Pathophysiology Of Fetal Growth Restriction Research Articles

First trimester maternal tryptophan metabolism and embryonic and fetal growth: the Rotterdam Periconceptional Cohort (Predict Study).

What is the association between first trimester maternal tryptophan (TRP) metabolites and embryonic and fetal growth? Higher 5-hydroxytryptophan (5-HTP) concentrations are associated with reduced embryonic growth and fetal growth and with an increased risk of small-for-gestational age (SGA), while higher kynurenine (KYN) concentrations are associated with a reduced risk of SGA. The maternal TRP metabolism is involved in many critical processes for embryonic and fetal growth, including immune modulation and regulation of vascular tone. Disturbances in TRP metabolism are associated with adverse maternal and fetal outcomes. This study was embedded within the Rotterdam Periconceptional Cohort (Predict Study), an ongoing prospective observational cohort conducted at a tertiary hospital from November 2010 onwards. A total of 1115 women were included before 11 weeks of gestation between November 2010 and December 2020. Maternal serum samples were collected between 7 and 11 weeks of gestation, and TRP metabolites (TRP, KYN, 5-HTP, 5-hydroxytryptamine, and 5-hydroxyindoleacetic acid) were determined using a validated liquid chromatography (tandem) mass spectrometry method. Serial 3D ultrasound scans were performed at 7, 9, and 11 weeks of gestation to accurately assess features of embryonic growth, including crown-rump length (CRL) and embryonic volume (EV) offline using virtual reality systems. Fetal growth parameters were retrieved from medical records and standardized according to Dutch reference curves. Mixed models were used to assess associations between maternal TRP metabolites and CRL and EV trajectories. Linear and logistic regression models were utilized to investigate associations with estimated fetal weight (EFW) and birthweight, and with SGA, respectively. All analyses were adjusted for potential confounders. Maternal 5-HTP concentrations and the maternal 5-HTP/TRP ratio were inversely associated with embryonic growth (5-HTP, √CRL: β = -0.015, 95% CI = -0.028 to -0.001; 5-HTP 3√EV: β = -0.009, 95% CI = -0.016 to -0.003). An increased maternal 5-HTP/TRP ratio was also associated with lower EFW and birthweight, and with an increased risk of SGA (odds ratio (OR) = 1.006, 95% CI = 1.00-1.013). In contrast, higher maternal KYN concentrations were associated with a reduced risk of SGA in the unadjusted models (OR = 0.548, 95% CI = 0.320-0.921). Residual confounding cannot be ruled out because of the observational design of this study. Moreover, this study was conducted in a single tertiary hospital, which assures high internal validity but may limit external validity. The novel finding that maternal 5-HTP concentrations are associated with a smaller embryo and fetus implies that disturbances of the maternal serotonin pathway in the first trimester of pregnancy are potentially involved in the pathophysiology of fetal growth restriction. The association between higher maternal KYN concentrations and a reduced risk of SGA substantiate the evidence that the KYN pathway has an important role in fetal growth. More research is needed to delve deeper into the potential role of the maternal TRP metabolism during the periconception period and pregnancy outcome for mother and offspring. This study was funded by the Department of Obstetrics and Gynecology and the Department of Clinical Chemistry of the Erasmus MC, University Medical Center, Rotterdam, the Netherlands. The authors have no competing interests to disclose. N/A.

The differential regulation of placenta trophoblast bisphosphoglycerate mutase in fetal growth restriction: preclinical study in mice and observational histological study of human placenta.

