Widespread macromolecular interaction perturbations in human genetic disorders.

How disease-associated mutations impair protein activities in the context of biological networks remains mostly undetermined. Although a few renowned alleles are well characterized, functional information is missing for over 100,000 disease-associated variants. Here we functionally profile several thousand missense mutations across a spectrum of Mendelian disorders using various interaction assays. The majority of disease-associated alleles exhibit wild-type chaperone binding profiles, suggesting they preserve protein folding or stability. While common variants from healthy individuals rarely affect interactions, two-thirds of disease-associated alleles perturb protein-protein interactions, with half corresponding to "edgetic" alleles affecting only a subset of interactions while leaving most other interactions unperturbed. With transcription factors, many alleles that leave protein-protein interactions intact affect DNA binding. Different mutations in the same gene leading to different interaction profiles often result in distinct disease phenotypes. Thus disease-associated alleles that perturb distinct protein activities rather than grossly affecting folding and stability are relatively widespread.

Amniocentesis in pregnancies at or beyond 24 weeks: An international multicenter study.

BACKGROUND: Amniocentesis for genetic diagnosis is most commonly done between 15 and 22 weeks of gestation, but can be performed at later gestational ages. The safety and genetic diagnostic accuracy of amniocentesis have been well-established through numerous large-scale, multicenter studies for procedures before 24 weeks, but comprehensive data on late amniocentesis remain sparse. OBJECTIVES: To evaluate the indications, diagnostic yield, safety, and maternal and fetal outcomes associated with amniocentesis performed at or beyond 24 weeks of gestation. STUDY DESIGN: We conducted an international, multicenter retrospective cohort study examining pregnant individuals who underwent amniocentesis for prenatal diagnostic testing at gestational ages between 24w0d and 36w6d. The study, spanning from 2011 to 2022, involved nine referral centers. We included singleton or twin pregnancies with documented outcomes, excluding cases where other invasive procedures were performed during pregnancy or if amniocentesis was conducted for obstetric indications. We analyzed indications for late amniocentesis, types of genetic tests performed, their results, and the diagnostic yield, along with pregnancy outcomes and post-procedure complications. RESULTS: Of the 752 pregnant individuals included in our study, late amniocentesis was primarily performed for the prenatal diagnosis of structural anomalies (91.6%), followed by suspected fetal infection (2.3%) and high-risk findings from cell-free DNA screening (1.9%). The median gestational age at the time of the procedure was 28w5d, and 98.3% of pregnant individuals received results of genetic testing before birth or pregnancy termination. The diagnostic yield was 22.9%, and a diagnosis was made 2.4 times more often for fetuses with anomalies in multiple organ systems (36.4%) compared to those with anomalies in a single organ system (15.3%). Additionally, the diagnostic yield varied depending on the specific organ system involved, with the highest yield for musculoskeletal anomalies (36.7%) and hydrops fetalis (36.4%) when a single organ system or entity was affected. The most prevalent genetic diagnoses were aneuploidies (46.8%), followed by copy number variants (26.3%) and monogenic disorders (22.2%). The median gestational age at delivery was 38w3d, with an average of 59 days between the procedure and delivery date. The overall complication rate within two weeks post-procedure was 1.2%. We found no significant difference in the rate of preterm delivery between pregnant individuals undergoing amniocentesis between 24-28 weeks and those between 28-32 weeks, reinforcing the procedure's safety across these gestational periods. CONCLUSIONS: Late amniocentesis, at or after 24 weeks gestation, especially for pregnancies complicated by multiple congenital anomalies, has a high diagnostic yield and a low complication rate, underscoring its clinical utility. It provides pregnant individuals and their providers with a comprehensive diagnostic evaluation and results before delivery, enabling informed counseling and optimized perinatal and neonatal care planning.

Discussion of Identity and Implicit Bias: A Strategy to Address Racism and Social Justice in Pediatric Nursing Education.

ABSTRACT: Nurse educators must weave discussions of systemic racism, social justice, social determinants of health, and psychosocial influences throughout the curriculum. For an online pediatric course, an activity was developed to raise awareness of implicit bias. This experience interfused assigned readings from the literature, introspection of identity, and guided discussion. Framed by principles of transformative learning, faculty facilitated an online dialogue involving groups of 5 to 10 students through aggregated self-descriptors and open prompts. Ground rules for the discussion established psychological safety. This activity complements other schoolwide racial justice initiatives.

Parental Height and Weight Influence Offspring Adiposity at 2 Years; Findings from the ROLO Kids Birth Cohort Study.

