Fetal Growth Restriction Pregnancies Research Articles

TREATMENT OF EARLY-ONSET FETAL GROWTH RESTRICTION WITH LOW MOLECULAR WEIGHT HEPARIN DOES NOT PROLONG GESTATION: A RANDOMIZED CLINICAL TRIAL

Although there is a biological basis for it, there is scarce evidence on the effect of heparin in ameliorating placental insufficiency and maximizing gestational age at delivery among fetal growth restriction (FGR) pregnancies. To explore the effectiveness of treatment using low molecular weight heparin (LMWH) at a prophylactic dose started at the time of diagnosis in prolonging gestation in pregnancies with early-onset fetal growth restriction (FGR). This was a phase III, multicenter, triple-blind, parallel-arm randomized clinical trial conducted in two university hospitals in Spain. Singleton pregnancies qualifying for early-onset placental FGR according to the adapted Delphi consensus (20+0-31+6 weeks at diagnosis with umbilical artery Doppler with absent/reversed diastolic flow; or estimated fetal weight <10th percentile plus pulsatility index (PI) of umbilical artery Doppler >95th percentile; or estimated fetal weight <10th percentile plus mean PI of uterine artery Doppler >95th) were randomized to receive either subcutaneous treatment with bemiparin 3500 IU/0.2 mL/day or a placebo from inclusion at diagnosis to the time of delivery. The primary outcomes were prolongation of pregnancy from inclusion to live birth (days) and gestational age at live birth (days). 49 patients were included (23 in the LMWH group and 26 in the placebo group). In the LMWH group, the median prolongation of pregnancy was 42 days, while in the placebo group it was 41.5 days (median difference 0.5 days [95% CI -22.7 to 6.3] (p=0.667) and in the LMWH group, the median gestational age at delivery was 35.1 weeks, while in the placebo group, it was 34.6 weeks (median difference 0.5 weeks [95% CI -3.4 to 1.2] (p=0.639). The use of prophylactic dose LMWH started at the time of diagnosis does not prolong pregnancy in individuals with early-onset fetal restriction.

Placental Malaria Induces a Unique Methylation Profile Associated with Fetal Growth Restriction.

Fetal growth restriction (FGR) is associated with perinatal death and adverse birth outcomes, as well as long-term complications, including increased childhood morbidity, abnormal neurodevelopment, and cardio-metabolic diseases in adulthood. Placental epigenetic reprogramming associated with FGR may mediate these long-term outcomes. Placental malaria (PM), characterized by sequestration of Plasmodium falciparum-infected erythrocytes in placental intervillous space, is the leading global cause of FGR, but its impact on placental epigenetics is unknown. We hypothesized that placental methylomic profiling would reveal common and distinct mechanistic pathways of non-malarial and PM-associated FGR. We analyzed placentas from a US cohort with no malaria exposure (n = 12) and a cohort from eastern Uganda, a region with a high prevalence of malaria (n = 12). From each site, 8 cases of FGR (defined as birth weight <10%ile for gestational age by Intergrowth-21 standard curves) and 4 healthy controls with normal weight were analyzed. PM was diagnosed by placental histopathology. We compared the methylation levels of over 850K CpGs of the placentas using Infinium MethylationEPIC v1 microarray. Non-malarial FGR was associated with 65 differentially methylated CpGs (DMCs), whereas PM-FGR was associated with 133 DMCs, compared to their corresponding controls without FGR. One DMC (cg16389901, located in the promoter region of BMP4) was commonly hypomethylated in both groups. We identified 522 DMCs between non-malarial FGR vs. PM-FGR placentas, which was independent of differing geographic location or cellular composition. Placentas with PM-associated FGR have distinct methylation profiles as compared to placentas with non-malarial FGR, suggesting novel epigenetic reprogramming in response to malaria. Larger cohort studies are needed to determine the distinct long-term health outcomes in PM-associated FGR pregnancies.