Fetal growth restriction (FGR) is a pregnancy complication in which a newborn fails to achieve its growth potential, increasing the risk of perinatal morbidity and mortality. Chronic maternal gestational hypoxia, as well as placental insufficiency are associated with increased FGR incidence; however, the molecular mechanisms underlying FGR remain unknown. Pregnant mice were subjected to acute or chronic hypoxia (12.5% O2) resulting in reduced fetal weight. Placenta oxygen transport was assessed by blood oxygenation level dependent (BOLD) contrast magnetic resonance imaging (MRI). The placentae were analyzed via immunohistochemistry and in situ hybridization. Human placentae were selected from FGR and matched controls and analyzed by immunohistochemistry (IHC). Maternal and cord sera were analyzed by mass spectrometry. We show that murine acute and chronic gestational hypoxia recapitulates FGR phenotype and affects placental structure and morphology. Gestational hypoxia decreased labyrinth area, increased the incidence of red blood cells (RBCs) in the labyrinth while expanding the placental spiral arteries (SpA) diameter. Hypoxic placentae exhibited higher hemoglobin-oxygen affinity compared to the control. Placental abundance of Bisphosphoglycerate mutase (BPGM) was upregulated in the syncytiotrophoblast and spiral artery trophoblast cells (SpA TGCs) in the murine gestational hypoxia groups compared to the control. Hif1α levels were higher in the acute hypoxia group compared to the control. In contrast, human FGR placentae exhibited reduced BPGM levels in the syncytiotrophoblast layer compared to placentae from healthy uncomplicated pregnancies. Levels of 2,3 BPG, the product of BPGM, were lower in cord serum of human FGR placentae compared to control. Polar expression of BPGM was found in both human and mouse placentae syncytiotrophoblast, with higher expression facing the maternal circulation. Moreover, in the murine SpA TGCs expression of BPGM was concentrated exclusively in the apical cell side, in direct proximity to the maternal circulation. This study suggests a possible involvement of placental BPGM in maternal-fetal oxygen transfer, and in the pathophysiology of FGR. This work was supported by the Weizmann Krenter Foundation and the Weizmann - Ichilov (Tel Aviv Sourasky Medical Center) Collaborative Grant in Biomedical Research, by the Minerva Foundation, by the ISF KillCorona grant 3777/19.

Placental proteome in late‑onset of fetal growth restriction.

Fetal growth restriction (FGR) occurs when the fetus does not reach its genetically programmed intrauterine potential for growth and affects ~5–10% of pregnancies. This condition is one of the leading causes of perinatal mortality and morbidity associated with obstetric and neonatal complications. Placental dysfunction in FGR causes an impairment in the transfer of nutrients and oxygen from the mother to the developing fetus. Maternal adaptations to placental insufficiency may also play a role in the pathophysiology of FGR. The present study aimed to compare the proteome of the placentas of 18 women with the physiological course of pregnancy and eutrophic fetus [estimated fetal weight (EFW) >10th percentile; control group] and 18 women with late FGR (EFW <10th percentile) diagnosed after 32 weeks of pregnancy, according to the Delphi consensus (study group). The U. Mann-Whitney test was used to compare two independent groups. The R. Spearman correlation coefficient significance test was used to assess the existence of a relationship between the analyzed measurable parameters. P<0.05 was considered to indicate a statistically significant difference. The tests showed the presence of 356 different proteins which were responsible for the regulation of gene transcription control, inhibiting the activity of proteolytic enzymes, regulation of trophoblast proliferation and angiogenesis and inflammatory response. In the FGR placental proteome, other detected proteins were mostly involved in response to oxidative stress, cellular oxidation and detoxication, apoptosis, hemostatic and catabolic processes, energy transduction protein interactions, cell proliferation, differentiation and intracellular signaling. The present study used chromatographic mass-spectrometry to compare the placental proteome profiles in pregnancies complicated by late-onset FGR and normal pregnancy. Comparative analysis of proteomes from normal and FGR placentas showed significant differences. Further research is needed to clarify maternal and fetal adaptations to FGR.

Placental expression of miR-517-5p and miR-518f-5p: Fetal sex-specific relations with human fetoplacental growth

