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

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

Comparison of fully and semi-automated area-based methods for measuring mammographic density and predicting breast cancer risk.

BACKGROUND: Mammographic density is a strong risk factor for breast cancer but the lack of valid fully automated methods for quantifying it has precluded its use in clinical and screening settings. We compared the performance of a recently developed automated approach, based on the public domain ImageJ programme, to the well-established semi-automated Cumulus method. METHODS: We undertook a case-control study within the intervention arm of the Age Trial, in which ∼54,000 British women were offered annual mammography at ages 40-49 years. A total of 299 breast cancer cases diagnosed during follow-up and 422 matched (on screening centre, date of birth and dates of screenings) controls were included. Medio-lateral oblique (MLO) images taken closest to age 41 and at least one year before the index case's diagnosis were digitised for each participant. Cumulus readings were performed in the left MLO and ImageJ-based readings in both left and right MLOs. Conditional logistic regression was used to examine density-breast cancer associations. RESULTS: The association between density readings taken from one single MLO and breast cancer risk was weaker for the ImageJ-based method than for Cumulus (age-body mass index-adjusted odds ratio (OR) per one s.d. increase in percent density (95% CI): 1.52 (1.24-1.86) and 1.61 (1.33-1.94), respectively). The ImageJ-based density-cancer association strengthened when the mean of left-right MLO readings was used: OR=1.61 (1.31-1.98). CONCLUSIONS: The mean of left-right MLO readings yielded by the ImageJ-based method was as strong a predictor of risk as Cumulus readings from a single MLO image. The ImageJ-based method, using the mean of two measurements, is a valid automated alternative to Cumulus for measuring density in analogue films

Body mass index trajectories from 2 to 18 years - exploring differences between European cohorts.

BACKGROUND: In recent decades, there has been an increase in the prevalence of childhood overweight in most high-income countries. Within northern Europe, prevalence tends to be higher in the UK compared with the Scandinavian countries. We aimed to study differences in body mass index (BMI) trajectories between large cohorts of children from UK and Scandinavian populations. METHODS: We compared BMI trajectories in participants from the English Avon Longitudinal Study of Parents and Children born in 1991-1993 (ALSPAC) (N = 6517), the Northern Finland Birth Cohorts born in 1966 (NFBC1966) (N = 3321) and 1986 (NFBC1986) (N = 4764), and the Danish Aarhus Birth Cohort born in 1990-1992 (ABC) (N = 1920). We used multilevel models to estimate BMI trajectories from 2 to 18 years. We explored whether cohort differences were explained by maternal BMI, height, education or smoking during pregnancy and whether differences were attributable to changes in the degree of skew in the BMI distribution. RESULTS: Differences in mean BMI between the cohorts were small but emerged early and persisted in most cases across childhood. Girls in ALSPAC had a higher BMI than all other cohorts throughout childhood, e.g. compared with the NFBC1986 BMI was 2.2-3.5% higher. For boys, the difference emerging over time (comparing the two NFBC's) exceeded the differences across populations (comparing NFBC1986, ABC and ALSPAC). BMI distribution demonstrated increasing right skew with age. CONCLUSION: Population-level differences between cohorts were small, tended to emerge very early, persisted across childhood, and demonstrated an increase in the right-hand tail of the BMI distribution

Universal late pregnancy ultrasound screening to predict adverse outcomes in nulliparous women: a systematic review and cost-effectiveness analysis.