Ultrasound shear wave elastography of the placenta: a potential tool for early detection of fetal growth restriction

BackgroundSonographic placental elastography has recently been employed as a non-invasive tool to investigate the structural alterations associated with various conditions such as pre-eclampsia, gestational diabetes and fetal growth restriction (FGR). The study was conducted based on the hypothesis that the placental elasticity might differ with varying severity of FGR and with that of appropriate for gestational age (AGA) pregnancies. MethodsThis study involved 121 pregnant women, with 54 in the normal group and 67 in the FGR group, which was defined as the fetal weight below the 10th percentile for gestational age. The FGR pregnancies were sub grouped into different stages based on the presence and extent of Doppler abnormalities. Shear-wave elastography was carried out to investigate the placental elasticity values, which were compared using the Kruskal-Wallis test. A P value of ≤0.05 was considered significant. ResultsThe placental elasticity differed significantly between pregnancies with and without FGR and among the different stages of FGR. There was a significant difference in PE (kPa) and SWV (m/s) among groups, with a p-value of 0.000001. PE and SWV in FGR pregnancies were significantly higher compared to AGA as a whole using t-test with p values of <0.0001. Doppler indices of umbilical, uterine and fetal middle cerebral arteries also correlated significantly with these. ConclusionThe study suggests that placental elasticity values reflect structural alterations associated with FGR and could serve as a valuable tool in the early detection and staging of this condition.

Cardiovascular Adaptation in Fetal Growth Restriction: A Longitudinal Study From Fetuses at Term to the First Year of Life.

To investigate longitudinal trends in fetal and offspring cardiovascular adaptation in fetal growth restriction (FGR). Prospective longitudinal study. Fetal Medicine Unit. Thirty-five FGR pregnancies and 37 healthy controls assessed as term fetuses (mean age 37 ± 1 weeks) and again in infancy (mean age 8 ± 2 months). Conventional echocardiographic techniques, tissue Doppler imaging and speckle tracking echocardiography. Left ventricular (LV) and right ventricular (RV) geometry and function. Echocardiographic parameters were normalised by ventricular size adjusting for differences in body weight between groups. Compared to healthy controls, late FGR fetuses showed significant alterations in cardiac geometry with more globular LV chamber (LV sphericity index, 0.56 vs. 0.52), increase in biventricular global longitudinal systolic contractility (MAPSE, 0.29 vs. 0.25 mm; TAPSE, 0.42 vs. 0.37 mm) and elevated cardiac output (combined CO: 592 vs. 497 mL/min/kg, p < 0.01 for all). Indices of LV diastolic function in FGR fetuses were significantly impaired with myocardial diastolic velocities (LV A', 0.30 vs. 0.26 cm/s; IVS E', 0.19 vs. 0.16 cm/s) and LV torsion (1.2 vs. 3.5 deg./cm, p < 0.01 for all). At postnatal assessment, FGR offspring revealed persistently increased SAPSE (0.27 vs. 0.24 mm), LV longitudinal strain (-19.0 vs. -16.0%), reduced LV torsion (1.6 vs. 2.1 deg./cm) and elevated CO (791 vs. 574 mL/min/kg, p < 0.01 for all). Perinatal cardiac remodelling and myocardial dysfunction in late FGR fetuses is most likely due to chronic placental hypoxaemia. Persistent changes in cardiac geometry and function in FGR offspring may reflect fetal cardiovascular maladaptation that could predispose to long-term cardiovascular complications in later life.

Study of Ultrasonographic Changes of the Adrenal Gland in Growth Restricted Fetus

Background: Fetuses with Fetal Growth Restriction (FGR) are at increased risk of chronic intra-uterine hypoxia, due to increased secretion of corticosterone from the fetal adrenal glands. This plays a major role in the cardiovascular and circulatory adaptation of FGR fetuses. These modifications are untimely identified by sonographic imaging. Objective: To study the association between ultrasound features of the adrenal gland and growth restriction in the fetus. Methods: A total of 104 pregnant women (52 FGR pregnancies and 52 controls) were evaluated between 28 and 36 weeks of gestation. All the study participants underwent transabdominal ultrasonography to measure bilateral fetal adrenal gland volume and fetal zone volume, corrected for gestational age. They were followed up until delivery. The two groups were compared to analyze the perinatal outcome in relation to ultrasonographic changes in the adrenal gland. Results: The adrenal gland measurements were significantly larger in fetuses with FGR as compared to the control group. FGR group had a larger corrected adrenal gland volume(cAGV) and fetal zone and adrenal gland (FZ/AG)ratio A statistically significant correlation was found between the two groups regarding gestational age at delivery, birth weight, APGAR score, and NICU admissions. Perinatal morbidity was found to be higher among women diagnosed with FGR, i.e., 14 (53.84%). Conclusion: Fetal adrenal gland size measurement is important to identify FGR fetuses that are vulnerable to hypoxia. It helps the obstetrician prepare for effective in-utero management to reduce perinatal morbidity and mortality.

