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Background: The great obstetrical syndromes of fetal growth restriction and hypertensive disorders of pregnancy can occur individually or be interrelated. Placental pathologic findings often overlap between these conditions, regardless of whether 1 or both diagnoses are present. Quantification of placental villous structures in each of these settings may identify distinct differences in developmental pathways., Objective: This study aimed to determine how the quantity and surface area of placental villi and vessels differ between severe, early-onset fetal growth restriction with absent or reversed umbilical artery Doppler indices and hypertensive disorders of pregnancy or the 2 conditions combined among subjects with disease severity that warrant early preterm delivery. We hypothesized that the trajectories of placental morphogenesis diverge after a common initiating insult of deep defective placentation. Specifically, we postulated that only villi are affected in pregnancy-related hypertension, whereas both villous and vascular structures are proportionally diminished in severe fetal growth restriction with no additional effect when hypertension is concomitantly present., Study Design: In this retrospective cohort study, paraffin-embedded placental tissue was obtained from 4 groups, namely (1) patients with severe fetal growth restriction with absent or reversed umbilical artery end-diastolic velocities and hypertensive disorders of pregnancy, (2) patients with severe fetal growth restriction with absent or reversed umbilical artery Doppler indices and no hypertension, (3) gestational age-matched, appropriately grown pregnancies with hypertensive disease, and (4) gestational age-matched, appropriately grown pregnancies without hypertension. Dual immunohistochemistry for cytokeratin-7 (trophoblast) and CD34 (endothelial cells) was performed, followed by artificial intelligence-driven morphometric analyses. The number of villi, total villous area, number of fetoplacental vessels, and total vascular area across villi within a uniform region of interest were quantified. Quantitative analyses of placental structures were modeled using linear regression., Results: Placentas from pregnancies complicated by hypertensive disorders of pregnancy exhibited significantly fewer stem villi (-282 stem villi; 95% confidence interval, -467 to -98; P<.01), a smaller stem villous area (-4.3 mm 2 ; 95% confidence interval, -7.3 to -1.2; P<.01), and fewer stem villous vessels (-4967 stem villous vessels; 95% confidence interval, -8501 to -1433; P<.01) with no difference in the total vascular area. In contrast, placental abnormalities in cases with severe growth restriction were limited to terminal villi with global decreases in the number of villi (-873 terminal villi; 95% confidence interval, -1501 to -246; P<.01), the villous area (-1.5 mm 2 ; 95% confidence interval, -2.7 to -0.4; P<.01), the number of blood vessels (-5165 terminal villous vessels; 95% confidence interval, -8201 to -2128; P<.01), and the vascular area (-0.6 mm 2 ; 95% confidence interval, -1.1 to -0.1; P=.02). The combination of hypertension and growth restriction had no additional effect beyond the individual impact of each state., Conclusion: Pregnancies complicated by hypertensive disorders of pregnancy exhibited defects in the stem villi only, whereas placental abnormalities in severely growth restricted pregnancies with absent or reversed umbilical artery end-diastolic velocities were limited to the terminal villi. There were no significant statistical interactions in the combination of growth restriction and hypertension, suggesting that distinct pathophysiological pathways downstream of the initial insult of defective placentation are involved in each entity and do not synergize to lead to more severe pathologic consequences. Delineating mechanisms that underly the divergence in placental development after a common inciting event of defective deep placentation may shed light on new targets for prevention or treatment., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Assessing the umbilical artery pulsatility index via Doppler measurements plays a crucial role in evaluating fetal growth impairment., Objective: This study aimed to investigate perinatal outcomes associated with discordant pulsatility indices of umbilical arteries in fetuses with growth restriction., Study Design: In this retrospective cohort study, all singleton pregnancies were included if their estimated fetal weight and/or abdominal circumference fell below the 10th percentile for gestational age (2017-2022). Eligible cases included singleton pregnancies with concurrent sampling of both umbilical arteries within 14 days of birth at the ultrasound evaluation closest to delivery. The exclusion criteria included births before 22 weeks of gestation, evidence of absent or reverse end-diastolic flow in either umbilical artery, and known fetal genetic or structural anomalies. The study compared cases with discordant umbilical artery pulsatility index values (defined as 1 umbilical artery pulsatility index at ≤95th percentile and the other umbilical artery pulsatility index at >95th percentile for gestational age) to pregnancies where both umbilical artery pulsatility indices had normal pulsatility index values and those with both umbilical arteries displaying abnormal pulsatility index values. The primary outcome assessed was the occurrence of composite adverse neonatal outcomes. Multivariable logistic regressions were performed, adjusting for relevant covariates., Results: The study encompassed 1014 patients, including 194 patients (19.1%) with discordant umbilical artery pulsatility index values among those who had both umbilical arteries sampled close to delivery, 671 patients (66.2%) with both umbilical arteries having normal pulsatility index values, and 149 patients (14.7%) with both umbilical arteries exhibiting abnormal values. Pregnancies with discordant umbilical artery pulsatility index values displayed compromised sonographic parameters compared with those with both umbilical arteries showing normal pulsatility index values. Similarly, the number of abnormal umbilical artery pulsatility index values was associated with adverse perinatal outcomes in a dose-response manner. Cases with 1 abnormal (discordant) umbilical artery pulsatility index value showed favorable sonographic parameters and perinatal outcomes compared with cases with both abnormal umbilical artery pulsatility index values, and cases with both abnormal umbilical artery pulsatility index values showed worse sonographic parameters and perinatal outcomes compared with cases with discordant UA PI values. Multivariate analysis revealed that discordant umbilical artery pulsatility indices were significantly and independently associated with composite adverse perinatal outcomes, with an adjusted odds ratio of 1.75 (95% confidence interval, 1.24-2.47; P = .002)., Conclusion: Evaluating the resistance indices of both umbilical arteries may provide useful data and assist in assessing adverse perinatal outcomes among fetuses with growth restriction., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Pregnancies with small-for-gestational-age fetuses are at increased risk of adverse maternal-fetal outcomes. Previous studies examining the relationship between maternal hemodynamics and fetal growth were mainly focused on high-risk pregnancies and those with fetuses with extreme birthweights, such as less than the 3rd or 10th percentile and assumed a similar growth pattern in fetuses above the 10th percentile throughout gestation., Objective: This study aimed to evaluate the trends in maternal cardiac function, fetal growth, and oxygenation with advancing gestational age in a routine obstetrical population and all ranges of birthweight percentiles., Study Design: This was a prospective, longitudinal study assessing maternal cardiac output and peripheral vascular resistance by bioreactance at 11 +0 to 13 +6 , 19 +0 to 24 +0 , 30 +0 to 34 +0 , and 35 +0 to 37 +0 weeks' gestation, sonographic estimated fetal weight in the last 3 visits and the ratio of the middle cerebral artery by umbilical artery pulsatility indices or cerebroplacental ratio in the last 2 visits. Women were divided into the following 5 groups according to birthweight percentile: group 1, <10th percentile (n=261); group 2, 10 to 19.9 percentile (n=180); group 3, 20 to 29.9 percentile (n=189); group 4, 30 to 69.9 percentile (n=651); and group 5, ≥70th percentile (n=508). The multilevel linear mixed-effects model was performed to compare the repeated measures of hemodynamic variables and z scores of the estimated fetal weight and cerebroplacental ratio., Results: In visit 2, compared with visit 1, in all groups, cardiac output increased, and peripheral vascular resistance decreased. At visit 3, groups 1, 2, and 3, compared with 4 and 5, demonstrated an abrupt decrease in cardiac output and increase in peripheral vascular resistance. From visit 2, group 1 had a constant decline in estimated fetal weight, coinciding with the steepest decline in maternal cardiac output and rise in peripheral vascular resistance. In contrast, in groups 4 and 5, the estimated fetal weight had a stable or accelerative pattern, coinciding with the greatest increase in cardiac output and lowest peripheral vascular resistance. Groups 2 and 3 showed a stable growth pattern with intermediate cardiac output and peripheral vascular resistance. Increasing birthweight was associated with higher cerebroplacental ratio. Groups 3, 4, and 5 had stable cerebroplacental ratio across visits 3 and 4, whereas groups 1 and 2 demonstrated a significant decline (P<.001)., Conclusion: In a general obstetrical population, maternal cardiac adaptation at 32 weeks' gestation parallels the pattern of fetal growth and oxygenation; babies with birthweight<20th percentile have progressive decline in fetal cerebroplacental ratio, decline in maternal cardiac output, and increase in peripheral vascular resistance., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

