AutoFB: Automating Fetal Biometry Estimation from Standard Ultrasound Planes

During pregnancy, ultrasound examination in the second trimester can assess fetal size according to standardized charts. To achieve a reproducible and accurate measurement, a sonographer needs to identify three standard 2D planes of the fetal anatomy (head, abdomen, femur) and manually mark the key anatomical landmarks on the image for accurate biometry and fetal weight estimation. This can be a time-consuming operator-dependent task, especially for a trainee sonographer. Computer-assisted techniques can help in automating the fetal biometry computation process. In this paper, we present a unified automated framework for estimating all measurements needed for the fetal weight assessment. The proposed framework semantically segments the key fetal anatomies using state-of-the-art segmentation models, followed by region fitting and scale recovery for the biometry estimation. We present an ablation study of segmentation algorithms to show their robustness through 4-fold cross-validation on a dataset of 349 ultrasound standard plane images from 42 pregnancies. Moreover, we show that the network with the best segmentation performance tends to be more accurate for biometry estimation. Furthermore, we demonstrate that the error between clinically measured and predicted fetal biometry is lower than the permissible error during routine clinical measurements

AutoFB: Automating Fetal Biometry Estimation from Standard Ultrasound Planes

During pregnancy, ultrasound examination in the second trimester can assess fetal size according to standardized charts. To achieve a reproducible and accurate measurement, a sonographer needs to identify three standard 2D planes of the fetal anatomy (head, abdomen, femur) and manually mark the key anatomical landmarks on the image for accurate biometry and fetal weight estimation. This can be a time-consuming operator-dependent task, especially for a trainee sonographer. Computer-assisted techniques can help in automating the fetal biometry computation process. In this paper, we present a unified automated framework for estimating all measurements needed for the fetal weight assessment. The proposed framework semantically segments the key fetal anatomies using state-of-the-art segmentation models, followed by region fitting and scale recovery for the biometry estimation. We present an ablation study of segmentation algorithms to show their robustness through 4-fold cross-validation on a dataset of 349 ultrasound standard plane images from 42 pregnancies. Moreover, we show that the network with the best segmentation performance tends to be more accurate for biometry estimation. Furthermore, we demonstrate that the error between clinically measured and predicted fetal biometry is lower than the permissible error during routine clinical measurements

Peri- and Postnatal Effects of Prenatal Adenoviral VEGF Gene Therapy in Growth-Restricted Sheep

Uterine artery (UtA) adenovirus vector (Ad)-mediated over-expression of vascular endothelial growth factor (VEGF) enhances uterine blood flow in normal sheep pregnancy and increases fetal growth in the overnourished adolescent sheep model of fetal growth restriction (FGR). Herein we examined its impact on gestation length, neonatal survival, early postnatal growth and metabolism. Singleton-bearing ewes were evenly allocated to receive Ad.VEGF-A165(5 x 10(10)particles/ml, 10 ml, n =17) or Saline (10 ml, n = 16) injected into each UtA at laparotomy (0.6 gestation). Fetal growth was serially monitored (blind) by ultrasound until delivery. Lambs were weighed and blood-sampled weekly and a glucose tolerance test performed (68d postnatal age). Hepatic DNA/RNA was extracted at necropsy (83d postnatal age) to examine methylation status of eight somatotropic axis genes. ITALIC! IGF1mRNA and protein expression were measured by RT-PCR and radioimmunoassay, respectively. All pregnancies remained viable following Ad.VEGF-A165treatment. Fetal abdominal circumference and renal volume were greater in Ad.VEGF-A165versus Saline groups at 21/28 days (p ≤ 0.04) post-injection. At delivery, gestation length (p = 0.07), lamb birthweight (p = 0.08), umbilical girth (p = 0.06) and plasma glucose (p=0.09) tended to be greater in Ad.VEGF-A165treated lambs. Levels of neonatal intervention required to ensure survival was equivalent between groups. Absolute postnatal growth rate (p = 0.02), insulin area-under-the-curve (p = 0.04) and carcass weight at necropsy (p = 0.04) were increased by Ad.VEGF-A165treatment. There was no impact on markers of insulin sensitivity or methylation/expression of key genes involved in somatic growth. Ad.VEGF-A165gene therapy increased fetal growth in a sheep FGR model and lambs continued to thrive during the neonatal and early postnatal period

