Critical congenital heart disease: contemporary prenatal screening performance and outcomes in a multi-centre perinatology service.

BACKGROUND: Prenatal detection of critical congenital heart disease (CCHD) optimises perinatal decision-making and neonatal outcomes. The objective of this study was to determine the prenatal screening performance, care pathways and perinatal outcomes for prenatally and postnatally diagnosed cases of CCHD over a four-year period. STUDY DESIGN: This retrospective cohort study in a tertiary centre and its two affiliated secondary sites examined all cases of CCHD, including cases of pregnancy termination and in-utero fetal death, neonatal death and liveborn babies that underwent cardiac catheterization or surgery in the first six weeks of life. Prenatal and postnatal data were ascertained from the first trimester assessment for all patients diagnosed prenatally. Cases requiring intervention that were first identified in the postnatal period were included to determine prenatal detection rates. Follow-up for all cases of CCHD continued to one year of age. RESULTS: In a consecutive cohort of 49,950 pregnancies in a 4-year period 01/2019 to 12/2022, a prenatal diagnosis of CCHD was made in 96 cases, yielding a prevalence of 1.9 per 1000 births. The prenatal detection for right duct-dependant heart pathology and congenital heart block was 100%, 85% for left duct-dependant pathology and 93% for transposition of the great arteries (TGA). In the prenatally diagnosed group, 37% of cases were complicated by extracardiac structural abnormalities, a genetic diagnosis or both. All cases of prenatal detection were identified in the context of routine anatomy screening rather than specialist Fetal Cardiac screening services. Almost half of all pregnancies complicated by CCHD did not undergo neonatal cardiac intervention, by virtue of parental choice determined either prenatally or after birth. An additional eight babies were diagnosed with CCHD in the neonatal period, such that the prenatal detection rate for CCHD was 92% (96/104, 95% CI = 84%-96%). Survival at 1-year for infants deemed suitable for CCHD surgery was 85%. CONCLUSION: In a large unselected population, optimal rates of prenatal detection of critical congenital heart disease can be achieved by a protocolised approach to mid-trimester fetal anatomy ultrasound, underpinned by a programme of sonographer education and training. The cardiac abnormalities most likely to evade prenatal detection are left-sided obstructive lesions.

Complement pathway changes at age 12 are associated with psychotic experiences at age 18 in a longitudinal population-based study: evidence for a role of stress.

The complement cascade is a major component of the immune defence against infection, and there is increasing evidence for a role of dysregulated complement in major psychiatric disorders. We undertook a directed proteomic analysis of the complement signalling pathway (n = 29 proteins) using data-independent acquisition. Participants were recruited from the UK avon longitudinal study of parents and children (ALSPAC) cohort who participated in psychiatric assessment interviews at ages 12 and 18. Protein expression levels at age 12 among individuals who reported psychotic experiences (PEs) at age 18 (n = 64) were compared with age-matched controls (n = 67). Six out of the 29 targeted complement proteins or protein subcomponents were significantly upregulated following correction for multiple comparisons (VTN↑, C1RL↑, C8B↑, C8A↑, CFH↑, and C5↑). We then undertook an unbiased plasma proteomic analysis of mice exposed to chronic social stress and observed dysregulation of 11 complement proteins, including three that were altered in the same direction in individuals with PE (C1R↑, CFH↑, and C5↑). Our findings indicate that dysregulation of the complement protein pathway in blood is associated with incidence of psychotic experiences and that these changes may reflect exposure to stress.

The RECIPE study: reducing emergency Caesareans and improving the Primiparous experience: a blinded, prospective, observational study.

