The relationship between human placental morphometry and ultrasonic measurements of utero-placental blood flow and fetal growth.

INTRODUCTION: Ultrasonic fetal biometry and arterial Doppler flow velocimetry are widely used to assess the risk of pregnancy complications. There is an extensive literature on the relationship between pregnancy outcomes and the size and shape of the placenta. However, ultrasonic fetal biometry and arterial Doppler flow velocimetry have not previously been studied in relation to postnatal placental morphometry in detail. METHODS: We conducted a prospective cohort study of nulliparous women in The Rosie Hospital, Cambridge (UK). We studied a group of 2120 women who had complete data on uterine and umbilical Doppler velocimetry and fetal biometry at 20, 28 and 36 weeks' gestational age, digital images of the placenta available, and delivered a liveborn infant at term. Associations were expressed as the difference in the standard deviation (SD) score of the gestational age adjusted ultrasound measurement (z-score) comparing the lowest and highest decile of the given placental morphometric measurement. RESULTS: The lowest decile of placental surface area was associated with 0.87 SD higher uterine artery Doppler mean pulsatility index (PI) at 20 weeks (95% CI: 0.68 to 1.07, P < 0.001). The lowest decile of placental weight was associated with 0.73 SD higher umbilical artery Doppler PI at 36 weeks (95% CI: 0.54 to 0.93, P < 0.001). The lowest decile of both placental weight and placental area were associated with reduced growth velocity of the fetal abdominal circumference between 20 and 36 weeks (both P < 0.001). CONCLUSION: Placental area and weight are associated with uterine and umbilical blood flow, respectively, and both are associated with fetal growth rate.This study was funded by the NIHR Cambridge Comprehensive Biomedical Research Centre (grant number A019057) and Stillbirth and Neonatal Death Society (SANDS). GE donated two ultrasound machines for use in the project.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.placenta.2015.12.00

Fetal and infant growth and the risk of obesity during early childhood: the Generation R Study.

OBJECTIVE: To examine whether infant growth rates are influenced by fetal growth characteristics and are associated with the risks of overweight and obesity in early childhood. DESIGN: This study was embedded in the Generation R Study, a population-based prospective cohort study from fetal life onward. METHODS: Fetal growth characteristics (femur length (FL) and estimated fetal weight (EFW)) were assessed in the second and third trimesters and at birth (length and weight). Infant peak weight velocity (PWV), peak height velocity (PHV), and body mass index at adiposity peak (BMIAP) were derived for 6267 infants with multiple height and weight measurements. RESULTS: EFW measured during the second trimester was positively associated with PWV and BMIAP during infancy. Subjects with a smaller weight gain between the third trimester and birth had a higher PWV. FL measured during the second trimester was positively associated with PHV. Gradual length gain between the second and third trimesters and between the third trimester and birth were associated with higher PHV. Compared with infants in the lowest quintile, the infants in the highest quintile of PWV had strongly increased risks of overweight/obesity at the age of 4 years (odds ratio (95% confidence interval): 15.01 (9.63, 23.38)). CONCLUSION: Fetal growth characteristics strongly influence infant growth rates. A higher PWV, which generally occurs in the first month after birth, was associated with an increased risk of overweight and obesity at 4 years of age. Longer follow-up studies are necessary to determine how fetal and infant growth patterns affect the risk of disease in later life

Genome-wide oxidative bisulfite sequencing identifies sex-specific methylation differences in the human placenta.

DNA methylation is an important regulator of gene function. Fetal sex is associated with the risk of several specific pregnancy complications related to placental function. However, the association between fetal sex and placental DNA methylation remains poorly understood. We carried out whole-genome oxidative bisulfite sequencing in the placentas of two healthy female and two healthy male pregnancies generating an average genome depth of coverage of 25x. Most highly ranked differentially methylated regions (DMRs) were located on the X chromosome but we identified a 225 kb sex-specific DMR in the body of the CUB and Sushi Multiple Domains 1 (CSMD1) gene on chromosome 8. The sex-specific differential methylation pattern observed in this region was validated in additional placentas using in-solution target capture. In a new RNA-seq data set from 64 female and 67 male placentas, CSMD1 mRNA was 1.8-fold higher in male than in female placentas (P value = 8.5 × 10-7, Mann-Whitney test). Exon-level quantification of CSMD1 mRNA from these 131 placentas suggested a likely placenta-specific CSMD1 isoform not detected in the 21 somatic tissues analyzed. We show that the gene body of an autosomal gene, CSMD1, is differentially methylated in a sex- and placental-specific manner, displaying sex-specific differences in placental transcript abundance

Scoping the impact of the national child measurement programme feedback on the child obesity pathway: study protocol.