OBJECTIVE: The perinatal period and in utero environment are important for fetal growth, development, and fetal programming. This study aimed to determine the effect of parental anthropometry and the maternal metabolic milieu on offspring adiposity at 2 years of age. STUDY DESIGN: This longitudinal birth cohort includes analysis of maternal (n = 337) and paternal (n = 219) anthropometry and maternal and fetal metabolic markers (n = 337), including glucose, homeostatic model of assessment (HOMA), C-peptide, and leptin from participants of the ROLO (the Randomized Control Trial of Low) pregnancy study, and their partners, to determine an association with offspring anthropometry at two years of age. RESULTS: Linear regression, when adjusted for confounders, indicated maternal and paternal anthropometry and was associated with offspring weight and length at 2 years of age. Maternal height was negatively associated with general adiposity in the total cohort of children (p = 0.002) and in female children (p = 0.006) and central adiposity in the total child cohort (p < 0.001). Paternal height was also negatively associated with general adiposity in all children (p = 0.002) and central adiposity in total (p = 0.023) and female children (p = 0.008). Maternal glucose, insulin resistance, and fetal C-peptide positively correlated with anthropometry in total, male, and female children. CONCLUSION: Parental anthropometry in the perinatal period has a long-lasting effect on offspring anthropometry beyond the neonatal period. Maternal and fetal metabolic factors influence adiposity, and this extends beyond the perinatal period. Parental adiposity may play a significant role in early childhood adiposity and may be a target for interventions to decrease the risk of early childhood obesity. KEY POINTS: · Parental height and weight were associated with offspring anthropometry and measures of offspring adiposity at 2 years of age.. · Maternal glucose, insulin resistance, and fetal C-peptide correlated with offspring anthropometry.. · Parental anthropometry has long-term effect on offspring adiposity and is seen at 2 years of age..

Do you pay to go private?: a single centre comparison of induction of labour and caesarean section rates in private versus public patients.

BACKGROUND: The aim of this study was to compare rates of induction and subsequent caesarean delivery among nulliparous women with private versus publicly funded health care at a single institution. This is a retrospective cohort study using the electronic booking and delivery records of nulliparous women with singleton pregnancies who delivered between 2010 and 2015 in an Irish Tertiary Maternity Hospital (approx. 9000 deliveries per annum). METHODS: Data were extracted from the National Maternity Hospital (NMH), Dublin, Patient Administration System (PAS) on all nulliparous women who delivered a liveborn infant at ≥37 weeks gestation during the 6-year period. At NMH, all women in spontaneous labour are managed according to a standardised intrapartum protocol. Twenty-two thousand two hundred thirty-two women met the inclusion criteria. Of these, 2520 (12.8%) were private patients; the remainder (19,712; 87.2%) were public. Mode of and gestational age at delivery, rates of and indications for induction of labour, rates of pre-labour caesarean section, and maternal and neonatal outcomes were examined. Rates of labour intervention and subsequent maternal and neonatal outcomes were compared between those with and without private health cover. RESULTS: Women attending privately were more than twice as likely to have a pre-labour caesarean section (12.7% vs. 6.5%, RR = 2.0, [CI 1.8-2.2])); this finding persisted following adjustment for differences in maternal age and body mass index (BMI) (adjusted relative risk 1.74, [CI 1.5-2.0]). Women with private cover were also more likely to have induction of labour and significantly less likely to labour spontaneously. Women who attended privately were significantly more likely to have an operative vaginal delivery, whether labour commenced spontaneously or was induced. CONCLUSIONS: These findings demonstrate significant differences in rates of obstetric intervention between those with private and public health cover. This division is unlikely to be explained by differences in clinical risk factors as no significant difference in outcomes following spontaneous onset of labour were noted. Further research is required to determine the roots of the disparity between private and public decision-making. This should focus on the relative contributions of both mothers and maternity care professionals in clinical decision making, and the potential implications of these choices.

Associations of Neonatal Noncardiac Surgery with Brain Structure and Neurodevelopment: A Prospective Case-Control Study.

