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Objectives: This systematic review explores cardiac adaptation in monochorionic (MC) twins with twin-twin transfusion syndrome (TTTS) or selective fetal growth restriction (sFGR) and assesses the risk of congenital heart defects (CHDs)., Methods: Adhering to PRISMA guidelines, 63 studies were reviewed (49 on cardiac adaptation, 13 on CHD, one on both). A narrative synthesis of cardiac adaptation patterns was performed. Additionally, a meta-analysis compared the livebirth prevalence of CHD in TTTS and sFGR against uncomplicated MC twins., Results: In TTTS recipients, cardiac function may be impaired for diastolic, systolic, as well as global functions, while in donors, cardiac function is generally preserved. In sFGR, large twins may show hypertrophic cardiomyopathy, and small twins may show impaired systolic function. Co-occurrence of TTTS and sFGR magnifies cardiac impact but is often underreported. Meta-analysis for CHD prevalence revealed a relative risk ratio of 3.5 (95% CI: 2.5-4.9) for TTTS and 2.2 (95%CI: 1.3-3.5) for sFGR compared with uncomplicated MC twins., Conclusions: This study highlights the well-documented cardiac adaptation in TTTS, contrasting with limited understanding in sFGR. Elevated CHD risks were observed in both conditions. Enhanced cardiovascular surveillance is warranted in complicated MC twin pregnancies. Future research should explore cardiac adaptation in sFGR and its long-term consequences., (© 2024 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Objective: To determine whether the presence of brain sparing in fetal growth restricted (FGR) fetuses involves elevation of the cerebral injury biomarker S100B in maternal circulation., Methods: We included 63 women with suspected small for gestational age (SGA) fetuses between 24 and 35 +6/7 weeks of gestation. Maternal plasma angiogenic factors measurements and sonographic evaluation were performed at recruitment. Next, we subdivided our SGA cohort into three groups: SGA fetuses, FGR fetuses without brain-sparing, and FGR fetuses with brain-sparing (FGR-BS). Serum S100B concentration was calculated as S100B µg/L, S100B MoM, and the ratio S100B/ estimated fetal weight (EFW). We also report one case of S100B concentration surge in maternal serum following the diagnosis of fetal intraventricular hemorrhage (IVH)., Results: The FGR-BS group had higher maternal S100B µg/L (p < 0.01, p < 0.05, respectively), S100B MoM (p < 0.001, p < 0.001, respectively), and S100B/EFW (p < 0.001, p < 0.01, respectively), compared to the SGA and FGR groups. In the case report, maternal serum S100B concentrations were 0.0346 µg/L before, and 0.0874 µg/L after IVH occurrence., Conclusions: S100B concentration in maternal serum increased in pregnancies complicated by FGR and brain sparing. These results may substantiate in-utero cerebral injury and may explain the adverse neurocognitive outcomes reported for this group., (© 2021 John Wiley & Sons Ltd.)

Objective: Evaluate survival in twin twin transfusion syndrome (TTTS) with and without selective fetal growth restriction (sFGR) after fetoscopic laser surgery (FLS)., Methods: Retrospective study of monochorionic diamniotic twins undergoing FLS. The cohort was classified as TTTS and TTTS with sFGR. Baseline, intra-operative and postoperative variables were analyzed. Mann-Whitney U, Pearson chi-square, Fisher's exact, t-test and receiver operating characteristic (ROC) curve analysis were performed., Results: Four hundred and ninety-two pregnancies were included, 304 (61.78%) TTTS and 188 (38.22%) TTTS with sFGR. No difference in donor outcomes. TTTS group had higher donor estimated fetal weight (EFW%) percentile (19.7 ± 18.8 vs. 2.2 ± 2.1, p < 0.001). Significant predictors for demise at 30 days were 37% intertwin weight discordance (IWD) with donor EFW% < first (area under ROC curve [AUC] = 0.85, p = 0.001) or IWD >25% and intertwin umbilical artery pulsatility index discordance (DUAPI) ≥0.4 (AUC = 0.71, p = 0.001)., Conclusion: Combination of IWD of 37% and donor EFW%

Objective: To clarify the relationships between placental characteristics and birthweight discordance in three types of selective intrauterine growth restriction (sIUGR) in monochorionic diamniotic twins., Methods: A retrospective cohort study was conducted between april 2013 and april 2020. Associations between placental characteristics and birthweight discordance were evaluated through multiple linear regression analyses with two models for each sIUGR type. Model A was adjusted for gestational age, Model B additionally adjusted for the impact of placental characteristics interacted., Results: In cases of type I sIUGR, birthweight discordance ratio was positively associated with placental territory discordance ratio [(β = 0.181,95%CI(0.072,0.290), p < 0.05), (β = 0.239,95%CI(0.125, 0.353), p < 0.05)] under both Model A and Model B. In-type II sIUGR [(β = -0.012,95%CI(-0.020, -0.004), p < 0.05) (β = -0.010,95%CI (-0.018, -0.002), p < 0.05)] and type III sIUGR [(β = -0.011,95%CI (-0.021, -0.001), p < 0.05), (β = -0.012,95%CI(-0.022, -0.003), p < 0.05)], birthweight discordance ratio was negatively associated with the total diameter of all the anastomoses as calculated with both Model A and Model B., Conclusion: Birthweight discordance is primarily related to placental territory discordance in type I sIUGR, whereas vascular anastomoses play important roles for growth-restricted fetal compensation in type II and III sIUGR., (© 2021 John Wiley & Sons Ltd.)

Introduction: Early-onset fetal growth restriction is a pregnancy complication often coinciding with abnormal Doppler flow in the umbilical artery. Absent or reversed end-diastolic flow in the umbilical artery is associated with adverse perinatal outcome. As the optimal management of this condition is unclear, the objective of this study was to analyze the time interval from admission to delivery of pregnancies with early-onset fetal growth restriction, while pursuing a policy of postponing delivery unless active management of labor would be required because of fetal distress or maternal condition. We also assessed short- and long-term perinatal outcome., Material and Methods: In this historical cohort study, all pregnant women with singleton pregnancies, admitted during 2004-2015 with early-onset fetal growth restriction were included. Pregnancies with absent or reversed end-diastolic flow (AREDF) were compared with pregnancies with a positive end-diastolic Doppler flow (PEDF). Time until delivery was determined and perinatal outcome was assessed for both groups., Results: In our study, 111 women were allocated to the PEDF group and 109 to the AREDF group. In the AREDF group, fetal distress was more often an indication for delivery, in comparison with the PEDF group (p = .004). Median time until delivery in patients admitted between 26 and 28 weeks' gestation was 6+5 weeks in the PEDF group and 1+4 weeks in the AREDF group (p = .001). No statistically significant difference was found between the Doppler groups in the composite adverse neonatal outcome, which includes at least one of the following outcomes: infant respiratory distress syndrome, sepsis, bronchopulmonary dysplasia, necrotizing enterocolitis, intraventricular hemorrhage >grade 2, periventricular leukomalacia and perinatal death (p = .63)., Conclusions: In this study, comprising pregnancies with early-onset fetal growth restriction, fetal distress was observed more frequently in the AREDF group with the consequence of delivery at an earlier stage of gestation, compared with the PEDF group. AREDF was not associated with increased perinatal morbidity and mortality compared with PEDF., (© 2021 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Objective: To identify antenatal predictors of adverse perinatal outcomes in a population of preterm fetuses with early placental insufficiency diagnosed by Doppler abnormalities., Method: In this cross-sectional study of a cohort of singleton pregnant women diagnosed with early placental insufficiency, relationships between perinatal variables (arterial and venous Doppler, gestational age, birth weight, oligohydramnios, estimated fetal weight, and fetal weight z-scores) and major neonatal complications were analyzed by logistic regression., Results: Two hundred sixty-five women were delivered, between 24 and 33 weeks gestation. The overall frequency of intact survival was 57.9% (n = 154). Gestational age thresholds for best prediction of survival was 27 + 6 weeks and for intact survival was 29 + 0 weeks gestation. Fetal weight and absent/reversed ductus venosus a-wave were the main predictors of survival in the regression model. When fetal weight was substituted for fetal weight z-score, ductus venosus abnormal Doppler predicted mortality and absent or reversed umbilical artery diastolic velocities predicted intact survival., Conclusions: This study illustrates the impact of gestational age and fetal weight on perinatal outcomes in early placental insufficiency, with well-defined thresholds. Gestational age and fetal weight, or a combination of fetal weight z-scores and fetal Doppler parameters, were the best predictors of intact survival in our sample., (© 2019 John Wiley & Sons, Ltd.)

