Late Fetal Growth Restriction Research Articles

AT-rich interactive domain-containing protein 1A (ARID1A) expression in placentas with late fetal growth restriction

BACKGROUND: Fetal growth restriction, which is considered as a multifactorial pathology, is a critical problem in obstetrics. The role of mitochondrial dysfunction in the pathogenesis of fetal growth restriction is not yet clear. However, it is known that it leads to oxidative stress, damage to cells and tissues, and dysfunction of key mechanisms for maintaining energy balance, the outcome of which may be the development of placental insufficiency. It is likely that AT-rich interactive domain-containing protein 1A (ARID1A) is involved in the development and function of the human placenta and may be an important marker in the development of fetal growth restriction. AIM: The aim of this study was to evaluate ARID1A protein expression in the placental villous tree in late fetal growth restriction. MATERIALS AND METHODS: This study included 50 placentas from children born at full-term gestation (37–40 weeks). The main study group consisted of placentas with late fetal growth restriction and without major extragenital pathology (n = 35). The control group comprised 15 placentas without fetal growth restriction (n = 15). Histological (n = 50) and immunohistochemical examinations of placentas (15 placentas in the main group and 10 placentas in the control group) using primary monoclonal antibodies to ARID1A were performed. RESULTS: In the study group with fetal growth restriction, chronic placental insufficiency was verified in all cases, dissociated chronic placental insufficiency (25 cases; 71.4%) being predominant, of which 23 cases (92%) were compensated, including 16 cases (69.6%) with moderate circulatory disorders. Hypoplastic chronic placental insufficiency was diagnosed in ten cases (28.6%) and was subcompensated with the presence of pronounced circulatory disorders. In the arteries of the stem villi, the ARID1A protein expression area did not differ between the study groups (p = 0.096), while in the veins in the stem villi with fetal growth restriction, we verified a decrease compared to control (p = 0.05). In the vascular bed of the villi with subcompensated dissociated chronic placental insufficiency, ARID1A protein expression was higher compared to hypoplastic chronic placental insufficiency (p = 0.041). CONCLUSIONS: Chronic placental insufficiency combined with fetal growth restriction is a serious complication of pregnancy with the development of structural and functional abnormalities and dysregulation of placental mechanisms. The ARIDA1A protein expression data obtained, depending on the degree of compensation for chronic placental insufficiency, may indicate the activation of compensatory metabolic mechanisms to maintain the functional activity of the placenta and preserve the viability of the fetus.

Maternal cardiovascular profile is altered in the pre-clinical phase of normotensive early and late fetal growth restriction

BackgroundMaternal cardiovascular profile of patients developing late fetal growth restriction is yet to be well characterized, although a subclinical impairment of maternal hemodynamics and cardiac function may be present before pregnancy, becoming evident because of the hemodynamic alterations of pregnancy. ObjectivesOur objective was to investigate if maternal hemodynamics and the cardiovascular profile might be different in the preclinical stages (22-24 weeks gestation) of early and late fetal growth restriction in normotensive patients. Study designThis was a prospective echocardiographic study of 1152 normotensive nulliparous pregnant women at 22-24 weeks’ gestation. The echocardiographic evaluation included morphological parameters (left ventricular mass index and relative wall thickness, left atrial volume index) as well as systolic and diastolic maternal left ventricular function (ejection fraction, left ventricular LV global longitudinal strain, E/A, and E/e'). Patients were followed until the end of pregnancy to note the development of normotensive early or late fetal growth restriction. Results1049 patients had no complications, 73 were classified as late fetal growth restriction and 30 as early fetal growth restriction. Left Ventricular MorphologyLeft ventricular end-diastolic diameter was greater in uneventful pregnancies (4.84±0.28 cm) vs late (4.67±0.26 cm) and vs early fetal growth restriction (4.55±0.26 cm) (p<0.001), whereas left ventricular end-systolic diameter was smaller in uneventful pregnancies (2.66±0.39 cm) vs late (2.83±0.40 cm) and early fetal growth restriction (2.82±0.38 cm) (p<0.001). Relative wall thickness was slightly higher in early (0.34±0.05) and late fetal growth restriction (0.35±0.04) vs uneventful pregnancies (0.32±0.05) (p<0.05). Systolic Left Ventricular FunctionAt 22-24 weeks’ cardiac output was higher in uneventful pregnancies (6.58±1.07 L/min) vs late (5.40±0.97 L/min) and vs early fetal growth restriction (4.76±1.05 L/min) (p<0.001), with the lowest values in the early onset group. Left ventricular global longitudinal strain was lower in AGA (-21.6±2.0%), and progressively higher in late (-20.1±2.2%) and early fetal growth restriction (-18.5±2.3%) (p<0.001). Diastolic Left Ventricular FunctionE/e’ ratio showed intermediate values in the late fetal growth restriction (7.90±2.73) vs AGA (7.24±2.43) and vs early fetal growth restriction (10.76±3.25) (p<0.001). Total Peripheral Vascular ResistanceTotal Peripheral Vascular Resistance was also intermediate in the late fetal growth restriction (1300±199 dyne·s·cm-5) vs AGA (993±175 dyne·s·cm-5) and vs early fetal growth restriction (1488±255 dyne·s·cm-5) (p<0.001). ConclusionsEarly and late fetal growth restriction share similar maternal hemodynamic and cardiovascular profiles with a different degree of expression. These features are already present at 22-24 weeks gestation and are characterized by a hypodynamic state. The degree of these cardiovascular changes may influence the timing of the manifestation of the disease: a hypovolemic, high resistance, low cardiac output state might be associated to early onset fetal growth restriction, whereas a milder hypovolemic state seems to favor a development of the disease in the final stages of pregnancy.