BACKGROUND: The RECIPE study aims to validate a risk prediction model for intrapartum caesarean delivery which has been developed by our group. The Genesis study was a prospective observational study carried out by the Perinatal Ireland Research Consortium across 7 clinical centres in Ireland between October 2012 and June 2015. Genesis investigated a range of maternal and fetal parameters in a prospective blinded study of 2336 singleton pregnancies between 39 + 0-41 + 0 weeks' gestational age. This resulted in the development of a risk prediction model for Caesarean Delivery in nulliparous women at term. The RECIPE study now proposes to provide external validation of this risk prediction tool. METHODS: In order to externally validate the model, we aim to include a centre which was not involved in the original study. We propose a trial of risk-assignment for intrapartum caesarean amongst nulliparous women with a singleton pregnancy between 38 + 0 and 40 + 6 weeks' gestational age who are planning a vaginal birth. Results of the risk prediction tool will be concealed from participants and from midwives and doctors providing labour care.. Participants will be invited for an ultrasound scan and delivery details will be collated postnatally. The principal aim of this study is to externally validate the risk prediction model. This prediction model holds the potential to accurately identify nulliparous women who are likely to achieve an uncomplicated vaginal birth and those at high prospect of requiring an unplanned caesarean delivery. DISCUSSION: Validation of the Genesis prediction model would enable more accurate counselling for women in the antenatal setting regarding their own likelihood of requiring an intrapartum Caesarean section. It would also provide valuable personalised information to women about the anticipated course of their own labour. We believe that this is an issue of national relevance that will impact positively on obstetric practice, and will positively empower women to make considered, personalised choices surrounding labour and delivery.

An abnormal cerebroplacental ratio (CPR) is predictive of early childhood delayed neurodevelopment in the setting of fetal growth restriction.

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

The Impact of Aspirin on Ultrasound Markers of Uteroplacental Flow in Low-Risk Pregnancy: Secondary Analysis of a Multicenter RCT.

OBJECTIVE: This article evaluates the effect of low-dose aspirin on uterine artery (UtA) Doppler, placental volume, and vascularization flow indices in low-risk pregnancy. STUDY DESIGN: In this secondary analysis of the TEST randomized controlled trial, low-risk nulliparous women were originally randomized at 11 weeks to: (1) routine aspirin 75 mg; (2) no aspirin; and (3) aspirin based upon the preeclampsia Fetal Medicine Foundation screening test. UtA Doppler, three-dimensional (3D) placental volume, and vascularization flow indices were assessed prior to and 6 weeks postaspirin commencement. RESULTS: A total of 546 women were included (aspirin n = 192, no aspirin n = 354). Between first and second trimesters, aspirin use was not associated with a change in UtA Doppler, placental volume, or vascular flow indices. There was no significant difference in the change in UtA Doppler pulsatility index (PI) Z-scores or notching (PI Z-score -0.2 vs. -0.2, p = 0.17), nor was there a significant change in placental volume Z-score and vascular flow indices (volume Z-score change: 0.74 vs. 0.62, p = 0.34). CONCLUSION: Low-dose aspirin commenced at 11 weeks in low-risk women does not appear to improve uterine and placental perfusion or placental volume. Any perceived effect on uteroplacental vasculature is not reflected in changes in placental volume nor uteroplacental flow as assessed by two-dimensional and 3D ultrasound.

Visuospatial abilities and fine motor experiences influence acquisition and maintenance of fundamentals of laparoscopic surgery (FLS) task performance.