Maternal Innate Immune Reprogramming After Complicated Pregnancy.

Preeclampsia (PE) and fetal growth restriction (FGR) are often associated with maternal inflammation and an increased risk of cardiovascular and metabolic disease in the affected mothers. The mechanism responsible for this increased risk of subsequent disease may involve reprogramming of innate immune cells, characterized by epigenetic modifications. Circulating monocytes from women with PE, FGR, or uncomplicated pregnancies (control) were isolated before labor. Cytokine release from monocytes following exposure to lipopolysaccharide (LPS) and the presence of lysine 4-trimethylated histone 3 (H3K4me3) within TNF promoter sequences were evaluated. Single-cell transcriptomic profiles of circulating monocytes from women with PE or uncomplicated pregnancies were assessed. Monocytes from women with PE or FGR exhibited increased IL-10 secretion and decreased IL-1β and GM-CSF secretion in response to LPS. While TNFα secretion was not significantly different in cultures of control monocytes versus those from complicated pregnancies with or without LPS exposure, monocytes from complicated pregnancies had significantly decreased levels of H3K4me3 associated with TNF promoter sequences. Cluster quantification and pathway analysis of differentially expressed genes revealed an increased proportion of anti-inflammatory myeloid cells and a lower proportion of inflammatory non-classical monocytes among the circulating monocyte population in women with PE. Monocytes from women with PE and FGR exhibit an immune tolerance phenotype before initiation of labor. Further investigation is required to determine whether this tolerogenic phenotype persists after the affected pregnancy and contributes to increased risk of subsequent disease.

Pregnancy outcomes in correlation with placental histopathology in pregnancies complicated by fetal growth restriction with vs. without reduced fetal movements.

Fetal movements are crucial indicators of fetal well-being, with reduced fetal movements (RFM) suggesting potential fetal compromise. Fetal growth restriction (FGR), often linked to placental insufficiency, is a major cause of perinatal morbidity and mortality. This study aimed to investigate the neonatal, labor, and placental outcomes of FGR pregnancies with and without RFM at term. In this retrospective study, data from all term, singleton deliveries with FGR and concomitant RFM were obtained and compared to an equal control group of FGR without RFM. Maternal characteristics, pregnancy and neonatal outcomes, and placental histology were compared. The primary outcome was a composite of adverse neonatal outcomes. A multivariable regression analysis was performed to identify independent associations with adverse neonatal outcomes. During the study period, 250 FGR neonates with concomitant RFM and an equal control group were identified. The groups did not differ in maternal demographics aside from significantly higher rates of maternal smoking in the RFM group (p < 0.001). Polyhydramnios and oligohydramnios (p = 0.032 and p = 0.007, respectively) and meconium-stained amniotic fluid (p < 0.001) were more prevalent in the FGR+RFM group. Additionally, the RFM group showed higher rates of adverse neonatal outcomes despite having larger neonates (p = 0.047 and p < 0.001, respectively). No significant differences were observed in placental findings. Logistic regression identified RFM as an independent predictor of adverse neonatal outcomes (aOR 2.45, 95% CI 1.27-4.73, p = 0.008). Reduced fetal movements are significant and independent predictors of worse neonatal outcomes in FGR pregnancies, suggesting an additional acute insult on top of underlying placental insufficiency.

Association of Amniotic Fluid Volume and Fetal Cardiac and Cerebrovascular Parameters in Fetal Growth Restriction.

To investigate the prevalence of oligohydramnios, brain sparing, and cardiac dysfunctionamong a cohort of fetal growth restriction (FGR). To assess the prevalence of oligohydramnios amongst a large sample of FGR fetuses, we screened a database of ultrasounds of FGR pregnancies from our maternal-fetal medicine clinics (clinical cohort) for diminished amniotic fluid volume. Using a threshold of a maximum vertical pocket (MVP) of <2 cm for "oligohydramnios," and 2 to 3 cm as a "reduced fluid" group, trends of Doppler values and cardiac parameters were assessed from pregnancies in an ongoing research study (comprehensive cohort). In the clinical cohort, oligohydramnios was identified in only 2/229 (0.8%) and reduced fluid in 19/229 (8%). In the comprehensive cohort, oligohydramnios was seen in 3/126 (2.3%) and reduced fluid in 14/126 (11.1%). A high rate of cardiac and Doppler abnormalities were observed in the oligohydramnios group of the comprehensive cohort. The patients with oligohydramnios had a distinctly different cardiac phenotype with small (2/3 with cardiac area <5th%) (P = 0.01) and round (3/3 with global sphericity index <5th%) (P = 0.02) hearts. Oligohydramnios, when present with FGR, is accompanied by high rates of cerebral and cardiovascular abnormalities.