Maternal serum vasohibin-1 and vasohibin-2 concentrations in pregnant women diagnosed with late fetal growth restriction or small for gestational age fetus

Aims: Vasohibin 1, a member of the vasohibin family, is an inhibitor of angiogenesis, while vasohibin 2 stimulates angiogenesis. Placental expressions of vasohibins and their relationship with preeclampsia have been investigated, but their effects on intrauterine fetal growth are unknown. In this context, we aimed to investigate the concentrations of vasohibin 1 and 2 in the serum of pregnant women diagnosed with late fetal growth restriction (FGR) or small for gestational age (SGA) in the third trimester. Methods: This prospective non-interventional cohort study was conducted on 81 pregnant women, 26 of whom were diagnosed with late FGR, 28 were SGA, and 27 were healthy controls. Three groups were compared in terms of serum vasohibin 1 and 2 concentrations in the third trimester. Results: Three groups were similar in terms of demographic characteristics and gestational age at blood sampling for vasohibin 1 and 2 (p &lt; 0.05). The median vasohibin 1 concentration was determined as 1227.41 ng/mL in the late FGR group, 1311.15 ng/mL in the SGA group, and 1391.38 ng/mL in the control group (p = 0.139). The median vasohibin 2 concentration was determined as 11.24 ng/mL in the late FGR group, 11.86 ng/mL in the SGA group, and 14.34 ng/mL in the control group (p = 0.198). Conclusion: Serum vasohibin 1 and 2 concentrations were found to be similar in pregnant women diagnosed with late FGR and SGA and pregnant women with AGA fetuses. Vasohibin 1 and 2 are involved in the regulation of placental angiogenesis, but their roles in intrauterine fetal growth remain unclear.

Prediction of preterm birth in growth-restricted and appropriate-for-gestational-age infants using maternal PlGF and the sFlt-1/PlGF ratio-A prospective study.

To assess the utility of placental growth factor (PlGF) levels and the soluble fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratio to predict preterm birth (PTB) for infants with fetal growth restriction (FGR) and those appropriate for gestational age (AGA). Prospective, observational cohort study. Tertiary maternity hospital in Australia. There were 320 singleton pregnancies: 141 (44.1%) AGA, 83 (25.9%) early FGR (<32+0 weeks) and 109 (30.0%) late FGR (≥32+0 weeks). Maternal serum PlGF and sFlt-1/PlGF ratio were measured at 4-weekly intervals from recruitment to delivery. Low maternal PlGF levels and elevated sFlt-1/PlGF ratio were defined as <100 ng/L and >5.78 if <28 weeks and >38 if ≥28 weeks respectively. Cox proportional hazards models were used. The analysis period was defined as the time from the first measurement of PlGF and sFlt-1/PlGF ratio to the time of birth or censoring. The primary study outcome was overall PTB. The relative risks (RR) of birth within 1, 2 and 3 weeks and for medically indicated and spontaneous PTB were also ascertained. The early FGR cohort had lower median PlGF levels (54 versus 229 ng/L, p < 0.001) and higher median sFlt-1 levels (2774 ng/L versus 2096 ng/L, p < 0.001) and sFlt-1/PlGF ratio higher (35 versus 10, p < 0.001). Both PlGF <100 ng/L and elevated sFlt-1/PlGF ratio were strongly predictive for PTB as well as PTB within 1, 2 and 3 weeks of diagnosis. For both FGR and AGA groups, PlGF <100 ng/L or raised sFlt-1/PlGF ratio were strongly associated with increased risk for medically indicated PTB. The highest RR was seen in the FGR cohort when PlGF was <100 ng/L (RR 35.20, 95% CI 11.48-175.46). Low maternal PlGF levels and elevated sFlt-1/PlGF ratio are potentially useful to predict PTB in both FGR and AGA pregnancies.

