB before 37 weeks of pregnancy (aOR 3.35, 95% CI 2.14–5.23, P < 0.001), PB before 34 weeks of pregnancy (aOR 2.25, 95% CI 1.36–3.74, P = 0.002), Apgar score less than 7 at 1 min (aOR 2.25, 95% CI 1.36–3.74, P = 0.002), NICU admission (aOR 2.29, 95% CI 1.48–3.55, P < 0.001). Using LMWH increased the mean birth weight in PB before 32 weeks of pregnancy (mean ± standard deviation [SD] 1126.4 ± 520.0 g, P = 0.020), PB before 37 weeks of pregnancy (mean ± SD 1563.9 ± 502.7 g, P = 0.019), early‐onset FGR (mean ± SD 2125.2 ± 665.7 g, P < 0.001), late‐onset FGR (mean ± SD 2343.4 ± 507.9, P < 0.001), and non‐severe FGR (mean ± SD 2231.1 ± 607.2 g, P < 0.001). Conclusion: Use of LMWH can significantly improve the fetal and neonatal outcomes among pregnant women with placenta‐mediated FGR, particularly reducing the risk of intrauterine fetal death. Synopsis: Low‐molecular‐weight heparin use can significantly improve fetal and neonatal outcomes in pregnant women with placenta‐mediated FGR, particularly reducing the risk of intrauterine fetal death. [ABSTRACT FROM AUTHOR]

Aim: The associations between the aetiology of preterm birth and later neurodevelopmental outcomes are unclear. A systematic review and meta‐analysis examined the existing evidence. Methods: The PubMed and Embase databases were searched for papers published in English from inception to 16 December 2020. We included original papers on the causes of preterm birth and the risks of cerebral palsy (CP) and suboptimal cognitive development. Two reviewers independently evaluated the studies and extracted the data. Results: The literature search yielded 5472 papers and 13 were selected. The aetiology of preterm birth was classified under spontaneous or medically indicated delivery. A meta‐analysis was performed, comprising 104 902 preterm infants from 11 papers on CP. Preterm infants born after a medically indicated delivery had a lower CP risk than infants born after spontaneous delivery, with a pooled odds ratio of 0.59 (95% confidence interval 0.40–0.86). This result was robust in the subgroup and sensitivity analyses. Cognitive development was reported in three papers, which suggested that worse outcomes were associated with medically indicated deliveries. Conclusion: The aetiology of preterm delivery may contribute to the risk of CP and cognitive delay. Further research is needed, using individual‐level meta‐analyses to adjust for possible confounders, notably gestational age. [ABSTRACT FROM AUTHOR]

• Placental insufficiency is emerging as a contributor to spontaneous preterm birth. • Thrombin may be involved in mechanisms leading to spontaneous preterm birth. • PAPP-A and PlGF may prove useful in the prediction in spontaneous preterm birth. Preterm Birth (delivery before 37 weeks of gestation) is the leading cause of childhood mortality and is also associated with significant morbidity both in the neonatal period and beyond. The aetiology of spontaneous preterm birth is unclear and likely multifactorial incorporating factors such as infection/inflammation and cervical injury. Placental insufficiency is emerging as an additional contributor to spontaneous preterm delivery; however, the mechanisms by which this occurs are not fully understood. Serum biomarkers and imaging techniques have been investigated as potential predictors of placental insufficiency, however none have yet been found to have a sufficient predictive value. This review examines the evidence for the role of the placenta in preterm birth, preterm prelabour rupture of the membranes and abruption as well as highlighting areas where further research is required. [ABSTRACT FROM AUTHOR]

