Reduced gyrification in fetal growth restriction with prenatal magnetic resonance images.

Placental-related fetal growth restriction, resulting from placental dysfunction, impacts 3-5% of pregnancies and is linked to elevated risk of adverse neurodevelopmental outcomes. In response, the fetus employs a mechanism known as brain-sparing, redirecting blood flow to the cerebral circuit, for adequate supply to the brain. In this study we aimed to quantitatively evaluate disparities in gyrification and brain volumes among fetal growth restriction, small for gestational age and appropriate-for gestational-age fetuses. Additionally, we compared fetal growth restriction fetuses with and without brain-sparing. The study encompassed 106 fetuses: 35 fetal growth restriction (14 with and 21 without brain-sparing), 8 small for gestational age, and 63 appropriate for gestational age. Gyrification, supratentorial, and infratentorial brain volumes were automatically computed from T2-weighted magnetic resonance images, following semi-automatic brain segmentation. Fetal growth restriction fetuses exhibited significantly reduced gyrification and brain volumes compared to appropriate for gestational age (P < 0.001). Small for gestational age fetuses displayed significantly reduced gyrification (P = 0.038) and smaller supratentorial volume (P < 0.001) compared to appropriate for gestational age. Moreover, fetal growth restriction fetuses with BS demonstrated reduced gyrification compared to those without BS (P = 0.04), with no significant differences observed in brain volumes. These findings demonstrate that brain development is affected in fetuses with fetal growth restriction, more severely than in small for gestational age, and support the concept that vasodilatation of the fetal middle cerebral artery reflects more severe hypoxemia, affecting brain development.

Three-Dimensional Fractional Moving Blood Volume: A Robust Bedside Tool for Evaluation of Fetal Multiorgan Perfusion.

INTRODUCTION: Three-dimensional fractional moving blood volume (3D-FMBV) may provide superior noninvasive measurement of feto-placental perfusion compared to current methods. This study investigated the feasibility and repeatability of producing 3D-FMBV measurements of the placenta, fetal liver, kidney, and brain in a single ultrasound consultation. METHODS: The placenta, fetal liver, kidney, and brain were scanned in triplicate using 3D power Doppler ultrasound (3D-PDU) in 48 women ≥22 weeks of gestation with healthy fetuses. 3D-FMBV was calculated by two analyzers. Feasibility was assessed as the percentage of cases where 3D-FMBV could be evaluated; repeatability (intraobserver and interobserver) using two-way mixed measure intraclass correlation coefficients (ICCs). RESULTS: 3D-FMBV was calculated for 100% of scanned organs. Intraobserver ICCs (95% CI) were good to excellent; 0.93 (0.88-0.96) and 0.87 (0.78-0.92) for placenta, 0.95 (0.92-0.97) and 0.98 (0.96-0.99) for fetal liver, 0.96 (0.94-0.98) and 0.91 (0.85-0.95) for fetal kidney, and 0.98 (0.97-0.99) and 0.97 (0.95-0.98) for fetal brain. Interobserver ICCs (95% CI) were 0.50 (0.08-0.73), 0.92 (0.85-0.96), 0.89 (0.78-0.94), and 0.71 (0.46-0.85) for placenta, fetal liver, kidney, and brain. CONCLUSION: Feto-placental perfusion assessment with 3D-FMBV is highly reliable in healthy pregnancies ≥22 weeks of gestation and can be feasibly calculated in four feto-placental vascular beds in a single ultrasound consultation.

Cardiovascular decline in offspring during the perinatal period in an ovine model of fetal growth restriction.