Effects of uterine Doppler on midbrain growth and cortical development in late onset fetal growth restricted fetuses: a prospective cross-sectional study

Objective To investigate midbrain growth, including corpus callusum (CC), cerebellar vermis (CV) and cortical development in late fetal growth restriction (FGR) depending on uterine artery (UtA) Pulsatility Index (PI) values. Methods This was a prospective study including singleton fetuses with late FGR characterized by abnormal cerebral placental ratio (CPR). According to UtA PI values, the FGR fetuses were subdivided into normal ≤95th centile) and abnormal (>95th centile). Neurosonography was performed at 33–44 weeks of gestations to assess CC and CV lengths and the depth of Sylvian fissure (SF), parieto-occipital (POF) and calcarine fissures (CF). Neurosonographic variables were normalized for fetal head circumference size. Results The study cohort included 60 fetuses with late FGR, 39 with normal UtA PI and 21 with abnormal PI values. The latter group showed significant differences in CC (median (interquartile range) normal 35.9 (28.49–45.53) vs abnormal UtA PI 25.31(19.76–35.13) mm; p < 0.0022), CV (normal 25.78 (18.19–29.35) abnormal UtA PI 17.03 (14.07–24.16)mm; p = 0.0067); SF (normal 10.58 (8.99–11.97)vs abnormal UtA PI 7.44 (6.23–8.46) mm; p < 0.0001), POF (normal 6.85 (6.35–8.14) vs abnormal UtA PI 4.82 (3.46–7.75) mm; p < = 0.0184) and CF (normal 04.157 (2.85–5.41) vs abnormal UtA PI 2.33 (2.49–4.01)); p < 0.0382). Conclusions Late onset FGR fetuses with abnormal UtA PI showed shorter CC and CV length and delayed cortical development compared to those with normal uterine PI. These findings support the existence of a link between abnormal brain development and changes in utero placental circulation.

First trimester prediction models for small-for- gestational age and fetal growth restricted fetuses without the presence of preeclampsia

We established efficient first trimester prediction models for small-for-gestational age (SGA) and fetal growth restriction (FGR) without the presence of preeclampsia (PE) regardless of the gestational age of the onset of the disease [early FGR occurring before 32 gestational week or late FGR occurring after 32 gestational week]. The retrospective study was performed on singleton Caucasian pregnancies (n = 6440) during the period 11/2012–3/2020. Finally, 4469 out of 6440 pregnancies had complete medical records since they delivered in the Institute for the Care of Mother and Child, Prague, Czech Republic. The study included all cases diagnosed with SGA (n = 37) or FGR (n = 82) without PE, and 80 selected normal pregnancies. Four microRNAs (miR-1-3p, miR-20a-5p, miR-146a-5p, and miR-181a-5p) identified 75.68 % SGA cases at 10.0 % false positive rate (FPR). Eight microRNAs (miR-1-3p, miR-20a-5p, miR-20b-5p, miR-126-3p, miR-130b-3p, miR-146a-5p, miR-181a-5p, and miR-499a-5p) identified 83.80 % SGA cases at 10.0 % FPR. The prediction model for SGA based on microRNAs was further improved via implementation of maternal clinical characteristics [maternal age and BMI, an infertility treatment by assisted reproductive technology (ART), first trimester screening for PE and/or FGR and for spontaneous preterm, both by FMF algorithm]. Then 81.08 % and 89.19 % pregnancies developing SGA were identified at 10.0 % FPR in case of utilization of 4 microRNA and 8 microRNA biomarkers. Simplified prediction model for SGA based on limited number of maternal clinical characteristics (maternal age and BMI, an infertility treatment by ART, and 4 microRNAs) does not improve the detection rate of SGA (70.27 % SGA cases at 10.0 % FPR) when compared with prediction model for SGA based just on the expression profile of 4 or 8 microRNAs biomarkers. Seven microRNAs only (miR-16-5p, miR-20a-5p, miR-145-5p, miR-146a-5p, miR-181a-5p, miR-342-3p, and miR-574-3p) identified 42.68 % FGR cases at 10.0 % FPR (AUC 0.725). However, the combination of 10 microRNAs only (miR-16-5p, miR-20a-5p, miR-100-5p, miR-143-3p, miR-145-5p, miR-146a-5p, miR-181a-5p, miR-195-5p, miR-342-3p, and miR-574-3p) reached a higher discrimination power (AUC 0.774). It identified 40.24 % FGR cases at 10.0 % FPR. The prediction model for any subtype of FGR based on microRNAs was further improved via implementation of maternal clinical characteristics [maternal age and BMI, an infertility treatment by ART, the parity (nulliparity), the occurrence of SGA or FGR in previous gestation, and the occurrence of any autoimmune disorder, and the presence of chronic hypertension]. Then 64.63 % and 65.85 % pregnancies destinated to develop FGR were identified at 10.0 % FPR in case of utilization of 7 microRNA biomarkers or 10 microRNA biomarkers. When other clinical variables next to those ones mentioned above such as first trimester screening for PE and/or FGR and for spontaneous preterm, both by FMF algorithm, were added to the prediction model for FGR, the detection power was even increased to 74.39 % cases and 78.05 % cases at 10.0 % FPR.