• There is an association between maternal and fetal Doppler in early labour with the occurrence of labour complications. • A predictive model including early labour CPR and mean UtA Doppler allows the identification of over three out of four women at low-risk of intrapartum hypoxia that are submitted to obstetric intervention due to suspected intrapartum fetal compromise. • The predictive model has a good capacity to rule out and a moderate capacity to rule in OI due to IFC, albeit with poor predictive value. • The predictive model including antenatal and intrapartum characteristics combined with abnormal CPR and mean UtA PI may be used as a screening tool for subclinical uteroplacental insufficiency manifesting during active labor. The evidence-based management of human labor includes the antepartum identification of patients at risk for intrapartum hypoxia. However, available evidence has shown that most of the hypoxic-related complications occur among pregnancies classified at low-risk for intrapartum hypoxia, thus suggesting that the current strategy to identify the pregnancies at risk for intrapartum fetal hypoxia has limited accuracy. To evaluate the role of the combined assessment of the cerebroplacental ratio (CPR) and uterine arteries (UtA) Doppler in the prediction of obstetric intervention (OI) for suspected intrapartum fetal compromise (IFC) within a cohort of low-risk singleton term pregnancies in early labor. Prospective multicentre observational study conducted across four tertiary Maternity Units between January 2016 and September 2019. Low-risk term pregnancies with spontaneous onset of labor were included. A two-step multivariable model was developed to assess the risk of OI for suspected IFC. The baseline model included antenatal and intrapartum characteristics, while the combined model included antenatal and intrapartum characteristics plus Doppler anomalies such as CPR MoM < 10th percentile and mean UtA Doppler PI MoM ≥ 95th percentile. Predictive performance was determined by receiver–operating characteristics curve analysis. 804 women were included. At logistic regression analysis, CPR MoM < 10th percentile (aOR 1.269, 95 % CI 1.188–1.356, P < 0.001), mean UtA PI MoM ≥ 95th percentile (aOR 1.012, 95 % CI 1.001–1.022, P = 0.04) were independently associated with OI for suspected IFC. At ROC curve analysis, the combined model including antenatal characteristics plus abnormal CPR and mean UtA PI yielded an AUC of 0.78, 95 %CI(0.71–0.85), p < 0.001, which was significantly higher than the baseline model (AUC 0.61, 95 %CI(0.54–0.69), p = 0.007) (p < 0.001). The combined model was associated with a 0.78 (95 % CI 0.67–0.89) sensitivity, 0.68 (95 % CI 0.65–0.72) specificity, 0.15 (95 % CI 0.11–0.19) PPV, and 0.98 (0.96–0.99) NPV, 2.48 (95 % CI 2.07–2.97) LR + and 0.32 (95 % CI 0.19–0.53) LR- for OI due to suspected IFC. A predictive model including antenatal and intrapartum characteristics combined with abnormal CPR and mean UtA PI has a good capacity to rule out and a moderate capacity to rule in OI due to IFC, albeit with poor predictive value. [ABSTRACT FROM AUTHOR]

Objectives: Blood‐oxygen‐level‐dependent (BOLD) magnetic resonance imaging (MRI) facilitates the non‐invasive in‐vivo evaluation of placental oxygenation. The aims of this study were to identify and quantify a relative BOLD effect in response to hyperoxia in the human placenta and to compare it between pregnancies with and those without fetal growth restriction (FGR). Methods: This was a prospective multicenter study (NCT02238301) of 19 pregnancies with FGR (estimated fetal weight (EFW) on ultrasound < 5th centile) and 75 non‐FGR pregnancies (controls) recruited at two centers in Paris, France. Using a 1.5‐Tesla MRI system, the same multi‐echo gradient‐recalled echo (GRE) sequences were performed at both centers to obtain placental T2* values at baseline and in hyperoxic conditions. The relative BOLD effect was calculated according to the equation 100 × (hyperoxic T2* − baseline T2*)/baseline T2*. Baseline T2* values and relative BOLD effect were compared according to EFW (FGR vs non‐FGR), presence/absence of Doppler anomalies and birth weight (small‐for‐gestational age (SGA) vs non‐SGA). Results: We observed a relative BOLD effect in response to hyperoxia in the human placenta (median, 33.8% (interquartile range (IQR), 22.5–48.0%)). The relative BOLD effect did not differ significantly between pregnancies with and those without FGR (median, 34.4% (IQR, 24.1–48.5%) vs 33.7% (22.7–47.4%); P = 0.95). Baseline T2* Z‐score adjusted for gestational age at MRI was significantly lower in FGR pregnancies compared with non‐FGR pregnancies (median, −1.27 (IQR, −4.87 to −0.10) vs 0.33 (IQR, −0.81 to 1.02); P = 0.001). Baseline T2* Z‐score was also significantly lower in those pregnancies that subsequently delivered a SGA neonate (n = 23) compared with those that delivered a non‐SGA neonate (n = 62) (median, −0.75 (IQR, −3.48 to 0.29) vs 0.35 (IQR, −0.79 to 1.05); P = 0.01). Conclusions: Our study confirms a BOLD effect in the human placenta and that baseline T2* values are significantly lower in pregnancies with FGR. Further studies are needed to evaluate whether such parameters may detect placental insufficiency before it has a clinical impact on fetal growth. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

