Faculty Bibliography

OBJECTIVE:Obstetric hypertensive emergency is defined as having systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥110 mmHg, confirmed 15 min apart. ACOG recommends that acute-onset, severe hypertension be treated with first line-therapy (IV labetalol, IV hydralazine or PO nifedipine) within 60 minutes to reduce risk of maternal morbidity and mortality. Therefore, our objective was to identify barriers that lead to delayed treatment of obstetric hypertensive emergency. STUDY DESIGN/METHODS:A retrospective cohort study was performed comparing women appropriately treated within 60 minutes versus those with delay in first line therapy. We identified 604 patients with discharge diagnoses of chronic hypertension, gestational hypertension or preeclampsia using ICD-10 codes and obstetric antihypertensive usage in a pharmacy database at one academic institution from January 2017 - June 2018. 267 subjects (44.2%) experienced obstetric hypertensive emergency in the intrapartum period or within two days of delivery. 213 subjects 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 ran-sum and sample t-tests were used to compare the two 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<0.05. RESULTS:Of the 213 women, 110 (51.6%) had delayed treatment vs. 103 (48.4%) who were treated within 60 min. Patients who had delayed treatment were 3.2 times more likely to present with an initial BP in the non-severe range vs those who had timely treatment (OR=3.24, 95% CI:1.85-5.68). Timeliness of treatment was associated with presence or absence of preeclampsia symptoms-- patients without pre-eclampsia symptoms were 2.7 times more likely to have delayed treatment (OR=2.68, 95%CI:1.50-4.80). Patients with HTN emergencies that occurred overnight between 10pm-6am were 2.7 times more likely to have delayed treatment vs. those that occurred between 6am-10pm (OR 2.72, 95% CI: 1.27-5.83). Delayed treatment also had an association with race, with Caucasian patients being 1.8 times more likely to have delayed treatment (OR=1.79; 95% CI: 1.04-3.08). Patients treated under 60 min had a lower gestational age at presentation vs those with delayed treatment (34.6±5wk vs. 36.6±4wks, respectively, p <0.001). For every 1 week increase in gestational age at presentation, there was a 9% increase in the likelihood of delayed treatment (OR 1.11; 95%CI:1.04-1.19). Another factor associated with delay of treatment was presenting complaint of labor symptoms, which made patients 2.2 times as likely to experience treatment delay (OR=2.17; 95%CI: 1.07-4.41). CONCLUSION/CONCLUSIONS:Initial blood pressure in non-severe range, absence of preeclampsia symptoms, presentation overnight, Caucasian race, presenting complaint of labor symptoms, and increasing gestational age at presentation are barriers that lead to delay in treatment of obstetric hypertensive emergency. Quality improvement initiatives targeting these barriers should be instituted to improve timely treatment.

BACKGROUND:While elevated second trimester maternal serum alpha fetoprotein (msAFP) has been associated with adverse pregnancy outcomes, the utility of first trimester msAFP in predicting these outcomes is limited. Some laboratories have been including msAFP as part of the first trimester analyte screening for aneuploidy and preeclampsia, offering its potential utility in predicting pregnancy outcomes. OBJECTIVE:Our primary objective was to determine the association between elevated first trimester msAFP and preeclampsia, as well as ischemic placental disease (a composite of preeclampsia, fetal growth restriction and/or placental abruption). Secondary outcomes included early onset preeclampsia requiring delivery at <34 weeks gestation, fetal growth restriction, placental abruption, preterm delivery, fetal demise, and spontaneous abortion. STUDY DESIGN/METHODS:An IRB-approved multi-site retrospective cohort study was performed including all patients with first trimester msAFP as part of routine first trimester aneuploidy screening from April 2015-January 2017. Pregnancies with multiple gestations, known structural or chromosomal abnormalities, known malignancy, and incomplete delivery records were excluded. Delivery records were reviewed for baseline characteristics and adverse pregnancy outcomes. The optimal cut-off point for first trimester msAFP to predict these outcomes was assessed and an elevated msAFP was considered > 2.0 MoM. Fisher exact test and odds ratios were used to determine the association between elevated first trimester msAFP and adverse pregnancy outcomes. Spearman correlation coefficient assessed the relationship between first and second trimester msAFP. RESULTS:Of 1478 patients with first trimester msAFP, 1280 had complete records available for review (86.6%). There was no association demonstrated between elevated first trimester msAFP (> 2.0 MoM) and the primary outcome, overall preeclampsia (5.8% vs. 4.6%, OR 1.29, 95% CI 0.58, 2.91). However, there was an increased incidence of ischemic placental disease, 15.8% vs 7.7% (OR 2.26, 95% CI 1.33-3.87) in those with an elevated AFP. Also, elevated first trimester msAFP was associated with a higher incidence of fetal growth restriction (7.5% vs 2.3%, OR 3.40, 95% CI 1.56-7.42) and preterm birth (18.3% vs 10.3%, OR 1.95, 95% CI 1.18-3.21). Also, a positive correlation between first and second trimester msAFP was demonstrated (rho = 0.46, P< 0.0001). CONCLUSIONS:Elevated first trimester msAFP is associated with ischemic placental disease, fetal growth restriction, and preterm birth. This suggests that elevated msAFP may help to identify high risk pregnancies as early as the first trimester of pregnancy. Future studies are necessary to determine if addition of first trimester msAFP to existing algorithms can improve the early detection of ischemic placental disease.

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/METHODS: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/CONCLUSIONS: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.

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 (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.

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.