Can maternal inflammatory and nutritional status, evaluated by the hemoglobin, albumin, lymphocyte, and platelet (HALP) score and the prognostic nutritional index (PNI) in the first trimester, predict late-onset fetal growth restriction?

OBJECTIVE: The aim of this study was to evaluate the potential of immunonutritional markers, specifically the hemoglobin, albumin, lymphocyte, and platelet (HALP) score and the prognostic nutritional index (PNI), in predicting late-onset fetal growth restriction (LO-FGR) during the first trimester. MATERIALS AND METHODS: This retrospective study was conducted at a tertiary care center between October 2022 and August 2023. The study included a total of 213 singleton pregnancies, with 99 women in the LO-FGR group and 114 in the healthy control group, matched by maternal age and gestational age at delivery. All blood samples were collected between 11 and 14 weeks of gestation (during the first-trimester screening test). We analyzed first-trimester laboratory parameters, specifically focusing on hemoglobin levels, white blood cells (WBCs), lymphocytes, platelets, and albumin levels. Afterwards, we calculated the HALP score and PNI, and then compared the values of both groups. RESULTS: Both HALP score (3.58 ± 1.31 vs. 4.19 ± 1.8, p = 0.012) and PNI (36.75 ± 2.9 vs. 39.37 ± 3.96, p < 0.001) were significantly lower in the FGR group than in the control group. The HALP score cut-off value of < 3.43 in predicting FGR had a sensitivity of 62.3% and specificity of 54.5% (AUC = 0.600, 95% CI: 0.528-0.672, p = 0.012). The PNI cut-off value of < 37.9 in predicting FGR had a sensitivity of 65.8% and specificity of 62.9% (AUC = 0.707, 95% CI: 0.632-0.778, p < 0.001). While the HALP score was not a significant predictor of composite adverse neonatal outcomes in the FGR group, PNI showed a cut-off value of < 37.7 with a sensitivity of 60.9% and specificity of 59.7% (AUC = 0.657, 95% CI: 0.581-0.733, p < 0.001). CONCLUSION: The HALP score and PNI are valuable prognostic tools for predicting the risk of FGR in the first trimester. Low PNI values are also associated with composite adverse neonatal outcomes in pregnancies complicated by FGR.

Role of Inflammatory Markers and Doppler Parameters in Late-Onset Fetal Growth Restriction: A Machine-Learning Approach.

OBJECTIVES: This study evaluates the association of novel inflammatory markers and Doppler parameters in late-onset FGR (fetal growth restriction), utilizing a machine-learning approach to enhance predictive accuracy. MATERIALS AND METHODS: A retrospective case-control study was conducted at the Department of Perinatology, Ministry of Health Etlik City Hospital, Ankara, from 2023 to 2024. The study included 240 patients between 32 and 37 weeks of gestation, divided equally between patients diagnosed with late-onset FGR and a control group. We focused on novel inflammatory markers-systemic immune-inflammation index (SII), systemic inflammatory response index (SIRI), and neutrophil-percentage-to-albumin ratio (NPAR)-and their correlation with Doppler parameters of umbilical and uterine arteries. Machine-learning algorithms were employed to analyze the data collected, including demographic, neonatal, and clinical parameters, to develop a predictive model for FGR. RESULTS: The machine-learning model, specifically the Random Forest algorithm, effectively integrated the inflammatory markers with Doppler parameters to predict FGR. NPAR showed a significant correlation with FGR presence, providing a robust tool in the predictive model (Accuracy 77%, area under the curve [AUC] 0.851). In contrast, SII and SIRI, while useful, did not achieve the same level of predictive accuracy (Accuracy 75% AUC 0.818 and Accuracy 73% AUC 0.793, respectively). The model highlighted the potential of combining ultrasound measurements with inflammatory markers to improve diagnostic accuracy for late-onset FGR. CONCLUSIONS: This study illustrates the efficacy of integrating machines with traditional diagnostic methods to enhance the prediction of late-onset FGR. Further research with a larger cohort is recommended to validate these findings and refine the predictive model, which could lead to improved clinical outcomes for affected pregnancies. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT06372938.

