Aris T. Papageorghiou

Foetal growth restriction (FGR) refers to a foetus that does not reach its genetically predetermined growth potential. It is well recognised that growth-restricted foetuses are at increased risk of stillbirth, foetal compromise, early neonatal death and neonatal morbidity. Later in life, they are prone to health problems, including increased risk of cardiovascular diseases and neurodevelopmental disorders. Interventions for preventing and treating FGR have been studied in many trials, but evidence is often difficult to synthesise and compare because of differences in the selection and definition of outcomes. To enable future trials to measure similar, meaningful outcomes, we are developing two core outcome sets (COS) – one for prevention and the other for treatment of FGR. We will review the literature to identify previously reported outcomes. An international panel of relevant stakeholders who have experience of FGR (parent or carer of a baby that was growth restricted, health professional involved in the care of mothers and babies affected by FGR, a person with expertise in FGR research) will rate the importance of each of those outcomes in a series of three sequential online rounds of a Delphi study. Participants will be able to add items to the proposed list in round 1. A final face-to-face consensus meeting will be held with representatives of each stakeholder group at which a final list of outcomes for inclusion in the COS will be agreed. The development of COSs in FGR will ensure the collection and reporting of a minimum dataset agreed by stakeholder consensus and will reduce inconsistencies in the reporting of outcomes across relevant trials. Such standardisation in the reporting of outcomes will improve synthesis of evidence and generalisability of knowledge in the future by reducing heterogeneity in outcomes between trials and thus improve the results of systematic reviews and meta-analyses. Ultimately, we hope that the COSs will lead to an improvement in the quality of evidence-based clinical practice, enhance patient care, and improve the quality and consistency of research. Not applicable. This study is registered in the Core Outcome Measures for Effectiveness (COMET) database.

Objective: To assess a comprehensive package of ultrasound quality control in the Fetal Growth Longitudinal Study of the INTERGROWTH‐21^st Project, a large multicenter study of fetal growth.Methods: Quality control (QC) measures were performed for 20 313 ultrasound scan images obtained prospectively from 4321 fetuses at 14–41 weeks' gestation in eight geographical locations. At the time of each ultrasound examination, three fetal biometric variables (head circumference (HC), abdominal circumference (AC) and femur length (FL)) were measured in triplicate on separately generated images. All measurements were taken in a blinded fashion. QC had two elements: (1) qualitative QC: visual assessment by sonographers at each study site of their images based on specific criteria, with 10% of images being re‐assessed at the Oxford‐based Ultrasound Quality Unit (compared using an adjusted kappa statistic); and (2) quantitative QC: assessment of measurement data by comparing the first, second and third measurements (intraobserver variability), remeasurement of caliper replacement in 10% (interobserver variability), both by Bland–Altman plots and plotting frequency histograms of the SD of triplicate measurements and assessing how many were above or below 2 SD of the expected distribution. The system allowed the sonographers' performances to be monitored regularly.Results: A high level of agreement between self‐ and external scoring was demonstrated for all measurements (κ = 0.99 (95% CI, 0.98–0.99) for HC, 0.98 (95% CI, 0.97–0.99) for AC and 0.96 (95% CI, 0.95–0.98) for FL). Intraobserver 95% limits of agreement (LoA) of ultrasound measures for HC, AC and FL were ± 3.3%, ± 5.6% and ± 6.2%, respectively; the corresponding values for interobserver LoA were ± 4.4%, ± 6.0% and ± 5.6%. The SD distribution of triplicate measurements for all biometric variables showed excessive variability for three of 31 sonographers, allowing prompt identification and retraining.Conclusions: Qualitative and quantitative QC monitoring was feasible and highly reproducible in a large multicenter research study, which facilitated the production of high‐quality ultrasound images. We recommend that the QC system we developed is implemented in future research studies and clinical practice. