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1.  Maternal gestational vitamin D supplementation and offspring bone health: a multicentre randomised, double-blind, placebo-controlled trial (MAVIDOS) 
Maternal vitamin D status has been associated with lower bone mass of the offspring in many, but not all, observational studies. However, proof that maternal vitamin D repletion during pregnancy improves offspring bone mass is lacking.
Between 06/10/2008 and 11/02/2014, we randomly assigned pregnant women with a serum 25-hydroxyvitamin D [25(OH)D] 25-100nmol/l at 12 weeks’ gestation to either 1000IU/day cholecalciferol or matched placebo from 14 weeks’ gestation until delivery. Serum 25(OH)D was measured at 14 and 34 weeks’ gestation. Neonatal whole body bone mineral, assessed within 2 weeks after birth (n=665) by dual-energy X-ray absorptiometry (DXA), was the primary outcome. Secondary pre-specified analyses explored interactions with study centre, maternal ethnicity, parity, compliance, protocol completion, baseline BMI, baseline 25(OH)D and change in 25(OH)D from 14 to 34 weeks; and offspring sex and season of birth.
We found no difference in neonatal whole body bone mineral content (BMC) of infants born to mothers randomised to 1000IU/day cholecalciferol compared with infants born to mothers randomised to placebo [61.6g (95%CI: 60.3, 62.8g) vs 60.5g (95%CI: 59.3, 61.7g) respectively, p=0.21].
Supplementation of mothers with 1000IU/day cholecalciferol during pregnancy did not lead to increased offspring whole body BMC compared with placebo.
PMCID: PMC4843969  PMID: 26944421
Vitamin D; cholecalciferol; supplementation; trial; osteoporosis; epidemiology; DXA; pregnancy; neonate
2.  Gestational weight gain standards based on women enrolled in the Fetal Growth Longitudinal Study of the INTERGROWTH-21st Project: a prospective longitudinal cohort study 
Objective To describe patterns in maternal gestational weight gain (GWG) in healthy pregnancies 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, April 2009 to March 2014.
Participants Healthy, well nourished, and educated women enrolled in the Fetal Growth Longitudinal Study component of the INTERGROWTH-21st Project, who had a body mass index (BMI) of 18.50-24.99 in the first trimester of pregnancy.
Main outcome measures Maternal weight measured with standardised methods and identical equipment every five weeks (plus/minus one week) from the first antenatal visit (<14 weeks’ gestation) to delivery. After confirmation that data from the study sites could be pooled, a multilevel, linear regression analysis accounting for repeated measures, adjusted for gestational age, was applied to produce the GWG values.
Results 13 108 pregnant women at <14 weeks’ gestation were screened, and 4607 met the eligibility criteria, provided consent, and were enrolled. The variance within sites (59.6%) was six times higher than the variance between sites (9.6%). The mean GWGs were 1.64 kg, 2.86 kg, 2.86 kg, 2.59 kg, and 2.56 kg for the gestational age windows 14-18+6 weeks, 19-23+6 weeks, 24-28+6 weeks, 29-33+6 weeks, and 34-40+0 weeks, respectively. Total mean weight gain at 40 weeks’ gestation was 13.7 (SD 4.5) kg for 3097 eligible women with a normal BMI in the first trimester. Of all the weight measurements, 71.7% (10 639/14 846) and 94.9% (14 085/14 846) fell within the expected 1 SD and 2 SD thresholds, respectively. Data were used to determine fitted 3rd, 10th, 25th, 50th, 75th, 90th, and 97th smoothed GWG centiles by exact week of gestation, with equations for the mean and standard deviation to calculate any desired centiles according to gestational age in exact weeks.
Conclusions Weight gain in pregnancy is similar across the eight populations studied. Therefore, the standards generated in this study of healthy, well nourished women may be used to guide recommendations on optimal gestational weight gain worldwide.
PMCID: PMC4770850  PMID: 26926301
3.  International standards for symphysis-fundal height based on serial measurements from the Fetal Growth Longitudinal Study of the INTERGROWTH-21st Project: prospective cohort study in eight countries 
The BMJ  2016;355:i5662.
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-21st 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.
PMCID: PMC5098415  PMID: 27821614
4.  Feature-based fuzzy connectedness segmentation of ultrasound images with an object completion step 
Medical Image Analysis  2015;26(1):30-46.
