Cotyledon-Specific Flow Evaluation of Rhesus Macaque Placental Injury Using Ferumoxytol Dynamic Contrast-Enhanced MRI.

BACKGROUND: Recently, dynamic contrast-enhanced (DCE) MRI with ferumoxytol as contrast agent has recently been introduced for the noninvasive assessment of placental structure and function throughout. However, it has not been demonstrated under pathological conditions. PURPOSE: To measure cotyledon-specific rhesus macaque maternal placental blood flow using ferumoxytol DCE MRI in a novel animal model for local placental injury. STUDY TYPE: Prospective animal model. SUBJECTS: Placental injections of Tisseel (three with 0.5 mL and two with 1.5 mL), monocyte chemoattractant protein 1 (three with 100 µg), and three with saline as controls were performed in a total of 11 rhesus macaque pregnancies at approximate gestational day (GD 101). DCE MRI scans were performed prior (GD 100) and after (GD 115 and GD 145) the injection (term = GD 165). FIELD STRENGTH/SEQUENCE: 3 T, T1-weighted spoiled gradient echo sequence (product sequence, DISCO). ASSESSMENT: Source images were inspected for motion artefacts from the mother or fetus. Placenta segmentation and DCE processing were performed for the dynamic image series to measure cotyledon specific volume, flow, and normalized flow. Overall placental histopathology was conducted for controls, Tisseel, and MCP-1 animals and regions of tissue infarctions and necrosis were documented. Visual inspections for potential necrotic tissue were conducted for the two Tisseelx3 animals. STATISTICAL TESTS: Wilcoxon rank sum test, significance level P < 0.05. RESULTS: No motion artefacts were observed. For the group treated with 1.5 mL of Tisseel, significantly lower cotyledon volume, flow, and normalized flow per cotyledon were observed for the third gestational time point of imaging (day ~145), with mean normalized flow of 0.53 minute-1 . Preliminary histopathological analysis shows areas of tissue necrosis from a selected cotyledon in one Tisseel-treated (single dose) animal and both Tisseelx3 (triple dose) animals. DATA CONCLUSION: This study demonstrates the feasibility of cotyledon-specific functional analysis at multiple gestational time points and injury detection in a placental rhesus macaque model through ferumoxytol-enhanced DCE MRI. LEVEL OF EVIDENCE: NA TECHNICAL EFFICACY: Stage 2.

Surgical transversus abdominis plane block with liposomal bupivacaine at cesarean: a pilot randomized trial.

BACKGROUND: Postcesarean pain control is challenging. In addition to intrathecal morphine, recent studies have shown that liposomal bupivacaine administered via conventional transversus abdominis plane block reduces postcesarean opioid use. However, whether the administration of liposomal bupivacaine via a surgical approach also reduces opioid use is unknown. OBJECTIVE: This study aimed to investigate whether the administration of liposomal bupivacaine via surgical transversus abdominis plane block (TAP block) reduces the cumulative dose of opioids administered in the first 48 hours after cesarean delivery among participants who also receive intrathecal morphine. STUDY DESIGN: This was a pilot single-blind randomized controlled trial of 60 parturients undergoing cesarean delivery at a community tertiary referral hospital staffed by academic physicians. Immediately before fascial closure during cesarean delivery, a total of 80 mL of dilute bupivacaine plus liposomal bupivacaine or dilute bupivacaine alone was administered via surgical transversus abdominis plane block (40 mL on each side). The primary outcome was a median cumulative opioid dose received within the first 48 hours after cesarean delivery measured in morphine milligram equivalents. In addition, opioid use at other time points, pain scores, and participant satisfaction were assessed. A sample size of 60 was determined to be adequate to inform a potential future adequately powered randomized trial. The primary outcome of morphine milligram equivalents and pain scores were compared using a Wilcoxon rank-sum test. RESULTS: Between October 11, 2021, and August 29, 2022, 60 participants were randomized and analyzed: 31 were allocated to liposomal bupivacaine plus regular bupivacaine (intervention group), and 29 were allocated to regular bupivacaine alone (control group). Participants allocated to the intervention group used a median cumulative dose of 2 morphine milligram equivalents of opioids (interquartile range, 0-24) in the first 48 hours compared with 8 morphine milligram equivalents (interquartile range, 0-40) among participants allocated to the control group (P=.236). The percentage of participants who used ≤15 morphine milligram equivalents of opioids was 61% in the intervention arm and 41% in the control arm (P=.123), and the percentage who used zero opioids was 45% in the intervention arm and 34% in the control arm (P=.399). The total number of opioid pills prescribed at discharge was fewer in the intervention arm than in the control arm (P=.029). Patient satisfaction with the intervention group and control group was similar. CONCLUSION: Our pilot study suggests that liposomal bupivacaine administered via surgical transversus abdominis plane block is worth critical evaluation as an adjunctive analgesic modality in an adequately powered randomized trial.

