Idiopathic Fetal Growth Research Articles

Reduced Endothelial Progenitor Cells: A Possible Biomarker for Idiopathic Fetal Growth Restriction in Human Pregnancies.

Circulating endothelial progenitor cells (EPCs) may be necessary throughout pregnancy by ensuring proper placentation and embryonic growth. The lack of standardized EPC quantification techniques has prevented conclusive proof of an increase in EPC during pregnancy. The purpose of this study was to determine whether EPC levels change for healthy and idiopathic fetal growth restriction (FGR) pregnancies. The study population consisted of 48 healthy pregnant females with no previous history of IUGR (10 in the first trimester, 15 in the second, and 23 in the third), 48 women with pregnancy complicated by idiopathic FGR, and 15 non-pregnant women. By using flow cytometry, EPCs in maternal blood were recognized as CD45dim/CD34/KDR cells. ELISA was used to measure plasmatic cytokines. We ascertained a progressive rise in EPCs in healthy pregnancies that was apparent in the first but more pronounced in the third trimester. At comparable gestational ages, FGR-complicated pregnancies had impaired EPC growth. Placental growth factor and stromal-derived factor-1 levels in the blood were significantly lower in FGR than in healthy pregnancies, which may have contributed to the degradation of the EPCs. The count in EPCs might hold considerable promise toward developing a peculiar authentication marker for observing pregnancies, and could be the focus of cutting-edge tactics for the prognosis and treatment of FGR pregnancies.

Serum levels of kynurenine in pregnancies with fetal growth restriction and oligohydramnios.

Kynurinine (KYN) and its metabolites, which are released during the metabolism of tryptophan, an essential amino acid, have many important functions, such as cellular energy production, regulation of vascular tone, and regulation of the immune system. In this study, we aimed to detect serum KYN levels, which may be anindicator of KYN pathway activity, in idiopathic fetal growth restriction (FGR) and oligohydramnios cases whose pathophysiology is known to be affected by multiple factors, such as placental hypoperfusion, immune dysregulation, and maternal nutrition disorder, and to investigate their relationship with these common obstetric complications. This cross-sectional case-control study was carried out in the antenatal outpatient clinics of Ankara City Hospital between July and December 2021. While the study group consisted of pregnant women with idiopathic isolated FGR and oligohydramnios, the control group consisted of low-risk patients who did not have any problems. The clinical features of the patients, such as age, body mass indexes, and gestational week, were recorded by measuring basic laboratory parameters and serum KYN levels. A total of 110 patients were included in this study. The patients were divided into three groups: FGR, oligohydramnios, and the control group. There was no significant difference between the patients' ages, weeks of gestation, or body mass indexes. Serum KYN level was calculated as 57.8±13.4pg/mL in IUGR, 75.3±10.8pg/mL in oligohydramnios and 95.1±13.3pg/mL in the control group (p<0.001). Serum KYN levels were lower in pregnant women complicated with FGR and oligohydramnios more prominently in pregnant women diagnosed with FGR than in normal pregnancies. The results suggest that KYN plays an important role in either the etiopathogenesis or the response to these two obstetric pathologies.

Maternal serum midkine level in fetal growth restriction: a case-control study.

To compare maternal serum midkine (MK) level in pregnant women with idiopathic fetal growth restriction (FGR) and healthy. In addition, we assessed the value of maternal serum MK level in predicting neonatal intensive care unit (NICU) admission. A total of 144 pregnant women were included, 72 with idiopathic FGR and 72 healthy in this study. The control group was matched for the mother's age, parity, gestational age, and pre-pregnancy body mass index (BMI) with the idiopathic FGR group at the time of recruitment into the study and sample collection. Serum MK level is higher in the idiopathic FGR than the control group (0.24ng/mL (0.19-0.32) vs. 0.18ng/mL (0.14-0.23), p<0.001). In addition, we compared the maternal serum MK level of those with and without NICU admission in the FGR group (0.25ng/mL (0.19-0.37) vs. 0.21ng/mL (0.18-0.28), p=0.014). We performed ROC curve analysis to serum MK level predicting NICU admission in the FGR group (AUC: 0.668, %95 CI [0.550, 0.785], p=0.014). A sensitivity of 63% and a specificity of 62% for the serum MK level were achieved with a cut-off value of 0.22 for NICU admission. To the best of our knowledge, this study is the first to compare maternal serum MK level in pregnant women with idiopathic FGR and healthy. We showed that maternal serum MK level was significantly elevated in pregnant women with FGR than healthy.