OBJECTIVE: To examine the associations of neonatal noncardiac surgery with newborn brain structure and neurodevelopment at 2 years of age. STUDY DESIGN: Infants requiring neonatal noncardiac surgery for congenital diaphragmatic hernia, esophageal atresia, or anterior abdominal wall defect were compared with infants who did not require surgery, matched for sex, gestation at birth, and postmenstrual age at magnetic resonance imaging. Cerebral magnetic resonance imaging was performed at a mean (SD) postmenstrual age of 41.6 (1.7) weeks. Images were assessed qualitatively for brain maturation and injury and quantitatively for measures of brain size, cerebrospinal fluid spaces, and global abnormality. Neurodevelopment was then assessed at 2 years using the Bayley Scales of Infant and Toddler Development, 3rd edition. RESULTS: Infants requiring surgery (n = 39) were 5.9 times (95% CI, 1.9-19.5; P < .01) more likely to have delayed gyral maturation and 9.8 times (95% CI, 1.2-446; P = .01) more likely to have white matter signal abnormalities compared with controls (n = 39). Cases were more likely to have higher global abnormality scores, smaller biparietal diameters, and larger ventricular sizes than controls. Infants who had surgery had lower mean composite scores in the language (mean difference, -12.5; 95% CI, -22.4 to -2.7) and motor domains (mean difference, -13.4; 95% CI, -21.1 to -5.6) compared with controls. CONCLUSIONS: Infants requiring neonatal noncardiac surgery have smaller brains with more abnormalities compared with matched controls and have associated neurodevelopmental impairment at 2 years of age. Prospective studies with preoperative and postoperative imaging would assist in determining the timing of brain injury.

Brain structure and neurological and behavioural functioning in infants born preterm.

AIM: To examine: (1) relationships between brain structure, and concurrently assessed neurological and behavioural functioning, in infants born preterm at term-equivalent age (TEA; approximately 38-44wks); and (2) whether brain structure-function relationships differ between infants born very (24-29wks) and moderate-late (32-36wks) preterm. METHOD: A total of 257 infants (91 very preterm, 166 moderate-late preterm; 120 males, 137 females) had structural magnetic resonance imaging (MRI) and neurological and behavioural assessments (Prechtl's general movements assessment, Neonatal Intensive Care Unit Network Neurobehavioral Scale [NNNS] and Hammersmith Neonatal Neurological Examination [HNNE]). Two hundred and sixty-three infants (90 very preterm, 173 moderate-late preterm; 131 males, 132 females) had diffusion MRI and assessments. Associations were investigated between assessment scores and global brain volumes using linear regressions, regional brain volumes using Voxel-Based Morphometry, and white matter microstructure using Tract-Based Spatial Statistics. RESULTS: Suboptimal scores on some assessments were associated with lower fractional anisotropy and/or higher axial, radial, and mean diffusivities in some tracts: NNNS attention and reflexes, and HNNE total score and tone, were associated with the corpus callosum and optic radiation; NNNS quality of movement with the corona radiata; HNNE abnormal signs with several major tracts. Brain structure-function associations generally did not differ between the very and moderate-late preterm groups. INTERPRETATION: White matter microstructural alterations may be associated with suboptimal neurological and behavioural performance in some domains at TEA in infants born preterm. Brain structure-function relationships are similar for infants born very preterm and moderate-late preterm. WHAT THIS PAPER ADDS: Brain volume is not related to neurological/behavioural function in infants born preterm at term. White matter microstructure is related to some neurological/behavioural domains at term. Brain-behaviour relationships are generally similar for infants born very preterm and moderate-late preterm.

ESTRUCTURA CEREBRAL Y FUNCIONAMIENTO NEUROLÓGICO Y CONDUCTUAL EN LACTANTES PREMATUROS: OBJETIVO: Examinar: (1) las relaciones entre la estructura del cerebro y el funcionamiento neurológico y conductual evaluado simultáneamente en bebés nacidos prematuros a la edad equivalente al término (EET; aproximadamente 38 a 44 semanas); (2) si las relaciones estructura-función cerebral difieren entre los bebés nacidos muy prematuros (24-29 semanas) y prematuros-moderados-tardíos (32-36 semanas). MÉTODO: Un total de 257 bebés (91 muy prematuros, 166 prematuros moderados tardíos; 120 varones, 137 mujeres) tuvieron imágenes de resonancia magnética estructural (IRM) y evaluaciones neurológicas y conductuales (evaluación general de los movimientos de Prechtl, red de unidades de cuidados intensivos neonatales, escala neuroconductual [NNNS] y Hammersmith Neonatal Neurological Examination [HNNE]). Doscientos sesenta y tres bebés (90 muy prematuros, 173 moderados tardíos; 131 varones, 132 mujeres) se sometieron a RMN de difusión y evaluaciones. Se investigaron las asociaciones entre los puntajes de evaluación y los volúmenes cerebrales globales utilizando regresiones lineales, los volúmenes cerebrales regionales utilizando Morfometría Basada en Voxel y la microestructura de la materia blanca utilizando Estadísticas Espaciales Basadas en Tractos. RESULTADOS: Las puntuaciones subóptimas en algunas evaluaciones se asociaron con una menor anisotropía fraccional y / o mayores difusividades axiales, radiales y medias en algunos tractos: la atención y los reflejos NNNS, y la puntuación total y el tono HNNE, se asociaron con el cuerpo calloso y la radiación óptica; Calidad de movimiento NNNS con la corona radiata; Signos anormales de HNNE con varios tractos importantes. Las asociaciones estructura-función cerebral generalmente no difirieron entre los grupos prematuros muy moderados y tardíos. INTERPRETACIÓN: Las alteraciones microestructurales de la materia blanca pueden asociarse con un desempeño neurológico y de comportamiento subóptimo en algunos dominios neurológicos y conductuales en bebés nacidos prematuros evaluados a la EET. Las relaciones cerebro-estructura-comportamiento son similares para los bebés nacidos muy prematuros y para los prematuros moderados-tardíos.