Frequent first-trimester pregnancy loss in rhesus macaques infected with African-lineage Zika virus.

In the 2016 Zika virus (ZIKV) pandemic, a previously unrecognized risk of birth defects surfaced in babies whose mothers were infected with Asian-lineage ZIKV during pregnancy. Less is known about the impacts of gestational African-lineage ZIKV infections. Given high human immunodeficiency virus (HIV) burdens in regions where African-lineage ZIKV circulates, we evaluated whether pregnant rhesus macaques infected with simian immunodeficiency virus (SIV) have a higher risk of African-lineage ZIKV-associated birth defects. Remarkably, in both SIV+ and SIV- animals, ZIKV infection early in the first trimester caused a high incidence (78%) of spontaneous pregnancy loss within 20 days. These findings suggest a significant risk for early pregnancy loss associated with African-lineage ZIKV infection and provide the first consistent ZIKV-associated phenotype in macaques for testing medical countermeasures.

Clinical application of a previously validated pregnancy-specific screening tool for sleep apnea in a cohort with a high prevalence of obesity.

Objective: The purpose of this project was to determine the positive predictive value of existing obstructive sleep apnea (OSA) screening tools in clinical use, in a real-world clinical population of gravidae, and to explore the development of a new questionnaire for screening for OSA during pregnancy. Methods: Pregnant people were administered sleep screening questionnaires as part of routine clinical care. These included Facco's four variable OSA screening tool, the STOP-BANG, and the Epworth Sleepiness Scale. Those who screened positive were referred for diagnostic sleep testing, typically with a type III home monitoring device. Here we analyzed the screening responses used by those who completed diagnostic testing to determine the positive predictive value of the existing tools. Results: 159 pregnant people completed diagnostic OSA testing and were included in this analysis. The positive predictive value of Facco's four variable sleep screening tool was 74.3%, STOP-BANG was 75.3%, and the Epworth Sleepiness Scale was 69.8%. Our sample size was insufficient to create a new screening tool. Conclusions: Here we calculated the positive predictive value of Facco's 4 variable screening tool for screening for OSA in pregnancy in a real-world pregnant population. While we were not able to generate a new screening tool for screening for OSA during pregnancy, both STOP-BANG and Facco's four variable tool had positive predictive values over 70% in our population which was characterized by high BMI and advanced maternal age. Increased clinical use of the pregnancy-specific tool may be warranted.

Continuous positive airway pressure treatment of obstructive sleep apnea and hypertensive complications in high-risk pregnancy.

PURPOSE: To evaluate whether or not continuous positive airway pressure (CPAP) treatment in pregnancies complicated by obstructive sleep apnea (OSA) is associated with a decrease in hypertensive disorders of pregnancy. METHODS: This was a retrospective cohort study of perinatal outcomes in women who underwent objective OSA testing and treatment as part of routine clinical care during pregnancy. Where diagnostic criteria for OSA were reached (respiratory event index (REI) ≥ 5 events per hour), patients were offered CPAP therapy. Obstetrical outcomes were compared between the control group (no OSA), the group with untreated OSA (OSA diagnosed, not CPAP compliant), and the group with treated OSA (OSA diagnosed and CPAP compliant), with CPAP compliance defined as CPAP use ≥ 4 h, 70% of the time or greater. A composite hypertension outcome combined diagnoses of gestational hypertension (gHTN) and preeclampsia (PreE) of any severity. RESULTS: The study comprised outcomes from 177 completed pregnancies. Our cohort was characterized by obesity, with average body mass indices > 35 kg/m2, and average maternal age > 30 years old. CPAP was initiated at an average gestational age of 23 weeks (12.1-35.3 weeks), and average CPAP use was 5.9 h (4-8.5 h). The composite hypertension outcome occurred in 43% of those without OSA (N = 77), 64% of those with untreated OSA (N = 77), and 57% of those with treated OSA, compliant with CPAP (N = 23) (p = 0.034). CONCLUSION: Real-world data in this small study suggest that CPAP therapy may modulate the increased risk of hypertensive complications in pregnancies complicated by OSA.