Fetal growth restriction (FGR) increases the risk cardiovascular disease (CVD) in adulthood. Placental insufficiency and subsequent chronic fetal hypoxemia are causal factors for FGR, leading to a redistribution of blood flow that prioritizes vital organs. Subclinical signs of cardiovascular dysfunction are evident in growth-restricted neonates; however, the mechanisms programming for CVD in adulthood remain unknown. This study aimed to determine the potential mechanisms underlying structural and functional changes within the heart and essential (carotid) and nonessential (femoral) vascular beds in growth-restricted lambs. Placental insufficiency was surgically induced in ewes at 89 days gestational age (dGA, term = 148dGA). Three age groups were investigated: fetal (126dGA), newborn (24 h after preterm birth), and 4-wk-old lambs. In vivo and histological assessments of cardiovascular indices were undertaken. Resistance femoral artery function was assessed via in vitro wire myography and blockade of key vasoactive pathways including nitric oxide, prostanoids, and endothelium-dependent hyperpolarization. All lambs were normotensive throughout the first 4 wk of life. Overall, the FGR cohort had more globular hearts compared with controls (P = 0.0374). A progressive decline in endothelium-dependent vasodilation was demonstrated in FGR lambs compared with controls. Further investigation revealed that impairment of the prostanoid pathway may drive this reduction in vasodilatory capacity. Clinical indicators of CVD were not observed in our FGR lambs. However, subclinical signs of cardiovascular dysfunction were present in our FGR offspring. This study provides insight into potential mechanisms, such as the prostanoid pathway, that may warrant therapeutic interventions to improve cardiovascular development in growth-restricted newborns.NEW & NOTEWORTHY Our findings provide novel insight into the potential mechanisms that program for cardiovascular dysfunction in growth-restricted neonates as our growth-restricted lambs exhibited a progressive decline in endothelium-dependent vasodilation in the femoral artery between birth and 4 wk of age. Subsequent analyses indicated that this reduction in vasodilatory capacity is likely to be mediated by the prostanoid pathway and prostanoids could be a potential target for therapeutic interventions for fetal growth restriction (FGR).

Reduced fetal growth velocity and weight loss are associated with adverse perinatal outcome in fetuses at risk of growth restriction.

BACKGROUND: Although fetal size is associated with adverse perinatal outcome, the relationship between fetal growth velocity and adverse perinatal outcome is unclear. OBJECTIVE: This study aimed to evaluate the relationship between fetal growth velocity and signs of cerebral blood flow redistribution, and their association with birthweight and adverse perinatal outcome. STUDY DESIGN: This study was a secondary analysis of the TRUFFLE-2 multicenter observational prospective feasibility study of fetuses at risk of fetal growth restriction between 32+0 and 36+6 weeks of gestation (n=856), evaluated by ultrasound biometry and umbilical and middle cerebral artery Doppler. Individual fetal growth velocity was calculated from the difference of birthweight and estimated fetal weight at 3, 2, and 1 week before delivery, and by linear regression of all available estimated fetal weight measurements. Fetal estimated weight and birthweight were expressed as absolute value and as multiple of the median for statistical calculation. The coefficients of the individual linear regression of estimated fetal weight measurements (growth velocity; g/wk) were plotted against the last umbilical-cerebral ratio with subclassification for perinatal outcome. The association of these measurements with adverse perinatal outcome was assessed. The adverse perinatal outcome was a composite of abnormal condition at birth or major neonatal morbidity. RESULTS: Adverse perinatal outcome was more frequent among fetuses whose antenatal growth was <100 g/wk, irrespective of signs of cerebral blood flow redistribution. Infants with birthweight <0.65 multiple of the median were enrolled earlier, had the lowest fetal growth velocity, higher umbilical-cerebral ratio, and were more likely to have adverse perinatal outcome. A decreasing fetal growth velocity was observed in 163 (19%) women in whom the estimated fetal weight multiple of the median regression coefficient was <-0.025, and who had higher umbilical-cerebral ratio values and more frequent adverse perinatal outcome; 67 (41%; 8% of total group) of these women had negative growth velocity. Estimated fetal weight and umbilical-cerebral ratio at admission and fetal growth velocity combined by logistic regression had a higher association with adverse perinatal outcome than any of those parameters separately (relative risk, 3.3; 95% confidence interval, 2.3-4.8). CONCLUSION: In fetuses at risk of late preterm fetal growth restriction, reduced growth velocity is associated with an increased risk of adverse perinatal outcome, irrespective of signs of cerebral blood flow redistribution. Some fetuses showed negative growth velocity, suggesting catabolic metabolism.

Adaptive Growth of the Ductus Arteriosus and Aortic Isthmus in Various Ductus-Dependent Complex Congenital Heart Diseases.