ObjectiveWe aimed to assess association of chromosome 19 miRNA cluster microRNAs (miR-517-5p and miR-518f-5p) expression with maternal, placental and newborn parameters and with their potential angiogenesis-associated target genes ENG, VEGF and FLT in a set of 68 small- (SGA, n = 30) and appropriate- (AGA, n = 38) for gestational age full-term singleton pregnancies, in relation to fetal sex. Study designIn this retrospective case-control study, placental transcript abundances of miR-517-5p and miR-518f-5p were assessed by real-time quantitative PCR after normalization to reference miRNA, mir-16-5p. Placental transcript abundances of VEGF, FLT and ENG were assessed after normalizing to a set of reference genes. ResultsPlacental miR-517-5p transcript abundance was negatively associated with birth weight [β = −88.778, P = 0.006, 95% confidence interval (CI): −151.645, −25.911] and placental weight (β = −14.683, P = 0.007, 95% CI: −25.254, −4.112) and this association with birth weight was specific to the AGA births (β = −59.207, P = 0.037, 95% CI: −114.522, −3.891). miR-518f-5p transcript abundance was negatively associated with placental weight (β = −6.250, P = 0.034, 95% CI: −11.940, −0.559) specifically in the AGA male births (n = 16). Placental VEGF transcript abundance was negatively associated with that of miR-517-5p specifically in SGA female births (n = 14; Spearman's ρ = −0.705, P = 0.005) and with miR-518f-5p transcript abundance specifically in SGA births (Spearman's ρ = −0.437, P = 0.016) and in SGA male births (n = 16; Spearman's ρ = −0.516, P = 0.041). ConclusionWe conclude that placental miR-517-5p could be playing a key role in the pathophysiology of fetal growth restriction, which can be potentially targeted through maternal lifestyle modifications for improving fetoplacental growth.

Physiopathology of late-onset fetal growth restriction.

Fetal growth restriction (FGR) is defined as the inability of the fetus to reach its potential for genetic determination. FGR can have several causes, including genetic syndromes, chromosomal diseases, and infections; however, a vast majority of cases are probably attributed to impaired uterine and placental circulation. The relationships between abnormal placental development and FGR are complex, and studies are generally few, presenting confounding factors. Damage to the uteroplacental circulation associated with vasculogenesis and villus angiogenesis dysfunction are the main factors involved in subsequent FGR. The main receptors involved in FGR include hypoxia-inducible factor (HIF 1, 2, and 3), vascular endothelial growth factor (VEGF), placental growth factor (PlGF), vascular endothelial growth factor C (VEGF-C), soluble Flt-1, soluble endoglin (Seng), angiopoietin-1 and -2 (Ang-1 and Ang-2), tyrosine kinase receptor 1 (Flt-1), tyrosine kinase receptor 2 (Flt-2), vascular endothelial growth factor receptor (VEGFR) 1, 2 and 3, kinase domain receptor (KDR), and vascular endothelial growth factor receptor A (VEGFR-A). Furthermore, failure in trophoblastic invasion and remodeling of spiral arteries has been associated with FGR owing to poor placental perfusion. There are several possible causes for poor remodeling of spiral arteries, which probably vary on a case-to-case basis. Changes in the placental form, macroscopic and microscopic vascular lesions, inflammation, and genetic changes are also related to FGR. Based on gestational age at diagnosis, FGR can be classified as early- (˂32 weeks) and late-onset (≥32 weeks). Moreover, there exist several theories regarding possible pathophysiological differences between early- and late-onset FGR, with some postulating that it the same disease but at different stages or severity. Another hypothesis suggests that the change in the trophoblastic invasion of spiral arteries would be milder. In this article, we address the main mechanisms described in the pathophysiology of FGR and, later, the specific findings in late-onset FGR.

Upregulation of ENDOU in cytotrophoblasts from placenta complicated with preeclampsia and fetal growth restriction.

Placental hypoplasia is associated with the pathophysiology of fetal growth restriction and preeclampsia. The placenta consists of differentiated trophoblasts, including cytotrophoblasts, syncytiotrophoblasts, and extravillous trophoblasts. Cytotrophoblasts are thought to have stem-like characteristics and the ability to differentiate into syncytiotrophoblasts and extravillous trophoblasts. However, it is poorly understood whether isolated cytotrophoblasts derived from hypoplastic placentas have specific features compared with those in normal placentas. This study aimed to determine the features of cytotrophoblasts in hypoplastic placentas. Differentially expressed proteins between isolated cytotrophoblasts from hypoplastic placenta with fetal growth restriction and those from the normal placenta were determined by liquid chromatography-tandem mass spectrometry. Among 6,802 proteins, 1,253 and 2,129 proteins were more than 2-fold upregulated and downregulated, respectively. Among them, ENDOU (endonuclease, poly(U) specific), which has high homology with the coronavirus endoribonuclease nonstructural protein 15 (Nsp15), showed a significantly increased expression in cytotrophoblasts from the placenta with fetal growth restriction related to preeclampsia compared with those in normal control placenta. These results provide insight into the pathological mechanisms of placental hypoplasia and additional information on preeclamptic symptoms in cases of SARS-CoV-2 infected placenta, although further investigation is needed.