Delta neutrophil index (DNI) as a potential biomarker for fetal growth restriction: insights from maternal hematological changes and neonatal outcomes.

BACKGROUND: This study investigates the role of Delta Neutrophil Index (DNI), an inflammation marker, in late-onset fetal growth restriction (LO-FGR) and its prediction of composite adverse neonatal outcomes. METHODS: A retrospective study was conducted on 684 pregnant women (456 with normal fetal development and 228 with LO-FGR) who delivered at Health Sciences University Etlik Zubeyde Hanim Women's Health Training and Research Hospital between January 1, 2015, and June 30, 2018. Composite adverse neonatal outcomes were defined as at least one of the following: 5th minute APGAR score < 7, respiratory distress syndrome (RDS), or neonatal intensive care unit (NICU) admission. RESULTS: The FGR group had significantly higher levels of neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), monocyte to lymphocyte ratio (MLR), and DNI compared to controls (p < 0.05, for all). For FGR diagnosis, the DNI demonstrated the highest area under the curve (AUC = 0.677, 95% CI: 0.642-0.711) with a cut-off value of > -2.9, yielding a sensitivity of 78.41%, a specificity of 52.97%, a positive likelihood ratio (+ LR) of 1.68, and a negative likelihood ratio (-LR) of 0.37 (p < 0.001). For predicting composite adverse neonatal outcomes in the FGR group, DNI again demonstrated superior performance with an AUC of 0.635 (95% CI: 0.598-0.670), a cut-off value of > -2.2, a sensitivity of 69.90%, a specificity of 55.36%, a + LR of 1.56, and a -LR of 0.51 (p < 0.001). NLR, PLR, and MLR had AUCs below 0.55, indicating poor discriminative ability, with none reaching statistical significance. CONCLUSION: This study highlights the potential role of DNI as a promising biomarker for detecting inflammatory processes associated with LO-FGR and its complications.

Integrated transcriptomic analysis and machine learning for characterizing diagnostic biomarkers and immune cell infiltration in fetal growth restriction.

Background: Fetal growth restriction (FGR) occurs in 10% of pregnancies worldwide. Placenta dysfunction, as one of the most common causes of FGR, is associated with various poor perinatal outcomes. The main objectives of this study were to screen potential diagnostic biomarkers for FGR and to evaluate the function of immune cell infiltration in the process of FGR. Methods: Firstly, differential expression genes (DEGs) were identified in two Gene Expression Omnibus (GEO) datasets, and gene set enrichment analysis was performed. Diagnosis-related key genes were identified by using three machine learning algorithms (least absolute shrinkage and selection operator, random forest, and support vector machine model), and the nomogram was then developed. The receiver operating characteristic curve, calibration curve, and decision curve analysis curve were used to verify the validity of the diagnostic model. Using cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT), the characteristics of immune cell infiltration in placental tissue of FGR were evaluated and the candidate key immune cells of FGR were screened. In addition, this study also validated the diagnostic efficacy of TREM1 in the real world and explored associations between TREM1 and various clinical features. Results: By overlapping the genes selected by three machine learning algorithms, four key genes were identified from 290 DEGs, and the diagnostic model based on the key genes showed good predictive performance (AUC = 0.971). The analysis of immune cell infiltration indicated that a variety of immune cells may be involved in the development of FGR, and nine candidate key immune cells of FGR were screened. Results from real-world data further validated TREM1 as an effective diagnostic biomarker (AUC = 0.894) and TREM1 expression was associated with increased uterine artery PI (UtA-PI) (p-value = 0.029). Conclusion: Four candidate hub genes (SCD, SPINK1, TREM1, and HIST1H2BB) were identified, and the nomogram was constructed for FGR diagnosis. TREM1 was not only associated with a variety of key immune cells but also correlated with increased UtA-PI. The results of this study could provide some new clues for future research on the prediction and treatment of FGR.

