Impact of Pregnancy on the Pharmacokinetics and Metabolism of Nicotinamide in Humans.

In pre-eclampsia models, nicotinamide (NAM) has protective effects in pre-eclampsia and is being evaluated as a therapeutic nutraceutical in clinical studies. NAM undergoes extensive hepatic metabolism by NAM N-methyltransferase to methylnicotinamide (MNA), which is subsequently metabolized to methyl-2-pyridone-5-carboxamide (M2PY) by aldehyde oxidase. However, the pharmacokinetics of NAM and its major metabolites has never been studied in pregnant individuals. Blood samples were collected before and 1, 2, 4, 8, and 24 hours after single 1 g oral NAM dose in healthy pregnant (gestational age 24-33 weeks) and nonpregnant female volunteers (n = 6/group). Pooled urine was collected from 0 to 8 hours. NAM, MNA, and M2PY area under the concentration-time curve (AUC) data were analyzed by noncompartmental analysis. No difference in the plasma AUC0→24 of NAM (median (25%-75%): 463 (436-576) vs. 510 (423, 725) µM*hour, P = 0.430) and its intermediate metabolite MNA (89.1 (60.4, 124.4) vs. 83.8 (62.7, 93.7) µM*hour, P = 0.515) was observed in pregnant and nonpregnant volunteers, respectively; however, the terminal metabolite M2PY AUC0 → 24 was significantly lower in pregnant individuals (218 (188, 254) vs. 597 (460, 653) µM*hour, P < 0.001). NAM renal clearance (CLR ; P = 0.184), MNA CLR (P = 0.180), and total metabolite formation clearance (P = 0.405) did not differ across groups; however, M2PY CLR was significantly higher in pregnant individuals (10.5 (9.3-11.3) vs. 7.5 (6.4-8.5) L/h, P = 0.002). These findings demonstrate that the PK of NAM and systemic exposure to its intermediate metabolite MNA are not significantly altered during pregnancy, and systemic exposure to NAM's major metabolite M2PY was reduced during pregnancy due to increased renal elimination.

Characteristics and Outcomes of Patients With Pregnancy-Related End-Stage Kidney Disease.

Importance: The incidence of pregnancy-related acute kidney injury is increasing and is associated with significant maternal morbidity including progression to end-stage kidney disease (ESKD). Little is known about characteristics and long-term outcomes of patients who develop pregnancy-related ESKD. Objectives: To examine the characteristics and clinical outcomes of patients with pregnancy-related ESKD and to investigate associations between pre-ESKD nephrology care and outcomes. Design, Setting, and Participants: This was a cohort study of 183 640 reproductive-aged women with incident ESKD between January 1, 2000, and November 20, 2020, from the US Renal Data System and maternal data from births captured in the US Centers for Disease Control and Prevention publicly available natality data. Data were analyzed from December 2022 to June 2023. Exposure: Pregnancy-related primary cause of ESKD, per International Classification of Diseases, Ninth Revision (ICD-9) and ICD-10 codes reported at ESKD onset by the primary nephrologist on Centers for Medicare and Medicaid Services form 2728. Main Outcomes Measures: Multivariable Cox proportional hazards and competing risk models were constructed to examine time to (1) mortality, (2) access to kidney transplant (joining the waiting list or receiving a live donor transplant), and (3) receipt of transplant after joining the waitlist. Results: A total of 341 patients with a pregnancy-related primary cause of ESKD were identified (mean [SD] age 30.2 [7.3]). Compared with the general US birthing population, Black patients were overrepresented among those with pregnancy-related ESKD (109 patients [31.9%] vs 585 268 patients [16.2%]). In adjusted analyses, patients with pregnancy-related ESKD had similar or lower hazards of mortality compared with those with glomerulonephritis or cystic kidney disease (adjusted hazard ratio [aHR], 0.96; 95% CI, 0.76-1.19), diabetes or hypertension (aHR, 0.49; 95% CI, 0.39-0.61), or other or unknown primary causes of ESKD (aHR, 0.60; 95% CI, 0.48-0.75). Despite this, patients with pregnancy-related ESKD had significantly lower access to kidney transplant compared with those with other causes of ESKD, including (1) glomerulonephritis or cystic kidney disease (adjusted subhazard ratio [aSHR], 0.51; 95% CI, 0.43-0.66), (2) diabetes or hypertension (aSHR, 0.81; 95% CI, 0.67-0.98), and (3) other or unkown cause (aSHR, 0.82; 95% CI, 0.67-0.99). Those with pregnancy-related ESKD were less likely to have nephrology care or have a graft or arteriovenous fistula placed before ESKD onset (nephrology care: adjusted relative risk [aRR], 0.47; 95% CI, 0.40-0.56; graft or arteriovenous fistula placed: aRR, 0.31; 95% CI, 0.17-0.57). Conclusion and Relevance: In this study, those with pregnancy-related ESKD had reduced access to transplant and nephrology care, which could exacerbate existing disparities in a disproportionately Black population. Increased access to care could improve quality of life and health outcomes among these young adults with high potential for long-term survival.