Background: The diagnostic criteria for preeclampsia have evolved from the traditional definition of de novo hypertension and proteinuria to a broader definition of hypertension with evidence of end-organ dysfunction. Although this change is endorsed by various societies such as the International Society for the Study of Hypertension in Pregnancy and the American College of Obstetricians and Gynecologists, there remains controversy with regard to the implementation of broader definitions and the most appropriate definition of end-organ dysfunction., Objective: This study aimed to assess the impact of different diagnostic criteria for preeclampsia on rates of disease diagnosis, disease severity, and adverse outcomes and to identify associations between each component of the different diagnostic criteria and adverse pregnancy outcomes., Study Design: We performed a retrospective cohort study of singleton pregnancies at Monash Health between January 1, 2016 and July 31, 2018. Within this population, all cases of gestational hypertension and preeclampsia were reclassified according to the International Society for the Study of Hypertension in Pregnancy 2001, American College of Obstetricians and Gynecologists 2018, and International Society for the Study of Hypertension in Pregnancy 2018 criteria. Differences in incidence of preeclampsia and maternal and perinatal outcomes were compared between the International Society for the Study of Hypertension in Pregnancy 2001 group and the extra cases identified by American College of Obstetricians and Gynecologists 2018 and International Society for the Study of Hypertension in Pregnancy 2018. Outcomes assessed included biochemical markers of preeclampsia, a composite of adverse maternal outcomes, and a composite of adverse perinatal outcomes. Multiple logistic regression analysis was also performed to assess each component of the American College of Obstetricians and Gynecologists 2018 and International Society for the Study of Hypertension in Pregnancy 2018 criteria and their associations with adverse maternal and perinatal outcomes., Results: Of 22,094 pregnancies, 751 (3.4%) women had preeclampsia as defined by any of the 3 criteria. Compared with International Society for the Study of Hypertension in Pregnancy 2001, the American College of Obstetricians and Gynecologists 2018 criteria identified an extra 42 women (n=654 vs n=696, 6.4% relative increase) with preeclampsia, and International Society for the Study of Hypertension in Pregnancy 2018 identified an extra 97 women (n=654 vs n=751, 14.8% relative increase). The additional women identified by International Society for the Study of Hypertension in Pregnancy 2018 exhibited a milder form of disease with lower rates of severe hypertension (62.4% vs 44.3%; P<.01) and magnesium sulfate use (11.9% vs 4.1%; P<.05) and a trend toward lower rates of adverse maternal outcomes (9.8% vs 4.1%). These women also delivered at a later gestation, and their babies had a lower number of neonatal intensive care unit admissions and adverse perinatal outcomes. Objective features such as fetal growth restriction, thrombocytopenia, renal and liver impairment, and proteinuria were associated with an increased risk of adverse maternal and perinatal outcomes, whereas subjective neurologic features demonstrated poorer associations., Conclusion: Implementation of broader definitions of preeclampsia will result in an increased incidence of disease diagnosis. However, because women who exclusively fulfill the new criteria have a milder phenotype of the disease, it remains uncertain whether this will translate to improved outcomes., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To determine whether abnormal global, transverse, and longitudinal ventricular contractility of the heart in fetuses with an estimated fetal weight <10th centile is present, irrespective of Doppler studies of the umbilical artery and cerebroplacental ratio., Study Design: This was a retrospective study of 50 fetuses with an estimated fetal weight <10th centile that were classified based on Doppler results from the pulsatility indices of the umbilical artery and middle cerebral artery, and the calculated cerebroplacental ratio (pulsatility indices of the umbilical artery/middle cerebral artery). Right and left ventricular measurements were categorized into 3 groups: (1) global ventricular contractility (fractional area change), (2) transverse ventricular contractility (24-segment transverse fractional shortening), and (3) basal-apical longitudinal contractility (longitudinal strain, longitudinal displacement fractional shortening, and basal lateral and septal wall annular plane systolic excursion). Z scores for the above measurements were computed for fetuses with an estimated fetal weight <10th centile using the mean and standard deviation derived from normal controls. Ventricular contractility measurements were considered abnormal if their Z score values were <5th centile (z score <-1.65) or >95th centile (Z score >1.65), depending on the specific ventricular measurement., Results: The average gestational age at the time of the examination was 32 weeks 4 days (standard deviation 3 weeks 4 days). None of the 50 study fetuses demonstrated absent or reverse flow of the umbilical artery Doppler waveform. Eighty-eight percent (44/50) of fetuses had one or more abnormal measurements of cardiac contractility of 1 or both ventricles. Analysis of right ventricular contractility demonstrated 78% (39/50) to have 1 or more abnormal measurements, which were grouped as follows: global contractility 38% (19/50), transverse contractility 66% (33/50); and longitudinal contractility 48% (24/50). Analysis of left ventricular contractility demonstrated 1 or more abnormal measurements in 58% (29/50) that were grouped as follows: global contractility 38% (19/50); transverse contractility 40% (20/50); and longitudinal contractility 40% (20/50). Of the 50 study fetuses, 25 had normal pulsatility index of the umbilical artery and cerebroplacental ratios, 80% of whom had 1 or more abnormalities of right ventricular contractility and 56% of whom had 1 or more abnormalities of left ventricular contractility. Abnormal ventricular contractility for these fetuses was present in all 3 groups of measurements; global, transverse, and longitudinal. Those with an isolated abnormal pulsatility index of the umbilical artery (n=11) had abnormalities of transverse contractility of the right ventricular and global contractility in the left ventricle. When an isolated cerebroplacental ratio abnormality was present, the right ventricle demonstrated abnormal global, transverse, and longitudinal contractility, with the left ventricle only demonstrating abnormalities in transverse contractility. When both the pulsatility index of the umbilical artery and cerebroplacental ratio were abnormal (3/50), transverse and longitudinal contractility measurements were abnormal for both ventricles, as well as abnormal global contractility of the left ventricle., Conclusions: High rates of abnormal ventricular contractility were present in fetuses with an estimated fetal weight <10th centile, irrespective of the Doppler findings of the pulsatility index of the umbilical artery, and/or cerebroplacental ratio. Abnormalities of ventricular contractility were more prevalent in transverse measurements than global or longitudinal measurements. Abnormal transverse contractility was more common in the right than the left ventricle. Fetuses with estimated fetal weight less than the 10th centile may be considered to undergo assessment of ventricular contractility, even when Doppler measurements of the pulsatility index of the umbilical artery, and cerebroplacental ratio are normal., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Fetal growth restriction accounts for a significant proportion of perinatal morbidity and death. The cerebroplacental ratio is gaining much interest as a useful tool in differentiating the "at-risk" fetus in both fetal growth restriction and appropriate-for-gestational-age pregnancies. The Prospective Observational Trial to Optimize Pediatric Health in Fetal Growth Restriction group has demonstrated previously that the presence of this "brain-sparing" effect is associated significantly with adverse perinatal outcomes in the fetal growth restriction cohort. However, data about neurodevelopment in children from pregnancies that are complicated by fetal growth restriction are sparse and conflicting., Objective: The aim of the Prospective Observational Trial to Optimize Pediatric Health in Fetal Growth Restriction NeuroDevelopmental Assessment Study was to determine whether children born after fetal growth-restricted pregnancies are at additional risk of adverse early childhood developmental outcomes compared with children born small for gestational age. The objective of this secondary analysis was to describe the role of cerebroplacental ratio in the prediction of adverse early childhood neurodevelopmental outcome., Study Design: Participants were recruited prospectively from the Perinatal Ireland multicenter observational Prospective Observational Trial to Optimize Pediatric Health in Fetal Growth Restriction study cohort. Fetal growth restriction was defined as birthweight <10th percentile with abnormal antenatal umbilical artery Doppler indices. Small for gestational age was defined similarly in the absence of abnormal Doppler indices. Cerebroplacental ratio was calculated with the pulsatility indices of the middle cerebral artery and divided by umbilical artery with an abnormal value <1. Children (n=375) were assessed at 3 years with the use of the Ages and Stages Questionnaire and the Bayley Scales of Infant and Toddler Development, 3rd edition. Small-for-gestational-age pregnancies with normal Doppler indices were compared with (1) fetal growth-restricted cases with abnormal umbilical artery Doppler and normal cerebroplacental ratio or (2) fetal growth restriction cases with both abnormal umbilical artery and cerebroplacental ratio. Statistical analysis was performed with statistical software via 2-sample t-test with Bonferroni adjustment, and a probability value of .00625 was considered significant., Results: Assessments were performed on 198 small-for-gestational-age children, 136 fetal growth-restricted children with abnormal umbilical artery Doppler images and normal cerebroplacental ratio, and 41 fetal growth-restricted children with both abnormal umbilical artery Doppler and cerebroplacental ratio. At 3 years of age, although there were no differences in head circumference, children who also had an abnormal cerebroplacental ratio had persistently shorter stature (P=.005) and lower weight (P=.18). Children from fetal growth restriction-affected pregnancies demonstrated poorer neurodevelopmental outcome than their small-for-gestational-age counterparts. Fetal growth-restricted pregnancies with an abnormal cerebroplacental ratio had significantly poorer neurologic outcome at 3 years of age across all measured variables., Conclusion: We have demonstrated that growth-restricted pregnancies with a cerebroplacental ratio <1 have a significantly increased risk of delayed neurodevelopment at 3 years of age when compared with pregnancies with abnormal umbilical artery Doppler evidence alone. This study further substantiates the benefit of routine assessment of cerebroplacental ratio in fetal growth-restricted pregnancies and for counseling parents regarding the long-term outcome of affected infants., (Copyright © 2019. Published by Elsevier Inc.)

Background: Infants born small for gestational age because of pathologic placenta-mediated fetal growth restriction can be difficult to distinguish from those who are constitutionally small. Additionally, even among fetal growth-restricted pregnancies with evident placental disease, considerable heterogeneity in clinical outcomes and long-term consequences has been observed. Gene expression studies of fetal growth-restricted placentas also have limited consistency in their findings, which is likely due to the presence of different molecular subtypes of disease. In our previous study on preeclampsia, another heterogeneous placenta-centric disorder of pregnancy, we found that, by clustering placentas based only on their gene expression profiles, multiple subtypes of preeclampsia, including several with co-occurring suspected fetal growth restriction, could be identified., Objective: The purpose of this study was to discover placental subtypes of normotensive small-for-gestational-age pregnancies with suspected fetal growth restriction through the use of unsupervised clustering of placental gene expression data and to investigate their relationships with hypertensive suspected fetal growth-restricted placental subtypes., Study Design: A new dataset of 20 placentas from normotensive small-for-gestational-age pregnancies (birthweight <10th percentile for gestational age and sex) with suspected fetal growth restriction (ultrasound features of placental insufficiency) underwent genome-wide messenger RNA expression assessment and blinded detailed histopathologic evaluation. These samples were then combined with a subset of samples from our previously published preeclampsia cohort (n=77) to form an aggregate fetal growth-focused cohort (n=97) of placentas from normotensive small-for-gestational-age, hypertensive (preeclampsia and chronic hypertensive) small-for-gestational-age, and normotensive average-for-gestational-age pregnancies. Gene expression data were subjected to unsupervised clustering, and clinical and histopathologic features were correlated to the identified sample clusters., Results: Clustering of the aggregate dataset revealed 3 transcriptional subtypes of placentas from normotensive small-for-gestational-age/suspected fetal growth-restricted pregnancies, with differential enrichment of clinical and histopathologic findings. The first subtype exhibited either no placental disease or mild maternal vascular malperfusion lesions, and, co-clustered with the healthy average-for-gestational-age control subjects; the second subtype showed more severe evidence of hypoxic damage and lesions of maternal vascular malperfusion, and the third subtype demonstrated an immune/inflammatory response and histologic features of a maternal-fetal interface disturbance. Furthermore, all 3 of these normotensive small-for-gestational-age subtypes co-clustered with a group of placentas from hypertensive small-for-gestational-age pregnancies with more severe clinical outcomes, but very comparable transcriptional and histologic placental profiles., Conclusion: Overall, this study provides evidence for at least 2 pathologic placental causes of normotensive small-for-gestational-age, likely representing true fetal growth restriction. These subtypes also show considerable similarity in gene expression and histopathology to our previously identified "canonical" and "immunologic" preeclampsia placental subtypes. Furthermore, we discovered a subtype of normotensive small-for-gestational-age (with suspected fetal growth restriction) with minimal placental disease that may represent both constitutionally small infants and mild fetal growth restriction, although these cannot be distinguished with the currently available data. Future work that focuses on the identification of etiology-driven biomarkers and therapeutic interventions for each subtype of fetal growth restriction is warranted., (Copyright © 2018. Published by Elsevier Inc.)