Expression and significance of CEMIP and CYP11B2 in serum in women with foetal growth restriction.

BACKGROUND: Foetal growth restriction (FGR) occurs when a foetus fails to reach its growth potential. This observational study assessed the expression and significance of cell migration-including protein (CEMIP) and aldosterone synthase (CYP11B2) in the serum of pregnant women with FGR. METHODS: 40 singleton FGR-suffered pregnant women, as well as 40 normal singleton pregnant women, were enrolled. The expression of CEMIP and CYP11B2 in serum was detected in early pregnancy. The correlations between parameters were evaluated. The predictive variables for FGR were determined. The diagnostic value of CEMIP and CYP11B2 for FGR was analysed. RESULTS: CEMIP and CYP11B2 mRNA expression in the serum of pregnant women with FGR decreased (both P < 0.001). CEMIP (95%CI: 0.802-0.921, P < 0.001) and CYP11B2 (95%CI: 0.795-0.907, P < 0.001) mRNA expression in serum and soluble fms like tyrosine kinase-1 (sFLT1)/placental growth factor (PlGF) ratio (95%CI: 0.866-0.974, P < 0.001) were independent predictors of FGR, and CEMIP (r = -0.578, P = 0.001) and CYP11B2 (r = -0.602, P < 0.001) mRNA expression in serum were negatively correlated with sFLT1/PlGF ratio. CEMIP (AUC = 0.741) and CYP11B2 (AUC = 0.764) mRNA expression in serum had good diagnostic value for FGR. CONCLUSION: The expression of CEMIP and CYP11B2 is reduced in the serum of pregnant women with FGR and may become new diagnostic markers for FGR.

Foetal growth restriction is the inability of the foetus to reach its growth potential in the uterus due to various factors. This study aimed to investigate the expression and significance of cell migration-including protein and aldosterone synthase in serum of pregnant women with foetal growth restriction. In our study, we found that the expression of cell migration-including protein and aldosterone synthase in serum of pregnant women with foetal growth restriction were decreased. Cell migration-including protein and aldosterone synthase expression was negatively correlated with soluble fms like tyrosine kinase-1/placental growth factor ratio. In addition, the study also found that cell migration-including protein and aldosterone synthase expression in serum had good diagnostic value for foetal growth restriction.

Mobil Monitoring Doppler Ultrasound (MoMDUS) study: protocol for a prospective, observational study investigating the use of artificial intelligence and low-cost Doppler ultrasound for the automated quantification of hypertension, pre-eclampsia and fetal growth restriction in rural Guatemala.

INTRODUCTION: Undetected high-risk conditions in pregnancy are a leading cause of perinatal mortality in low-income and middle-income countries. A key contributor to adverse perinatal outcomes in these settings is limited access to high-quality screening and timely referral to care. Recently, a low-cost one-dimensional Doppler ultrasound (1-D DUS) device was developed that front-line workers in rural Guatemala used to collect quality maternal and fetal data. Further, we demonstrated with retrospective preliminary data that 1-D DUS signal could be processed using artificial intelligence and deep-learning algorithms to accurately estimate fetal gestational age, intrauterine growth and maternal blood pressure. This protocol describes a prospective observational pregnancy cohort study designed to prospectively evaluate these preliminary findings. METHODS AND ANALYSIS: This is a prospective observational cohort study conducted in rural Guatemala. In this study, we will follow pregnant women (N =700) recruited prior to 18 6/7 weeks gestation until their delivery and early postpartum period. During pregnancy, trained nurses will collect data on prenatal risk factors and obstetrical care. Every 4 weeks, the research team will collect maternal weight, blood pressure and 1-D DUS recordings of fetal heart tones. Additionally, we will conduct three serial obstetric ultrasounds to evaluate for fetal growth restriction (FGR), and one postpartum visit to record maternal blood pressure and neonatal weight and length. We will compare the test characteristics (receiver operator curves) of 1-D DUS algorithms developed by deep-learning methods to two-dimensional fetal ultrasound survey and published clinical pre-eclampsia risk prediction algorithms for predicting FGR and pre-eclampsia, respectively. ETHICS AND DISSEMINATION: Results of this study will be disseminated at scientific conferences and through peer-reviewed articles. Deidentified data sets will be made available through public repositories. The study has been approved by the institutional ethics committees of Maya Health Alliance and Emory University.