Does Daily Self-Weighing Contribute to Postpartum Weight Loss? A Secondary Analysis of Daily Postpartum Weights among Women with Hypertensive Disorders of Pregnancy.

OBJECTIVE: This study was aimed to examine the impact of daily self-weighing via remote monitoring on postpartum weight loss. STUDY DESIGN: This was a secondary analysis of a nonrandomized controlled trial comprised of postpartum women with diagnosed hypertensive-related disorders in pregnancy who received a tablet device linked to Bluetooth-enabled equipment including a scale and blood pressure cuff. In addition to blood pressure monitoring, participants were instructed to perform daily self-weighing. The primary outcome of this study was to determine whether postpartum women who performed daily self-weighing lost more weight than those who did not, with a 42-day endpoint based on a 6-week postpartum visit weight. RESULTS: Overall, 214 women participated in this program and 214 received usual care. Median weight loss for women participating in the remote blood pressure monitoring system was 23.0 (interquartile range [IQR]: 17-30) pounds versus 23.0 (IQR: 17-29) pounds among controls. Weight loss did not vary by prepregnancy obesity (median: 20 pounds [IQR: 17-28 pounds] for nonobese and 23 [IQR: 17-30] pounds for women with obesity, p = 0.16). Women who weighed themselves more than half of follow-up days lost a median of 24 pounds (IQR: 17-30 pounds) compared with 20.5 pounds (IQR: 14-29 pounds), p = 0.06. Women who weighed themselves more than half of follow-up days lost a mean of 11.4% (standard deviation [SD] = 0.41%) of body weight compared with 9.1% (SD = 0.74%; p = 0.01). The amount of weight loss in the telehealth group was correlated with the number of daily weights performed (Pearson's correlation coefficient 0.164, p = 0.025). Postpartum weight loss for daily self-weighing participants was most notable in the first 2 weeks with ongoing weight loss up to the 42-day (6-week) endpoint of this secondary analysis. CONCLUSION: Daily self-weighing alone may be insufficient to promote postpartum weight loss. However, there was a slight trend toward more weight loss with more frequent weighing. KEY POINTS: · Daily self-weighing is insufficient for postpartum weight loss.. · Women who weighed themselves more lost slightly more weight.. · Weight loss was the most notable in the first 2 weeks.. · Its use as one part of a program may be worth studying..

SERUM GLP-2 is Increased in Association with Excess Gestational Weight Gain.

OBJECTIVE: Obesity in pregnancy bears unique maternal and fetal risks. Obesity has also been associated with chronic inflammation, including elevated serum levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Higher serum lipopolysaccharide (LPS) levels have been implicated in driving this inflammation, a phenomenon called metabolic endotoxemia (ME). GLP-2, a proglucagon-derived peptide, is believed to be integral in maintaining the integrity of the intestine in the face of LPS-mediated endotoxemia. We hypothesized that obesity and/or excess weight gain in pregnancy would be associated with an increase in maternal and neonatal markers of ME, as well as GLP-2. STUDY DESIGN: Paired maternal and neonatal (cord blood) serum samples (n = 159) were obtained from our pregnancy biobank repository. Serum levels of LPS, endotoxin core antibody-immunoglobulin M (EndoCAb-IgM), and GLP-2 were measured by ELISA. IL-6 and TNF-α were measured using a Milliplex assay. Results were stratified by maternal body mass index (BMI), maternal diabetes, and gestational weight gain (GWG). RESULTS: Maternal IL-6 is significantly decreased in the obese, diabetic cohort compared with the nonobese, nondiabetic cohorts (95.28 vs. 99.48 pg/mL, p = 0.047), whereas GLP-2 is significantly increased (1.92 vs. 2.89 ng/mL, p = 0.026). Neonatal TNF-α is significantly decreased in the obese cohort compared with the nonobese cohort (12.43 vs. 13.93 pg/mL, p = 0.044). Maternal GLP-2 is significantly increased in women with excess GWG compared with those with normal GWG (2.27 vs. 1.48 ng/mL, p = 0.014). We further found that neonatal IL-6 and TNF-α are negatively correlated with maternal BMI (-0.186, p = 0.036 and -0.179, p = 0.044, respectively) and that maternal and neonatal IL-6 showed a positive correlation (0.348, p < 0.001). CONCLUSION: Although we observed altered levels of markers of inflammation (IL-6 and TNF-α) with maternal obesity and diabetes, no changes in LPS or endoCAb-IgM were observed. We hypothesize that the increased GLP-2 levels in maternal serum in association with excess GWG may protect against ME in pregnancy. KEY POINTS: · Maternal serum levels of GLP-2, a proglucagon-derived peptide, are increased in obese, diabetic gravidae.. · Maternal serum GLP-2 levels are also increased in association with excess gestational weight gain compared with normal gestational weight gain.. · GLP-2 may be increased in association with obesity and weight gain to protect against metabolic endotoxemia in pregnancy..

