Fetal Growth Restriction Pregnancies Research Articles

P01.08: Neonatal outcomes after induction of labour in singleton term fetal growth restricted pregnancies with umbilical artery Doppler velocity pulsatility index > 95th centile

P01.08: Neonatal outcomes after induction of labour in singleton term fetal growth restricted pregnancies with umbilical artery Doppler velocity pulsatility index > 95^th centile

Isolation of Plasma Membrane Vesicles from Mouse Placenta at Term and Measurement of System A and System β Amino Acid Transporter Activity

Placental amino acid transport is essential for optimal fetal growth and development, with a reduced fetal provision of amino acids being implicated as a potential cause of fetal growth restriction (FGR). Understanding placental insufficiency related FGR has been aided by the development of mouse models that have features of the human disease. However, to take maximal advantage of these, methods are required to study placental function in the mouse. Here, we report a method to isolate plasma membrane vesicles from mouse placenta near-term and have used these to investigate two amino acid transporters, systems A and β, the activities of which are reduced in human placental microvillous plasma membrane (MVM) vesicles from FGR pregnancies. Plasma membrane vesicles were isolated at embryonic day 18 by a protocol involving homogenisation, MgCl2 precipitation and centrifugation. Vesicles were enriched 11.3±0.5-fold in alkaline phosphatase activity as compared to initial homogenate, with minimal intracellular organelle contamination as judged by marker analyses. Cytochemistry revealed alkaline phosphatase was localised between trophoblast layers I and II, with intense reaction product deposited on the maternal-facing plasma membrane of layer II, suggesting that vesicles were derived from this trophoblast membrane. System A and system β activity in mouse placental vesicles, measured as Na+-dependent uptake of 14C-methylaminoisobutyric acid (MeAIB) and 3H-taurine respectively confirmed localisation of these transporters to the maternal-facing plasma membrane of layer II. Comparison to human placental MVM showed that system A activity was comparable at initial rate between species whilst system β activity was significantly lower in mouse. This mirrored the lower expression of TAUT observed in mouse placental vesicles. We conclude that syncytiotrophoblast layer II-derived plasma membrane vesicles can be isolated and used to examine transporter function.

O973 Doppler velocimetry and microscopic lesions of placenta in fetal growth restricted pregnancies

O973 Doppler velocimetry and microscopic lesions of placenta in fetal growth restricted pregnancies

Expression of Enzymes Regulating Placental Ammonia Homeostasis in Human Fetal Growth Restricted Pregnancies

Functional placental insufficiency results in impaired feto-placental exchange, and subsequently in fetal growth restriction (FGR). We hypothesized that reductions in placental amino acid transporter activities in FGR pregnancies may be accompanied by abnormal expression of placental ammonia-handling enzymes. Term placentas were obtained from growth restricted ( N = 11) and normal ( N = 17) human pregnancies, and examined for glutamate dehydrogenase (GDH), glutamine synthetase (GS) and glutaminase (GA) mRNA and protein expression. Northern and Western blots were normalized on human actin mRNA and protein expression. For GA, the presence of mRNA coding the kidney isoform, and the absence of mRNA coding the liver isoform of the enzyme were demonstrated in the human placenta. In FGR pregnancies, placental expression of GDH mRNA was reduced ( P < 0.05) compared to normal pregnancies (1.576 ± 0.144 vs. 2.092 ± 0.177, respectively; mean ± SE), whereas GS and GA mRNA expression was not different between the two types of pregnancy. GDH protein expression were also reduced ( P < 0.05) in FGR placentas compared to normal placentas (1.055 ± 0.079 vs. 1.322 ± 0.053, respectively; mean ± SE). The GS and GA protein expression was not different in FGR pregnancies. Our data indicate that in cases of FGR, glutamate-to-oxoglutarate transformation in the placenta is limited, yet glutamine synthesis from and decomposition to glutamate seems to be preserved. This may reflect down-regulation of GDH in response to decreased fetal liver output and reduced umbilical artery glutamate concentrations in human FGR pregnancies.