BACKGROUND: Currently, pregnant women are screened using ultrasound to perform gestational aging, typically at around 12 weeks' gestation, and around the middle of pregnancy. Ultrasound scans thereafter are performed for clinical indications only. OBJECTIVES: We sought to assess the case for offering universal late pregnancy ultrasound to all nulliparous women in the UK. The main questions addressed were the diagnostic effectiveness of universal late pregnancy ultrasound to predict adverse outcomes and the cost-effectiveness of either implementing universal ultrasound or conducting further research in this area. DESIGN: We performed diagnostic test accuracy reviews of five ultrasonic measurements in late pregnancy. We conducted cost-effectiveness and value-of-information analyses of screening for fetal presentation, screening for small for gestational age fetuses and screening for large for gestational age fetuses. Finally, we conducted a survey and a focus group to determine the willingness of women to participate in a future randomised controlled trial. DATA SOURCES: We searched MEDLINE, EMBASE and the Cochrane Library from inception to June 2019. REVIEW METHODS: The protocol for the review was designed a priori and registered. Eligible studies were identified using keywords, with no restrictions for language or location. The risk of bias in studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. Health economic modelling employed a decision tree analysed via Monte Carlo simulation. Health outcomes were from the fetal perspective and presented as quality-adjusted life-years. Costs were from the perspective of the public sector, defined as NHS England, and the costs of special educational needs. All costs and quality-adjusted life-years were discounted by 3.5% per annum and the reference case time horizon was 20 years. RESULTS: Umbilical artery Doppler flow velocimetry, cerebroplacental ratio, severe oligohydramnios and borderline oligohydramnios were all either non-predictive or weakly predictive of the risk of neonatal morbidity (summary positive likelihood ratios between 1 and 2) and were all weakly predictive of the risk of delivering a small for gestational age infant (summary positive likelihood ratios between 2 and 4). Suspicion of fetal macrosomia is strongly predictive of the risk of delivering a large infant, but it is only weakly, albeit statistically significantly, predictive of the risk of shoulder dystocia. Very few studies blinded the result of the ultrasound scan and most studies were rated as being at a high risk of bias as a result of treatment paradox, ascertainment bias or iatrogenic harm. Health economic analysis indicated that universal ultrasound for fetal presentation only may be both clinically and economically justified on the basis of existing evidence. Universal ultrasound including fetal biometry was of borderline cost-effectiveness and was sensitive to assumptions. Value-of-information analysis indicated that the parameter that had the largest impact on decision uncertainty was the net difference in cost between an induced delivery and expectant management. LIMITATIONS: The primary literature on the diagnostic effectiveness of ultrasound in late pregnancy is weak. Value-of-information analysis may have underestimated the uncertainty in the literature as it was focused on the internal validity of parameters, which is quantified, whereas the greatest uncertainty may be in the external validity to the research question, which is unquantified. CONCLUSIONS: Universal screening for presentation at term may be justified on the basis of current knowledge. The current literature does not support universal ultrasonic screening for fetal growth disorders. FUTURE WORK: We describe proof-of-principle randomised controlled trials that could better inform the case for screening using ultrasound in late pregnancy. STUDY REGISTRATION: This study is registered as PROSPERO CRD42017064093. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 15. See the NIHR Journals Library website for further project information

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

Placental Streptococcus agalactiae DNA is associated with neonatal unit admission and foetal pro-inflammatory cytokines in term infants.

Streptococcus agalactiae (Group B Streptococcus; GBS) is a common cause of sepsis in neonates. Previous work detected GBS DNA in the placenta in ~5% of women before the onset of labour, but the clinical significance of this finding is unknown. Here we re-analysed this dataset as a case control study of neonatal unit (NNU) admission. Of 436 infants born at term (≥37 weeks of gestation), 7/30 with placental GBS and 34/406 without placental GBS were admitted to the NNU (odds ratio (OR) 3.3, 95% confidence interval (CI) 1.3-7.8). We then performed a validation study using non-overlapping subjects from the same cohort. This included a further 239 cases of term NNU admission and 686 term controls: 16/36 with placental GBS and 223/889 without GBS were admitted to the NNU (OR 2.4, 95% CI 1.2-4.6). Of the 36 infants with placental GBS, 10 were admitted to the NNU with evidence of probable but culture-negative sepsis (OR 4.8, 95% CI 2.2-10.3), 2 were admitted with proven GBS sepsis (OR 66.6, 95% CI 7.3-963.7), 6 were admitted and had chorioamnionitis (inflammation of the foetal membranes) (OR 5.3, 95% CI 2.0-13.4), and 5 were admitted and had funisitis (inflammation of the umbilical cord) (OR 6.7, 95% CI 12.5-17.7). Foetal cytokine storm (two or more pro-inflammatory cytokines >10 times median control levels in umbilical cord blood) was present in 36% of infants with placental GBS DNA and 4% of cases where the placenta was negative (OR 14.2, 95% CI 3.6-60.8). Overall, ~1 in 200 term births had GBS detected in the placenta, which was associated with infant NNU admission and morbidity