Abnormal Umbilical Artery Doppler Studies Research Articles

Outcomes among Neonates after a Diagnosis of Persistent or Transient Fetal Growth Restriction Delivered at Term.

This study aimed to evaluate whether transient fetal growth restriction (FGR) that resolves prior to delivery confers a similar risk of neonatal morbidity as uncomplicated FGR that persists at term. This is a secondary analysis of a medical record abstraction study of singleton live-born pregnancies delivered at a tertiary care center between 2002 and 2013. Patients with fetuses that had either persistent or transient FGR and delivered at 38 weeks or later were included. Patients with abnormal umbilical artery Doppler studies were excluded. Persistent FGR was defined as estimated fetal weight (EFW) <10th percentile by gestational age from diagnosis through delivery. Transient FGR was defined as EFW <10th percentile on at least one ultrasound, but not on the last ultrasound prior to delivery. The primary outcome was a composite of neonatal morbidity: neonatal intensive care unit admission, Apgar's score <7 at 5 minutes, neonatal resuscitation, arterial cord pH <7.1, respiratory distress syndrome, transient tachypnea of the newborn, hypoglycemia, sepsis, or death. Baseline characteristics and obstetric and neonatal outcomes were compared using Wilcoxon's rank-sum and Fisher's exact test. Log binomial regression was used to adjust for confounders. Of 777 patients studied, 686 (88%) had persistent FGR and 91 (12%) had transient FGR. Patients with transient FGR were more likely to have a higher body mass index, gestational diabetes, diagnosed with FGR earlier in pregnancy, have spontaneous labor, and deliver at later gestational ages. There was no difference in the composite neonatal outcome (relative risk = 1.03, 95% confidence interval [CI] 0.72, 1.47) for transient versus persistent FGR after adjusting for confounders (adjusted relative risk = 0.79, 95% CI 0.54, 1.17). There were no differences in cesarean delivery or delivery complications between groups. Neonates born at term after transient FGR do not appear to have differences in composite morbidity compared with those where uncomplicated FGR persists at term. · No differences in neonatal outcomes in uncomplicated persistent versus transient FGR at term.. · Transient FGR pregnancies more likely to deliver at later gestational ages.. · No differences in mode of delivery or obstetric complications in persistent versus transient FGR at term..

Diagnosis of mid-second trimester fetal growth restriction and associated outcomes

Objective To evaluate maternal and neonatal outcomes of low-risk singleton pregnancies, without underlying maternal medical conditions or genetic and fetal anomalies associated with fetal growth restriction, that were diagnosed with fetal growth restriction (FGR) (EFW < 10th %) in the mid-second trimester (between 17 and 22 weeks and 6 days’ gestation). Methods A retrospective cohort study of all women who underwent a routine fetal anatomy ultrasound between 17 and 22 weeks and 6 days’ gestation at a community-based academic hospital was performed to identify subjects with an EFW <10th%. Pregnancies with inadequate dating, multiple gestations, preexisting maternal vascular disease (chronic hypertension and pregestational diabetes), lethal fetal anomalies, and abnormal prenatal genetic screening were excluded. Descriptive statistics were computed to describe the study population. Subjects were stratified into two groups, estimated fetal weight (EFW) <5th% and EFW 5th–9th%. The primary outcome was a small for gestational age neonate (SGA) at delivery. Secondary outcomes included a composite adverse neonatal outcome, perinatal death, hypertensive disorders of pregnancy, medically indicated delivery, and mode of delivery. A comparison of the two groups, EFW <5th% and EFW 5th–9th %, was performed. Continuous variables were compared utilizing Wilcoxon Rank Sum tests and categorical variables were compared using Fisher’s exact test or Chi-squared tests, and a dichotomous composite variable for adverse neonatal outcomes was also calculated. Results In total, 3,868 unique patient records were screened. Thirty-two patient records (0.8% of the total screened records) were eligible for inclusion. The primary outcome, SGA at delivery, occurred in 13/32 (41%) of the subjects. The secondary outcomes of the composite neonatal morbidity occurred in 9/32 (28%), hypertensive disorders of pregnancy in 10/32 (31%), and medically indicated delivery at <28 weeks gestation in 7/32 (22%) of the subjects. When comparing EFW <5th% and EFW 5th–9th%, EFW <5th% had a larger percentage of SGA newborns (66% vs. 25%, p = .02, OR = 8.0 95% CI 1.5–42.5). EFW <5th% was also significantly associated with a greater composite adverse neonatal outcome when compared to EFW 5th–9th% (54% vs. 10%, p = .015). The subgroup with an EFW <5th% also had higher rates of adverse outcomes including preeclampsia (42% vs. 10%, p = .073), abnormal umbilical artery Doppler studies (50% vs. 15%, p = .049), and medically indicated delivery <28 weeks (42% vs. 10%, p = .07). Conclusions Early onset FGR is a associated with high rates of SGA at delivery, as well as several adverse maternal and neonatal outcomes which include hypertensive disorders of pregnancy, a greater composite neonatal morbidity, perinatal death, and medically indicated preterm delivery. EFW <5th% was associated with worse outcomes when compared to those with an EFW 5th%–9th%.