Differential Changes in Akt and AMPK Phosphorylation Regulating mTOR Activity in the Placentas of Pregnancies Complicated by Fetal Growth Restriction and Gestational Diabetes Mellitus With Large-For-Gestational Age Infants.

Background: Dysregulation of placental mechanistic target of rapamycin (mTOR) activity has been implicated in the pathophysiology of pregnancies complicated by idiopathic fetal growth restriction (FGR) and gestational diabetes mellitus (GDM) with large-for-gestational-age (LGA) infants. However, the underlying mechanisms remain unclear.Methods: We obtained placentas from women with normal pregnancies (n = 11) and pregnancies complicated by FGR (n = 12) or GDM with LGA infants (n = 12) to compare the levels of total and phosphorylated forms of Akt, AMPK, TSC2, and mTOR among the three groups and used primary cytotrophoblast cells isolated from 30 normal term placentas to study the effects of oxygen–glucose deprivation (OGD) and increasing glucose concentrations on the changes of these factors in vitro.Results: Placentas from FGR pregnancies had lower phosphorylated Akt (p-Akt) levels (P < 0.05), higher p-AMPKα levels (P < 0.01), and lower mTOR phosphorylation (P < 0.05) compared to that of normal pregnant women. Conversely, women with GDM and LGA infants had higher p-Akt (P < 0.001), lower p-AMPKα (P < 0.05), and higher p-mTOR levels (P < 0.05) in the placentas than normal pregnant women. Furthermore, primary cytotrophoblast cells subjected to OGD had lower p-Akt and p-mTOR (both P < 0.05) and higher p-AMPKα levels (P < 0.05) than those cultured under standard conditions, but increasing glucose concentrations had opposite effects on the respective levels. Administering compound C, an AMPK inhibitor, did not significantly affect Akt phosphorylation but partially reversed mTOR phosphorylation. Administering LY294002, an Akt inhibitor, decreased p-mTOR levels, but did not change the levels of total and phosphorylated AMPKα.Conclusion: These results suggest that Akt and AMPK are involved in the regulation of trophoblast mTOR activity in the placentas of pregnancies complicated by FGR and GDM with LGA infants.

Changes of dendritic cell and natural killer cell on the cord blood with idiopathic fetal growth restriction

Objective To investigate the characteristics of dendritic cells (DC) and natural killer cells (NK) in umbilical cord blood of pregnant patients diagnosed with idiopathic fetal growth restriction (IFGR). Methods A prospective study cohort of IFGR patients was established who were in the third trimester (28–36 weeks), with a healthy, pregnant woman cohort selected as controls. Umbilical cord blood was collected. Results The study included 50 pregnant women in the IFGR group and 50 pregnant women in the healthy, control group. The incidence of SGA in the IFGR group was 52.0%, and the incidence of preterm birth was 18.0%. The incidence of neonatal complications in neonates with live birth in the IFGR group was 12.0%. The birth weight, body length and placental weight of the newborns in the IFGR group were significantly lower than those in the control group (p < .05). Flow cytometry revealed no significant difference in the proportion or maturity of DC in umbilical cord blood between IFGR group and control group (p > .05). The proportion of NK cells in umbilical cord blood of IFGR group was significantly higher than that of normal control group. The proportion of CD56dimCD16+ NK cells was also significantly higher than that of the normal control group (p < .05), but the expression of NK cell surface killing activator receptor NKG2D and inhibitory receptor NKG2A was not statistically significant (p > .05). Conclusion The number and proportion of DC cells in cord blood may not be the key factors affecting the outcomes observed during FGR pregnancies. However, we found the proportion of NK cells in cord blood to be significantly increased, as well as the ratio of CD56dimCD16 + NK to CD56highCD16-NK to be imbalanced, which may be one of the pathogenesis of the pathological pregnancy leading to IFGR.

