Remote patient monitoring for management of diabetes mellitus in pregnancy is associated with improved maternal and neonatal outcomes.

BACKGROUND: Diabetes mellitus is a common medical complication of pregnancy, and its treatment is complex. Recent years have seen an increase in the application of mobile health tools and advanced technologies, such as remote patient monitoring, with the aim of improving care for diabetes mellitus in pregnancy. Previous studies of these technologies for the treatment of diabetes in pregnancy have been small and have not clearly shown clinical benefit with implementation. OBJECTIVE: Remote patient monitoring allows clinicians to monitor patients' health data (such as glucose values) in near real-time, between office visits, to make timely adjustments to care. Our objective was to determine if using remote patient monitoring for the management of diabetes in pregnancy leads to an improvement in maternal and neonatal outcomes. STUDY DESIGN: This was a retrospective cohort study of pregnant patients with diabetes mellitus managed by the maternal-fetal medicine practice at one academic institution between October 2019 and April 2021. This practice transitioned from paper-based blood glucose logs to remote patient monitoring in February 2020. Remote patient monitoring options included (1) device integration with Bluetooth glucometers that automatically uploaded measured glucose values to the patient's Epic MyChart application or (2) manual entry in which patients manually logged their glucose readings into their MyChart application. Values in the MyChart application directly transferred to the patient's electronic health record for review and management by clinicians. In total, 533 patients were studied. We compared 173 patients managed with paper logs to 360 patients managed with remote patient monitoring (176 device integration and 184 manual entry). Our primary outcomes were composite maternal morbidity (which included third- and fourth-degree lacerations, chorioamnionitis, postpartum hemorrhage requiring transfusion, postpartum hysterectomy, wound infection or separation, venous thromboembolism, and maternal admission to the intensive care unit) and composite neonatal morbidity (which included umbilical cord pH <7.00, 5 minute Apgar score <7, respiratory morbidity, hyperbilirubinemia, meconium aspiration, intraventricular hemorrhage, necrotizing enterocolitis, sepsis, pneumonia, seizures, hypoxic ischemic encephalopathy, shoulder dystocia, trauma, brain or body cooling, and neonatal intensive care unit admission). Secondary outcomes were measures of glycemic control and the individual components of the primary composite outcomes. We also performed a secondary analysis in which the patients who used the two different remote patient monitoring options (device integration vs manual entry) were compared. Chi-square, Fisher's exact, 2-sample t, and Mann-Whitney tests were used to compare the groups. A result was considered statistically significant at P<.05. RESULTS: Maternal baseline characteristics were not significantly different between the remote patient monitoring and paper groups aside from a slightly higher baseline rate of chronic hypertension in the remote patient monitoring group (6.1% vs 1.2%; P=.011). The primary outcomes of composite maternal and composite neonatal morbidity were not significantly different between the groups. However, remote patient monitoring patients submitted more glucose values (177 vs 146; P=.008), were more likely to achieve glycemic control in target range (79.2% vs 52.0%; P<.0001), and achieved the target range sooner (median, 3.3 vs 4.1 weeks; P=.025) than patients managed with paper logs. This was achieved without increasing in-person visits. Remote patient monitoring patients had lower rates of preeclampsia (5.8% vs 15.0%; P=.0006) and their infants had lower rates of neonatal hypoglycemia in the first 24 hours of life (29.8% vs 51.7%; P<.0001). CONCLUSION: Remote patient monitoring for the management of diabetes mellitus in pregnancy is superior to a traditional paper-based approach in achieving glycemic control and is associated with improved maternal and neonatal outcomes.

Application of telemedicine video visits in a maternal-fetal medicine practice at the epicenter of the COVID-19 pandemic.