To longitudinally and cross-sectionally study the differences in the uterine artery pulsatility index (UTPI), umbilical artery pulsatility index (UAPI) and placental vascularization indices (PVIs, derived from 3-dimensional power Doppler) between normal and placental insufficiency pregnancies throughout gestation. UTPI, UAPI and PVI were measured 6 times at 4- to 5- week intervals from 11 to 13+6 weeks–36 weeks. Preeclampsia (PE) and fetal growth restriction (FGR) were defined as placental insufficiency. Comparisons of UTPI, UAPI and PVI between normal and insufficiency groups were performed by one-way repeated measures analysis of variance. A total of 125 women were included: monitored regularly from the first trimester to 36 weeks of gestation: 109 with normal pregnancies and 16 with placental insufficiency. Longitudinal study of the normal pregnancy group showed that UTPI and UAPI decreased significantly every 4 weeks, while PVIs increased significantly every 8 weeks until term. In the placental insufficiency group however, this decrease occurred slower at 8 weeks intervals and UTPI stabilized after 24 weeks. No significant difference was noted in PVIs throughout pregnancy. Cross-sectional study from different stages of gestation showed that UTPI was higher in the insufficiency group from 15 weeks onward and PVIs were lower after 32 weeks. Compared to high-risk pregnancies with normal outcome, UTPI and UAPI needed a longer time to reach a significant change in those with clinical confirmation of placental insufficiency pregnancies and no significant change was found in PVI throughout gestation. UTPI was the earliest factor in detecting adverse outcome pregnancies. • Longitudinal investigation of utero-placental circulation in different outcomes. • Cross-sectional comparison of hemodynamic changes in different outcomes. • Changes in VI and VFI were smaller than in UTPI and UAPI. • Hemodynamic changes were smaller in placental insufficient pregnancies. • UTPI was the earliest factor in detecting adverse outcome pregnancies. [ABSTRACT FROM AUTHOR]

The introduction of noninvasive prenatal testing has resulted in substantial reductions to previously accepted false-positive rates of prenatal screening. Despite this, the possibility of false-positive results remains a challenging consideration in clinical practice, particularly considering the increasing uptake of genome-wide noninvasive prenatal testing, and the subsequent increased proportion of high-risk results attributable to various biological events besides fetal aneuploidy. Confined placental mosaicism, whereby chromosome anomalies exclusively affect the placenta, is perhaps the most widely accepted cause of false-positive noninvasive prenatal testing. There remains, however, a substantial degree of ambiguity in the literature pertaining to the clinical ramifications of confined placental mosaicism and its potential association with placental insufficiency, and consequentially adverse pregnancy outcomes including fetal growth restriction. Other causes of false-positive noninvasive prenatal testing include vanishing twin syndrome, in which the cell-free DNA from a demised aneuploidy-affected twin triggers a high-risk result, technical failures, and maternal origins of abnormal cell-free DNA such as uterine fibroids or unrecognized mosaicisms. Most concerningly, maternal malignancies are also a documented cause of false-positive screening results. In this review, we compile what is currently known about the various causes of false-positive noninvasive prenatal testing. [Display omitted] [ABSTRACT FROM AUTHOR]

Early onset fetal growth restriction (FGR) is one of the main adverse pregnancy conditions, often associated with poor neonatal outcomes. Frequently, early onset FGR is associated with early onset hypertensive disorders of pregnancy (HDP), and in particular preeclampsia (PE). However, to date, it is still an open question whether pregnancies complicated by early FGR plus HDP (FGR-HDP) and those complicated by early onset FGR without HDP (normotensive-FGR (n-FGR)) show different prenatal and postnatal outcomes and, consequently, should benefit from different management and long-term follow-up. Recent data support the hypothesis that the presence of PE may have an additional impact on maternal hemodynamic impairment and placental lesions, increasing the risk of poor neonatal outcomes in pregnancy affected by early onset FGR-HDP compared to pregnancy affected by early onset n-FGR. This review aims to elucidate this poor studied topic, comparing the clinical characteristics, perinatal outcomes, and potential long-term sequelae of early onset FGR-HDP and early onset n-FGR. [ABSTRACT FROM AUTHOR]