BACKGROUND: Minimally invasive surgery poses a unique learning curve due to the requirement for non-intuitive psychomotor skills. The fundamentals of laparoscopic surgery (FLS) program trains and certifies residents in such skills. However, innate predictors of FLS performance and maintenance remain to be described. This single-centre observational study aimed to assess for candidate factors influencing the acquisition and maintenance of FLS performance amongst a surgically naïve cohort. METHODS: Laparoscopically naïve medical students were recruited from pre-clinical university grades. Participants completed five visuospatial/psychomotor tests and a questionnaire surveying non-surgical experiences and personality traits. Individuals completed baseline assessments of FLS standard tasks followed by an intensive training course over week one and two on inanimate box trainers. A post-training assessment was performed in week three to evaluate acquisition. Participants were withdrawn from exposure and retested at four 1-month intervals to assess maintenance requirements. RESULTS: Forty-nine participants enrolled with 35 (71.4%) and 33 (67.3%) completing acquisition and maintenance phases, respectively. Mean age of participants was 19.3 (± 1.2) years with 68.6% female predominance. Participants demonstrated significant improvements in all five tasks during the acquisition (p < 0.05) period and maintenance of skills with task exposure at 1-month intervals. Significant predictors of skill acquisition included: card rotations for intracorporeal knot (p = 0.027) and combined tasks (p = 0.028) and cube comparisons for extracorporeal knot (p = 0.040). During skill maintenance: Card rotations predicted performance across all tasks (p < 0.05), Cube comparisons for tasks 1/2/4/5 (p < 0.05), PicSOR for peg transfer (p = 0.017) and grooved pegboard for peg transfer (p = 0.023) and ligating-loop (p = 0.038) tasks. Musical instrument experience demonstrated associations with skill acquisition in peg transfer (p = 0.042) and intracorporeal knot (p = 0.034) while video gaming predicted performance in these tasks (p < 0.05) during the maintenance phase. A sporting background or competitive personality did not influence skill performance. CONCLUSIONS: Multiple visuospatial abilities and non-surgical experiences positively influenced FLS performance during skill acquisition and/or maintenance. Further consideration to these individual factors may facilitate selection of more technically adaptable surgical residents.

Playing to your skills: a randomised controlled trial evaluating a dedicated video game for minimally invasive surgery.

BACKGROUND: Video gaming demands elements of visual attention, hand-eye coordination and depth perception which may be contiguous with laparoscopic skill development. General video gaming has demonstrated altered cortical plasticity and improved baseline/acquisition of minimally invasive skills. The present study aimed to evaluate for skill acquisition associated with a commercially available dedicated laparoscopic video game (Underground) and its unique (laparoscopic-like) controller for the Nintendo®Wii U™ console. METHODS: This single-blinded randomised controlled study was conducted with laparoscopically naive student volunteers of limited (< 3 h/week) video gaming backgrounds. Baseline laparoscopic skills were assessed using four basic tasks on the Virtual Reality (VR) simulator (LAP MentorTM, 3D systems, Colorado, USA). Twenty participants were randomised to two groups; Group A was requested to complete 5 h of video gaming (Underground) per week and Group B to avoid gaming beyond their normal frequency. After 4 weeks participants were reassessed using the same VR tasks. Changes in simulator performances were assessed for each group and for intergroup variances using mixed model regression. RESULTS: Significant inter- and intragroup performances were present for the video gaming and controls across four basic tasks. The video gaming group demonstrated significant improvements in thirty-one of the metrics examined including dominant (p ≤ 0.004) and non-dominant (p < 0.050) instrument movements, pathlengths (p ≤ 0.040), time taken (p ≤ 0.021) and end score [p ≤ 0.046, (task-dependent)]. The control group demonstrated improvements in fourteen measures. The video gaming group demonstrated significant (p < 0.05) improvements compared to the control in five metrics. Despite encouraged gameplay and the console in participants' domiciles, voluntary engagement was lower than directed due to factors including: game enjoyment (33.3%), lack of available time (22.2%) and entertainment distractions (11.1%). CONCLUSION: Our work revealed significant value in training using a dedicated laparoscopic video game for acquisition of virtual laparoscopic skills. This novel serious game may provide foundations for future surgical developments on game consoles in the home environment.

The Effects of Prenatal Iron Deficiency and Risperidone Treatment on the Rat Frontal Cortex: A Proteomic Analysis.

Prenatal iron deficiency (pID) has been described to increase the risk for neurodevelopmental disorders such as autism and schizophrenia; however, the precise molecular mechanisms are still unknown. Here, we utilized high-throughput MS to examine the proteomic effects of pID in adulthood on the rat frontal cortex area (FCA). In addition, the FCA proteome was examined in adulthood following risperidone treatment in adolescence to see if these effects could be prevented. We identified 1501 proteins of which 100 were significantly differentially expressed in the FCA at postnatal day 90. Pathway analysis of proteins affected by pID revealed changes in metabolic processes, including the tricyclic acid cycle, mitochondrial dysfunction, and P13K/Akt signaling. Interestingly, most of these protein changes were not present in the adult pID offspring who received risperidone in adolescence. Considering the link between pID and several neurodevelopmental disorders such as autism and schizophrenia these presented results bring new perspectives to understand the role of iron in metabolic pathways and provide novel biomarkers for future studies of pID.