The ductus venosus plays a critical role in circulatory adaptation to hypoxia in fetal growth restriction but the mechanisms still remain controversial. Increased shunting of blood through the ductus venosus under hypoxic conditions has been shown in animal and human studies. The hemodynamic laws governing the accelerated flow in this vessel suggest that any dilation at its isthmus, which increases the blood flow shunting to the heart, is associated with a low, absent or reversed a-wave and a high pulsatility index. Cardiac dysfunction associated with increased atrial pressure as well as reduced ventricular compliance might be predominant mechanisms determining the profile of ductus venosus velocity waveforms in severe fetal growth restriction with signs of hypoxic compromise. Understanding the pathophysiology of the ductus venosus will underpin translation of the hypotheses developed through biostatistics toward explaining with more confidence Doppler changes in the fetal circulation in predicting clinical outcomes., (© 2019 Nordic Federation of Societies of Obstetrics and Gynecology.)

We investigated menstrual cycles in intrauterine growth restricted (IUGR, 7-10 years, n = 8) and age-matched control (n = 10) baboons. Cycle duration and plasma anti-Mullerian hormone were similar. IUGR spent more days per cycle swollen and had elevated early morning fasted serum cortisol, suggesting normal fertility in the presence of increased psychosocial stress., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Women with a history of placenta-related pregnancy complications, such as preeclampsia, intrauterine growth restriction or preterm delivery, have an increased risk for recurrence of such complications. This recurrence is likely the result of underlying endothelial dysfunction that leads to abnormal placentation, especially in complications with an early onset. This study provides an overview of biomarkers of placental development and function in pregnancies from women with a history of placenta-related complications., Material and Methods: A systematic literature search was conducted limited to human studies and including keywords related to a history of placenta-related complications and markers of placental development and function. Two independent reviewers assessed eligibility and quality of 1553 retrieved unique articles., Results: Five articles reporting on placental development and function in women with an obstetric history of preeclampsia (n = 3), intrauterine growth restriction (n = 1) and preterm delivery (n = 2) were eligible for quality assessment. We identified associations between a history of preeclampsia and abnormal placental histological findings at term in the current pregnancy, but found contradictory results regarding presence of uterine artery notching. In women with a history of very preterm delivery (<32 weeks), one study showed associations with abnormal placental histology., Conclusion: Literature on the association between a history of placenta-related complications and placental development and function in subsequent pregnancies is scarce and studies are heterogeneous. However, literature shows that placenta-related pregnancy complications are associated with subsequent placental histology., (© 2017 Nordic Federation of Societies of Obstetrics and Gynecology.)

Introduction: Current knowledge of the fetoplacental vasculature in fetal growth restriction (FGR) due to placental dysfunction focuses on the microvasculature rather than the macrovasculature. The aim of this study was to investigate the feasibility of computed tomography angiography to analyze the fetoplacental macrovasculature in normal and FGR pregnancies., Material and Methods: We included 29 placentas (22-42 weeks of gestation) from normal birthweight pregnancies and eight placentas (26-37 weeks of gestation) from FGR pregnancies (birthweight < -15% and abnormal umbilical Doppler flow). We performed postpartum placental computed tomography angiography followed by semi-automatic three-dimensional image segmentation., Results: A median of nine (range seven to eleven) vessel generations was identified. In normal birthweight placentas, gestational age was positively linearly correlated with macrovascular volume (p = 0.002), vascular surface area (p < 0.0005) and number of vessel junctions (p = 0.012), but not with vessel diameter and inter-branch length. The FGR placentas had a lower weight (p = 0.004) and smaller convex volume (p = 0.022) (smallest convex volume containing the macrovasculature); however, macrovascular volume was not significantly reduced. Hence, macrovascular density given as macrovascular outcomes per placental volume was increased in FGR placentas: macrovascular volume per convex volume (p = 0.004), vascular surface area per convex volume (p = 0.004) and number of vessel junctions per convex volume (p = 0.037)., Conclusions: Evaluation of the fetoplacental macrovasculature is feasible with computed tomography angiography. In normal birthweight placentas, macrovascular volume and surface area increase as pregnancy advances by vessel branching rather than increased vessel diameter and elongation. The FGR placenta was smaller; however, the macrovascular volume was within normal range because of an increased macrovascular density., (© 2018 Nordic Federation of Societies of Obstetrics and Gynecology.)

Background: Most developmental programming studies on maternal nutrient reduction (MNR) are in altricial rodents whose maternal nutritional burden and offspring developmental trajectory differ from precocial non-human primates and humans., Methods: Control (CTR) baboon mothers ate ad libitum; MNR mothers ate 70% global control diet in pregnancy and lactation., Results: We present offspring morphometry, blood cortisol, and adrenocorticotropin (ACTH) during second half of gestation (G) and first three postnatal years. Moderate MNR produced intrauterine growth restriction (IUGR). IUGR males (n=43) and females (n=28) were smaller than CTR males (n=50) and females (n=47) in many measurements at many ages. In CTR, fetal ACTH increased 228% and cortisol 48% between 0.65G and 0.9G. IUGR ACTH was elevated at 0.65G and cortisol at 0.9G. 0.9G maternal gestational weight gain, fetal weight, and placenta weight were correlated., Conclusions: Moderate IUGR decreased body weight and morphometric measurements at key time points and altered hypothalamo-pituitary-adrenal function., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To investigate the association between maternal vascular murmurs (MVMs) and fetal growth restriction (defined as small-for-gestational-age [SGA] fetus) and abnormal Doppler pulsatility index (PI) of the uterine and/or umbilical arteries., Methods: A cross-sectional study of women aged 18 years or older with a singleton pregnancy at 28-34 weeks was conducted at Regional Hospital Viborg, Denmark, between May 1 and August 1, 2013. Ultrasound fetal biometry was performed and the Doppler PI of the umbilical and uterine arteries was determined. An estimated fetal weight (EFW) at or below the 10th percentile was defined as SGA. Microphone recordings from the lower abdomen were divided into heart valve sounds and MVMs., Results: The final analysis included 63 participants, with 25 classified as SGA and 38 as non-SGA. The mean pregnancy duration was 32.4 ± 1.4 weeks. In total, 17 participants had MVMs. There was a clear association between MVMs and a composite of SGA and an abnormal PI of the uterine and/or the umbilical artery (P<0.001), but not between MVMs and SGA only (P=0.154)., Conclusion: Maternal vascular murmurs are significantly associated with fetal growth restriction, but not with SGA per se., (© 2017 International Federation of Gynecology and Obstetrics.)

Objective: To study fetal aortic isthmus (AoI) shunt dynamics in monochorionic (MC) twins., Methods: Normal and complicated MC pregnancies were prospectively enrolled. The relationship of isthmus flow index (IFI) with Doppler parameters of umbilical artery (UA), descending aorta, middle cerebral artery, and ductus venosus and with left and right ventricular cardiac output and stroke volume was studied., Results: The IFI was obtained in 180 examinations from 48 pregnancies (24 twin-twin transfusion syndrome, TTTS; 4 selective intrauterine growth restriction, sIUGR; 12 TTTS + sIUGR; and 8 uncomplicated). Median gestational age was 20.9 weeks. AoI diastolic flow was reversed in three cases. UA pulsatility index (PI) and ductus venosus-PI z-scores were negatively correlated with the IFI (r s -0.40 and -0.26, respectively, p < 0.001). Regression analysis identified only UA-PI as a determinant of the IFI (p < 0.001). The IFI was significantly correlated with left ventricular cardiac output and stroke volume. It did not differ between TTTS donors and recipients. sIUGR fetuses had significantly lower IFI compared with normal-grown counterparts (p < 0.001)., Conclusion: In MC gestations, AoI shunting is predominantly determined by placental flow resistance, while cerebral impedance and volume status have no impact. In MC twins, the relationship between AoI flow and outcome deserves further study in the setting of sIUGR. © 2017 John Wiley & Sons, Ltd., (© 2017 John Wiley & Sons, Ltd.)