Fetal Cerebroplacental Artery Ratio versus Uterine Artery Doppler Ultrasonography for Prediction of Late Onset Intrauterine Fetal Growth Restriction among High Risk Pregnant Women

Fetal Cerebroplacental Artery Ratio versus Uterine Artery Doppler Ultrasonography for Prediction of Late Onset Intrauterine Fetal Growth Restriction among High Risk Pregnant Women

Exploring the impact of maternal supine position on placental perfusion in late gestation fetal growth restriction by magnetic resonance imaging.

Exploring the impact of maternal supine position on placental perfusion in late gestation fetal growth restriction by magnetic resonance imaging.

OC05.04: The added value of the cerebroplacental ratio in late preterm fetal growth restriction: a contemporary urban cohort in the USA

OC05.04: The added value of the cerebroplacental ratio in late preterm fetal growth restriction: a contemporary urban cohort in the USA

Do differences in diagnostic criteria for late fetal growth restriction matter?

Criteria for diagnosis of fetal growth restriction differ widely according to national and international guidelines, and further heterogeneity arises from the use of different biometric and Doppler reference charts, making the diagnosis of fetal growth restriction highly variable. This study aimed to compare fetal growth restriction definitions between Delphi consensus and Society for Maternal-Fetal Medicine definitions, using different standards/charts for fetal biometry and different reference ranges for Doppler velocimetry parameters. From the TRUFFLE 2 feasibility study (856 women with singleton pregnancy at 32+0 to 36+6 weeks of gestation and at risk of fetal growth restriction), we selected 564 women with available mid-pregnancy biometry. For the comparison, we used standards/charts for estimated fetal weight and abdominal circumference from Hadlock, INTERGROWTH-21st, and GROW and Chitty. Percentiles for umbilical artery pulsatility index and its ratios with middle cerebral artery pulsatility index were calculated using Arduini and Ebbing reference charts. Sensitivity and specificity for low birthweight and adverse perinatal outcome were evaluated. Different combinations of definitions and reference charts identified substantially different proportions of fetuses within our population as having fetal growth restriction, varying from 38% (with Delphi consensus definition, INTERGROWTH-21st biometric standards, and Arduini Doppler reference ranges) to 93% (with Society for Maternal-Fetal Medicine definition and Hadlock biometric standards). None of the different combinations tested appeared effective, with relative risk for birthweight <10th percentile between 1.4 and 2.1. Birthweight <10th percentile was observed most frequently when selection was made with the GROW/Chitty charts, slightly less with the Hadlock standard, and least frequently with the INTERGROWTH-21st standard. Using the Ebbing Doppler reference ranges resulted in a far higher proportion identified as having fetal growth restriction compared with the Arduini Doppler reference ranges, whereas Delphi consensus definition with Ebbing Doppler reference ranges produced similar results to those of the Society for Maternal-Fetal Medicine definition. Application of Delphi consensus definition with Arduini Doppler reference ranges was significantly associated with adverse perinatal outcome, with any biometric standards/charts. The Society for Maternal-Fetal Medicine definition could not accurately detect adverse perinatal outcome irrespective of estimated fetal weight standard/chart used. Different combinations of fetal growth restriction definitions, biometry standards/charts, and Doppler reference ranges identify different proportions of fetuses with fetal growth restriction. The difference in adverse perinatal outcome may be modest, but can have a significant impact in terms of rate of intervention.

Investigation of serum afamin concentration in pregnant women diagnosed with late fetal growth restriction or small for gestational age fetus

Objective To investigate the afamin concentration in the serum of pregnant women diagnosed with late fetal growth restriction (FGR) or small for gestational age (SGA) in the third trimester. Methods This prospective case-control study was conducted on 126 pregnant women, 42 of whom were diagnosed with late FGR in the third trimester, 43 were SGA, and 41 were healthy controls. The groups were compared in terms of maternal serum afamin concentrations. Results Three groups were similar in terms of demographic characteristics and gestational age at blood sampling for afamin (p < .05). The median afamin concentration was determined as 199 ng/mL in the late FGR group, 153 ng/mL in the SGA group, and 108 ng/mL in the control group (p = .000). In the post-hoc analysis, while maternal serum afamin concentrations were found to be significantly higher in the late FGR group and SGA group compared to the control group but, this significance could not be shown between the FGR group and the SGA group (p = .00001, p = .005, p = .137, respectively). In the ROC analysis, the optimal cutoff value of serum afamin concentration to predict late FGR was determined as 141 ng/mL, with a sensitivity of 66.6% and a specificity of 85.3%. Conclusions The serum afamin concentration in the third trimester was found to be higher in pregnant women with late FGR compared to the SGA and control groups. Although afamin is seen as a promising molecule in the clinical prediction of late FGR, this needs to be supported by large series of studies.