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.

Prenatal prediction of significant intertwin birthweight discordance using standard second and third trimester sonographic parameters.

INTRODUCTION: Our study aim was to evaluate standard ultrasound-derived fetal biometric parameters in the prediction of clinically significant intertwin birthweight discordance defined as ≥18%. MATERIAL AND METHODS: This was a secondary analysis of a prospective cohort study of 1028 unselected twin pairs recruited over a two-year period. Dichorionic twins underwent two-weekly ultrasonographic surveillance from 24 weeks' gestation, with surveillance of monochorionic twins two-weekly from 16 weeks. Ultrasonographic biometric data from 24 to 36 weeks were evaluated for the prediction of an intertwin birthweight discordance threshold ≥18%. Umbilical artery Doppler waveform data was also analyzed to evaluate whether it was predictive of birthweight discordance. RESULTS: Of the 956 twin pairs analyzed for discordance, 208 pairs were found to have a clinically significant birthweight discordance ≥18%. All biometric parameters were predictive of significant inter-twin birthweight discordance at low cut-offs, with low discriminatory powers when ROC curves were analyzed. Discordance in estimated fetal weight was predictive of a significant birthweight discordance at all gestational categories with cut-offs between 8 and 11%. A low-discriminatory power and poor sensitivity and specificity were also observed. An abnormal umbilical artery Doppler was predictive of birthweight discordance ≥18% between 28 and 32 weeks' gestation, although with poor sensitivity and specificity. CONCLUSIONS: Calculation of estimated fetal weight and birthweight discordance between twins allows minimal margin for error. These margins make it difficult to accurately predict those who are at or above the discordance threshold of 18%. These findings highlight that small intertwin discrepancies in weight and biometry should not be overlooked and merit further investigation.

Mechanistic interrogation of combination bevacizumab/dual PI3K/mTOR inhibitor response in glioblastoma implementing novel MR and PET imaging biomarkers.

PURPOSE: Resistance to bevacizumab (BEV) in glioblastoma is believed to occur via activation of molecular networks including the mTOR/PI3K pathway. Using an MR/PET molecular imaging biomarker approach, we investigated the response to combining BEV with the mTOR/PI3K inhibitor BEZ235. METHODS: Tumours were established by orthotopically implanting U87MG-luc2 cells in mice. Animals were treated with BEZ235 and/or BEV, and imaged using diffusion-weighted-MRI, T2-weighted and T2*-weighted before and after administration of superparamagnetic iron oxide contrast agent. Maps for changes in relaxation rates (ΔR2, ΔR2* and apparent diffusion coefficient) were calculated. Vessel size index and microvessel density index were derived. 3'-Deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) PET and O-(2-[(18)F]fluoroethyl)-L-tyrosine ([(18)F]FET) PET were further performed and tumour endothelium/proliferation markers assessed by immunohistochemistry. RESULTS: Treatment with BEV resulted in a pronounced decrease in tumour volume (T2-weighted MRI). No additive effect on tumour volume was observed with the BEV/BEZ235 combination compared with BEV monotherapy. The Ki67 proliferation index and [(18)F]FLT uptake studies were used to support the observations. Using ΔR2* and ΔR2 values, respectively, the BEV/BEZ235 combination significantly reduced tumour microvessel volume in comparison to BEV alone. Decreased microvessel density index was further observed in animals treated with the combination, supported by von Willebrand factor (vWF) immunohistochemistry. [(18)F]FET uptake was decreased following treatment with BEV alone, but was not further reduced following treatment with the combination. vWF immunohistochemistry analysis showed that the mean tumour vessel size was increased in all cohorts. CONCLUSION: Assessing MR imaging biomarker parameters together with [(18)F]FET and [(18)F]FLT PET provided information on mechanism of action of the drug combination and clues as to potential clinical responses. Following translation to clinical use, treatment with a BEV/BEZ235 combination could reduce peritumoral oedema obviating the requirement for steroids. The use of hypothesis-driven molecular imaging studies facilitates the preclinical evaluation of drug response. Studies of this kind may more accurately predict the clinical potential of the BEV/BEZ235 combination regimen as a novel therapeutic approach in oncology.