BACKGROUND: The National Child Measurement Programme was established to measure the height and weight of children at primary school in England and provides parents with feedback about their child's weight status. In this study we will evaluate the impact of the National Child Measurement Programme feedback on parental risk perceptions of overweight, lifestyle behaviour and health service use. METHODS: The study will be a prospective cohort study of parents of children enrolled in the National Child Measurement Programme and key service providers from 5 primary care trusts (administrative bodies responsible for providing primary and secondary care services). We will conduct baseline questionnaires, followed by provision of weight feedback and 3 follow up questionnaires over the course of a year. Questionnaires will measure change in parental risk perception of overweight, health behaviours and health service use. Qualitative interviews will be used to identify barriers and facilitators to change. This study will produce preliminary data on National Health Service costs associated with weight feedback and determine which feedback approach (letter and letter plus telephone) is more effective. DISCUSSION: This study will provide the first large scale evaluation of the National Child Measurement Programme feedback. Findings from this evaluation will inform future planning of the National Child Measurement Programme.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Analytical strategies in human growth research

Human growth research requires knowledge of longitudinal statistical methods that can be analytically challenging. Even the assessment of growth between two ages is not as simple as subtracting the first measurement from the second, for example. This article provides an overview of the key analytical strategies available to human biologists in increasing order of complexity, starting with a review on how to express cross-sectional measurements of size, before covering growth (conditional regression models, regression with conditional growth measures), growth curves (individual growth curves, mixed effects growth curves, latent growth curves), and patterns of growth (growth mixture modeling). The article is not a statistical treatise and has been written by a human biologist for human biologists; as such, it should be accessible to anyone with training in at least basic statistics. A summary table linking each analytical strategy to its applications is provided to help investigators match their hypotheses and measurement schedules to an analysis plan. In addition, worked examples using data on non-Hispanic white participants in the Fels Longitudinal Study are used to illustrate how the analytical strategies might be applied to gain novel insight into human growth and its determinants and consequences. All too often, serial measurements are treated as cross-sectional in analyses that do not harness the power of longitudinal data. The broad goal of this article is to encourage the rigorous application of longitudinal statistical methods to human growth research

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

Is Cerebroplacental Ratio A Marker of Impaired Fetal Growth Velocity and Adverse Pregnancy Outcome?

BACKGROUND: The cerebroplacental ratio has been proposed as a marker of failure to reach growth potential near term. Low cerebroplacental ratio, regardless of the fetal size, is independently associated with the need for operative delivery for presumed fetal compromise and with neonatal unit admission at term. OBJECTIVE: The main aim of this study was to evaluate whether the cerebroplacental ratio at term is a marker of reduced fetal growth rate. The secondary aim was to investigate the relationship between low cerebroplacental ratio at term, reduced fetal growth velocity and adverse pregnancy outcome. DESIGN: retrospective cohort study of singleton pregnancies in a tertiary referral center. The abdominal circumference was measured at 20-24 weeks' gestation, and both abdominal circumference and fetal Dopplers recorded at or beyond 35 weeks, within two weeks of delivery. Abdominal circumference and birthweight values were converted into Z scores and centiles, respectively, and fetal Doppler parameters into multiples of median, adjusting for gestational age. Abdominal circumference growth velocity was quantified using the difference in abdominal circumference Z score, comparing the scan at or beyond 35 weeks with the scan at 20-24 weeks. Both univariable and multivariable logistic regression analyses were performed to investigate the association between low cerebroplacental ratio, low abdominal circumference growth velocity (in the lowest decile), and to identify and adjust for potential confounders. As a sensitivity analysis, we refitted the model excluding the data on pregnancies with small for gestational age neonates. RESULTS: The study included 7944 pregnancies. Low cerebroplacental ratio multiples of median was significantly associated with both low abdominal circumference growth velocity (adjusted OR 2.10; 95%CI 1.71-2.57, p<0.001) and small for gestational age (adjusted OR 3.60; 95%CI 3.04-4.25, p<0.001). After the exclusion of pregnancies resulting in small for gestational age neonates, low cerebroplacental ratio multiples of median remained significantly associated with both low abdominal circumference growth velocity (adjusted OR 1.76; 95%CI 1.34-2.30, p<0.001) and birthweight centile (adjusted OR 0.99; 95%CI 0.998-0.995, p<0.001). The need for operative delivery for fetal compromise was significantly associated with low cerebroplacental ratio (adjusted OR 1.40; 95%CI 1.10-1.78, p=0.006), even after adjusting for both the umbilical artery pulsatility index multiples of median and middle cerebral artery pulsatility index multiples of median. The results were similar even after the exclusion of pregnancies resulting in small for gestational age neonates (adjusted OR 1.39; 95%CI 1.06-1.84, p=0.018). Low cerebroplacental ratio multiples of median remained significantly associated with the risk of operative delivery for presumed fetal compromise (p<0.001), even after adjusting for the known antenatal and intrapartum risk factors. These associations persisted even after exclusion of small for gestational age births. In appropriate for gestational age sized fetuses, abdominal circumference growth velocity was significantly lower in those with low cerebroplacental ratio multiples of median than in those with normal cerebroplacental ratio multiples of median (p<0.001). CONCLUSION: Cerebroplacental ratio is a marker of impaired fetal growth velocity and adverse pregnancy outcome, even in fetuses whose size is considered appropriate using conventional biometry

