Placental pathology and fetal growth outcomes in pregnancies complicated by maternal obesity.

BACKGROUND: The rising prevalence of maternal obesity presents a significant health concern because of the possible implications for obstetric complications and neonatal outcomes. Understanding the impact of obesity on placental structure and function as well as fetal growth and infant outcomes is important to improve the care of these potentially high-risk pregnancies. This study aimed to determine the effect of elevated maternal BMI on histopathologic patterns of placental injury and its consequences on fetal growth. METHODS: Data were collected from an ongoing cohort of maternal-infant dyads in the UCSD Obstetric Registry spanning 2011-2020. Maternal characteristics, including BMI, hypertensive disease and diabetes, placental gross and histopathology, and infant characteristics, including sex and birthweight, were recorded and analyzed. ANOVA and chi-square tests were used in initial analyses, followed by log-binomial and linear regression models adjusted for relevant confounders to determine associations between maternal BMI, specific patterns of placental injury, and infant birthweight percentiles. RESULTS: Among 1366 maternal-infant dyads, placentas from mothers with overweight and obesity were heavier and demonstrated higher adjusted relative risks of chronic villitis (CV), decidual vasculopathy, intervillous thrombosis, and normoblastemia. Placental efficiency, determined by fetal-placental weight ratio, was decreased with increasing BMI. Maternal obesity was associated with higher rates of preterm birth and higher birthweight percentiles. Multiple placental lesions, including maternal (MVM) and fetal vascular malperfusion (FVM), exhibited significant effects on birthweight percentiles; however, only MVM showed a differential effect based on maternal obesity. CONCLUSIONS: Presence of obesity in pregnancy is associated with increased rates of placental patterns of injury, decreased placental efficiency, and increased birthweight percentiles. While placental lesions, such as CV, have the potential to negatively impact fetal growth, the resulting birthweight percentiles demonstrate a more complex relationship between maternal obesity and fetal growth, that likely involves placental and fetal adaptation to the altered in utero environment.

iPSC-based modeling of preeclampsia identifies epigenetic defects in extravillous trophoblast differentiation.

Preeclampsia (PE) is a hypertensive pregnancy disorder with increased risk of maternal and fetal morbidity and mortality. Abnormal extravillous trophoblast (EVT) development and function is considered to be the underlying cause of PE, but has not been previously modeled in vitro. We previously derived induced pluripotent stem cells (iPSCs) from placentas of PE patients and characterized abnormalities in formation of syncytiotrophoblast and responses to changes in oxygen tension. In this study, we converted these primed iPSC to naïve iPSC, and then derived trophoblast stem cells (TSCs) and EVT to evaluate molecular mechanisms underlying PE. We found that primed (but not naïve) iPSC-derived PE-EVT have reduced surface HLA-G, blunted invasive capacity, and altered EVT-specific gene expression. These abnormalities correlated with promoter hypermethylation of genes associated with the epithelial-mesenchymal transition pathway, specifically in primed-iPSC derived PE-EVT. Our findings indicate that abnormal epigenetic regulation might play a role in PE pathogenesis.

Postcontractile blood oxygenation level-dependent (BOLD) response in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is characterized by a progressive replacement of muscle by fat and fibrous tissue, muscle weakness, and loss of functional abilities. Impaired vasodilatory and blood flow responses to muscle activation have also been observed in DMD and associated with mislocalization of neuronal nitric oxide synthase mu (nNOSµ) from the sarcolemma. The objective of this study was to determine whether the postcontractile blood oxygen level-dependent (BOLD) MRI response is impaired in DMD and correlated with established markers of disease severity in DMD, including MRI muscle fat fraction (FF) and clinical functional measures. Young boys with DMD (n = 16, 5-14 yr) and unaffected controls (n = 16, 5-14 yr) were evaluated using postcontractile BOLD, FF, and functional assessments. The BOLD response was measured following five brief (2 s) maximal voluntary dorsiflexion contractions, each separated by 1 min of rest. FFs from the anterior compartment lower leg muscles were quantified via chemical shift-encoded imaging. Functional abilities were assessed using the 10 m walk/run and the 6-min walk distance (6MWD). The peak BOLD responses in the tibialis anterior and extensor digitorum longus were reduced (P < 0.001) in DMD compared with controls. Furthermore, the anterior compartment peak BOLD response correlated with function (6MWD ρ = 0.87, P < 0.0001; 10 m walk/run time ρ = -0.78, P < 0.001) and FF (ρ = -0.52, P = 0.05). The reduced postcontractile BOLD response in DMD may reflect impaired microvascular function. The relationship observed between the postcontractile peak BOLD response and functional measures and FF suggests that the BOLD response is altered with disease severity in DMD.NEW & NOTEWORTHY This study examined the postcontractile blood oxygen level-dependent (BOLD) response in boys with Duchenne muscular dystrophy (DMD) and unaffected controls, and correlated this measure to markers of disease severity. Our findings indicate that the postcontractile BOLD response is impaired in DMD after brief muscle contractions, is correlated to disease severity, and may be valuable to implement in future studies to evaluate treatments targeting microvascular function in DMD.