Epigenetic regulation by hypoxia, N-acetylcysteine and hydrogen sulphide of the fetal vasculature in growth restricted offspring: A study in humans and chicken embryos.

Fetal growth restriction (FGR) is a common outcome in human suboptimal gestation and is related to prenatal origins of cardiovascular dysfunction in offspring. Despite this, therapy of human translational potential has not been identified. Using human umbilical and placental vessels and the chicken embryo model, we combined cellular, molecular, and functional studies to determine whether N-acetylcysteine (NAC) and hydrogen sulphide (H2S) protect cardiovascular function in growth-restricted unborn offspring. In human umbilical and placental arteries from control or FGR pregnancy and in vessels from near-term chicken embryos incubated under normoxic or hypoxic conditions, we determined the expression of the H2S gene CTH (i.e. cystathionine γ-lyase) (via quantitative PCR), the production of H2S (enzymatic activity), the DNA methylation profile (pyrosequencing) and vasodilator reactivity (wire myography) in the presence and absence of NAC treatment. The data show that FGR and hypoxia increased CTH expression in the embryonic/fetal vasculature in both species. NAC treatment increased aortic CTH expression and H2S production and enhanced third-order femoral artery dilator responses to the H2S donor sodium hydrosulphide in chicken embryos. NAC treatment also restored impaired endothelial relaxation in human third-to-fourth order chorionic arteries from FGR pregnancies and in third-order femoral arteries from hypoxic chicken embryos. This NAC-induced protection against endothelial dysfunction in hypoxic chicken embryos was mediated via nitric oxide independent mechanisms. Both developmental hypoxia and NAC promoted vascular changes in CTH DNA and NOS3methylation patterns in chicken embryos. Combined, therefore, the data support that the effects of NAC and H2S offer a powerful mechanism of human translational potential against fetal cardiovascular dysfunction in complicated pregnancy. KEY POINTS: Gestation complicated by chronic fetal hypoxia and fetal growth restriction (FGR) increases a prenatal origin of cardiovascular disease in offspring, increasing interest in antenatal therapy to prevent against a fetal origin of cardiovascular dysfunction. We investigated the effects between N-acetylcysteine (NAC) and hydrogen sulphide (H2S) in the vasculature in FGR human pregnancy and in chronically hypoxic chicken embryos. Combining cellular, molecular, epigenetic and functional studies, we show that the vascular expression and synthesis of H2S is enhanced in hypoxic and FGR unborn offspring in both species and this acts to protect their vasculature. Therefore, the NAC/H2S pathway offers a powerful therapeutic mechanism of human translational potential against fetal cardiovascular dysfunction in complicated pregnancy.

Long-Term Maternal and Neonatal Outcomes Following Birth in Fetal Growth Restricted Pregnancies

Long-Term Maternal and Neonatal Outcomes Following Birth in Fetal Growth Restricted Pregnancies

Externally validated nomogram for predicting short-term pregnancy outcome of singleton pregnancies with fetal growth restriction (FGR)

ObjectiveThis study aimed at developing an available predictive model of singleton pregnancies with fetal growth restriction (FGR) for accurate and individualised prognosis assessment.MethodsThe prediction nomogram was developed by using multivariable...

Fetal growth restriction exhibits various mTOR signaling in different regions of mouse placentas with altered lipid metabolism