Background: Preeclampsia and fetal growth restriction are considered to be placentally mediated disorders. The clinical manifestations are widely held to relate to gestation age at onset with early- and late-onset preeclampsia considered to be phenotypically distinct. Recent studies have reported conflicting findings in relation to cardiovascular function, and in particular cardiac output, in preeclampsia and fetal growth restriction., Objective: We conducted this study to examine the possible relation between cardiac output and peripheral vascular resistance in preeclampsia and fetal growth restriction., Study Design: We investigated maternal cardiovascular function in relation to clinical subtype in 45 pathological pregnancies (14 preeclampsia only, 16 fetal growth restriction only, 15 preeclampsia and fetal growth restriction) and compared these with 107 healthy person observations. Cardiac output was the primary outcome measure and was assessed using an inert gas-rebreathing method (Innocor), from which peripheral vascular resistance was derived; arterial function was assessed by Vicorder, a cuff-based oscillometric device. Cardiovascular parameters were normalized for gestational age in relation to healthy pregnancies using Z scores, thus allowing for comparison across the gestational range of 24-40 weeks., Results: Compared with healthy control pregnancies, women with preeclampsia had higher cardiac output Z scores (1.87 ± 1.35; P = .0001) and lower peripheral vascular resistance Z scores (-0.76 ± 0.89; P = .025); those with fetal growth restriction had higher peripheral vascular resistance Z scores (0.57 ± 1.18; P = .04) and those with both preeclampsia and fetal growth restriction had lower cardiac output Z scores (-0.80 ± 1.3 P = .007) and higher peripheral vascular resistance Z scores (2.16 ± 1.96; P = .0001). These changes were not related to gestational age of onset. All those affected by preeclampsia and/or fetal growth restriction had abnormally raised augmentation index and pulse wave velocity. Furthermore, in preeclampsia, low cardiac output was associated with low birthweight and high cardiac output with high birthweight (r = 0.42, P = .03)., Conclusion: Preeclampsia is associated with high cardiac output, but if preeclampsia presents with fetal growth restriction, the opposite is true; both conditions are nevertheless defined by hypertension. Fetal growth restriction without preeclampsia is associated with high peripheral vascular resistance. Although early and late gestation preeclampsias are considered to be different diseases, we show that the hemodynamic characteristics of preeclampsia were unrelated to gestational age at onset but were strongly associated with the presence or absence of fetal growth restriction. Fetal growth restriction more commonly coexists with preeclampsia at early gestation, thus explaining the conflicting results of previous studies. Furthermore, antihypertensive agents act by reducing cardiac output or peripheral vascular resistance and are administered without reference to cardiovascular function in preeclampsia. The underlying pathology (preeclampsia, fetal growth restriction, preeclampsia and fetal growth restriction) defines cardiovascular phenotype, providing a rational basis for choice of therapy in which high or low cardiac output or peripheral vascular resistance is the predominant feature., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Placental-related fetal growth restriction arises primarily due to deficient remodeling of the uterine spiral arteries supplying the placenta during early pregnancy. The resultant malperfusion induces cell stress within the placental tissues, leading to selective suppression of protein synthesis and reduced cell proliferation. These effects are compounded in more severe cases by increased infarction and fibrin deposition. Consequently, there is a reduction in villous volume and surface area for maternal-fetal exchange. Extensive dysregulation of imprinted and nonimprinted gene expression occurs, affecting placental transport, endocrine, metabolic, and immune functions. Secondary changes involving dedifferentiation of smooth muscle cells surrounding the fetal arteries within placental stem villi correlate with absent or reversed end-diastolic umbilical artery blood flow, and with a reduction in birthweight. Many of the morphological changes, principally the intraplacental vascular lesions, can be imaged using ultrasound or magnetic resonance imaging scanning, enabling their development and progression to be followed in vivo. The changes are more severe in cases of growth restriction associated with preeclampsia compared to those with growth restriction alone, consistent with the greater degree of maternal vasculopathy reported in the former and more extensive macroscopic placental damage including infarcts, extensive fibrin deposition and microscopic villous developmental defects, atherosis of the spiral arteries, and noninfectious villitis. The higher level of stress may activate proinflammatory and apoptotic pathways within the syncytiotrophoblast, releasing factors that cause the maternal endothelial cell activation that distinguishes between the 2 conditions. Congenital anomalies of the umbilical cord and placental shape are the only placental-related conditions that are not associated with maldevelopment of the uteroplacental circulation, and their impact on fetal growth is limited., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: The objective of the study was to establish the risk of fetal death in early-onset growth-restricted fetuses with absent or reversed end-diastolic velocities in the umbilical artery or ductus venosus., Data Sources: A systematic search was performed to identify relevant studies published in English, Spanish, French, Italian, or German using the databases PubMed, ISI Web of Science, and SCOPUS, without publication time restrictions., Study Eligibility Criteria: The study criteria included observational cohort studies and randomized controlled trials of early-onset growth-restricted fetuses (diagnosed before 34 weeks of gestation), with information on the rate of fetal death occurring before 34 weeks of gestation and absent or reversed end-diastolic velocities in the umbilical artery and/or ductus venosus., Study Appraisal and Synthesis Methods: For quality assessment, 2 reviewers independently assessed the risk of bias using the Newcastle-Ottawa Scale for observational studies and the Cochrane Collaboration's tool for randomized trials. For the meta-analysis, odds ratio for both fixed and random-effects models (weighting by inverse of variance) were used. Heterogeneity between studies was assessed using tau 2 , χ2 (Cochrane Q), and I 2 statistics. Publication bias was assessed by a funnel plot for meta-analyses and quantified by the Egger method., Results: A total of 31 studies were included in this meta-analysis. The odds ratios for fetal death (random-effects models) were 3.59 (95% confidence interval, 2.3-5.6), 7.27 (95% confidence interval, 4.6-11.4), and 11.6 (95% confidence interval, 6.3-19.7) for growth-restricted fetuses with umbilical artery absent end-diastolic velocities, umbilical artery reversed end-diastolic velocities, and ductus venosus absent or reversed end-diastolic velocities, respectively. There was no substantial heterogeneity among studies for any of the analyses., Conclusion: Early-onset growth-restricted fetuses with either umbilical artery or ductus venosus absent or reserved end-diastolic velocities are at a substantially increased risk for fetal death., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The cerebroplacental ratio has been proposed as a marker of failure to reach growth potential near term. Low cerebroplacental ratio, regardless of the fetal size, is independently associated with the need for operative delivery for presumed fetal compromise and with neonatal unit admission at term., Objective: The main aim of this study was to evaluate whether the cerebroplacental ratio at term is a marker of reduced fetal growth rate. The secondary aim was to investigate the relationship between a low cerebroplacental ratio at term, reduced fetal growth velocity, and adverse pregnancy outcome., Study Design: This was a retrospective cohort study of singleton pregnancies in a tertiary referral center. The abdominal circumference was measured at 20-24 weeks' gestation and both abdominal circumference and fetal Dopplers recorded at or beyond 35 weeks, within 2 weeks of delivery. Abdominal circumference and birthweight values were converted into Z scores and centiles, respectively, and fetal Doppler parameters into multiples of median, adjusting for gestational age. Abdominal circumference growth velocity was quantified using the difference in the abdominal circumference Z score, comparing the scan at or beyond 35 weeks with the scan at 20-24 weeks. Both univariable and multivariable logistic regression analyses were performed to investigate the association between low cerebroplacental ratio and the low abdominal circumference growth velocity (in the lowest decile) and to identify and adjust for potential confounders. As a sensitivity analysis, we refitted the model excluding the data on pregnancies with small-for-gestational-age neonates., Results: The study included 7944 pregnancies. Low cerebroplacental ratio multiples of median was significantly associated with both low abdominal circumference growth velocity (adjusted odds ratio, 2.10; 95% confidence interval, 1.71-2.57, P <0.001) and small for gestational age (adjusted odds ratio, 3.60; 95% confidence interval, 3.04-4.25, P < .001). After the exclusion of pregnancies resulting in small-for-gestational-age neonates, a low cerebroplacental ratio multiples of the median remained significantly associated with both low abdominal circumference growth velocity (adjusted odds ratio, 1.76; 95% confidence interval, 1.34-2.30, P < .001) and birthweight centile (adjusted odds ratio, 0.99; 95% confidence interval, 0.998-0.995, P < .001). The need for operative delivery for fetal compromise was significantly associated with a low cerebroplacental ratio (adjusted odds ratio, 1.40; 95% confidence interval, 1.10-1.78, P = .006), even after adjusting for both the umbilical artery pulsatility index multiples of the median and middle cerebral artery pulsatility index multiples of median. The results were similar, even after the exclusion of pregnancies resulting in small-for-gestational-age neonates (adjusted odds ratio, 1.39; 95% confidence interval, 1.06-1.84, P = .018). Low cerebroplacental ratio multiples of the median remained significantly associated with the risk of operative delivery for presumed fetal compromise (P < .001), even after adjusting for the known antenatal and intrapartum risk factors. These associations persisted, even after the exclusion of small-for-gestational-age births. In appropriate-for-gestational-age-sized fetuses, abdominal circumference growth velocity was significantly lower in those with a low cerebroplacental ratio multiples of the median than in those with normal cerebroplacental ratio multiples of the median (P < .001)., Conclusion: The cerebroplacental ratio is a marker of impaired fetal growth velocity and adverse pregnancy outcome, even in fetuses whose size is considered appropriate using conventional biometry., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Intrauterine growth restriction accounts for a significant proportion of perinatal morbidity and mortality currently encountered in obstetric practice. The primary goal of antenatal care is the early recognition of such conditions to allow treatment and optimization of both maternal and fetal outcomes. Management of pregnancies complicated by intrauterine growth restriction remains one of the greatest challenges in obstetrics. Frequently, however, clinical evidence of underlying uteroplacental dysfunction may only emerge at a late stage in the disease process. With advanced disease the only therapeutic intervention is delivery of the fetus and placenta. The cerebroplacental ratio is gaining much interest as a useful tool in differentiating the at-risk fetus in both intrauterine growth restriction and the appropriate-for-gestational-age setting. The cerebroplacental ratio quantifies the redistribution of the cardiac output resulting in a brain-sparing effect. The Prospective Observational Trial to Optimize Pediatric Health in Intrauterine Growth Restriction group previously demonstrated that the presence of a brain-sparing effect is significantly associated with an adverse perinatal outcome in the intrauterine growth restriction cohort., Objective: The aim of the Prospective Observational Trial to Optimize Pediatric Health in Intrauterine Growth Restriction study was to evaluate the optimal management of fetuses with an estimated fetal weight <10th centile. The objective of this secondary analysis was to evaluate if normalizing cerebroplacental ratio predicts adverse perinatal outcome., Study Design: In all, 1116 consecutive singleton pregnancies with intrauterine growth restriction completed the study protocol over 2 years at 7 centers, undergoing serial sonographic evaluation and multivessel Doppler measurement. Cerebroplacental ratio was calculated using the pulsatility and resistance indices of the middle cerebral and umbilical artery. Abnormal cerebroplacental ratio was defined as <1.0. Adverse perinatal outcome was defined as a composite of intraventricular hemorrhage, periventricular leukomalacia, hypoxic ischemic encephalopathy, necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, and death., Results: Data for cerebroplacental ratio calculation were available in 881 cases, with a mean gestational age of 33 (interquartile range, 28.7-35.9) weeks. Of the 87 cases of abnormal serial cerebroplacental ratio with an initial value <1.0, 52% (n = 45) of cases remained abnormal and 22% of these (n = 10) had an adverse perinatal outcome. The remaining 48% (n = 42) demonstrated normalizing cerebroplacental ratio on serial sonography, and 5% of these (n = 2) had an adverse perinatal outcome. Mean gestation at delivery was 33.4 weeks (n = 45) in the continuing abnormal cerebroplacental ratio group and 36.5 weeks (n = 42) in the normalizing cerebroplacental ratio group (P value <.001)., Conclusion: The Prospective Observational Trial to Optimize Pediatric Health in Intrauterine Growth Restriction group previously demonstrated that the presence of a brain-sparing effect was significantly associated with an adverse perinatal outcome in our intrauterine growth restriction cohort. It was hypothesized that a normalizing cerebroplacental ratio would be a further predictor of an adverse outcome due to the loss of this compensatory mechanism. However, in this subanalysis we did not demonstrate an additional poor prognostic effect when the cerebroplacental ratio value returned to a value >1.0. Overall, this secondary analysis demonstrated the importance of a serial abnormal cerebroplacental ratio value of <1 within the <34 weeks' gestation population. Contrary to our proposed hypothesis, we recognize that reversion of an abnormal cerebroplacental ratio to a normal ratio is not associated with a heightened degree of adverse perinatal outcome., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Phase-rectified signal averaging, an innovative signal processing technique, can be used to investigate quasi-periodic oscillations in noisy, nonstationary signals that are obtained from fetal heart rate. Phase-rectified signal averaging is currently the best method to predict survival after myocardial infarction in adult cardiology. Application of this method to fetal medicine has established significantly better identification than with short-term variation by computerized cardiotocography of growth-restricted fetuses., Objective: The aim of this study was to determine the longitudinal progression of phase-rectified signal averaging indices in severely growth-restricted human fetuses and the prognostic accuracy of the technique in relation to perinatal and neurologic outcome., Study Design: Raw data from cardiotocography monitoring of 279 human fetuses were obtained from 8 centers that took part in the multicenter European "TRUFFLE" trial on optimal timing of delivery in fetal growth restriction. Average acceleration and deceleration capacities were calculated by phase-rectified signal averaging to establish progression from 5 days to 1 day before delivery and were compared with short-term variation progression. The receiver operating characteristic curves of average acceleration and deceleration capacities and short-term variation were calculated and compared between techniques for short- and intermediate-term outcome., Results: Average acceleration and deceleration capacities and short-term variation showed a progressive decrease in their diagnostic indices of fetal health from the first examination 5 days before delivery to 1 day before delivery. However, this decrease was significant 3 days before delivery for average acceleration and deceleration capacities, but 2 days before delivery for short-term variation. Compared with analysis of changes in short-term variation, analysis of (delta) average acceleration and deceleration capacities better predicted values of Apgar scores <7 and antenatal death (area under the curve for prediction of antenatal death: delta average acceleration capacity, 0.62 [confidence interval, 0.19-1.0]; delta short-term variation, 0.54 [confidence interval, 0.13-0.97]; P=.006; area under the curve for prediction Apgar <7: average deceleration capacity <24 hours before delivery, 0.64 [confidence interval, 0.52-0.76]; short-term variation <24 hours before delivery, 0.53 [confidence interval, 0.40-0.65]; P=.015). Neither phase-rectified signal averaging indices nor short-term variation showed predictive power for developmental disability at 2 years of age (Bayley developmental quotient, <95 or <85)., Conclusion: The phase-rectified signal averaging method seems to be at least as good as short-term variation to monitor progressive deterioration of severely growth-restricted fetuses. Our findings suggest that for short-term outcomes such as Apgar score, phase-rectified signal averaging indices could be an even better test than short-term variation. Overall, our findings confirm the possible value of prospective trials based on phase-rectified signal averaging indices of autonomic nervous system of severely growth-restricted fetuses., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Intrauterine growth restriction is associated with short- and long-term neurodevelopmental problems. Structural brain changes underlying these alterations have been described with the use of different magnetic resonance-based methods that include changes in whole structural brain networks. However, evaluation of specific brain circuits and its correlation with related functions has not been investigated in intrauterine growth restriction., Objectives: In this study, we aimed to investigate differences in tractography-related