Objective: To identify the correlation between the renal vascularization index (VI), the flow index (FI) and the vascularization and flow index (VFI) and placental and fetal hemodynamics in fetuses with growth restriction., Method: Bidimensional ultrasound and three-dimensional power Doppler with the VOCAL technique were used to determine the renal vascular indexes and fetal and placental hemodynamics in fetuses below the 10th percentile for fetal weight. Partial correlation analysis (controlled for renal depth and gestational age) was performed. The fetuses were divided into four groups according to their hemodynamic picture, and renal indexes were compared between the groups., Results: Eighty-one fetuses were evaluated. VI, FI and VFI showed negative correlation with the ductus venosus pulsatility index. VI and VFI showed positive correlations with the amniotic fluid index. The group of fetuses with the worst hemodynamic picture (abnormal umbilical artery, middle cerebral artery and ductus venosus pulsatility indexes) showed significantly lower VI and VFI than the group with no changes in these pulsatility indexes., Conclusions: Renal vascularization indexes were inversely correlated with ductus venosus pulsatility indexes and were diminished in fetuses showing hemodynamic compromise. These changes might be related to postnatal renal impairment. © 2017 John Wiley & Sons, Ltd., (© 2017 John Wiley & Sons, Ltd.)

Introduction: The pulsatility indices of the umbilical and uterine arteries are used as the surrogate measures of utero-placental perfusion. Combining the two might simplify the evaluation of total placental vascular impedance, possibly improve prediction of adverse outcomes, and help identify pregnancies with suspected fetal growth restriction that need more intense surveillance., Material and Methods: Umbilical and uterine blood flow velocities were recorded using pulsed-wave Doppler in a longitudinal study of 53 low-risk pregnancies (248 observations) during 20-40 weeks of gestation. Pulsatility indices was calculated for each of these vessels. A new placental pulsatility index was constructed as: (umbilical artery pulsatility index + mean of the left and right uterine artery pulsatility indices)/2, and mean +2 SD defined as abnormal. Gestational age-specific reference percentiles were calculated for the second half of pregnancy and related to values obtained from 340 pregnancies with suspected intra-uterine growth restriction to test its ability to predict adverse pregnancy outcome., Results: The placental pulsatility index was closely associated with gestational age and decreased with advancing gestation in normal pregnancy. The placental pulsatility index had a higher sensitivity and comparable specificity in predicting adverse outcome in pregnancies suspected of intra-uterine fetal growth restriction when compared with conventional umbilical and uterine artery pulsatility indices., Conclusions: The new placental pulsatility index, reflecting placental vascular impedance on both the fetal and maternal side of placenta, improves prediction of adverse outcome in pregnancies suspected of intra-uterine fetal growth restriction., (© 2017 Nordic Federation of Societies of Obstetrics and Gynecology.)

Introduction: Fetal growth restriction is associated with short-term and long-term mortality and morbidity. We hypothesized that adverse outcome in children with fetal growth restriction at primary school age is associated with fetoplacental circulatory abnormalities., Material and Methods: Comprehensive ultrasonographic assessment of fetoplacental hemodynamics was performed in 72 growth-restricted fetuses prenatally, and short-term outcome data were collected. At the median age of 9 years, mortality and morbidity were determined using medical charts and questionnaires. The impact of abnormal fetoplacental hemodynamics on mortality and morbidity with significant developmental disorders or delay were studied., Results: Fetal growth restriction children with adverse long-term outcome were delivered earlier and with lower birthweights than were those with non-compromised outcome. Seventy percent of the fetal growth restriction group showed non-compromised long-term outcomes and participated in mainstream education at the appropriate age level. Absent/retrograde diastolic flow in the umbilical artery (p < 0.001), negative A-wave in the ductus venosus (p = 0.006), cardiomegaly (p = 0.02), hydrops (p = 0.006) and cardiovascular profile score <6 (p = 0.002) were associated with increased risk of adverse outcome. After adjustment for gestational age, these parameters demonstrated hazard ratios of 5.0-16.5 for adverse long-term outcome; increased systemic venous pulsatility and low cardiovascular profile score had the highest predictive power., Conclusions: Absent or reversed end-diastolic flow in the umbilical artery, reversed A-wave in the ductus venosus, cardiomegaly, hydrops, and low cardiovascular profile score are associated with adverse outcomes at primary school age in fetal growth restriction children. These fetal parameters play a significant role in the prediction of long-term outcomes for fetal growth restriction children., (© 2016 Nordic Federation of Societies of Obstetrics and Gynecology.)

The key determinant to a fetus maintaining its health is through adequate perfusion and oxygen transfer mediated by the functioning placenta. When this equilibrium is distorted, a number of physiological changes, including reduced fetal growth, occur to favor survival. Technologies have been developed to monitor these changes with a view to prolong intrauterine maturity while reducing the risks of stillbirth. Many of these strategies involve complex interpretation, for example Doppler ultrasound for fetal blood flow and computerized analysis of fetal heart rate changes. However, even with these modalities of fetal assessment to determine the optimal timing of delivery, fetal movements remain integral to clinical decision-making. In high-risk cohorts with fetal growth restriction, the manifestation of a reduction in perceived movements may warrant an expedited delivery. Despite this, there has been little evolution in the development of technologies to objectively evaluate fetal movement behavior for clinical application. This review explores the available literature on the value of fetal movement analysis as a method of assessing fetal wellbeing, and demonstrates how interdisciplinary developments in this area may aid in the improvement of clinical outcomes., (© 2016 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

There is a search for rescue therapy against fetal origins of cardiovascular disease in pregnancy complicated by chronic fetal hypoxia, particularly following clinical diagnosis of fetal growth restriction (FGR). Melatonin protects the placenta in adverse pregnancy; however, whether melatonin protects the fetal heart and vasculature in hypoxic pregnancy independent of effects on the placenta is unknown. Whether melatonin can rescue fetal cardiovascular dysfunction when treatment commences following FGR diagnosis is also unknown. We isolated the effects of melatonin on the developing cardiovascular system of the chick embryo during hypoxic incubation. We tested the hypothesis that melatonin directly protects the fetal cardiovascular system in adverse development and that it can rescue dysfunction following FGR diagnosis. Chick embryos were incubated under normoxia or hypoxia (14% O2) from day 1 ± melatonin treatment (1 mg/kg/day) from day 13 of incubation (term ~21 days). Melatonin in hypoxic chick embryos rescued cardiac systolic dysfunction, impaired cardiac contractility and relaxability, increased cardiac sympathetic dominance, and endothelial dysfunction in peripheral circulations. The mechanisms involved included reduced oxidative stress, enhanced antioxidant capacity and restored vascular endothelial growth factor expression, and NO bioavailability. Melatonin treatment of the chick embryo starting at day 13 of incubation, equivalent to ca. 25 wk of gestation in human pregnancy, rescues early origins of cardiovascular dysfunction during hypoxic development. Melatonin may be a suitable antioxidant candidate for translation to human therapy to protect the fetal cardiovascular system in adverse pregnancy., (© 2015 The Authors. Journal of Pineal Research. Published by John Wiley & Sons Ltd.)