1070 Neonatal outcomes in patients with resolved versus persistent uncomplicated fetal growth restriction

When fetal growth restriction (FGR) resolves prior to delivery, antenatal testing is discontinued. The objective of this study was to evaluate if FGR that resolves confers a similar risk of neonatal morbidity compared to persistent uncomplicated FGR. This is a secondary analysis of a large, NIH-funded medical record abstraction study of singleton pregnancies delivered at a tertiary care center between 2002 and 2013. Women with either persistent or resolved FGR who delivered at 38 weeks or more were included. FGR was defined as persistent estimated fetal weight (EFW) < 10%ile. Resolved FGR was defined as EFW < 10%ile on at least one ultrasound (US), but EFW > 10%ile at last US prior to delivery. Women with abnormal umbilical artery Doppler studies were excluded. The primary outcome was a composite of neonatal morbidity: NICU admission, Apgar < 7 at 5 minutes, neonatal resuscitation, cord pH < 7.1, RDS, TTN, hypoglycemia, sepsis or death. Secondary outcomes were individual items in the composite. Baseline characteristics, obstetric and neonatal outcomes were compared using Wilcoxon rank-sum and Fisher’s exact test. Logistic regression was used to adjust for confounders. Of 777 women studied, 686 (88%) had persistent FGR and 91 (12%) had resolved FGR. Women with resolved FGR were more likely to have higher body mass index, gestational diabetes, preexisting diabetes, diagnosed with FGR earlier, had spontaneous labor and delivered at later gestational ages. There was no difference in the composite neonatal outcome (RR 1.03, 95% CI, 0.72, 1.47) for resolved versus persistent FGR even when adjusting for confounders (aRR 0.79, 95% CI 0.54, 1.17). There were no differences in cesarean delivery or delivery complications between groups. Though women with resolved FGR are managed differently than those with persistent FGR, resolved FGR fetuses do not have improved composite morbidity immediately after delivery compared to those where FGR persists. Future research is needed to determine whether additional surveillance results in improved outcomes in fetuses with resolved FGR.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

504 Fetal growth restriction and latency from diagnosis to delivery in early onset preeclampsia

Early onset preeclampsia (PE) is associated with increased maternal and neonatal morbidity, including fetal growth restriction (FGR). Data on the benefit of expectant management in women with early onset PE with severe features (SF) in the setting of FGR are limited. Therefore, we aimed to determine whether FGR shortens the latency from PE diagnosis till delivery, in women undergoing expectant management of early onset PE with SF. Retrospective chart review of women with early onset PE with SF that developed < 34 weeks of gestation, who delivered at a single tertiary care center between 2011-2020. Women were excluded if delivery was planned after completion of antenatal corticosteroids, fetal demise at time of PE diagnosis or fetal anomaly. Our primary outcome was latency from diagnosis of PE to delivery. Sub-analysis was performed to further evaluate the FGR group based on estimated fetal weight (EFW) ≤3% or abnormal Doppler studies defined as >95% systolic/diastolic umbilical artery Doppler (UAD) flow, absent or reversed UAD. Of 261 patients identified, 236 patients met criteria for analysis, with 80 (33.6%) FGR and 156 (66.4%) appropriately grown for gestational age (AGA) fetuses. There were no differences in maternal age, BMI at time of delivery, ethnicity/race, nulliparity, chronic hypertension or need for acute anti-hypertensive therapy. Patients with FGR were more likely to use tobacco and be delivered via cesarean compared with those with AGA fetuses. Pregnancies complicated by FGR were diagnosed with PE and delivered at earlier GA compared with those with AGA fetuses. (Table 1) There were no differences in latency between the two groups with median of 3 [IQR 1-5] vs 2 [1-4] days. There were no differences in the composites of maternal or neonatal outcomes. Similar patterns were observed in sub-analysis of FGR by EFW ≤3% and abnormal UAD studies. (Table 2) In patients with early onset PE with SF, FGR did not impact latency or worsen short term maternal and neonatal outcomes. Further research is needed to determine long term maternal and child outcomes.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Perinatal outcome of growth restricted fetuses with abnormal umbilical artery Doppler waveforms compared to growth restricted fetuses with normal umbilical artery Doppler waveforms at a tertiary referral hospital in urban Ethiopia.