Sex-Biased lncRNA Signature in Fetal Growth Restriction (FGR).

Impaired fetal growth is one of the most important causes of prematurity, stillbirth and infant mortality. The pathogenesis of idiopathic fetal growth restriction (FGR) is poorly understood but is thought to be multifactorial and comprise a range of genetic causes. This research aimed to investigate non-coding RNAs (lncRNAs) in the placentas of male and female fetuses affected by FGR. RNA-Seq data were analyzed to detect lncRNAs, their potential target genes and circular RNAs (circRNAs); a differential analysis was also performed. The multilevel bioinformatic analysis enabled the detection of 23,137 placental lncRNAs and 4263 of them were classified as novel. In FGR-affected female fetuses’ placentas (ff-FGR), among 19 transcriptionally active regions (TARs), five differentially expressed lncRNAs (DELs) and 12 differentially expressed protein-coding genes (DEGs) were identified. Within 232 differentially expressed TARs identified in male fetuses (mf-FGR), 33 encompassed novel and 176 known lncRNAs, and 52 DEGs were upregulated, while 180 revealed decreased expression. In ff-FGR ACTA2-AS1, lncRNA expression was significantly correlated with five DEGs, and in mf-FGR, 25 TARs were associated with DELs correlated with 157 unique DEGs. Backsplicing circRNA processes were detected in the range of H19 lncRNA, in both ff- and mf-FGR placentas. The performed global lncRNAs characteristics in terms of fetal sex showed dysregulation of DELs, DEGs and circRNAs that may affect fetus growth and pregnancy outcomes. In female placentas, DELs and DEGs were associated mainly with the vasculature, while in male placentas, disturbed expression predominantly affected immune processes.

Can Inflammatory Hematological Parameters be a Guide to Late-onset Fetal Growth Restriction?

To compare the rates obtained from hematological parameters in cases of late-onset idiopathic fetal growth restriction (FGR) with healthy pregnancies and to evaluate the effect on neonatal outcomes. The study group consisted of 63 pregnant women with late-onset idiopathic FGR and the control group consisted of 91 healthy pregnant women. The determined rates were calculated from the control hemograms of patients at 28 weeks. Both groups were compared for neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and other parameters. NLR, leukocyte and neutrophil levels were significantly higher in the FGR group (p<0.05). There was no significant difference in PLR, platelet and lymphocyte levels between the groups (p>0.05). To predict FGR, the best cut-off value of NLR was determined to be 4.11 with 56% sensitivity and 88% specificity values. Neutrophil, lymphocyte and platelet interactions have an important role in FGR development. Inflammation can be involved in the etiopathogenesis in late-onset FGR.

The role of insulin-like growth factor 2 receptor-mediated homeobox gene expression in human placental apoptosis, and its implications in idiopathic fetal growth restriction.