The placenta is a temporary organ that is essential for a healthy pregnancy. It performs several important functions, including the transport of nutrients, the removal of waste products and the metabolism of certain substances. Placental disorders have been found to account for over 50% of stillbirths. Despite this, there are currently no methods available to directly and non-invasively assess placental function in utero. The primary aim of this pilot study was to investigate the use of (1)H MRS for this purpose. (1)H MRS offers the possibility to detect several placental metabolites, including choline, lipids and the amino acids glutamine and glutamate (Glx), which are vital to fetal development and placental function. Here, in utero placental spectra were acquired from nine small for gestational age (SGA) pregnancies, a cohort who are at increased risk of perinatal morbidity and mortality, and from nine healthy gestation-matched pregnancies. All subjects were between 26 and 39 weeks of gestation. Placenta Glx, choline and lipids at 1.3 and 0.9 ppm were quantified as amplitude ratios to that of intrinsic H2O. Wilcoxon signed rank tests indicated a significant difference in Glx/H2O (p = 0.024) between the two groups, but not in choline/H2O (p = 0.722) or in either lipid/H2O ratio (1.3 ppm, p = 0.813; 0.9 ppm, p = 0.058). This study has demonstrated that (1)H MRS has potential for the detection of placental metabolites in utero. This warrants further investigation as a tool for the monitoring of placental function., (Copyright © 2015 John Wiley & Sons, Ltd.)

Objective: To test the hypothesis that the pulmonary vein pulsatility index (PVPI) is higher in fetuses with growth restriction (IUGR) than in normal fetuses., Methods: Twenty-two fetuses with IUGR and twenty-one (21) fetuses with appropriate growth for gestational age from healthy mothers were studied. PVPI was calculated by Doppler echocardiography [maximal velocity (systolic or diastolic peak) - pre-systolic peak / mean velocity]. Obstetric ultrasound was used to assess fetal biometry and Doppler to assess the uterine, umbilical and middle cerebral arteries PI. Statistical analysis used t test and Pearson's correlation., Results: Mean gestational age was 31.5 +/- 2.1 weeks in the control group and 31.4 +/- 3.1 weeks in IUGR (P = 0.91). The PI of uterine and umbilical arteries were higher in IUGR than in controls (P < 0.001). Mean PVPI in IUGR fetuses was 1.31 +/- 0.41, and in controls it was 0.83 +/- 0.11 (P < 0.001)., Conclusion: The pulsatility index of pulmonary venous flow in fetuses with growth restriction is higher than in normal fetuses, probably as a result of left atrial dynamics alteration secondary or not to fetal left ventricular diastolic dysfunction. © 2014 John Wiley & Sons, Ltd., (© 2014 John Wiley & Sons, Ltd.)

Objective: To investigate the association between prenatal growth patterns as estimated by biparietal diameter and cardio-metabolic risk at 20 years., Design: Follow-up study., Setting: Denmark 1988-2009., Population: Two cohorts of children born between 1988 and 1990 (n=707) and followed up in 2008-2009 (n=333-509)., Methods: We have access to biparietal diameter from early ultrasound scan and birthweight. For each gender, biparietal diameter and birthweight, gestational age-specific growth-z-scores were calculated. A change in growth trajectory was depicted as a shift in z-score for the two growth measures. Multiple linear regression modeling was used to estimate associations between biparietal diameter and birthweight z-scores and later cardio-metabolic risk factors as well as estimating whether changing growth trajectory was associated with later cardio-metabolic risk., Main Outcome Measures: Self-reported anthropometrics and clinically measured blood pressure, heart rate and biochemical measures associated with cardio-metabolic health., Results: After adjustments, biparietal diameter was not associated with any of the outcomes. Birthweight was positively associated with both adult height and weight and inversely associated with insulin, triglyceride and insulin resistance. Also, the data indicated a U-shaped association between growth in the second half of pregnancy and adult body mass index among individuals with a low biparietal diameter in mid-pregnancy., Conclusion: Different patterns of intrauterine growth may be associated with later risk of cardio-metabolic disease., (© 2014 Nordic Federation of Societies of Obstetrics and Gynecology.)

Objective: To test if serum YKL-40 is increased in women developing preeclampsia or small-for-gestational age fetuses. We also assessed the association between uterine artery pulsatility index, notching and serum YKL-40 levels., Design: Prospective cohort study., Setting: A primary referral unit for obstetric ultrasound., Population: A total of 1214 unselected pregnant women enrolled at nuchal translucency examination between 11(+3) and 13(+6)  weeks of gestation., Methods: All women had ultrasound and blood sample collection at the nuchal translucency scan, a 20-week malformation scan and 25-week and 32-week fetal growth examinations. Uterine artery Doppler was assessed and outcome was registered from medical records., Main Outcome Measures: Preeclampsia, hypertension, small-for-gestational age., Results: Serum YKL-40 was associated with increasing maternal age (p < 0.0001), body mass index (p = 0.0002), primiparity (p = 0.0003), and hypertension (p = 0.015). Serum YKL-40 increased from 12 to 20 weeks and decreased from 20-25 and 25-32 weeks of gestation. No association was found between preeclampsia and serum YKL-40. Small-for-gestational-age at birth was significantly associated with a 5.4% increase in serum YKL-40 at 32 weeks of gestation (95% CI 1.5-9.3, p = 0.005). An association was found between uterine artery pulsatility index at 32 weeks and small-for-gestational age (p = 0.0015) but not between YKL-40 and uterine artery notching (p = 0.83)., Conclusions: Serum YKL-40 was not associated with preeclampsia. Increasing serum YKL-40 was related to maternal age, body mass index and small-for-gestational age and may reflect an exaggerated inflammatory response., (© 2014 Nordic Federation of Societies of Obstetrics and Gynecology.)

Objective: To determine the incidence of fetal brain injury by fetal brain magnetic resonance imaging (MRI) in pregnancies complicated with preterm labor (PL), preterm premature rupture of the membranes (PPROM), and intrauterine growth restriction (IUGR), and to compare fetal brain MRI with prenatal surveillance methods, and with immediate and long-term neurodevelopmental outcome., Methods: Between February 2007 and January 2009, high-risk pregnancies were analyzed by MRI at 1.5 Tesla after 24 weeks of gestation at the Clinical Hospital Center Zagreb, Croatia. Long-term outcome was defined as neurodevelopmental outcome at 24 months., Results: Among 70 pregnancies analyzed, 40.0% had abnormal fetal brain MRI. The highest incidence occurred in the PL group. There was no correlation between abnormal MRI and fetal surveillance methods (ultrasound, Doppler blood flow analysis, cardiotocography, biophysical profile) or immediate neonatal outcome (1-minute Apgar score, umbilical cord pH). Via MRI, fetal brain injury would have been diagnosed for 45.7% of fetuses with a long-term neurodevelopmental handicap. Binary logistic regression showed that, as compared with other surveillance methods, fetal brain MRI was the best predictor of long-term neurodevelopmental disability., Conclusion: PL, IUGR, and PPROM were associated with an early intrauterine CNS insult that was not accurately detected by existing prenatal testing options., (Copyright © 2014 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.)

We describe the hemodynamic changes observed in fetuses with extra cardiac conditions such as intrauterine growth restriction, tumors, twin-twin transfusion syndrome, congenital infections, and in fetuses of mothers with diabetes. In most fetuses with mild extra cardiac disease, the alterations in fetal cardiac function remain subclinical. Cardiac function assessment has however helped us to achieve a better understanding of the pathophysiology of these diseases. In fetuses at the more severe end of the disease spectrum, functional echocardiography may help in guiding clinical decision-making regarding the need for either delivery or fetal therapy. The growth-restricted fetus represents a special indication for routine cardiac function assessment, as in utero hemodynamic changes may help optimize the timing of delivery. Moreover, in intrauterine growth restriction, the altered hemodynamics causes cardiovascular remodeling, which can result in an increased risk of postnatal cardiovascular disease., (© 2013 John Wiley & Sons, Ltd.)

Subject: This study investigates the placental autophagic activity in growth-restricted fetuses in the monochorionic (MC) twin model., Patients and Methods: Forty MC twins were prospectively enrolled in this study, including 21 with and 19 without selective intrauterine growth restriction (sIUGR), defined as birth weight below the tenth percentile. The sIUGR group was subdivided on the basis of present versus absent or reversed umbilical artery end-diastolic flow at Doppler. Placenta samples were taken after delivery from each twin placenta territories. After protein extraction, Western blot was used to determine light chain 3 (LC3)-II placental protein expression in sIUGR and appropriately grown (appropriate-for-gestational age, AGA) twins., Results: The LC3-II was significantly higher in the sIUGR twin placental territory than in their AGA counterparts. In the sIUGR group, LC3-II fold change was significantly increased compared with that in the AGA cotwins (2.28 vs 1.04, p < 0.05). Placental LC3-II protein expression was particularly stimulated in the MC sIUGR group with abnormal umbilical artery Doppler flow compared with AGA controls (p < 0.05, one-way analysis of variance test)., Conclusions: In MC twins, the placental autophagic activity is different between sIUGR and AGA cotwins. The placenta territory with the least blood flow perfusion has the highest autophagic activity., (© 2013 John Wiley & Sons, Ltd.)