Intrauterine growth restriction is defined as a fetal weight below the 10th percentile for a given gestational age and can be identified using umbilical artery Doppler velocimetry which is a non-invasive technique. The objective of this study was to determine the perinatal outcome of growth-restricted fetuses with abnormal umbilical artery Doppler study compared to those with normal umbilical artery Doppler waveforms at a tertiary referral hospital in Ethiopia. A prospective cohort study was conducted among pregnant mothers with fetal growth restriction admitted for labour and delivery from September 2018-February 2019. The data were entered and analyzed using SPSS version 23. After conducting descriptive analysis, exploring the entire data, and checking for, statistical associations between abnormal umbilical artery Doppler and outcome variables, multiple logistic regression was conducted to control for confounders. A total of 170 pregnant mothers complicated with growth-restricted fetuses were included in the study, among which 133 were with normal umbilical artery Doppler studies and 37 were with abnormal umbilical artery Doppler studies. Four (3%) of normal and 9(24.3%) of abnormal umbilical artery Doppler studies ended in perinatal death-value = 0.001. Twenty (15%) of normal and 24(64.9%) of abnormal umbilical artery Doppler study neonates required neonatal intensive care admission-value = 0.002. Growth restricted fetuses complicated with abnormal Doppler were two times more likely to require neonatal intensive care unit admissions compared to growth-restricted fetuses with normal umbilical artery Doppler flow, P-value 0.002, (OR = 2.059,95%CI 1.449-2.926). Growth restricted fetuses complicated with abnormal Doppler were four times more likely to end in early neonatal death compared to growth-restricted fetuses with normal umbilical artery Doppler flow, P-value 0.001, (OR = 4.136, 95%CI 3.423-4.998). However, the study is unmatched and there is a possibility of gestational age confounding the result and should be seen with the context of preterm morbidity and mortality. The abnormal umbilical artery Doppler waveform is associated with cesarean section delivery, neonatal intensive care unit admission, respiratory distress syndrome, neonatal sepsis, neonatal hyperbilirubinemia, and early neonatal death compared to normal umbilical artery Doppler flow.

1028: Utility of the cerebroplacental ratio (CPR) in marijuana exposed growth restricted fetuses

Severe fetal growth disorders are associated with an increased risk of adverse perinatal outcome (APO). The CPR represents the interaction of alterations in blood flow to the fetal brain and placenta. It is calculated by dividing the Doppler indices of the middle cerebral artery (MCA) by those of the umbilical artery (UA). CPR has been toted as a superior reflection of fetal hypoxia/acidemia and therefore a better predictor of APO. We sought to determine the role of CPR as a predictor of severe fetal growth restriction (FGR), defined as an estimated fetal weight (EFW) less than the 5th percentile, in a study population of marijuana (MJ) exposed FGR fetuses. This was a retrospective cohort study of high-risk singleton pregnancies over a four-year period. Self-identified daily MJ users with FGR fetuses, defined as fetuses with an EFW less than the 10th percentile, in the 3rd trimester were isolated. Fetal biometry, amniotic fluid indices, and CPRs were calculated. A CPR < 1 was considered abnormal. FGR fetuses with normal and abnormal CPRs were then compared. 26 /192 (13.5%) of MJ exposed fetuses were diagnosed with FGR in 3rd trimester. 12/26 (46%) had an abnormal CPR and 14 had a normal CPR (mean CPR 0.60 vs 1.57, p = 0.0001). The mean EFW percentile was lower in the abnormal CPR group in comparison to the group with normal CPR (3.33 vs 7.64, p=0.0001). Both groups showed evidence of brain sparing with an overall mean head circumference of 17.55 in comparison to a mean abdominal circumference of 5.63. A CPR < 1 was associated with more severe FGR, oligohydramnios, and abnormal UA Doppler studies (see table 1). Approximately half of the MJ exposed FGR fetuses had an abnormal CPR. In this subset of patients, > 90% had severe FGR, a higher proportion had absence/reversal of end diastolic flow in the UA, and a higher proportion had oligohydramnios. This demonstrates that an abnormal CPR identifies a group of FGR fetuses at a greater risk for severe FGR and possibly APO.

Monitoring of Systemic Lupus Erythematosus Pregnancies: A Systematic Literature Review.

Few data exist to guide the frequency and type of monitoring in systemic lupus erythematosus (SLE) pregnancies. A systematic literature review was performed to address this gap in the literature. A systematic review of original articles (1975-2015) was performed using Medline, Embase, and Cochrane Library. We included search terms for SLE, pregnancy, and monitoring. We also hand-searched reference lists, review articles, and grey literature for additional relevant articles. The search yielded a total of 1106 articles. After removing 117 duplicates, 929 articles that were evidently unrelated to our topic based on title and/or abstract, and 7 that were in a language other than English or French, 53 articles were included for full-text review. Following a more in-depth review, 15 were excluded: 6 did not use any measure of SLE activity and 6 did not specifically address SLE monitoring in pregnancy; 1 case series, 1 review, and 1 metaanalysis were removed. Among the 38 included studies, presence of active disease, antiphospholipid (aPL) antibodies positivity, and abnormal uterine and umbilical artery Doppler studies predicted poor pregnancy outcomes. No studies evaluated an evidence-based approach to the frequency of monitoring. Few existing studies address monitoring for optimal care during SLE pregnancies. The available data imply roles for aPL antibodies measurement (prior to pregnancy and/or during the first trimester), uterine and umbilical artery Doppler studies in the second trimester, and following disease activity. Optimal frequency of monitoring is not addressed in the existing literature.