BACKGROUND: Telemedicine in obstetrics has mostly been described in the rural areas that have limited access to subspecialties. During the COVID-19 pandemic, health systems rapidly expanded telemedicine services for urgent and nonurgent healthcare delivery, even in urban settings. The New York University health system implemented a prompt systemwide expansion of video-enabled telemedicine visits, increasing telemedicine to >8000 visits daily within 6 weeks of the beginning of the pandemic. There are limited studies that explore patient and provider satisfaction of telemedicine visits in obstetrical patients during the COVID-19 epidemic, particularly in the United States. OBJECTIVE: This study aimed to evaluate both the patients' and the providers' satisfaction with the administration of maternal-fetal medicine services through telemedicine and to identify the factors that drive the patients' desire for future obstetrical telemedicine services. STUDY DESIGN: A cross-sectional survey was administered to patients who completed a telemedicine video visit with the Division of Maternal-Fetal Medicine at the New York University Langone Hospital-Long Island from March 19, 2020, to May 26, 2020. A 10-question survey assessing the patients' digital experience and desire for future use was either administered by telephone or self-administered by the patients via a link after obtaining verbal consent. The survey responses were scored from 1-strongly disagree to 5-strongly agree. We analyzed the demographics and survey responses of the patients who agreed to vs those who answered neutral or disagree to the question "I would like telehealth to be an option for future obstetric visits." The providers also answered a similar 10-question survey. The median scores were compared using appropriate tests. A P value of <.05 was considered significant. RESULTS: A total of 253 patients participated in 433 telemedicine visits, and 165 patients completed the survey, resulting in a 65% survey response rate. Overall, there were high rates of patient satisfaction in all areas assessed. Those who desired future telemedicine had significantly greater agreeability that they were able to see and hear their provider easily (5 [4.5, 5] vs 5 [4, 5]; P=.014) and that the lack of physical activity was not an issue (5 [4, 5] vs 5 [4, 5]; P=.032). They were also more likely to agree that the telemedicine visits were as good as in-person visits (4 [3, 5] vs 3 [2, 3]; P<.001) and that telehealth made it easier for them to see doctors or specialists (5 [4, 5] vs 3 [2, 3]; P<.001). The patients seeking consults for poor obstetrical history were more likely to desire future telemedicine compared with other visit types (19 (90%) vs 2 (10%); P=.05). Provider survey responses also demonstrated high levels of satisfaction, with 83% agreeing that they would like telemedicine to be an option for future obstetrical visits. CONCLUSION: We demonstrated that maternal-fetal medicine obstetrical patients and providers were highly satisfied with the implementation of telemedicine during the initial wave of the COVID-19 pandemic and a majority of them desire telemedicine as an option for future visits. A patient's desire for future telemedicine visits was significantly affected by their digital experience, the perception of a lack of need for physical contact, perceived time saved on travel, and access to healthcare providers. Health systems need to continue to improve healthcare delivery and invest in innovative solutions to conduct physical examinations remotely.

FAM213A is linked to prognostic significance in acute myeloid leukemia through regulation of oxidative stress and myelopoiesis.

Accurate prediction of malignancies is important in choosing therapeutic strategies. Although there are many genetic and cytogenetic prognostic factors for acute myeloid leukemia (AML), prognosis is difficult to predict because of the heterogeneity of AML. Prognostic factors, including messenger RNA (mRNA) expression, have been determined for other malignancies, but not for AML. A total of 402 patients from The Cancer Genome Atlas, GSE12417 (GPL96, 97), and GSE12417 (GPL570) were included in this study. In Kaplan-Meier curve analyses, high expression of family with sequence similarity 213 member A (FAM213A), which activates antioxidant proteins, was associated with worse prognosis of AML. Similar to the results of the survival curve, C-indices and area under the curve values were high. Current prognostic factors of AML, unlike those of other cancers, do not take mRNA expression into consideration. Thus, the development of mRNA-based prognostic factors would be beneficial for accurate prediction of the survival of AML patients. Additionally, in vivo validation using zebrafish revealed that fam213a is important for myelopoiesis at the developmental stage and is a negative regulator of the p53 tumor suppressor gene. The findings implicate fam213a as a novel prognostic factor for AML patients.