Fetal growth restriction (FGR) is caused by poor placental development and function early in gestation. It is well known that placentas from women with FGR exhibit reduced cell growth, elevated levels of apoptosis and perturbed expression of the growth factors, cytokines and the homeobox gene family of transcription factors. Previous studies have reported that insulin-like growth factor-2 (IGF2) interacts with its receptor-2 (IGF2R) to regulate villous trophoblast survival and apoptosis. In this study, we hypothesized that human placental IGF2R-mediated homeobox gene expression is altered in FGR and contributes to abnormal trophoblast function. This study was designed to determine the association between IGF2R, homeobox gene expression and cell survival in pregnancies affected by FGR. Third trimester placentas were collected from FGR-affected pregnancies (n = 29) and gestation matched with control pregnancies (n = 30). Functional analyses were then performed in vitro using term placental explants (n = 4) and BeWo trophoblast cells. mRNA expression was determined by real-time PCR, while protein expression was examined by immunoblotting and immunohistochemistry. siRNA transfection was used to silence IGF2R expression in placental explants and the BeWo cell-line. cDNA arrays were used to screen for downstream targets of IGF2R, specifically homeobox gene transcription factors and apoptosis-related genes. Functional effects of silencing IGF2R were then verified by β-hCG ELISA, caspase activity assays and a real-time electrical cell-impedance assay for differentiation, apoptosis and cell growth potential, respectively. IGF2R expression was significantly decreased in placentas from pregnancies complicated by idiopathic FGR (P < 0.05 versus control). siRNA-mediated IGF2R knockdown in term placental explants and the trophoblast cell line BeWo resulted in altered expression of homeobox gene transcription factors, including increased expression of distal-less homeobox gene 5 (DLX5), and decreased expression of H2.0-Like Homeobox 1 (HLX) (P < 0.05 versus control). Knockdown of IGF2R transcription increased the expression and activity of caspase-6 and caspase-8 in placental explants, decreased BeWo proliferation and increased BeWo differentiation (all P < 0.05 compared to respective controls). This is the first study linking IGF2R placental expression with changes in the expression of homeobox genes that control cellular signalling pathways responsible for increased trophoblast cell apoptosis, which is a characteristic feature of FGR.

NLRP7 is increased in human idiopathic fetal growth restriction and plays a critical role in trophoblast differentiation.

Fetal growth restriction (FGR) the leading cause of perinatal mortality and morbidity is highly related to abnormal placental development, and placentas from FGR pregnancies are often characterized by increased inflammation. However, the mechanisms of FGR-associated inflammation are far from being understood. NLRP7, a member of a family of receptors involved in the innate immune responses, has been shown to be associated with gestational trophoblastic diseases. Here, we characterized the expression and the functional role of NLRP7 in the placenta and investigated its involvement in the pathogenesis of FGR. We used primary trophoblasts and placental explants that were collected during early pregnancy, and established trophoblast-derived cell lines, human placental villi, and serum samples from early pregnancy (n = 38) and from FGR (n = 40) and age-matched controls (n = 32). Our results show that NLRP7 (i) is predominantly expressed in the trophoblasts during the hypoxic period of placental development and its expression is upregulated by hypoxia and (ii) increases trophoblast proliferation ([3H]-thymidine) and controls the precocious differentiation of trophoblasts towards syncytium (syncytin 1 and 2 and β-hCG production and xCELLigence analysis) and towards invasive extravillous trophoblast (2D and 3D cultures). We have also demonstrated that NLRP7 inflammasome activation in trophoblast cells increases IL-1β, but not IL-18 secretion. In relation to the FGR, we demonstrated that major components of NLRP7 inflammasome machinery are increased and that IL-1β but not IL-18 circulating levels are increased in FGR. Altogether, our results identified NLRP7 as a critical placental factor and provided evidence for its deregulation in FGR. NLRP7 inflammasome is abundantly expressed by trophoblast cells. It is regulated by a key parameter of placental development, hypoxia. It controls trophoblast proliferation, migration, and invasion and exhibits anti-apoptotic role. NLRP7 machinery is deregulated in FGR pregnancies. KEY MESSAGES: NLRP7 inflammasome is abundantly expressed by trophoblast cells. It is regulated by a key parameter of placental development, hypoxia. It controls trophoblast proliferation, migration, and invasion and exhibits anti-apoptotic role. NLRP7 machinery is deregulated in FGR pregnancies.