Aurora kinase mRNA expression is reduced with increasing gestational age and in severe early onset fetal growth restriction

IntroductionOxidative damage and biochemical ageing are implicated in placental dysfunction and potentially fetal death. Cellular senescence may play a role in the pathophysiology of fetal growth restriction (FGR) and preeclampsia (PE). Aurora kinases (AURKA, B and C) are important regulators of cellular division in mitosis and meiosis with implications in cellular senescence. We aimed to investigate whether aurora kinase expression is altered with placental dysfunction or placental ageing. MethodsPlacenta and blood was obtained across gestation from pregnancies complicated by PE, FGR or both PE and FGR, as well as gestation-matched control samples. Expression of AURKA, B and C mRNA was examined using real time qPCR in both the placenta and maternal circulation. ResultsPlacental aurora kinase expression decreased as gestation progressed: AURKA and AURKB were significantly reduced at 37–40 weeks, whereas AURKC was significantly reduced at 34–37 weeks, when compared to <34 weeks. In the maternal circulation, the mRNA level of AURKB was significantly reduced at >40 weeks compared to <34 weeks gestation. A significant reduction in AURKC was seen in FGR pregnancies <34 weeks compared to gestation-matched controls. ConclusionPlacental AURK expression is reduced with increased gestation. Circulating AURKB mRNA reduces at >40 weeks gestation, when compared to <34 weeks. AURKC is significantly reduced in placentas from pregnancies complicated by severe early onset (<34 weeks) FGR compared with gestation-matched controls. The functional role of aurora kinase in the placenta and in gestational age warrants further investigation.

Serum zinc, selenium, iron, and copper levels in pregnant women with fetal growth restriction

Background: Fetal growth restriction is associated with many adverse effects and increases the risk of perinatal mortality by more than ten-fold. Zinc, selenium, iron, and copper have important roles in cell proliferation, inflammation, and oxidative stress which possibly serve as the basis for development of fetal growth restriction. Objective: To compare serum zinc, selenium, iron, and copper plasma levels between normal pregnancies and pregnancies with fetal growth restriction. Materials and Methods: The present was a cross-sectional study conducted at Obstetrics Emergency Unit of Cipto Mangunkusumo Hospital Jakarta from February until May 2017. Normal pregnant women and pregnant women with fetal growth restriction were recruited in this study. Maternal blood samples were taken before labor, and serum zinc, selenium, iron, and copper levels measurements were done. Results: Thirty normal pregnancies and 30 pregnancies with fetal growth restriction were enrolled in this study. Mean serum zinc, selenium, iron, and copper levels in normal pregnancy were 42.07 µg/dL, 69.80 µg/L, 70.50 µg/dL, and 2177 µg/L, respectively. Meanwhile, mean serum zinc, selenium, iron, and copper levels in pregnancy with fetal growth restriction were 43.53 µg/dL, 80.83 µg/L, 106 µg/dL, and 2,133.5 µg/L, respectively. There were significant differences in serum selenium concentrations (p = 0.013) and serum iron concentrations (p = 0.009) between the two groups. There were no significant differences in serum zinc and copper levels between both groups. Conclusion: Serum selenium and iron levels were higher in pregnancies with fetal growth restriction. Conclusion: The present study indicates the significant roles of micronutrients and oxidative stress in the pathophysiology of fetal growth restriction.

Maternal Erythrocyte ENT1-Mediated AMPK Activation and Oxygen Delivery: A Missing Component Counteracting Placental Hypoxia, Dysfunction, and Fetal Growth Restriction