Identification of factors associated with delayed treatment of obstetric hypertensive emergencies.

BACKGROUND: Obstetric hypertensive emergency is defined as having systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥110 mm Hg, confirmed 15 minutes apart. The American College of Obstetricians and Gynecologists recommends that acute-onset, severe hypertension be treated with first line-therapy (intravenous labetalol, intravenous hydralazine or oral nifedipine) within 60 minutes to reduce risk of maternal morbidity and death. OBJECTIVE: Our objective was to identify barriers that lead to delayed treatment of obstetric hypertensive emergency. STUDY DESIGN: A retrospective cohort study was performed that compared women who were treated appropriately within 60 minutes vs those with delay in first-line therapy. We identified 604 patients with discharge diagnoses of chronic hypertension, gestational hypertension, or preeclampsia using International Classification of Diseases-10 codes and obstetric antihypertensive usage in a pharmacy database at 1 academic institution from January 2017 through June 2018. Of these, 267 women (44.2%) experienced obstetric hypertensive emergency in the intrapartum period or within 2 days of delivery; the results from 213 women were used for analysis. We evaluated maternal characteristics, presenting symptoms and circumstances, timing of hypertensive emergency, gestational age at presentation, and administered medications. Chi square, Fisher's exact, Wilcoxon rank-sum, and sample t-tests were used to compare the 2 groups. Univariable logistic regression was applied to determine predictors of delayed treatment. Multivariable regression model was also performed; C-statistic and Hosmer and Lemeshow goodness-of-fit test were used to assess the model fit. A result was considered statistically significant at P<.05. RESULTS: Of the 213 women, 110 (51.6%) had delayed treatment vs 103 (48.4%) who were treated within 60 minutes. Patients who had delayed treatment were 3.2 times more likely to have an initial blood pressure in the nonsevere range vs those who had timely treatment (odds ratio, 3.24; 95% confidence interval, 1.85-5.68). Timeliness of treatment was associated with presence or absence of preeclampsia symptoms; patients without preeclampsia symptoms were 2.7 times more likely to have delayed treatment (odds ratio, 2.68; 95% confidence interval, 1.50-4.80). Patients with hypertensive emergencies that occurred overnight between 10 pm and 6 am were 2.7 times more likely to have delayed treatment vs those emergencies that occurred between 6 am and 10 pm (odds ratio, 2.72; 95% confidence interval, 1.27-5.83). Delayed treatment also had an association with race, with white patients being 1.8 times more likely to have delayed treatment (odds ratio, 1.79; 95% confidence interval, 1.04-3.08). Patients who were treated at <60 minutes had a lower gestational age at presentation vs those with delayed treatment (34.6±5 vs 36.6±4 weeks, respectively; P<.001). For every 1-week increase in gestational age at presentation, there was a 9% increase in the likelihood of delayed treatment (odds ratio, 1.11; 95% confidence interval, 1.04-1.19). Another factor that was associated with delay of treatment was having a complaint of labor symptoms, which made patients 2.2 times as likely to experience treatment delay (odds ratio, 2.17; 95% confidence interval, 1.07-4.41). CONCLUSION: Initial blood pressure in the nonsevere range, absence of preeclampsia symptoms, presentation overnight, white race, having complaint of labor symptoms, and increasing gestational age at presentation are barriers that lead to a delay in the treatment of obstetric hypertensive emergency. Quality improvement initiatives that target these barriers should be instituted to improve timely treatment.

Software-guided insulin dosing improves intrapartum glycemic management in women with diabetes mellitus.