Thiol-disulfide homoestasis in pregnancies with fetal growth restriction

Aim: To investigate the role of dynamic thiol-disulfide homeostasis in preeclamptic and idiopathic fetal growth restricted (FGR) pregnancies.Material and method: In this prospective case-control study, a total of 110 singleton pregnancies with FGR (study group) (51 preeclamptic and 59 idiopathic FGR’s cases) were compared with 68 healthy pregnant controls at the same gestational weeks (control group). For serum disulfide-thiol homeostasis, a newly used method described by Erel and Neselioglu was used.Results: Serum native thiol and total thiol levels were lower in FGR pregnancies (285.63 ± 55.92 µmol/L, 324.41 ± 44.18 µmol/L, respectively) than control group (324.41 ± 44.18 µmol/L, 362.98 ± 51.43 µmol/L, p < .001, p = .004, respectively). In subgroup analysis, only preeclamptic FGR’s have lower native and total thiol levels (254.41 ± 59.55, 324.41 ± 44.18 µmol/L, respectively) compare to both idiopathic FGR’s and control’s. There was no difference in native and total thiol levels with idiopathic FGR’s with controls. Idiopathic FGR’s have higher levels of disulfide than preeclamptic FGR’s (21.72 ± 17.72 versus 16.80 ± 11.20 µmol/L). The serum albumin and total protein levels were positively and spot urine protein/creatinine ratio, 24-h urine protein levels were negatively correlated with native thiol and total thiol levels.Conclusion: The balance of thiol-disulfide homeostasis was shifted and native and total thiol levels were decreased only in preeclamptic FGR pregnancies. The serum disulfide level was increased in idiopathic FGR pregnancies compare to preeclamptic FGR pregnancies which may be a sign of oxidative stress in idiopathic FGR pregnancies with normal thiol pool.

Placental Vitamin D-Binding Protein Expression in Human Idiopathic Fetal Growth Restriction.

Vitamin D-binding protein is a multifunctional serum protein with multiple actions related to normal health. Vitamin D-binding protein transports vitamin D and influences the metabolism of this key hormone but it also has additional immunomodulatory and actin-clearing properties. We investigated whether vitamin D-binding protein expression is altered in fetal growth restriction-associated placental dysfunction. Protein was extracted from 35 placentae derived from 17 healthy control subjects and 18 gestation-matched subjects with fetal growth restriction (FGR). FGR subjects were further subdivided as idiopathic (n = 9) and nonidiopathic (n = 9). Vitamin D-binding protein and 25(OH) vitamin D were measured by ELISA and normalized to protein concentration. The results showed significantly reduced levels of placental vitamin D-binding protein (control versus FGR, p < 0.05, Student's t-test) that were strongly associated with idiopathic fetal growth restriction (p < 0.01, Kruskal-Wallis), whereas levels of vitamin D-binding protein were not associated with placental 25(OH) vitamin D stores (p = 0.295, Pearson's correlation). As such, vitamin D-binding protein may be a factor in unexplained placental dysfunction associated with idiopathic fetal growth restriction and may potentially serve as a biomarker of this disease.

Placental tryptophan metabolism and serotonin transport are disrupted in idiopathic human fetal growth restriction

Placental tryptophan metabolism and serotonin transport are disrupted in idiopathic human fetal growth restriction

Decreased placental vitamin D receptor contributes to aberrant cell-cycle gene regulation in human idiopathic fetal growth restriction

Decreased placental vitamin D receptor contributes to aberrant cell-cycle gene regulation in human idiopathic fetal growth restriction

Idiopathic Fetal Growth Restriction: Repercussion of Modulation in Oxidative Stress.

Oxidative stress has been proposed as one of the causes involved in idiopathic fetal growth restriction (IFGR). However, the exact relationship between oxidative stress and IFGR is not understood. This study aimed at understanding the role of oxidative stress and antioxidant status in IFGR materno-fetal dyads and matched controls. 75 materno-fetal dyads with IFGR were enrolled with equal number of normal low risk controls. Malondialdehyde (MDA) levels were measured as marker of oxidative stress, while paraoxonase-1 (PON1) activity and total antioxidant capacity (TAC) of serum were measured as markers of antioxidant status. MDA levels were increased in both maternal and cord blood of IFGR neonates as compared to controls (p<0.001). TAC of serum were found to be decreased in IFGR (both maternal and cord blood) as compared to controls (p<0.001; p<0.05, respectively). PON1 activity was found to be decreased in the IFGR mothers while it was found increased in IFGR cord blood (p<0.01; p<0.001)). IFGR is a state of increased oxidative stress. Decreased PON1 enzymatic activity in mothers is also associated with IFGR.