ESTRUTURA CEREBRAL E FUNCIONAMENTO NEUROLÓGICO E COMPORTAMENTAL EM LACTENTES NASCIDOS PREMATUROS: OBJETIVO: Examinar: (1) relações entre estrutura cerebral, e funcionamento neurológico e comportamental avaliados simultaneamente, em lactentes nascidos prematuros na idade equivalente ao termo (IET; aproximadamente 38-44 semanas); 2) se a relação entre estrutura e função cerebral difere entre crianças nascidas muito prematuras (24-29sem) e moderadas-tardias (32-36sem). MÉTODO: Um total de 257 lactentes (91 muito prematuros, 166 prematuros moderados-tardios; 120 do sexo masculino, 137 do sexo feminino) tiveram imagens de ressonância magnética (IRM) e avaliações neurológicas e comportamentais (avaliação dos movimentos gerais de Prechtl, Escala Neurocomportamental da rede de Unidade de Cuidados Intensivos Neonatais [NNNS] e o Exame Neurológico Neonatal de Hammersmith [HNNE]). Duzentos e sessenta e três lactentes (90 muito prematuros, 173 prematuros moderados-tardios; 131 do sexo masculino, 132 do sexo feminino) relizaram IRM por difusão e as demais avaliações. Associações foram investigadas entre os escores das avaliações e volumes cerebrais globais usando regressões lineares, volumens cerebrais regionais usando Morfometria baseada em voxels, e micro-estrutura da substância branca usando Estatística especial baseada em tractos. RESULTADOS: Escores subótimos em algumas avaliações foram associada scom menor anisotropia fractional e/ou maior difusividade axial, radial e média em alguns tractos: atenção e reflexos no NNNS, escore total e de tônus no HNNE, foram associados com o corpo caloso e radiação óptica; qualidade do movimento no NNNS com a coroa radiada; sinais anormais no HNNE com vários tractos importantes. Associações entre estrutura e função do cérebro geralmente não diferiram entre os grupos de prematuros muito prematuros e moderados-tardios. INTERPRETAÇÃO: Alterações da microestrutura da substância branca podem estar associadas a desempenho neurológico e comportamental subótimos em alguns domínios na IET em lactentes prematuros. Relações entre estrutura e função cerebral são similares para lactentes muito prematuros e moderados-tardios.

Neurobehaviour at term-equivalent age and neurodevelopmental outcomes at 2 years in infants born moderate-to-late preterm.

AIM: To examine the association between newborn neurobehavioural assessments and neurodevelopmental outcomes at 2 years in infants born moderate-to-late preterm (MLPT). METHOD: Two-hundred and one infants born MLPT (born 32-36+6 wks' gestation) were assessed with the Hammersmith Neonatal Neurological Examination (HNNE) and NICU Network Neurobehavioral Scale (NNNS), with suboptimal performance defined as scores lower than the 10th centile. Development was assessed at 2 years corrected age with the Bayley Scales of Infant and Toddler Development 3rd Edition, with delay defined as scores less than 1 standard deviation (SD) below the mean. The relationships between neurobehaviour at term and Bayley-III cognitive, language, and motor scales at 2 years were examined using linear regression. RESULTS: Increased odds for cognitive delay were associated with suboptimal HNNE total scores (odds ratio [OR] 2.66; 95% confidence interval [CI] 1.14-6.23, p=0.020) and suboptimal NNNS excitability (OR 3.01; 95% CI 1.33-6.82, p=0.008) and lethargy (OR 4.05; 95% CI 1.75-9.31, p=0.001) scores. Suboptimal lethargy scores on the NNNS were associated with increased odds of language (OR 5.64; 95% CI 1.33-23.85, p=0.019) and motor delay (OR: 6.86; 95% CI 1.64-28.71, p=0.08). INTERPRETATION: Suboptimal performance on specific aspects of newborn neurobehavioural assessments is associated with neurodevelopmental delay at 2 years in children born MLPT.