Highligts•Novel US segmentation approach based on the fuzzy connectedness framework.•Use of local phase and feature asymmetry to define affinity function.•Shape-based object completion step to detect and complete one or more gaps.•Novel regional entropy-based quantitative image quality assessment approach.•Method performs well across a variety of image qualities from clinical practice.
Graphical abstract
Medical ultrasound (US) image segmentation and quantification can be challenging due to signal dropouts, missing boundaries, and presence of speckle, which gives images of similar objects quite different appearance. Typically, purely intensity-based methods do not lead to a good segmentation of the structures of interest. Prior work has shown that local phase and feature asymmetry, derived from the monogenic signal, extract structural information from US images. This paper proposes a new US segmentation approach based on the fuzzy connectedness framework. The approach uses local phase and feature asymmetry to define a novel affinity function, which drives the segmentation algorithm, incorporates a shape-based object completion step, and regularises the result by mean curvature flow. To appreciate the accuracy and robustness of the methodology across clinical data of varying appearance and quality, a novel entropy-based quantitative image quality assessment of the different regions of interest is introduced. The new method is applied to 81 US images of the fetal arm acquired at multiple gestational ages, as a means to define a new automated image-based biomarker of fetal nutrition. Quantitative and qualitative evaluation shows that the segmentation method is comparable to manual delineations and robust across image qualities that are typical of clinical practice.
PMCID: PMC4686006  PMID: 26319973
Image segmentation; Ultrasound; Shape completion; Fetal imaging; Image quality
5.  “You cannot know if it’s a baby or not a baby”: uptake, provision and perceptions of antenatal care and routine antenatal ultrasound scanning in rural Kenya 
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.
PMCID: PMC4446960  PMID: 26021564
Perceptions of antenatal care; Obstetric ultrasound scanning; Antenatal care timing; Gestational age; Confirmation of pregnancy; Sub-Saharan Africa
6.  Learning-based prediction of gestational age from ultrasound images of the fetal brain 
Medical Image Analysis  2015;21(1):72-86.
Graphical abstract
•We present a model to predict gestational age from 3D fetal brain ultrasound images.•A feature-based model characterizes spatial and temporal brain development.•We capitalize on sonographic image patterns and clinical measures to predict age.•Use of clinical measurements and neuroimage information improves age predictions.•We identify the most age-discriminating brain anatomies in early brain development.
We propose an automated framework for predicting gestational age (GA) and neurodevelopmental maturation of a fetus based on 3D ultrasound (US) brain image appearance. Our method capitalizes on age-related sonographic image patterns in conjunction with clinical measurements to develop, for the first time, a predictive age model which improves on the GA-prediction potential of US images. The framework benefits from a manifold surface representation of the fetal head which delineates the inner skull boundary and serves as a common coordinate system based on cranial position. This allows for fast and efficient sampling of anatomically-corresponding brain regions to achieve like-for-like structural comparison of different developmental stages. We develop bespoke features which capture neurosonographic patterns in 3D images, and using a regression forest classifier, we characterize structural brain development both spatially and temporally to capture the natural variation existing in a healthy population (N=447) over an age range of active brain maturation (18–34 weeks).
On a routine clinical dataset (N=187) our age prediction results strongly correlate with true GA (r=0.98,accurate within±6.10days), confirming the link between maturational progression and neurosonographic activity observable across gestation. Our model also outperforms current clinical methods by ±4.57 days in the third trimester—a period complicated by biological variations in the fetal population. Through feature selection, the model successfully identified the most age-discriminating anatomies over this age range as being the Sylvian fissure, cingulate, and callosal sulci.
PMCID: PMC4339204  PMID: 25624045
Fetal brain ultrasound; Gestational age; Regression forest; Surface parametrization; Brain development
7.  STRIDER: Sildenafil therapy in dismal prognosis early-onset intrauterine growth restriction – a protocol for a systematic review with individual participant data and aggregate data meta-analysis and trial sequential analysis 
Systematic Reviews  2014;3:23.
In pregnancies complicated by early-onset extreme fetal growth restriction, there is a high risk of preterm birth and an overall dismal fetal prognosis. Sildenafil has been suggested to improve this prognosis. The first aim of this review is to assess whether sildenafil benefits or harms these babies. The second aim is to analyse if these effects are modified in a clinically meaningful way by factors related to the women or the trial protocol.