Genetic Analysis of a Fetus with 14q11.2 Microdeletion in Ultrasound Abnormalities.

BACKGROUND: This study aimed to explore the genetic basis of a fetus with ultrasound indicating a thickening of the nuchal translucency (NT) and a choroid plexus cyst. METHODS: Fetal amniotic fluid and peripheral blood were collected for a G-banding karyotype analysis and single nucleotide polymorphism array (SNP-array) detection. RESULTS: The chromosome karyotypes of the fetus and its parents were normal. SNP-array showed the fetus had carried 277 kb microdeletion at 14q11.2, which was a new mutation. After the induced abortion, the fetus was diagnosed with macrocephaly. CONCLUSIONS: A prenatal diagnosis of a fetus with 14q11.2 microdeletion-induced intrauterine growth retardation was confirmed, which has provided guidance for the subsequent pregnancy.

Chondroitin Sulfate Proteoglycan 4 (CSPG4) as a Potential Biomarker for Fetal Growth Restriction: Insights from an Umbilical Cord Blood Analysis.

BACKGROUND: This study aimed to evaluate the umbilical cord blood chondroitin sulfate proteoglycan 4 (CSPG4) concentrations in pregnancies complicated with fetal growth restriction (FGR) and aimed to investigate the rela-tionship between the CSPG4 levels in these pregnancies and adverse neonatal outcomes. METHODS: This prospective case-control study was conducted between August 2023 and January 2024. The study included 80 singleton pregnancies at 35 to 39 weeks of gestation. Among these, 40 were diagnosed with FGR and 40 served as the control group. After the delivery, samples of the cord blood were collected prior to the placental delivery. RESULTS: The CSPG4 levels were significantly higher in the study group (FGR), 1,153 (1,059 - 1,261) pg/mL, than in the control group, 1,107 (873 - 1,197) pg/mL (p = 0.024). When all patients were evaluated, the CSPG4 levels showed a positive correlation with the systolic/diastolic (S/D) ratio of the umbilical arteries (r = 0.276, p = 0.013). A statistically significant negative correlation was observed between the levels of CSPG4 in the umbilical cord blood and the Apgar scores at the 1st (r = -0.256, p = 0.022) and 5th (r = -0.250, p = 0.026) minutes. The discriminatory power of the umbilical cord CSPG4 level in the determination of composite adverse neonatal outcomes was evaluated by ROC analysis and a cutoff point of > 1,091.25 pg/mL, showing a sensitivity of 93.3%, a specificity of 46.2%, and an AUC of 0.661 (95% CI: 0.547 - 0.763, p = 0.019). CONCLUSIONS: Elevated levels of CSPG4 have been observed in the umbilical cord blood in pregnancies complicated by FGR; higher levels are associated with adverse neonatal outcomes.

Prenatal Diagnosis of Fetuses with 4q35 Deletion: Case Series and Review of the Literature.

INTRODUCTION: 4q35 deletion is a rare chromosomal syndrome with a wide range of phenotypes, which can be challenging to detect through prenatal ultrasound. This study aimed to summarize the fetal phenotypes of patients with 4q35 deletion. CASE PRESENTATION: The study included four fetuses with 4q35 deletion, with detailed records of prenatal ultrasound and genetic testing results. These cases included following phenotypes, fetal growth restriction (FGR) (2/4), cystic hygroma (2/4), single umbilical artery (1/4), and fused kidney (1/4). One case was terminated, while the other three were born and showed no obvious abnormalities at the 1-year follow-up. Previous reports have described the fetal phenotype of 4q35 deletion in 6 patients from five families, with prenatal phenotypes including FGR (2/6), cardiac structural abnormalities (1/6), brain ventriculomegaly (1/6), oligohydramnios (1/6), and multicystic dysplastic kidneys (1/6). CONCLUSION: Overall, the phenotypes of fetuses with 4q35 deletion are diverse, with FGR potentially being a significant phenotype in these cases.