Background. Gestational diabetes mellitus is the most frequent metabolic disorder during pregnancy. Its prevalence is steadily increasing worldwide. In the setting of hyperinsulinism, this pathology may cause various structural and functional changes in the placenta, as well as a reduction in oxygen supply to the fetus. This may result in fetal hypoxia and increased risk of fetal growth restriction. Therefore, research into the specific features of gestation course in patients with gestational diabetes mellitus in order to prevent its complications appears relevant. Objective. To study the specific features of gestation, delivery, and perinatal outcomes in patients with non-insulin dependent gestational diabetes mellitus. Methods. We conducted an observational cohort study of the case histories of 120 women with singleton pregnancies of the second and third trimesters with diagnosed non-insulin dependent gestational diabetes mellitus, their labor and delivery records, and the medical records of the newborns. All the patients were managed at the Ural Research Institute of Maternity and Child Care during 2021–2023. The main group comprised 70 patients whose pregnancy was complicated by sub- and decompensated forms of placental insufficiency. The comparison group comprised 50 pregnant women without pathologies of the fetoplacental complex. The obstetric history, gestation course of the present pregnancy and its outcomes, as well as the condition of the newborns, were analyzed. The obtained data were processed by the methods of variation statistics using Microsoft Excel spreadsheets (Microsoft, USA) and Statistica 13 (DellInc., USA) and MedCalc 15.8 (MedCalcSoftware, Belgium) applications. The null hypothesis was rejected at p > 0.05. Results. Gestational diabetes mellitus in previous pregnancies was statistically significantly less frequent in the main group (2.9% (n = 2)) than in the comparison group (18.0% (n = 9)) ( p > 0.05). Placental insufficiency in the main group was characterized by fetal growth restriction, which was associated with impaired uteroplacental blood flow in 58.6% (n = 41) of the cases. In the main group, the pregnancy ended in preterm delivery in 21.4% (n = 15) of the cases; in 78.6% (n = 55) of the cases, the delivery was at term. There were no preterm births in the comparison group, p > 0.05. Cesarean section was performed in 62.9% (n = 44) of patients in the main group, compared to 20.0% (n = 10) in the comparison group ( p > 0.05). Newborns of the main group required respiratory support more often (p > 0.05). Conclusion. The mechanism of placental insufficiency in patients with non-insulin dependent gestational disorders of carbohydrate metabolism remains to be elucidated. Further research should investigate the predictors of fetoplacental complex pathologies in this group of patients in order to reduce the number of perinatal complications.

This review focuses on the management of reproductive issues in women who have antiphospholipid syndrome (APS) or are carriers of antiphospholipid antibodies (aPL). The importance of aPL detection during preconception counselling relies on their pathogenic potential for placental insufficiency and related obstetric complications. The risk of adverse pregnancy outcomes can be minimized by individualized risk stratification and tailored treatment aimed at preventing placental insufficiency. Combination therapy of low-dose acetylsalicylic acid and heparin is the mainstay of prophylaxis during pregnancy; immunomodulation, especially with hydroxychloroquine, should be considered in refractory cases. Supplementary ultrasound surveillance is useful to detect fetal growth restriction and correctly tailor the time of delivery. The individual aPL profile must be considered in the stratification of thrombotic risk, such as during assisted reproduction techniques requiring hormonal ovarian stimulation or during the follow-up after pregnancy in order to prevent the first vascular event. [ABSTRACT FROM AUTHOR]

We report the case of a four-year-old male patient with a complex medical history born prematurely as the result of intrauterine growth restriction due to placental insufficiency. His clinical manifestations included severe neurodevelopmental deficits, global developmental delay, Pierre-Robin sequence, and intractable epilepsy with both generalized and focal features. The proband's low levels of citrulline and lactic acidosis provoked by administration of Depakoke were evocative of a mitochondrial etiology. The proband's genotype–phenotype correlation remained undefined in the absence of nuclear and mitochondrial pathogenic variants detected by deep sequencing of both genomes. However, live-cell mitochondrial metabolic investigations provided evidence of a deficient oxidative-phosphorylation pathway responsible for adenosine triphosphate (ATP) synthesis, leading to chronic energy crisis in the proband. In addition, our metabolic analysis revealed metabolic plasticity in favor of glycolysis for ATP synthesis. Our mitochondrial morphometric analysis by transmission electron microscopy confirmed the suspected mitochondrial etiology, as the proband's mitochondria exhibited an immature morphology with poorly developed and rare cristae. Thus, our results support the concept that suboptimal levels of intrauterine oxygen and nutrients alter fetal mitochondrial metabolic reprogramming toward oxidative phosphorylation (OXPHOS) leading to a deficient postnatal mitochondrial energy metabolism. In conclusion, our collective studies shed light on the long-term postnatal mitochondrial pathophysiology caused by intrauterine growth restriction due to idiopathic placental insufficiency and its negative impact on the energy-demanding development of the fetal and postnatal brain. [ABSTRACT FROM AUTHOR]