BACKGROUND: The ductus arteriosus (DA) is critical in maintaining postnatal circulation in neonates with obstructed systemic circulation (OSC) and pulmonary circulation (OPC). We hypothesized that the size of the DA and aortic isthmus (AoI) undergoes adaptive growth in utero to counteract the hemodynamic challenges in these congenital heart diseases (CHD). METHODS: Postnatal echocardiograms of neonates diagnosed prenatally with ductal-dependent CHD who were started on prostaglandins within 24 h of birth were reviewed. We assessed the cross-sectional area of the aortic valve opening, pulmonary valve opening, AoI, and DA by calculating (diameter)2/body surface area. Neonates were classified into OSC or OPC then subgrouped depending upon the patency of semilunar valves: OSC with and without aortic atresia (OSC-AA and OSC-nAA, respectively) and OPC with and without pulmonary atresia (OPC-PA and OPC-nPA, respectively). RESULTS: Ninety-four cases were studied. The DA in OSC was significantly larger than OPC, and the DA in OSC-AA was significantly larger than OSC-nAA. The size of the AoI was significantly larger in OPC than OSC and larger in OSC-AA than OSC-nAA. Within the OSC-nAA group, there was no significant difference in the size of the DA, AoI, or pulmonary valve opening between those with retrograde flow (RF) at the AoI and without (nRF) except the aortic valve opening was significantly larger in nRF. All groups had comparable cross-sectional areas of systemic output. CONCLUSIONS: Our findings suggest that DA and AoI show compensatory growth to maintain critical blood flow to vital organs against primary anatomical abnormalities in ductus-dependent CHD. (249 words).

Fetal Biometric Assessment and Infant Developmental Prognosis of the Tadalafil Treatment for Fetal Growth Restriction.

Background and Objectives: Tadalafil is expected to treat fetal growth restriction (FGR), a risk factor for stillbirth and neonatal morbidity. This study aimed to evaluate the fetal biometric growth pattern of fetuses with FGR treated with tadalafil by ultrasonographic assessment. Materials and Methods: This was a retrospective study. Fifty fetuses diagnosed with FGR and treated by maternal administration of tadalafil and ten controls who received conventional treatment at Mie University Hospital from 2015 to 2019 were assessed. Fetal biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC), femur length (FL), and estimated fetal weight (EFW) at the start of treatment and at two weeks and four weeks of treatment were mainly assessed by ultrasound examination. The Wilcoxon signed-rank test was used to assess the measures. The Kyoto Scale of Psychological Development (KSPD) was used to assess the developmental prognosis on tadalafil-treated children at 1.5 years of corrected age (CA) and 3 years old. Results: The median gestational age at the start of treatment was 30 and 31 weeks in the tadalafil and control groups, respectively, and the median gestational age at delivery was 37 weeks in both groups. The Z-score of HC was significantly increased at 4 weeks of treatment (p = 0.005), and the umbilical artery resistance index was significantly decreased (p = 0.049), while no significant difference was observed in the control group. The number of cases with an abnormal score of less than 70 on the KSPD test was 19% for P-M, 8% for C-A, 19% for L-S, and 11% for total area at 1.5 years CA. At 3 years old, the respective scores were 16%, 21%, 16%, and 16%. Conclusions: Tadalafil treatment for FGR may maintain fetal HC growth and infants' neuro-developmental prognosis.

Altered cerebrovascular regulation in low birthweight swine.

Full-term low birthweight (LBW) offspring exhibit peripheral vascular dysfunction in the postnatal period; however, whether such impairments extend to the cerebrovasculature remains to be elucidated. We used a swine model to test the hypothesis that LBW offspring would exhibit cerebrovascular dysfunction at later stages of life. Offspring from 14 sows were identified as normal birthweight (NBW) or LBW and were assessed at 28 (similar to end of infancy) and 56 (similar to childhood) days of age. LBW swine had lower absolute brain mass, but demonstrated evidence of brain sparing (increased brain mass scaled to body mass) at 56 days of age. The cerebral pulsatility index, based on transcranial Doppler, was increased in LBW swine. Moreover, arterial myography of isolated cerebral arteries revealed impaired vasoreactivity to bradykinin and reduced contribution of nitric oxide (NO) to vasorelaxation in the LBW swine. Immunoblotting demonstrated a lower ratio of phosphorylated-to-total endothelial NO synthase in LBW offspring. This impairment in NO signaling was greater at 28 vs. 56 days of age. Vasomotor responses to sodium nitroprusside (NO-donor) were unaltered, while Leu31, Pro34 neuropeptide Y-induced vasoconstriction was enhanced in LBW swine. Increases in total Y1 receptor protein content in the LBW group were not significant. In summary, LBW offspring displayed signs of cerebrovascular dysfunction at 28 and 56 days of age, evidenced by altered cerebral hemodynamics (reflective of increased impedance) coupled with endothelial dysfunction and altered vasomotor control. Overall, the data reveal that normal variance in birthweight of full-term offspring can influence cerebrovascular function later in life.