Background: Insufficient oxygen supply is associated with the pathophysiology of fetal growth restriction (FGR). Although the erythrocyte (RBC) is the most abundant and only cell type to deliver oxygen, its function and regulatory mechanism in FGR remains unknown. Recently, adenosine uptake by equilibrative nucleoside transporter 1 (ENT1), a key adenosine transporter expressed in RBCs, was reported to be crucial for RBCs to deliver oxygen. We aimed to investigate the involvement of RBCs' oxygen delivering capacity in maintaining fetal growth by focusing on RBC ENT1. Methods and Results: The mating strategy was to delete ENT1 only on the maternal RBCs but not in the placentas or fetuses to assess the effect of maternal RBC ENT1 on fetal growth. Specifically, EpoR-Cre+ (EPO) female mouse was used as a control and Ent1f/f-EpoR-Cre+ (E1FE) female mouse as an experimental mouse and mated with WT male mouse. As a result, E1FE dams showed FGR phenotype with reduction of 12.9% in fetal weight compared to EPO group. The maternal RBCs showed decrease in p50 and 2,3-BPG in E1FE, indicating decreased oxygen delivery in E1FE RBCs. To determine the molecular basis underlying the FGR phenotype seen in EIFE dams, we conducted a metabolomics screening of the RBCs isolated from controls and EIFE dams. It showed that adenosine metabolism inside the RBCs is the most impacted pathway. Specifically, it showed decrease in adenosine, AMP, and hypoxanthine, but adenine, ADP, and ATP did not show any reduction, implicating that ENT1-mediated uptake of adenosine is largely converted to AMP. We then incubated either WT or ENT1 KO RBCs with isotopically 13C15N labeled adenosine and traced the metabolism of intracellular adenosine derived from labeled adenosine. Indeed, adenosine was rapidly phosphorylated to AMP upon uptake, and 13C15N labeled AMP levels were lower in the ENT1 KO RBCs compared to controls. These findings provide evidence that 1) the most affected metabolic pathway in the RBCs of EIFE dam is adenosine metabolism; 2) ENT1-mediated uptake of extracellular adenosine is largely converted to AMP but not ATP. We hypothesized that decreased AMP/ATP ratio underlies the reduced 2,3-BPG production by lowering AMPK activity and subsequently decreasing BPG mutase (BPGM) activity. We measured AMPK phosphorylation and BPGM activity in the RBCs from E1FE and EPO dams. Both AMPK and BPGM activity were decreased in RBCs of E1FE dams compared to controls. Thus, we conclude that i) adenosine derived from uptake via ENT1 is largely converted to AMP; ii) lack of maternal RBC ENT1 lowers AMP/ATP ratio and activity of AMPK and BPGM in maternal RBC. We conducted immunofluorescence staining to assess hypoxia in the placentas, and confirmed the increased expression of HIF-1α in the placentas from E1FE dams. To determine functional changes of these placentas, we conducted metabolomics profiling in both the placenta and maternal plasma. Of all the metabolites altered, amino acids (AA) were the most reduced metabolites in E1FE placentas. In contrast, AA were the most accumulated in maternal plasma. We then injected isotopically labelled 13C15N AA mix in both controls and EIFE dams 24 hours prior to sacrifice. 13C15N AA level was decreased in the placentas in EIFE compared to the controls, while it was accumulated in plasma of EIFE, indicating reduced AA transporter function in the placentas of EIFE. Finally, we performed real time PCR to quantify the mRNA of the known main transporters of AA in the mouse placenta. It showed reduction of LAT1 mRNA in E1FE placenta, where there was no difference in LAT2, SNAT1, or SNAT2. Western blot of the placenta lysates confirmed the expression of LAT1 was indeed reduced. To validate our mouse finding and determine if HIF-1α elevation directly induces LAT1 mRNA in humans, we treated cultured human trophoblast cell line (HTR-8/SVneo cells) with or without DMOG, a cell permeable prolyl-4-hydroxylase inhibitor. After confirming DMOG upregulated HIF-1α, we found stabilized HIF-1α induced LAT1 mRNA levels. Thus, we conclude that elevated HIF-1α underlies the reduction of LAT1 mRNA in cultured human trophoblasts. Conclusion: Our findings suggest that maternal RBCs' oxygen delivering capacity mediated by ENT1 is essential for maintaining adequate placental oxygenation to support fetal growth via AA transporter function. Strategies to improve RBCs' function to deliver oxygen may provide new therapeutic possibilities for FGR. Figure Disclosures No relevant conflicts of interest to declare.

Is there a role for placental senescence in the genesis of obstetric complications and fetal growth restriction?

The placenta ages as pregnancy advances, yet its continued function is required for a successful pregnancy outcome. Placental aging is a physiological phenomenon; however, there are some placentas that show signs of aging earlier than others. Premature placental senescence and aging are implicated in a number of adverse pregnancy outcomes, including fetal growth restriction, preeclampsia, spontaneous preterm birth, and intrauterine fetal death. Here we discuss cellular senescence, a state of terminal proliferation arrest, and how senescence is regulated. We also explore the role of physiological placental senescence and how aberrant placental senescence alters placental function, contributing to the pathophysiology of fetal growth restriction, preeclampsia, spontaneous preterm labor/birth, and unexplained fetal death.