metrics in cortico-striatal-thalamic and motor networks in intrauterine growth restricted children and whether these parameters were related with their specific function in order to explore its potential use as an imaging biomarker of altered neurodevelopment., Methods: We included a group of 24 intrauterine growth restriction subjects and 27 control subjects that were scanned at 1 year old; we acquired T1-weighted and 30 directions diffusion magnetic resonance images. Each subject brain was segmented in 93 regions with the use of anatomical automatic labeling atlas, and deterministic tractography was performed. Brain regions included in motor and cortico-striatal-thalamic networks were defined based in functional and anatomic criteria. Within the streamlines that resulted from the whole brain tractography, those belonging to each specific circuit were selected and tractography-related metrics that included number of streamlines, fractional anisotropy, and integrity were calculated for each network. We evaluated differences between both groups and further explored the correlation of these parameters with the results of socioemotional, cognitive, and motor scales from Bayley Scale at 2 years of age., Results: Reduced fractional anisotropy (cortico-striatal-thalamic, 0.319 ± 0.018 vs 0.315 ± 0.015; P = .010; motor, 0.322 ± 0.019 vs 0.319 ± 0.020; P = .019) and integrity cortico-striatal-thalamic (0.407 ± 0.040 vs 0.399 ± 0.034; P = .018; motor, 0.417 ± 0.044 vs 0.409 ± 0.046; P = .016) in both networks were observed in the intrauterine growth restriction group, with no differences in number of streamlines. More importantly, strong specific correlation was found between tractography-related metrics and its relative function in both networks in intrauterine growth restricted children. Motor network metrics were correlated specifically with motor scale results (fractional anisotropy: rho = 0.857; integrity: rho = 0.740); cortico-striatal-thalamic network metrics were correlated with cognitive (fractional anisotropy: rho = 0.793; integrity, rho = 0.762) and socioemotional scale (fractional anisotropy: rho = 0.850; integrity: rho = 0.877)., Conclusions: These results support the existence of altered brain connectivity in intrauterine growth restriction demonstrated by altered connectivity in motor and cortico-striatal-thalamic networks, with reduced fractional anisotropy and integrity. The specific correlation between tractography-related metrics and neurodevelopmental outcomes in intrauterine growth restriction shows the potential to use this approach to develop imaging biomarkers to predict specific neurodevelopmental outcome in infants who are at risk because of intrauterine growth restriction and other prenatal diseases., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Late-onset intrauterine growth restriction (IUGR) results from a failure of the placenta to supply adequate nutrients and oxygen to the rapidly growing late-gestation fetus. Limitations in current monitoring methods present the need for additional techniques for more accurate diagnosis of IUGR in utero. New magnetic resonance imaging (MRI) technology now provides a noninvasive technique for fetal hemodynamic assessment, which could provide additional information over conventional Doppler methods., Objective: The objective of the study was to use new MRI techniques to measure hemodynamic parameters and brain growth in late-onset IUGR fetuses., Study Design: This was a prospective observational case control study to compare the flow and T2 of blood in the major fetal vessels and brain imaging findings using MRI. Indexed fetal oxygen delivery and consumption were calculated. Middle cerebral artery and umbilical artery pulsatility indexes and cerebroplacental ratio were acquired using ultrasound. A score of ≥ 2 of the 4 following parameters defined IUGR: (1) birthweight the third centile or less or 20% or greater drop in the centile in estimated fetal weight; (2) lowest cerebroplacental ratio after 30 weeks less than the fifth centile; (3) ponderal index < 2.2; and (4) placental histology meets predefined criteria for placental underperfusion. Measurements were compared between the 2 groups (Student t test) and correlations between parameters were analyzed (Pearson's correlation). MRI measurements were compared with Doppler parameters for identifying IUGR defined by postnatal criteria (birthweight, placental histology, ponderal index) using receiver-operating characteristic curves., Results: We studied 14 IUGR and 26 non-IUGR fetuses at 35 weeks' gestation. IUGR fetuses had lower umbilical vein (P = .004) and pulmonary blood flow (P = .01) and higher superior vena caval flow (P < .0001) by MRI. IUGR fetuses had asymmetric growth but smaller brains than normal fetuses (P < .0001). Newborns with IUGR also had smaller brains with otherwise essentially normal findings on MRI. Vessel T2s, oxygen delivery, oxygen consumption, middle cerebral artery pulsatility index, and cerebroplacental ratio were all significantly lower in IUGR fetuses, whereas there was no significant difference in umbilical artery pulsatility index. IUGR score correlated positively with superior vena caval flow and inversely with oxygen delivery, oxygen consumption, umbilical vein T2, and cerebroplacental ratio. Receiver-operating characteristic curves revealed equivalent performance of MRI and Doppler techniques in identifying IUGR that was defined based on postnatal parameters with superior vena caval flow area under the curve of 0.94 (95% confidence interval, 0.87-1.00) vs a cerebroplacental ratio area under the curve of 0.80 (95% confidence interval, 0.64-0.97)., Conclusion: MRI revealed the expected circulatory redistribution in response to hypoxia in IUGR fetuses. The reduced oxygen delivery in IUGR fetuses indicated impaired placental oxygen transport, whereas reduced oxygen consumption presumably reflected metabolic adaptation to diminished substrate delivery, resulting in slower fetal growth. Despite brain sparing, placental insufficiency limits fetal brain growth. Superior vena caval flow and umbilical vein T2 by MRI may be useful new markers of late-onset IUGR., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Growth-restricted fetuses with absent or reversed end-diastolic velocities in the umbilical artery are at substantially increased risk for adverse perinatal and long-term outcome, even in comparison to growth-restricted fetuses with preserved end-diastolic velocities. Translational studies show that this Doppler velocimetry correlates with fetoplacental blood flow, with absent or reversed end-diastolic velocities signifying abnormally elevated resistance within the placental vasculature. The fetoplacental vasculature is unique in that it is not subject to autonomic regulation, unlike other vascular beds. Instead, humoral mediators, many of which are synthesized by local endothelial cells, regulate placental vascular resistance. Existing data demonstrate that in growth-restricted pregnancies complicated by absent or reversed umbilical artery end-diastolic velocities, an imbalance in production of these vasoactive substances occurs, favoring vasoconstriction. Morphologically, placentas from these pregnancies also demonstrate impaired angiogenesis, whereby vessels within the terminal villi are sparsely branched, abnormally thin, and elongated. This structural deviation from normal placental angiogenesis restricts blood flow and further contributes to elevated fetoplacental vascular resistance. Although considerable work has been done in the field of fetoplacental vascular development and function, much remains unknown about the mechanisms underlying impaired development and function of the human fetoplacental vasculature, especially in the context of severe fetal growth restriction with absent or reversed umbilical artery end-diastolic velocities. Fetoplacental endothelial cells are key regulators of angiogenesis and vasomotor tone. A thorough understanding of their role in placental vascular biology carries the significant potential of discovering clinically relevant and innovative approaches to prevention and treatment of fetal growth restriction with compromised umbilical artery end-diastolic velocities., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Abnormal placentation is responsible for most failures in pregnancy; however, an understanding of placental functions remains largely concealed from noninvasive, in vivo investigations. Magnetic resonance imaging (MRI) is safe in pregnancy for magnetic fields of up to 3 Tesla and is being used increasingly to improve the accuracy of prenatal imaging. Functional MRI (fMRI) of the placenta has not yet been validated in a clinical setting, and most data are derived from animal studies. FMRI could be used to further explore placental functions that are related to vascularization, oxygenation, and metabolism in human pregnancies by the use of various enhancement processes. Dynamic contrast-enhanced MRI is best able to quantify placental perfusion, permeability, and blood volume fractions. However, the transplacental passage of Gadolinium-based contrast agents represents a significant safety concern for this procedure in humans. There are alternative contrast agents that may be safer in pregnancy or that do not cross the placenta. Arterial spin labeling MRI relies on magnetically labeled water to quantify the blood flows within the placenta. A disadvantage of this technique is a poorer signal-to-noise ratio. Based on arterial spin labeling, placental perfusion in normal pregnancy is 176 ± 91 mL × min(-1) × 100 g(-1) and decreases in cases with intrauterine growth restriction. Blood oxygen level-dependent and oxygen-enhanced MRIs do not assess perfusion but measure the response of the placenta to changes in oxygen levels with the use of hemoglobin as an endogenous contrast agent. Diffusion-weighted imaging and intravoxel incoherent motion MRI do not require exogenous contrast agents, instead they use the movement of water molecules within tissues. The apparent diffusion coefficient and perfusion fraction are significantly lower in placentas of growth-restricted fetuses when compared with normal pregnancies. Magnetic resonance spectroscopy has the ability to extract information regarding metabolites from the placenta noninvasively and in vivo. There are marked differences in all 3 metabolites N-acetyl aspartate/choline levels, inositol/choline ratio between small, and adequately grown fetuses. Current research is focused on the ability of each fMRI technique to make a timely diagnosis of abnormal placentation that would allow for appropriate planning of follow-up examinations and optimal scheduling of delivery. These research programs will benefit from the use of well-defined sequences, standardized imaging protocols, and robust computational methods., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Alterations in fetal growth trajectory, either in terms of individual organs or the fetal body, constitute part of a suite of adaptive responses that the fetus can make to a developmental challenge such as inadequate nutrition. Nonetheless, despite substantial changes in nutrition in many countries over recent centuries, mean birthweight has changed relatively little. Low birthweight is recognized as a risk factor for later noncommunicable disease, although the developmental origins of such risk are graded across the full range of fetal growth and birthweight. Many parental and environmental factors, some biological and some cultural, can influence fetal growth, and these should not be viewed as abnormal. We argue that the suggestion of establishing a universal standard for optimal fetal growth ignores the breadth of these normal fetal responses. It may influence practice adversely, through incorrect estimation of gestational age and unnecessary elective deliveries. It raises ethical as well as practical issues., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: We assessed brain metabolite levels by magnetic resonance spectroscopy (MRS) in 1-year-old infants born small at term, as compared with infants born appropriate for gestational age (AGA), and their association with neurodevelopment at 2 years of age., Study Design: A total of 40 infants born small (birthweight <10th centile for gestational age) and 30 AGA infants underwent brain MRS at age 1 year on a 3-T scanner. Small-born infants were subclassified as late intrauterine growth restriction or as small for gestational age, based on the presence or absence of prenatal Doppler and birthweight predictors of an adverse perinatal outcome, respectively. Single-voxel proton magnetic resonance spectroscopy ((1)H-MRS) data were acquired from the frontal lobe at short echo time. Neurodevelopment was evaluated at 2 years of age using the Bayley Scales of Infant and Toddler Development, Third Edition, assessing cognitive, language, motor, social-emotional, and adaptive behavior scales., Results: As compared with AGA controls, infants born small showed significantly higher levels of glutamate and total N-acetylaspartate (NAAt) to creatine (Cr) ratio at age 1 year, and lower Bayley Scales of Infant and Toddler Development, Third Edition scores at 2 years. The subgroup with late intrauterine growth restriction further showed lower estimated glutathione levels at age 1 year. Significant correlations were observed for estimated glutathione levels with adaptive scores, and for myo-inositol with language scores. Significant associations were also noticed for NAA/Cr with cognitive scores, and for glutamate/Cr with motor scores., Conclusion: Infants born small show brain metabolite differences at 1 year of age, which are correlated with later neurodevelopment. These results support further research on MRS to develop imaging biomarkers of abnormal neurodevelopment., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The cerebroplacental ratio (CPR) is emerging as an important predictor of adverse pregnancy outcome, and this has implications for the assessment of fetal well-being in fetuses diagnosed as small for gestational age (SGA) and those appropriate for gestational age close to term. Interest in this assessment tool has been rekindled because of recent reports associating an abnormal ratio with adverse perinatal events and associated postnatal neurological outcome. Fetuses with an abnormal CPR that are appropriate for gestational age or have late-onset SGA (>34 weeks of gestation) have a higher incidence of fetal distress in labor requiring emergency cesarean delivery, a lower cord pH, and an increased admission rate to the newborn intensive care unit when compared with fetuses with a normal CPR. Fetuses with early-onset SGA (<34 weeks of gestation) with an abnormal CPR have a higher incidence of the following when compared with fetuses with a normal CPR: (1) lower gestational age at birth, (2) lower mean birthweight, (3) lower birthweight centile, (4) birthweight less than the 10th centile, (5) higher rate of cesarean delivery for fetal distress in labor, (6) higher rate of Apgar scores less than 7 at 5 minutes, (7) an increased rate of neonatal acidosis, (8) an increased rate of newborn intensive care unit admissions, (9) higher rate of adverse neonatal outcome, and (10) a greater incidence of perinatal death. The CPR is also an earlier predictor of adverse outcome than the biophysical profile, umbilical artery, or middle cerebral artery. In conclusion, the CPR should be considered as an assessment tool in fetuses undergoing third-trimester ultrasound examination, irrespective of the findings of the individual umbilical artery and middle cerebral artery measurements. A CPR calculator is available at http://www.ajog.org/pb/assets/raw/Health%20Advance/journals/ymob/CPR/index.htm., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: The purpose of this study was to evaluate the surveillance characteristics that precede stillbirth in growth-restricted fetuses that receive integrated Doppler and biophysical profile scoring (BPS)., Study Design: Nine hundred eighty-seven singleton pregnancies that were complicated by fetal growth restriction had multivessel Doppler scans (umbilical and middle cerebral arteries [MCA], ductus venosus, and umbilical vein) and BPS. Surveillance findings were compared between live births and stillbirths., Results: Forty-seven stillbirths occurred in 2 clusters, 37 at <34 weeks of gestation and 10 thereafter. Before 34 weeks of gestation, stillbirths had parallel escalation of umbilical artery and ductus venosus Doppler findings followed by abnormal BPS. At ≥34 weeks of gestation, only a decline in MCA pulsatility index was observed, and 75% of stillbirths were unanticipated by the BPS., Conclusion: Before 34 weeks of gestation, multivessel Doppler abnormality anticipates an abnormal BPS and subsequent stillbirth. After 34 weeks of gestation, stillbirths occur after MCA brain-sparing in a shorter interval than predicted by a normal BPS. Recognition of these differences in clinical behavior requires consideration for the planning of monitoring intervals in preterm and term fetal growth restriction., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: We sought to determine the cause of adverse perinatal outcome in fetal growth restriction (FGR) where umbilical artery (UA) Doppler was normal, as identified from the Prospective Observational Trial to Optimize Pediatric Health (PORTO). We compared cases of adverse outcome where UA Doppler was normal and abnormal., Study Design: The PORTO study was a national multicenter study of >1100 ultrasound-dated singleton pregnancies with an estimated fetal weight <10th centile. Each pregnancy underwent intensive ultrasound, including multivessel Doppler. UA Doppler was considered abnormal when the pulsatility index was >95th centile or end-diastolic flow was absent/reversed. Adverse perinatal outcome was defined as a composite of intraventricular hemorrhage, periventricular leukomalacia, hypoxic ischemic encephalopathy, necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, or death., Results: In all, 57 (5.0%) of the 1116 fetuses had an adverse perinatal outcome. Nine (1.3%) of 698 fetuses with normal UA Doppler had an adverse outcome, compared with 48 (11.5%) of 418 with abnormal UA Doppler (P < .0001). There were 2 perinatal deaths in the normal group and 6 in the abnormal group (P = .01). The perinatal deaths in the normal group were 1 case of pulmonary hypoplasia after prolonged preterm rupture of the membranes from 12 weeks' gestation and a case of placental abruption. Gestation at delivery was 33 ± 3 vs 31 ± 4 weeks (P = .05) and mean birthweight was 1830 ± 737 vs 1146 ± 508 g (P = .001) in the respective groups. Neonatal sepsis was the commonest adverse outcome in both groups: 0.1% and 0.4%, respectively (P = .01)., Conclusion: Adverse perinatal outcome is uncommon in FGR with normal UA Doppler. The cases we identified were associated with heterogenous pathologies. FGR with normal UA blood flow is a largely benign condition., (Copyright © 2014. Published by Elsevier Inc.)

