Competing risk models of stillbirth inform populations but not individuals.

This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1111/1471-0528.1394

Blinded ultrasonic fetal biometry at 36 weeks and the risk of emergency caesarean delivery: A prospective cohort study of 3,047 low risk nulliparous women

OBJECTIVES: We studied the risk of emergency caesarean delivery (CD) using blinded ultrasonographic estimated fetal weight (EFW) at 36 weeks of gestational age (wkGA): (1) to compare the association for customised and non-customised EFW, (2) to determine whether adding ultrasonic EFW improved prediction based on maternal characteristics alone, and (3) to determine whether women at high predicted risk of emergency CD had higher risks of maternal and perinatal morbidity than other women. METHODS: We studied 3,047 low risk women (no pre-existing medical conditions or acquired complications of pregnancy) from the Pregnancy Outcome Prediction study (Cambridge UK) who had ultrasonic EFW at ~36 weeks gestational age, where women and clinicians were blinded to the result. RESULTS: Blinded EFW was strongly associated with the risk of emergency CD (coefficient for a 1 standard deviation increase in EFW = 0.39 [95% CI 0.30 to 0.48], odds ratio [OR] = 1.48 [95% CI 1.35 to 1.62]). The coefficient for customised EFW was similar (0.42 [95% CI 0.33 to 0.51], OR = 1.53 [95% CI 1.39 to 1.67]), hence, for simplicity, non-customised EFW was subsequently employed. Maternal characteristics (age, height, body mass index, and weight gain between 12 and 36 weeks) when combined in a multivariate logistic regression model were moderately predictive for emergency CD (AUROCC = 0.68). Adding blinded EFW to the model increased the AUROCC to 0.71 and this model was more predictive (P < 0.0001). When using this model and defining screen positive as a predicted risk of emergency CD ≥40%, 189 (6.2%) women screened positive and the proportion delivered by caesarean was 48%. Compared with screen negative women, they had elevated risks (relative risk [95% CI]) of severe postpartum hemorrhage (2.49 [1.83 to 3.38]), any adverse neonatal outcome (1.86 [1.22 to 2.82]), and severe adverse neonatal outcome (4.03 [1.35 to 12.03]). The risks of these events were also higher compared to women who had a term CD for breech presentation. The model was similarly predictive of the risk of emergency CD and perinatal morbidity when evaluated using routinely collected data from 55,337 births in Scotland between 2003 and 2008. CONCLUSIONS: Ultrasonic EFW at 36 weeks, combined with maternal characteristics, identifies women who are at increased risk of subsequent emergency CD. These women were at increased risk of maternal and perinatal morbidity compared with women at low risk of emergency CD and with women having CD for breech presentation at term

The pregnancy outcome prediction (POP) study: Investigating the relationship between serial prenatal ultrasonography, biomarkers, placental phenotype and adverse pregnancy outcomes

Placental dysfunction is implicated in many major complications of pregnancy associated with adverse maternal and infant outcome, such as preeclampsia, fetal growth restriction and stillbirth. Yet, despite years of intensive research, screening for these complications is still largely based upon clinical grounds rather than ultrasonic and/or biochemical assessment of placental function. One of the few widely employed methods for assessment of risk, low first trimester levels of PAPP-A (Pregnancy Associated Plasma Protein A), was identified through secondary analysis of data collected to identify new methods of screening for Down's syndrome rather than as a purposeful search for screening tests for abnormal placentation. Development of improved methods for population screening requires better mechanistic understanding of the pathways leading to placentally-related complications of human pregnancy. This is in addition to a need for identification of biomarkers which reflect the underlying pathology, while predicting associated disease with high sensitivity and specificity. In this paper, we outline some of the challenges and opportunities in this area. Furthermore, we illustrate how some of these can be addressed in research studies using the example of the Pregnancy Outcome Prediction (POP) study, a prospective cohort study conducted in Cambridge, UK.This study was funded by the NIHR Cambridge Comprehensive Biomedical Research Centre [grant number A019057], the Medical Research Council [grant number MR/K021133/1] and the Stillbirth and Neonatal Death Society (SANDS)

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

Bias modelling in evidence synthesis

Policy decisions often require synthesis of evidence from multiple sources, and the source studies typically vary in rigour and in relevance to the target question. We present simple methods of allowing for differences in rigour (or lack of internal bias) and relevance (or lack of external bias) in evidence synthesis. The methods are developed in the context of reanalysing a UK National Institute for Clinical Excellence technology appraisal in antenatal care, which includes eight comparative studies. Many were historically controlled, only one was a randomized trial and doses, populations and outcomes varied between studies and differed from the target UK setting. Using elicited opinion, we construct prior distributions to represent the biases in each study and perform a bias‐adjusted meta‐analysis. Adjustment had the effect of shifting the combined estimate away from the null by approximately 10%, and the variance of the combined estimate was almost tripled. Our generic bias modelling approach allows decisions to be based on all available evidence, with less rigorous or less relevant studies downweighted by using computationally simple methods

Universal versus selective ultrasonography to screen for large for gestational age infants and associated morbidity