Metformin Plus Insulin for Preexisting Diabetes or Gestational Diabetes in Early Pregnancy: The MOMPOD Randomized Clinical Trial.

Importance: Insulin is recommended for pregnant persons with preexisting type 2 diabetes or diabetes diagnosed early in pregnancy. The addition of metformin to insulin may improve neonatal outcomes. Objective: To estimate the effect of metformin added to insulin for preexisting type 2 or diabetes diagnosed early in pregnancy on a composite adverse neonatal outcome. Design, Setting, and Participants: This randomized clinical trial in 17 US centers enrolled pregnant adults aged 18 to 45 years with preexisting type 2 diabetes or diabetes diagnosed prior to 23 weeks' gestation between April 2019 and November 2021. Each participant was treated with insulin and was assigned to add either metformin or placebo. Follow-up was completed in May 2022. Intervention: Metformin 1000 mg or placebo orally twice per day from enrollment (11 weeks -<23 weeks) through delivery. Main Outcome and Measures: The primary outcome was a composite of neonatal complications including perinatal death, preterm birth, large or small for gestational age, and hyperbilirubinemia requiring phototherapy. Prespecified secondary outcomes included maternal hypoglycemia and neonatal fat mass at birth, and prespecified subgroup analyses by maternal body mass index less than 30 vs 30 or greater and those with preexisting vs diabetes early in pregnancy. Results: Of the 831 participants randomized, 794 took at least 1 dose of the study agent and were included in the primary analysis (397 in the placebo group and 397 in the metformin group). Participants' mean (SD) age was 32.9 (5.6) years; 234 (29%) were Black, and 412 (52%) were Hispanic. The composite adverse neonatal outcome occurred in 280 (71%) of the metformin group and in 292 (74%) of the placebo group (adjusted odds ratio, 0.86 [95% CI 0.63-1.19]). The most commonly occurring events in the primary outcome in both groups were preterm birth, neonatal hypoglycemia, and delivery of a large-for-gestational-age infant. The study was halted at 75% accrual for futility in detecting a significant difference in the primary outcome. Prespecified secondary outcomes and subgroup analyses were similar between groups. Of individual components of the composite adverse neonatal outcome, metformin-exposed neonates had lower odds to be large for gestational age (adjusted odds ratio, 0.63 [95% CI, 0.46-0.86]) when compared with the placebo group. Conclusions and Relevance: Using metformin plus insulin to treat preexisting type 2 or gestational diabetes diagnosed early in pregnancy did not reduce a composite neonatal adverse outcome. The effect of reduction in odds of a large-for-gestational-age infant observed after adding metformin to insulin warrants further investigation. Trial Registration: ClinicalTrials.gov Identifier: NCT02932475.

Postpartum readmission for hypertension and pre-eclampsia: development and validation of a predictive model.

OBJECTIVE: To develop a model for predicting postpartum readmission for hypertension and pre-eclampsia at delivery discharge and assess external validation or model transportability across clinical sites. DESIGN: Prediction model using data available in the electronic health record from two clinical sites. SETTING: Two tertiary care health systems from the Southern (2014-2015) and Northeastern USA (2017-2019). POPULATION: A total of 28 201 postpartum individuals: 10 100 in the South and 18 101 in the Northeast. METHODS: An internal-external cross validation (IECV) approach was used to assess external validation or model transportability across the two sites. In IECV, data from each health system were first used to develop and internally validate a prediction model; each model was then externally validated using the other health system. Models were fit using penalised logistic regression, and accuracy was estimated using discrimination (concordance index), calibration curves and decision curves. Internal validation was performed using bootstrapping with bias-corrected performance measures. Decision curve analysis was used to display potential cut points where the model provided net benefit for clinical decision-making. MAIN OUTCOME MEASURES: The outcome was postpartum readmission for either hypertension or pre-eclampsia <6 weeks after delivery. RESULTS: The postpartum readmission rate for hypertension and pre-eclampsia overall was 0.9% (0.3% and 1.2% by site, respectively). The final model included six variables: age, parity, maximum postpartum diastolic blood pressure, birthweight, pre-eclampsia before discharge and delivery mode (and interaction between pre-eclampsia × delivery mode). Discrimination was adequate at both health systems on internal validation (c-statistic South: 0.88; 95% confidence interval [CI] 0.87-0.89; Northeast: 0.74; 95% CI 0.74-0.74). In IECV, discrimination was inconsistent across sites, with improved discrimination for the Northeastern model on the Southern cohort (c-statistic 0.61 and 0.86, respectively), but calibration was not adequate. Next, model updating was performed using the combined dataset to develop a new model. This final model had adequate discrimination (c-statistic: 0.80, 95% CI 0.80-0.80), moderate calibration (intercept -0.153, slope 0.960, Emax 0.042) and provided superior net benefit at clinical decision-making thresholds between 1% and 7% for interventions preventing readmission. An online calculator is provided here. CONCLUSIONS: Postpartum readmission for hypertension and pre-eclampsia may be accurately predicted but further model validation is needed. Model updating using data from multiple sites will be needed before use across clinical settings.