The role of the brain-sparing effect of growth-restricted fetuses in newborn germinal matrix/intraventricular hemorrhage.

OBJECTIVES: The aim of the study was to evaluate the effect of the brain-sparing effect (BSE) of fetal growth restriction (FGR) in newborn germinal matrix/intraventricular hemorrhage (GM/IVH). METHODS: A total of 320 patients who delivered prior to the 34th gestational week were analyzed from data records. 201 patients were divided into two groups according to cerebro-placental ratio (CPR): early fetal growth restriction (FGR) with abnormal CPR group (n=104) and appropriate for gestational age with normal Doppler group (control) (n=97). Using the normal middle cerebral artery (MCA) Doppler as a reference, multivariate logistic regression analysis was used to assess the association between the BSE and the primary outcome. RESULTS: The rate of Grade I-II germinal matrix/intraventricular hemorrhage (GM/IVH) was 31(29.8%) in the group possessing early FGR with abnormal CPR and 7(7.2%) in the control group, showing a statistically significant difference. The rate of grade III-IV GM/IVH was 7(6.7%) in the group possessing early FGR with abnormal CPR and 2 (2.1%) in the control group, showing no statistically significant difference. We found that gestational age at delivery <32 weeks was an independent risk factor for GM/IVH. In addition, we found that other variables such as the presence of preeclampsia, fetal weight percentile <10, emergency CS delivery, 48-h completion after the first steroid administration and 24-h completion rate after MgSO4 administration were not independently associated with the primary outcome. CONCLUSIONS: Our results indicate that the rate of GM-IVH was increased in the group possessing early FGR with abnormal CPR; however, multivariate logistic regression analysis showed that BSE was not an independent risk factor for GM/IVH.

Blood-Brain Barrier Disintegration in Growth-Restricted Fetuses with Brain Sparing Effect.

The endothelial cells of the blood-brain barrier adhere closely, which is provided by tight junctions (TJs). The aim of the study was to assess the damage to the endothelial TJs in pregnancy, complicated by fetal growth restriction (FGR) and circulatory centralization (brain-sparing effect, BS). The serum concentrations of NR1 subunit of the N-methyl-D-aspartate receptor (NR1), nucleoside diphosphate kinase A (NME1), S100 calcium-binding protein B (S100B), occludin (OCLN), claudin-5 (CLN5), and zonula occludens protein - 1 (zo-1), and the placental expressions of OCLN, claudin-4 (CLN4), CLN5, and zo-1 were assessed with ELISA. The significantly higher serum NME1 concentrations and the serum CLN5/zo-1 index were observed in FGR pregnancy with BS, as compared to the FGR group without BS. The FGR newborns with BS were about 20 times more likely to develop an intraventricular hemorrhage (IVH) than the FGR infants without BS. The cerebroplacental ratio (CPR) allowed to predict the IVH in growth-restricted fetuses. The significantly lower placental CLN4 expression was observed in the FGR group with BS and who postnatally developed an IVH, as compared to the growth-restricted infants with BS without IVH signs. Pregnancy complicated by FGR and BS is associated with the destabilization of the fetal blood-brain barrier. The IVH in newborns is reflected in the inhibition of the placental CLN4 expression, which may be a useful marker in the prediction of an IVH among growth-restricted fetuses.

Brain-Derived Neurotrophic Factor Levels in Cord Blood from Growth Restricted Fetuses with Doppler Alteration Compared to Adequate for Gestational Age Fetuses.