To achieve the purpose of the study, based on developed clinical and laboratory criteria, a prospective study of the course of pregnancy and its outcomes was conducted in 62 pregnant women aged 18 to 39 years (average age 27.98±5.3) for the period from 2019 to 2022. with undifferentiated connective tissue dysplasia (UCTD), which formed a high-risk group for the development of pathology of the fetoplacental system. All pregnant women were divided into 2 groups: main (n = 36), comparison (n = 32). The first group of the study (main) consisted of 36 pregnant women with UCTD, carriers of cytomegalovirus infection, the second group (comparison) 32 pregnant women with UCTD, without carriage of cytomegalovirus infection. The control group consisted of 24 pregnant women without the presence of UCTD and cytomegalovirus infection at the time of the study. The conducted studies found that disturbances in the cellular immune system in women with UCTD increased the frequency of the infectious process. In the third trimester, women in the main group were more likely to have threatened labor (15 women (41.7±8.2% in the main group and 6 women (18.8±6.9%) in the comparison group); oligohydramnios (9 women (25 .0±7.2%) and 3 women (9.4±5.1%); intrauterine growth retardation syndrome (28 women (77.8±6.9% and 19 women (59.4±8.6 %). This was reflected in the high concentration of IgM and an increase in the relative number of CD16+ and CD20+ lymphocytes in pregnant women of the main group. Histological examination confirmed a higher frequency of infection of the ovum in pregnant women with UCTD, carriers of cytomegalovirus, which was limited to the placenta and was not accompanied by intrauterine infection of the fetus. The presence of UCTD in pregnant women with persistent infection of the herpesvirus family increases the risk of unfavorable implementation of the infectious process, and this should be taken into account when making a prognosis for the development of obstetric and perinatal complications and justifies the advisability of carrying out treatment and preventive measures during pregnancy and in the postpartum period. [ABSTRACT FROM AUTHOR]

Fetal growth restriction (FGR) is a complication diagnosed in about 10% of pregnancies and is associated with significant perinatal mortality and morbidity. Both the diagnosis and the correct management of cases of intrauterine growth restriction remain a challenge of modern obstetrics. A normal placental development is essential for a proper intrauterine physical and neurological growth of the fetus throughout pregnancy. Various pathophysiological situations may reflect in abnormal placental development linked with severe pregnancy disorders. In this paper we aim to exemplify sonographic aspects in various placental pathology associated with FGR along with the recommended management. Placental insufficiency is the most common risk factor for FGR and it cannot be directly measured and objectified, remaining a diagnostic of exclusion. The risk for perinatal adverse outcomes in placenta accreta spectrum cases is increased trough the pathological implantation especially in depth. In pregnancies complicated with placental insufficiency, secondary macroscopic lesions can be noted, as parabasal and intervillous thrombosis, hematomas, extensive fibrin deposits and infarcts areas. Even if, over time, multiple studies have targeted methods of preventing intrauterine growth restriction through actions on the mother, the effectiveness of no treatment has been demonstrate [ABSTRACT FROM AUTHOR]

Background: Intrauterine growth restriction (IUGR) is said to be in neonates whose birth weight is less than tenth percentile of the average for gestational age. IUGR is associated with short and long-term complications which can severely impact quality of life. Placental size, weight and shape may vary within wide extreme values. Ability to transfer nutrients is related to placental size. Decreased placental surface area and size are associated with increased risk of IUGR. Umbilical cord is the key marker for intrauterine complications. It is one of the most important part of fetoplacental unit that transfer vital nutrients to fetus. This current study was taken to find out the difference in placental morphometric features and to find the correlation between placental and neonatal weight. Materials and methods: This study included 100 samples which were equally divided into cases and controls. Placenta was collected after delivery and the data is measured quantitatively. Results: Central insertion of umbilical cord observed in IUGR in our study was 40%, eccentric was 20%, marginal was 38%, velamentous insertion was 2% while furcate insertion observed was nil in our study. Conclusion: Central and marginal insertion was prevalent in IUGR in our study. Types of cord insertion plays also plays role in transfer of nutrients. Vasculature being the most important factor the growth of fetus, any imbalance in it will alter the growth. [ABSTRACT FROM AUTHOR]