Single-center serological surveillance of SARS-CoV-2 in pregnant patients presenting to labor and delivery.

OBJECTIVE: To measure maternal/fetal SARS-CoV-2 antibody levels. METHODS: A prospective observational study of eligible parturients admitted to the hospital for infant delivery was conducted between April and September 2020. SARS-CoV-2 antibody levels were measured in maternal and umbilical cord specimens using an in-house ELISA based on the receptor-binding domain (RBD) of the spike protein. Among SARS-CoV-2 seropositive patients, spike RBD antibody isotypes (IgG, IgM, and IgA) and ACE2 inhibiting antibodies were measured. RESULTS: In total, 402 mothers were enrolled and spike RBD antibodies in 388 pregnancies were measured (336 maternal and 52 cord specimens). Of them, 19 were positive (15 maternal, 4 cord) resulting in a seroprevalence estimate of 4.8% (95% confidence interval 2.9-7.4). Of the 15 positive maternal specimens, all had cord blood tested. Of the 15 paired specimens, 14 (93.3%) were concordant. Four of the 15 pairs were from symptomatic mothers, and all four showed high spike-ACE2 blocking antibody levels, compared to only 3 of 11 (27.3%) from asymptomatic mothers. CONCLUSION: A variable antibody response to SARS-CoV-2 in pregnancy among asymptomatic infections compared to symptomatic infections was found, the significance of which is unknown. Although transfer of transplacental neutralizing antibodies occurred, additional research is needed to determine how long maternal antibodies can protect the infant against SARS-CoV-2 infection.

Clinical and economic evaluation of a proteomic biomarker preterm birth risk predictor: cost-effectiveness modeling of prenatal interventions applied to predicted higher-risk pregnancies within a large and diverse cohort.

OBJECTIVES: Preterm birth occurs in more than 10% of U.S. births and is the leading cause of U.S. neonatal deaths, with estimated annual costs exceeding $25 billion USD. Using real-world data, we modeled the potential clinical and economic utility of a prematurity-reduction program comprising screening in a racially and ethnically diverse population with a validated proteomic biomarker risk predictor, followed by case management with or without pharmacological treatment. METHODS: The ACCORDANT microsimulation model used individual patient data from a prespecified, randomly selected sub-cohort (N = 847) of a multicenter, observational study of U.S. subjects receiving standard obstetric care with masked risk predictor assessment (TREETOP; NCT02787213). All subjects were included in three arms across 500 simulated trials: standard of care (SoC, control); risk predictor/case management comprising increased outreach, education and specialist care (RP-CM, active); and multimodal management (risk predictor/case management with pharmacological treatment) (RP-MM, active). In the active arms, only subjects stratified as higher risk by the predictor were modeled as receiving the intervention, whereas lower-risk subjects received standard care. Higher-risk subjects' gestational ages at birth were shifted based on published efficacies, and dependent outcomes, calibrated using national datasets, were changed accordingly. Subjects otherwise retained their original TREETOP outcomes. Arms were compared using survival analysis for neonatal and maternal hospital length of stay, bootstrap intervals for neonatal cost, and Fisher's exact test for neonatal morbidity/mortality (significance, p < .05). RESULTS: The model predicted improvements for all outcomes. RP-CM decreased neonatal and maternal hospital stay by 19% (p = .029) and 8.5% (p = .001), respectively; neonatal costs' point estimate by 16% (p = .098); and moderate-to-severe neonatal morbidity/mortality by 29% (p = .025). RP-MM strengthened observed reductions and significance. Point estimates of benefit did not differ by race/ethnicity. CONCLUSIONS: Modeled evaluation of a biomarker-based test-and-treat strategy in a diverse population predicts clinically and economically meaningful improvements in neonatal and maternal outcomes.

Preterm birth, defined as delivery before 37 weeks' gestation, is the leading cause of illness and death in newborns. In the United States, more than 10% of infants are born prematurely, and this rate is substantially higher in lower-income, inner-city and Black populations. Prematurity associates with greatly increased risk of short- and long-term medical complications and can generate significant costs throughout the lives of affected children. Annual U.S. health care costs to manage short- and long-term prematurity complications are estimated to exceed $25 billion.Clinical interventions, including case management (increased patient outreach, education and specialist care), pharmacological treatment and their combination can provide benefit to pregnancies at higher risk for preterm birth. Early and sensitive risk detection, however, remains a challenge.We have developed and validated a proteomic biomarker risk predictor for early identification of pregnancies at increased risk of preterm birth. The ACCORDANT study modeled treatments with real-world patient data from a racially and ethnically diverse U.S. population to compare the benefits of risk predictor testing plus clinical intervention for higher-risk pregnancies versus no testing and standard care. Measured outcomes included neonatal and maternal length of hospital stay, associated costs and neonatal morbidity and mortality. The model projected improved outcomes and reduced costs across all subjects, including ethnic and racial minority populations, when predicted higher-risk pregnancies were treated using case management with or without pharmacological treatment. The biomarker risk predictor shows high potential to be a clinically important component of risk stratification for pregnant women, leading to tangible gains in reducing the impact of preterm birth.