Morphometric traits to estimate brain and liver weight and their ratio for the diagnosis of intrauterine growth restriction in newborn piglets.

Intrauterine growth restriction (IUGR) is defined as inadequate foetal growth during gestation. In response to placenta insufficiency, IUGR piglets prioritise brain development as a survival mechanism. This adaptation leads to a higher brain-to-liver weight ratio (BrW/LW) at birth. This study assessed the potential of using morphometric traits to estimate brain (BrW) and liver (LW) weights, enabling non-invasive diagnosis of IUGR in newborn piglets. At birth, body weight (BtW) of individual piglets (n = 144) was recorded. One day (± 1) after birth, BrW and LW were measured with computed tomography (n = 94) or by weighing the organs after natural death or euthanasia (n = 50). Additionally, 20 morphometric traits were captured from images of each piglet and correlated with the BrW and LW. The morphometric traits that showed a r ≥ 0.70 in linear correlation with the BrW or LW were selected. Each selected trait was combined as an independent variable with BtW to develop multiple linear regression models to predict the BrW and LW. Six models were chosen based on the highest adjusted R2 value: three for estimating BrW and three for LW. The dataset was then randomly divided into a training (75% of the data) and a testing (remaining 25%) subsets. Within the training subset, three equations to predict the BrW and three to predict the LW were extrapolated from the six selected models. The equations were then applied to the testing subset. The accuracy of the equations in predicting organ weight was assessed by calculating mean absolute and mean absolute percentage error (MAE and MAPE) between predicted and actual BrW and LW. To predict the BrW/LW, an equation including BtW and the two morphometric traits which better predicted BrW and LW was used. In the testing dataset, the equation combining ear distance and BtW better estimated the BrW. The equation performed with a MAE of 1.95 and a MAPE of 0.06 between the true and estimated weight of the brain. For the liver, the equation combining the abdominal area delimited by a square and BtW displayed the best performance, with a MAE of 9.29 and a MAPE of 0.17 between the true and estimated weight. Finally, the MAE and MAPE between the actual and estimated BrW/LW were 0.14 and 0.17, respectively. These findings suggest that specific morphometric traits can be used to estimate brain and liver weights, facilitating accurate and non-invasive identification of IUGR in newborn piglets.

Small for gestational age: concept, diagnosis and neonatal characterization, follow-up and recommendations.

Newborns who do not reach a weight appropriate for their gestational age and sex can be classified in different ways. This article defines the concepts of small for gestational age (SGA) and intrauterine growth restriction, as well as the underlying causes of these conditions, with the goal of establishing consensus definitions for these patients, in whom treatment with growth hormone throughout childhood may be indicated and who may be at risk of developing endocrine or metabolic disorders in puberty and adulthood. Most SGA children experience spontaneous catch-up growth that is usually completed by age 2 years. In SGA children who remain short, treatment with recombinant human growth hormone is effective, increasing adult height. Small for gestational age infants with rapid catch-up growth and marked weight gain are at increased risk of premature adrenarche, early puberty, polycystic ovary syndrome (girls), insulin resistance and obesity, all of which are risk factors for type 2 diabetes and metabolic syndrome in adulthood. The SGA status can affect different areas of neurodevelopment and manifest at different stages in life; neurodevelopmental outcomes are better in SGA infants with spontaneous catch-up growth. Due to the potential risks associated with SGA, adequate characterization of these patients at birth is imperative, as it allows initiation of appropriate follow-up and early detection of abnormalities.

Low fetal fraction and adverse pregnancy outcomes- systematic review of the literature and metanalysis.