Differential expression of the inflammation marker IL12p40 in the at-risk mental state for psychosis: a predictor of transition to psychotic disorder?

BACKGROUND: The identification of biomarkers of transition from the at-risk mental state (ARMS) to psychotic disorder is important because early treatment of psychosis is associated with improved outcome. Increasing evidence points to an inflammatory contribution to psychosis. We questioned whether raised levels of plasma inflammatory markers predict transition from ARMS to psychotic disorder and whether any such predictors could be reduced by omega-3 (ω-3) polyunsaturated fatty acids (PUFAs). METHODS: We measured the levels of 40 neuroinflammation biomarkers using a commercially available immunoassay kit. Firstly, we compared inflammatory markers in subjects in the ARMS who transitioned to psychotic disorder (n = 11) compared to subjects who did not (n = 28). Then we compared inflammatory markers in all subjects before and after ω-3 PUFA treatment (n = 40). RESULTS: Our data provides preliminary evidence that elevations in the baseline plasma levels of the inflammatory marker IL12/IL23p40 are associated with transition from ARMS to psychotic disorder. IL12/IL23p40 levels did not change following 12 weeks administration of ω-3 PUFAs. These findings provide evidence that elevated plasma IL12/IL23p40 is a potential biomarker of increased risk for transition to psychotic disorder. CONCLUSION: Further studies are required to confirm and extend this finding. Our results do not provide support for the possibility that administration of ω-3 PUFAs act to reduced transition to psychotic disorder by reducing blood levels of IL12/IL23p40. TRIAL REGISTRATION: ClinicalTrials.gov, a service of the U.S. National Institutes of Health, Identifier: NCT00396643 , last updated December 20, 2007. Retrospectively registered.

Neuro-developmental outcome of a large cohort of growth discordant twins.

UNLABELLED: Our aims were to study the effect of birthweight growth discordance (≥20%) on neuro-developmental outcome of monochorionic and dichorionic twins and to compare the relative effects of foetal growth discordance and prematurity on cognitive outcome. We performed a cross-sectional multicentre prospective follow-up study from a cohort of 948 twin pregnancies. One hundred nineteen birthweight-discordant twin pairs were examined (24 monochorionic pairs) and were matched for gestational age at delivery with 111 concordant control pairs. Participants were assessed with the Bayley Scales between 24 and 42 months of age. Analysis was by paired t test for intra-twin pair differences and by multiple linear regression. Compared to the larger twin of a discordant pair, the smaller twin performed significantly worse in cognition (mean composite cognitive score difference = -1.7, 95% confidence interval (CI) = 0.3-3.1, p = 0.01) and also in language and motor skills. Prematurity prior to 33 weeks' gestation, however, had a far greater impact on cognitive outcomes (mean cognitive composite score difference = -5.8, 95% CI = 1.2-10.5, p = 0.008). CONCLUSION: Birthweight growth discordance of ≥20% confers an independent adverse effect on long-term neuro-development of the smaller twin. However, prior to 33 weeks' gestation, gestational age at birth adversely affects cognitive development to a greater extent than foetal growth discordance.

Altered Platelet Function in Intrauterine Growth Restriction: A Cause or a Consequence of Uteroplacental Disease?