The effect of maternal position on placental blood flow and fetoplacental oxygenation in late gestation fetal growth restriction: a magnetic resonance imaging study.

Fetal growth restriction (FGR) and maternal supine going-to-sleep position are both risk factors for late stillbirth. This study aimed to use magnetic resonance imaging (MRI) to quantify the effect of maternal supine position on maternal-placental and fetoplacental blood flow, placental oxygen transfer and fetal oxygenation in FGR and healthy pregnancies. Twelve women with FGR and 27 women with healthy pregnancies at 34-38weeks' gestation underwent MRI in both left lateral and supine positions. Phase-contrast MRI and a functional MRI technique (DECIDE) were used to measure blood flow in the maternal internal iliac arteries (IIAs) and umbilical vein (UV), placental oxygen transfer (placental flux), fetal oxygen saturation (FO2 ), and fetal oxygen delivery (delivery flux). The presence of FGR, compared to healthy pregnancies, was associated with a 7.8% lower FO2 (P=0.02), reduced placental flux, and reduced delivery flux. Maternal supine positioning caused a 3.8% reduction in FO2 (P=0.001), and significant reductions in total IIA flow, placental flux, UV flow and delivery flux compared to maternal left lateral position. The effect of maternal supine position on fetal oxygen delivery was independent of FGR pregnancy, meaning that supine positioning has an additive effect of reducing fetal oxygenation further in women with FGR, compared to women with appropriately grown for age pregnancies. Meanwhile, the effect of maternal supine positioning on placental oxygen transfer was not independent of the effect of FGR. Therefore, growth-restricted fetuses, which are chronically hypoxaemic, experience a relatively greater decline in oxygen transfer when mothers lie supine in late gestation compared to appropriately growing fetuses. KEY POINTS: Fetal growth restriction (FGR) is the most common risk factor associated with stillbirth, and early recognition and timely delivery is vital to reduce this risk. Maternal supine going-to-sleep position is found to increase the risk of late stillbirth but when combined with having a FGR pregnancy, maternal supine position leads to 15 times greater odds of stillbirth compared to supine sleeping with appropriately grown for age (AGA) pregnancies. Using MRI, this study quantifies the chronic hypoxaemia experienced by growth-restricted fetuses due to 13.5% lower placental oxygen transfer and 26% lower fetal oxygen delivery compared to AGA fetuses. With maternal supine positioning, there is a 23% reduction in maternal-placental blood flow and a further 14% reduction in fetal oxygen delivery for both FGR and AGA pregnancies, but this effect is proportionally greater for growth-restricted fetuses. This knowledge emphasises the importance of avoiding supine positioning in late pregnancy, particularly for vulnerable FGR pregnancies.

Current views on the diagnosis and prognosis of fetal growth restriction (A literature review)

Fetal growth restriction remains a leading cause of preterm birth and neurological disorders in children and is associated with high neonatal and perinatal morbidity and mortality. Fetal growth restriction is strongly associated with preeclampsia, placental insufficiency, and does not tend to decrease in frequency. The terms small for gestational age and fetal growth restriction are similar in terms of fetometry, however, in modern literature, these concepts differ based on blood flow disorders in the mother-placenta-fetus system and perinatal complications. A deep understanding of the multifactorial pathogenesis of early and late fetal growth restriction will allow for developing targeted therapy of placental insufficiency. Determining the role of new placental growth biomarkers plays a significant role in understanding the pathogenesis of placental dysfunction and developing measures to predict placenta-associated pregnancy complications.&#x0D; This review article highlights new approaches to effective fetal growth restriction screening. Recent advances in ultrasound diagnosis of fetal growth restriction provide the basis for multivariate testing that can provide cost-effective screening for placental-associated pregnancy complications, including fetal growth restriction.

Management of late-onset fetal growth restriction: pragmatic approach.