The STRIDER (Sildenafil Therapy In Dismal prognosis Early-onset intrauterine growth Restriction) Individual Participant Data (IPD) Study Group will conduct a prospective IPD and aggregate data systematic review with meta-analysis and trial sequential analysis. The STRIDER IPD Study Group started trial planning and funding applications in 2012. Three trials will be launched in 2014, recruiting for three years. Further trials are planned to commence in 2015.
The primary outcome for babies is being alive at term gestation without evidence of serious adverse neonatal outcome. The latter is defined as severe central nervous system injury (severe intraventricular haemorrhage (grade 3 and 4) or cystic periventricular leukomalacia, demonstrated by ultrasound and/or magnetic resonance imaging) or other severe morbidity (bronchopulmonary dysplasia, retinopathy of prematurity requiring treatment, or necrotising enterocolitis requiring surgery). The secondary outcomes are improved fetal growth velocity assessed by ultrasound abdominal circumference measurements, gestational age and birth weight (centile) at delivery, and age-adequate performance on the two-year Bayley scales of infant and toddler development-III (composite cognitive score and composite motor score). Subgroup and sensitivity analyses in the IPD meta-analysis include assessment of the influence of several patient characteristics: an abnormal or normal serum level of placental growth factor, absent/reversed umbilical arterial end diastolic flow at commencement of treatment, and other patient characteristics available at baseline such as gestational age and estimated fetal weight. The secondary outcomes for mothers include co-incidence and severity of the maternal syndrome of pre-eclampsia, mortality, and other serious adverse events.
Trials are expected to start in 2013–2014 and end in 2016–2017. Data analyses of individual trials are expected to finish in 2019. Given the pre-planned and agreed IPD protocol, these results should be available in 2020.
PMCID: PMC3975177  PMID: 24618418
Adverse neonatal outcome; Fetal growth restriction; Individual participant data meta-analysis; Sildenafil
8.  Estimation of gestational age in early pregnancy from crown-rump length when gestational age range is truncated: the case study of the INTERGROWTH-21st Project 
Fetal ultrasound scanning is considered vital for routine antenatal care with first trimester scans recommended for accurate estimation of gestational age (GA). A reliable estimate of gestational age is key information underpinning clinical care and allows estimation of expected date of delivery. Fetal crown-rump length (CRL) is recommended over last menstrual period for estimating GA when measured in early pregnancy i.e. 9+0-13+6 weeks.
The INTERGROWTH-21st Project is the largest prospective study to collect data on CRL in geographically diverse populations and with a high level of quality control measures in place. We aim to develop a new gestational age estimation equation based on the crown-rump length (CRL) from women recruited between 9+0-13+6 weeks. The main statistical challenge is modelling data when the outcome variable (GA) is truncated at both ends, i.e. at 9 and 14 weeks.
We explored three alternative statistical approaches to overcome the truncation of GA. To evaluate these strategies we generated a data set with no truncation of GA that was similar to the INTERGROWTH-21st Project CRL data, which we used to explore the performance of different methods of analysis of these data when we imposed truncation at 9 and 14 weeks of gestation. These 3 methods were first tested in a simulation based study using a previously published dating equation by Verburg et al. and evaluated how well each of them performed in relation to the model from which the data were generated. After evaluating the 3 approaches using simulated data based on the Verburg equations, the best approach will be applied to the INTERGROWTH-21st Project data to estimate GA from CRL.
Results of these rather “ad hoc” statistical methods correspond very closely to the “real data” for Verburg, a data set that is similar to the INTERGROWTH-21st project CRL data set.
We are confident that we can use these approaches to get reliable estimates based on INTERGROWTH-21st Project CRL data. These approaches may be a solution to other truncation problems involving similar data though their application to other settings would need to be evaluated.
PMCID: PMC4029763  PMID: 24314232
Truncation; INTERGROWTH-21st project; Crown-rump length; Gestational age; Simulation; Extrapolation; Restriction; Inversion
9.  Registration of 3D fetal neurosonography and MRI☆ 
Medical Image Analysis  2013;17(8):1137-1150.
Graphical abstract
•A novel method for affine registration of fetal neurosonography and brain MRI proposed.•Conversion of fetal MRI into pseudo US image described.•All data were successfully aligned using robust block-matching approach.•Average of 27 US volumes revealed near-complete anatomy of the fetal brain.