The role of different strain backgrounds in bacterial endotoxin-mediated sensitization to neonatal hypoxic-ischemic brain damage

Genetic background is known to influence the outcome in mouse models of human disease, and previous experimental studies have shown strain variability in the neonatal mouse model of hypoxia-ischemia. To further map out this variability, we compared five commonly used mouse strains: C57BL/6, 129SVJ, BALB/c, CD1 and FVB in a pure hypoxic-ischemic setup and following pre-sensitization with lipopolysaccharide (LPS). Postnatal day 7 pups were subjected to unilateral carotid artery occlusion followed by continuous 30 min 8% oxygen exposure at 36 °C. Twelve hours prior, a third of the pups received a single intraperitoneal LPS (0.6 μg/g) or a saline (vehicle) administration, respectively; a further third underwent hypoxia-ischemia alone without preceding injection. Both C57BL/6 and 129SVJ strains showed minimal response to 30min hypoxia-ischemia alone, BALB/c demonstrated a moderate response, and both CD1 and FVB revealed the highest brain damage. LPS pre-sensitization led to substantial increase in overall brain infarction, microglial and astrocyte response and cell death in four of the five strains, with exception of BALB/c that only showed a significant effect with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Saline administration prior to hypoxia-ischemia resulted in an increase in inflammatory-associated markers, particularly in the astroglial activation of C57BL/6 mice, and in combined microglial activation and neuronal cell loss in FVB mice. Finally, two of the four strongly affected strains--C57BL/6 and CD1--revealed pronounced contralateral astrogliosis with a neuroanatomical localization similar to that observed on the occluded hemisphere. Overall, the current findings demonstrate strain differences in response to hypoxia-ischemia alone, to stress associated with vehicle injection, and to LPS-mediated pre-sensitization, which partially explains the high variability seen in the neonatal mouse models of hypoxia-ischemia. These results can be useful in future studies of fetal/neonatal response to inflammation and reduced oxygen-blood supply

BiometryNet: Landmark-based Fetal Biometry Estimation from Standard Ultrasound Planes

Fetal growth assessment from ultrasound is based on a few biometric measurements that are performed manually and assessed relative to the expected gestational age. Reliable biometry estimation depends on the precise detection of landmarks in standard ultrasound planes. Manual annotation can be time-consuming and operator dependent task, and may results in high measurements variability. Existing methods for automatic fetal biometry rely on initial automatic fetal structure segmentation followed by geometric landmark detection. However, segmentation annotations are time-consuming and may be inaccurate, and landmark detection requires developing measurement-specific geometric methods. This paper describes BiometryNet, an end-to-end landmark regression framework for fetal biometry estimation that overcomes these limitations. It includes a novel Dynamic Orientation Determination (DOD) method for enforcing measurement-specific orientation consistency during network training. DOD reduces variabilities in network training, increases landmark localization accuracy, thus yields accurate and robust biometric measurements. To validate our method, we assembled a dataset of 3,398 ultrasound images from 1,829 subjects acquired in three clinical sites with seven different ultrasound devices. Comparison and cross-validation of three different biometric measurements on two independent datasets shows that BiometryNet is robust and yields accurate measurements whose errors are lower than the clinically permissible errors, outperforming other existing automated biometry estimation methods. Code is available at https://github.com/netanellavisdris/fetalbiometry

Perinatal and long term effects of maternal uterine artery adenoviral VEGF-A165 gene therapy in the growth restricted guinea pig fetus

