The mechanism of cytochrome P450 2D6 (CYP2D6) induction during pregnancy has not been evaluated in humans. This study assessed the changes in CYP2D6 and CYP3A activities during pregnancy and ...postpartum, and the effect of vitamin A administration on CYP2D6 activity. Forty‐seven pregnant CYP2D6 extensive metabolizers (with CYP2D6 activity scores of 1 to 2) received dextromethorphan (DM) 30 mg orally as a single dose during 3 study windows (at 25 to 28 weeks of gestation, study day 1; at 28 to 32 weeks of gestation, study day 2; and at ≥3 months postpartum, study day 3). Participants were randomly assigned to groups with no supplemental vitamin A (control) or with supplemental vitamin A (10 000 IU/day orally for 3 to 4 weeks) after study day 1. Concentrations of DM and its metabolites, dextrorphan (DX) and 3‐hydroxymorphinan (3HM), were determined from a 2‐hour post‐dose plasma sample and cumulative 4‐hour urine sample using liquid chromatography–mass spectrometry. Change in CYP2D6 activity was assessed using DX/DM plasma and urine metabolic ratios. The activity change in CYP3A was also assessed using the 3HM/DM urine metabolic ratio. The DX/DM urine ratio was significantly higher (43%) in pregnancy compared with postpartum (P = .03), indicating increased CYP2D6 activity. The DX/DM plasma ratio was substantially higher in the participants, with an activity score of 1.0 during pregnancy (P = .04) compared with postpartum. The 3HM/DM urinary ratio was significantly higher (92%) during pregnancy, reflecting increased CYP3A activity (P = .02). Vitamin A supplementation did not change CYP2D6 activity during pregnancy; however, plasma all‐trans retinoic acid (atRA) concentrations were positively correlated with increased CYP2D6 activity during pregnancy and postpartum. Further research is needed to elucidate the mechanisms of increased CYP2D6 activity during pregnancy.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Bupropion (BUP) is a chiral antidepressant and smoking cessation aide with benefits and side effects correlated with parent and active metabolite concentrations. BUP is metabolized by CYP2B6, ...CYP2C19, and CYP3A4 to hydroxy-BUP (OH-BUP) as well as by 11β-hydroxysteroid dehydrogenase-1 and aldo-keto reductases to threohydrobupropion (Threo) and erythrohydrobupropion (Erythro), respectively. As pregnancy alters the activity of drug-metabolizing enzymes, the authors hypothesized that BUP metabolism and BUP metabolite concentrations would be altered during pregnancy, potentially affecting the efficacy and safety of BUP in pregnant women.
Pregnant women (n = 8) taking BUP chronically were enrolled, and steady-state plasma samples and dosing interval urine samples were collected during pregnancy and postpartum. Maternal and umbilical cord venous blood samples were collected at delivery from 3 subjects, and cord blood/maternal plasma concentration ratios were calculated. The concentrations of BUP stereoisomers and their metabolites were measured. Paired t tests were used to compare pharmacokinetic parameters during pregnancy and postpartum.
No significant changes were observed in the steady-state plasma concentrations, metabolite to parent ratios, formation clearances, or renal clearance of any of the compounds during pregnancy when compared with postpartum. The umbilical cord venous plasma concentrations of BUP and its metabolites were 30%-60% lower than maternal plasma concentrations.
This study showed that there are no clinically meaningful differences in the stereoselective disposition of BUP or its metabolites during pregnancy, indicating that dose adjustment during pregnancy may not be necessary. The results also showed that the placenta provides a partial barrier for bupropion and its metabolite distribution to the fetus, with possible placental efflux transport of bupropion and its metabolites.
Pregnancy is associated with numerous changes in physiological and metabolic processes to ensure successful progression to full term. One such change is the alteration of arachidonic acid (AA) ...metabolism and formation of eicosanoids. This study explores the changes in AA metabolites formed through the cytochrome P450 mediated pathway to epoxyeicosatrienoic (EET), dihydroxyeicosatrienoic (DHET), and hydroxyeicosatetraenoic (HETE) acids which have been implicated in blood pressure regulation and inflammatory responses that are important for a healthy pregnancy.
The study determines circulating levels of EETs, DHETs and HETEs extracted from erythrocyte membranes and measured by mass spectroscopy during the progression of a normal pregnancy. Blood samples, from 25 women, were collected at three time points including 25–28 weeks gestation, 28–32 weeks gestation, and the non-pregnant control at 3–4 months postpartum.
Results demonstrate that healthy pregnancy is associated with significant increases in 8,9-DHET, 11,12-DHET and 14,15-DHET and a decrease in trans 8,9-EET during 28–32 weeks gestation compared to 3–4 months postpartum. These differences are likely due to several mechanisms including an increase in soluble epoxide hydrolase activity, a decrease in glutathione conjugation, and altered cytochrome P450 enzyme expression and/or activity that occurs during pregnancy.