Objective A limited number of platelet function studies in intrauterine growth restriction (IUGR) have yielded conflicting results. We sought to evaluate platelet reactivity in IUGR using a novel platelet aggregation assay. Study Design Pregnancies with IUGR were recruited from 24 weeks' gestation (estimated fetal weight < 10th centile) and had platelet function testing performed after diagnosis. A modification of light transmission aggregometry created dose-response curves of platelet reactivity in response to multiple agonists at differing concentrations. Findings were compared with healthy third trimester controls. IUGR cases with a subsequent normal birth weight were analyzed separately. Results In this study, 33 pregnancies retained their IUGR diagnosis at birth, demonstrating significantly reduced platelet reactivity in response to all agonists (arachidonic acid, adenosine diphosphate, collagen, thrombin receptor-activating peptide, and epinephrine) when compared with 36 healthy pregnancy controls (p < 0.0001). Similar results were obtained for cases demonstrating an increasing in utero growth trajectory. When IUGR preceded preeclampsia or gestational hypertension, platelet function was significantly reduced compared with normotensive IUGR. Conclusion Using this comprehensive platelet assay, we have demonstrated a functional impairment of platelets in IUGR. This may reflect platelet-derived placental growth factor release. Further evaluation of platelet function may aid in the development of future platelet-targeted therapies for uteroplacental disease.

Gestational hypertensive disease in twin pregnancy: Influence on outcomes in a large national prospective cohort.

OBJECTIVE: Gestational hypertensive disease (GHD) is associated with pregnancy-related complications and poor maternal and fetal outcomes in singleton pregnancies. We sought to examine the influence of GHD in a large prospective cohort of twin pregnancies. STUDY DESIGN: The ESPRIT study was a national multicenter observational cohort study of 1028 structurally normal twin pregnancies. Each pregnancy underwent sonographic surveillance with two-week ultrasound from 24 weeks for dichorionic and from 16 weeks for monochorionic gestations. Characteristics and demographics as well as labour and delivery outcome data were prospectively recorded. Perinatal mortality, admission to the neonatal intensive care unit (NICU) and a composite of morbidity of respiratory distress syndrome, hypoxic ischaemic encephalopathy, periventricular leukomalacia, necrotising enterocolitis and sepsis were documented for all cases. Outcomes for patients with documented GHD (pre-eclampsia and gestational hypertension) were compared with those without GHD. RESULTS: Perinatal outcome data were recorded for 977 patients. Women with GHD had a higher body mass index (27.1 ± 6.4 vs 25.2 ± 4.5, P < 0.0001) than those without and were more likely to be nulliparous (65% (59/92) vs 46% (407/885), P = 0.001). Both groups had similar mean birthweights, but those with GHD were more likely to have a birthweight discordance ≥18% (35% (32/92) vs 20% (179/885), P = 0.001). Rates of caesarean delivery were higher in those twin pregnancies affected by GHD, and while the rate of composite morbidity was similar in both groups, twins in the GHD group had higher rates of NICU admission. CONCLUSION: In twin gestations, gestational hypertension independently confers an increased risk for emergency caesarean delivery, birthweight discordance and NICU admission, such that intensive maternal-fetal monitoring is justified when hypertension develops in a twin pregnancy.

The effect of maternal obesity on sonographic fetal weight estimation and perinatal outcome in pregnancies complicated by fetal growth restriction.

PURPOSE: Maternal obesity represents a challenge in the sonographic (US) assessment of fetal weight, and is a recognized risk factor for adverse pregnancy outcome. The objective of this secondary analysis of data from the Prospective Observational Trial to Optimize Pediatric Health in fetal growth restriction (FGR) Study (PORTO) was to describe the effect of maternal obesity on the accuracy of US in determining the estimated fetal weight (EFW) and the perinatal outcome of pregnancies affected by FGR. METHODS: Between 2010 and 2012, 1,116 women with nonanomalous singleton pregnancies with an EFW in less than the tenth centile were recruited for the PORTO study. Maternal body mass index (BMI) was divided into five subcategories: normal (BMI < 24.9 kg/m(2) ), overweight (25-29.9), obese class 1 (30-34.9), obese class 2 (35-39.9), and obese class 3 (>40). The accuracy of the EFW was determined in women who delivered within 2 weeks of their last US scan. Perinatal outcomes were analyzed by BMI subcategory. RESULTS: Of the 1,074 patients with complete records, 691 (64%) were of normal weight, 258 (24%) were overweight, 93 (9%) were in obese class 1, 32 (3%) were in obese class 2, and none were in obese class 3. Overall, the EFW determined prior to delivery was within 6% of the actual birth weight in all BMI subcategories. Overweight and obese women delivered more commonly by cesarean section and at earlier gestational ages than did women with a normal BMI (p = 0.0008), resulting in lower birth weights (p = 0.0031) and significantly increased composite perinatal morbidity (p < 0.0001) and mortality (p = 0.0215) rates. CONCLUSIONS: US examination is reliable for assessing the weight of fetuses with FGR in overweight women. Maternal obesity, however, has a significant adverse effect on perinatal outcomes. Thus, health education should focus on awareness of this adverse effect, with optimization of prepregnancy weight as its main goal.