Behavioural Susceptibility Theory: Professor Jane Wardle and the Role of Appetite in Genetic Risk of Obesity

Purpose of Review: There is considerable variability in human body weight, despite the ubiquity of the 'obesogenic' environment. Human body weight has a strong genetic basis and it has been hypothesised that genetic susceptibility to the environment explains variation in human body weight, with differences in appetite being implicated as the mediating mechanism; so-called 'behavioural susceptibility theory' (BST), first described by Professor Jane Wardle. This review summarises the evidence for the role of appetite as a mediator of genetic risk of obesity. Recent Findings: Variation in appetitive traits is observable from infancy, drives early weight gain and is highly heritable in infancy and childhood. Obesity-related common genetic variants identified through genome-wide association studies show associations with appetitive traits, and appetite mediates part of the observed association between genetic risk and adiposity. Summary: Obesity results from an interaction between genetic susceptibility to overeating and exposure to an 'obesogenic' food environment

Role of uteroplacental and fetal Doppler in identifying fetal growth restriction at term.

Identification of the fetus at risk of adverse outcome at term is a challenge to both clinicians and researchers alike. Despite the fact that fetal growth restriction (FGR) is a known risk factor for stillbirth, at least two thirds of the stillbirth cases at term are not small for gestational age (SGA) - a commonly used proxy for FGR. However, the majority of SGA fetuses are constitutionally small babies and do not suffer from adverse perinatal outcome. The cerebroplacental ratio (CPR) is emerging as a marker of failure to reach growth potential at term. CPR is an independent predictor of intrapartum fetal distress, admission to the neonatal unit at term, stillbirth, perinatal death and neonatal morbidity. Raised uterine artery Doppler resistance in the third trimester is independently associated with significantly lower birthweight and CPR. The combination of the estimated fetal weight, CPR and uterine Doppler in the third trimester can identify the majority of fetuses at risk of stillbirth

Risk factors associated with adverse perinatal outcome in planned vaginal breech labors at term : a retrospective population-based case-control study

Background: Vaginal breech delivery is associated with adverse perinatal outcome. The aim of this study was to identify factors associated with adverse perinatal outcome in term breech pregnancies, and to provide clinicians an aid in selecting women for a trial of vaginal labor with the fetus in breech position. Methods: We conducted a retrospective, nationwide, Finnish population-based case-control study. All planned singleton vaginal deliveries at term with the fetus in breech position between the years 2005 and 2014 were analyzed. The study's end point was a composite set of adverse perinatal outcomes. All infants with an adverse outcome were compared to the infants with normal outcomes. A multivariate logistic regression model was used to analyze the data. Results: An adverse perinatal outcome was recorded for 73 (1.5%) infants. According to the study results fetal growth restriction (adjusted odds ratio, 2.94; 95% CI, 1.30-6.67), oligohydramnios (adjusted odds ratio, 2.94; 95% CI, 1.15-7.18), a history of cesarean section (adjusted odds ratio, 2.94; 95% CI, 1.28-6.77, gestational diabetes (adjusted odds ratio, 2.89; 95% CI, 1.54-5.40), epidural anesthesia (adjusted odds ratio, 2.20; 95% CI, 1.29-3.75) and nulliparity (adjusted odds ratio, 1.84; 95% CI, 1.10-3.08) were associated with adverse perinatal outcome. Conclusions: Adverse perinatal outcome in planned vaginal breech labor at term is associated with fetal growth restriction, oligohydramnios, previous cesarean delivery, gestational diabetes, nulliparity and epidural anesthesia.Peer reviewe