Placental vitamin D receptor expression is decreased in human idiopathic fetal growth restriction.

Fetal growth restriction (FGR) affects up to 5 % of pregnancies worldwide, and trophoblast function plays a significant role on the outcome. An epidemiological study has linked vitamin D deficiency to adverse perinatal outcomes, which include decreased birth weight. The placenta as an important source of vitamin D regulates its metabolism through the vitamin D receptor (VDR), but the mechanism by which VDR regulates trophoblast function is poorly understood. Our study aimed at determining placental VDR expression in FGR and gestation-matched control (GMC) pregnancies and identifying the actions of VDR in trophoblast differentiation and apoptosis. Placentae were collected from a well-defined cohort of idiopathic FGR and GMC pregnancies. VDR mRNA and protein expressions were determined by PCR, immunohistochemistry and immunoblotting, while functional consequences of VDR inactivation in vitro were determined on BeWo cells by determining changes in differentiation, attachment and apoptosis. Significant decreases in VDR mRNA expression (p = 0.0005) and protein expression (p = 0.0003) were observed in the FGR samples, while VDR inactivation, which showed markers for differentiation, cell attachment and apoptosis, was significantly increased. Thus, decreased placental VDR may contribute to uncontrolled premature differentiation and apoptosis of trophoblasts that are characteristics of idiopathic FGR pregnancies. Fetal growth restriction (FGR) affects up to 5 % of all pregnancies worldwide. FGR is the second highest cause of perinatal mortality and morbidity. The placenta plays a pivotal role in vitamin D metabolism during pregnancy. Vitamin D deficiency is associated with adverse pregnancy outcomes. Placental vitamin D receptor expression is decreased in FGR.

An EG-VEGF-Dependent Decrease in Homeobox Gene NKX3.1 Contributes to Cytotrophoblast Dysfunction: A Possible Mechanism in Human Fetal Growth Restriction.

Idiopathic fetal growth restriction (FGR) is frequently associated with placental insufficiency. Previous reports have provided evidence that endocrine gland-derived vascular endothelial growth factor (EG-VEGF), a placental secreted protein, is expressed during the first trimester of pregnancy, controls both trophoblast proliferation and invasion, and its increased expression is associated with human FGR. In this study, we hypothesize that EG-VEGF-dependent changes in placental homeobox gene expressions contribute to trophoblast dysfunction in idiopathic FGR. The changes in EG-VEGF-dependent homeobox gene expressions were determined using a homeobox gene cDNA array on placental explants of 8-12 wks gestation after stimulation with EG-VEGF in vitro for 24 h. The homeobox gene array identified a greater-than-five-fold increase in HOXA9, HOXC8, HOXC10, HOXD1, HOXD8, HOXD9 and HOXD11, while NKX 3.1 showed a greater-than-two-fold decrease in mRNA expression compared with untreated controls. Homeobox gene NKX3.1 was selected as a candidate because it is a downstream target of EG-VEGF and its expression and functional roles are largely unknown in control and idiopathic FGR-affected placentae. Real-time PCR and immunoblotting showed a significant decrease in NKX3.1 mRNA and protein levels, respectively, in placentae from FGR compared with control pregnancies. Gene inactivation in vitro using short-interference RNA specific for NKX3.1 demonstrated an increase in BeWo cell differentiation and a decrease in HTR-8/SVneo proliferation. We conclude that the decreased expression of homeobox gene NKX3.1 downstream of EG-VEGF may contribute to the trophoblast dysfunction associated with idiopathic FGR pregnancies.