BACKGROUND: During labor, maintenance of maternal euglycemia is critical to decrease the risk of neonatal hypoglycemia and associated morbidities. When continuous intravenous insulin infusion is needed, standardized insulin dosing charts have been used for titration of insulin to maintain glucose in target range. The GlucoStabilizer software program (Indiana University Health Inc, Indianapolis, IN) is a software-guided insulin dosing system that calculates the dose of intravenous insulin that is needed based on metabolic parameters, target glucose concentration, and an individual's response to insulin. Although this tool has been validated and shown to reduce both hypoglycemia and errors in critical care settings, the utility of this software has not been examined in obstetrics. OBJECTIVE: The purpose of this study was to determine whether the use of intravenous insulin dosing software in women with pregestational or gestational diabetes mellitus that requires intrapartum insulin infusion can improve the rate of glucose concentration in target range (70-100 mg/dL; 3.9-5.5 mmol/L) at the time delivery. STUDY DESIGN: We performed a retrospective cohort study comparing laboring patients with diabetes mellitus that required insulin infusion who were dosed by standard insulin dosing chart vs the GlucoStabilizer software program from January 2012 to December 2017. The GlucoStabilizer software program, which was implemented in May 2016, replaced the standard intravenous insulin dosing chart. Inclusion criteria were women with pregestational or gestational diabetes mellitus who were treated with an intravenous insulin infusion intrapartum for at least 2 hours. Maternal characteristics, glucose values in labor, and neonatal outcomes were extracted from delivery and neonatal records. The primary outcome was the percentage of women who achieved the target glucose range (defined as a blood glucose between 70-100 mg/dL; 3.9-5.5 mmol/L) before delivery. Parametric and nonparametric statistics were used to compare both groups; a probability value of <.05 was considered statistically significant. RESULTS: We identified 22 patients who were dosed by a standard insulin dosing chart and 11 patients who were dosed by the GlucoStabilizer software program during intrapartum management. The GlucoStabilizer software program was superior in achieving glucose values in target range at delivery (81.8% vs 9.1%; P<.001) compared with standard insulin dosing without increasing maternal hypoglycemia (0% vs 4.3%; P=.99). Patients whose insulin dosing was managed by the GlucoStabilizer software program also had lower mean capillary blood glucose values compared with the standard insulin infusion (102.9±5.9 mg/dL [5.7±0.33 mmol/L] vs 121.7±5.9 mg/dL [6.8±0.33 mmol/L]; P=.02). Before the initiation of the infusion, both groups demonstrated mean capillary blood glucose values outside of target range (122.6±8.8 mg/dL [6.7±0.49 mmol/L] for the GlucoStabilizer software program vs 131.9±10.1 mg/dL [7.3±0.56 mmol/L] for standard insulin treatment group; P=not significant). There were no significant differences in baseline maternal characteristics between the groups or neonatal outcomes. CONCLUSION: This study is the first to demonstrate that the use of software-guided intravenous insulin dosing in obstetrics can improve intrapartum glycemic management without increasing hypoglycemia in women with both pregestational and gestational diabetes mellitus that is treated with an insulin infusion.

Intrauterine Hyperglycemia Is Associated with an Impaired Postnatal Response to Oxidative Damage.

Hyperglycemia and other adverse exposures early in life that reprogram stem cells may lead to long-lasting phenotypic influences over the lifetime of an individual. Hyperglycemia and oxidative stress cause DNA damage when they exceed the protective capabilities of the cell, in turn affecting cellular function. DNA damage in response to hyperglycemia and oxidative stress was studied in human umbilical cord mesenchymal stem cells (hUC-MSCs) from large-for-gestational-age (LGA) infants of mothers with gestational diabetes mellitus (LGA-GDM) and control subjects. We tested the response of these cells to hyperglycemia and oxidative stress, measuring reactive oxygen species (ROS) levels and antioxidant enzyme activities. We find that hUC-MSCs from LGA-GDM infants have increased DNA damage when exposed to oxidative stress. With the addition of hyperglycemic conditions, these cells have an increase in ROS and a decrease in antioxidant glutathione peroxidase (GPx) activity, indicating a mechanism for the increased ROS and DNA damage. This study demonstrates that a memory of in utero hyperglycemia, mediated through downregulation of GPx activity, leads to an increased susceptibility to oxidative stress. The alteration of GPx function in self-renewing stem cells, can mediate the effect of intrauterine hyperglycemia to be propagated into adulthood and contribute to disease susceptibility.