Background and Objectives: Fetal growth restriction (FGR) is a severe obstetric disease characterized by a low fetal size entailing a set of undesired consequences. For instance, previous studies have noticed a worrisome association between FGR with an abnormal neurodevelopment. However, the precise link between FGR and neurodevelopmental alterations are not yet fully understood yet. Brain-derived neurotrophic factor (BDNF) is a critical neurotrophin strongly implicated in neurodevelopmental and other neurological processes. In addition, serum levels of BDNF appears to be an interesting indicator of pathological pregnancies, being correlated with the neonatal brain levels. Therefore, the aim of this study is to analyze the blood levels of BDNF in the cord blood from fetuses with FGR in comparison to those with weight appropriate for gestational age (AGA). Materials and Methods: In this study, 130 subjects were recruited: 91 in group A (AGA fetuses); 39 in group B (16 FGR fetuses with exclusively middle cerebral artery (MCA) pulsatility index (PI) < 5th percentile and 23 with umbilical artery (UA) PI > 95th percentile). Serum levels of BDNF were determined through ELISA reactions in these groups. Results: Our results show a significant decrease in cord blood levels of BDNF in FGR and more prominently in those with UA PI >95th percentile in comparison to AGA. FGR fetuses with exclusively decreased MCA PI below the 5th percentile also show reduced levels of BDNF than AGA, although this difference was not statistically significant. Conclusions: Overall, our study reports a potential pathophysiological link between reduced levels of BDNF and neurodevelopmental alterations in fetuses with FGR. However, further studies should be conducted in those FGR subjects with MCA PI < 5th percentile in order to understand the possible implications of BDNF in this group.

Fetal cerebral blood-flow redistribution: analysis of Doppler reference charts and association of different thresholds with adverse perinatal outcome.

OBJECTIVES: First, to compare published Doppler reference charts of the ratios of flow in the fetal middle cerebral and umbilical arteries (i.e. the cerebroplacental ratio (CPR) and umbilicocerebral ratio (UCR)). Second, to assess the association of thresholds of CPR and UCR based on these charts with short-term composite adverse perinatal outcome in a cohort of pregnancies considered to be at risk of late preterm fetal growth restriction. METHODS: Studies presenting reference charts for CPR or UCR were searched for in PubMed. Formulae for plotting the median and the 10th percentile (for CPR) or the 90th percentile (for UCR) against gestational age were extracted from the publication or calculated from the published tables. Data from a prospective European multicenter observational cohort study of singleton pregnancies at risk of fetal growth restriction at 32 + 0 to 36 + 6 weeks' gestation, in which fetal arterial Doppler measurements were collected longitudinally, were used to compare the different charts. Specifically, the association of UCR and CPR thresholds (CPR < 10th percentile or UCR ≥ 90th percentile and multiples of the median (MoM) values) with composite adverse perinatal outcome was analyzed. The association was also compared between chart-based thresholds and absolute thresholds. Composite adverse perinatal outcome comprised both abnormal condition at birth and major neonatal morbidity. RESULTS: Ten studies presenting reference charts for CPR or UCR were retrieved. There were large differences between the charts in the 10th and 90th percentile values of CPR and UCR, respectively, while median values were more similar. In the gestational-age range of 28-36 weeks, there was no relationship between UCR or CPR and gestational age. From the prospective observational study, 856 pregnancies at risk of late-onset preterm fetal growth restriction were included in the analysis. The association of abnormal UCR or CPR with composite adverse perinatal outcome was similar for percentile thresholds or MoM values, as calculated from the charts, and for absolute thresholds, both on univariable analysis and after adjustment for gestational age at measurement, estimated fetal weight MoM and pre-eclampsia. The adjusted odds ratio for composite adverse perinatal outcome was 3.3 (95% CI, 1.7-6.4) for an absolute UCR threshold of ≥ 0.9 or an absolute CPR threshold of < 1.11 (corresponding to ≥ 1.75 MoM), and 1.6 (95% CI, 0.9-2.9) for an absolute UCR threshold of ≥ 0.7 to < 0.9 or an absolute CPR threshold of ≥ 1.11 to < 1.43 (corresponding to ≥ 1.25 to < 1.75 MoM). CONCLUSIONS: In the gestational-age range of 32 to 36 weeks, adjustment of CPR or UCR for gestational age is not necessary when assessing the risk of adverse outcome in pregnancies at risk of fetal growth restriction. The adoption of absolute CPR or UCR thresholds, independent of reference charts, is feasible and makes clinical assessment simpler than if using percentiles or other gestational-age normalized units. The high variability in percentile threshold values among the commonly used UCR and CPR reference charts hinders reliable diagnosis and clinical management of late preterm fetal growth restriction. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Cardiovascular and Cerebrovascular Implications of Growth Restriction: Mechanisms and Potential Treatments.