Placental Vascular Sonobiopsy Using Three-dimensional Power Doppler Ultrasound in Normal and Growth Restricted Fetuses

Objective To investigate placental vascular sonobiopsy using three-dimensional (3D) power Doppler ultrasound to assess placental vascularization in normal and growth restricted fetuses. Methods Placental vascular sonobiopsy using 3D power Doppler ultrasound with the VOCAL imaging analysis program was performed on 208 normal fetuses between 12 and 40 weeks of gestation and 13 pregnancies with fetal growth restriction (FGR) at 22–39 weeks' gestation. Only pregnancies with an entirely visualized anterior placenta were included in the study. 3D power Doppler indices related to placental vascularization (vascularization index (VI), flow index (FI) and vascularization flow index (VFI)) were calculated in each placenta. Intra- and inter-class correlation coefficients and intra- and inter-observer agreements of measurements were assessed. Results A weak linear relationship was found between the gestational age and VI, FI, and VFI, respectively. VI values in 8 of 13 FGR pregnancies (61.5%), FI value in one FGR pregnancy (7.7%) and VFI values of 6 FGR pregnancies (46.2%) were below −1.5SD of the reference ranges for VI, FI and VFI, respectively. After 32 weeks of gestation, VI, FI, and VFI values in 10 FGR pregnancies were significantly lower compared to 79 normal pregnancies, respectively ( P < 0.01). All 3D power Doppler indices (VI, FI and VFI) showed a correlation greater than 0.85, with good intra- and inter-observer agreements. Conclusion Our findings suggest that placental vascular sonobiopsy using 3D power Doppler ultrasound may provide new information on the assessment of placental vascularization in normal and FGR pregnancies, while placental perfusion is reduced in FGR compared to normal pregnancy. However, the data and its interpretation in our study should be taken with some degree of caution because of the small number of FGR subjects studied. Further studies involving a larger sample size of FGR pregnancies are needed to confirm the usefulness of placental vascular sonobiopsy using 3D power Doppler ultrasound in clinical practice.

Placental pathologies associated with intra-uterine fetal growth restriction complicated with and without oligohydramnios

To compare the placental pathologies and perinatal outcomes in fetal growth restriction (FGR) pregnancies with and without oligohydramnios. A retrospective cohort study, comparing placental findings in all singleton deliveries with FGR. Macroscopic placental findings were available for 1,104 singleton FGR pregnancies. A total of 397 placentas were microscopically examined; of which 89 placentas were of FGR neonates who had oligohydramnios. No significant differences in placental vascular mal-perfusion were found between pregnancies with and without oligohydramnios (69.3 vs. 74.3%; P = 0.357). Likewise, no significant differences were noted between the groups regarding diffuse villous fibrosis (10.1 vs. 4.9%; P = 0.573), and amnion cell metaplasia (65.9 vs. 64.3%; P = 0.779). Cases of FGR complicated with oligohydramnios had significantly higher rates of perinatal mortality (9.9 vs. 5.9%; P = 0.028), preterm deliveries (34.9 +/- 3.4 vs. 35.4 +/- 3.1 weeks of pregnancy; P = 0.041), and lower birth weight (1,737 +/- 542 vs. 1,845 +/- 467 g; P = 0.002) compared to FGR without oligohydramnios. Oligohydramnios is a significant risk factor for adverse perinatal outcome in FGR pregnancies; nevertheless, no significant differences in placental pathologies were noted.

Functional and Complementary Phosphorylation State Attributes of Human Insulin-like Growth Factor-Binding Protein-1 (IGFBP-1) Isoforms Resolved by Free Flow Electrophoresis