We propose a method for registration of 3D fetal brain ultrasound with a reconstructed magnetic resonance fetal brain volume. This method, for the first time, allows the alignment of models of the fetal brain built from magnetic resonance images with 3D fetal brain ultrasound, opening possibilities to develop new, prior information based image analysis methods for 3D fetal neurosonography. The reconstructed magnetic resonance volume is first segmented using a probabilistic atlas and a pseudo ultrasound image volume is simulated from the segmentation. This pseudo ultrasound image is then affinely aligned with clinical ultrasound fetal brain volumes using a robust block-matching approach that can deal with intensity artefacts and missing features in the ultrasound images. A qualitative and quantitative evaluation demonstrates good performance of the method for our application, in comparison with other tested approaches. The intensity average of 27 ultrasound images co-aligned with the pseudo ultrasound template shows good correlation with anatomy of the fetal brain as seen in the reconstructed magnetic resonance image.
PMCID: PMC3807810  PMID: 23969169
Fetal 3D ultrasound; MR ultrasound registration; Fetal neurosonography; Block matching
10.  Ultrasound Evidence of Early Fetal Growth Restriction after Maternal Malaria Infection 
PLoS ONE  2012;7(2):e31411.
Intermittent preventive treatment (IPT), the main strategy to prevent malaria and reduce anaemia and low birthweight, focuses on the second half of pregnancy. However, intrauterine growth restriction may occur earlier in pregnancy. The aim of this study was to measure the effects of malaria in the first half of pregnancy by comparing the fetal biparietal diameter (BPD) of infected and uninfected women whose pregnancies had been accurately dated by crown rump length (CRL) before 14 weeks of gestation.
Methodology/Principal Findings
In 3,779 women living on the Thai-Myanmar border who delivered a normal singleton live born baby between 2001–10 and who had gestational age estimated by CRL measurement <14 weeks, the observed and expected BPD z-scores (<24 weeks) in pregnancies that were (n = 336) and were not (n = 3,443) complicated by malaria between the two scans were compared. The mean (standard deviation) fetal BPD z-scores in women with Plasmodium (P) falciparum and/or P.vivax malaria infections were significantly lower than in non-infected pregnancies; −0.57 (1.13) versus −0.10 (1.17), p<0.001. Even a single or an asymptomatic malaria episode resulted in a significantly lower z-score. Fetal female sex (p<0.001) and low body mass index (p = 0.01) were also independently associated with a smaller BPD in multivariate analysis.
Despite early treatment in all positive women, one or more (a)symptomatic P.falciparum or P.vivax malaria infections in the first half of pregnancy result in a smaller than expected mid-trimester fetal head diameter. Strategies to prevent malaria in pregnancy should include early pregnancy.
PMCID: PMC3276538  PMID: 22347473
11.  MAVIDOS Maternal Vitamin D Osteoporosis Study: study protocol for a randomized controlled trial. The MAVIDOS Study Group 
Trials  2012;13:13.
MAVIDOS is a randomised, double-blind, placebo-controlled trial (ISRCTN82927713, registered 2008 Apr 11), funded by Arthritis Research UK, MRC, Bupa Foundation and NIHR.
Osteoporosis is a major public health problem as a result of associated fragility fractures. Skeletal strength increases from birth to a peak in early adulthood. This peak predicts osteoporosis risk in later life. Vitamin D insufficiency in pregnancy is common (31% in a recent Southampton cohort) and predicts reduced bone mass in the offspring. In this study we aim to test whether offspring of mothers supplemented with vitamin D in pregnancy have higher bone mass at birth than those whose mothers were not supplemented.
Women have their vitamin D status assessed after ultrasound scanning in the twelfth week of pregnancy at 3 trial centres (Southampton, Sheffield, Oxford). Women with circulating 25(OH)-vitamin D levels 25-100 nmol/l are randomised in a double-blind design to either oral vitamin D supplement (1000 IU cholecalciferol/day, n = 477) or placebo at 14 weeks (n = 477). Questionnaire data include parity, sunlight exposure, dietary information, and cigarette and alcohol consumption. At 19 and 34 weeks maternal anthropometry is assessed and blood samples taken to measure 25(OH)-vitamin D, PTH and biochemistry. At delivery venous umbilical cord blood is collected, together with umbilical cord and placental tissue. The babies undergo DXA assessment of bone mass within the first 14 days after birth, with the primary outcome being whole body bone mineral content adjusted for gestational age and age. Children are then followed up with yearly assessment of health, diet, physical activity and anthropometric measures, with repeat assessment of bone mass by DXA at age 4 years.