Fetal growth restriction (FGR) is a common complication of pregnancy and can have significant impact on obstetric and neonatal outcomes. Increasing evidence has shown that the inhibited mechanistic target of rapamycin (mTOR) signaling in placenta is associated with FGR. However, interpretation of existing research is limited due to inconsistent methodologies and varying understanding of the mechanism by which mTOR activity contributes to FGR. Hereby, we have demonstrated that different anatomic regions of human and mouse placentas exhibited different levels of mTOR activity in normal compared to FGR pregnancies. When using the rapamycin-induced FGR mouse model, we found that placentas of FGR pregnancies exhibited abnormal morphological changes and reduced mTOR activity in the decidual-junctional layer. Using transcriptomics and lipidomics, we revealed that lipid and energy metabolism was significantly disrupted in the placentas of FGR mice. Finally, we demonstrated that maternal physical exercise during gestation in our FGR mouse model was associated with increased fetal and placental weight as well as increased placental mTOR activity and lipid metabolism. Collectively, our data indicate that the inhibited placental mTOR signaling contributes to FGR with altered lipid metabolism in mouse placentas, and maternal exercise could be an effective method to reduce the occurrence of FGR or alleviate the adverse outcomes associated with FGR.Graphical Human and mouse placentas have different mTOR signaling activities in different anatomic regions in normal and FGR pregnancies.Pregnant mice with FGR induced by rapamycin show smaller placentas, decreased mTOR activity in DJ layer of placenta and altered lipid metabolism.Maternal exercise partially alleviates the abnormal outcomes of FGR model.

FGR-associated placental insufficiency and capillary angiogenesis involves disruptions in human placental miRNAs and mRNAs

Fetal growth restriction (FGR) is one of the most common pregnancy complications culminating in adverse fetal outcome, including preterm birth, neonatal mortality and stillbirth. Compromised placental development and function, especially disruption in angiogenesis and inadequate nutrient supply are contributing factors. Fetal sex also influences placental function. Knowledge of gene expression changes and epigenetic factors contributing to placental dysfunction in FGR pregnancies will help identify biomarkers and help target interventions. This study tested the hypothesis that FGR pregnancies are associated with disruptions in miRNA - an epigenetic factor and mRNAs involving key mediators of angiogenesis and microvessel development. Changes in expression of key genes/proteins involved in placental dysfunction by RT-PCR and immunohistochemistry and miRNA changes by RNA sequencing were undertaken with term placenta from 12 control and 20 FGR pregnancies. Findings showed changes in expression of genes involved in steroidogenesis, steroid action, IGF family members, inflammatory cytokines and angiogenic factors in FGR pregnancies. In addition, upregulation of MIR451A and downregulation of MIR543 in placentas from FGR group with female newborns and upregulation of MIR520G in placentas from FGR group with male newborns were also noted. MIR451A and MIR543 have been implicated in angiogenesis. Consistent with gene changes, CD34, the microvessel angiogenesis marker, also showed reduced staining only in female FGR group. These findings provide evidence that epigentically regulated gene expression changes in angiogenesis and capillary development influence placental impairment in FGR pregnancies. Our preliminary observations also support for these changes to be driven in a sex-specific manner.

Umbilical–portal–systemic venous shunt and intrauterine growth restriction: an inquiry from a prospective study

BackgroundThe investigation of the fetal umbilical-portal venous system is based on the premise that congenital anomalies of this system may be related to adverse perinatal outcomes. Several retrospective small studies have reported a well-established association between umbilical–portal–systemic venous shunts and fetal growth restriction. However, the prevalence of portosystemic shunts in the fetal growth restricted population is yet to be determined. ObjectivesThe aims of this study were:1. To determine the prevalence of fetal umbilical–portal–systemic venous shunts in pregnancies complicated by fetal growth restriction.2. To compare the perinatal and neonatal outcome of fetal growth restriction pregnancies with and without umbilical–portal–systemic venous shunts. Study DesignA prospective cross-sectional study of pregnancies diagnosed with fetal growth restriction, as defined by the Society for Maternal-Fetal Medicine fetal growth restriction guidelines. All participants underwent a detailed anomaly scan supplemented with a targeted scan of the fetal portal system. Venous shunts were diagnosed using color Doppler mode. The perinatal outcomes of fetal growth restriction pregnancies with and without umbilical–portal–systemic venous shunts were compared. ResultsOne hundred and fifty cases of fetal growth restriction were recruited. The prevalence of umbilical–portal–systemic venous shunts in our cohort was 9.3% (n=14). Compared to the control group (fetal growth restriction without umbilical–portal–systemic venous shunts, n=136), the study group had a significantly lower mean gestational age at time of fetal growth restriction diagnosis [29.7 (±5.6) vs. 32.47 (±4.6) weeks of gestation, p=0.036] as well as an earlier gestational week at delivery [33.50 (±6.0) vs. 36.13 (±2.8), p=0.005]. The study group had a higher rate of fetal death (21.4% vs. 0.7%, p<0.001) and accordingly a lower rate of live births (71.4% vs. 95.6%, p=0.001). Associated additional fetal vascular anomalies were significantly more prevalent in the study group compared to controls (35.7% vs. 4.4%, respectively, p=<0.001). The rate of other associated anomalies was similar. The study group had a significantly lower rate of abnormal uterine artery Doppler indices (0% vs. 40.4% p=0.011) and a higher rate of abnormal ductus venosus Doppler indices (64.3% vs. 23% p=0.001). There were no cases of hypertensive disorders of pregnancy in the study group compared to 12.5% in the control group (p=0.16). Other perinatal and neonatal outcomes were comparable. ConclusionsUmbilical–portal–systemic venous shunt is a relatively common finding in growth restricted fetuses. Compared to fetal growth restriction pregnancies with a normal portal system, these pregnancies complicated by FGR and umbilical–portal–systemic venous shunt are associated with different Doppler flow pattern, increased risk for fetal death, earlier presentation of fetal growth restriction, lower gestational age at delivery, additional congenital vascular anomalies and a lower rate of pregnancy induced hypertensive disorders. Meticulous sonographic evaluation of the portal system should be considered in the prenatal workup of fetal growth restriction, as umbilical–portal–systemic venous shunts may have implications on perinatal outcome.

