Vascular Intrauterine Growth Restriction Research Articles

Vasculoplacental complications in pregnant women with HIV infection: a case-control study

Data from the international literature suggest that there may be an association between maternal human immunodeficiency virus (HIV) infection and vasculoplacental complications during pregnancy. Studies on this subject have reached discordant conclusions. The aim of this study was to assess the incidence of vasculoplacental complications during pregnancy in women with and without HIV infection. This single-center case-control study compared the incidence of pregnancy-related hypertension, preeclampsia, eclampsia, and vascular intrauterine growth restriction in 280 women with HIV and 560 women not infected with HIV, matched for age, parity, and geographic origin. The incidence rates of pregnancy-related hypertension, preeclampsia, eclampsia, and vascular growth restriction did not differ between the women with and without HIV infection. The overall incidence of vasculoplacental complications did not differ between the 2 groups (7.5% vs 9.8%, respectively; P = .27). The risk of these was not associated with exposure to antiretroviral treatments, viral load, or CD4 T-cell counts at the beginning of pregnancy. This study shows no difference in the incidence of vasculoplacental complications between women with and without HIV infection.

Transcriptomic analysis of human placenta in intrauterine growth restriction.

Intrauterine growth restriction (IUGR) is a frequent complication of pregnancy defined as a restriction of fetal growth. The objective of this work was to improve the knowledge on the pathophysiology of IUGR using a genome-wide method of expression analysis. We analyzed differentially expressed genes in pooled placental tissues from vascular IUGR (four pools of three placentas) and normal pregnancies (four pools of three placentas) using a long nucleotide microarray platform (Nimblegen). We first did a global bioinformatics analysis based only on P value without any a priori. We secondly focused on "target" genes among the most modified ones. Finally, reverse transcription quantitative polymerase chain reaction (RT-qPCR) was performed on an extended panel of tissue samples (n = 62) on selected "target". We identified 636 modified genes among which 206 were upregulated (1.5 and higher; P < 0.05). Groups of patients were classified unambiguously. Genes involved in mitochondrial function and oxidative phosphorylation were decreased affecting three out of five complexes of the respiratory chain of the mitochondria, and thus energy production and metabolism. Among the most induced genes, we identified LEP, IGFBP1, and RBP4. Complementary studies on the role and function of LEP, IGFBP1, and RBP4 in IUGR pathophysiology and also in fetal programming remain necessary.

Enhanced prevalence of plasmatic soluble MHC class I chain-related molecule in vascular pregnancy diseases.

The major histocompatibility complex class I related chain (MIC) is a stress-inducible protein modulating the function of immune natural killer (NK) cells, a major leukocyte subset involved in proper trophoblast invasion and spiral artery remodeling. Aim of the study was to evaluate whether upregulation of soluble MIC (sMIC) may reflect immune disorders associated to vascular pregnancy diseases (VPD). sMIC was more frequently detected in the plasma of women with a diagnostic of VPD (32%) than in normal term-matched pregnancies (1.6%, P < 0.0001), with highest prevalence in intrauterine fetal death (IUDF, 44%) and vascular intrauterine growth restriction (IUGR, 39%). sMIC levels were higher in preeclampsia (PE) than in IUFD (P < 0.01) and vascular IUGR (P < 0.05). sMIC detection was associated with bilateral early diastolic uterine notches (P = 0.037), thrombocytopenia (P = 0.03), and high proteinuria (P = 0.03) in PE and with the vascular etiology of IUGR (P = 0.0038). Incubation of sMIC-positive PE plasma resulted in downregulation of NKG2D expression and NK cell-mediated IFN-γ production in vitro. Our work thus suggests that detection of sMIC molecule in maternal plasma may constitute a hallmark of altered maternal immune functions that contributes to vascular disorders that complicate pregnancy, notably by impairing NK-cell mediated production of IFN-γ, an essential cytokine favoring vascular modeling.

OS047. Quantification of placental vascularization in a rabbit model ofIUGR with three-dimensional power doppler angiography

Placental dysfunction is known to be a major cause of pregnancy complications, such as perinatal loss, preeclampsia, and intrauterine growth restriction (IUGR). Inadequate remodeling of the spiral arteries resulting in decreased blood flowto the placenta has been implicated in the pathophysiology of preeclampsia and IUGR. 3D power Doppler angiography (PDA) is a noninvasive and safe way to study blood flow within an organ or region of interest. The aim of this study was to evaluate PDA as a method to quantify placental perfusion in a pharmacological rabbit model of vascular IUGR induced by inhibition of NO synthesis. Our objective was to evaluate the 3D power Doppler angiography (PDA) in terms of feasibility and ability to detect placental hypo-perfusion in an experimental rabbit model of intrauterine growth restriction (IUGR). Fourteen pregnant females were treated with NG-nitro-L-arginine methylester (L-NAME), a nitric oxide synthase inhibitor, from day 24 to day 28 of gestation, to induce an IUGR. Concomitantly, 8 pregnant rabbits were used as controls. On day 28, 3D power Doppler indices were quantified in each uteroplacental unit. A total number of 180 live fetuses were obtained, 180 from the L-NAME group and 72 from the control group. G28 fetal weight was significantly lower in the L-NAME group than in the control group (27.40±0.55g vs 33.14±0.62g,p<0.0001). In the L-Name group the vascularization index (VI) was significantly lower than in the control group (2.6 [1.4;6.0] vs 7.6 [3.5;12.6],p<0.05). Similar results were obtained for the Flow Index (FI) and the Vascularization Flow Index (VFI). The number of fetuses considered as small for gestational age (SGA;weight<10th centile) was significantly higher in the L-NAME group than in the control group (47/108 vs 7/72,p<0.0001). The VI was significantly lower in the SGA group than in the eutrophic group (3.46 [0.46;5.9] vs 7.50 [4.22;10.9] p<0.05). Similar results were obtained for FI and VFI. This experiment study demonstrates that quantitative 3D PDA indices are sensitive enough to detect placental vascular insufficiency in an experimental model of IUGR.