Fetal growth restriction (FGR) is a common disorder in which a fetus is unable to achieve its genetically determined potential size. High concentrations of insulin-like growth factor-binding protein-1 (IGFBP-1) have been associated with FGR. Phosphorylation of IGFBP-1 is a mechanism by which insulin-like growth factor-I (IGF-I) bioavailability can be modulated in FGR. In this study a novel strategy was designed to determine a link between IGF-I affinity and the concomitant phosphorylation state characteristics of IGFBP-1 phosphoisoforms. Using free flow electrophoresis (FFE), multiple IGFBP-1 phosphoisoforms in amniotic fluid were resolved within pH 4.43-5.09. The binding of IGFBP-1 for IGF-I in each FFE fraction was determined with BIAcore biosensor analysis. The IGF-I affinity (K(D)) for different IGFBP-1 isoforms ranged between 1.12e-08 and 4.59e-07. LC-MS/MS characterization revealed four phosphorylation sites, Ser(P)(98), Ser(P)(101), Ser(P)(119), and Ser(P)(169), of which Ser(P)(98) was new. Although the IGF-I binding affinity for IGFBP-1 phosphoisoforms across the FFE fractions did not correlate with phosphopeptide intensities for Ser(P)(101), Ser(P)(98), and Ser(P)(169) sites, a clear association was recorded with Ser(P)(119). Our data demonstrate that phosphorylation at Ser(119) plays a significant role in modulating affinity of IGFBP-1 for IGF-I. In addition, an altered profile of IGFBP-1 phosphoisoforms was revealed between FGR and healthy pregnancies that may result from potential site-specific phosphorylation. This study provides a strong basis for use of this novel approach in establishing the linkage between phosphorylation of IGFBP-1 and FGR. This overall strategy will also be broadly applicable to other phosphoproteins with clinical and functional significance.

205. Homeobox gene TGIF is increased in human idiopathic fetal growth restriction

Fetal Growth Restriction (FGR) is a clinically significant pregnancy disorder in which the fetus fails to achieve its full growth potential in utero. Recently, we identified a novel homeobox gene TGIF, in the placenta using microarray expression profiling (1). Targeted mutation of tgif in mouse results in placental dysfunction (2). In this study, we have investigated TGIF expression levels in idiopathic FGR. FGR-affected placental samples were collected based on strict clinical criteria to ensure inclusion of cases at the severe end of the spectrum of the disease. TGIF mRNA expression was analysed in placentae obtained from pregnancies complicated by idiopathic FGR and gestation-matched control pregnancies (n = 25 each). Real-time PCR showed a significant increase in TGIF mRNA levels in FGR-affected placentae and gestation-matched controls [1.29 ± 0.06 FGR v. 0.78 ± 0.04 Control, P &lt; 0.001]. western blotting using a TGIF polyclonal antibody revealed significantly increased levels of TGIF protein in term FGR-affected placentae compared with term controls [3970 ± 1101 (n = 10) v. 2323 ± 644 (n = 10), P &lt; 0.05]. The spatial distribution of TGIF protein by immunohistochemistry revealed immunoreactive TGIF protein in residual cytotrophoblast cells, syncytiotrophoblast cells, microvascular endothelial cells and in stromal cells. We conclude that increased expression of homeobox gene TGIF may be a contributing factor to the developmental abnormalities seen in the FGR-affected placentae. (1) Murthi P, Hiden U, Rajaraman G, Kalionis B. Placenta May 29, [Epub ahead of print]. (2) Bartholin L, Melhuish TA et al. Dev Biol. 2008 May 2. [Epub ahead of print].