Maternal, placental and fetal response to a non-viral, polymeric nanoparticle gene therapy in nonhuman primates.

Background: Currently, there are no placenta-targeted treatments to alter the in utero environment. Water-soluble polymers have a distinguished record of clinical relevance outside of pregnancy. We have demonstrated the effective delivery of polymer-based nanoparticles containing a non-viral human insulin-like 1 growth factor ( IGF1 ) transgene to correct placental insufficiency in small animal models of fetal growth restriction (FGR). Our goal was to extend these studies to the pregnant nonhuman primate (NHP) and assess maternal, placental and fetal responses to nanoparticle-mediated IGF1 treatment. Methods: Pregnant macaques underwent ultrasound-guided intraplacental injections of nanoparticles ( GFP- or IGF1- expressing plasmid under the control of the trophoblast-specific PLAC1 promoter complexed with a HPMA-DMEAMA co-polymer) at approximately gestational day 100 (term = 165 days). Fetectomy was performed 24 h ( GFP ; n =1), 48 h ( IGF1 ; n = 3) or 10 days ( IGF1 ; n = 3) after nanoparticle delivery. Routine pathological assessment was performed on biopsied maternal tissues, and placental and fetal tissues. Maternal blood was analyzed for complete blood count (CBC), immunomodulatory proteins and growth factors, progesterone (P4) and estradiol (E2). Placental ERK/AKT/mTOR signaling was assessed using western blot and qPCR. Findings: Fluorescent microscopy and in situ hybridization confirmed placental uptake and transgene expression in villous syncytiotrophoblast. No off-target expression was observed in maternal and fetal tissues. Histopathological assessment of the placenta recorded observations not necessarily related to the IGF1 nanoparticle treatment. In maternal blood, CBCs, P4 and E2 remained within the normal range for pregnant macaques across the treatment period. Changes to placental ERK and AKT signaling at 48 h and 10 d after IGF1 nanoparticle treatment indicated an upregulation in placental homeostatic mechanisms to prevent over activity in the normal pregnancy environment. Interpretation: Maternal toxicity profile analysis and lack of adverse reaction to nanoparticle-mediated IGF1 treatment, combined with changes in placental signaling to maintain homeostasis indicates no deleterious impact of treatment. Funding: National Institutes of Health, and Wisconsin National Primate Research Center.

Racial disparities in post-operative pain experience and treatment following cesarean birth.

OBJECTIVE: To evaluate racial/ethnic differences in post-operative pain experience and opioid medication use (morphine milligram equivalent) in the first 24 h following cesarean birth. METHODS: This study was a single-center retrospective cohort of birthing persons who underwent cesarean deliveries between 1/1/16 and 12/31/17. A total of 2,228 cesarean deliveries were analyzed. The primary outcome was average pain, which was the mean of all documented self-reported pain scores (0-10 scale) during the first 24 h post-delivery. The secondary outcome included oral morphine equivalents used in the first 24 h post-delivery. Linear regression was performed to examine whether the race/ethnicity of the birthing parent was associated with mean pain scores and oral morphine equivalents, controlling for confounding variables. RESULTS: In multivariate analyses non-Hispanic Black birthing persons reported higher mean pain scores (Coefficient: 0.61, 95% confidence interval [0.39-0.82], p < .001]) than non-Hispanic White birthing persons, but received similar quantities of morphine milligram equivalent (Coefficient: -0.98 mg, 95% confidence interval [-5.93-3.97], p = .698]). Non-Hispanic Asian birthing persons reported similar reported mean pain scores to those of non-Hispanic White birthing persons (Coefficient: 0.02 mg, 95% confidence interval [-0.17-0.22], p = .834]), but received less morphine milligram equivalent (Coefficient: -5.47 mg, 95% confidence interval [-10.05 to -0.90], p = .019). When controlling for reported mean pain scores, both non-Hispanic Black (Coefficient: -6.36 mg, 95% confidence interval [-10.97 to -1.75], p = .007) and non-Hispanic Asian birthing persons (Coefficient: -5.66 mg, 95% confidence interval [-9.89 to -1.43], p = .009) received significantly less morphine milligram equivalents. CONCLUSION: Despite reporting higher mean pain scores, non-Hispanic Black birthing persons did not receive higher quantities of morphine milligram equivalent. Non-Hispanic Asian birthing persons received lower quantities of morphine milligram equivalent despite reporting similar pain scores to non-Hispanic White birthing persons. These differences suggest disparities in post-operative pain management for birthing persons of color in our study population.