Fetal growth restriction (FGR) is a common complication of pregnancy, resulting in a fetus that fails to reach its genetically determined growth potential. Whilst the fetal cardiovascular response to acute hypoxia is well established, the fetal defence to chronic hypoxia is not well understood due to experiment constraints. Growth restriction results primarily from reduced oxygen and nutrient supply to the developing fetus, resulting in chronic hypoxia. The fetus adapts to chronic hypoxia by redistributing cardiac output via brain sparing in an attempt to preserve function in the developing brain. This review highlights the impact of brain sparing on the developing fetal cardiovascular and cerebrovascular systems, as well as emerging long-term effects in offspring that were growth restricted at birth. Here, we explore the pathogenesis associated with brain sparing within the cerebrovascular system. An increased understanding of the mechanistic pathways will be critical to preventing neuropathological outcomes, including motor dysfunction such as cerebral palsy, or behaviour dysfunctions including autism and attention-deficit/hyperactivity disorder (ADHD).

Volume blood flow-based indices of fetal brain sparing in the second half of pregnancy: A longitudinal study.

INTRODUCTION: Cerebroplacental ratio (CPR) and umbilicocerebral ratio (UCR) are clinically used as a measure of fetal brain sparing. These are calculated as the ratios between the pulsatility indices (PIs) of middle cerebral (MCA) and umbilical (UA) arteries, and are an indirect representation of the balance between cerebral and placental perfusion. Volume blood flow (Q)-based ratios, ie Q-CPR or Q-UCR, would directly reflect the distribution of fetal cardiac output to the placenta and brain. Thus, we aimed to determine the development pattern of Q-CPR and Q-UCR during the second half of pregnancy, construct reference intervals, and evaluate their association with CPR and UCR. MATERIAL AND METHODS: In a longitudinal cohort study of low-risk pregnancies, the inner diameter of the fetal superior vena cava (SVC) and umbilical vein (UV) was measured and velocity waveforms were obtained from the MCA, UA, UV and SVC using ultrasound at approximately 4-weekly intervals from 20 to 41 weeks. The CPR was calculated as PIMCA /PIUA and the inverse ratio was the UCR. Cerebral and placental blood flows were estimated as the product of mean velocity and cross-sectional area of the SVC and UV, respectively. Q-CPR was calculated as QSVC /QUV and the inverse as the Q-UCR. Gestational age-specific reference intervals were calculated and associations between variables were tested using multilevel regression modeling. RESULTS: Longitudinal reference intervals of Q-CPR and Q-UCR were established based on 471 paired measurements of QSVC and QUV obtained serially from 134 singleton pregnancies. The mean Q-CPR increased from 0.4 to 0.8 during the second half of pregnancy and Q-UCR declined from 2.5 to 1.3, while the CPR and UCR had U-shaped curves but in opposite directions. No significant correlation was found between CPR and Q-CPR (R = 0.10; P = .051), or UCR and Q-UCR (R = 0.09; P = .11), and the agreement between PI-based and Q-based indices of fetal brain sparing was poor. CONCLUSIONS: Indices of fetal brain sparing based on placental and cerebral volume blood flow differ from those calculated from UA and MCA PIs. They correlated poorly with conventional CPR and UCR, indicating that they may provide additional/different physiological information. Reference values of Q-CPR and Q-UCR established here can be useful to investigate their clinical value further.

The effect of maternal position on fetal middle cerebral artery Doppler indices and its association with adverse perinatal outcomes: a pilot study.