Maternal Cardiac Function in Fetal Growth Restriction

Fetal growth restriction (FGR) is often associated with defective trophoblast invasion. Because normal placentation is believed to trigger the typical maternal cardiovascular changes of pregnancy (decreased systemic vascular tone and increased plasma volume, heart rate, and cardiac output), the investigators theorized that FGR pregnancies might be associated inadequate or abnormal maternal cardiovascular function. This cross-sectional study, carried out at a tertiary referral fetal medicine unit, evaluated central hemodynamic function in 107 women with normal singleton pregnancies and 20 others whose pregnancies were complicated by severe FGR (estimated fetal weight <3%) at 25 to 37 weeks gestation. The women with normal pregnancies were evaluated between 10 and 40 weeks gestation to establish the normal cardiovascular changes of pregnancy, and the women with FGR fetuses were evaluated within 10 days before delivery. All participants were normotensive and had no apparent medical problems. Left ventricular function was assessed by 2-dimensional and M-mode echocardiography. There were 18 live births and 2 intrauterine deaths in the FGR group. The mean gestational age at delivery was 32 weeks. Cardiac output (CO) and stroke volume (SV) increased to a maximum at 30 weeks gestation, whereas long axis shortening at both the septal and lateral annulus increased steadily up to 20 weeks; then all 4 measurements slowly decreased toward term. In the FGR pregnancies, CO, SV, and long axis shortening followed the same pattern, but the measurements were much lower than in normal pregnancies. In the normal pregnancies, maternal heart rate increased linearly and ejection time decreased linearly with advancing gestation; both heart rate and ejection time were lower in the FGR group. In both normal and FGR pregnancies, mean arterial pressure and tricuspid valve replacement (TVR) declined in parallel, reaching minimal levels at 20 weeks and then increasing slowly until term. However, although mean arterial pressure was the same in both groups, in the FGR group, the TVR was much higher. Multiple regression analysis demonstrated that the differences between the normal and FGR pregnancies, namely increased TVR and reduced systolic function as evidenced by lower CO, SV, heart rate, ejection time, and septal and lateral long axis shortening in the FGR group, were related to gestational age but not maternal height, weight, age, or race. FGR appears to be associated with reduced maternal systolic cardiac function and increased TVR, but diastolic cardiac function is unchanged and blood pressure remains normal. Conceivably, lack of expansion of the intravascular space in FGR may be responsible for most, if not all, of these findings.

Homeobox gene DLX4 expression is increased in idiopathic human fetal growth restriction

Idiopathic fetal growth restriction (FGR) is often associated with placental insufficiency. Previously, we isolated and characterized homeobox gene DLX4 from the placenta and provided evidence that DLX4 may regulate placental development. Here, we have investigated whether DLX4 expression levels were altered in idiopathic FGR. FGR-affected placentae were collected based on strict clinical criteria. DLX4 mRNA expression was analysed in placentae obtained from pregnancies complicated by idiopathic FGR and gestation-matched control pregnancies (n = 25 each). Initial RT-PCR results showed a qualitative increase in DLX4 mRNA in both FGR-affected placentae and gestation-matched controls. Real-time PCR showed a 3-fold increase in DLX4 mRNA levels in FGR-affected placentae compared with gestation-matched controls (P < 0.005). Western immunoblotting using a rabbit DLX4 polyclonal antibody revealed significantly increased levels of DLX4 protein in term FGR-affected placentae compared with term controls [5500.1 +/- 21.8 (n = 10) versus 3533.2 +/- 22.4 (n = 10); P < 0.001]. Qualitative immunohistochemical analyses of term placentae showed moderately increased immunoreactivity for DLX4 antigen in the FGR-affected placentae in syncytiotrophoblasts, residual cytotrophoblast cells and endothelial cells of the fetal capillaries compared with gestation-matched control term placentae. We conclude that the increased expression of homeobox gene DLX4 may be a contributing factor to the developmental abnormalities seen in the FGR-affected placentae.

OP07.05: Early uterine artery Doppler and maternal biochemical markers as a screening test for pre‐eclampsia and fetal growth restriction in pregnancies at risk

OP07.05: Early uterine artery Doppler and maternal biochemical markers as a screening test for pre‐eclampsia and fetal growth restriction in pregnancies at risk

Homeobox gene ESX1L expression is decreased in human pre-term idiopathic fetal growth restriction

Fetal growth restriction (FGR) is a clinically significant pregnancy disorder in which the fetus fails to achieve its full growth potential in utero. This study involved idiopathic FGR, which is frequently associated with placental dysfunction. Here, we investigated mRNA levels of the human placental homeobox gene ESX1L in pre-term and term idiopathic FGR pregnancies compared with gestation-matched controls. Real-time PCR quantitation showed ESX1L levels in control placentae decreased between pre-term and term [0.7 +/- 0.20 (27-35 weeks, n = 13) versus 0.2 +/- 0.06 (36-41 weeks, n = 12), t-test, P < 0.005]. ESX1L levels in FGR-affected placentae were significantly lower than in gestation-matched controls, and there was no significant change between pre-term FGR and term FGR [0.32 +/- 0.04 (27-36 weeks, n = 11) versus 0.31 +/- 0.02 (36-41 weeks, n = 14), t-test, P = 0.82]. Multiple linear regression analysis revealed a rapid decline in ESX1L expression in control placentae [0.075-fold of the calibrator for each week of gestation (95% CI = -0.105 to -0.045, P < 0.0005)]. In FGR-affected placentae, ESX1L levels were lower than in gestation-matched controls, and the decline in ESX1L levels with gestation was not significant [0.001-fold of the calibrator for each week of gestation (95% CI = -0.030 to 0.010, P < 0.3]. The linear relationship between ESX1L mRNA levels in FGR-affected placentae and gestation-matched controls during gestation was significantly different (likelihood ratio test for interaction, P = 0.0005). Our findings were consistent with a potential role for the ESX1L gene within the growth control mechanism of the fetus, through its effect on placental function.

