Gestational dating by metabolic profile at birth: a California cohort study.

BackgroundAccurate gestational dating is a critical component of obstetric and newborn care. In the absence of early ultrasound, many clinicians rely on less accurate measures, such as last menstrual period or symphysis-fundal height during pregnancy, or Dubowitz scoring or the Ballard (or New Ballard) method at birth. These measures often underestimate or overestimate gestational age and can lead to misclassification of babies as born preterm, which has both short- and long-term clinical care and public health implications.ObjectiveWe sought to evaluate whether metabolic markers in newborns measured as part of routine screening for treatable inborn errors of metabolism can be used to develop a population-level metabolic gestational dating algorithm that is robust despite intrauterine growth restriction and can be used when fetal ultrasound dating is not available. We focused specifically on the ability of these markers to differentiate preterm births (PTBs) (<37 weeks) from term births and to assign a specific gestational age in the PTB group.Study designWe evaluated a cohort of 729,503 singleton newborns with a California birth in 2005 through 2011 who had routine newborn metabolic screening and fetal ultrasound dating at 11-20 weeks' gestation. Using training and testing subsets (divided in a ratio of 3:1) we evaluated the association among PTB, target newborn characteristics, acylcarnitines, amino acids, thyroid-stimulating hormone, 17-hydroxyprogesterone, and galactose-1-phosphate-uridyl-transferase. We used multivariate backward stepwise regression to test for associations and linear discriminate analyses to create a linear function for PTB and to assign a specific week of gestation. We used sensitivity, specificity, and positive predictive value to evaluate the performance of linear functions.ResultsAlong with birthweight and infant age at test, we included 35 of the 51 metabolic markers measured in the final multivariate model comparing PTBs and term births. Using a linear discriminate analyses-derived linear function, we were able to sort PTBs and term births accurately with sensitivities and specificities of ≥95% in both the training and testing subsets. Assignment of a specific week of gestation in those identified as PTBs resulted in the correct assignment of week ±2 weeks in 89.8% of all newborns in the training and 91.7% of those in the testing subset. When PTB rates were modeled using the metabolic dating algorithm compared to fetal ultrasound, PTB rates were 7.15% vs 6.11% in the training subset and 7.31% vs 6.25% in the testing subset.ConclusionWhen considered in combination with birthweight and hours of age at test, metabolic profile evaluated within 8 days of birth appears to be a useful measure of PTB and, among those born preterm, of specific week of gestation ±2 weeks. Dating by metabolic profile may be useful in instances where there is no fetal ultrasound due to lack of availability or late entry into care

Combined Diffusion-Relaxometry MRI to Identify Dysfunction in the Human Placenta

Purpose: A combined diffusion-relaxometry MR acquisition and analysis pipeline for in-vivo human placenta, which allows for exploration of coupling between T2* and apparent diffusion coefficient (ADC) measurements in a sub 10 minute scan time. Methods: We present a novel acquisition combining a diffusion prepared spin-echo with subsequent gradient echoes. The placentas of 17 pregnant women were scanned in-vivo, including both healthy controls and participants with various pregnancy complications. We estimate the joint T2*-ADC spectra using an inverse Laplace transform. Results: T2*-ADC spectra demonstrate clear quantitative separation between normal and dysfunctional placentas. Conclusions: Combined T2*-diffusivity MRI is promising for assessing fetal and maternal health during pregnancy. The T2*-ADC spectrum potentially provides additional information on tissue microstructure, compared to measuring these two contrasts separately. The presented method is immediately applicable to the study of other organs

Fetal whole-heart 4D imaging using motion-corrected multi-planar real-time MRI

Purpose: To develop a MRI acquisition and reconstruction framework for volumetric cine visualisation of the fetal heart and great vessels in the presence of maternal and fetal motion. Methods: Four-dimensional depiction was achieved using a highly-accelerated multi-planar real-time balanced steady state free precession acquisition combined with retrospective image-domain techniques for motion correction, cardiac synchronisation and outlier rejection. The framework was evaluated and optimised using a numerical phantom, and evaluated in a study of 20 mid- to late-gestational age human fetal subjects. Reconstructed cine volumes were evaluated by experienced cardiologists and compared with matched ultrasound. A preliminary assessment of flow-sensitive reconstruction using the velocity information encoded in the phase of dynamic images is included. Results: Reconstructed cine volumes could be visualised in any 2D plane without the need for highly-specific scan plane prescription prior to acquisition or for maternal breath hold to minimise motion. Reconstruction was fully automated aside from user-specified masks of the fetal heart and chest. The framework proved robust when applied to fetal data and simulations confirmed that spatial and temporal features could be reliably recovered. Expert evaluation suggested the reconstructed volumes can be used for comprehensive assessment of the fetal heart, either as an adjunct to ultrasound or in combination with other MRI techniques. Conclusion: The proposed methods show promise as a framework for motion-compensated 4D assessment of the fetal heart and great vessels

Assessing within-subject rates of change of placental MRI diffusion metrics in normal pregnancy