As far as we are aware, this randomised trial is one of the first ever tests of the early life origins hypothesis in human participants and has the potential to inform public health policy regarding vitamin D supplementation in pregnancy. It will also provide a valuable resource in which to study the influence of maternal vitamin D status on other childhood outcomes such as glucose tolerance, blood pressure, cardiovascular function, IQ and immunology.
PMCID: PMC3395865  PMID: 22314083
Vitamin D; cholecalciferol; supplementation; trial; osteoporosis; DXA; pregnancy; neonate
12.  Effect of malaria on placental volume measured using three-dimensional ultrasound: a pilot study 
Malaria Journal  2012;11:5.
The presence of malaria parasites and histopathological changes in the placenta are associated with a reduction in birth weight, principally due to intrauterine growth restriction. The aim of this study was to examine the feasibility of studying early pregnancy placental volumes using three-dimensional (3D) ultrasound in a malaria endemic area, as a small volume in the second trimester may be an indicator of intra-uterine growth restriction and placental insufficiency.
Placenta volumes were acquired using a portable ultrasound machine and a 3D ultrasound transducer and estimated using the Virtual Organ Computer-aided AnaLysis (VOCAL) image analysis software package. Intra-observer reliability and limits of agreement of the placenta volume measurements were calculated. Polynomial regression models for the mean and standard deviation as a function of gestational age for the placental volumes of uninfected women were created and tested. Based on these equations each measurement was converted into a z -score. The z-scores of the placental volumes of malaria infected and uninfected women were then compared.
Eighty-four women (uninfected = 65; infected = 19) with a posterior placenta delivered congenitally normal, live born, single babies. The mean placental volumes in the uninfected women were modeled to fit 5th, 10th, 50th, 90th and 95th centiles for 14-24 weeks' gestation. Most placenta volumes in the infected women were below the 50th centile for gestational age; most of those with Plasmodium falciparum were below the 10th centile. The 95% intra-observer limits of agreement for first and second measurements were ± 37.0 mL and ± 25.4 mL at 30 degrees and 15 degrees rotation respectively.
The new technique of 3D ultrasound volumetry of the placenta may be useful to improve our understanding of the pathophysiological constraints on foetal growth caused by malaria infection in early pregnancy.
PMCID: PMC3317826  PMID: 22222152
Malaria; Pregnancy; Three-dimensional ultrasound; Placenta volume; IUGR
13.  A link between high serum levels of human chorionic gonadotrophin and chorionic expression of its mature functional receptor (LHCGR) in Down's syndrome pregnancies 
Human chorionic gonadotrophin (hCG) is released from placental trophoblasts and is involved in establishing pregnancy by maintaining progesterone secretion from the corpus luteum. Serum hCG is detected in the maternal circulation within the first 2–3 wks of gestation and peaks at the end of the first trimester before declining. In Down's syndrome (DS) pregnancies, serum hCG remains significantly high compared to gestation age-matched uncompromised pregnancies. It has been proposed that increased serum hCG levels could be due to transcriptional hyper-activation of the CGB (hCG beta) gene, or an increased half life of glycosylated hCG hormone, or both. Another possibility is that serum hCG levels remain high due to reduced availability of the hormone's cognate receptor, LHCGR, leading to lack of hormone utilization. We have tested this hypothesis by quantifying the expression of the hCG beta (CGB) RNA, LHCGR RNA and LHCGR proteins in chorionic villous samples. We demonstrate that chorionic expression of hCG beta (CGB) mRNA directly correlates with high serum hCG levels. The steady-state synthesis of LHCGR mRNA (exons 1–5) in DS pregnancies was significantly higher than that of controls, but the expression of full-length LHCGR mRNA (exons 1–11) in DS was comparable to that of uncompromised pregnancies. However, the synthesis of high molecular weight mature LHCGR proteins was significantly reduced in DS compared to uncompromised pregnancies, suggesting a lack of utilization of circulating hCG in DS pregnancies.
PMCID: PMC1190215  PMID: 15969756

Results 1-13 (13)