There is limited prospective evidence to guide the management of late-onset fetal growth restriction (FGR) and its differentiation from small-for-gestational age. The aim of this study was to assess prospectively a novel protocol in which ultrasound criteria were used to classify women with suspected late FGR into two groups: those at low risk, who were managed expectantly until the anticipated date of delivery, and those at high risk, who were delivered soon after 37 weeks of gestation. We also compared the outcome of this prospective cohort with that of a historical cohort of women presenting similarly with suspected late FGR, in order to evaluate the impact of the new protocol. This was a prospective study of women with a non-anomalous singleton pregnancy at ≥ 32 weeks' gestation attending a tertiary hospital in London, UK, between February 2018 and September 2019, with estimated fetal weight (EFW) ≤ 10th centile, or EFW > 10th centile in addition to a decrease in fetal abdominal circumference of ≥ 50 centiles compared with a previous scan, umbilical artery Doppler pulsatility index > 95th centile or cerebroplacental ratio < 5th centile. Women were classified as low or high risk based on ultrasound and Doppler criteria. Women in the low-risk group were delivered by 41 weeks of gestation, unless they subsequently met high-risk criteria, whereas women in the high-risk group (EFW < 3rd centile, umbilical artery Doppler pulsatility index > 95th centile or EFW between 3rd and 10th centiles (inclusive) with abdominal circumference drop or abnormal Dopplers) were delivered at or soon after 37 weeks. The primary outcome was adverse neonatal outcome and included hypothermia, hypoglycemia, neonatal unit admission, jaundice requiring treatment, suspected infection, feeding difficulties, 1-min Apgar score < 7, hospital readmission and any severe adverse neonatal outcome (perinatal death, resuscitation using inotropes or mechanical ventilation, 5-min Apgar score < 7, metabolic acidosis, sepsis, and cerebral, cardiac or respiratory morbidity). Secondary outcomes were adverse maternal outcome (operative delivery for abnormal fetal heart rate) and severe adverse neonatal outcome. Women managed according to the new protocol were compared with a historical cohort of 323 women delivered prior to the implementation of the new protocol, for whom management was guided by individual clinician expertise. Over 18 months, 321 women were recruited to the prospective cohort, of whom 156 were classified as low risk and 165 were high risk. Adverse neonatal outcome was significantly less common in the low-risk compared with the high-risk group (45% vs 58%; adjusted odds ratio (aOR), 0.6 (95% CI, 0.4-0.9); P = 0.022). There was no significant difference in the rate of adverse maternal outcome (18% vs 24%; aOR, 0.7 (95% CI, 0.4-1.2); P = 0.142) or severe adverse neonatal outcome (3.8% vs 8.5%; aOR, 0.5 (95% CI, 0.2-1.3); P = 0.153) between the low- and high-risk groups. Compared with women in the historical cohort classified retrospectively as low risk, low-risk women managed under the new protocol had a lower rate of adverse neonatal outcome (45% vs 58%; aOR, 0.6 (95% CI, 0.4-0.9); P = 0.026). Appropriate risk stratification to guide management of late FGR was associated with a reduced rate of adverse neonatal outcome in low-risk pregnancies. In clinical practice, a policy of expectantly managing women with a low-risk late-onset FGR pregnancy at term could improve neonatal and long-term development. Randomized controlled trials are needed to assess the effect of an evidence-based conservative management protocol for late FGR on perinatal morbidity and mortality and long-term neurodevelopment. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

A New Antioxidant Marker in Cord Blood of Fetuses with Late Fetal Growth Restriction: Humanin

Purpose: This study investigated the Humanin levels in the umbilical cord blood of fetuses with late fetal growth restriction (FGR) and ­evaluated their association with perinatal outcomes. Materials and Methods: A total of 95 single pregnancies between 32–41 wk (45 with late FGR and 50 controls) were included. Doppler parameters, birth weight and the need for neonatal intensive care unit admission (NICU) were assessed. Correlations between Humanin levels and these parameters were analyzed. Results: Higher Humanin levels were found in fetuses with late FGR compared to the control group (p < 0.05). No significant correlation was observed between Humanin levels and Doppler parameters. Elevated Humanin levels were associated with an increased need for NICU (p < 0.05). Conclusions: The statistically higher levels of Humanin in fetuses with late FGR may suggest the potential of Humanin as an indicator of late FGR. Further research is needed to explore the clinical utility of Humanin.

Evidence of Placental Aging in Late SGA, Fetal Growth Restriction and Stillbirth-A Systematic Review.

During pregnancy, the placenta undergoes a natural aging process, which is considered normal. However, it has been hypothesized that an abnormally accelerated and premature aging of the placenta may contribute to placenta-related health issues. Placental senescence has been linked to several obstetric complications, including abnormal fetal growth, preeclampsia, preterm birth, and stillbirth, with stillbirth being the most challenging. A systematic search was conducted on Pubmed, Embase, and Scopus databases. Twenty-two full-text articles were identified for the final synthesis. Of these, 15 presented original research and 7 presented narrative reviews. There is a paucity of evidence in the literature on the role of placental aging in late small for gestational age (SGA), fetal growth restriction (FGR), and stillbirth. For future research, guidelines for both planning and reporting research must be implemented. The inclusion criteria should include clear differentiation between early and late SGA and FGR. As for stillbirths, only those with no other known cause of stillbirth should be included in the studies. This means excluding stillbirths due to congenital defects, infections, placental abruption, and maternal conditions affecting feto-maternal hemodynamics.