Background: Placental insufficiency is an important mechanism underlying early-onset fetal growth restriction (eoFGR). Reduced placental function causes impaired metabolic and gaseous exchange. This unfavorable placental environment is among other processes characterized by increased oxidative stress. Systemic free thiols (FT) are known for their reactive oxygen species scavenging capacity, and higher plasma levels of FT are associated with a better outcome in a multitude of ischemic and inflammatory diseases. We aimed to investigate the relationships between systemic FT levels and maternal and perinatal clinical characteristics and outcomes. Study design: In a post hoc analysis of the Dutch Strider study, a cohort of women with eoFGR, we investigated the association between the maternal redox status (FT) levels at study inclusion, placental biomarkers, and maternal and neonatal outcomes in 108 patients. Results: FT were significantly lower in pregnancies complicated with eoFGR with concurrent maternal hypertensive disorders (pregnancy-induced hypertension; ρ = −0.281 p = 0.004, pre-eclampsia; ρ = −0.505 p = 0.000). In addition, lower FT levels were significantly associated with higher systolic (ρ = −0.348 p = 0.001) and diastolic blood pressure (ρ = −0.266 p = 0.014), but not with the severity of eoFGR. FT levels were inversely associated with sFlt (ρ = −0.366, p < 0.001). A strong relation between systemic FT levels and PlGF levels was observed in women with pre-eclampsia at delivery (ρ = 0.452, p = 0.002), which was not found in women without hypertensive disorders (ρ = 0.008, p = 0.958). Conclusions: In women with pregnancies complicated with eoFGR, FT levels reflect the severity of maternal disease related to the underlying placental insufficiency rather than the severity of the placental dysfunction as reflected in eoFGR or perinatal outcomes. [ABSTRACT FROM AUTHOR]

Objective: Placental infection with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) can lead to placental insufficiency and in‐utero fetal death (IUFD). The objective of this study was to confirm and quantify the extent to which fetoplacental infection with SARS‐CoV‐2 is a cause of fetal death. Methods: This was a multicenter retrospective cohort study of fetal deaths that underwent postmortem examination between January 2020 and January 2022 in three fetal pathology units in Paris, France. All cases of IUFD and termination of pregnancy (TOP) occurring in 31 maternity hospitals in the Paris region undergo detailed placental pathological examination in these units. Databases were searched for cases of IUFD and TOP. Cases with fetal malformation or cytogenetic abnormality were excluded to avoid bias. We included cases of IUFD with a placental or undetermined cause and cases of TOP in the context of severe intrauterine growth restriction (IUGR). Placentas were sent to a single virology unit for reverse‐transcription polymerase chain reaction (RT‐PCR) testing by a single laboratory technician blinded to the initial postmortem examination report. Our primary endpoint was the proportion of positive placental SARS‐CoV‐2 RT‐PCR tests in the cohort. Results: Among 147 722 deliveries occurring over 2 years, 788 postmortem examinations for IUFD and TOP for severe IUGR were recorded, of which 462 (58.6%) were included. A total of 13/462 (2.8%) placentas tested positive for SARS‐CoV‐2 by RT‐PCR. Wild‐type virus and alpha and delta variants were identified. All positive cases had histological lesions consistent with placental dysfunction. There was a strong correlation between SARS‐CoV‐2 placentitis and the presence of chronic intervillositis and/or massive fibrin deposits in the placenta. When both lesion types were present, the specificity and negative predictive value for the diagnosis of placental SARS‐CoV‐2 infection were 0.99 (95% CI, 0.98–1.00) and 0.96 (95% CI, 0.94–0.98), respectively. Conclusions: At the height of the SARS‐CoV‐2 pandemic, the cause of more than half of fetal deaths in the Paris area was determined by postmortem analysis to be of placental or undetermined origin. Of these cases, 2.8% were due to placental SARS‐CoV‐2 infection with a specific pattern of histological involvement. This study highlights the need for SARS‐CoV‐2 screening in stillbirth assessment. The impact of vaccination coverage remains to be established. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Objectives: The placental dysfunction underlying fetal growth restriction (FGR) may result in severe adverse perinatal outcome (SAPO) related to fetal hypoxia. Traditionally, the diagnostic criteria for FGR have been based on fetal size, an approach that is inherently flawed because it often results in either over‐ or underdiagnosis. The anomaly ultrasound scan at 20 weeks' gestation may be an appropriate time at which to set a benchmark for growth potential of the individual fetus. We hypothesized that the fetal growth trajectory from that point onwards may be informative regarding third‐trimester placental dysfunction. The aim of this study was to investigate the predictive value for SAPO of a slow fetal growth trajectory between 18 + 0 to 23 + 6 weeks and 32 + 0 to 36 + 6 weeks' gestation in a large, low‐risk population. Methods: This was a post‐hoc data analysis of the IUGR Risk Selection (IRIS) study, a Dutch nationwide cluster‐randomized trial assessing the (cost‐)effectiveness of routine third‐trimester sonography in reducing SAPO. In the current analysis, for the first ultrasound examination we used ultrasound data from the routine anomaly scan at 18 + 0 to 23 + 6 weeks' gestation, and for the second we used data from an ultrasound examination performed between 32 + 0 and 36 + 6 weeks' gestation. Using multilevel logistic regression, we analyzed whether SAPO was predicted by a slow fetal growth trajectory, which was defined as a decline in abdominal circumference (AC) and/or estimated fetal weight (EFW) of more than 20 percentiles or more than 50 percentiles or as an AC growth velocity (ACGV) < 10th percentile (p10). In addition, we analyzed the combination of these indicators of slow fetal growth with small‐for‐gestational age (SGA) (AC or EFW < p10) and severe SGA (AC/EFW < 3rd percentile) at 32 + 0 to 36 + 6 weeks' gestation. Results: Our sample included the data of 6296 low‐risk singleton pregnancies, among which 82 (1.3%) newborns experienced at least one SAPO. Standalone declines in AC or EFW of > 20 or > 50 percentiles or ACGV < p10 were not associated with increased odds of SAPO. EFW < p10 between 32 + 0 and 36 + 6 weeks' gestation combined with a decline in EFW of > 20 percentiles was associated with an increased rate of SAPO. The combination of AC or EFW < p10 between 32 + 0 and 36 + 6 weeks' gestation with ACGV < p10 was also associated with increased odds of SAPO. The odds ratios of these associations were higher if the neonate was SGA at birth. Conclusions: In a low‐risk population, a slow fetal growth trajectory as a standalone criterion does not distinguish adequately between fetuses with FGR and those that are constitutionally small. This absence of association may be a result of diagnostic inaccuracies and/or post‐diagnostic (e.g. intervention and selection) biases. We conclude that new approaches to detect placental insufficiency should integrate information from diagnostic tools such as maternal serum biomarkers and Doppler ultrasound measurements. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