Objective: The aim of the Prospective Observational Trial to Optimize Pediatric Health in IUGR Study was to evaluate the optimal management of fetuses with an estimated fetal weight less than the 10th centile. The objective of this secondary analysis was to describe the role of the cerebroplacental ratio (CPR) in the prediction of adverse perinatal outcome., Study Design: More than 1100 consecutive singleton pregnancies with intrauterine growth restriction (IUGR) were recruited over 2 years at 7 centers, undergoing serial sonographic evaluation including multivessel Doppler measurement. CPR was calculated using the pulsatility and resistance indices of the middle cerebral and umbilical artery. Adverse perinatal outcome was defined as a composite of intraventricular hemorrhage, periventricular leukomalacia, hypoxic ischemic encephalopathy, necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, and death., Results: Data for CPR calculation was available in 881 cases, which was performed at a mean gestational age of 33 weeks (interquarile range, 28.7-35.9). Of the 146 cases with CPR less than 1, 18% (n = 27) had an adverse perinatal outcome. This conferred an 11-fold increased risk (odds ratio, 11.7; P < .0001) when compared with cases with normal CPR (2%; 14 of 735). An abnormal CPR was present in all 3 cases of mortality. Prediction of adverse outcomes was comparable when using all definitions of abnormal CPR., Conclusion: Irrespective of the CPR calculation used, brain sparing is significantly associated with an adverse perinatal outcome in IUGR. This adds further weight to integrating CPR evaluation into the clinical assessment of IUGR pregnancies. The impact of this finding on long-term neurodevelopmental outcomes in this patient cohort is underway., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Objective: Intrauterine growth restricted (IUGR) fetuses experience cardiovascular remodeling that persists into infancy and has been related to cardiovascular outcomes in adulthood. Hypertension in infancy has been demonstrated to be a strong risk factor for later cardiovascular disease. Close monitoring together with dietary interventions have shown to improve cardiovascular health in hypertensive children; however, not all IUGR infants show increased blood pressure. We evaluated the potential of fetal echocardiography for predicting hypertension and arterial remodeling in 6-month-old IUGR infants., Study Design: One hundred consecutive IUGR and 100 control fetuses were observed into infancy. Fetal assessment included perinatal Doppler imaging, cardiac morphometry, ejection fraction, cardiac output, isovolumic relaxation time (IVRT), tricuspid annular-plane systolic excursion (TAPSE), and tissue Doppler imaging. Infant hypertension and arterial remodeling were defined as mean blood pressure of >95th percentile together with aortic intima-media thickness of >75th percentile at 6 months of age. Odds ratio were obtained for fetal parameters that were associated with infant outcomes., Results: Fetal TAPSE, right sphericity index, IVRT, and cerebroplacental ratio were the strongest predictors for postnatal vascular remodeling. A cardiovascular risk score that was based on fetal TAPSE, cerebroplacental ratio, right sphericity index, and IVRT was highly predictive of infant hypertension and arterial remodeling (area under the curve, 0.87; 95% confidence interval, 0.79-0.93; P < .001)., Conclusion: Fetal echocardiographic parameters identify a high-risk group within the IUGR fetuses who could be targeted for early screening of blood pressure and other cardiovascular risk factors and for promoting healthy diet and physical exercise., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Objective: The purpose of this study was to assess whether abnormal cardiac function in human fetuses with intrauterine growth restriction (IUGR) is associated with ultrastructural differences in the cardiomyocyte sarcomere., Study Design: Nine severe early-onset IUGR fetuses and 9 normally grown fetuses (appropriate growth for gestational age) who died in the perinatal period were included prospectively. Cardiac function was assessed by echocardiography and levels of B-type natriuretic peptide and troponin-I. Heart sections were imaged by second harmonic generation microscopy, which allowed unstained visualization of cardiomyocyte's sarcomere length., Results: Echocardiographic and biochemical markers showed signs of severe cardiac dysfunction in IUGR fetuses. Second harmonic generation microscopy demonstrated a significantly shorter sarcomere length in IUGR as compared with appropriate growth for gestational age fetuses., Conclusion: IUGR is associated with changes in the cardiomyocyte contractile machinery in the form of shorter sarcomere length, which could help to explain the cardiac dysfunction previously documented in IUGR., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Objective: The objective of the study was to investigate the distribution of umbilical venous flow rates, measured in early labor, in a cohort of normal term pregnancies and to establish the relationship between umbilical venous flow and subsequent intrapartum outcome., Study Design: Five hundred eighty-nine women with uncomplicated, term, singleton pregnancies were recruited to this prospective observational study prior to active labor (dilation of 4 cm or less) at Queen Charlotte's and Chelsea Hospital (London, UK). All participants underwent an ultrasound examination, during which fetal biometry, umbilical venous flow velocity, and umbilical vein diameter were recorded. Umbilical venous flow rate was then calculated. Following delivery, intrapartum and neonatal outcomes were correlated with the ultrasound findings. Cases were subdivided according to mode of delivery, and mean umbilical venous flow rates were compared between the groups. Cases were also subdivided according to umbilical venous flow rate (less than the 20th centile, 20th-80th centile, and greater than the 80th centile), and the incidence of diagnoses of fetal compromise was compared., Results: Fetuses delivered by emergency cesarean for presumed fetal compromise had the lowest umbilical venous flow rates (both corrected for and uncorrected for birthweight) (P = .02 and P = .001, respectively). Fetuses with the lowest umbilical venous flow rates were significantly more likely to require emergency cesarean for presumed fetal compromise than those with the highest flow rates (15.7% vs 5.6%, relative risk, 2.83; 95% confidence interval, 1.16-6.91)., Conclusion: Fetuses with the lowest umbilical venous flow rates are at increased risk of a subsequent diagnosis of intrapartum fetal compromise. Measurement of umbilical venous flow could contribute to the risk stratification of pregnancies prior to labor., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Objective: Obstructive sleep apnea, a breathing disorder caused by the repetitive collapse of the upper airway during sleep, results in a state of chronic intermittent hypoxia (CIH). Although the etiology and consequences of CIH are extensively investigated in the adult, the developmental ramifications of this disease process are unknown., Design: This study was done to investigate the effect of CIH during gestation on offspring development. Pregnant female Spraque-Dawley rats were exposed to daily CIH throughout the gestational period., Results: Postnatal day-1 offspring from CIH mothers were asymmetrically growth restricted, with decreased body weights and elevated brain-weight:liver-weight ratios. Furthermore, CIH newborns had elevated heart- and brain-weight:body weight ratios, and decreased liver-weight:body weight ratios. By adulthood, body weights of growth restricted offspring were significantly greater, as were the liver-weight:body weight ratios. CIH offspring also had greater body fat deposition, were hyperglycemic and had elevated plasma levels of insulin during development into adults., Conclusion: These data suggest that alteration of the maternal intrauterine environment by gestational CIH effects the long-term development of the offspring and increases the risk of the offspring to metabolic diseases in adulthood., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Objective: The objective of the study was to evaluate cortical development parameters by magnetic resonance imaging (MRI) in late-onset intrauterine growth-restricted (IUGR) fetuses and normally grown fetuses., Study Design: A total of 52 IUGR and 50 control fetuses were imaged using a 3T MRI scanner at 37 weeks of gestational age. T2 half-Fourier acquisition single-shot turbo spin-echo anatomical acquisitions were obtained in 3 planes. Cortical sulcation (fissures depth corrected by biparietal diameter), brain volumetry, and asymmetry indices were assessed by means of manual delineation and compared between cases and controls., Results: Late-onset IUGR fetuses had significantly deeper measurements in the left insula (late-onset IUGR: 0.293 vs control: 0.267; P = .02) and right insula (0.379 vs 0.318; P < .01) and the left cingulate fissure (0.096 vs 0.087; P = .03) and significantly lower intracranial (441.25 cm(3) vs 515.82 cm(3); P < .01), brain (276.47 cm(3) vs 312.07 cm(3); P < .01), and left opercular volumes (2.52 cm(3) vs 3.02 cm(3); P < .01). IUGR fetuses showed significantly higher right insular asymmetry indices., Conclusion: Late-onset IUGR fetuses had a different pattern of cortical development assessed by MRI, supporting the existence of in utero brain reorganization. Cortical development could be useful to define fetal brain imaging-phenotypes characteristic of IUGR., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Objective: We sought to evaluate the risk of intrauterine fetal death (IUFD) in small-for-gestational-age (SGA) fetuses., Study Design: We analyzed a retrospective cohort of all births in the United States in 2005, as recorded in a national database. We calculated the risk of IUFD within 3 sets of SGA threshold categories as well as within non-SGA pregnancies using the number of at-risk fetuses as the denominator., Results: The risk of IUFD increased with gestational age and was inversely proportional to percentile of birthweight for gestational age. The risk for IUFD in those <3rd percentile was as high as 58.0 IUFDs per 10,000 at-risk fetuses, 43.9 for <5th percentile, and 26.3 for <10th percentile compared to 5.1 for non-SGA gestations., Conclusion: There is an increase in the risk of IUFD in SGA fetuses compared to non-SGA fetuses at all gestational ages with the greatest risk demonstrated in the lowest percentile cohort evaluated., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Objective: The objective of the study was to assess the use of mean, lowest, and highest pulsatility index (PI) of the uterine arteries to screen for adverse pregnany outcome in twin pregnancies., Study Design: This was a screening study of 423 twin pregnancies. Relationship between PI at 20-22 weeks and adverse pregnancy outcome was evaluated., Results: Mean, lowest, and highest PI above the 95th centile were significant risk factors for preeclampsia and adverse pregnancy outcome in monochorionic and dichorionic twins. We calculated a sensitivity for preeclampsia for mean, highest, and lowest PI of 35%, 29%, and 27%, respectively., Conclusion: Increased mean, lowest, and highest PI is associated with a higher risk of preeclampsia and adverse pregnancy outcome in twins. We observed the highest sensitivity and specificity by using highest PI. The high incidence of preeclampsia in twins makes it attractive to use the PI of the uterine artery for risk stratification in twins., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Clinical and experimental evidence indicates that angiogenic imbalances may participate in the mechanisms of disease of several pregnancy complications, some of which may be life threatening. This article reviews current evidence in support of this view and the possibility that the fetus may play a central role in these imbalances; it also reviews recent experimental observations that modulation of angiogenic imbalances during pregnancy may have prophylactic and/or therapeutic value., (Copyright (c) 2010 Mosby, Inc. All rights reserved.)