Placental pathology in pregnancies with late fetal growth restriction and abnormal cerebroplacental ratio

IntroductionLate fetal growth restriction (FGR) is associated with mild growth restriction and normal or mild abnormal doppler flows. The cerebroplacental ratio (CPR) has been demonstrated as more sensitive to hypoxia than its individual components in these fetuses. We hypothesized that abnormal CPR in late FGR is reflected in specific placental vascular malperfusion lesions. MethodsRetrospective cohort study of late FGR newborns between 2012 and 2022 in a tertiary hospital. Overall, 361 cases were included: 104 with pathological CPR (study group), and 257 with normal doppler flows (control group). The primary outcome was a composite of maternal vascular malperfusion lesions (MVM) and fetal vascular malperfusion lesions (FVM). Secondary outcomes were macroscopic placental characteristics and various obstetrical and neonatal outcomes. ResultsThe study group had lower birthweight compared with the normal CPR group (2063.5 ± 470.5 vs. 2351.6 ± 387.4 g. P < 0.0001), higher rates of composite adverse neonatal outcomes (34.2% vs. 22.5%, p < 0.0001), lower mean placental weight (318 ± 71.6 vs. 356.6 ± 76.5 g, p < 0.0001), as well as a higher prevalence of Vascular lesions of MVM (15.3% vs. 5.0%, p = 0.002), villous lesions of FVM (37.5% vs. 24.9%, p = 0.02), and composite FVM lesions (36.5% vs. 25.6%, p = 0.04). On multivariate regression analysis for MVM lesions and composite FVM lesions, abnormal CPR was found as an independent risk factor (aOR 2.17, 95% CI 1.63–4.19, and aOR 1.31, 95% CI 1.09–3.97, respectively). DiscussionsAbnormal CPR in late FGR is reflected in placental histopathologic vascular malperfusion lesions, and the incidence of these lesions is higher than in FGR placentas with normal CPR.

Association between antenatal diagnosis of late fetal growth restriction and educational outcomes in mid-childhood: A UK prospective cohort study with long-term data linkage study

Fetal growth restriction (FGR) is associated with a suboptimal intrauterine environment, which may adversely impact fetal neurodevelopment. However, analysing neurodevelopmental outcomes by observed birthweight fails to differentiate between true FGR and constitutionally small infants and cannot account for iatrogenic intervention. This study aimed to determine the relationship between antenatal FGR and mid-childhood (age 5 to 7 years) educational outcomes. The Pregnancy Outcome Prediction Study (2008-2012) was a prospective birth cohort conducted in a single maternity hospital in Cambridge, United Kingdom. Clinicians were blinded to the antenatal diagnosis of FGR. FGR was defined as estimated fetal weight (EFW) <10th percentile at approximately 36 weeks of gestation, plus one or more indicators of placental dysfunction, including ultrasonic markers and maternal serum levels of placental biomarkers. A total of 2,754 children delivered at term were divided into 4 groups: FGR, appropriate-for-gestational age (AGA) with markers of placental dysfunction, healthy small-for-gestational age (SGA), and healthy AGA (referent). Educational outcomes (assessed at 5 to 7 years using UK national standards) were assessed with respect to FGR status using regression models adjusted for relevant covariates, including maternal, pregnancy, and socioeconomic factors. Compared to healthy AGA (N = 1,429), children with FGR (N = 250) were at higher risk of "below national standard" educational performance at 6 years (18% versus 11%; aOR 1.68; 95% CI 1.12 to 2.48, p = 0.01). By age 7, children with FGR were more likely to perform below standard in reading (21% versus 15%; aOR 1.46; 95% CI 0.99 to 2.13, p = 0.05), writing (28% versus 23%; aOR 1.46; 95% CI 1.02 to 2.07, p = 0.04), and mathematics (24% versus 16%; aOR 1.49; 95% CI 1.02 to 2.15, p = 0.03). This was consistent whether FGR was defined by ultrasound or biochemical markers. The educational attainment of healthy SGA children (N = 126) was comparable to healthy AGA, although this comparison may be underpowered. Our study design relied on linkage of routinely collected educational data according to nationally standardised metrics; this design allowed a high percentage of eligible participants to be included in the analysis (75%) but excludes those children educated outside of government-funded schools in the UK. Our focus on pragmatic and validated measures of educational attainment does not exclude more subtle effects of the intrauterine environment on specific aspects of neurodevelopment. Compared to children with normal fetal growth and no markers of placental dysfunction, FGR is associated with poorer educational attainment in mid-childhood.

Comparative Analysis of the Placental Microbiome in Pregnancies with Late Fetal Growth Restriction versus Physiological Pregnancies.