Phenotypic expression and polymorphism of Glutathione S Transferase gene in materno-fetal dyads with idiopathic fetal growth restriction

IntroductionIncidence of fetal growth restriction (FGR) in India is quite high, and FGR has been found to be associated with various non-infectious diseases including coronary artery disease, diabetes mellitus and metabolic syndrome. Moreover, 40% of FGR is termed idiopathic (IFGR) for which cause is not known. Oxidative stress, which is postulated to have a role in FGR, is modulated by polymorphism of antioxidant genes. This study aims to examine association of GST polymorphism and enzymatic activity with incidence of FGR. Materials and methods150 unrelated live births participated as dyads (mother and neonate). 75 consecutive IFGR materno-fetal dyads (referred subsequently as IFGR mother and IFGR neonate) were recruited as cases. Polymorphic analysis of GSTT1 and GSTM1 were carried out by multiplex PCR. Glutathione-S-transferase activity in serum was measured using 1-chloro-2, 4-dinitrobenzene (CDNB) as substrate. ResultsIncidence of GSTT1 null type is significantly higher in IFGR fetus and their mothers (p < 0.01). Incidence of GSTM1 null type is significantly higher in IFGR fetus (p = 0.001). GST activity levels in mothers giving birth to IFGR babies was about 50% of the values found in the control group (p < 0.001). The GST activity levels in control group was found to be 50% higher than the FGR babies (p = 0.001). ConclusionOur results show that there is definite association between polymorphism of GST genes and incidence of IFGR. Simultaneously, our study also found a correlation between maternal GST activity and fetal weight.

Decorin: a possible marker for fetal growth restriction

The aim of this study was to compare decorin (DCN) levels between pregnancies complicated by idiopathic fetal growth restriction (FGR) and uncomplicated pregnancies and to determine the relationship between DCN levels and clinical parameters. The study population consisted of two groups: control group consisted of 13 women with uncomplicated singleton pregnancies in the third trimester. Study group consisted of 14 singleton pregnancies complicated by idiopathic FGR who were admitted to the hospital for delivery in the third trimester of pregnancy. Maternal and fetal DCN levels were measured. Color Doppler flow assessments were performed. Relationship between DCN levels and clinical parameters was determined. Maternal DCN serum levels were significantly higher in complicated pregnancies by idiopathic FGR (p = 0.01). A statistically significant negative correlation was observed between maternal DCN serum levels and neonatal birth weight (r = −0.0506; p = 0.007). There was a significant correlation between umbilical artery (UA) DCN levels and UA S/D ratio (r = 0.512; p = 0.006) and UA RI (r = 0.405; p = 0.036). The risk of high DCN maternal serum levels (>7986.6 pg/mL) in pregnancy complicated by FGR was 8.25 times higher (RR = 8.25; 95% CI, 1.4–46.8). The results of our study showed that the presence of increased DCN levels in women with FGR could contribute to pathogenesis of the disease.

Decreased VDR expression contributes to reduced feto-placental growth in idiopathic human fetal growth restriction

Decreased VDR expression contributes to reduced feto-placental growth in idiopathic human fetal growth restriction

Downstream targets of the homeobox gene DLX3 are differentially expressed in the placentae of pregnancies affected by human idiopathic fetal growth restriction

Human idiopathic fetal growth restriction (FGR) is associated with placental insufficiency. Previously, we reported that the expression of homeobox gene Distal-less 3 (DLX3) is increased in idiopathic FGR placentae and is a regulator of villous trophoblast differentiation. Here, we identify the downstream targets of DLX3 in trophoblast-derived cell lines. We modelled the high levels of DLX3 in FGR using an over-expression plasmid construct and complemented this using short-interference RNA (siRNA) for inactivation in cultured cells. Using a real-time PCR-based gene profiling, candidate target genes of DLX3 over-expression and inactivation were identified as regulators of trophoblast differentiation; GATA2 and PPARγ. The expression of GATA2 and PPARγ were further assessed in placental tissues and showed increased mRNA and protein levels in FGR-affected tissues compared with gestation-matched controls. We conclude that DLX3 orchestrates the expression of multiple regulators of trophoblast differentiation and that expression of these regulatory genes is abnormal in FGR.