Homeobox Gene HLX1Expression Is Decreased in Idiopathic Human Fetal Growth Restriction

Fetal growth restriction (FGR) is a clinically significant pregnancy disorder in which the fetus fails to achieve its full growth potential in utero. Identifiable causes of FGR account for approximately 30% of cases, but the remainder are idiopathic and are frequently associated with placental malfunction. Previously, we isolated the homeobox gene HLX1 and provided evidence for a regulatory role in normal placental development. Here, we investigated whether placental HLX1 expression levels are changed in placentas from idiopathic FGR pregnancies. Real-time polymerase chain reaction quantitation showed reduced HLX1 mRNA levels with advancing gestation age (preterm control placentas, 27 to 35 weeks, 1.1 +/- 0.3, n = 13, versus term placentas 36 to 41 weeks, 0.74 +/- 0.02, n = 12, P < 0.005). FGR-affected placentas had significantly lower levels of HLX1 expression compared with gestation age-matched controls (0.36 +/- 0.07 versus 1.05 +/- 0.2, n = 25, P < 0.001). Immunoblotting with a rabbit polyclonal HLX1 antibody revealed reduced levels of HLX1 in FGR-affected placentas compared with controls (481.07 +/- 12.3 versus 2766.7 +/- 30.3, n = 10, P < 0.001). Immunohistochemistry showed a qualitative decrease in HLX1 immunoreactivity in FGR-affected term placentas compared with controls. This is the first demonstration that a homeobox transcriptional regulator shows altered expression in an important human placental disorder, suggesting that decreased HLX1 levels contribute to the abnormalities in placental developmental seen in idiopathic FGR.

Placental apoptosis and adhesion molecules expression in the placenta and the maternal placental bed of pregnancies complicated by fetal growth restriction with and without pre-eclampsia

SummaryThe aim of the study was to examine the expression of adhesion molecules VCAM-1 and ICAM-3 in placental tissue samples and placental bed (maternal decidual tissue) biopsies of pregnancies complicated by pre-eclampsia (PE) and fetal growth restriction (FGR), and to determine whether PE and FGR are associated with an increase in placental apoptosis. We studied placentas and placental bed samples of 49 third trimester pregnancies complicated by FGR (26 with associated PE, 23 without PE) and 25 normotensive healthy pregnant women. Placental apoptosis was assessed by the TUNEL method. Immunohistochemistry was used to assess expression of the VCAM-1 and ICAM-3. There was no significant difference in the staining intensity of VCAM-1 in placentas ( p = 0.472) and placental bed biopsies ( p = 0.754) of women delivering appropriate for gestational age and growth restricted fetuses (with and without associated PE). The amount of lymphocytes staining positively with ICAM-3 was significantly higher in both placental and placental bed biopsies of women delivering growth restricted fetuses compared with control pregnancies ( p < 0.001). Fetal growth restricted pregnancies with associated PE showed higher staining of ICAM-3 in placental compared with placental bed samples ( p = 0.049). In fetal growth restricted placentas, apoptotic nuclei were more abundant compared with control placentas ( p < 0.001). Increased expression of ICAM-3 on lymphocyte surface of both maternal and fetal side, suggests lymphocyte overactivation in PE and FGR. Increased placental apoptosis may play an important role in the pathogenesis or sequelae of PE.