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.

Maternal serum fatty acid binding protein-4 level is upregulated in fetal growth restriction with abnormal Doppler flow patterns.

This study aimed to determine fatty acid binding protein-4 (FABP-4) concentrations in maternal serum of fetal growth restriction (FGR) pregnancies and controls of normal pregnancies. Furthermore, we hypothesized that the alterations in FABP-4 levels might correlate with FGR severity. We performed this prospective case-control study with 83 pregnant women. The study groups included 26 FGR pregnancies without abnormal fetal Doppler flow patterns and 25 pregnancies complicated with FGR accompanied by abnormal fetal Doppler flow patterns. The median serum FABP-4 concentrations were significantly higher in the FGR cases with abnormal Doppler flow pattern group (2.09 ng/mL) than in the FGR cases without abnormal Doppler flow pattern group (1.62 ng/mL) and the control group (1.20 ng/mL, p < 0.001). A significant negative correlation was observed between maternal serum FABP-4 levels and time to birth from blood sample collection (r = -0.356 and p = 0.001), gestational week at birth (r = -0.386 and p < 0.001), and birth weight (r = -0.394 and p < 0.001). A 1.35 ng/mL cut-off value of serum FABP-4 level could be used to discriminate FGR cases with a 78.4% sensitivity and 60.6% specificity. The optimal cut-off value of FABP-4 levels as an indicator for the diagnosis of FGR with abnormal Doppler flow pattern was estimated to be 1.76 ng/mL, which yielded a sensitivity of 84.0% and a specificity of 75.8%. FABP-4 is a crucial biomarker in the diagnosis and determining the severity of pregnancies with restricted fetal growth. We consider that FABP-4 is a powerful, reliable, and unique biomarker to diagnose FGR pregnancies.

Liposome-Encapsulated Anti-inflammatory Proteins for Targeted Delivery to the Placenta to Treat Fetal Growth Restriction.

Fetal growth restriction (FGR), the failure of a fetus to reach its genetically determined growth potential, is a serious complication affecting up to 10% of pregnancies. FGR is a major risk factor for stillbirth and, in the survivors, neurodevelopmental disorders. We have recently identified that the anti-inflammatory and pro-resolving molecule, lipoxin A4 (LXA4) and its soluble receptor, formyl-peptide receptor-2 (FPR-2) are significantly decreased in human placentas from FGR pregnancy. The LXA4 synthetic analog Compound 43 (C43) is considered a safe, anti-inflammatory therapy and is being developed as a treatment for disease conditions with an inflammatory basis, for example, asthma in children. Identification of therapies to treat FGR in utero comes with the need to mitigate their potential side effects and the use of nanoparticle-mediated delivery systems could facilitate this. Our current studies are focused on targeting the resolution of inflammation observed in FGR placentas, by synthesizing liposome-encapsulated C43 as a novel therapeutic to improve placental function in FGR. In this chapter, we provide a detailed methodological procedure for the preparation of liposomes and conjugation of the peptide sequences, which selectively bind to the outer placental syncytiotrophoblast layer or the vascular endothelium of the uterine spiral arterioles.

Impact of fetal growth restriction on pregnancy outcome in women undergoing expectant management for preterm pre-eclampsia.