Objective: The objective of the study was to evaluate the association between placental histological patterns and umbilical artery (UA) Doppler velocimetry in pregnancies complicated by fetal growth restriction (FGR)., Methods: A cohort of 126 FGR pregnancies was followed according to a standard protocol. Placental lesions were diagnosed according to consensus nomenclature and standardized criteria., Results: Pulsatility index was normal in 45 (35.7%) and increased in 44 (34.9%) women. End-diastolic UA Doppler flow was absent in 27 (21.4%) and reversed in 10 (7.9%). Fifty-four women (42.9%) had preeclampsia. In preeclampsia, increasing Doppler abnormalities, from normal to reversed UA end-diastolic flow, were directly associated only with an increased number of placental syncytial knots. In normotensive pregnancies, Doppler abnormalities were associated with increased intervillous fibrin deposits, villous hypoplasia, syncytial knots, placental site giant cells, immature intermediate trophoblast, and with pattern of lesions indicating superficial implantation and maternal vascular underperfusion. In the whole cohort, increase of syncytial knots [odds ratio (OR) = 28.7; 95% confidence interval (CI) = 2.75-298.5], intervillous fibrin deposits (OR = 2.1; 95% CI = 1.04-4.28), placental site giant cells (OR = 3.0; 95% CI = 1.05-8.84), and patterns suggesting maternal underperfusion (OR = 2.9; 95% CI = 1.0-7.1) were independently associated with increased rates of absent/reversed UA end-diastolic flow., Conclusions: In pregnancies complicated by FGR, abnormalities of UA Doppler velocimetry were associated with placental lesions indicating superficial implantation and maternal vascular underperfusion., (© 2012 John Wiley & Sons, Ltd.)

Objectives: This study's aim was to evaluate the effect of preeclampsia and intrauterine growth restriction (IUGR) on fetal cardiac function, and the relationship of the latter with adverse pregnancy outcomes., Material and Methods: We did a cross-sectional study of 132 women with uncomplicated singleton pregnancies, 34 with preeclampsia without IUGR, and 12 with preeclampsia and IUGR. Fetal cardiac structure and function were evaluated using fetal two-dimension ultrasound, pulsed wave Doppler and tissue Doppler imaging (TDI). Data were analyzed by t-tests, ANOVA, Chi-square tests, or Wilcoxon rank-sum test., Results: Compared with the normal pregnancy group, mitral/tricuspid early systolic peak velocity of annulus/late diastolic peak velocity of annulus (Sa) and left ventricular (LV)/right ventricular (RV) early diastolic peak velocity at the annulus (Ea) in TDI decreased in preeclampsia with or without IUGR (P < 0.05). LV/RV Ea underwent a gestational decrease in preeclampsia with or without IUGR (P < 0.05). The changes in mitral/tricuspid Sa and LV Sa associated with preeclampsia were even more pronounced with preterm delivery at less than 34 gestational weeks and stillbirth (P < 0.05)., Conclusions: Intrauterine growth restriction influences fetal cardiac function in the presence of preeclampsia, and TDI may be a sensitive and preferable method to detect such changes. Fetal LV/RV Ea is a potential marker for early fetal cardiac diastolic impairment, and mitral/tricuspid Sa and LV Sa may be predictors for adverse pregnancy outcomes., (© 2012 John Wiley & Sons, Ltd.)

Objective: To determine the association between Doppler changes in the fetal vertebral (VA), middle cerebral (MCA), and umbilical arteries (UA) and severity of growth restriction (FGR) in fetuses delivered after 34 weeks., Method: Five hundred seventy-one Doppler examinations of the VA, MCA, and UA were performed between 26 and 41 weeks of gestation. Values were converted into multiples of the median and divided into birth weight (BW) categories: BW>P10(th) , BW

Objective: To identify pathological placental differences between early-onset and late-onset preeclampsia, in relation to fetal growth restriction (FGR)., Methods: Placentas from patients with preeclampsia were analyzed for lesions of maternal vascular supply consistent with maternal underperfusion and lesions of fetal vascular supply consistent with fetal thrombo-occlusive disease. Findings were compared between patients who gave birth before 34 weeks (early-onset preeclampsia) and after 34 weeks (late-onset preeclampsia)., Results: Compared with the late-onset group (n = 93), the early-onset group (n = 37) had higher rates of FGR (62.2% vs 25.8%, P < 0.001) and lesions of maternal vascular supply (95% vs 60%, P < 0.001). Within the early-onset group, cases with FGR (n = 23) had more lesions of fetal vascular supply (47.8% vs 7%, P = 0.01), with similar high rates of lesions of maternal vascular supply (91% vs 100%) compared with those without FGR. Within the late-onset preeclampsia group, cases with FGR (n = 24) had higher rates of maternal vascular supply lesions (88% vs 51%, P = 0.003) than those without FGR, but similar rates of fetal vascular supply lesions (25% vs 16%, P = 0.32)., Conclusion: The placental fetal vascular supply lesions in combination with maternal vascular lesions are more dominant in early-onset preeclampsia with FGR as compared with early-onset preeclampsia without FGR., (© 2012 John Wiley & Sons, Ltd.)

Objective: The authors aimed to study the contractility responses of normal and fetal growth restriction (FGR) placentas to prostaglandin E(2) (PGE(2) ) and to correlate the results to subsequent placental histological analysis., Method: A dual-perfused single cotyledon model was used. Placentas from pregnancies complicated by FGR and from normal pregnancies were obtained. Selected cotyledons were cannulated and dually perfused. Following stabilization, three concentrations of PGE(2) (0.05, 0.1, and 0.15 mg/mL) were administered to the fetal arterial side causing contraction/relaxation response. Fetal perfusion pressure was measured continuously during these contraction and relaxation phases. Following the perfusion experiments, the placentas were analyzed for fetal or maternal origin vascular lesions., Results: A total of 21 complete experiments were performed (16 normal, 5 FGR). In response to PGE(2) , FGR placentas exhibited lower change in the perfusion pressure and lower relaxation time constant. Basal perfusion pressure did not differ significantly between the two groups. Placental histopathology lesions, fetal or maternal origin, were more common in the FGR compared with the controls placentas, 80% versus 25%, respectively, P=  0.047., Conclusions: The lower vascular reactivity in response to PGE(2) and the presence of fetal and maternal vascular placental lesions suggest a mechanism explaining the altered vascular supply in FGR., (© 2012 John Wiley & Sons, Ltd.)

Assessment of the fetal cerebral circulation provides important information on the hemodynamic changes associated with chronic hypoxia and intrauterine growth restriction. Despite the incorporation of new US parameters, the landmark for the fetal brain hemodynamic evaluation is still the middle cerebral artery. However, new vascular territories, such as the anterior and posterior cerebral arteries, might provide additional information on the onset of the brain sparing effect. The fractional moving blood volume estimation and three-dimensional power Doppler ultrasound indices are new techniques that seem to be promising in identifying cases at earlier stages of vascular deterioration; still, they are not available for clinical application and more information is needed on the reproducibility and advantages of three-dimensional power Doppler ultrasound blood flow indices. In the past, the brain sparing effect was considered as a protective mechanism; however, recent information challenges this concept. There is growing evidence of an association between brain sparing effect and increased risk of abnormal neurodevelopment after birth. Even in mild late-onset intrauterine growth restriction affected fetuses with normal umbilical artery blood flow, increased cerebral blood perfusion can be associated with a substantial risk of abnormal neuroadaptation and neurodevelopment during childhood., (© 2012 John Wiley & Sons, Ltd.)