Maternal immune activation induces changes in myelin and metabolic proteins, some of which can be prevented with risperidone in adolescence.

BACKGROUND: Maternal infection is a risk factor for schizophrenia but the molecular and cellular mechanisms are not fully known. Myelin abnormalities are amongst the most robust neuropathological changes observed in schizophrenia, and preliminary evidence suggests that prenatal inflammation may play a role. METHODS: Label-free liquid chromatography-mass spectrometry was performed on the prefrontal cortex (PFC) of adult rat offspring born to dams that were exposed on gestational day 15 to the viral mimic polyinosinic:polycytidylic acid [poly(I:C), 4 mg/kg] or saline and treated with the atypical antipsychotic drug risperidone (0.045 mg/kg) or saline in adolescence. Western blotting was employed to validate protein changes. RESULTS: Over 1,000 proteins were quantified in the PFC with pathway analyses implicating changes in core metabolic pathways, following prenatal poly(I:C) exposure. Some of these protein changes were absent in the PFC of poly(I:C)-treated offspring that subsequently received risperidone treatment in adolescence. Particularly interesting reductions in the expression of the myelin-related proteins myelin basic protein isoform 3 (MBP1) and rhombex 29 were observed, which were reversed by risperidone treatment. Validation by Western blotting confirmed changes in MBP1 and mitogen-activated kinase 1 (MAPK1). Western blotting was extended to assess the MAPK signalling proteins due to their roles in inflammation, namely phosphorylated MAPK1 and phosphorylated MAPK-activated protein kinase 2. Both were upregulated by poly(I:C) treatment and reversed by risperidone treatment. CONCLUSIONS: Overall, our data suggest that maternal inflammation may contribute to an increased risk for schizophrenia through mechanisms involving metabolic function and myelin formation and that risperidone in adolescence may prevent or reverse such changes.

A Patent Ductus Arteriosus Severity Score Predicts Chronic Lung Disease or Death before Discharge.

OBJECTIVES: To test the hypothesis that a patent ductus arteriosus (PDA) severity score (PDAsc) incorporating markers of pulmonary overcirculation and left ventricular (LV) diastolic function can predict chronic lung disease or death before discharge (CLD/death). STUDY DESIGN: A multicenter prospective observational study was conducted for infants <29 weeks gestation. An echocardiogram was carried out on day 2 to measure PDA diameter and maximum flow velocity, LV output, diastolic flow in the descending aorta and celiac trunk, and variables of LV function using tissue Doppler imaging. Predictors of CLD/death were identified using logistic regression methods. A PDAsc was created and a receiver operating characteristic curve was constructed to assess its ability to predict CLD/death. RESULTS: We studied 141 infants at a mean (SD) gestation and birthweight of 26 (1.4) weeks and 952 (235) g, respectively. Five variables were identified that were independently associated with CLD/death (gestation at birth, PDA diameter, maximum flow velocity, LV output, and LV a' wave). The PDAsc had a range from 0 (low risk) to 13 (high risk). Infants who developed CLD/death had a higher score than those who did not (7.3 [1.8] vs 3.8 [2.0], P < .001). PDAsc had an area under the curve of 0.92 (95% CI 0.86-0.97, P < .001) for the ability to predict CLD/death. A PDAsc cut-off of 5 has sensitivity and specificity of 92% and 87%, and positive and negative predictive values of 92% and 82%, respectively. CONCLUSIONS: A PDAsc on day 2 can predict the later occurrence of CLD/death further highlighting the association between PDA significance and morbidity.