Placental expression of the insulin receptor binding protein GRB10: Relation to human fetoplacental growth and fetal gender

IntroductionImprinted genes play an important role in mammalian fetoplacental growth and development. We have evaluated whether the placental expression of two imprinted genes, growth factor receptor-binding protein 10 (GRB10) and pleckstrin homology-like domain, family A, member 2 (PHLDA2) correlate with human fetoplacental growth parameters. MethodsPlacentae (n = 77) were collected from small- (SGA) and appropriate- (AGA) for gestational age full-term singleton pregnancies (n = 36 SGA and 41 AGA). Placentae and neonates were weighed at birth. Realtime quantitative PCR was performed to assess placental transcript abundance of GRB10 and PHLDA2 normalized to a panel of reference genes. ResultsPlacental GRB10 transcript abundance associated positively with placental weight (r = 0.307, P = 0.007), birth weight (r = 0.267, P = 0.019) and neonatal head circumference (r = 0.280, P = 0.014). Placental GRB10 transcript levels were significantly lower in male SGA placentae compared to the male AGA placentae. Placental PHLDA2 transcript abundance did not show any associations with maternal, placental or neonatal parameters. DiscussionPlacental GRB10 expression was found to be associated positively with placental weight, birth weight, and neonatal head circumference, especially in males. Hence, we speculate that placental GRB10 plays a role in regulating fetoplacental growth and thereby in the pathophysiology of fetal growth restriction in the context of fetal gender.

Abnormal pressure-wave reflection in pregnant women with chronic hypertension: association with maternal and fetal outcomes.

The current study tested the hypothesis that abnormal pressure-wave reflection may have an important role in identifying pregnant women with chronic hypertension who might develop pre-eclampsia (PE) and/or fetal growth restriction. Pulse-wave analyses were performed to assess maternal arterial stiffness during 26-32 weeks of gestation in 41 women with chronic hypertension. We measured the central systolic pressure (CSP) and augmentation index (AIx) noninvasively using pulse waveforms of the radial artery with an automated applanation tonometric system. In a multiple regression analysis that included AIx-75 (AIx at a heart rate of 75 beats per minute), brachial systolic pressure, maternal height, smoking status, gestational age at testing and the presence of antihypertensive treatment at testing as independent determinants, AIx-75 was the only significant determinant of birth weight, whereas the brachial systolic pressure was not. In pregnant women with chronic hypertension who subsequently developed both superimposed PE and fetal growth restriction, CSP, AIx, AIx-75, and the brachial systolic and pulse pressures were all significantly higher than those who did not develop superimposed PE nor small for gestational age. In contrast, AIx-75 was the only significantly elevated hemodynamic parameter in patients who developed fetal growth restriction but not superimposed PE. In addition, CSP was the only significantly elevated hemodynamic parameter in patients who developed superimposed PE but not fetal growth restriction. Abnormal pressure-wave reflection during 26-32 weeks of gestation showed a stronger correlation with birth weight than conventional brachial blood pressure. Our findings might provide new insight into the pathophysiology of fetal growth restriction as well as superimposed PE in pregnancies complicated with chronic hypertension.

Inhibition of peroxisome proliferator-activated receptor γ: a potential link between chronic maternal hypoxia and impaired fetal growth.