Objective: Pregnancy-induced hypertension/preeclampsia (PIH) and fetal growth restriction (FGR) share a common placental origin. The pathologic classification that divides placental lesions to maternal or fetal origin was compared between these disorders., Study Design: Placentas from pregnancies that were complicated by PIH, normotensive FGR, or by both (combined) were analyzed, and lesions were classified as those consistent with maternal under-perfusion and with fetal thromboocclusive disease., Results: Maternal vascular lesions were more common in the PIH group and combined group (61% and 59%, respectively), compared with the FGR group (16.2%; P < .001), and villous lesions were more common in the combined group, compared with the FGR and PIH groups (79.5%, 53.5%, and 46.9%, respectively; P = .004). Fetal villous changes were observed in 16.2% in the FGR group, compared with 3.1% in the PIH group (P = .03), and chronic villitis was 15.2% in the FGR group vs 1.6% in the PIH group (P = .004)., Conclusion: Placental lesions correspond with different clinical presentations., (Copyright 2010 Mosby, Inc. All rights reserved.)

Objective: Normotensive intrauterine growth restriction and preeclampsia share a similar placenta pathophysiology, whereas maternal clinical manifestations differ. Clinical symptoms of preeclampsia are partly attributed to vascular endothelial dysfunction, but it is unclear whether this phenomenon plays a role in intrauterine growth restriction. Therefore, we investigated microvascular endothelial function in women with intrauterine growth restriction., Study Design: Laser Doppler fluxmetry was used combined with iontophoresis of acetylcholine and sodium nitroprusside, namely, endothelium-dependent and endothelium-independent vasodilators. We studied 12 women with intrauterine growth restriction and 16 controls in the third trimester of pregnancy. All women had prepregnancy body mass indexes < 26., Results: Acetylcholine-mediated vasodilatation was significantly increased in women with intrauterine growth restriction compared with controls (743% +/- 120% vs 390% +/- 67%, P = .01); sodium nitroprusside-mediated vasodilatation was not different (360% +/- 55% vs 363% +/- 65%, P > .99)., Conclusion: Nonobese women with normotensive intrauterine growth restriction show abnormal endothelium-dependent microvascular vasodilatation, suggesting endothelial dysfunction as in preeclampsia. Obviously, for the clinical manifestation of preeclampsia additional factors are required, and a role of metabolic syndrome and obesity has been suggested.