Metabolism of AA through the cytochrome P450 pathway generates physiologically important eicosanoids that could play an important role in the progression of a healthy pregnancy. Establishing the changes that occur during normal pregnancy may, in the future, help in early detection of pregnancy complications including preeclampsia.
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•Pregnancy is associated with an increase in 8,9-DHET, 11,12-DHET and 14,15-DHET.•Pregnancy is associated with a decrease in trans 8,9-EET.•Pregnancy did not alter HETE content.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Rates of pregestational (PGDM) and gestational diabetes (GDM), and their associated pregnancy complications, are rising. Pregnancies complicated by diabetes have increased cesarean delivery (CD) ...rates; however, there are limited data regarding the current rates of, and contributing factors to, these deliveries. The Robson Ten Group Classification System (TGCS) is a clinically relevant, standardized framework that can be used to evaluate and analyze cesarean rates. The objective of this study was to evaluate rates of, and indications for, intrapartum, unplanned CD among pregnancies complicated by diabetes, compared to normoglycemic (NG) pregnancies, in a large United States birth cohort.
This retrospective cohort study used chart-abstracted data on births between 24 and 42 weeks' gestation at 17 hospitals that contributed to the Obstetrical Care Outcome Assessment Program database between 01/2016 and 03/2019. The CD rate for NG pregnancies, and pregnancies complicated by gestational and PGDM was calculated and compared using the Robson TGCS. The indications for intrapartum CD in patients with term, singleton, vertex gestations without a prior cesarean were then analyzed. Univariate and multivariate logistic regression models were used to compare the cesarean rate and indications for CD, between the diabetic groups and the NG group. Results were adjusted for maternal age, BMI, neonatal birth weight, and insurance status, as well as clustering by hospital.
A total of 86,381 pregnant people were included in the study cohort. Of these 76,272 (88.3%) were NG, 8591 (9.9%) had GDM, and 1518 (1.8%) had PGDM. Compared to NG patients, overall cesarean rates were higher in patients with GDM (40.3% vs. 29.7%; aOR 1.25, 95%CI 1.18-1.31) and PGDM (60.0% vs. 29.7%; aOR 2.53, 95%CI 2.04-3.13). This finding remained true when the cohort was restricted to term, singleton, vertex laboring patients without a prior cesarean; compared to NG patients, the cesarean rate was higher in patients with GDM (17.4% vs. 12.2%, aOR 1.37, 95%CI 1.29-1.45) and PGDM (26.0% vs. 12.2%, aOR 2.55, 95%CI 2.00-3.25). The cesarean rate for fetal indications was similar in the GDM (5.7%) and NG (4.4%) groups, while those patients with PGDM had a significantly higher rate (10.4%; aOR 2.01, 95%CI 1.43-2.83). Similarly, the rate of cesarean for labor dystocia in patients with PGDM was significantly higher than in NG patients (16.9% vs. 7.0%, and aOR 2.28, 95%CI 1.66-3.13) while patients with GDM had an intermediate rate (10.6% vs. 7.0%, aOR 1.49, 95%CI 1.40-1.57).
The CD rate is significantly higher in pregnancies complicated by diabetes, particularly pregestational, compared to NG pregnancies. Despite controlling for maternal factors and birth weight, pregnancies complicated by diabetes are more likely to undergo an unplanned intrapartum cesarean secondary to labor dystocia than their NG counterparts, but only pregnancies complicated by PGDM have an increased risk of cesarean for fetal indications. More research is needed to understand whether this higher cesarean rate is due to factors intrinsic to diabetes in laboring patients or is due to a difference in the way clinicians manage diabetics in labor.
INTRODUCTION:Enhanced recovery after surgery (ERAS) pathways are standardized, evidence-based approaches to the care of surgical patients. One component of ERAS pathways is maintaining euglycemia ...pre- and post-operatively.
METHODS:We conducted an IRB approved retrospective cohort study evaluating capillary blood glucose (CBG) values among women on the ERAS cesarean delivery pathway (ERAS CD) during the first year of implementation (4/1/2017–3/31/2018, n=531). Pregestational diabetics on insulin prior to pregnancy were excluded. ERAS CD pathway patients received a pre-op, 1-hour post-op, and post-op day 1 and 2 CBG. We calculated average CBG and percentage of time in-range, defined as any CBG between 70–140 mg/dL for all patients on the ERAS CD pathway, and stratified for type 2 diabetics (T2DM), gestational diabetics (GDM), and non-diabetics.
RESULTS:Most patients had CBGs in-range preoperatively (n=268, 95.4%)89.6% for T2DM, 89.8% for GDM, and 97.1% for non-diabetics. The average pre-op CBG was 87.5±15.7 mg/dL overall, 96.2±30.4 mg/dL for T2DM, 90.4±17.0 mg/dL for GDM, and 86.4±14.8 mg/dL for non-diabetics. Post-operatively, 94.3% (n=502) of patients had CBGs in-range66.8% for T2DM, 87.1% for GDM, and 95.5% for non-diabetics. The average post-op CBG was 90.9±17.8 mg/dL overall, 99.2±26.6 mg/dL for T2DM, 94.9±20.6 mg/dL for GDM, and 90.2±17.2 mg/dL for non-diabetics.