A comparative analysis of the placental microbiome in pregnancies with late fetal growth restriction (FGR) was performed with normal pregnancies to assess the impact of bacteria on placental development and function. The presence of microorganisms in the placenta, amniotic fluid, fetal membranes and umbilical cord blood throughout pregnancy disproves the theory of the "sterile uterus". FGR occurs when the fetus is unable to follow a biophysically determined growth path. Bacterial infections have been linked to maternal overproduction of pro-inflammatory cytokines, as well as various short- and long-term problems. Proteomics and bioinformatics studies of placental biomass allowed the development of new diagnostic options. In this study, the microbiome of normal and FGR placentas was analyzed by LC-ESI-MS/MS mass spectrometry, and the bacteria present in both placentas were identified by analysis of a set of bacterial proteins. Thirty-six pregnant Caucasian women participated in the study, including 18 women with normal pregnancy and eutrophic fetuses (EFW > 10th percentile) and 18 women with late FGR diagnosed after 32 weeks of gestation. Based on the analysis of the proteinogram, 166 bacterial proteins were detected in the material taken from the placentas in the study group. Of these, 21 proteins had an exponentially modified protein abundance index (emPAI) value of 0 and were not included in further analysis. Of the remaining 145 proteins, 52 were also present in the material from the control group. The remaining 93 proteins were present only in the material collected from the study group. Based on the proteinogram analysis, 732 bacterial proteins were detected in the material taken from the control group. Of these, 104 proteins had an emPAI value of 0 and were not included in further analysis. Of the remaining 628 proteins, 52 were also present in the material from the study group. The remaining 576 proteins were present only in the material taken from the control group. In both groups, we considered the result of ns prot ≥ 60 as the cut-off value for the agreement of the detected protein with its theoretical counterpart. Our study found significantly higher emPAI values of proteins representative of the following bacteria: Actinopolyspora erythraea, Listeria costaricensis, E. coli, Methylobacterium, Acidobacteria bacterium, Bacteroidetes bacterium, Paenisporsarcina sp., Thiodiazotropha endol oripes and Clostridiales bacterium. On the other hand, in the control group statistically more frequently, based on proteomic data, the following were found: Flavobacterial bacterium, Aureimonas sp. and Bacillus cereus. Our study showed that placental dysbiosis may be an important factor in the etiology of FGR. The presence of numerous bacterial proteins present in the control material may indicate their protective role, while the presence of bacterial proteins detected only in the material taken from the placentas of the study group may indicate their potentially pathogenic nature. This phenomenon is probably important in the development of the immune system in early life, and the placental microbiota and its metabolites may have great potential in the screening, prevention, diagnosis and treatment of FGR.

Evaluation of fetal cardiac function in fetal growth restriction via fetal HQ analysis based on two-dimensional STI.

Abnormalities of the fetal cardiovascular system caused by fetal growth restriction (FGR) may lead to adverse outcomes. The fetal cardiac function assessment is of great significance for treatment selection and prognostic evaluation of fetuses with FGR. This study aimed to explore the value of fetal HQ analysis based on speckle tracking imaging (STI) to evaluate the global and regional cardiac function of fetuses with early-onset or late-onset FGR. From June 2020 to November 2022, 30 pregnant women with early-onset FGR (21-38 gestational weeks) and 30 pregnant women with late-onset FGR (21-38 gestational weeks) in the Department of Ultrasound, Shandong Maternal and Child Health Hospital were enrolled. Also, 60 healthy volunteer pregnant women were enrolled as two control groups according to the principle of matching gestational weeks (21-38 gestational weeks). The fetal cardiac functions, including fetal cardiac global spherical index (GSI), left ventricular ejection fraction (LVEF), fractional area change (FAC) of both ventricles, global longitudinal strain (GLS) of both ventricles, 24-segmental fractional shortening (FS), 24-segmental end-diastolic ventricular diameter (EDD), and 24-segmental spherical index (SI), were assessed using fetal HQ. The standard biological values of fetuses and Doppler blood flow parameters of fetuses and mothers were measured. The estimated fetal weight (EFW) measured by the last prenatal ultrasound was calculated, and the weights of newborns were followed up. Among early FGR, late FGR and total control group, significant differences were found in global cardiac indexes of right ventricle (RV), left ventricle (LV) and GSI. For the segmental cardiac indexes, there are significant differences in three groups except parameter of LVSI. Compared with the control group at the same gestational week, the Doppler indexes including MCAPI and CPR in both the early-onset FGR group and the late-onset FGR group were significantly different. The intra- and inter-observer correlation coefficients of RV FAC, LV FAC, RV GLS, and LV GLS were good. Further, the intra- and inter-observer variability in FAC and GLS was small, as analyzed using the Bland-Altman scatter plot. Fetal HQ software based on STI showed that FGR affected the global and segmental cardiac function of both ventricles. FGR no matter early-onset or late-onset altered Doppler indexes significantly. The FAC and the GLS had satisfactory repeatability in evaluating fetal cardiac function.