Chronic exposure to hypoxia raises the risk of pregnancy disorders characterized by maternal vascular dysfunction and diminished fetal growth. In an effort to identify novel pathways for these hypoxia-related effects, we assessed gene expression profiles of peripheral blood mononuclear cells (PBMCs) obtained from 43 female, high-altitude or sea-level residents in the nonpregnant state or during pregnancy (20 or 36 wk). Hypoxia-related fetal growth restriction becomes apparent between 25 and 29 wk of gestation and continues until delivery. Our sampling strategy was designed to capture changes occurring before (20 wk) and during (36 wk) the time frame of slowed fetal growth. PBMC gene expression profiles were generated using human gene expression microarrays and compared between altitudes. Biological pathways were identified using pathway analysis. Modest transcriptional differences were observed between altitudes in the nonpregnant state. Of the genes that were differentially expressed at high altitude vs. sea level during pregnancy (20 wk: 59 probes mapped to 41 genes; 36 wk: 985 probes mapped to 700 genes), several are of pathological relevance for fetal growth restriction. In particular, transcriptional changes were consistent with the negative regulation of peroxisome proliferator-activated receptor γ (PPARγ) at high altitude; such effects were accompanied by reduced birth weight (P <0.05) and head circumference (P <0.01) at high altitude vs. sea level. Our findings indicate that chronic exposure to hypoxia during pregnancy alters maternal gene expression patterns in general and, in particular, expression of key genes involved in metabolic homeostasis that have been proposed to play a role in the pathophysiology of fetal growth restriction.

Assessment of Redox Imbalance in Idiopathic Fetal Growth Restricted Pregnancies

Background: Fetal growth restriction (FGR) is one of the most significant causes of perinatal morbidity and mortality. The known causes are poor maternal nutrition, hypertensive disorders complicating pregnancy, maternal medical disorders (multiple pregnancy, congenital fetal malformations), and lifestyle influences. However, in vast majority of cases, the cause still remains unknown. Recent studies have suggested the role of oxidative stress in the pathophysiology of FGR. The aim of this study was to evaluate non-enzymatic oxidative stress biomarkers in maternal and cord blood of idiopathic FGR cases. Methods: A total of 100 women subjects aged 18 to 35 years, who fulfilled the recruitment criteria, were enrolled in the study after taking an informed written consent. Non-enzymatic oxidative stress was measured by the quantification of 8-hydroxy-2-deoxy-guanosine (8-OHdG), malondialdehyde (MDA), protein carbonyl, reduced glutathione (GSH) and ferric reducing ability of plasma (FRAP) in maternal and cord blood samples of FGR pregnancies of idiopathic origin and compared with those of normal healthy mother-infant pairs. Results: The levels of 8-OHdG, MDA and protein carbonyl were significantly higher in the ‘idiopathic’ FGR group as compared to the controls, where as the GSH and FRAP were significantly lower. Conclusion: Increased oxidative stress has been found significantly associated with the increased risk of developing idiopathic FGR.

Birthweight placental weight ratio of appropriate‐for‐dates and light‐for‐dates infants in preterm delivery

Although birthweight placental weight ratio (BPR) may be a promising indicator which reflects pathophysiology of fetal growth restriction (FGR), the standard of BPR changes throughout gestation in a Japanese population has not been established as far as we know. Therefore, we first examined BPR of appropriate-for-dates (AFD) infants in each gestational week in preterm deliveries. We then compared it with that in a group of light-for-dates (LFD) infants born from mothers with and without pregnancy-induced hypertension (PIH). Placentas of a singleton pregnancy with 373 AFD and 110 LFD infants delivered from 22 to 36weeks of gestation in our hospital during the period between September 2000 and December 2008 were included. We examined the placental weight and BPR of each gestational week in AFD and LFD groups. And the mean BPR and placental weight in the three groups (AFD: LFD with PIH: LFD without PIH) were compared according to gestational periods. The placental weight and BPR were significantly correlated to the gestational week both in AFD and LFD groups. We found that although the mean BPR in LFD-PIH(-) group was significantly lower than those both in AFD group and in LFD-PIH(+) group in 22-29weeks, the mean BPR in 30-36weeks was not statistically different among these three groups. Our result in the AFD group may be useful as one of the standards of BPR changes throughout gestation in a Japanese population for future studies. We believe that BPR may be a clinically useful indicator which reflects pathophysiology of FGR.

Loss of imprinting and aberrant methylation of IGF2 in placentas from pregnancies complicated with fetal growth restriction

The objective of this study was to investigate the hypothesis that the altered epigenetic mechanisms that regulate IGF2 imprinting in placentas from fetal growth restricted (FGR) pregnancies affect IGF2 expression leading to impaired fetal growth. We investigated gene transcription, genotyping and the methylation patterns of IGF2 from 31 and 17 placentas from FGR-complicated and normal pregnancies, respectively. A statistically significant decrease in IGF2 mRNA levels was observed in the placentas from the FGR pregnancies. Loss of imprinting (LOI) was only detected in the abnormal placentas. The evaluation of the percentage of the methylated reference (PMR) of two different potentially differentially methylated regions (DMR) demonstrated significant PMR values in both sites for the normal and FGR pregnancies with no significant differences. Our results suggest the involvement of the IGF2 imprinted gene in placental function and fetal growth and the possible association of epigenetic alterations with the pathophysiology of fetal growth restriction.