Intrauterine Growth Restriction in the Triad: Understanding Outcomes Associated with Differential Management of Severe Early IUGR

Objective:&#x0D; Preterm delivery of growth restricted (IUGR) fetuses prior to 32 wks is rarely indicated, occurring in &lt;1.9% of all pregnancies. We sought to determine if delaying delivery until non-reassuring fetal heart tracing (NRFT) increases adverse outcomes.&#x0D; Materials and Methods:&#x0D; This is a cohort of pregnant women with IUGR identified prior to 32wks. Serial fetal growth and umbilical artery Doppler (UAD) were assessed. Two groups were compared: those delivered for abnormal UAD studies and those delivered for non-reassuring fetal heart tracing (NRFHT). Fetuses with absent (AEDF) or reversed end diastolic flow (REDF) were placed on continuous monitoring until delivery. Maternal comorbidities, delivery indications, and neonatal outcomes were compared between the 2 groups. T-test and Chi-square were performed where appropriate.&#x0D; Results:&#x0D; 43 singleton gestations with IUGR were identified at &lt;32 weeks gestation from 2012-2015. Pregnancies were excluded for multiple gestation or when delivered for maternal deterioration. Mean GA at diagnosis 24.7 +/-3.1wks (range 18-30.3wks). 30 delivered for abnormal UAD and 13 for NRFT. Pregnancy characteristics were similar between groups. Those women who progressed to urgent delivery due to NRFT were more likely to undergo cesarean (CD) than SVD (p=0.01). 83.9% of both groups were delivered via CD and were significantly smaller compared to those able to be born via SVD (p=0.026). Women with HTN, preeclampsia or GHTN were also more likely to undergo CD than SVD (p=0.04). Expectant management for abnormal UAD did not decrease requirement for CPR at delivery or incidence of IVH, RDS, or death. Although not statistically significant, the length of stay was 50.9 days in those delivered for Doppler while 61.2 days in the group delivered emergently (p=0.23); see Table 1.&#x0D; Conclusion:&#x0D; Expectant management for fetal growth restriction and waiting to deliver until there was NRFT does not appear to decrease neonatal morbidity/mortality, increases risk for emergency CD, and may increase length of stay in NICU. 

849: What should a MFM do with an abnormal umbilical artery doppler (UAD) study in a normally grown fetus?

849: What should a MFM do with an abnormal umbilical artery doppler (UAD) study in a normally grown fetus?

Postnatal systemic blood flow in neonates with abnormal fetal umbilical artery Doppler.

Objective. Abnormal umbilical artery Doppler (UAD) studies are associated with poor neonatal outcomes. We sought to determine if postnatal measures of systemic blood flow (SBF), as measured by functional echocardiography (fECHO), could identify which fetuses with abnormal UAD were at the highest risk of adverse outcomes. Study Design. This is a retrospective review of fetuses with abnormal UAD who received fECHO in the first 72 hours of life. Measures of SBF (right ventricular output (RVO) and superior vena cava (SVC) flow) were performed and compared with prenatal variables and postnatal outcomes. Result. 63 subjects had abnormal UAD, 20 of which also had fECHO. Six subjects had abnormal flow. Gestational age at delivery was similar between the two groups. Those with abnormal SBF had fewer days of abnormal UAD prior to delivery and developed RDS (P < 0.001). Conclusion. Postnatal measures of SBF were associated with poor postnatal outcomes in fetuses with abnormal UAD. Future studies incorporating antenatal measures of SBF may help obstetricians determine which pregnancies complicated by UAD are likely to have postnatal morbidity.

Maternal serum copeptin as a marker for fetal growth restriction

Abstract Objectives Copeptin is a hormone of endogenous stress. The aim was to evaluate whether the measurement of maternal serum copeptin is useful for differentiation between fetal growth retardation and constitutionally small fetuses among small for gestational age fetuses. Study Design prospective case control clinical study. Patients and Methods Maternal serum copeptin levels were measured by ELISA technique in 53 pregnant females subdivided into a control group (group 1) of 20 women with normal gestation & a group of 33 pregnant women with small for gestational age fetuses. The small for gestational age fetuses were subclassified into constitutionally small fetuses (17 cases) with normal umbilical artery Doppler studies (group 2), and fetal growth restriction with abnormal umbilical artery Doppler studies (16 idiopathic cases) as group 3. Results The fetal growth restricted group had a significantly higher maternal serum copeptin levels as compared with the control group ( P P Conclusion Maternal serum copeptin level can differentiate between the normal sized and small for gestational age fetuses. Also, it can differentiate between constitutionally small and growth restricted fetuses.