The concept of developmental origins of health and disease and the epidemic of noncommunicable diseases in low- and middle-income countries has increased the focus on low birth weight (LBW). Most studies linking LBW to future risk of metabolic diseases have focused on maternal nutrition and anemia. Several studies have shown that LBWis linked to skeletal muscle insulin resistance and future risk of type 2 diabetes, possibly caused by permanent modifications in skeletal muscle morphology and biochemistry leading to lowered functional capacity and physical activity in adult life. In some parts of the world, malaria infection during pregnancy is the most common cause of anemia and LBW. By causing disruption to nutrient supply, as well as hypoxia, placental malaria and anemia negatively impact intrauterine fetal development. Thus, in utero exposure to placental malaria and consequent LBW may impart a higher risk of developing type 2 diabetes in early adult life. This has not been investigated systematically. Worldwide, an estimated 125 million pregnancies occur annually in malarial areas with a vast potential for intrauterine growth restriction, LBW, and subsequent risk of metabolic dysfunction, including type 2 diabetes; this potential link also opens an opportunity for early prevention of future metabolic diseases by paying greater attention to malaria during pregnancy., (Copyright © 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd.. All rights reserved.)

Objective: Decreased fetal heart rate variability is associated with higher perinatal morbidity and mortality in intrauterine growth restriction (IUGR). This study used a new method [phase-rectified signal averaging (PRSA)] to calculate acceleration- and deceleration-related fluctuations of the fetal heart rate., Method: Cardiotocograms from 74 growth-restricted and 161 normal fetuses were included. Both groups were matched for gestational age. The transformed PRSA signal was quantified by the acceleration-related parameter-averaged acceleration capacity (AAC) and compared to the standard short-term variation (STV). Mann-Whitney test and receiver operator characteristic (ROC) curves were used for statistical analysis., Results: For AAC, the median values of the IUGR group and control group were 1.97 bpm [interquartile range (IQR): 1.66-2.23] and 2.49 bpm (IQR: 2.24-2.72), respectively. For STV, these values were 5.44 ms (IQR: 4.49-7.38) and 7.79 ms (IQR: 6.35-9.66), respectively. The area under the ROC curve was 81.4% for AAC and 70.5% for STV., Conclusion: The results of AAC are in both groups comparable to STV. Longitudinal studies are needed to investigate the association of AAC with the clinical outcome of the newborn., (Copyright © 2011 John Wiley & Sons, Ltd.)

Objective: To present fetal magnetic resonance imaging (MRI) ocular measurement ranges by gestational age (GA) in normal and growth-restricted fetuses., Methods: A total of 298 pregnant women from the 18th to the 39th week of gestation were imaged using MRI. Ocular measurements including binocular distance (BOD), interocular distance (IOD), transverse ocular diameter (OD) and anterior-posterior (AP) OD were measured. The curve estimation analyses for linear, logarithmic and quadratic models were performed. The ocular measurements of the fetuses with intrauterine growth restriction (IUGR) were compared with that of the normal fetuses., Results: The fetal eye resembles an ellipsoid with significantly longer OD and shorter AP (t = - 22.07, p < 0.001). The quadratic model was the best model in predicting growth of the fetal BOD, IOD, OD and AP. The ocular measurements of the fetuses with IUGR were significantly different from that of the normal fetuses (BOD: t = 3.58, p < 0.001; IOD: t = 5.73, p < 0.001; OD: t = 3.52, p < 0.001; AP: t = 2.19, p < 0.05)., Conclusion: Fetal ocular growth can be readily assessed by fetal MRI. Using the normative data provided in this study, fetal ocular anomalies may be detected. Ocular size is frequently reduced in the condition of IUGR, with potential pathologic impact on postnatal vision.

Selective intrauterine growth restriction (sIUGR) occurs in 10 to 15% of monochorionic (MC) twins, and it is associated with a substantial increase in perinatal mortality and morbidity. Clinical evolution is largely influenced by the existence of intertwin placental anastomoses: pregnancies with similar degrees of fetal weight discordance are associated with remarkable differences in clinical behavior and outcome. We have proposed a classification of sIUGR into three types according to umbilical artery (UA) Doppler findings (I-normal, II-absent/reverse end-diastolic flow, III-intermittent absent/reverse end-diastolic flow), which correlates with distinct clinical behavior, placental features and may assist in counseling and management. In terms of prognosis, sIUGR can roughly be divided in two groups: type I cases, with a fairly good outcome, and types II and III, with a substantial risk for a poor outcome. Management of types II and III may consist in expectant management until deterioration of the IUGR fetus is observed, with the option of cord occlusion if this occurs before viability. Alternatively, active management can be considered electively, including cord occlusion or laser coagulation. Both therapies seem to increase the chances of intact survival of the larger fetus, while they entail, or increase the chances of, intrauterine demise of the IUGR fetus., ((c) 2010 John Wiley & Sons, Ltd.)

Objective: To investigate the relationship between cardiovascular function in women with pre-eclampsia and fetal growth restriction (FGR) using impedance cardiography., Method: This retrospective study was performed with 639 participants allocated to one of 4 groups, a pre-eclampsia (PE) with FGR group, a PE without FGR group, a pregnancy-induced hypertension (PIH) without FGR group, and normal pregnancy (NP) group. Hemodynamic monitoring was performed noninvasively using impedance cardiography., Results: Mean arterial pressure and peripheral resistance were significantly higher, and cardiac output and maternal systolic function were significantly lower, in the 2 PE groups than in the PIH and NP groups, and these differences were the greatest between the NP and the PE with FGR groups., Conclusion: Impedance cardiography allowed to observe a gradual increase in peripheral resistance and cardiac output from the NP group to the PIH, the PE without FGR, and the PE with FGR groups. The most reduced systolic function and cardiac output and the most increased peripheral resistance was observed in the PE with FGR group., (Copyright (c) 2010 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.)

Preeclampsia and intrauterine growth restriction (IUGR) are major contributors to perinatal mortality and morbidity worldwide. Both are characterized by impaired trophoblastic invasion of the maternal spiral arteries and their conversion from narrow muscular vessels to wide non-muscular channels. Despite improvement in the understanding of the pathophysiology of these conditions, ability to accurately identify pregnant woman who will develop them is limited. This greatly impairs the development and testing of preventive interventions. While different measures of placental dysfunction have been associated with increased risk for adverse pregnancy outcomes, the ability of any single one to accurately predict these outcomes is poor. Developing predictive tests is further challenged by difficulty in the timing of the measurements, as both the structural and biochemical characteristics of the placenta change with increasing gestational age. The ideal screening test would accurately predict the development of adverse pregnancy outcomes early enough to provide a window for preventive interventions. Improvement in ultrasound technology provides potentially useful novel tools for evaluating placental structure, but measurements need to be standardized in order to be useful. Maternal serum analyte screening is a noninvasive test of placental biochemical function, but present serum marker alone is not sufficiently accurate to suggest its routine use in clinical practice. The use of first trimester biochemical markers in combination with uterine artery Doppler screening is promising as a potential screening tool. Prospective longitudinal studies using standardized methodology are necessary to further evaluate the choice of parameters and strategies of combination to achieve the best predictive models., (Copyright (c) 2010 John Wiley & Sons, Ltd.)