PURPOSE: While cell-free DNA (cfDNA) screening has emerged as a screening modality for common aneuploidies, further research and several publications over the past decade suggested some correlation between the low concentrations of cfDNA and a number of pregnancy-related complications. The primary goal of this systematic review and meta-analysis was to assess the potential value of low-ff levels in the prediction of subsequent PE/PIH, GDM, SGA/FGR, and PTB. The meta-analysis results aim at summarizing the currently available literature data and determining the clinical relevance of this biochemical marker and the potential necessity for additional investigation of its utility in complications other than the detection of common aneuploidies. METHODS: This systematic review and meta-analysis was designed according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. It included all observational studies that reported low -ff levels after the performance of non-invasive prenatal testing (NIPT) as part of the screening for chromosomal abnormalities and their association with adverse pregnancy outcomes, namely the subsequent development of hypertensive disorders of pregnancy, gestational diabetes, preterm birth, and the detection of small for gestational age fetuses or growth-restricted fetuses. The Medline (1966-2041), Scopus (2004-2024), Clinicaltrials.gov (2008-2024), EMBASE (1980-2024), Cochrane Central Register of Controlled Trials CENTRAL (1999-2024) and Google Scholar (2004-2024) databases were used in our primary search along with the reference lists of electronically retrieved full-text papers. The date of our last search was set at February 29, 2024. RESULTS: Our search identified 128 potentially relevant studies and,overall, 8 studies were included in the present systematic review that enrolled a total of 72,507 patients. Low ff of cfDNA cfDNA was positively associated with HDP (OR 1.66, 95% CI 1.34, 2.06, I-square test: 56%). Low ff of cfDNA was positively associated with GDM (OR 1.27, 95% CI 1.03, 1.56, I-square test: 76%). Furthermore, low ff levels were positively associated with SGA/FGR (OR 1.63, 95% CI 1.32, 2.03, I-square test: 0%). Low ff levels were positively correlated with the risk for PTB but the association did not manage to reach a statistical significant level (OR 1.22, 95% CI 0.89, 1.67, I-square test: 66%). CONCLUSION: Our study suggests that low ff is associated with increased risk of adverse perinatal outcomes, including PE/PIH, GDM, and SGA/FGR. However, the relationship between ff and PTB remains unclear due to conflicting evidence. It should be emphasized that further research is needed to reveal the underlying mechanisms behind the association of low ff with adverse pregnancy outcomes and explore its potential role in an overall prenatal screening, which could potentially not be limited to detecting aneuploidies.

Placental pathology lesions: International Society for Ultrasound in Obstetrics and Gynecology vs Society for Maternal-Fetal Medicine fetal growth restriction definitions.

BACKGROUND: Research on the definition of fetal growth restriction (FGR) has focused on predicting adverse perinatal outcomes. A significant limitation of this approach is that the individual outcomes of interest could be related to the condition and the treatment. Evaluation of outcomes that reflect the pathophysiology of FGR may overcome this limitation. OBJECTIVE: To compare the diagnostic performance of the FGR definitions established by the International Society for Ultrasound in Obstetrics and Gynecology (ISUOG) and the Society for Maternal-Fetal Medicine (SMFM) to predict placental histopathological findings associated with placental insufficiency and a composite adverse neonatal outcome (ANeO). STUDY DESIGN: In this retrospective cohort study of singleton pregnancies, the ISUOG and the SMFM guidelines were used to identify pregnancies with FGR and a corresponding control group. The primary outcome was the prediction of placental histopathological findings associated with placental insufficiency, defined as lesions associated with maternal vascular malperfusion (MVM). A composite ANeO (ie, umbilical artery pH≤7.1, Apgar score at 5 minutes ≤4, neonatal intensive care unit admission, hypoglycemia, respiratory distress syndrome requiring mechanical ventilation, intrapartum fetal distress requiring expedited delivery, and perinatal death) was investigated as a secondary outcome. Sensitivity, specificity, positive and negative predictive values, and the areas under the receiver-operating-characteristics curves were determined for each FGR definition. Logistic regression models were used to assess the association between each definition and the studied outcomes. A subgroup analysis of the diagnostic performance of both definitions stratifying the population in early and late FGR was also performed. RESULTS: Both societies' definitions showed a similar diagnostic performance as well as a significant association with the primary (ISUOG adjusted odds ratio 3.01 [95% confidence interval 2.42, 3.75]; SMFM adjusted odds ratio 2.85 [95% confidence interval 2.31, 3.51]) and secondary outcomes (ISUOG adjusted odds ratio 1.95 [95% confidence interval 1.56, 2.43]; SMFM adjusted odds ratio 2.12 [95% confidence interval 1.70, 2.65]). Furthermore, both FGR definitions had a limited discriminatory capacity for placental histopathological findings of MVM and the composite ANeO (area under the receiver-operating-characteristics curve ISUOG 0.63 [95% confidence interval 0.61, 0.65], 0.59 [95% confidence interval 0.56, 0.61]; area under the receiver-operating-characteristics SMFM 0.63 [95% confidence interval 0.61, 0.66], 0.60 [95% confidence interval 0.57, 0.62]). CONCLUSION: The ISUOG and the SMFM FGR definitions have limited discriminatory capacity for placental histopathological findings associated with placental insufficiency and a composite ANeO. El resumen está disponible en Español al final del artículo.