Combined Sonographic Testing Index and Prediction of Adverse Outcome in Preterm Fetal Growth Restriction

We sought to test the hypothesis that a combined sonographic scoring system (CSTI) that incorporates features of the biophysical profile (BPP) and multivessel Doppler evaluation improves prediction of adverse outcomes in preterm intrauterine growth restriction. This was a prospective cohort study of growth-restricted fetuses with abnormal umbilical artery (UA) Doppler studies, defined as pulsatility index (PI) > 95 th percentile for gestational age or absent/reversed end diastolic flow. Fetuses were followed with weekly BPP and Doppler evaluation of the UA, middle cerebral artery (MCA), and ductus venosus (DV) until the time of delivery. The cerebroplacental Doppler ratio (CPR) was then calculated (MCA PI/UA PI). MCA PI < 5 th percentile, MCA peak systolic velocity (PSV) > 1.5 multiples of the median, DV PI > 95 th percentile with or without absent/reversed flow, and CPR < 1.08 were considered abnormal. Using logistic regression modeling, a weighted scoring index for the prediction of a composite fetal vulnerability index (FVI), which included 5-minute Apgar score < 3, cord pH < 7.2, seizures, necrotizing enterocolitis, grade 4 intraventricular hemorrhage, periventricular leukomalacia, and neonatal death, was developed. A receiver operating characteristic (ROC) curve was used to identify the best score associated with the FVI. Of 66 patients meeting inclusion criteria over a 5-year period, 17 (25.8%) had a positive FVI. Abnormal BPP (< 8), MCA PI, MCA PSV, DV PI, and CPR were observed in 6, 27.3, 13.6, 56.1, and 33.3% of patients, respectively. From the logistic regression model, a CSTI was developed including a score of 1 for abnormal BPP, 3 for MCA PSV, 1 for DV, 6 for CPR, and 3 for oligohydramnios. The ROC curve identified a score of ≥ 7 to be the best predictor of FVI with sensitivity of 35.1% and specificity of 91.8% and a positive likelihood ratio of 4.3 (area under ROC curve 0.73). These test characteristics were better than those for any of the individual component antenatal tests. Although this novel scoring system performs modestly in predicting adverse outcomes in FGR, it appears to perform better than any individual antenatal test currently available.

Egr‐1 transcription activation exists in placental endothelium when vascular disease is present

To seek evidence of early vascular injury in the placental villous microcirculation in placental insufficiency identified by a high-resistance umbilical Doppler study by examining for expression of fibroblast growth factor receptor-1 (FGFR-1), its transcription factor, early growth response factor-1 (Egr-1) and plasma fibroblast growth factor-2 (FGF-2). Case-control study. University teaching hospital. Placentas and umbilical vein blood were collected at delivery from 12 women with normal pregnancy delivered at term and 14 with placental vascular disease defined by an abnormal umbilical artery Doppler study. Microvascular endothelial cells were isolated from fresh human placentas using collagenase digestion and Dynabeads coated with monoclonal antibody against CD31. RNA was extracted from the isolated endothelial cells. The messenger RNA (mRNA) expression of FGFR-1 and Egr-1 production were assessed by reverse transcription polymerase chain reaction and factored relative to 18S ribosomal RNA. To confirm that FGF-2 was playing a significant role in this microvascular endothelial cell injury in the placenta, we also measured the soluble fraction of FGF-2 in fetal plasma from same groups of pregnancies using an enzyme-linked immunosorbent assay. Microvascular endothelial cells expression of Egr-1mRNA, FGFR-1 mRNA and presence of soluble FGF-2 in fetal plasma. The soluble level of FGF-2 in the fetal placental circulation from pregnancy with placental vascular disease was increased when compared with normal pregnancy (median 10.15 pg/ml and interquartile range 5.34-21.83 pg/ml versus 4.46 pg/ml and 3.69-5.66 pg/ml; P < 0.05). Microvascular endothelial cells from the placental villi with placental vascular disease showed upregulation of both FGFR-1 mRNA expression (median 0.72 and interquartile range 0.40-1.64 versus 0.34 and 0.19-0.71; P<0.05) and Egr-1 expression (median 0.79 and interquartile range 0.27-1.86 versus 0.23 and 0.17-0.67; P<0.05) in comparison with normal pregnancy. Endothelial cells from the placental villi are upregulated for expression of Egr-1 transcription factor gene in placental vascular disease. The FGFR-1 activation and increase in FGF-2 in the fetal circulation are known to be very early features of the response of endothelium to injury. Egr-1 is a promoter of many key pathophysiologically relevant target genes, which influence the development of subsequent vascular lesions. This change may occur before the pathological features recognised on microscopy.