Better Estimation of Spontaneous Preterm Birth Prediction Performance through Improved Gestational Age Dating.

The clinical management of pregnancy and spontaneous preterm birth (sPTB) relies on estimates of gestational age (GA). Our objective was to evaluate the effect of GA dating uncertainty on the observed performance of a validated proteomic biomarker risk predictor, and then to test the generalizability of that effect in a broader range of GA at blood draw. In a secondary analysis of a prospective clinical trial (PAPR; NCT01371019), we compared two GA dating categories: both ultrasound and dating by last menstrual period (LMP) (all subjects) and excluding dating by LMP (excluding LMP). The risk predictor's performance was observed at the validated risk predictor threshold both in weeks 191/7-206/7 and extended to weeks 180/7-206/7. Strict blinding and independent statistical analyses were employed. The validated biomarker risk predictor showed greater observed sensitivity of 88% at 75% specificity (increases of 17% and 1%) in more reliably dated (excluding-LMP) subjects, relative to all subjects. Excluding dating by LMP significantly improved the sensitivity in weeks 191/7-206/7. In the broader blood draw window, the previously validated risk predictor threshold significantly stratified higher and lower risk of sPTB, and the risk predictor again showed significantly greater observed sensitivity in excluding-LMP subjects. These findings have implications for testing the performance of models aimed at predicting PTB.

Euglycemia after antenatal late preterm steroids: a multicenter, randomized controlled trial.

BACKGROUND: Late preterm steroid administration can induce transient maternal and thus fetal hyperglycemia, which can increase production of fetal insulin and C-peptide. Infants delivered in this setting are subsequently at increased risk for hypoglycemia. Although maternal glycemic control before delivery is a key component of care for parturients with diabetes, this intervention has not been studied in the setting of late preterm steroid administration. OBJECTIVE: This study aimed to determine the effect of maternal screening for and treatment of hyperglycemia after late preterm steroid administration on fetal C-peptide levels and other metabolic markers. STUDY DESIGN: This was a multicenter, randomized trial (NCT03076775) of nondiabetic parturients with a singleton gestation receiving betamethasone at 34 0/7 weeks to 36 5/7 weeks for anticipated preterm birth. Participants randomized to maternal glycemic control received fasting and 1-hour postprandial or serial intrapartum capillary blood glucose screening with insulin treatment as indicated. Those randomized to expectant management did not receive any glucose screening or treatment. The primary outcome was fetal C-peptide level measured from umbilical cord blood at delivery. Secondary outcomes included other fetal metabolic markers and neonatal hypoglycemia (glucose level <40 mg/dL). Baseline characteristics and outcomes were compared between the groups. We estimated that we would need a sample size of 144 to provide >90% power to show a 1 ng/mL decrease in C-peptide concentration (±1.5 ng/mL) at ⍺=0.05 using a 2-sample t test and 1 interim analysis. After the interim analysis, the trial was stopped for futility. RESULTS: Of 491 screened parturients, 163 (33%) were deemed eligible and 86 (53%) were randomized to 1 of the treatment groups (June 2017 to February 2021). One person was lost to follow-up because of delivery at another hospital. Baseline characteristics were similar between groups. The median interval from betamethasone administration to delivery was 24 hours (interquartile range, 13-96 hours) and did not differ between groups (P=.82). Most (82%) randomized to maternal glycemic control had hyperglycemia: 80% had at least 1 fasting glucose level >95 mg/dL, 75% had at least one 1-hour postprandial glucose level >140 mg/dL, and 80% had at least 1 intrapartum glucose level >110 mg/dL. In addition, 15% had at least 1 glucose level >180 mg/dL. None had maternal hypoglycemia after insulin treatment. Compared with expectant management, maternal glycemic control did not affect the median fetal C-peptide level (1.02; interquartile range, 0.52-1.85 vs 1.09; interquartile range, 0.61-1.65; P=.97) or other metabolic markers. Maternal glycemic control also did not affect neonatal hypoglycemia (49% vs 51%; P=.83) or other secondary neonatal or maternal outcomes. There was no evidence of effect modification by gestational age or body mass index at randomization, indication for betamethasone, duration from betamethasone to delivery, maternal race or ethnicity, or neonatal sex. In addition, the results were unchanged in a sensitivity analysis using a per-protocol approach. CONCLUSION: Maternal hyperglycemia was observed in most nondiabetic parturients after receiving late preterm betamethasone. However, there was no improvement in fetal metabolic status, neonatal hypoglycemia, or other neonatal or maternal outcomes with maternal glycemic control. Therefore, maternal glucose surveillance and treatment does not seem to be beneficial in nondiabetic parturients receiving late preterm steroids.

Skin preparation type and post-cesarean infection with use of adjunctive azithromycin prophylaxis.