Diagnosis and management of selective fetal growth restriction in monochorionic twin pregnancies: A cross-sectional international survey.

OBJECTIVE: To identify current practices in the management of selective fetal growth restriction (sFGR) in monochorionic diamniotic (MCDA) twin pregnancies. DESIGN: Cross-sectional survey. SETTING: International. POPULATION: Clinicians involved in the management of MCDA twin pregnancies with sFGR. METHODS: A structured, self-administered survey. MAIN OUTCOME MEASURES: Clinical practices and attitudes to diagnostic criteria and management strategies. RESULTS: Overall, 62.8% (113/180) of clinicians completed the survey; of which, 66.4% (75/113) of the respondents reported that they would use an estimated fetal weight (EFW) of <10th centile for the smaller twin and an inter-twin EFW discordance of >25% for the diagnosis of sFGR. For early-onset type I sFGR, 79.8% (75/94) of respondents expressed that expectant management would be their routine practice. On the other hand, for early-onset type II and type III sFGR, 19.3% (17/88) and 35.7% (30/84) of respondents would manage these pregnancies expectantly, whereas 71.6% (63/88) and 57.1% (48/84) would refer these pregnancies to a fetal intervention centre or would offer fetal intervention for type II and type III cases, respectively. Moreover, 39.0% (16/41) of the respondents would consider fetoscopic laser surgery (FLS) for early-onset type I sFGR, whereas 41.5% (17/41) would offer either FLS or selective feticide, and 12.2% (5/41) would exclusively offer selective feticide. For early-onset type II and type III sFGR cases, 25.9% (21/81) and 31.4% (22/70) would exclusively offer FLS, respectively, whereas 33.3% (27/81) and 32.9% (23/70) would exclusively offer selective feticide. CONCLUSIONS: There is significant variation in clinician practices and attitudes towards the management of early-onset sFGR in MCDA twin pregnancies, especially for type II and type III cases, highlighting the need for high-level evidence to guide management.

Plasma metabolites are altered before and after diagnosis of preeclampsia or fetal growth restriction.