Objective: To evaluate the prognostic significance of the interaction between umbilical artery (UA) and middle cerebral artery (MCA) Doppler measurements in pregnancies complicated by fetal growth restriction (FGR)., Design: Cohort study., Setting: Third-level Perinatology Center in Northern Italy., Population: A study of 184 singleton pregnancies at 24-35 weeks' gestational age complicated by FGR and abnormal UA Doppler measurements., Methods: FGR was diagnosed by serial ultrasonograms. Neonatal brain damage was defined as the presence of cystic leukomalacia or grade III-IV intraventricular hemorrhage., Main Outcome Measures: Perinatal death and neonatal brain damage., Results: The prevalence of fetal/neonatal death or brain damage was 18.2% (16/88) in pregnancies with UA absent/reversed diastolic flow and 4.2% (4/96) in those with increased UA Doppler pulsatility. Stepwise logistic regression identified decreasing gestational age (OR=1.75, 95% confidence interval, CI=1.35-2.22) and absent/reversed UA blood flow (OR=3.34, 95% CI=1.1-10.9) as predictors of fetal/neonatal death or brain damage. A MCA pulsatility index below the 10th percentile was a risk factor for fetal/neonatal death or brain damage among women with absent/reversed UA diastolic flow (14/53 as compared to 2/35; OR=5.9, CI =1.4-40.3) but not in pregnancies with forward velocity (1/33 as compared to 3/63; OR=0.63, 95% CI=0.02-6.13, Synergy index=27.7, p=0.007)., Conclusions: In pregnancies complicated by FGR and absent/reversed UA end diastolic flow, vasodilatation of the MCA is a risk factor for neonatal death or brain damage.

Objective: 'Normal' fetal activity is recognized as a sign of fetal well-being and concerns for decreased fetal movements is a frequent cause of non-scheduled antenatal visits. The aim of this study was to identify maternal characteristics in women presenting decreased fetal movements in a total population, to identify the risk of adverse outcomes and assess the management provided., Design: Prospective population-based cohort., Setting: Fourteen delivery units in Norway., Population: A total of 2,374 pregnancies presenting with a perception of decreased fetal movements and 614 control/referent cases., Methods: All singleton third trimester pregnancies presenting with a perception of decreased fetal movements were registered from June 2004 through October 2005. Pregnancies never examined for this condition were collected as a cross-sectional sample from the same population. Main outcome measures. Fetal growth restriction, preterm birth and stillbirth., Results: Mothers with decreased fetal movements were more often smokers, overweight and primiparous. Of the women, 32% presented with perceived absence of fetal movements, of whom 25% waited for more than 24 hours without any movements. Abnormal findings were identified in 16% of examinations. Decreased fetal movements were associated with adverse pregnancy outcome in 26%, including preterm birth and fetal growth restriction. An intervention or repeated consultations were performed in 41% of cases, including 14% admissions to maternity ward. None of the included hospitals had written guidelines for management., Conclusions: A perception of decreased fetal movements is significantly associated with adverse pregnancy outcome such as preterm birth, fetal growth restriction and stillbirth. Guidelines for management and information to pregnant women are needed.

Objectives: To examine the effects of betamethasone administration on umbilical artery (UA), middle cerebral artery (MCA) and ductus venosus (DV) Doppler flow., Design: Longitudinal prospective study., Setting: Fetal Surveillance Unit, Department of Obstetrics and Gynecology, University of São Paulo, São Paulo, Brazil., Population: Thirty-two singleton pregnancies complicated by fetal growth restriction with absent end-diastolic flow in the UA., Methods: Pulsatility index (PI) of the UA, MCA and DV was measured from 26 to 34 weeks prior to and within 24 or 48 hours after starting betamethasone treatment course. Analysis of variance for repeated measures was used to determine the changes in the fetal hemodynamic Doppler flow following maternal corticosteroid administration., Main Outcome Measures: Improvement of UA-PI within 24 hours and DV-PIV (venous pulsatility) within 48 hours from the first betamethasone dose., Results: Mean gestational age at delivery was 29.3 (+/-1.8) weeks and birthweight was 806.6 (+/-228.2) g. A reduction in the UA-PI was observed in 29 (90.6%) cases, with return of end-diastolic flow in 22 (68.7%). The mean UA-PI were 2.84 (+/-0.52) before corticosteroid administration, 2.07 (+/-0.56) within 24 hours and 2.42 (+/-0.75) after 48 hours, with a significant difference along the evaluations (p<0.001). No significant changes in the MCA Doppler were observed. DV-PIV decreased from 1.06 (+/-0.23) prior corticosteroids administration to 0.73 (+/-0.16) within 24 hours and 0.70 (+/-0.19) after 48 hours (p<0.001)., Conclusions: There was reduction in the umbilical artery and in the DV pulsatility indices within 24 hours from betamethasone administration that was maintained up to 48 hours.

OBJECTIVE. Fetal liver blood supply is an important determinant of fetal growth and adaptation. Most fetal liver blood supply is from the umbilical vein, but the portal vein contributes 14-20% and studies of low-risk pregnancies suggest the splanchnic arteries are also involved in the homeostasis of fetal liver perfusion. Here we determine the circulatory pattern of the fetal liver in intrauterine growth restriction (IUGR). DESIGN. Cross-sectional study. POPULATION. Thirty-one IUGR fetuses (estimated fetal weight <5th centile). METHODS. Pulsatility index (PI) measurements of the umbilical, middle cerebral, splenic, hepatic, and superior mesenteric arteries were compared with a reference population and related to umbilical venous flow, umbilico-caval pressure gradient (assessed by ductus venosus peak velocity) and venous distribution within the liver (assessed by flow velocity in the left portal vein). RESULTS. Thirteen of 31 IUGR fetuses had umbilical artery PI > 97.5 centile and 13 showed a middle cerebral artery brain-sparing pattern (PI Z-score < - 2). In IUGR, umbilical venous flow was lower and less umbilical blood was distributed to the right liver lobe, while the umbilico-caval pressure gradient was kept normal. The hepatic and splenic arteries, but not the superior mesenteric artery, had low PI compared with the reference population. CONCLUSIONS. IUGR fetuses with increased or normal umbilical artery PI maintained venous perfusion pressure to the liver while distributing less umbilical blood to the right liver lobe. They showed regional splanchnic arterial redistribution with low splenic and hepatic artery PI, implying increased portal venous flow and direct arterial contribution to hepatic perfusion, respectively.

Objective: To correlate Doppler results with hematological indices at birth in small-for-gestational-age (SGA) fetuses., Design: Prospective study., Setting: Tertiary teaching hospital, Sao Paulo, Brazil. Population. One hundred singleton pregnancies with SGA fetuses of > 27 weeks gestational age., Methods: All women had Doppler velocimetry of the umbilical arteries, middle cerebral artery, and ductus venosus within < 72 hours prior to delivery. After birth, umbilical artery blood was collected for hematological analysis., Main Outcome Measures: The association between fetal Doppler velocimetry pulsatility index (PI) and some hematological indices., Results: Umbilical artery PI showed a positive correlation with nucleated red blood cell count in the umbilical cord (r = 0.46; p < 0.01), and a negative correlation with platelet count (r = -0.53; p < 0.01) and white blood cell count (r = -0.42; p < 0.01). Middle cerebral artery PI was positively correlated with platelet count (r = 0.43; p < 0.01) and white blood cell count (r = 0.38; p < 0.01), and was negatively correlated with nucleated red blood cell count (r = -0.39; p < 0.01). The ductus venosus pulsatility index showed a positive correlation with nucleated red blood cell count (r = 0.36; p < 0.01), and a negative correlation with platelet count (r = -0.37; p < 0.01) and white blood cell count (r = -0.26; p < 0.01)., Conclusion: A significant positive or negative correlation between nucleated red blood cell, platelet and white blood cell counts, and Doppler indices suggests an association between placental insufficiency and the fetal hematological response.

Background: To study changes in umbilical vein (UV) blood flow velocity, diameter and blood flow volume in intrauterine growth retardation (IUGR) fetuses who die in utero (IUD-IUGR)., Methods: Twelve singleton IUGR fetuses who died in utero below 600 g were included. All cases had abnormal uterine and umbilical arteries PI. UV diameter and velocity were measured at the time of diagnosis, and at the last exam, within 24 hours prior to intrauterine death. UV flow was calculated per unit weight (mL/min/kg) and abdominal circumference (AC) (mL/min/cm). UV diameter and velocity were normalized per unit AC. Findings were compared to 14 severe viable-IUGR and 22 normal gestational age-matched fetuses., Results: UV flow (mL/min/kg) was significantly lower in IUD-IUGR compared to viable-IUGR (87 +/- 30 mL/min/kg) and control fetuses (131 +/- 33 mL/min/kg) both at the first (79 +/- 40 mL/min/kg) (P < 0.0001), and at the last exam (54 +/- 29 mL/min/kg) (P < 0.0001). No significant longitudinal flow changes were observed. UV velocity/AC was significantly reduced both in IUD-IUGR and viable-IUGR compared to normal fetuses. UV diameter/AC, was significantly reduced only in IUD-IUGR and not in viable-IUGR compared to normal fetuses., Conclusions: UV flow (mL/min/kg) was significantly lower in IUD-IUGR fetuses both versus viable-IUGR and normal fetuses. A low flow was due to a decreased UV flow velocity, but also due to a reduced vessel size. This significantly smaller UV size observed in IUGR fetuses with the worst outcome could be considered a severe prognostic sign because of the diagnosis of severe growth restriction., (Copyright (c) 2008 John Wiley & Sons, Ltd.)