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Objectives: To determine the sensitivity and specificity of first‐trimester ultrasound for the detection of fetal abnormalities and to establish which factors might impact on screening performance.Methods: A systematic review and meta‐analysis of all relevant publications was performed to assess the diagnostic accuracy of two‐dimensional transabdominal and transvaginal ultrasound in the detection of congenital fetal anomalies prior to 14 weeks' gestation. The reference standard was detection of abnormalities at birth or postmortem. Factors that may impact on detection rates were evaluated, including population characteristics, gestational age, healthcare setting, ultrasound modality, use of an anatomical checklist for detection of first‐trimester anomalies and type of malformation included in the study. In an effort to reduce the impact of study heterogeneity on the results of the meta‐analysis, data from the studies were analyzed within subgroups of major anomaliesvsall types of anomaly and low‐risk/unselected populationsvshigh‐risk populations.Results: An electronic search (until 29 July 2015) identified 2225 relevant citations, from which a total of 30 studies, published between 1991 and 2014, were selected for inclusion. The pooled estimate for the detection of major abnormalities in low‐risk or unselected populations (19 studies, 115 731 fetuses) was 46.10% (95%CI, 36.88–55.46%). The detection rate for all abnormalities in low‐risk or unselected populations (14 studies, 97 976 fetuses) was 32.35% (95%CI, 22.45–43.12%), whereas in high‐risk populations (six studies, 2841 fetuses) it was 61.18% (95%CI, 37.71–82.19%). Of the factors examined for their impact on detection rate, there was a statistically significant relationship (P < 0.0001) between the use of a standardized anatomical protocol during first‐trimester anomaly screening and its sensitivity for the detection of fetal anomalies in all subgroups.Conclusions: Detection rates of first‐trimester fetal anomalies ranged from 32% in low‐risk groups to more than 60% in high‐risk groups, demonstrating that first‐trimester ultrasound has the potential to identify a large proportion of fetuses affected with structural anomalies. The use of a standardized anatomical protocol improves the sensitivity of first‐trimester ultrasound screening for all anomalies and major anomalies in populations of varying risk. The development and introduction of international protocols with standard anatomical views should be undertaken in order to optimize first‐trimester anomaly detection. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Objectives: Single nucleotide polymorphisms (SNP) in genes related to vitamin D metabolism have been associated with 25-hydroxyvitamin D (25(OH)D) status, but these relationships have not been examined in pregnancy or following antenatal vitamin D supplementation. We assessed whether SNPs in DHCR7 (7-dehydrocholesterol reductase), CYP2R1 (25-hydroxylase), CYP24A1 (24-hydroxylase) and GC (Vitamin D binding protein) were associated with the response to antenatal vitamin D supplementation. Methods: MAVIDOS is a randomised double-blind placebo-controlled trial of 1000IU/day cholecalciferol from 14 weeks gestation until delivery in women with a baseline 25(OH)D of 25–100 nmol/l. Anthropometry, serum 25(OH)D (Diasorin Liaison), health and diet were assessed at 14 and 34 weeks gestation. Genotyping of rs12785878 (DHCR7), rs10741657 (CYP2R1), rs6013897 (CYP24A1) and rs2282679 (GC) was undertaken by LGC Genomics (Hoddeston, UK) using KASP™ competitive allele-specific PCR. Multiple linear regression was performed using an additive model with the homozygous minor allele as the reference group (beta represents the change in outcome per additional major allele), adjusting for a number of previously identified determinants of 25(OH)D. Results: 712 women (367 placebo, 345 cholecalciferol) were included (95.8% White ethnicity). Only rs12785878 (DHCR7) was associated with baseline 25(OH)D (β=4.1 nmol/l (95% CI 2.2, 6.1), PCYP2R1) (β=−4.1 nmol/l (95%CI −7.1, −1.2), P=0.006) and rs2282679 (GC) (β=4.4 nmol/l (95%CI 1.2, 7.6), P=0.007) were associated with achieved 25(OH)D after supplementation, but rs12785878 and rs6013897 were not. Conclusion: Genetic variation in DHCR7, which encodes 7-dehyrocholesterol reductase in the cholesterol/vitamin D biosynthesis pathway in the skin appears to modify baseline 25(OH)D, whereas the response to antenatal cholecalciferol supplementation was associated with SNPs in CYP2R1 and GC, which may alter 25-hydroxylase activity and vitamin D binding protein synthesis. Women with more risk alleles may require higher supplement doses to achieve vitamin D repletion in pregnancy. Disclosure: The authors declared no competing interests.