Placental vascular disease and toll-like receptor 4 gene expression

Vascular disease in the placenta, which is identified by the study of umbilical artery Doppler flow velocity waveforms, is associated with endothelial cell activation and a proinflammatory cytokine response in the villous placental circulation. We studied toll-like receptor 4 expression (the ligand is lipopolysaccharide) to examine whether infection may cause these inflammatory components of placental vascular disease through an innate immune response. Microvessel endothelial cells were isolated from human placentae with collagenase digestion and then extracted with Dynabeads that were coated with monoclonal antibody against CD31. We studied 13 placentae from normal pregnancies that were delivered at term and 15 pregnancies with umbilical placental vascular disease that was defined by an abnormal umbilical artery Doppler study. We extracted RNA from the isolated endothelial cells. The messenger RNA expression of toll-like receptor 4 production was assessed by reverse transcriptase-polymerase chain reaction and factored relative to the glyceraldehyde-3-phosphate dehydrogenase and 18S ribosomal RNA genes. Microvessel endothelial cells from placental villi with placental vascular disease showed up-regulation of toll-like receptor 4 expression (toll-like receptor 4/18S, 1.92 +/- 0.37 vs 0.99 +/- 0.19; P < .05; toll-like receptor 4/glyceraldehyde-3-phosphate dehydrogenase, 2.20 +/- 0.36 vs 1.25 +/- 0.22; P < .05) in comparison with normal pregnancy. Up-regulation of toll-like receptor 4 gene in the endothelium of the placental villi is present in placental vascular disease, which may result from exposure of this endothelium to the toll-like receptor 4 ligand lipopolysaccharide in vivo. Directly extracted endothelial cells were used to avoid the possibility for change in behavior in tissue culture. We conclude that Gram-negative infection and lipopolysaccharide stimulation may cause placental vascular disease.

Interaction between risk factors for fetal growth retardation associated with abnormal umbilical artery Doppler studies.

The role of antenatal risk factors associated with the occurrence of fetal growth restriction complicated by abnormal umbilical artery Doppler studies has not yet been studied extensively. We evaluated the role and the interactions of antenatal antecedents of fetal growth restriction complicated by abnormal umbilical artery end-diastolic velocities. We compared antenatal variables in 183 pregnancies complicated by fetal growth retardation and abnormal umbilical artery Doppler studies and 549 appropriately grown fetuses with normal end-diastolic velocity waveform in the umbilical artery. Logistic regression was used to evaluate the association between antenatal variables and fetal growth retardation and to test for interaction. In logistic models, increasing maternal age [odds ratio (OR) 1.06, 95% confidence interval (CI) 1.01-1.11], nulliparity (OR 2.2, 95% CI 1.37-3.5), smoking during pregnancy (OR 2.56, 95% CI 1.56-4.22), preeclampsia (OR 27.5, 95% CI 15.1-49.9), first-trimester hemorrhage (OR 2.25, 95% CI 1.32-3.82) and low (< 0.2 kg/week) weight gain in pregnancy (OR 3.48, 95% CI 1.71-3.05) were significantly associated with an increased risk of fetal growth restriction complicated by abnormal Doppler studies. These risk factors were also significantly correlated with the occurrence of absent/reversed end-diastolic blood flow in the umbilical artery. Maternal smoking during pregnancy interacted negatively with preeclampsia but positively with a low weight gain in pregnancy. The results of this study have shown that antenatal risk factors for intrauterine growth retardation (IUGR) complicated by abnormal Doppler studies are similar to those associated with the birth of a small-for-gestational-age infant. Preeclampsia, maternal smoking and low weight gain in pregnancy play a significant causal role in the origin of fetal growth restriction associated with abnormal uteroplacental blood flow.

Microvascular endothelial cell activation is present in the umbilical placental microcirculation in fetal placental vascular disease