OBJECTIVE: To compare the frequency of postoperative surgical site infection (SSI) by type of skin preparation used for unscheduled cesarean in the setting of adjunctive azithromycin prophylaxis. METHODS: Secondary analysis of a multi-center randomized controlled trial of adjunctive azithromycin (500 mg intravenous) versus placebo in women who were ≥24 weeks gestation and undergoing unscheduled cesarean (i.e. during labor or ≥4 h after membrane rupture). Type of skin preparation used was identified based on the protocol at the hospital at the time of delivery: iodine-alcohol, chlorhexidine, chlorhexidine-alcohol, or the combination of chlorhexidine-alcohol and iodine. The primary outcome of this analysis was incidence of post-operative SSI, as defined by CDC criteria. Multivariable logistic regression was applied for adjustments. RESULTS: All 2013 women in the primary trial were included in this analysis. Women were grouped according to type of skin preparation received: iodine-alcohol (n = 193), chlorhexidine (n = 733), chlorhexidine-alcohol (n = 656), and chlorhexidine-alcohol and iodine combined sequentially (n = 431). The unadjusted rates of wound infection ranged from 2.9% to 5.7%. Using iodine-alcohol as the referent, the adjusted odds ratios for wound SSI were 0.71 (95% CI 0.30-1.66) for chlorhexidine, 0.97 (95% CI 0.41-2.28) for chlorhexidine-alcohol, and 0.88 (95% CI 0.36-2.20) for chlorhexidine-alcohol with iodine combination. CONCLUSION: In women undergoing unscheduled cesarean delivery in a trial of adjunctive azithromycin, the type of skin preparation used did not appear to be associated with the frequency of wound SSI.

Implementation of a text-based postpartum blood pressure monitoring program at 3 different academic sites.

BACKGROUND: Up to 30% of patients with hypertensive disorders of pregnancy continue to have elevated blood pressures after delivery, often necessitating medication titration or hospital evaluation in the weeks following hospital discharge. A previous randomized controlled trial demonstrated that remote blood pressure monitoring programs led to an increase in the number of blood pressure measurements obtained and increased compliance with clinical guidelines regarding the monitoring of patients for persistent or worsening postpartum hypertension. OBJECTIVE: The aims of this study were to measure the program participant response rates during the first 10 days after hospital discharge, to assess the replicability and scalability of the program, and to evaluate patient satisfaction at 3 distinct sites. STUDY DESIGN: We conducted a prospective observational cohort study across 3 US academic medical centers during which postpartum participants with hypertensive disorders of pregnancy were enrolled in a previously validated, remote, text message-based blood pressure monitoring program known as Heart Safe Motherhood. English-speaking patients with access to a text message-enabled cell phone and with a diagnosis of hypertensive disorders of pregnancy were candidates for enrollment in the study. Each study site planned to enroll approximately 66 participants in this pilot implementation phase. All the enrolled participants received a validated blood pressure cuff, education on proper use of the device, and were sent text messages as a reminder to check their blood pressures twice daily for 10 days after discharge. They were asked to reply via text message with their blood pressure readings. All blood pressure readings were reviewed via a web-based platform by a physician. Physicians communicated with patients whose blood pressure levels exceeded 160 mm Hg systolic or 100 mm Hg diastolic to determine the next management steps. Enrollees were texted a survey at the end of the 10 days and the responses were recorded. The proportion of eligible parturients who were enrolled, the number of measured blood pressure values, and the postprogram survey results were measured. We assessed the number of patients who reported elevated blood pressures, required antihypertensive medication, and were readmitted for blood pressure control during the program duration. RESULTS: A total of 199 participants were enrolled in the program: 66 at site A, 67 at site B, and 66 at site C. In the 10 days after hospital discharge, 192 (97%) participants submitted at least 1 blood pressure measurement via text message. More enrolled patients submitted a blood pressure measurement on postpartum days 7 to 10 (171, 86%) than on days 1 to 4 (134, 67%). A total of 126 (63%) participants submitted blood pressures during both time frames. Elevated blood pressures were recorded for 70 (35%) participants, 32 (16%) of whom were started on oral antihypertensives after discussing their blood pressure measurements with an on-call provider. A total of 10 participants (5%) required hypertension-related readmission after delivery. The end-of-program survey was completed by 98 (49%) of the participants. Of those who completed the survey, 93% agreed that the program helped them to monitor their blood pressure (89% at site A; 88% at site B, and 100% at site C), and 93% would recommend it to friends or family members (94% at site A, 96% at site, and 88% at site C). CONCLUSION: Postpartum participants are willing and capable of using the Heart Safe Motherhood program for remote blood pressure monitoring and reported high satisfaction with the program across multiple sites. Our study demonstrated that this remote blood pressure monitoring program can be implemented successfully and demonstrated replicable efficacy at diverse sites.

Pregnancy-Related Hormones Increase UGT1A1-Mediated Labetalol Metabolism in Human Hepatocytes.