Uterine artery application of adenoviral vascular endothelial growth factor gene therapy (Ad.VEGF-A165) increases uterine blood flow and fetal growth in experimental animals with fetal growth restriction (FGR). Whether Ad.VEGF-A165 reduces lifelong cardiovascular disease risk imposed by FGR remains unknown. Here, pregnant guinea pigs fed 70% normal food intake to induce FGR received Ad.VEGF-A165 (1x1010 viral particles, n=15) or vehicle (n=10), delivered to the external surface of the uterine arteries, in mid-pregnancy. Ad libitum fed controls received vehicle only (n=14). Litter size, gestation length, and perinatal mortality were similar in control, untreated FGR and FGR+Ad.VEGF-A165 animals. Compared to controls, birth weight was lower in male but higher in female pups following maternal nutrient restriction, whilst both male and female FGR+Ad.VEGF-A165 pups were heavier than untreated FGR pups (P<0.05 ANOVA). Postnatal weight gain was 10-20% greater in female FGR+Ad.VEGF-A165 than untreated FGR pups, depending on age, although neither group differed from controls. Maternal nutrient restriction reduced heart weight in adult female offspring, irrespective of Ad.VEGF-A165 treatment, but did not alter ventricular wall thickness. In males, postnatal weight gain and heart morphology were not affected by maternal treatment. Neither systolic, diastolic nor mean arterial pressure, adrenal weight, basal or challenged plasma cortisol were affected by maternal undernutrition or Ad.VEGF-A165 in either sex. Therefore, increased fetal growth conferred by maternal uterine artery Ad.VEGF-A165 is sustained postnatally in FGR female guinea pigs. In this study we did not find evidence for an effect of maternal nutrient restriction or Ad.VEGF-A165 therapy on adult offspring blood pressure

Dimensionless Squared Jerk - An Objective Differential to Assess Experienced and Novice Probe Movement in Obstetric Ultrasound

Objective: Widely accepted, validated and objective measures of ultrasound competency have not been established for clinical practice. Outcomes of training curricula are often based on arbitrary thresholds, such as the number of clinical cases completed. We aimed to define metrics against which competency could be measured. Method: We undertook a prospective, observational study of obstetric sonographers at a UK University Teaching Hospital. Participants were either experienced in fetal ultrasound (n = 10, >200 ultrasound examinations) or novice operators (n = 10, <25 ultrasound examinations). We recorded probe motion data during the performance of biometry on a commercially available mid‐trimester phantom. Results: We report that Dimensionless squared jerk, an assessment of deliberate hand movements, independent of movement duration, extent, spurious peaks and dimension differed significantly different between groups, 19.26 (SD 3.02) for experienced and 22.08 (SD 1.05, p = 0.01) for novice operators, respectively. Experienced operator performance, was associated with a shorter time to task completion of 176.46 s (SD 47.31) compared to 666.94 s (SD 490.36, p = 0.0004) for novice operators. Probe travel was also shorter for experienced operators 521.23 mm (SD 27.41) versus 2234.82 mm (SD 188.50, p = 0.007) when compared to novice operators. Conclusion: Our results represent progress toward an objective assessment of technical skill in obstetric ultrasound. Repeating this methodology in a clinical environment may develop insight into the generalisability of these findings into ultrasound education

Total uterine artery blood volume flow rate in nulliparous women (TVFR) is associated with birthweight and gestation at delivery

OBJECTIVES: To investigate the relationship between total uterine artery blood volume flow rate (TVFR) and birthweight and gestation at delivery and to establish normal ranges of TVFR through pregnancy. METHODS: A prospective cohort study at University College London Hospital, in which 334 nulliparous women booking for antenatal care had measurement of TVFR by transabdominal ultrasound at 12, 20 and 24 weeks. RESULTS: 551 scans were performed. There was a significant and positive correlation between total uterine blood volume flow at 11-13 weeks (TVFR1) and 22-26 weeks (TVFR2) and birthweight. For every 100 unit increase in TVFR1 and TVFR2, there was a 45 g and 27 g increase in birthweight respectively. There was also a positive association between TVFR1 and gestation at delivery, with a 1.4 day increase in gestation for every 100 unit increase of TVFR1. CONCLUSION: Ultrasound measurement of TVFR in the first trimester is significantly associated with both birth weight and gestation at delivery