Metabolomics is the study of small molecules (metabolites), within cells, tissues and biofluids. Maternal metabolites can provide important insight into the health and development of both mother and fetus throughout pregnancy. This study assessed metabolic profiles in the maternal circulation prior to and at the time of diagnosis of preeclampsia and fetal growth restriction. Maternal plasma samples were collected from two independent cohorts: (1) Established disease cohort: 50 participants diagnosed with early-onset preeclampsia (< 34 weeks' gestation), 14 with early-onset fetal growth restriction, and 25 gestation-matched controls. (2) Prospective cohort, collected at 36 weeks' gestation before diagnosis: 17 participants later developed preeclampsia, 49 delivered infants with fetal growth restriction (birthweight < 5th centile), and 72 randomly selected controls. Metabolic evaluation was performed by Metabolomics Australia on the Agilent 6545 QTOF Mass Spectrometer. In the established disease cohort, 77 metabolites were altered in circulation from participants with preeclampsia - increased L-cysteine (3.73-fold), L-cystine (3.28-fold), L-acetylcarnitine (2.57-fold), and carnitine (1.53-fold) (p < 0.05). There were 53 metabolites dysregulated in participants who delivered a fetal growth restriction infant-including increased levulinic acid, citric acid (1.93-fold), and creatine (1.14-fold) (p < 0.05). In the prospective cohort, 30 metabolites were altered in participants who later developed preeclampsia at term - reduced glutaric acid (0.85-fold), porphobilinogen (0.77-fold) and amininohippuric acid (0.82-fold) (p < 0.05) was observed. There were 5 metabolites altered in participants who later delivered a fetal growth restriction infant - including reduced 3-methoxybenzenepropanoic acid (p < 0.05). Downstream pathway analysis revealed aminoacyl-tRNA biosynthesis to be most significantly altered in the established cohort in preeclampsia (13/48 hits, p < 0.001) and fetal growth restriction (7/48 hits, p < 0.001). The predictive cohort showed no significant pathway alterations. This study observed altered metabolites in maternal plasma collected before and after diagnosis of a preeclampsia or fetal growth restriction. While a significant number of metabolites were altered with established disease, few changes were observed in the predictive cohort. Thus, metabolites measured in this study may not be useful as predictors of preeclampsia or fetal growth restriction.

Does the use of angiogenic biomarkers for the management of preeclampsia and fetal growth restriction improve outcomes?: Challenging the current status quo.

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.

Oxidative stress biomarkers for fetal growth restriction in umbilical cord blood: A scoping review.

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.

Preconception lipid profile and the subsequent risk of pregnancy disorders characterized by uteroplacental dysfunction in a multi-ethnic population: the linked HELIUS-PERINED study.

BACKGROUND: Unfavorable lipid profile is associated with pregnancy disorders characterized by uteroplacental dysfunction, including hypertensive disorders of pregnancy, preterm birth and fetal growth restriction. None of current tools used to predict the risk of pregnancy complications include lipid levels. OBJECTIVE(S): In this study, we examined the association of preconception lipid profile with pregnancy disorders characterized by uteroplacental dysfunction in a multi-ethnic population, aiming to improve the identification of women at high risk for uteroplacental dysfunction using current prediction models. STUDY DESIGN: We conducted a linkage study combining lipid profile collected in the multi-ethnic HELIUS study (Amsterdam, 2011-2015), linked with national perinatal registry data on pregnancy complications after inclusion until 2019. We included 1177 women of Dutch, South-Asian Surinamese, African Surinamese, Ghanaian, Turkish, and Moroccan origin. Associations were studied using Poisson regression. The discriminative ability was assessed for different pregnancy complications of significantly associated lipid parameters when added to commonly used prediction tools for preeclampsia. RESULTS: Preconception triglyceride level was associated with prevalence of hypertensive disorders of pregnancy (e^triglyceride level (mmol/L) adjusted prevalence ratio 1.07, 95% CI 1.00 to 1.14). Age-adjusted prevalence of hypertensive disorders of pregnancy was also higher among women with high LDL-C level, high TC/HDL-C or ≥4 adverse lipid parameters, but most of these findings were not statistically significant when adjusted for demographic, lifestyle and medical characteristics. Addition of triglyceride level and other lipid parameters to the NICE guideline criteria and to the EXPECT prediction tool did not improve discriminative ability for hypertensive disorders of pregnancy, preterm birth or fetal growth restriction. CONCLUSION(S): Lipid profile did not aid in the identification of women at high risk for pregnancy disorders characterized by uteroplacental dysfunction. Further studies are needed to improve preconception prediction models for hypertensive disorders of pregnancy and other pregnancy disorders characterized by uteroplacental dysfunction using biomarkers or other easily available measurements.