Effects of Antenatal Uteroplacental Hypoperfusion on Neonatal Microvascularisation and Excitotoxin Sensitivity in Mice

Vascular intrauterine growth restriction (IUGR) occurs in about 5% of pregnancies and may reduce the incidence of periventricular leukomalacia in preterm newborns. We evaluated neonatal excitotoxicity in a murine model of vascular IUGR involving unilateral uterine ligation on embryonic day (E)13.5. Birth weight was significantly decreased in the ligation group compared with the sham group (p < 0.001). VEGFs, VEGF receptors (VEGFRs), and NMDA receptor subunit mRNAs in brain extracts were assayed using quantitative RT-PCR. Ligation was associated with increased mRNAs for the vascular marker PECAM-1 on postnatal day (PD)2 and VEGFR-3 on PD2 and PD10, contrasting with decreased VEGFA and VEGFC on PD10. Microvessel density was increased on PD7. Ligated and sham pups received intracerebral ibotenate (NMDA agonist) on PD2 or PD10. Cortical and white matter (WM) lesions after 5 d were reduced in ligated versus sham pups injected on PD2 (p < 0.001 and p < 0.01, respectively); this effect persisted on PD42 (p < 0.01 and p < 0.05, respectively). With ibotenate on PD10, lesions were exacerbated after 5 d in the ligated group in the cortex (p < 0.05) and WM (p < 0.05) and on PD42 in the cortex (p < 0.05). In conclusion, vascular IUGR offered only transient protection against neonatal excitotoxic lesions, possibly via angiogenesis.

Combination of promoter hypomethylation and PDX1 overexpression leads to TBX15 decrease in vascular IUGR placentas

Preeclampsia (PE) and vascular intra-uterine growth restriction (vIUGR) are two pathological obstetrical conditions originating from placental dysfunction. Recently, methylation changes at the placental level have been shown to be indicative of these diseases. The alteration of such epigenetic marks is therefore a novel pathway that might be critical for these pathologies. Here, we identified a region located in the distal promoter of the T-box-containing transcription factor TBX15 that is differentially methylated in pathological placentas. The level of methylation correlated significantly with the weight and stature of the newborn. The promoter was found to be hypomethylated in vIUGR coinciding with the down-regulation of its expression. PDX1, a transcription factor important for the regulation of insulin metabolism regulation was able to repress the TBX15 promoter in a methylation-dependent manner, which might, at least partially, explain the specific mRNA decrease of TBX15 observed in vIUGR placentas. Overall, the data presented herein suggest that TBX15 might be involved in the pathophysiology of placental diseases.

L-Arginine treatment for severe vascular fetal intrauterine growth restriction: A randomized double-bind controlled trial

Infants born with severe IUGR are exposed to higher neonatal mortality and morbidity rates, as compared with appropriate-for-gestational-age. They are exposed to a higher risk of developing chronic disease such as hypertension, coronary artery disease, obesity, and type 2 diabetes in adulthood. L-Arginine is a precursor of nitric oxide (NO) and may play a role in placental vascular mediation or local vasodilatation. The current study was designed to determine whether oral supplementation of gravid patients suffering from severe intrauterine growth restriction (IUGR) with L-arginine, would enhance birth weight and/or decrease neonatal morbidity. Forty-four patients with a singleton pregnancy who had been referred for IUGR detected by ultrasonic examination were included. Vascular IUGR was defined by fetal abdominal circumference less than or equal to the 3rd percentile, associated with abnormal uterine Doppler. After double-blind randomization, patients received either 14 g/day of L-arginine, or a placebo. The characteristics of the two groups of patients (IUGR with L-arginine vs IUGR with placebo) were similar upon randomization. There was no significant difference between the two groups concerning birth weight (1042+/-476 vs. 1068+/-452 g). At delivery, maternal and neonatal characteristics were similar in the two groups. There was no difference in the Clinical Risk Index for Babies (CRIB) score, the duration of ventilatory assistance, nor the delay between birth and full enteral feeding between the two groups. In this study which is, at the best of our knowledge, the first double-bind, multicenter, randomized trial in this condition, L-arginine is not an effective treatment for severe vascular growth restriction.