Cervical gene delivery of the antimicrobial peptide, Human β‐defensin (HBD)-3, in a mouse model of ascending infection-related preterm birth

Approximately 40% of preterm births are preceded by microbial invasion of the intrauterine space; ascent from the vagina being the most common pathway. Within the cervical canal, antimicrobial peptides and proteins (AMPs) are important components of the cervical barrier which help to prevent ascending vaginal infection. We investigated whether expression of the AMP, human β-defensin-3 (HBD3), in the cervical mucosa of pregnant mice could prevent bacterial ascent from the vagina into the uterine cavity. An adeno-associated virus vector containing both the HBD3 gene and GFP transgene (AAV8 HBD3.GFP) or control AAV8 GFP, was administered intravaginally into E13.5 pregnant mice. Ascending infection was induced at E16.5 using bioluminescent Escherichia coli (E. coli K1 A192PP-lux2). Bioluminescence imaging showed bacterial ascent into the uterine cavity, inflammatory events that led to premature delivery and a reduction in pups born alive, compared with uninfected controls. Interestingly, a significant reduction in uterine bioluminescence in the AAV8 HBD3.GFP-treated mice was observed 24 h post-E. coli infection, compared to AAV8 GFP treated mice, signifying reduced bacterial ascent in AAV8 HBD3.GFP-treated mice. Furthermore, there was a significant increase in the number of living pups in AAV HBD3.GFP-treated mice. We propose that HBD3 may be a potential candidate for augmenting cervical innate immunity to prevent ascending infection-related preterm birth and its associated neonatal consequences

Maternal PlGF and umbilical Dopplers predict pregnancy outcomes at diagnosis of early-onset fetal growth restriction

BACKGROUNDSevere, early-onset fetal growth restriction (FGR) causes significant fetal and neonatal mortality and morbidity. Predicting the outcome of affected pregnancies at the time of diagnosis is difficult, thus preventing accurate patient counseling. We investigated the use of maternal serum protein and ultrasound measurements at diagnosis to predict fetal or neonatal death and 3 secondary outcomes: fetal death or delivery at or before 28+0 weeks, development of abnormal umbilical artery (UmA) Doppler velocimetry, and slow fetal growth.METHODSWomen with singleton pregnancies (n = 142, estimated fetal weights [EFWs] below the third centile, less than 600 g, 20+0 to 26+6 weeks of gestation, no known chromosomal, genetic, or major structural abnormalities) were recruited from 4 European centers. Maternal serum from the discovery set (n = 63) was analyzed for 7 proteins linked to angiogenesis, 90 additional proteins associated with cardiovascular disease, and 5 proteins identified through pooled liquid chromatography and tandem mass spectrometry. Patient and clinician stakeholder priorities were used to select models tested in the validation set (n = 60), with final models calculated from combined data.RESULTSThe most discriminative model for fetal or neonatal death included the EFW z score (Hadlock 3 formula/Marsal chart), gestational age, and UmA Doppler category (AUC, 0.91; 95% CI, 0.86-0.97) but was less well calibrated than the model containing only the EFW z score (Hadlock 3/Marsal). The most discriminative model for fetal death or delivery at or before 28+0 weeks included maternal serum placental growth factor (PlGF) concentration and UmA Doppler category (AUC, 0.89; 95% CI, 0.83-0.94).CONCLUSIONUltrasound measurements and maternal serum PlGF concentration at diagnosis of severe, early-onset FGR predicted pregnancy outcomes of importance to patients and clinicians.TRIAL REGISTRATIONClinicalTrials.gov NCT02097667.FUNDINGThe European Union, Rosetrees Trust, Mitchell Charitable Trust