Objective To create international symphysis-fundal height standards derived from pregnancies of healthy women with good maternal and perinatal outcomes. Design Prospective longitudinal observational study. Setting Eight geographically diverse urban regions in Brazil, China, India, Italy, Kenya, Oman, United Kingdom, and United States. Participants Healthy, well nourished pregnant women enrolled into the Fetal Growth Longitudinal Study component of the INTERGROWTH-21^st Project at 9-14 weeks’ gestation, and followed up until birth. Main outcome measures Symphysis-fundal height was measured every five weeks from 14 weeks’ gestation until birth using standardised methods and dedicated research staff who were blinded to the symphysis-fundal height measurements by turning the tape measure so that numbers were not visible during examination. The best fitting curve was selected using second degree fractional polynomials and further modelled in a multilevel framework to account for the longitudinal design of the study. Results Of 13 108 women screened in the first trimester, 4607 (35.1%) met the study entry criteria. Of the eligible women, 4321 (93.8%) had pregnancies without major complications and delivered live singletons without congenital malformations. The median number of symphysis-fundal height measurements was 5.0 (range 1-7); 3976 (92.0%) women had four or more measurements. Symphysis-fundal height measurements increased almost linearly with gestational age; data were used to determine fitted 3rd, 50th, and 97th centile curves, which showed excellent agreement with observed values. Conclusions This study presents international standards to measure symphysis-fundal height as a first level screening tool for fetal growth disturbances.

Objective: Estimated fetal weight (EFW) and fetal biometry are complementary measures used to screen for fetal growth disturbances. Our aim was to provide international EFW standards to complement the INTERGROWTH‐21^st Fetal Growth Standards that are available for use worldwide.Methods: Women with an accurate gestational‐age assessment, who were enrolled in the prospective, international, multicenter, population‐based Fetal Growth Longitudinal Study (FGLS) and INTERBIO‐21^st Fetal Study (FS), two components of the INTERGROWTH‐21^st Project, had ultrasound scans every 5 weeks from 9–14 weeks' until 40 weeks' gestation. At each visit, measurements of fetal head circumference (HC), biparietal diameter, occipitofrontal diameter, abdominal circumference (AC) and femur length (FL) were obtained blindly by dedicated research sonographers using standardized methods and identical ultrasound machines. Birth weight was measured within 12 h of delivery by dedicated research anthropometrists using standardized methods and identical electronic scales. Live babies without any congenital abnormality, who were born within 14 days of the last ultrasound scan, were selected for inclusion. As most births occurred at around 40 weeks' gestation, we constructed a bootstrap model selection and estimation procedure based on resampling of the complete dataset under an approximately uniform distribution of birth weight, thus enriching the sample size at extremes of fetal sizes, to achieve consistent estimates across the full range of fetal weight. We constructed reference centiles using second‐degree fractional polynomial models.Results: Of the overall population, 2404 babies were born within 14 days of the last ultrasound scan. Mean time between the last scan and birth was 7.7 (range, 0–14) days and was uniformly distributed. Birth weight was best estimated as a function of AC and HC (without FL) as log(EFW) = 5.084820 − 54.06633 × (AC/100)³ − 95.80076 × (AC/100)³ × log(AC/100) + 3.136370 × (HC/100), where EFW is in g and AC and HC are in cm. All other measures, gestational age, symphysis–fundus height, amniotic fluid indices and interactions between biometric measures and gestational age, were not retained in the selection process because they did not improve the prediction of EFW. Applying the formula to FGLS biometric data (n = 4231) enabled gestational age‐specific EFW tables to be constructed. At term, the EFW centiles matched those of the INTERGROWTH‐21^st Newborn Size Standards but, at < 37 weeks' gestation, the EFW centiles were, as expected, higher than those of babies born preterm. Comparing EFW cross‐sectional values with the INTERGROWTH‐21^st Preterm Postnatal Growth Standards confirmed that preterm postnatal growth is a different biological process from intrauterine growth.Conclusions: We provide