Upper and Lower Extremities in Duchenne Muscular Dystrophy Evaluated with Quantitative MRI and Proton MR Spectroscopy in a Multicenter Cohort.

Background Upper extremity MRI and proton MR spectroscopy are increasingly considered to be outcome measures in Duchenne muscular dystrophy (DMD) clinical trials. Purpose To demonstrate the feasibility of acquiring upper extremity MRI and proton (1H) MR spectroscopy measures of T2 and fat fraction in a large, multicenter cohort (ImagingDMD) of ambulatory and nonambulatory individuals with DMD; compare upper and lower extremity muscles by using MRI and 1H MR spectroscopy; and correlate upper extremity MRI and 1H MR spectroscopy measures to function. Materials and Methods In this prospective cross-sectional study, MRI and 1H MR spectroscopy and functional assessment data were acquired from participants with DMD and unaffected control participants at three centers (from January 28, 2016, to April 24, 2018). T2 maps of the shoulder, upper arm, forearm, thigh, and calf were generated from a spin-echo sequence (repetition time msec/echo time msec, 3000/20-320). Fat fraction maps were generated from chemical shift-encoded imaging (eight echo times). Fat fraction and 1H2O T2 in the deltoid and biceps brachii were measured from single-voxel 1H MR spectroscopy (9000/11-243). Groups were compared by using Mann-Whitney test, and relationships between MRI and 1H MR spectroscopy and arm function were assessed by using Spearman correlation. Results This study evaluated 119 male participants with DMD (mean age, 12 years ± 3 [standard deviation]) and 38 unaffected male control participants (mean age, 12 years ± 3). Deltoid and biceps brachii muscles were different in participants with DMD versus control participants in all age groups by using quantitative T2 MRI (P < .001) and 1H MR spectroscopy fat fraction (P < .05). The deltoid, biceps brachii, and triceps brachii were affected to the same extent (P > .05) as the soleus and medial gastrocnemius. Negative correlations were observed between arm function and MRI (T2: range among muscles, ρ = -0.53 to -0.73 [P < .01]; fat fraction, ρ = -0.49 to -0.70 [P < .01]) and 1H MR spectroscopy fat fraction (ρ = -0.64 to -0.71; P < .01). Conclusion This multicenter study demonstrated early and progressive involvement of upper extremity muscles in Duchenne muscular dystrophy (DMD) and showed the feasibility of MRI and 1H MR spectroscopy to track disease progression over a wide range of ages in participants with DMD. © RSNA, 2020 Online supplemental material is available for this article.

Modeling disease trajectory in Duchenne muscular dystrophy.