Pregnancy-related hormones (PRH) are recognized as important regulators of hepatic cytochrome P450 enzyme expression and function. However, the impact of PRH on the hepatic expression and function of uridine diphosphate glucuronosyltransferases (UGTs) remains unclear. Using primary human hepatocytes, we evaluated the effect of PRH exposure on mRNA levels and protein concentrations of UGT1A1, UGT2B7, and other key UGT enzymes, and on the metabolism of labetalol (a UGT1A1 and UGT2B7 substrate commonly prescribed to treat hypertensive disorders of pregnancy). Sandwich-cultured human hepatocytes (SCHH) from female donors were exposed to the PRH estradiol, estriol, estetrol, progesterone, and cortisol individually or in combination. We quantified protein concentrations of UGT1A1, UGT2B7, and four additional UGT1A isoforms in SCHH membrane fractions and evaluated the metabolism of labetalol to its glucuronide metabolites in SCHH. PRH exposure increased mRNA levels and protein concentrations of UGT1A1 and UGT1A4 in SCHH. PRH exposure also significantly increased labetalol metabolism to its UGT1A1-derived glucuronide metabolite in a concentration-dependent manner, which positively correlated with PRH-induced changes in UGT1A1 protein concentrations. In contrast, PRH did not alter UGT2B7 mRNA levels or protein concentrations in SCHH, and formation of the UGT2B7-derived labetalol glucuronide metabolite was decreased following PRH exposure. Our findings demonstrate that PRH alter expression and function of UGT proteins in an isoform-specific manner and increase UGT1A1-mediated labetalol metabolism in human hepatocytes by inducing UGT1A1 protein concentrations. These results provide mechanistic insight into the increases in labetalol clearance observed in pregnant individuals.

Risk factors for postpartum readmission for preeclampsia or hypertension before delivery discharge among low-risk women: a case-control study.

BACKGROUND: Postpartum hypertension or preeclampsia is one of the most frequent reasons for readmission after delivery discharge, and risk factors for readmission remain poorly characterized. OBJECTIVE: This study aimed to determine risk factors of postpartum readmission for hypertension or preeclampsia among low-risk women before delivery discharge. STUDY DESIGN: We conducted a nested case-control study from 2012 to 2015 at a tertiary care medical center. Cases were identified using diagnostic codes for postpartum transient hypertension, mild preeclampsia, severe preeclampsia, eclampsia, superimposed preeclampsia, and unspecified hypertension and readmission within 6 weeks of delivery. Controls not readmitted for hypertension or preeclampsia were time matched within 4 weeks of the delivery date to each case. We fit multivariable logistic regression models to identify independent risk factors for postpartum readmission for hypertension or preeclampsia and then calculated a receiver operating characteristic curve of the final model to assess model discrimination. RESULTS: Within the source cohort resulting in 58 cases and 232 matched controls, the rate of postpartum readmission for preeclampsia or hypertension was 0.4% (n=58 of 14,503). The median time to readmission was 6 days (range, 2-15 days), and 40% of cases had an outpatient postpartum visit before readmission. In multivariable analysis, non-Hispanic black race (adjusted odds ratio, 2.14; 95% confidence interval, 0.99-4.59), gestational hypertension (adjusted odds ratio, 2.70; 95% confidence interval, 1.12-6.54), preeclampsia during delivery admission (adjusted odds ratio, 3.12; 95% confidence interval, 1.29-7.50), and maximum postpartum systolic blood pressure during delivery admission (adjusted odds ratio, 1.05; 95% confidence interval, 1.03-1.08) were risk factors for readmission. This model had a good discriminative ability to predict women who would require readmission for preeclampsia or hypertension (area under the curve, 0.83; 95% confidence interval, 0.74-0.89). Using these 4 factors to illustrate this model, the predicted risk of readmission ranged from <1% in the lowest risk scenario (eg, postpartum systolic blood pressure of 120 mm Hg + no hypertensive disorders of pregnancy + white race) to 26% in the highest risk scenario (eg, postpartum systolic blood pressure of 160 mm Hg + preeclampsia + black race). CONCLUSION: Risk factors of postpartum readmission for hypertension or preeclampsia can be identified at the time of delivery discharge among low-risk women, regardless of an antenatal hypertensive disorder. A next step could be using these risk factors to develop a predictive model to guide postpartum care.

Risk factors associated with prolonged neonatal intensive care unit stay after threatened late preterm birth.

OBJECTIVE: To identify risk factors associated with neonatal intermediate or intensive care unit (NICU) stay ≥3 days among women with threatened late preterm birth (PTB). STUDY DESIGN: Secondary analysis of women with nonanomalous, singleton gestations enrolled in multicenter trial of betamethasone versus placebo for late PTB. Maternal and obstetric characteristics at time of presentation with threatened PTB were compared between those with and without NICU stay ≥3 days. Multivariable logistic regression identified risk factors for NICU stay ≥3 days. RESULT: Of 2795 eligible mother-neonate dyads, 962 (34%) had NICU stay ≥3 days. Gestational age and fetal growth restriction as the reason for threatened PTB had the strongest association with NICU stay ≥3 days in the final model (AUC 0.76). CONCLUSION: Maternal and obstetric characteristics at the time of admission for threatened late PTB should be considered when counseling patients about the probability of NICU stay ≥3 days.