Reliability of Neurobehavioral Assessments from Birth to Term Equivalent Age in Preterm and Term Born Infants.

Neurobehavioral assessments provide insight into the functional integrity of the developing brain and help guide early intervention for preterm (<37 weeks' gestation) infants. In the context of shorter hospital stays, clinicians often need to assess preterm infants prior to term equivalent age. Few neurobehavioral assessments used in the preterm period have established interrater reliability. AIM: To evaluate the interrater reliability of the Hammersmith Neonatal Neurological Examination (HNNE) and the NICU Network Neurobehavioral Scale (NNNS), when used both preterm and at term (>36 weeks). METHODS: Thirty-five preterm infants and 11 term controls were recruited. Five assessors double-scored the HNNE and NNNS administered either preterm or at term. A one-way random effects, absolute, single-measures interclass correlation coefficient (ICC) was calculated to determine interrater reliability. RESULTS: Interrater reliability for the HNNE was excellent (ICC > 0.74) for optimality scores, and good (ICC 0.60-0.74) to excellent for subtotal scores, except for 'Tone Patterns' (ICC 0.54). On the NNNS, interrater reliability was predominantly excellent for all items. Interrater agreement was generally excellent at both time points. CONCLUSIONS: Overall, the HNNE and NNNS neurobehavioral assessments demonstrated mostly excellent interrater reliability when used prior to term and at term.

Brain Volumes at Term-Equivalent Age Are Associated with 2-Year Neurodevelopment in Moderate and Late Preterm Children.

OBJECTIVE: To explore the association between brain maturation, injury, and volumes at term-equivalent age with 2-year development in moderate and late preterm children. STUDY DESIGN: Moderate and late preterm infants were recruited at birth and assessed at age 2 years using the Bayley Scales of Infant and Toddler Development, Third Edition. Brain magnetic resonance imaging (MRI) was performed at term-equivalent age and qualitatively assessed for brain maturation (myelination of the posterior limb of the internal capsule and gyral folding) and injury. Brain volumes were measured using advanced segmentation techniques. The associations between brain MRI measures with developmental outcomes were explored using linear regression analyses. RESULTS: A total of 197 children underwent MRI and assessed using the Bayley Scales of Infant and Toddler Development, Third Edition. Larger total brain tissue volumes were associated with higher cognitive and language scores (adjusted coefficients per 10% increase in brain size; 95% CI of 3.2 [0.4, 5.6] and 5.6 [2.4, 8.8], respectively). Similar relationships were documented for white matter volumes with cognitive and language scores, multiple cerebral structures with language scores, and cerebellar volumes with motor scores. Larger cerebellar volumes were independently associated with better language and motor scores, after adjustment for other perinatal factors. There was little evidence of relationships between myelination of the posterior limb of the internal capsule, gyral folding, or injury with 2-year development. CONCLUSIONS: Larger total brain tissue, white matter, and cerebellar volumes at term-equivalent age are associated with better neurodevelopment in moderate and late preterm children. Brain volumes may be an important marker for neurodevelopmental deficits described in moderate and late preterm children.

Fetal metabolic influences of neonatal anthropometry and adiposity.

BACKGROUND: Large for gestational age infants have an increased risk of obesity, cardiovascular and metabolic complications during life. Knowledge of the key predictive factors of neonatal adiposity is required to devise targeted antenatal interventions. Our objective was to determine the fetal metabolic factors that influence regional neonatal adiposity in a cohort of women with previous large for gestational age offspring. METHODS: Data from the ROLO [Randomised COntrol Trial of LOw Glycaemic Index in Pregnancy] study were analysed in the ROLO Kids study. Neonatal anthropometric and skinfold measurements were compared with fetal leptin and C-peptide results from cord blood in 185 cases. Analyses were performed to examine the association between these metabolic factors and birthweight, anthropometry and markers of central and generalised adiposity. RESULTS: Fetal leptin was found to correlate with birthweight, general adiposity and multiple anthropometric measurements. On multiple regression analysis, fetal leptin remained significantly associated with adiposity, independent of gender, maternal BMI, gestational age or study group assignment, while fetal C-peptide was no longer significant. CONCLUSION: Fetal leptin may be an important predictor of regional neonatal adiposity. Interventional studies are required to assess the impact of neonatal adiposity on the subsequent risk of childhood obesity and to determine whether interventions which reduce circulating leptin levels have a role to play in improving neonatal adiposity measures.