Objective Fetal growth restriction is associated with an abnormal umbilical artery Doppler study. A vascular disease is present in the fetal umbilical placental microcirculation. We hypothesized that the local production of factors that are injurious to microvessel endothelium is responsible for this vascular disease and that endothelial cell activation is a feature of this. Because the expression of the cell adhesion molecules is associated with endothelial cell activation, we isolated endothelial cells from the microvessels of the umbilical placenta and examined them for evidence of gene expression of cell adhesion molecules. Study design Endothelial cells from the microcirculation of human placenta were isolated and purified with collagenase digestion and extraction with superparamagnetic beads that were coated with monoclonal antibody against CD31. Microvessel endothelial cells were isolated from the placentae of 13 women with a normal pregnancy and delivery at term and 10 placentas with umbilical placental vascular disease that was defined by abnormal umbilical artery Doppler study. Total RNA was extracted from isolated endothelial cells. The messenger RNA expressions of cell adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and platelet endothelial cell adhesion molecule-1) were assessed by semiquantitative reverse transcription–polymerase chain reaction. Results Microvessel endothelial cells from the fetal placentae of pregnancies that were complicated by umbilical placental vascular disease showed an enhanced expression of intercellular adhesion molecule-1 messenger RNA (2.12±0.45 vs 0.92±0.25) and platelet endothelial cell adhesion molecule-1 messenger RNA (4.29±0.87 vs 2.41±0.42) in comparison to normal pregnancies. There was no significant difference in expression of vascular cell adhesion molecule-1 messenger RNA (1.55±0.37 vs 1.68±0.38). Conclusion We have shown that vascular disease in the fetal umbilical placental circulation is associated with an increase in the expression of intercellular adhesion molecule-1 and platelet endothelial cell adhesion molecule-1 by microvessel endothelial cells. We postulate that locally released factors cause injury and activation to microvessel endothelial cells. In this regard, the process in the fetus is similar to that of atherothrombotic vascular disease of later life.

Interaction between risk factors for fetal growth retardation associated with abnormal umbilical artery Doppler studies

Background. The role of antenatal risk factors associated with the occurrence of fetal growth restriction complicated by abnormal umbilical artery Doppler studies has not yet been studied extensively. We evaluated the role and the interactions of antenatal antecedents of fetal growth restriction complicated by abnormal umbilical artery end-diastolic velocities. Methods. We compared antenatal variables in 183 pregnancies complicated by fetal growth retardation and abnormal umbilical artery Doppler studies and 549 appropriately grown fetuses with normal end-diastolic velocity waveform in the umbilical artery. Logistic regression was used to evaluate the association between antenatal variables and fetal growth retardation and to test for interaction. Results. In logistic models, increasing maternal age [odds ratio (OR) 1.06, 95% confidence interval (CI) 1.01–1.11], nulliparity (OR 2.2, 95% CI 1.37–3.5), smoking during pregnancy (OR 2.56, 95% CI 1.56–4.22), preeclampsia (OR 27.5, 95% CI 15.1–49.9), first-trimester hemorrhage (OR 2.25, 95% CI 1.32–3.82) and low (< 0.2 kg/week) weight gain in pregnancy (OR 3.48, 95% CI 1.71–3.05) were significantly associated with an increased risk of fetal growth restriction complicated by abnormal Doppler studies. These risk factors were also significantly correlated with the occurrence of absent/reversed end-diastolic blood flow in the umbilical artery. Maternal smoking during pregnancy interacted negatively with preeclampsia but positively with a low weight gain in pregnancy. Conclusions. The results of this study have shown that antenatal risk factors for intrauterine growth retardation (IUGR) complicated by abnormal Doppler studies are similar to those associated with the birth of a small-for-gestational-age infant. Preeclampsia, maternal smoking and low weight gain in pregnancy play a significant causal role in the origin of fetal growth restriction associated with abnormal uteroplacental blood flow.

A proinflammatory cytokine response is present in the fetal placental vasculature in placental insufficiency

Objective Vascular disease in the umbilical placental circulation is associated with fetal growth restriction and adverse outcome. It may be identified antenatally by the study of umbilical artery Doppler flow velocity waveforms. The cause of this vascular disease is unknown. We have previously provided indirect evidence for endothelial cell activation and a proinflammatory cytokine response. Recently, a family of inhibitors of cytokine signaling has been identified, referred to as the suppressors of cytokine signaling (SOCS). Activation of SOCS occurs when cytokines are produced in stimulated cells. We tested the hypothesis that endothelial cell activation was present in umbilical placental vascular disease and was associated with production of proinflammatory cytokines and members of the family of SOCS. Study design Placentas were collected at delivery and microvascular endothelial cells were isolated. We studied 13 normal pregnancies and 10 with umbilical placental vascular disease identified by an abnormal umbilical artery Doppler study. Placental pieces were digested with collagenase and purified by adherence to Dynabeads coated with monoclonal antibody against CD31. The RNA was extracted from isolated endothelial cells. The messenger RNA expression of cytokine production (interleukin-6 and interleukin-8) and the members of SOCS family (CIS, SOCS1, SOCS2, and SOCS3) were assessed by use of semiquantitative reverse transcriptase–polymerase chain reaction. Results In the microcirculation of the placenta, endothelial cell expression of interleukin-6 messenger RNA (2.50±0.60 vs 1.25±0.26) and interleukin-8 messenger RNA (2.83±0.55 vs 1.58±0.27) was up-regulated in umbilical placental vascular disease in comparison to normal pregnancy. The endothelial cell mRNA expression of SOCS2 (3.36±0.77 vs 1.76±0.29) and SOCS3 (2.77±0.60 vs 1.48±0.26) was enhanced in placental vascular disease. There was no significant difference in expression of CIS and SOCS1 in microvessel endothelial cells. Conclusion We have demonstrated that microvessel endothelium of the fetal placental vasculature produces both the proinflammatory cytokines (interleukin-6 and interleukin-8) and members of SOCS family (SOCS2 and SOCS3) in umbilical placental vascular disease. This cytokine production may play a key role in the interaction of endothelial cells of the placenta villi with neighboring cells. The up-regulation of SOCS2 and SOCS3 indicates these are the major negative regulators in umbilical placental microvessel endothelial cell activation pathways. By its occurrence, this also confirms the presence of a proinflammatory cytokine response.