an assessment of EFW, as an adjunct to routine ultrasound biometry, from 22 to 40 weeks' gestation. However, we strongly encourage clinicians to evaluate fetal growth using separate biometric measures such as HC and AC, as well as EFW, to avoid the minimalist approach of focusing on a single value. © 2016 Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Objective To compare the standard methods for ultrasound measurement of fetal head circumference (HC) and biparietal diameter (BPD) (outer‐to‐outer (BPDoo) vs outer‐to‐inner (BPDoi) caliper placement), and compare acquisition of these measurements in transthalamic (TT) vs transventricular (TV) planes. Methods This study utilized ultrasound images acquired from women participating in the Oxford arm of the INTERGROWTH‐21^st Project. In the first phase of the study, BPDoo and BPDoi were measured on stored images. In the second phase, real‐time measurements of BPD, occipitofrontal diameter (OFD) and HC in TT and TV planes were obtained by pairs of sonographers. Reproducibility of measurements made by the same (intraobserver) and by different (interobserver) sonographers, as well as the reproducibility of caliper placement and measurements obtained in different planes, was assessed using Bland–Altman plots. Results In Phase I, we analyzed ultrasound images of 108 singleton fetuses. The mean intraobserver and interobserver differences were < 2% (1.34 mm) and the 95% limits of agreement were < 5% (3 mm) for both BPDoo and BPDoi. Neither method for measuring BPD showed consistently better reproducibility. In Phase II, we analyzed ultrasound images of 100 different singleton fetuses. The mean intraobserver and interobserver differences were < 1% (2.26 mm) and the 95% limits of agreement were < 8% (14.45 mm) for all fetal head measurements obtained in TV and TT planes. Neither plane for measuring fetal head showed consistently better reproducibility. Measurement of HC using the ellipse facility was as reproducible as HC calculated from BPD and OFD. OFD by itself was the least reproducible of all fetal head measurements. Conclusions Measurements of BPDoi and BPDoo are equally reproducible; however, we believe BPDoo should be used in clinical practice as it allows fetal HC to be measured and compared with neonatal HC. For all head measurements, TV and TT planes provide equally reproducible values at any gestational age, and HC values are similar in both planes. Fetal head measurement in the TT plane is preferable as international standards in this plane are available; however, measurements in the TV plane can be plotted on the same standards. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Maternal vitamin D status has been positively associated with infant bone mass in observational studies. We therefore evaluated whether 1000 IU/day cholecalciferol during pregnancy would lead to greater offspring bone mass at birth, in a UK, multicentre, randomised, double-blind, placebo-controlled trial (MAVIDOS, ISRCTN82927713). At 12 weeks’ gestation, pregnant women with a serum 25-hydroxyvitamin D [25(OH)D] 25-100 nmol/l were randomised to either 1000 IU cholecalciferol or matched placebo daily until delivery. Plasma 25(OH)D concentration was measured centrally at 14 and 34 weeks’ gestation (Diasorin Liaison). Within 2 weeks after birth, infant whole body bone mineral content (BMC) was assessed by Dual-Energy X-ray Absorptiometry (Hologic Discovery, Hologic; or iDXA, GE-Lunar; measurements standardised). Infants born to mothers supplemented with cholecalciferol had non-significantly greater whole body BMC than infants born to mothers taking placebo (total n=665; mean (S.D.) 61.6 (11.7)g vs 60.5 (11.1)g, respectively, P=0.21). However, in a pre-specified analysis, there was an interaction between season of birth and treatment allocation (P=0.04): infants born in winter (December–February) to mothers randomised to cholecalciferol had greater BMC than those randomised to placebo (63.0±10.8 g vs 57.5±10.9 g, P=0.004), a difference>0.5S.D. Similar patterns were observed for bone area and bone mineral density. At 34 weeks’ gestation, the proportion of women with vitamin D sufficiency [25(OH)D>50 nmol/l] was increased (83.4% vs 36.5%, PP<0.001). No safety issues were identified. Maternal gestational supplementation with 1000 IU cholecalciferol increases bone mass in UK infants born during winter months, and prevents the seasonal decline in 25(OH)D in these mothers. The findings inform public health policy relating to antenatal vitamin D supplementation. *CC and NCH are joint first author.