Moderate and late preterm birth: effect on brain size and maturation at term-equivalent age.

PURPOSE: To compare the size of multiple brain structures, maturation in terms of both brain myelination and gyral development, and evidence of brain injury between moderate and late preterm (MLPT) and term-born infants at term-equivalent age. MATERIALS AND METHODS: The study was approved by the human research ethics committees of the participating hospitals, and informed parental consent was obtained for all infants. One hundred ninety-nine MLPT and 50 term-born infants underwent 3-T magnetic resonance (MR) imaging brain examinations at 38-44 weeks of corrected gestational age. T1- and T2-weighted MR images were compared between groups for size of multiple cerebral structures, degree of myelination in the posterior limb of the internal capsule, gyral maturation, signal intensity abnormalities, and presence of cysts by a single assessor who was blinded to the gestational group and perinatal course of the infants. Group differences were compared by using linear regression for continuous variables and logistic regression for categorical variables, and interrater and intrarater reliability was assessed by using intraclass correlation coefficients. RESULTS: Compared with those in the term-born control group, measurements of brain biparietal diameter, corpus callosum, basal ganglia and thalami, and cerebellum were smaller in infants in the MLPT group (all P ≤ .01), while extracerebral space was larger (P < .0001). Myelination of the posterior limb of the internal capsule was less developed, and gyral maturation was delayed in the MLPT group (both P < .001). Signal intensity abnormalities and cysts were uncommon in both groups, with 13 (6.5%) MLPT infants and one (2%) term infant having abnormalities. Inter- and intrarater reliability was good for most measures, with intraclass correlation coefficients generally greater than 0.68. CONCLUSION: MLPT birth is associated with smaller brain size, less-developed myelination of the posterior limb of the internal capsule, and more immature gyral folding than those associated with full-term birth. These brain changes may form the basis of some of the long-term neurodevelopmental deficits observed in MLPT children. Online supplemental material is available for this article.

Human uterine lower segment myometrial cell and nuclear volume at term: influence of maternal age.

Little is known about the cytoarchitecture of human myometrial cells in pregnancy, and whether or not this may be influenced by maternal characteristics such as age, parity and body mass index (BMI). The aim of this study was primarily to evaluate human myometrial smooth muscle cell (SMC) and nuclear volume in the third trimester of human pregnancy, and secondarily to investigate if these parameters are altered in relation to the maternal characteristics outlined above. Myometrial biopsies were obtained from 30 women undergoing elective caesarean delivery at term. One-micrometer sections were prepared for light microscopy and 100-nm sections for electron microscopy. The nucleator technique was used to assess nuclear volume from the light microscopy images. Point-counting methodology was used on transmission electron micrographs to assess the percentage of the cell volume occupied by the nucleus. Cell volume was calculated from these measurements. The euchromatin to heterochromatin (Eu/Het) ratio was determined to ascertain whether differences in nuclear volume were due to an increased range of genes being transcribed. The mean (±â€…SEM) nuclear volume was 175 ±â€…10 µm(3) , the nucleus occupied 1.5 ±â€…0.1% of the SMC and the mean cell size was 14 047 ±â€…1352 µm(3) . The Eu/Het ratio was 7.54 ±â€…0.4. The mean volume of heterochromatin and euchromatin in the nucleus was 21.5 ±â€…1.7 and 149 ±â€…9 µm(3) , respectively. A multivariate regression analysis revealed that advanced maternal age was associated with an increase in the percentage of the cell occupied by nucleus (R(2)  = 0.32, P = 0.004). There were no other significant effects of maternal age, BMI or parity on the measured parameters. These findings provide reliable volumes for human myometrial cells and their nuclei at term gestation, and show that nuclear volume fraction may be influenced by maternal age.

Identification of those most likely to benefit from a low-glycaemic index dietary intervention in pregnancy.