• Abnormal uterine artery Doppler entails placenta-insufficiency related risks. • Combined uterine artery Doppler and sFlt-1/PlGF provide criteria for tight follow-up. • sFlt-1/PlGF performs better in high-risk pregnancies for detecting adverse events when applying a cutoff of 38 or greater. To determine the optimal cutoff value for the soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio to predict maternal and fetal adverse events in pregnancies with uterine artery Doppler scans results above the 95th percentile in the late second trimester. Retrospective, observational cohort study on 116 asyntomatic patients with abnormal uterine artery Doppler scans at gestational week 25. The sFlt-1/PlGF ratio was determined within the weeks 25 to 29 of gestation and ROC curve analysis performed. The diagnostic validity of different cutoff values to predict severe maternal and fetal complications, i.e. preeclampsia, fetal growth restriction, placental abruption, and fetal death, was analyzed. An ideal cutoff for sFlt-1/PlGF ratios in pregnancies with abnormal uterine artery Doppler in the second trimester. Applying a cutoff point of 38, the area under the ROC curve was 0.89, generally considered low risk in fetal and maternal complication prediction. The sensitivity was 32.1%, the specificity 98.4%, the positive predictive value (PPV) 94.4%, and the negative predictive value (NPV) 63.3%. A cutoff value of 10, leading to the highest Youden index, performed best at detecting overall complications, increasing sensitivity to 69.8% and the NPV to 76.8%. at the cost of a reduced specificity and PPV. In pregnancies with abnormal uterine artery Doppler in the second trimester, an sFlt-1/PlGF cutoff value greater than equal to 38 improves its predictive power for adverse events. [ABSTRACT FROM AUTHOR]