Missed Opportunities for Early Diabetes Screening in Pregnancy.

OBJECTIVE: This study aimed to identify characteristics of women at risk of undiagnosed type 2 diabetes mellitus (T2DM) that fail to receive early pregnancy screening. STUDY DESIGN: This was a retrospective case-control study of at-risk women who initiated care at the University of North Carolina at Chapel Hill at <21 weeks from January 2015 to December 2015. In 2013, the American College of Obstetricians and Gynecologists and the American Diabetes Association recommended women with prior GDM, glucose intolerance, or body mass index (BMI) ≥ 30 kg/m2 receive early pregnancy screening for undiagnosed T2DM. We defined early screening as 1-hour 50-g glucose challenge test or hemoglobin A1c at <21 weeks' gestation. Cases were women who did not have early screening, and controls were women who did. Modified Poisson regression with robust error variance estimated relative risks of factors associated with missed early screening. RESULTS: Of the 1,932 women who initiated care at <21 weeks, 257 (13%) women were at risk of undiagnosed T2DM and, thus, candidates for early screening. However, 129 (50.2%) women were not screened. Higher BMI and prior GDM were associated with a lower relative risk of missed screening. CONCLUSION: Higher BMI and prior GDM increased the likelihood of early diabetes screening, but only half of at-risk women were screened. Provider education and best practice alert systems are needed to increase screening for undiagnosed T2DM.

Epidemiology of readmissions in early infancy following nonelective cesarean delivery.

OBJECTIVE: Determine incidence and risk factors for readmissions in early infancy. STUDY DESIGN: Secondary analysis of data from the Cesarean Section Optimal Antibiotic Prophylaxis trial. All unplanned revisits (unplanned clinic, ER visits, and hospital readmissions) and hospital readmissions (initial discharge to 3-month follow-up) were analyzed. RESULTS: 295 (15.9%) of 1850 infants had revisits with risk factors being ethnicity (adjusted odds ratio (aOR): 0.6 for Hispanic), maternal postpartum antibiotics (1.89), azithromycin treatment (1.22), small for gestational age (1.68), apnea (3.82), and hospital stay after birth >90th percentile (0.49). 71 (3.8%) of 1850 infants were readmitted with risk factors being antenatal steroids (aOR 2.49), elective repeat C/section (0.72), postpartum maternal antibiotics (2.22), O2 requirement after delivery room (2.82), and suspected/proven neonatal sepsis (0.55). CONCLUSION(S): Multiple risk factors were identified, suggesting potential impact on the neonatal microbiome (maternal postpartum antibiotics) or issues related to access/cost of care (Hispanic ethnicity associated with fewer revisits).

Pregnancy-Related Hormones Increase Nifedipine Metabolism in Human Hepatocytes by Inducing CYP3A4 Expression.

Pregnancy-related hormones (PRH) have emerged as key regulators of hepatic cytochrome P450 (CYP) enzyme expression and function. The impact of PRH on protein levels of CYP3A4 and other key CYP enzymes, and the metabolism of nifedipine (a CYP3A4 substrate commonly prescribed during pregnancy), was evaluated in primary human hepatocytes. Sandwich-cultured human hepatocytes (SCHH) from female donors were exposed to PRH (estradiol, estriol, estetrol, progesterone, and cortisol), individually or in combination as a cocktail. Absolute protein concentrations of twelve CYP isoforms in SCHH membrane fractions were quantified by nanoLC-MS/MS, and metabolism of nifedipine to dehydronifedipine in SCHH was evaluated. PRH significantly increased CYP3A4 protein concentrations and nifedipine metabolism to dehydronifedipine in a concentration-dependent manner. CYP3A4 mRNA levels in hepatocyte-derived exosomes positively correlated with CYP3A4 protein levels and dehydronifedipine formation in SCHH. PRH also increased CYP2B6, CYP2C8 and CYP2A6 levels. Our findings demonstrate that PRH increase nifedipine metabolism in SCHH by inducing CYP3A4 expression and alter expression of other key CYP proteins in an isoform-specific manner, and suggest that hepatocyte-derived exosomes warrant further investigation as biomarkers of hepatic CYP3A4 metabolism. Together, these results offer mechanistic insight into the increases in nifedipine metabolism and clearance observed in pregnant women.

Outpatient Penicillin Allergy Testing in Pregnant Women Who Report an Allergy.