The present study is a secondary analysis of the ROLO study, a randomised control trial of a low-glycaemic index (GI) diet in pregnancy to prevent the recurrence of fetal macrosomia. The objectives of the present study were to identify which women are most likely to respond to a low-GI dietary intervention in pregnancy with respect to three outcome measures: birth weight; maternal glucose intolerance; gestational weight gain (GWG). In early pregnancy, 372 women had their mid-upper arm circumference recorded and BMI calculated. Concentrations of glucose, insulin and leptin were measured in early pregnancy and at 28 weeks. At delivery, infant birth weight was recorded and fetal glucose, C-peptide and leptin concentrations were measured in the cord blood. Women who benefited in terms of infant birth weight were shorter, with a lower education level. Those who maintained weight gain within the GWG guidelines were less overweight in both their first and second pregnancies, with no difference being observed in maternal height. Women who at 28 weeks of gestation developed glucose intolerance, despite the low-GI diet, had a higher BMI and higher glucose concentrations in early pregnancy with more insulin resistance. They also had significantly higher-interval pregnancy weight gain. For each analysis, women who responded to the intervention had lower leptin concentrations in early pregnancy than those who did not. These findings suggest that the maternal metabolic environment in early pregnancy is important in determining later risks of excessive weight gain and metabolic disturbance, whereas birth weight is mediated more by genetic factors. It highlights key areas, which warrant further interrogation before future pregnancy intervention studies, in particular, maternal education level and inter-pregnancy weight gain.

Maternal and neonatal morbidity during off peak hours in a busy obstetric unit. Are deliveries after midnight more complicated?

OBJECTIVE: We sought to compare maternal and neonatal outcomes in deliveries occurring overnight with those in daylight hours. DESIGN: Prospective observational study. SETTING: Large national tertiary referral center. POPULATION: All singleton laboring nulliparous parturients delivering infants >500 g over a 2-year period, 1 January 2008 to 31 December 2009. METHODS: Details of intrapartum characteristics and neonatal outcomes of deliveries occurring between midnight and 08.00 h were compared with deliveries occurring outside of these hours. MAIN OUTCOME MEASURES: Maternal and neonatal morbidity. RESULTS: During the study period there were 8450 nulliparous deliveries. 2668 (31.6%) delivered between midnight and 08.00 h, and 5782 (68.4%) outside of these hours. There was a significant difference between the time periods in the number of babies born with a cord pH <7.1: 10.8% (44/406) of babies were born between midnight and 08.00 h, and 6.3% (63/1007) of babies were born outside these hours (p = 0.003). There was no significant difference in terms of Apgar score <7 at 5 min (p = 0.17). There was a trend toward a larger number of anal sphincter injuries occurring between midnight and 08.00 h (3% vs. 2.3%; p = 0.05). CONCLUSION: Our findings suggest that infants are more likely to be born with a pH <7.1 and there was a trend toward an increased rate of anal sphincter injury during time periods when staffing levels are low and clinician fatigue may play a role in decision-making and patient management. This may play a role in service provision planning and staff recruitment.

Obstetric and neonatal outcomes for women ≥ 45 years of age: a cohort study.

OBJECTIVE: To evaluate outcomes in women ≥ 45 years of age in comparison to a group of women aged 40 to 44 years. MATERIALS AND METHODS: A cohort study was conducted including women ≥ 45 years who delivered at > 24 weeks gestation during the period (1989-2011). Women aged 40 to 44 years formed the comparison group. The maternal demographics, mode of conception, maternal complications, timing and mode of delivery, neonatal features and postpartum complications were included as outcomes. Statistical analyses were performed using the t-test and Chi-square test. RESULTS: There were 67,278 deliveries; 140 occurred in women ≥ 45 years of age, (2.1/1,000). Compared with the 40 to 44 year age group (n = 139), women ≥ 45 years had higher body mass index (26.7 ± 4.7 vs. 24.6 ± 7.1, p = 0.01), and were more likely to have a previous pregnancy loss at < 24 weeks gestation (57.9 vs. 44.6%, p = 0.03). There was no difference in the incidence of maternal complications, preterm delivery, birthweight, Apgar scores or admission to neonatal intensive care. The presence of pre-existing maternal hypertension was associated with a poor outcome. Women ≥ 45 years were more likely to be delivered by cesarean section (45 vs. 30.2%, p = 0.01). CONCLUSION: Women aged ≥ 45 years have comparable outcomes to those aged 40 to 44 years, albeit the presence of pre-existing maternal disease is higher and associated with a poor outcome.

The association between TNF-α and insulin resistance in euglycemic women.

Chronic low levels of inflammation have links to obesity, diabetes and insulin resistance. We sought to assess the relationship between cytokine tumor necrosis factor (TNF-α) and insulin resistance in a healthy, euglycemic population. This is a prospective study of 574 non-diabetic mother and infant pairs. Maternal body mass index (BMI), TNF-α, glucose and insulin were measured in early pregnancy and at 28 weeks. Insulin resistance was calculated by HOMA index. At delivery birthweight was recorded and cord blood analysed for fetal C-peptide and TNF-α. In a multivariate model, maternal TNF-α in early pregnancy was predicted by maternal insulin resistance at the same time-point, (ß=0.54, p<0.01), and maternal TNF-α at 28 weeks was predicted by maternal insulin resistance in early pregnancy (ß=0.24, p<0.01) and at 28 weeks (ß=0.39, p<0.01). These results, in a large cohort of healthy, non-diabetic women have shown that insulin resistance, even at levels below those diagnostic of gestational diabetes, is associated with maternal and fetal inflammatory response. These findings have important implications for defining the pathways of fetal programming of later metabolic syndrome and childhood obesity.