Objective: The purpose of this study was to investigate fetal brain development of growth-restricted fetuses with auditory evoked responses (AER) that were recorded by the noninvasive magnetoencephalographic technique., Study Design: Serial fetal recordings that started at 27 weeks of gestation were conducted on a fetal magnetoencephalographic device that was especially designed for obstetric assessment. Fifteen normotrophic fetuses were compared with 14 hypotrophic fetuses. After birth, 10 of the hypotrophic fetuses were diagnosed with asymmetric growth restriction; 4 fetuses were classified as symmetrically small for gestational age., Results: Fetal AER latencies in both groups showed an average developmental decrease of 12.74 msec/wk (P = .0035). Hypotrophic fetuses had longer age-adjusted latencies compared with normotrophic fetuses, with a difference of 73.5 msec (P = .034). The subgroup of symmetrically growth-restricted fetuses showed the longest latencies for age, with a difference from the normotrophic fetuses of 120.0 msec (P = .045)., Conclusion: The results indicate that biomagnetically recorded AER can be used to monitor functional brain development in growth-restricted fetuses.

Objective: The purpose of this study was to assess cardiac function and cell damage in intrauterine growth-restricted (IUGR) fetuses across clinical Doppler stages of deterioration., Study Design: One hundred twenty appropriate-for-gestational-age and 81 IUGR fetuses were classified in stages 1/2/3 according umbilical artery present/absent/reversed end-diastolic blood flow, respectively. Cardiac function was assessed by modified-myocardial performance index, early-to-late diastolic filling ratios, cardiac output, and cord blood B-type natriuretic peptide; myocardial cell damage was assessed by heart fatty acid-binding protein, troponin-I, and high-sensitivity C-reactive protein., Results: Modified-myocardial performance index, blood B-type natriuretic peptide, and early-to-late diastolic filling ratios were increased in a stage-dependent manner in IUGR fetuses, compared with appropriate-for-gestational-age fetuses. Heart fatty acid-binding protein levels were higher in IUGR fetuses at stage 3, compared with control fetuses. Cardiac output, troponin-I, and high-sensitivity C-reactive protein did not increase in IUGR fetuses at any stage., Conclusion: IUGR fetuses showed signs of cardiac dysfunction from early stages. Cardiac dysfunction deteriorates further with the progression of fetal compromise, together with the appearance of biochemical signs of cell damage.

Objective: The aim of this study was to determine the biophysical profile (BPP) usefulness in the prediction of cord pH, base excess, and guidance regarding the timing of delivery in preterm intrauterine growth-restricted (IUGR) fetuses., Study Design: A BPP was performed daily in 48 IUGR fetuses and was considered abnormal when it was 2/10 on 1 single occasion or 4/10 on 2 consecutive occasions 2 hours apart., Results: The median gestational age and fetal weight for the total population was 27.6 weeks and 632 g, respectively. In 13 fetuses with a BPP of 6, there were 3 deaths, and 7 fetuses were acidemic. In 27 fetuses with a BPP of 8, there were 3 deaths, and 12 fetuses were acidemic., Conclusion: BPP alone is not a reliable test in the treatment of preterm IUGR fetuses, because of high false-positive and -negative results. The common notion of a good BPP providing reassurance for at least 24 hours is not applicable in severely preterm IUGR fetuses who weigh <1000 g.

Objective: Intrauterine growth-restricted (IUGR) newborns have increased risk of obesity-induced fatty liver and inflammation. We hypothesized that IUGR-induced inhibition of hepatic peroxisome proliferator-activated receptors (PPARs) is associated with an increased inflammatory response., Study Design: Rat control dams received ad libitum food, whereas study dams were 50% food restricted from pregnancy day 10 to 21 (IUGR). Pups were nursed by control dams and weaned to ad libitum feed. Hepatic protein expression of transcription factors, lipid enzymes, triglyceride content, and C-reactive protein (CRP) levels were analyzed in 1 day and 9 month old male offspring., Results: At 1 day of age, IUGR pups showed down-regulation of PPARalpha and PPARgamma and up-regulation of hepatic lipase and CRP. At 9 months of age, IUGR exhibited continued down-regulation of PPARalpha and PPARgamma with up-regulation of sterol regulatory element-binding protein-1 and fatty acid synthase. Furthermore, IUGR adults had increased hepatic triglyceride content and plasma CRP levels., Conclusions: The results suggest that developmental hepatic dysregulation may contribute to programmed obesity-induced inflammation in IUGR offspring.

Objective: The study hypothesis was that hemodynamic measurements in conjunction with uterine artery Doppler could enable selection of women at risk for the development of preeclampsia or fetal growth restriction., Study Design: Systolic (SBP) and diastolic blood pressure, heart rate (RR), cardiac output (CO), total peripheral resistance (TPR), phase difference of SBP and RR interval were measured serially before, during, and after pregnancy. At 20 weeks, uterine artery Doppler measurement was performed. Outcome was classified as preeclampsia (PE) or gestational hypertension (GH) with or without fetal growth restriction (FGR), FGR without PE or GH, and normal pregnancy (NP). Differences between these groups were assessed by 1-way analysis of variance and discriminant analysis., Results: In early pregnancy, in comparison with NP (n = 28), PE/GH had a higher SBP and phase difference of SBP-RR interval. CO was higher in PE/GH without FGR (n = 5) but not PE/GH with FGR (n = 5). FGR, either with or without PE/GH (n = 4), was associated with higher TPR. Conjunction with uterine Doppler allowed selection of 93% of women with an abnormal outcome with a specificity of 100%., Conclusion: The study supports our hypothesis that in early pregnancy, hemodynamic parameters differ from normal in women predisposed to develop preeclampsia or fetal growth restriction.