OBJECTIVE: To estimate the feasibility, acceptability, and safety of outpatient penicillin allergy testing among pregnant women. METHODS: We conducted a prospective cohort study at a large academic hospital from March 2019 to March 2020. We recruited pregnant women with a self-reported penicillin allergy who underwent allergy testing between 14 0/7 and 36 6/7 weeks of gestation. RESULTS: Of 127 eligible women pregnant women, 74 (58%, 95% CI 4-67%) accepted allergy testing. Fifty completed or intended to complete allergy testing, yielding a feasibility rate of 68% (95% CI 56-78%). Among the 46 women actually tested (who ranged in age from 18 to 42), 93% (95% CI 68-100%) had a negative test result. A systemic reaction (symptoms consistent with anaphylaxis) occurred in only 2 women (4%, 95% CI 0.5-15%) despite 20 (43%) reporting a severe allergy. No woman suffered an adverse event as a result of allergy testing. In multivariate analysis adjusting for age and parity, women with public insurance had decreased odds of undergoing penicillin allergy testing (adjusted odds ratio 0.24, 95% CI 0.08-0.69). CONCLUSION: Outpatient penicillin allergy testing is acceptable and feasible in pregnancy.

Performance of a proteomic preterm delivery predictor in a large independent prospective cohort.

BACKGROUND: Preterm birth remains a common and devastating complication of pregnancy. There remains a need for effective and accurate screening methods for preterm birth. Using a proteomic approach, we previously discovered and validated (Proteomic Assessment of Preterm Risk study, NCT01371019) a preterm birth predictor comprising a ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin. OBJECTIVE: To determine the performance of the ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin to predict both spontaneous and medically indicated very preterm births, in an independent cohort distinct from the one in which it was developed. STUDY DESIGN: This was a prospective observational study (Multicenter Assessment of a Spontaneous Preterm Birth Risk Predictor, NCT02787213) at 18 sites in the United States. Women had blood drawn at 170/7 to 216/7 weeks' gestation. For confirmation, we planned to analyze a randomly selected subgroup of women having blood drawn between 191/7 and 206/7 weeks' gestation, with the results of the remaining study participants blinded for future validation studies. Serum from participants was analyzed by mass spectrometry. Neonatal morbidity and mortality were analyzed using a composite score by a method from the PREGNANT trial (NCT00615550, Hassan et al). Scores of 0-3 reflect increasing numbers of morbidities or length of neonatal intensive care unit stay, and 4 represents perinatal mortality. RESULTS: A total of 5011 women were enrolled, with 847 included in this planned substudy analysis. There were 9 preterm birth cases at <320/7 weeks' gestation and 838 noncases at ≥320/7 weeks' gestation; 21 of 847 infants had neonatal composite morbidity and mortality index scores of ≥3, and 4 of 21 had a score of 4. The ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin ratio was substantially higher in both preterm births at <320/7 weeks' gestation and there were more severe neonatal outcomes. The ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin ratio was significantly predictive of birth at <320/7 weeks' gestation (area under the receiver operating characteristic curve, 0.71; 95% confidence interval, 0.55-0.87; P=.016). Stratification by body mass index, optimized in the previous validation study (22

Trends in Opioid and Psychotropic Prescription in Pregnancy in the United States From 2001 to 2015 in a Privately Insured Population : A Cross-sectional Study.

BACKGROUND: Opioid and psychotropic prescriptions are common during pregnancy. Little is known about coprescriptions of both medications in this setting. OBJECTIVE: To describe opioid prescription among women who are prescribed psychotropics compared with women who are not. DESIGN: Cross-sectional study. SETTING: U.S. commercial insurance beneficiaries from MarketScan (2001 to 2015). PARTICIPANTS: Pregnant women at 22 weeks' gestation or greater who were insured continuously for 3 months or more before pregnancy through delivery. MEASUREMENTS: Opioid prescription, dosage thresholds (morphine milligram equivalents [MME] of ≥50/day and ≥90/day), number of opioid agents (≥2), and duration (≥30 days) among those with and without prescription of psychotropics, from 2011 to 2015. RESULTS: Among 958 980 pregnant women, 10% received opioids only, 6% psychotropics only, and 2% opioids with coprescription of psychotropics. Opioid prescription was higher among women prescribed psychotropics versus those who were not (26.5% vs. 10.7%). From 2001 to 2015, psychotropic prescription overall increased from 4.4% to 7.6%, opioid prescription without coprescription of psychotropics decreased from 11.9% to 8.4%, and opioids with coprescription decreased from 28.1% to 22.0%. Morphine milligram equivalents of 50 or greater per day decreased for women with and without coprescription (29.6% to 17.3% and 22.8% to 18.5%, respectively); MME of 90 or greater per day also decreased in both groups (15.0% to 4.7% and 11.5% to 4.2%, respectively). Women prescribed opioids only were more likely to have an antepartum hospitalization compared with those with neither prescription, as were women with coprescription versus those prescribed psychotropics only. Compared with those prescribed opioids only, women with coprescriptions were more likely to exceed MME of 90 or greater per day and to be prescribed 2 or more opioid agents and for 30 days or longer. Number and duration of opioids increased with benzodiazepine and gabapentin coprescription. LIMITATION: Inability to determine appropriateness of prescribing or overdose events. CONCLUSION: Opioids are frequently coprescribed with psychotropic medication during pregnancy and are associated with antepartum hospitalization. A substantial proportion of pregnant women are prescribed opioids at doses that increase overdose risk and exceed daily recommendations. PRIMARY FUNDING SOURCE: None.