The influence of a low glycemic index dietary intervention on maternal dietary intake, glycemic index and gestational weight gain during pregnancy: a randomized controlled trial.

BACKGROUND: Maternal diet is known to impact pregnancy outcome. Following a low glycemic index (GI) diet during pregnancy has been shown to improve maternal glycemia and reduce infant birthweight and may be associated with a higher fibre intake. We assessed the impact of a low GI dietary intervention on maternal GI, nutritional intake and gestational weight gain (GWG) during pregnancy. Compliance and acceptability of the low GI diet was also examined. METHOD: Eight hundred women were randomised in early pregnancy to receive low GI and healthy eating dietary advice or to receive standard maternity care. The intervention group received dietary advice at a group education session before 22 weeks gestation. All women completed a 3 day food diary during each trimester of pregnancy. Two hundred and thirty five women from the intervention arm and 285 women from the control arm returned complete 3x3d FDs and were included in the present analysis. RESULTS: Maternal GI was significantly reduced in the intervention group at trimester 2 and 3. The numbers of women within the lowest quartile of GI increased from 37% in trimester 1 to 52% in trimester 3 (P < 0.001) among the intervention group. The intervention group had significantly lower energy intake (P < 0.05), higher protein (% TE) (P < 0.01) and higher dietary fibre intake (P < 0.01) post intervention. Consumption of food groups with known high GI values were significantly reduced among the intervention group. Women in the intervention low GI group were less likely to exceed the Institute of Medicine's GWG goals. CONCLUSION: A dietary intervention in early pregnancy had a positive influence on maternal GI, food and nutrient intakes and GWG. Following a low GI diet may be particularly beneficial for women at risk of exceeding the GWG goals for pregnancy.

Screening and treatment of iron deficiency anemia in pregnancy: A review and appraisal of current international guidelines.

Iron deficiency anemia (IDA) in pregnancy is a common diagnosis that is associated with adverse obstetric and neonatal outcomes. There remains uncertainty regarding how best to screen for, prevent, and treat established IDA in pregnancy. There is no consensus on the benefits of routine iron supplementation in pregnancy, with concerns regarding potential harmful effects of routine iron supplementation in women who are iron replete. Fourteen international guidelines were selected and appraised and compared by a multidisciplinary team. The AGREE II GRS tool was used. Each reviewer independently made their own assessment, and the scores from 1 to 7 were also collated and averaged for an overall score incorporating seven domains: process of development, clarity of presentation, completeness of reporting, clinical validity, and overall quality. The reviewers' scores were also individually compared according to discipline. The mean score across all the guidelines was 4.4 (range 3.5-6.5). Only half of the guidelines recommend routine iron in pregnancy. In terms of screening recommendations, five guidelines recommend screening with ferritin in addition to a full blood count in pregnancy, two recommend selective screening with ferritin for at risk groups only, and one guideline suggests using ferritin where feasible. Although many of the guidelines recommend similar doses of oral elemental iron of 100-200 mg daily for the treatment of established IDA in pregnancy, two recommend twice or three times daily dosing. Only five guidelines give hemoglobin rises to expect within specific timeframes. There remains a need to clarify the optimal screening method, dosing regimen, timing, and route of iron supplementation in pregnancy. Robust randomized controlled data are needed to guide appropriate prevention and management.

An unusual case of a giant fetal facial tumour and review of the literature.

We present the case of a pregnant 32-year-old woman who presented with a giant fetal facial tumour at 22 weeks. The mass, initially 4 × 3.5 × 3 cm in size, was largely cystic with a small solid component. It subsequently increased to 9 × 9 × 10 cm. Significant compression effects on the fetal orbit, temple and infratemporal fossa, with potential compression of the optic nerve, were noted on ultrasound and MRI. The cyst required drainage twice in the pregnancy: firstly to reduce the compression effects and secondly to facilitate caesarean delivery. Postnatally, the baby had significant compression and displacement of the craniofacial skeleton from the mass effect. Postnatal histology revealed a diagnosis of a teratoma. This case highlights the complexities and challenges surrounding the diagnosis and management of a giant fetal facial tumour.