OBJECTIVE: To quantify disease progression in individuals with Duchenne muscular dystrophy (DMD) using magnetic resonance biomarkers of leg muscles. METHODS: MRI and magnetic resonance spectroscopy (MRS) biomarkers were acquired from 104 participants with DMD and 51 healthy controls using a prospective observational study design with patients with DMD followed up yearly for up to 6 years. Fat fractions (FFs) in vastus lateralis and soleus muscles were determined with 1H MRS. MRI quantitative T2 (qT2) values were measured for 3 muscles of the upper leg and 5 muscles of the lower leg. Longitudinal changes in biomarkers were modeled with a cumulative distribution function using a nonlinear mixed-effects approach. RESULTS: MRS FF and MRI qT2 increased with DMD disease duration, with the progression time constants differing markedly between individuals and across muscles. The average age at half-maximal muscle involvement (µ) occurred 4.8 years earlier in vastus lateralis than soleus, and these measures were strongly associated with loss-of-ambulation age. Corticosteroid treatment was found to delay µ by 2.5 years on average across muscles, although there were marked differences between muscles with more slowly progressing muscles showing larger delay. CONCLUSIONS: MRS FF and MRI qT2 provide sensitive noninvasive measures of DMD progression. Modeling changes in these biomarkers across multiple muscles can be used to detect and monitor the therapeutic effects of corticosteroids on disease progression and to provide prognostic information on functional outcomes. This modeling approach provides a method to transform these MRI biomarkers into well-understood metrics, allowing concise summaries of DMD disease progression at individual and population levels. CLINICALTRIALSGOV IDENTIFIER: NCT01484678.

MR biomarkers predict clinical function in Duchenne muscular dystrophy.

OBJECTIVE: To investigate the potential of lower extremity magnetic resonance (MR) biomarkers to serve as endpoints in clinical trials of therapeutics for Duchenne muscular dystrophy (DMD) by characterizing the longitudinal progression of MR biomarkers over 48 months and assessing their relationship to changes in ambulatory clinical function. METHODS: One hundred sixty participants with DMD were enrolled in this longitudinal, natural history study and underwent MR data acquisition of the lower extremity muscles to determine muscle fat fraction (FF) and MRI T2 biomarkers of disease progression. In addition, 4 tests of ambulatory function were performed. Participants returned for follow-up data collection at 12, 24, 36, and 48 months. RESULTS: Longitudinal analysis of the MR biomarkers revealed that vastus lateralis FF, vastus lateralis MRI T2, and biceps femoris long head MRI T2 biomarkers were the fastest progressing biomarkers over time in this primarily ambulatory cohort. Biomarker values tended to demonstrate a nonlinear, sigmoidal trajectory over time. The lower extremity biomarkers predicted functional performance 12 and 24 months later, and the magnitude of change in an MR biomarker over time was related to the magnitude of change in function. Vastus lateralis FF, soleus FF, vastus lateralis MRI T2, and biceps femoris long head MRI T2 were the strongest predictors of future loss of function, including loss of ambulation. CONCLUSIONS: This study supports the strong relationship between lower extremity MR biomarkers and measures of clinical function, as well as the ability of MR biomarkers, particularly those from proximal muscles, to predict future ambulatory function and important clinical milestones. CLINICALTRIALSGOV IDENTIFIER: NCT01484678.

Commonly available outcome measures for use in Indian boys with Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder. It is still an incurable disease and many clinical trials are going on to find the cure for this disease. There is a need for sensitive and reliable measures for detecting the disease progression. This manuscript focuses on reviewing the different outcome measures which can be used in the Indian DMD patients.

Longitudinal timed function tests in Duchenne muscular dystrophy: ImagingDMD cohort natural history.

INTRODUCTION: Tests of ambulatory function are common clinical trial endpoints in Duchenne muscular dystrophy (DMD). Using these tests, the ImagingDMD study has generated a large data set that can describe the contemporary natural history of DMD in 5-12.9-year-olds. METHODS: Ninety-two corticosteroid-treated boys with DMD and 45 controls participated in this longitudinal study. Participants performed the 6-minute walk test (6MWT) and timed function tests (TFT: 10-m walk/run, climbing 4 stairs, supine to stand). RESULTS: Boys with DMD had impaired functional performance even at 5-6.9 years old. Boys older than 7 had significant declines in function over 1 year for 10-m walk/run and 6MWT. Eighty percent of participants could perform all functional tests at 9 years old. TFTs appear to be slightly more responsive and predictive of disease progression than the 6MWT in 7-12.9 year olds. DISCUSSION: This study provides insight into the contemporary natural history of key functional endpoints in DMD. Muscle Nerve 58: 631-638, 2018.