CONCLUSION:Preoperatively most patients had in-range CBGs. Postoperatively, CBGs for non-diabetics and GDM remained primarily in-range, while CBGs for T2DM were more variable. For non-diabetic women it may not be useful to check pre- or post-operative CBGs as most will be within range. Further studies are needed to evaluate this aspect of care.
INTRODUCTION:Enhanced recovery after surgery (ERAS) pathways are standardized, evidence-based approaches to the care of surgical patients. One component of ERAS pathways is maintaining euglycemia ...pre- and post-operatively.
METHODS:We conducted an IRB approved retrospective cohort study evaluating capillary blood glucose (CBG) values among women on the ERAS cesarean delivery pathway (ERAS CD) during the first year of implementation (4/1/2017–3/31/2018, n=531), compared to historical controls (3/1/2016–2/28/2017, n=661) in the year prior. Pregestational diabetics on insulin prior to pregnancy were excluded. ERAS CD pathway patients received preoperative carbohydrate loading as well as a pre-op, 1-hour post-op, and post-op day 1 and 2 CBG. We compared average CBG and percentage of time in-range, defined as any CBG between 70–140 mg/dL for both pre- and post-operative periods between the baseline and implementation groups using chi-square tests and Student t-tests.
RESULTS:The women on the ERAS CD pathway had a significantly higher percentage of in-range CBGs both in the pre- and post-operative time period (pre-op84.9% vs. 95.4%, P<.001; post-op77.2% vs. 94.3%, P<.001) compared to historical controls. The average pre- and post-operative CBGs were also significantly lower among women on the ERAS CD pathway (pre-op93.3±19.3 mg/dL vs. 87.5±15.7, P=.0033; post-op109.5±29.2 mg/dL vs. 90.9±17.8 mg/dL, P<.001).
CONCLUSION:Women on the ERAS CD pathway had significantly improved CBGs both pre- and post-operatively, as demonstrated by higher percentage of in-range CBGs and lower average CBGs during both time periods. This suggests that ERAS CD pathways may improve perioperative euglycemia, but further studies are needed to evaluate this.
Residents may benefit from simulated practice with personalized feedback to prepare for high-stakes disclosure conversations with patients after harmful errors and to meet American Council on ...Graduate Medical Education mandates. Ideally, feedback would come from patients who have experienced communication after medical harm, but medical researchers and leaders have found it difficult to reach this community, which has made this approach impractical at scale. The Video-Based Communication Assessment app is designed to engage crowdsourced laypeople to rate physician communication skills but has not been evaluated for use with medical harm scenarios.
We aimed to compare the reliability of 2 assessment groups (crowdsourced laypeople and patient advocates) in rating physician error disclosure communication skills using the Video-Based Communication Assessment app.
Internal medicine residents used the Video-Based Communication Assessment app; the case, which consisted of 3 sequential vignettes, depicted a delayed diagnosis of breast cancer. Panels of patient advocates who have experienced harmful medical error, either personally or through a family member, and crowdsourced laypeople used a 5-point scale to rate the residents' error disclosure communication skills (6 items) based on audiorecorded responses. Ratings were aggregated across items and vignettes to create a numerical communication score for each physician. We used analysis of variance, to compare stringency, and Pearson correlation between patient advocates and laypeople, to identify whether rank order would be preserved between groups. We used generalizability theory to examine the difference in assessment reliability between patient advocates and laypeople.
Internal medicine residents (n=20) used the Video-Based Communication Assessment app. All patient advocates (n=8) and 42 of 59 crowdsourced laypeople who had been recruited provided complete, high-quality ratings. Patient advocates rated communication more stringently than crowdsourced laypeople (patient advocates: mean 3.19, SD 0.55; laypeople: mean 3.55, SD 0.40; P<.001), but patient advocates' and crowdsourced laypeople's ratings of physicians were highly correlated (r=0.82, P<.001). Reliability for 8 raters and 6 vignettes was acceptable (patient advocates: G coefficient 0.82; crowdsourced laypeople: G coefficient 0.65). Decision studies estimated that 12 crowdsourced layperson raters and 9 vignettes would yield an acceptable G coefficient of 0.75.
Crowdsourced laypeople may represent a sustainable source of reliable assessments of physician error disclosure skills. For a simulated case involving delayed diagnosis of breast cancer, laypeople correctly identified high and low performers. However, at least 12 raters and 9 vignettes are required to ensure adequate reliability and future studies are warranted. Crowdsourced laypeople rate less stringently than raters who have experienced harm. Future research should examine the value of the Video-Based Communication Assessment app for formative assessment, summative assessment, and just-in-time coaching of error disclosure communication skills.
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