Time Course of Maternal Plasma Volume and Hormonal Changes in Women With Preeclampsia or Fetal Growth Restriction

We tested the hypothesis that women with idiopathic fetal growth restriction (FGR) or preeclampsia (PE) have lower concentrations of some water-retaining hormones, such as aldosterone and estradiol, either preceding or concomitant with the onset of the reduced plasma volume described in these women. Plasma volume and serum concentrations of estradiol, progesterone, and aldosterone were measured serially at monthly intervals in 135 pregnant women from week 10 until term. Twenty-three developed idiopathic FGR, 17 had PE, and 95 remained normotensive and delivered normal-size infants (controls). Changes over time for each variable were studied using mixed models. Maternal age, parity, and weight/height at term were similar in all of the groups. Birth weight, body length, and ponderal index were lower in FGR and PE than in controls. Plasma volume increased throughout pregnancy in controls but was lower in FGR and PE from week 14 to 17 until term. Aldosterone values were lower in PE from week 26 to 29 onwards and in FGR after week 34. Progesterone concentrations were higher in PE than either control or FGR from week 18 to 21 until term. In contrast, FGR pregnancies had reduced progesterone and estradiol concentrations after week 34. Progesterone:estradiol ratio was significantly higher only in the PE group. In mothers with idiopathic FGR or PE, less expansion in plasma volume occurred before alterations in hormonal concentrations. We speculate that the early rise in progesterone may have a pathogenic role in the development of preeclampsia.

Collagen fibril diameters in the umbilical arteries of preterm growth restricted fetuses

RESTRICTED FETUSES WENDY KINZLER, JOHN SMULIAN, CANDE ANANTH, DONALD GERECKE, RITAHAHN, GEORGE LAMBERT, MARIONGORDON, University of Medicine and Dentistry of New Jersey, Obstetrics, Gynecology and Reproductive Sciences, New Brunswick, New Jersey, Rutgers, The State University of New Jersey, Pharmacology and Toxicology, Rutgers College of Pharmacy, Piscataway, New Jersey, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey OBJECTIVE: Our previous work has demonstrated that fetal growth restriction (FGR) in preterm gestations is associated with changes in extracellular matrix (ECM) components which control fibril diameter. Our objective was to determine if actual collagen fibril diameters within the umbilical arterial wall are altered in FGR versus appropriately grown (AGA) fetuses delivered preterm (!37 weeks). STUDY DESIGN: Preterm FGR pregnancies (ultrasound-estimated fetal weight !10th% ile for gestational age and abnormal umbilical Doppler velocimetry) were compared with preterm AGA pregnancies. The umbilical artery was collected at delivery and prepared for examination by transmission electron microscopy. Because of potential differences in mechanical forces and hypoxic exposures between the inner and outer arterial wall, micrographs were taken at the outer, middle and inner 3rd at 30K magnification. Cross-sectional collagen fibril diameters were measured by the same examiner and converted from mm to nm using a standard magbar reference on each micrograph. The means and variances in fibril diameters were modeled using general linear models based on quasi-likelihood estimating functions. P!0.05 was considered significant. RESULTS: 1133 fibril diameters from 4 FGR pregnancies were compared with 1266 fibril diameters measured from 3 AGA pregnancies. Mean fibril diameters (95%CI) for FGR and AGA pregnancies were as follows: 33.7 (31.4-35.9) nm versus 37.4 (35.7-39.1) nm, P=0.04. The largest diameters were found in the outer 3rd of the arterial wall for both FGR and AGA pregnancies. Middle and inner 3rd diameters were similar among FGR pregnancies, while AGA pregnancies demonstrated a progressive decrease in fibril diameter toward the inner 3rd of the arterial wall. CONCLUSION: Collagen fibril diameters in the umbilical arteries of preterm FGR pregnancies are thinner than diameters of AGA pregnancies and vary depending on the arterial wall site which is sampled. This may be the result of ECM remodeling in FGR pregnancies and may contribute to the genesis of future cardiovascular disease.