Advanced aging phenotype is revealed by epigenetic modifications in rat liver after in utero malnutrition.

Adverse environmental exposures of mothers during fetal period predispose offspring to a range of age-related diseases earlier in life. Here, we set to determine whether a deregulated epigenetic pattern is similar in young animals whose mothers' nutrition was modulated during fetal growth to that acquired during normal aging in animals. Using a rodent model of maternal undernutrition (UN) or overnutrition (ON), we examined cytosine methylation profiles of liver from young female offspring and compared them to age-matched young controls and aged (20-month-old) animals. HELP-tagging, a genomewide restriction enzyme and sequencing assay demonstrates that fetal exposure to two different maternal diets is associated with nonrandom dysregulation of methylation levels with profiles similar to those seen in normal aging animals and occur in regions mapped to genes relevant to metabolic diseases and aging. Functional consequences were assessed by gene expression at 9 weeks old with more significant changes at 6 months of age. Early developmental exposures to unfavorable maternal diets result in altered methylation profiles and transcriptional dysregulation in Prkcb, Pc, Ncor2, and Smad3 that is also seen with normal aging. These Notch pathway and lipogenesis genes may be useful for prediction of later susceptibility to chronic disease.

Amnion as a surrogate tissue reporter of the effects of maternal preeclampsia on the fetus.

BACKGROUND: Preeclampsia, traditionally characterized by high blood pressure and proteinuria, is a common pregnancy complication, which affects 2-8 % of all pregnancies. Although children born to women with preeclampsia have a higher risk of hypertension in later life, the mechanism of this increased risk is unknown. DNA methylation is an epigenetic modification that has been studied as a mediator of cellular memory of adverse exposures in utero. Since each cell type in the body has a unique DNA profile, cell subtype composition is a major confounding factor in studies of tissues with heterogeneous cell types. The best way to avoid this confounding effect is by using purified cell types. However, using purified cell types in large cohort translational studies is difficult. The amnion, the inner layer of the fetal membranes of the placenta, is derived from the epiblast and consists of two cell types, which are easy to isolate from the delivered placenta. In this study, we demonstrate the value of using amnion samples for DNA methylation studies, revealing distinctive patterns between fetuses exposed to proteinuria or hypertension and fetuses from normal pregnancies. RESULTS: We performed a genome-wide DNA methylation analysis, HpaII tiny fragment Enrichment by Ligation-mediated PCR (HELP)-tagging, on 62 amnion samples from the placentas of uncomplicated, normal pregnancies and from those with complications of preeclampsia or hypertension. Using a regression model approach, we found 123, 85, and 99 loci with high-confidence hypertension-associated, proteinuria-associated, and hypertension- and proteinuria-associated DNA methylation changes, respectively. A gene ontology analysis showed DNA methylation changes to be selecting genes with different biological processes in exposure status. We also found that these differentially methylated regions overlap loci previously reported as differentially methylated regions in preeclampsia. CONCLUSIONS: Our findings support prior observations that preeclampsia is associated with changes of DNA methylation near genes that have previously been found to be dysregulated in preeclampsia. We propose that amniotic membranes represent a valuable surrogate fetal tissue on which to perform epigenome-wide association studies of adverse intrauterine conditions.

Sexual dimorphism in epigenomic responses of stem cells to extreme fetal growth.