Objective: Accurate gestational‐age (GA) estimation, preferably by ultrasound measurement of fetal crown–rump length before 14 weeks' gestation, is an important component of high‐quality antenatal care. The objective of this study was to determine how GA can best be estimated by fetal ultrasound for women who present for the first time late in pregnancy with uncertain or unknown menstrual dates.Methods: INTERGROWTH‐21^st was a large, prospective, multicenter, population‐based project performed in eight geographically defined urban populations. One of its principal components, the Fetal Growth Longitudinal Study, aimed to develop international fetal growth standards. Each participant had their certain menstrual dates confirmed by first‐trimester ultrasound examination. Fetal head circumference (HC), biparietal diameter (BPD), occipitofrontal diameter (OFD), abdominal circumference (AC) and femur length (FL) were measured every 5 weeks from 14 weeks' gestation until delivery. For each participant, a single, randomly selected ultrasound examination was used to explore all candidate biometric variables and permutations to build models to predict GA. Regression equations were ranked based upon minimization of the mean prediction error, goodness of fit and model complexity. An automated machine learning algorithm, the Genetic Algorithm, was adapted to evaluate > 64 000 potential polynomial equations as predictors.Results: Of the 4607 eligible women, 4321 (94%) had a pregnancy without major complications and delivered a live singleton without congenital malformations. After other exclusions (missing measurements in GA window and outliers), the final sample comprised 4229 women. Two skeletal measures, HC and FL, produced the best GA prediction, given by the equation log_e(GA) = 0.03243 × (log_e(HC))² + 0.001644 × FL × log_e(HC) + 3.813. When FL was not available, the best equation based on HC alone was log_e(GA) = 0.05970 × (log_e(HC))² + 0.000000006409 × (HC)³ + 3.3258. The estimated uncertainty of GA prediction (half width 95% interval) was 6–7 days at 14 weeks' gestation, 12–14 days at 26 weeks' gestation and > 14 days in the third trimester. The addition of FL to the HC model led to improved prediction intervals compared with using HC alone, but no further improvement in prediction was afforded by adding AC, BPD or OFD. Equations that included other measurements (BPD, OFD and AC) did not perform better.Conclusions: Among women initiating antenatal care late in pregnancy, a single set of ultrasound measurements combining HC and FL in the second trimester can be used to estimate GA with reasonable accuracy. We recommend this tool for underserved populations but considerable efforts should be implemented to improve early initiation of antenatal care worldwide. © 2016 Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Antenatal care early in pregnancy enables service providers to identify and manage risks to mother and fetus. In the global north, ultrasound scans are routinely offered in pregnancy to provide an accurate estimate of gestational age and identify potential problems. In sub-Saharan Africa, such services are rarely available and women often delay initiating antenatal care. This study describes the uptake and provision of antenatal care in a rural Kenyan hospital and explores how pregnant women and healthcare providers perceived the provision of ultrasound scanning, following its introduction in an international foetal growth study. A descriptive study, using qualitative and quantitative methods, was conducted in Kilifi District Hospital, Kenya, between June 2011 and April 2012. In-depth interviews were conducted with 10 nurses working in the antenatal clinic (ANC) and 59 pregnant women attending ANC. Structured observations of 357 ANC consultations and 30 ultrasound scans were made. Women sought antenatal care for information about the health of their baby and the protection provided by the ANC services. Uncertainty about pregnancy status contributed to delay in ANC attendance; more than 78 % of women were over 20 weeks’ gestation at their first visit. Healthcare workers found it difficult to detect pregnancies below 16 weeks gestation and, accurate assessment of gestational age below 20 weeks’ gestation could be problematic. Provision of services depended on the pregnancy being detected and gestational age assessed. The “seeing”, made possible through ultrasound scanning was perceived by pregnant women and healthcare workers to be beneficial: confirming the pregnancy, and providing reassurance about the fetus’ condition. Few participants raised concerns about ultrasound scanning. Uncertainty about pregnancy status and gestational age for women and healthcare providers is a key factor influencing timing of ANC attendance, contributing to delays and restricting early provision of ANC services. Ultrasound scanning was perceived to enhance antenatal care through confirmation of pregnancy status and enabling more accurate estimation of gestational age and the health status of the fetus. There is a need to make available more affordable means of pregnancy testing as a strategy towards encouraging early attendance, and delivery of antenatal care.