Objective The aim of this study was to compare position-related changes in fetal middle cerebral artery (MCA) Doppler pulsatility indices (PI). Methods A prospective study of 41 women with conditions associated with placental-pathology (chronic hypertension, pregestational diabetes, and abnormal analytes) and 34 women without those conditions was carried out. Fetal MCA Doppler velocity flow waveforms were obtained in maternal supine and left lateral decubitus positions. MCA PI Δ was calculated by subtracting the PI in the supine position from the PI in the left lateral position. Secondary outcomes included a composite of adverse perinatal outcomes (fetal growth restriction, oligohydramnios, and preeclampsia). χ2 and Student t-tests and repeated-measures analysis of variance were used. Results MCA PI Δ was significantly less for high-risk pregnant women ([P = 0.03]: high risk, left lateral PI, 1.90 ± 0.45 vs. supine PI, 1.88 ± 0.46 [Δ = 0.02]; low risk, left lateral PI, 1.90 ± 0.525 vs. supine PI, 1.68 ± 0.40 [Δ = 0.22]). MCA PI Δ was not significantly different between women who had a composite adverse outcome and women who did not have a composite adverse outcome (P = 0.843). Conclusion Our preliminary study highlights differences in position-related changes in fetal MCA PI between high-risk and low-risk pregnancies. These differences could reflect an attenuated ability of women with certain risk factors to respond to physiologic stress.

Region-specific changes in Mus musculus brain size and cell composition under chronic nutrient restriction.

Nutrition is one of the most influential environmental factors affecting the development of different tissues and organs. It is suggested that under nutrient restriction the growth of the brain is spared as a result of the differential allocation of resources from other organs. However, it is not clear whether this sparing occurs brain-wide. Here, we analyzed morphological changes and cell composition in different regions of the offspring mouse brain after maternal exposure to nutrient restriction during pregnancy and lactation. Using high-resolution magnetic resonance imaging, we found that brain regions were differentially sensitive to maternal protein restriction and exhibited particular patterns of volume reduction. The cerebellum was reduced in absolute and relative volume, while cortex volume was relatively preserved. Alterations in cell composition (examined by the isotropic fractionator method) and organization of white matter (measured by diffusor tensor images) were also region specific. These changes were not related to the metabolic rate of the regions and were only partially explained by their specific growth trajectories. This study is a first step towards understanding the mechanisms of regional brain sparing at microstructural and macrostructural levels resulting from undernutrition.

Do Doppler Changes Reflect Pathology of Placental Vascular Lesions in IUGR Pregnancies?

OBJECTIVES: Doppler assessment of uteroplacental (UP) and fetoplacental (FP) circulation detects abnormal waveforms in intrauterine growth-restricted (IUGR) pregnancies. Similarly, histopathology also reveals lesions of vascular compromise in IUGR placenta. We evaluated an association between Doppler and histopathological (HP) assessment of the maternal and fetal circulation in IUGR. METHODS: IUGR cases with both Doppler and histopathology assessment were selected from our database. Doppler patterns recorded UP and FP insufficiency. The HP vascular lesions were classified as maternal vascular underperfusion and fetal thrombotic vasculopathy (FTV). IUGRs were grouped based on (i) presence of preeclampsia (PE), (ii) clinical onset (early vs late) of IUGR (early onset [EO]/late onset), and (iii) gestational age (term, T/preterm, PT). RESULTS: Abnormal Doppler waveforms were present in 69 of the total 88 IUGR cases (78.4%). The most frequent pattern was fetoplacental insufficiency (FPI) (66%) which was combined with uteroplacental insufficiency (UPI) in 49%. HP showed vascular lesions in 52.3% and most frequent was FTV (38%). PE-associated IUGR (n = 49) had higher UPI pattern (75.5% vs 43.6%, P = .004), while normotensive IUGR had higher FPI pattern (28.2% vs 8.2%, P = .01). EO-IUGR (n = 55) and PT-IUGR (n = 52) had significant abnormal Doppler waveforms (P < .05) with higher combined patterns and brain sparing. Doppler was more sensitive for fetal vascular lesions than maternal (75.8% vs 66.7%). However, 42% of cases with normal Doppler findings showed HP vascular lesions. CONCLUSION: IUGR pregnancies harbor significant vascular compromise. Fetal circulatory lesions were more common in IUGR pregnancies. In a significant number of cases with normal Doppler report, vascular lesions were identified on histopathology, emphasizing placental examination in all cases of IUGR.