To assess whether coexisting fetal growth restriction (FGR) influences pregnancy latency among women with preterm pre-eclampsia undergoing expectant management. Secondary outcomes assessed were indication for delivery, mode of delivery and rate of serious adverse maternal and perinatal outcomes. We conducted a secondary analysis of the Pre-eclampsia Intervention (PIE) and the Pre-eclampsia Intervention 2 (PI2) trial data. These randomized controlled trials evaluated whether esomeprazole and metformin could prolong gestation of women diagnosed with pre-eclampsia between 26 and 32 weeks of gestation undergoing expectant management. Delivery indications were deteriorating maternal or fetal status, or reaching 34 weeks' gestation. FGR (defined by Delphi consensus) at the time of pre-eclampsia diagnosis was examined as a predictor of outcome. Only placebo data from PI2 were included, as the trial showed that metformin use was associated with prolonged gestation. All outcome data were collected prospectively from diagnosis of pre-eclampsia to 6 weeks after the expected due date. Of the 202 women included, 92 (45.5%) had FGR at the time of pre-eclampsia diagnosis. Median pregnancy latency was 6.8 days in the FGR group and 15.3 days in the control group (difference 8.5 days; adjusted 0.49-fold change (95% CI, 0.33-0.74); P < 0.001). FGR pregnancies were less likely to reach 34 weeks' gestation (12.0% vs 30.9%; adjusted relative risk (aRR), 0.44 (95% CI, 0.23-0.83)) and more likely to be delivered for suspected fetal compromise (64.1% vs 36.4%; aRR, 1.84 (95% CI, 1.36-2.47)). More women with FGR underwent a prelabor emergency Cesarean section (66.3% vs 43.6%; aRR, 1.56 (95% CI, 1.20-2.03)) and were less likely to have a successful induction of labor (4.3% vs 14.5%; aRR, 0.32 (95% CI, 0.10-1.00)), compared to those without FGR. The rate of maternal complications did not differ significantly between the two groups. FGR was associated with a higher rate of infant death (14.1% vs 4.5%; aRR, 3.26 (95% CI, 1.08-9.81)) and need for intubation and mechanical ventilation (15.2% vs 5.5%; aRR, 2.97 (95% CI, 1.11-7.90)). FGR is commonly present in women with early preterm pre-eclampsia and outcome is poorer. FGR is associated with shorter pregnancy latency, more emergency Cesarean deliveries, fewer successful inductions and increased rates of neonatal morbidity and mortality. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

EP18.17: Prediction of pre‐eclampsia and fetal growth restriction in pregnancies with systemic lupus erythematosus

EP18.17: Prediction of pre‐eclampsia and fetal growth restriction in pregnancies with systemic lupus erythematosus

Dysfunction of ZNF554 promotes ROS-induced apoptosis and autophagy in Fetal Growth Restriction via the p62-Keap1-Nrf2 pathway

Fetal growth restriction (FGR) is one of the most common complications of an abnormal pregnancy. Placental dysplasia has been established as a significant contributing factor to FGR. Zinc finger protein 554 (ZNF554) is a member of the Krüppel-associated box domain zinc finger protein subfamily, primarily expressed in the placenta and essential for maintaining normal pregnancy outcomes. However, its precise role in FGR remains uncertain. In this study, we confirmed that ZNF554 was low expressed in the placenta of the FGR pregnancy. To further elucidate the impact of ZNF554 on trophoblasts, we conducted experiments using siRNA and overexpression plasmids on HTR8/SVneo and JEG3 cells. Our findings revealed that silencing ZNF554 increased apoptosis and inhibited migration and invasion, while overexpression reduced apoptosis and promoted migration and invasion. Notably, ZNF554 knockdown decreased cellular antioxidant capacity and elevated the production of reactive oxygen species (ROS). Conversely, ZNF554 activated the nuclear factor E2-related factor 2 (NRF2) signaling pathway, exerting its antioxidant effects. Additionally, ZNF554 knockdown promoted cellular autophagy by suppressing P62 and enhancing LC3-II/LC3-I expression. Importantly, the antioxidant N-acetylcysteine (NAC) partially mitigated the impact of ZNF554 knockdown on mitochondrial ROS in trophoblast cells and subsequent effects on cellular autophagy and apoptosis. In conclusion, our results suggest that ZNF554 plays a pivotal role in modulating trophoblast cell invasion and may serve as a prognostic marker and potential therapeutic target for FGR.