Extreme fetal growth is associated with increased susceptibility to a range of adult diseases through an unknown mechanism of cellular memory. We tested whether heritable epigenetic processes in long-lived CD34(+) haematopoietic stem/progenitor cells showed evidence for re-programming associated with the extremes of fetal growth. Here we show that both fetal growth restriction and over-growth are associated with global shifts towards DNA hypermethylation, targeting cis-regulatory elements in proximity to genes involved in glucose homeostasis and stem cell function. We find a sexually dimorphic response; intrauterine growth restriction is associated with substantially greater epigenetic dysregulation in males, whereas large for gestational age growth predominantly affects females. The findings are consistent with extreme fetal growth interacting with variable fetal susceptibility to influence cellular ageing and metabolic characteristics through epigenetic mechanisms, potentially generating biomarkers that could identify infants at higher risk for chronic disease later in life.

Pregnancy complicated by obesity induces global transcript expression alterations in visceral and subcutaneous fat.

Maternal obesity is a significant risk factor for development of both maternal and fetal metabolic complications. Increase in visceral fat and insulin resistance is a metabolic hallmark of pregnancy, yet not much is known how obesity alters adipose cellular function and how this may contribute to pregnancy morbidities. We sought to identify alterations in genome-wide transcription expression in both visceral (omental) and abdominal subcutaneous fat deposits in pregnancy complicated by obesity. Visceral and abdominal subcutaneous fat deposits were collected from normal weight and obese pregnant women (n = 4/group) at the time of scheduled uncomplicated cesarean section. A genome-wide expression array (Affymetrix Human Exon 1.0 st platform), validated by quantitative real-time PCR, was utilized to establish the gene transcript expression profile in both visceral and abdominal subcutaneous fat in normal weight and obese pregnant women. Global alteration in gene expression was identified in pregnancy complicated by obesity. These regions of variations led to identification of indolethylamine N-methyltransferase, tissue factor pathway inhibitor-2, and ephrin type-B receptor 6, not previously associated with fat metabolism during pregnancy. In addition, subcutaneous fat of obese pregnant women demonstrated increased coding protein transcripts associated with apoptosis as compared to lean counterparts. Global alteration of gene expression in adipose tissue may contribute to adverse pregnancy outcomes associated with obesity.

Minireview: Epigenetics of obesity and diabetes in humans.

Understanding the determinants of human health and disease is overwhelmingly complex, particularly for common, late-onset, chronic disorders, such as obesity and diabetes. Elucidating the genetic and environmental factors that influence susceptibility to disruptions in energy homeostasis and metabolic regulation remain a challenge, and progress will entail the integration of multiple assessments of temporally dynamic environmental exposures in the context of each individual's genotype. To meet this challenge, researchers are increasingly exploring the epigenome, which is the malleable interface of gene-environment interactions. Epigenetic variation, whether innate or induced, contributes to variation in gene expression, the range of potential individual responses to internal and external cues, and risk for metabolic disease. Ultimately, advancement in our understanding of chronic disease susceptibility in humans will depend on refinement of exposure assessment tools and systems biology approaches to interpretation. In this review, we present recent progress in epigenetics of human obesity and diabetes, existing challenges, and the potential for new approaches to unravel the complex biology of metabolic dysregulation.

Aging per se increases the susceptibility to free fatty acid-induced insulin resistance.

Elevations in systemic free fatty acids (FFA) contribute to insulin resistance. To determine the effects of an acute elevation in FFA on insulin action with aging, we infused saline or intralipid (IL) during a hyperinsulinemic-euglycemic clamp in three groups of rats: young ad libitum-fed (YAL), old ad libitum-fed (OAL), and old on lifelong calorie restriction (OCR). The OCR group was included to distinguish between aging per se and age-related changes in body fat distribution. IL induced marked insulin resistance in both YAL and OCR, but the onset of insulin resistance was approximately two to three times more rapid in OCR as compared with YAL. In response to IL infusion, plasminogen-activating inhibitor-1 (PAI-1) expression was increased in subcutaneous fat from OAL animals. In visceral fat, a marked increase in PAI-1 and interleukin-6 expression was observed in OAL and OCR rats, but not YAL, in response to IL treatment. Thus, aging per se increases the inflammatory response to excess nutrients and vulnerability to FFA-induced insulin resistance with aging.