Pentaerythrityltetranitrate (PETN) improves utero- and feto-placental Doppler parameters in pregnancies with impaired utero-placental perfusion in mid-gestation - a secondary analysis of the PETN-pilot trial.

AIM: In pregnancies complicated by impaired utero-placental perfusion, pentaeritrithyltetranitrate (PETN) has been shown to reduce the risk of severe fetal growth restriction (FGR) and perinatal death by 39%. The effect is most likely related to the vasodilatative influence of PETN. To assess its impact on utero-placental and fetal perfusion, we analyzed the Doppler parameters measured during the PETN pilot-trial. METHODS: One hundred and eleven pregnancies presenting impaired utero-placental resistance at mid-gestation were included in the trial. Fifty-four women received PETN, while 57 received a placebo. Doppler velocimetry measurements were monitored biweekly. Statistical analysis was performed using a mixed linear model. RESULTS: Within the first week of treatment, the mean pulsatility index (PI) of the uterine artery (UtA) dropped more prominently in the PETN group [-0.20, 95% confidence interval (CI): -0.34 to -0.05, P=0.007). The adjusted relative risk (RR) for abnormal cerebro-placental ratio (CPR) was significantly reduced by PETN [RR 0.412 (95% CI: 0.181-0.941)]. Kaplan-Meier analysis demonstrates the postponement of absent end-diastolic flow (AED), absent or reverse end-diastolic flow (ARED), brain sparing and abnormal cerebroplacental ratio (CPR) in the PETN group. CONCLUSION: The demonstrated effect of PETN on utero-placental and feto-placental perfusion strengthens the evidence for a positive impact in pregnancies complicated by impaired placental perfusion and might explain the effect on neonatal outcome, as shown in the PETN-pilot trial.

Evaluation of normalization of cerebro-placental ratio as a potential predictor for adverse outcome in SGA fetuses.

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.

Correlation between Doppler flow patterns in growth-restricted fetuses and neonatal circulation.

OBJECTIVES: To investigate whether prenatal Doppler parameters in growth-restricted fetuses are correlated with neonatal circulatory changes. METHODS: In 43 cases of suspected fetal growth restriction (FGR), serial Doppler measurements of umbilical artery (UA) and middle cerebral artery (MCA) pulsatility index (PI) were performed. The last measurement, closest to delivery (< 1 week before birth), was used for analysis. Neonatal circulation was assessed for 2 h/day on Days 1-5, 8 and 15 by near-infrared spectroscopy (NIRS) of the cerebral, renal and splanchnic regions. We calculated fractional tissue oxygen extraction (FTOE) as: (arterial oxygen saturation - NIRS value)/arterial oxygen saturation. The following ratios were calculated: cerebroplacental ratio (CPR; MCA-PI/UA-PI), cerebrorenal ratio (CRR; cerebral/renal FTOE) and cerebrosplanchnic ratio (CSR; cerebral/splanchnic FTOE). Spearman's rank correlation coefficient (ρ) was calculated between prenatal Doppler parameters and neonatal NIRS variables. These analyses were carried out for the entire group, and separately for cases of early FGR (delivered < 34 weeks) and late FGR (≥ 34 weeks). RESULTS: Fetal Doppler parameters correlated with neonatal NIRS variables on Days 1-3: UA-PI correlated with renal FTOE (Day 1: ρ = 0.454, P < 0.01) and CRR (Day 1: ρ = -0.517, P < 0.001). MCA-PI correlated with cerebral FTOE on Day 2 (ρ = 0.469, P < 0.01), approached statistical significance on Day 3 but was not correlated on Day 1. CPR correlated with CRR (Day 1: ρ = 0.474, P < 0.01). Most associations lost their statistical significance when early and late FGR subgroups were considered separately. CONCLUSION: Low MCA-PI and low CPR, indicating brain sparing before birth, are associated with low CRR after birth, indicating relatively greater blood flow to the cerebrum than to the renal region. Based on the results of this study, it could be speculated that if brain sparing is present in the fetal circulation, it persists during the first 3 days after birth. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.