Hypomethylation along with increased H19 expression in placentas from pregnancies complicated with fetal growth restriction

The expression of imprinted genes is regulated by epigenetic modifications, such as DNA methylation. Many imprinted genes are expressed in the placenta and affect nutrient transfer capacity of the placental exchange barrier. The H19 gene is abundantly expressed by the human placenta and is implicated in the pathogenesis of congenital growth disorders such as Beckwith-Wiedemann (BWS) and Silver-Russell (SRS) syndromes. The aim of this study was to investigate the role of DNA methylation on H19 transcription and imprinting, in the pathophysiology of fetal growth restriction (FGR). Thirty one and 17 placentas from FGR-complicated and normal pregnancies were collected, respectively. We studied gene transcription, genotyping and methylation analysis of the AluI H19 on exon 5 polymorphism. Placental expression levels of H19 were significantly increased in the FGR group. The H19 mRNA levels were similar between normal placental samples that demonstrated loss and maintenance of imprinting. Placentas from growth-restricted pregnancies had lower methylation levels compared to normals, in the H19 promoter region. We have demonstrated an increased H19 transcription in the FGR group of placentas. The hypomethylation of the H19 promoters is compatible with the aberrant expression. The association of these two findings is reported for the first time in placental tissues, however, its significance remains unknown. Whether the results of this study represent an adaptation of the placenta to hypoperfusion, or they are part of FGR pathophysiology has to be further investigated.

Pathophysiology of fetal growth restriction: implications for diagnosis and surveillance.

Normal fetal growth depends on the genetically predetermined growth potential and is modulated by fetal, placental, maternal, and external factors. Fetuses with intrauterine growth restriction (IUGR) are at high risk for poor short- and long-term outcome. Although there are many underlying etiologies, IUGR resulting from placental insufficiency is most relevant clinically because outcome could be altered by appropriate diagnosis and timely delivery. A diagnostic approach that aims to separate IUGR resulting from placental disease from constitutionally small fetuses and those with other underlying etiologies (e.g., aneuploidy, viral infection, nonaneuploid syndromes) needs to integrate multiple imaging modalities. In placental-based IUGR, cardiovascular and behavioral responses are interrelated with the disease severity. Ultrasound assessment of fetal anatomy, amniotic fluid volume, and growth is complementary to the Doppler investigation of fetoplacental blood flow dynamics. A diagnostic approach to IUGR combining these modalities is presented in this review. Obstetricians & Gynecologists, Family Physicians. After completion of this article, the reader should be able to describe the development of the placental interface, to outline the mechanisms of placental insufficiency, and to list the manifestations of placental insufficiency and the tests that can be used to diagnose fetal growth restriction.

CURRENT CONCEPTS OF FETAL GROWTH RESTRICTION

In Brief Objective To update basic concepts and management strategies of fetal growth restriction (FGR). Data source An English literature search was conducted for pertinent articles related to FGR from 1976 to 1997. Original research articles, review articles, and book chapters were reviewed. Methods of study selection This study was divided into two parts. For this article, both human data and animal data pertinent to understanding causative factors, pathogenesis, clinical type, and pathophysiology were included. To perform a meaningful comparison, the concept of investigators and their methods of investigation were critically compared between the two study periods: 1976–1985 and 1986–1997. Tabulation, integration, and results Older concepts involving basic principles of FGR based on animal models during the first study period were integrated with new research findings obtained from human FGR during the second study period. By comparative analysis of older animal data and new human data, current concepts of FGR were synthesized. Conclusion Fetal growth restriction affects a heterogenous group of infants. Despite development of new technology for investigation, many older basic concepts related to FGR are still fundamentally sound. However, new investigations directly performed on human fetuses are a useful expansion of the older concepts. Current concepts involving pathogenesis and pathophysiology of fetal growth restriction are a useful expansion of older basic concepts.