Objective: The objective of the study was to evaluate whether maternal tobacco use is associated with an attenuation in fetal birthweight among women with nutritional and uteroplacental constraints., Study Design: A population-based retrospective analysis of term (37 weeks or longer) singleton pregnancies delivered in Utah from 1991 to 2001. Birthweight (BW) and percent small for gestational age (SGA) (less than 10% for gestational age) among self-identified smokers and nonsmokers were compared. Adjusted odds ratios (ORs) were calculated to measure the association of maternal smoking with delivery of an SGA infant controlling for potential confounders across maternal strata., Results: Among the 424,912 gestations, 37,076 occurred in self-identified smokers. Mean BW was significantly less and the prevalence of SGA infants was significantly greater in tobacco-exposed infants across all maternal BMI strata (P < .001) as well as pregnancies complicated by diabetes (P < .001) and hypertensive disorders (P < .001). In a multivariable logistic regression model, tobacco exposure remained the significant associative factor for SGA (OR 3.53, 95% confidence interval 2.61 to 4.79) after selecting for the first birth in the study interval (n = 283,916)., Conclusion: Self-identified tobacco use increases the risk of a SGA infant at term across maternal strata.

Objective: Nucleated red blood cells (NRBC) are fetal hematologic markers for placental dysfunction, hypoxemia, and asphyxia. NRBC count elevation at birth or persistence is linked statistically to adverse outcome, but clinical predictive value is variable. We studied novel indices to better define overall magnitude of NRBC response., Study Design: Peripheral NRBC count was obtained from preterm (<34 weeks of gestation) growth-restricted neonates within 2 hours of life. Daily counts and duration of NRBC count >30/100 white blood cells were determined. Mean counts (NRBC-mean), area under the curve (NRBC-AUC), and declination (NRBC-slope) were analyzed over week 1. NRBC parameters were related to major morbidity (bronchopulmonary dysplasia, grade III/IV intraventricular hemorrhage, necrotizing enterocolitis included) and neonatal death (NND)., Results: Twenty-two of 176 patients (12.5%) had acidosis. Complications included bronchopulmonary dysplasia (n = 36; 20.5%), intraventricular hemorrhage (n = 18; 10.2%), necrotizing enterocolitis (n = 18; 10.2%), NND (n = 18; 10.2%). NRBC-AUC and NRBC-mean correlated most strongly with pH, birthweight, and gestational age (Pearson coefficient -0.45 to -0.18; all P < .001). NRBC-AUC varied most between nonmorbid and morbid; NRBC-mean varied most between survivors and NND (all P < .001). NRBC persistence strongly predicted NND: clearance by day 4 was achieved by 80% of survivors and only 35% of NNDs. Logistic regression identified prematurity and persistent NRBC counts as primary morbidity determinants (r2 = 0.56; P < .01). Although the importance of individual NRBC counts varied, day-4 NRBC counts of >70 predicted morbidity best (sensitivity, 82%; specificity, 96%). Presence of morbidity and birthweight were prime determinants of death (r2 = 0.42; P < .01)., Conclusion: Simple daily NRBC counts provide clinical information that is equivalent to more complicated methods. The importance of prematurity and growth are emphasized, but elevated NRBC counts beyond day 3 are relevant independent predictors of adverse outcome.

Objective: The objective of the study was to test the hypothesis that the total number of cells in the cortical part of the cerebral wall is the same in intrauterine growth-restricted (IUGR) fetuses, compared with normally grown fetuses., Study Design: The total cell number in the cerebral wall was estimated in 9 severely affected IUGR fetuses and 15 controls using the optical fractionator. Cell numbers were estimated within 4 developmental zones. The gestational ages were 19-41 weeks., Results: The total cell number in the future cortex was significantly reduced in the IUGR fetuses, compared with controls. The daily increase in brain cells in the future cortex was only half of that of the controls. In the 3 other developmental zones, no significant differences in cell numbers could be demonstrated., Conclusions: IUGR in humans is associated with a severe reduction in cortical growth and a significant decrease in cell number in the future cortex.

Objective: The risk of pregnancy-induced hypertension (PIH) is decreased by smoking, but the mechanisms remain unclear. Our objective was to determine whether this association is dependent on decreased fetal growth., Methods: A population-based, retrospective cohort study in the United States was performed consisting of nulliparous women who delivered a singleton birth (n = 8,025,295) between 1995 and 2002. Fetal growth was defined as birthweight for gestational age and characterized as less than 1, 1-2, 3-4, 5-9, 10-19, ..., 90 or greater centiles. Risk and relative risk of PIH before and after adjusting for confounders were estimated., Results: Smoking was associated with decreased risk of PIH with up to a 46% decreased risk of PIH for growth-restricted babies (less than the 10th centile). This association, however, decreased with increasing birthweight centile and was nonsignificant at 20th or greater centile among heavy smokers, at 60th or greater centile for moderate, and 80th or greater centile for light smokers., Conclusion: Smoking was primarily associated with decreased risk of PIH among growth-restricted babies.

Objective: Modulation of growth of intrauterine growth restricted (IUGR) newborns causes either adult obesity or normalization of body weight and fat. We investigated the impact of rapid versus delayed catch-up growth of IUGR offspring on glucose and lipid profiles., Study Design: From 10 days to term gestation and through lactation, control pregnant rats received ad libitum food, whereas study rats were 50% food restricted. Cross-fostering techniques were used to examine effects of food restriction during pregnancy and/or lactation periods. Glucose and lipid profiles were determined in offspring at ages 1 day, 3 weeks, and 9 months., Results: Food restriction during pregnancy produced hypoglycemic IUGR pups. Those permitted rapid catch-up growth demonstrated adult obesity with insulin resistance (hyperglycemia/hyperinsulinemia) and hypertriglyceridemia. Conversely, IUGR exhibiting delayed catch-up growth demonstrated normal adult body weight and insulin deficiency (hyperglycemia/hypoinsulinemia) and elevated cholesterol levels as compared with controls. However, these adult offspring had higher glucose though similar insulin levels as control offspring nursed by food restricted dam., Conclusion: The timing and the rate of IUGR newborn catch-up growth causes markedly altered adult phenotypes. Although delayed newborn catch-up growth may be beneficial in the prevention of adult obesity, there may be significant adverse effects on pancreatic function.

Objective: The purpose of this study was to compare cardiac dynamics of high-risk and low-risk fetuses using beat to beat variability., Study Design: This study obtained 214 fetal magnetocardiography recordings from a group of high-risk fetuses with maternal conditions associated with placental insufficiency with the risk of developing intrauterine growth restriction or were already diagnosed with intrauterine growth restriction. For purpose of comparison, another 136 recordings were obtained from low-risk fetuses. The cardiac beat-to-beat intervals computed as RR intervals were analyzed from both groups using the mean and median interval, standard deviation of normal-to-normal intervals, root mean square of the successive differences, and the fraction of the normal-to-normal intervals (pNNx) that differ by more than the chosen tolerance level of 'x' milliseconds from the previous normal-to-normal intervals. Tests for significance between high-risk and low-risk fetuses were calculated using an independent samples t test within the following gestational age groups, 27-30 weeks, 31-35 weeks, and 36-40 weeks., Results: The root mean square of the successive differences, and the pNNx showed a significant difference between the low-risk and high-risk fetuses in the 31-35-week and the 36-40-week divisions. In the 31-35-week age division, low-risk fetuses had significantly lower root mean square of the successive differences, and pNN values than the high risk, but in the 36-40-week division, the low-risk fetuses had significantly higher root mean square of the successive differences, and pNN values., Conclusion: Cardiac dynamics for fetuses of mothers at risk for placental insufficiency mature quicker than fetuses not at risk for placental insufficiency.

Objective: Nucleated red blood cells (NRBCs) in fetal circulation have been proposed as a marker of chronic hypoxia in fetuses with intrauterine growth restriction (IUGR). We sought to determine the effects of chronic hypoxia, chronic nitric oxide inhibition with N(G)-nitro-L-arginine methyl ester (L-NAME), or both on NRBC counts, erythropoietin levels, and pathologic changes in an animal model of IUGR., Study Design: We assigned timed pregnant adult Sprague Dawley rats to the following groups: (1) 21% oxygen + saline solution (n = 7); (2) 21% oxygen + L-NAME (n = 8); (3) 10% oxygen + saline solution (n = 6); and (4) 10% oxygen + L-NAME (n = 6). We inserted osmotic pumps that were prefilled with saline solution or L-NAME subcutaneously on day 17 of gestation. The animals were placed in a Plexiglas hypoxic chamber, which ensured a constant hypoxic environment. The animals were killed on day 21 of gestation before the onset of spontaneous labor. We collected maternal and fetal blood for measurement of NRBC and erythropoietin levels. The results were interpreted in relationship to maternal arterial blood gases and hemoglobin and hematocrit levels. Fetuses were examined for gross abnormalities and histological abnormalities that are characteristic of vascular disruptions by a blind examiner to experimental manipulation., Results: Nitric oxide inhibition induced IUGR with maximal effect when both L-NAME and hypoxia treatments were combined. Inhibition of nitric oxide synthesis, but not chronic hypoxia, increased the number of fetal NRBCs and generalized hemorrhagic diathesis in utero. These features were aggravated significantly when the treatments were combined. Moreover, chronic hypoxia induced significant maternal metabolic acidosis and increased hematocrit and erythropoietin levels in maternal and fetal blood. Nitric oxide inhibition increased maternal hematocrit levels while decreasing maternal erythropoietin levels without significantly altering the maternal acid-base status. In contrast with chronic hypoxia, nitric oxide inhibition increased fetal NRBCs without affecting erythropoietin levels., Conclusion: Our findings indicate that the number of NRBCs in fetal circulation does not serve as a specific marker of chronic hypoxia that accompanies IUGR or of elevated erythropoietin levels but are an epiphenomenon that is related to the inhibition of nitric oxide.