Recent evidence has revealed associations between endocrine-disrupting chemicals (EDCs) and placental insufficiency due to altered placental growth, syncytialization, and trophoblast invasion. However, no epidemiologic study has reported associations between exposure to EDCs and asymmetric fetal growth restriction (FGR) caused by placenta insufficiency. The aim of this study was to evaluate the association between EDC exposure and asymmetric FGR. This was a prospective cohort study including women admitted for delivery to the Maternal Fetal Center at Seoul St. Mary’s Hospital between October 2021 and October 2022. Maternal urine and cord blood samples were collected, and the levels of bisphenol-A (BPA), monoethyl phthalates, and perfluorooctanoic acid in each specimen were analyzed. We investigated linear and non-linear associations between the levels of EDCs and fetal growth parameters, including the head circumference (HC)/abdominal circumference (AC) ratio as an asymmetric parameter. The levels of EDCs were compared between fetuses with and without asymmetric FGR. Of the EDCs, only the fetal levels of BPA showed a linear association with the HC/AC ratio after adjusting for confounding variables (β = 0.003, p

Melatonin (N-acetyl-5-methoxytryptamine) is a polypotent neuroendocrine lipid-soluble small molecule secreted mainly by the pineal gland. During gestation, melatonin levels in the mother at night rise as the pregnancy progresses and return to normal after delivery. The etiology of hypertensive disorder complicating pregnancy (HDCP) is multifaceted. An increasing number of evidence suggests the involvement of melatonin in the pathogenic process, and the regulation is related to its expression level, secretion rhythm and receptor level. Abnormal placental blood circulation, ischemia and hypoxia and systemic vascular endothelium dysfunction are the main pathological processes of HDCP. Through direct antioxidant effect, melatonin improves mitochondrial dysfunction and protects trophoblast cells from oxidative damage, thus participating in the regulation of placental oxidative stress level, and plays a protective role in preventing oxidative damage caused by hypoxic ischemia reperfusion of placenta, thus maintaining placental functional homeostasis. In addition, there is also evidence that melatonin can protect maternal vascular endothelium from oxidative stress by reducing the production and secretion of pro-inflammatory cytokines and vasoactive compounds, and participating in the regulation of systemic blood pressure in pregnant women. These confidences suggest that melatonin can be involved in the maintenance of placental and systemic vascular functional homeostasis during pregnancy through the regulation of oxidative stress. In this article, the effects of melatonin on HDCP and the related mechanisms are reviewed, and the positive role of melatonin in the pathogenesis of HDCP is summarized.

Objective: To study the morphology of the placenta in pregnant women with TB Methods: The morphology of the 26 placentas was evaluated in this study, out of which 15 were from women with various forms and localizations of TB (main group), while 11 were from healthy pregnant women (control group). The placentas were evaluated macroscopically. Central and peripheral zones of the placenta and umbilical cord were sampled and embedded in paraffin. Histological slides were stained with hematoxylin-eosin and examined using an Olympus CX-21 microscope with a Universal Infinity Optical System (UIS2). Results: Women in the main group were significantly more commonly underweight (p

Intrauterine growth-restricted (IUGR) fetuses exhibit systemic inflammation that contributes to programmed deficits in myoblast function and muscle growth. Thus, we sought to determine if targeting fetal inflammation improves muscle growth outcomes. Heat stress-induced IUGR fetal lambs were infused with eicosapentaenoic acid (IUGR+EPA; n = 9) or saline (IUGR; n = 8) for 5 days during late gestation and compared to saline-infused controls (n = 11). Circulating eicosapentaenoic acid was 42% less (p < 0.05) for IUGR fetuses but was recovered in IUGR+EPA fetuses. The infusion did not improve placental function or fetal O2 but resolved the 67% greater (p < 0.05) circulating TNFα observed in IUGR fetuses. This improved myoblast function and muscle growth, as the 23% reduction (p < 0.05) in the ex vivo differentiation of IUGR myoblasts was resolved in IUGR+EPA myoblasts. Semitendinosus, longissimus dorsi, and flexor digitorum superficialis muscles were 24–39% lighter (p < 0.05) for IUGR but not for IUGR+EPA fetuses. Elevated (p < 0.05) IL6R and reduced (p < 0.05) β2 adrenoceptor content in IUGR muscle indicated enhanced inflammatory sensitivity and diminished β2 adrenergic sensitivity. Although IL6R remained elevated, β2 adrenoceptor deficits were resolved in IUGR+EPA muscle, demonstrating a unique underlying mechanism for muscle dysregulation. These findings show that fetal inflammation contributes to IUGR muscle growth deficits and thus may be an effective target for intervention.