Objective: The objective of our study was to test the hypothesis that the availability and selective use of STAN in conjunction with cardiotocography for intrapartum monitoring, lowers the incidence of operative deliveries for fetal distress., Design: Observational study., Setting: Delivery suite of the National University Hospital, Singapore., Methods: The data regarding intrapartum cesarean sections and instrumental vaginal deliveries for presumed fetal distress and the condition of the neonate at birth (Apgar scores at one and five minutes and admission to neonatal intensive care unit (NICU) were collected over two consecutive three-year periods. In the first triennium, only external cardiotocography was used for intrapartum fetal surveillance and in the second triennium STAN monitoring was available for use in the delivery suite., Results: With the availability and selective use of STAN monitoring, there was a significant decrease in the number of instrumental deliveries for fetal distress (from 66 out of 520 (0.9%) to 36 out of 474 (0.5%), p<0.025), the number of admissions to the NICU (from 418 (5.6%) to 311 (4.6%), p<0.01) and the number of neonates with Apgar score of seven or less at five minutes (from 192 (2.6%), p<0.001 to 113 (1.7%), p<0.001). There was no significant difference in the incidence of emergency cesarean sections for fetal distress during the two time periods., Conclusion: Intrapartum monitoring of term fetuses with cardiotocography combined with selective use of ST analysis leads to a significant reduction in the number of operative deliveries for suspected fetal distress with no adverse effect on neonatal outcome.

Objective: To evaluate the impact of chorionicity on the perinatal outcomes of twin pregnancies complicated by twin-twin transfusion syndrome (TTS) or selective intrauterine growth restriction (sIUGR)., Method: Pregnancies with 127 monochorionic (MC) and 109 dichorionic (DC) twins were followed up, and TTS and sIUGR incidence as well as morbidity and mortality were evaluated., Results: The incidence of intrauterine fetal death was higher in MC than in DC pregnancies (6.5% vs. 1%), and higher in MC pregnancies complicated by TTS (5 deaths in 10 pregnancies [50%]) or sIUGR (2 in 9 [22%]). The incidence of sIUGR was similar in MC and DC pregnancies (7% vs. 5%), and the incidence of TTS was 8% in MC pregnancies (95% confidence interval, 3.2-12.8). Neonatal neurological and respiratory morbidity was higher among MC twins, and the increase in neonatal complications was linked to TTS and sIUGR. Uncomplicated MC and DC pregnancies had similar perinatal outcomes., Conclusion: The incidence of neonatal complications was higher in MC twins born of pregnancies complicated by TTS or sIUGR. Although the incidence of sIUGR was similar in MC and DC pregnancies, there was a trend towards worse outcomes in MC pregnancies affected by sIUGR.

Objective: To assess the role of uterine artery Doppler studies at 11-14 weeks in screening for pre-eclampsia (PET), small for gestational age (SGA) fetuses, and placental abruption., Methods: Prospective study on 1,123 women presenting for routine ultrasound examination at 11-14 weeks for nuchal translucency measurement. Uterine artery blood flow was studied by transvaginal colour Doppler, the mean pulsatility index (PI) was calculated, and the presence of a diastolic notch was recorded., Results: The mean, median and 95th centile of uterine artery PI were 1.71, 1.64 and 2.54, respectively. Bilateral notches were observed in 63.4%, and a unilateral notch in 18.4% of cases. The sensitivity of mean uterine artery PI>or=95th centile for PET, early onset severe PET necessitating delivery before 34 weeks, SGA

Background: N-terminal parathyroid hormone-related protein has a vital role in regulating cell growth and differentiation, uteroplacental vasodilatation, uterine muscle relaxation, and placental transport. These functions are compromised in intrauterine growth restriction. We aimed to investigate N-terminal parathyroid hormone-related protein concentrations in maternal, fetal, and neonatal plasma of intrauterine-growth-restricted and appropriate for gestational age pregnancies., Methods: Plasma N-terminal parathyroid hormone-related protein levels were determined in 40 mothers and their 20 intrauterine-growth-restricted and 20 appropriate for gestational age singleton full-term fetuses and neonates on postnatal days 1 and 4., Results: Fetal N-terminal parathyroid hormone-related protein levels were significantly lower in the intrauterine growth restriction group (b=1.166, 95%CI: 0.430-1.902, p=0.003) and correlated with the customized centiles of the infants (r=0.407, p=0.009). In the appropriate for gestational age group, neonatal day 1 N-terminal parathyroid hormone-related protein levels were significantly lower compared to maternal (p<0.001) and fetal (p=0.022) ones. Fetal and neonatal day 1 levels were significantly lower in males (b=-1.303, 95%CI: -2.508 to -0.097, p=0.036, and b=-0.802, 95%CI: -1.5 to -0.105, p=0.027, respectively). In the intrauterine growth restriction group, maternal N-terminal parathyroid hormone-related protein levels were significantly increased compared to fetal (p<0.001) and neonatal day 1 (p=0.001) levels., Conclusions: The reduced fetal N-terminal parathyroid hormone-related protein concentrations in intrauterine growth restriction may reflect compromised placental function and impaired fetal growth, suggesting that N-terminal parathyroid hormone-related protein may be involved in the pathogenesis of intrauterine growth restriction.

Measurements on subjects in longitudinal medical studies are often collected at several different times or under different experimental conditions. Such multiple observations on the same subject generally produce serially correlated outcomes. Traditional regression methods assume that observations within subjects are independent which is not true in longitudinal data. In this paper we develop a Bayesian analysis for the traditional non-linear random effects models with errors that follow a continuous time autoregressive process. In this way, unequally spaced observations do not present a problem in the analysis. Parameter estimation of this model is done via the Gibbs sampling algorithm. The method is illustrated with data coming from a study in pregnant women in Santiago, Chile, that involves the non-linear regression of plasma volume on gestational age.

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

Aim: The aim of this study is to review the clinical usefulness of Doppler velocimetry of the uterine artery for the detection of adverse obstetric outcome in a population of women with elevated mid-trimester serum beta-human chorionic gonadotrophin (betahCG)., Methods: Women with an unexplained elevated mid-trimester betahCG level (> or = 4.0 multiples of the median) are offered uterine artery Doppler assessment at 22-24 weeks of gestation. We have audited the clinical usefulness of this practice by reviewing the prevalence of the adverse outcomes of gestational hypertension, intrauterine growth restriction (IUGR) and preterm birth and the predictive capacity of the test when applied to this subgroup of high-risk patients., Results: Sixty-two women had an elevated serum betahCG and underwent Doppler study of uterine artery flow velocity waveform. Notching afforded better predictive utility for any outcome than the resistance index alone or in combination with notching. For a composite adverse outcome of any or all of gestational hypertension, birthweight < or = 10th centile, and preterm delivery, the presence of a uterine notch alone had sensitivity of 30.7% and specificity of 93.8%. For the identification of severe fetal growth restriction (< 5th centile) and/or preeclampsia, the presence of a notch offered a sensitivity of 50%, specificity of 96.3%, a positive likelihood ratio of 13.5, and a negative likelihood ratio of 0.5., Conclusions: The identification of uterine artery notching by means of Doppler ultrasound as a component of the surveillance of women with unexplained elevated betahCG levels significantly improves the prediction of preeclampsia and/or severe IUGR, although the low prevalence of 13% of these adverse outcomes limits the usefulness of the test in routine clinical practice.