Purpose Studying placental development informs when development is abnormal. Most placental MRI studies are cross-sectional and do not study the extent of individual variability throughout pregnancy. We aimed to explore how diffusion MRI measures of placental function and microstructure vary in individual healthy pregnancies throughout gestation. Methods Seventy-nine pregnant, low-risk participants (17 scanned twice and 62 scanned once) were included. T2-weighted anatomical imaging and a combined multi-echo spin-echo diffusion-weighted sequence were acquired at 3 T. Combined diffusion–relaxometry models were performed using both a -ADC and a bicompartmental -intravoxel-incoherent-motion ( ) model fit. Results There was a significant decline in placental and ADC (both P < 0.01) over gestation. These declines are consistent in individuals for (covariance = −0.47), but not ADC (covariance = −1.04). The model identified a consistent decline in individuals over gestation in from both the perfusing and diffusing placental compartments, but not in ADC values from either. The placental perfusing compartment fraction increased over gestation (P = 0.0017), but this increase was not consistent in individuals (covariance = 2.57). Conclusion Whole placental and ADC values decrease over gestation, although only values showed consistent trends within subjects. There was minimal individual variation in rates of change of values from perfusing and diffusing placental compartments, whereas trends in ADC values from these compartments were less consistent. These findings probably relate to the increased complexity of the bicompartmental model, and differences in how different placental regions evolve at a microstructural level. These placental MRI metrics from low-risk pregnancies provide a useful benchmark for clinical cohorts

Registration of 3D fetal neurosonography and MRI.

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

Abnormal Cortical Development after Premature Birth Shown by Altered Allometric Scaling of Brain Growth

BACKGROUND: We postulated that during ontogenesis cortical surface area and cerebral volume are related by a scaling law whose exponent gives a quantitative measure of cortical development. We used this approach to investigate the hypothesis that premature termination of the intrauterine environment by preterm birth reduces cortical development in a dose-dependent manner, providing a neural substrate for functional impairment. METHODS AND FINDINGS: We analyzed 274 magnetic resonance images that recorded brain growth from 23 to 48 wk of gestation in 113 extremely preterm infants born at 22 to 29 wk of gestation, 63 of whom underwent neurodevelopmental assessment at a median age of 2 y. Cortical surface area was related to cerebral volume by a scaling law with an exponent of 1.29 (95% confidence interval, 1.25–1.33), which was proportional to later neurodevelopmental impairment. Increasing prematurity and male gender were associated with a lower scaling exponent (p < 0.0001) independent of intrauterine or postnatal somatic growth. CONCLUSIONS: Human brain growth obeys an allometric scaling relation that is disrupted by preterm birth in a dose-dependent, sexually dimorphic fashion that directly parallels the incidence of neurodevelopmental impairments in preterm infants. This result focuses attention on brain growth and cortical development during the weeks following preterm delivery as a neural substrate for neurodevelopmental impairment after premature delivery

Stresses and strains on the human fetal skeleton during development

Mechanical forces generated by fetal kicks and movements result in stimulation of the fetal skeleton in the form of stress and strain. This stimulation is known to be critical for prenatal musculoskeletal development; indeed, abnormal or absent movements have been implicated in multiple congenital disorders. However, the mechanical stress and strain experienced by the developing human skeleton in utero have never before been characterized. Here, we quantify the biomechanics of fetal movements during the second half of gestation by modelling fetal movements captured using novel cine-magnetic resonance imaging technology. By tracking these movements, quantifying fetal kick and muscle forces, and applying them to three-dimensional geometries of the fetal skeleton, we test the hypothesis that stress and strain change over ontogeny. We find that fetal kick force increases significantly from 20 to 30 weeks' gestation, before decreasing towards term. However, stress and strain in the fetal skeleton rises significantly over the latter half of gestation. This increasing trend with gestational age is important because changes in fetal movement patterns in late pregnancy have been linked to poor fetal outcomes and musculoskeletal malformations. This research represents the first quantification of kick force and mechanical stress and strain due to fetal movements in the human skeleton in utero, thus advancing our understanding of the biomechanical environment of the uterus. Further, by revealing a potential link between fetal biomechanics and skeletal malformations, our work will stimulate future research in tissue engineering and mechanobiology

Slice-level diffusion encoding for motion and distortion correction

Advances in microstructural modelling are leading to growing requirements on diffusion MRI acquisitions, namely sensitivity to smaller structures and better resolution of the geometric orientations. The resulting acquisitions contain highly attenuated images that present particular challenges when there is motion and geometric distortion. This study proposes to address these challenges by breaking with the conventional one-volume-one-encoding paradigm employed in conventional diffusion imaging using single-shot Echo Planar Imaging. By enabling free choice of the diffusion encoding on the slice level, a higher temporal sampling of slices with low b-value can be achieved. These allow more robust motion correction, and in combination with a second reversed phase-encoded echo, also dynamic distortion correction. These proposed advances are validated on phantom and adult experiments and employed in a study of eight foetal subjects. Equivalence in obtained diffusion quantities with the conventional method is demonstrated as well as benefits in distortion and motion correction. The resulting capability can be combined with any acquisition parameters including multiband imaging and allows application to diffusion MRI studies in general