The Doppler Assessment in multiple pregnancy randomised controlled trial of ultrasound biometry versus umbilical artery Doppler ultrasound and biometry in twin pregnancy

Objective To assess the addition value of umbilical artery Doppler ultrasound added to standard ultrasound biometry measurements in the management of twin pregnancies. Design A prospective randomised controlled multicentre trial of women with twin pregnancies. Setting Tertiary level referral hospitals in Australia, New Zealand and Southeast Asia. Population Pregnant women with twin pregnancies. Methods Women were randomised at 25 weeks of gestation to receive either standard ultrasound biometric assessment or standard assessment plus Doppler ultrasound umbilical artery flow velocity waveform analysis. The studies were repeated at 30 and 35 weeks unless otherwise indicated. Physicians were advised to institute close fetal surveillance in the presence of an abnormal umbilical artery Doppler study or with biometry indicators of fetal compromise. Main outcome measures Standard obstetric (mode of delivery, perinatal mortality, hypertension, antenatal admissions and gestation at delivery) and neonatal (5 minute Apgar scores <5, admissions to neonatal nursery and requirements for ventilation) outcomes and statistical analysis was on intention-to-treat. Results There were no significant differences between the two groups with respect to demography, antenatal, peripartum and neonatal outcomes. There was no difference in the perinatal mortality rate in the no Doppler group ( n = 264), which was 11/1000 live births, and the Doppler group ( n = 262), which was 9/1000 live births. There were three unexplained intrauterine deaths in the no Doppler group and none in the Doppler group (OR 0.14, 95% CI 0.01–1.31). Two intrauterine deaths in the Doppler group were due to cord prolapse in labour and a fetomaternal haemorrhage, both very unlikely to be influenced by Doppler surveillance. Conclusions In this study, close surveillance in twin pregnancy resulted in a lower than expected fetal mortality from 25 weeks of gestation in both the no Doppler and Doppler groups. The lower rate of unexplained fetal death in the no Doppler group was not significantly different from the Doppler group.

The Doppler Assessment in multiple pregnancy randomised controlled trial of ultrasound biometry versus umbilical artery Doppler ultrasound and biometry in twin pregnancy

To assess the addition value of umbilical artery Doppler ultrasound added to standard ultrasound biometry measurements in the management of twin pregnancies. A prospective randomised controlled multicentre trial of women with twin pregnancies. Tertiary level referral hospitals in Australia, New Zealand and Southeast Asia. Pregnant women with twin pregnancies. Women were randomised at 25 weeks of gestation to receive either standard ultrasound biometric assessment or standard assessment plus Doppler ultrasound umbilical artery flow velocity waveform analysis. The studies were repeated at 30 and 35 weeks unless otherwise indicated. Physicians were advised to institute close fetal surveillance in the presence of an abnormal umbilical artery Doppler study or with biometry indicators of fetal compromise. Standard obstetric (mode of delivery, perinatal mortality, hypertension, antenatal admissions and gestation at delivery) and neonatal (5 minute Apgar scores <5, admissions to neonatal nursery and requirements for ventilation) outcomes and statistical analysis was on intention-to-treat. There were no significant differences between the two groups with respect to demography, antenatal, peripartum and neonatal outcomes. There was no difference in the perinatal mortality rate in the no Doppler group (n = 264), which was 11/1000 live births, and the Doppler group (n = 262), which was 9/1000 live births. There were three unexplained intrauterine deaths in the no Doppler group and none in the Doppler group (OR 0.14, 95% CI 0.01-1.31). Two intrauterine deaths in the Doppler group were due to cord prolapse in labour and a fetomaternal haemorrhage, both very unlikely to be influenced by Doppler surveillance. In this study, close surveillance in twin pregnancy resulted in a lower than expected fetal mortality from 25 weeks of gestation in both the no Doppler and Doppler groups. The lower rate of unexplained fetal death in the no Doppler group was not significantly different from the Doppler group.