Objective To compare the diagnostic effectiveness of selective versus universal ultrasonography as a screening test for large for gestational age (LGA) infants, and to determine whether previously described ultrasonic markers of excessive fetal growth could identify which suspected LGA fetuses were at increased risk of neonatal morbidity. Methods We analysed data from a prospective cohort study of nulliparous women, the Pregnancy Outcome Prediction study. All women had clinically indicated scans as per routine care. Additionally, all women had blinded ultrasonic estimated fetal weight (EFW) performed at around 36 weeks of gestational age (wkGA). Screen positive for LGA was defined as an EFW >90th percentile ≥34wkGA. Results The current analysis included 3,866 eligible women. Of these, 177 (5%) infants had a birth weight >90th percentile. 1,354 (35%) women had a clinically indicated ultrasonography ≥34wkGA. The sensitivity of selective ultrasonography was 27% and the sensitivity of universal ultrasonography was 38%. The specificity of both approaches was high (99% and 97%, respectively). Using universal ultrasonography, neonatal outcome differed (P for interaction) by abdominal circumference growth velocity (ACGV) for both any neonatal morbidity (P = 0.08) and severe adverse neonatal outcome (P = 0.03). LGA fetuses with increased ACGV had a relative risk (95% CI, P) of any neonatal morbidity of 2.0 (1.1-3.6, P = 0.04) and severe adverse neonatal outcome of 6.5 (2.0-21.1, P = 0.01), whereas LGA fetuses with normal ACGV were not at increased risk. Conclusion Screening using universal ultrasonographic fetal biometry increases the detection of LGA infants and combined with ACGV identifies infants at increased risk of adverse neonatal outcome.The work was supported by the National Institute for Health Research (NIHR) Cambridge Comprehensive Biomedical Research Centre (Women's Health theme), and a project grant from the Stillbirth and neonatal death society (Sands). The study was also supported GE Healthcare (donation of two Voluson i ultrasound systems for this study), and by the NIHR Cambridge Clinical Research Facility, where all research visits took place

Effect of Body Mass Index on pregnancy outcomes in nulliparous women delivering singleton babies

Peer reviewedPublisher PD

Can risk prediction models help us individualise stillbirth prevention? A systematic review and critical appraisal of published risk models.

BACKGROUND: Stillbirth prevention is an international priority - risk prediction models could individualise care and reduce unnecessary intervention, but their use requires evaluation. OBJECTIVES: To identify risk prediction models for stillbirth, and assess their potential accuracy and clinical benefit in practice. SEARCH STRATEGY: MEDLINE, Embase, DH-DATA and AMED databases were searched from inception to June 2019 using terms relevant to stillbirth, perinatal mortality and prediction models. The search was compliant with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. SELECTION CRITERIA: Studies developing and/or validating prediction models for risk of stillbirth developed for application during pregnancy. DATA COLLECTION AND ANALYSIS: Study screening and data extraction were conducted in duplicate, using the CHARMS checklist. Risk of bias was appraised using the PROBAST tool. RESULTS: The search identified 2751 citations. Fourteen studies reporting development of 69 models were included. Variables consistently included were: ethnicity, body mass index, uterine artery Doppler, pregnancy-associated plasma protein and placental growth factor. For almost all models there were significant concerns about risk of bias. Apparent model performance (i.e. in the development dataset) was highest in models developed for use later in pregnancy and including maternal characteristics, and ultrasound and biochemical variables, but few were internally validated and none were externally validated. CONCLUSIONS: Almost all models identified were at high risk of bias. There are first-trimester models of possible clinical benefit in early risk stratification; these require validation and clinical evaluation. There were few later pregnancy models but, if validated, these could be most relevant to individualised discussions around timing of birth. TWEETABLE ABSTRACT: Prediction models using maternal factors, blood tests and ultrasound could individualise stillbirth prevention, but existing models are at high risk of bias.The authors are collaborators in the IPPIC (International Prediction of Pregnancy Complications) stillbirth project, funded by Sands (the Stillbirth and Neonatal Death Society)

Evolutionary history of endogenous Human Herpesvirus 6 reflects human migration out of Africa

Human herpesvirus 6A and 6B (HHV-6) can integrate into the germline, and as a result, ∼70 million people harbor the genome of one of these viruses in every cell of their body. Until now, it has been largely unknown if 1) these integrations are ancient, 2) if they still occur, and 3) whether circulating virus strains differ from integrated ones. Here, we used next-generation sequencing and mining of public human genome data sets to generate the largest and most diverse collection of circulating and integrated HHV-6 genomes studied to date. In genomes of geographically dispersed, only distantly related people, we identified clades of integrated viruses that originated from a single ancestral event, confirming this with fluorescent in situ hybridization to directly observe the integration locus. In contrast to HHV-6B, circulating and integrated HHV-6A sequences form distinct clades, arguing against ongoing integration of circulating HHV-6A or “reactivation” of integrated HHV-6A. Taken together, our study provides the first comprehensive picture of the evolution of HHV-6, and reveals that integration of heritable HHV-6 has occurred since the time of, if not before, human migrations out of Africa