Placental Expression of Angiopoietin-1, Angiopoietin-2 and Tie-2 during Placental Development in an Ovine Model of Placental Insufficiency-Fetal Growth Restriction

Fetal growth restriction (FGR) is associated with increased perinatal morbidity and mortality, and often results from functional placental insufficiency. Placentation requires extensive vasculogenesis and subsequent angiogenesis, in both maternal and fetal tissues. Angiopoietin-1 (Ang-1) and Angiopoietin-2 (Ang-2) are angiogenic growth factors expressed in the placenta, and compete for binding to a common receptor, Tunica interna endothelial cell kinase-2 (Tie-2). Our objective was to examine Ang-1, Ang-2 and Tie-2 expression in ovine placental tissue obtained from normal and FGR pregnancies throughout gestation. Fetal cotyledon and maternal caruncle tissue concentrations of Ang-1, Ang-2 and Tie-2 mRNA were assessed by real-time reverse transcriptase-polymerase chain reaction and protein concentrations were assessed by Western immunoblot analysis, at 55, 90 and 135 d gestational age (dGA). Concentrations of Ang-1, Ang-2 and Tie-2 mRNA in FGR fetal cotyledons were increased at 55 dGA, and Tie-2 mRNA concentrations were decreased in FGR fetal cotyledons and maternal caruncles at 135 dGA. Immunoblot analysis demonstrated increased concentrations of Ang-2 in the fetal cotyledon at 55 dGA, and lower concentrations at 135 dGA. In contrast, concentrations of Tie-2 were increased at 90 dGA, but tended to decrease at 135 dGA in FGR maternal caruncles. The changes observed during early- to mid-gestation may result in increased branching angiogenesis, but may also set the stage for increased nonbranching angiogenesis during late gestation, altered placental architecture and placental insufficiency that result in FGR.

Prospective evaluation of intraplacental and umbilical vascular flow by color Doppler in normal birth weight and fetal growth restricted pregnancies

Prospective evaluation of intraplacental and umbilical vascular flow by color Doppler in normal birth weight and fetal growth restricted pregnancies

Chorionic plate artery function and Doppler indices in normal pregnancy and intrauterine growth restriction

In fetal growth restriction (FGR) abnormal umbilical artery (UA) Doppler waveform indices suggest increased vascular resistance and impaired placental blood flow. This study aimed to determine whether UA Doppler waveform indices were related to the vasoreactivity of placental chorionic plate small arteries in normal and FGR pregnancies. UA Doppler waveform analysis was performed 24 h before delivery in 23 normal term and 15 FGR pregnancies. Post-delivery responses of chorionic plate arteries to vasoactive agents were examined using the technique of wire myography. Altered vascular reactivity to agonists was demonstrated in chorionic plate arteries in FGR pregnancy. Constriction to U46619 (thromboxane mimetic) and relaxation to sodium nitroprusside (nitric oxide donor) were significantly increased in the arteries of FGR pregnancies compared with normal pregnancies. No relationship existed between Doppler indices and chorionic plate responses in normal or FGR pregnancies. Fetoplacental vascular reactivity is altered in FGR pregnancy independently of UA Doppler waveform indices. Altered function may be additive to the pathophysiology underlying abnormal Doppler waveforms and could contribute to the inappropriate control of vascular tone in FGR.

Extracellular matrix changes in the umbilical arteries of growth-restricted fetuses

This study was undertaken to determine whether the expression of extracellular matrix components (ECM) is altered in the umbilical arteries from preterm fetal growth-restricted (FGR) pregnancies. Preterm pregnancies with FGR were compared with appropriately grown preterm pregnancies. Umbilical artery messenger RNA (mRNA) levels for fibrillar collagens I and III, nonfibrillar collagen XIV, and decorin were determined by using relative reverse transcriptase polymerase chain reaction (RT-PCR). The mRNA expression was compared between cases and controls by using the Student t test. P < or = .05 was considered significant. Eight FGR cases and 5 control pregnancies were analyzed. Mean counts per minute (cpm) +/- SEM for collagen I and collagen III were increased in FGR pregnancies. There were no differences in mRNA expression of collagen XIV or decorin. Increased mRNA expression of collagen I and III, but not collagen XIV or decorin, is found in the umbilical arteries of preterm FGR pregnancies.