Fetal loss in pregnant rhesus macaques infected with high-dose African-lineage Zika virus.

Countermeasures against Zika virus (ZIKV), including vaccines, are frequently tested in nonhuman primates (NHP). Macaque models are important for understanding how ZIKV infections impact human pregnancy due to similarities in placental development. The lack of consistent adverse pregnancy outcomes in ZIKV-affected pregnancies poses a challenge in macaque studies where group sizes are often small (4-8 animals). Studies in small animal models suggest that African-lineage Zika viruses can cause more frequent and severe fetal outcomes. No adverse outcomes were observed in macaques exposed to 1x104 PFU (low dose) of African-lineage ZIKV at gestational day (GD) 45. Here, we exposed eight pregnant rhesus macaques to 1x108 PFU (high dose) of African-lineage ZIKV at GD 45 to test the hypothesis that adverse pregnancy outcomes are dose-dependent. Three of eight pregnancies ended prematurely with fetal death. ZIKV was detected in both fetal and placental tissues from all cases of early fetal loss. Further refinements of this exposure system (e.g., varying the dose and timing of infection) could lead to an even more consistent, unambiguous fetal loss phenotype for assessing ZIKV countermeasures in pregnancy. These data demonstrate that high-dose exposure to African-lineage ZIKV causes pregnancy loss in macaques and also suggest that ZIKV-induced first trimester pregnancy loss could be strain-specific.

Shift work and sleep duration are associated with adverse pregnancy outcomes in a predominantly Latinx population with high rates of obesity.

BACKGROUND: Shift work has been associated with adverse pregnancy outcomes. The objective of this study was to evaluate the association between sleep disturbances and adverse pregnancy outcomes. METHODS AND FINDINGS: This was a secondary analysis of a prospective study of participants enrolled in a prospective observational study wherein gravidae were screened for sleep apnea (2010-2012). A screening questionnaire with standard sleep apnea questionnaires as well as novel items about shift work and nocturnal sleep duration was administered at a prenatal care visit. Short sleep duration was defined as less than 7 hours. Prolonged sleep duration was defined as greater than 9 hours. In a cohort of 1125 pregnant people, 9.4% reported shift work at the time of screening. Gravidae who reported shift work were more likely than gravidae who reported no shift work to develop preeclampsia (28.3% versus 13.0%, P<0.001), preeclamspsia with severe features (16.0% versus 8.5%, P = 0.010), gestational diabetes (28.3% versus 19.9%, P = 0.041), and a composite of adverse obstetric outcomes (61.3% versus 47.8%, P = 0.008). After adjusting for potentially confounding variables, shift work was associated with an increased risk for preeclampsia with (adjusted relative risk (aRR) 1.70, 95% CI 1.03-2.79, p = 0.036) and without (aRR 2.03, 95% CI 1.43-2.90, p<0.001) severe features, and gestational diabetes mellitus class A1 (aRR 1.47, 95% CI 1.05-2.05, p = 0.023) and class A2 (aRR 1.67, 95% CI 1.13-2.44, p = 0.009). Sleep duration was associated with gestational diabetes (31.3% among those with short sleep duration, 25.2% among those with normal sleep duration and 14.0% among those with prolonged sleep duration, P<0.001) and gestational diabetes class A2 (29.5%, 17.9%, and 10.1%, respectively, P<0.001). Gravidae with prolonged sleep duration experienced less composite adverse pregnancy outcomes at 42.6% compared to 57.4% for those with short sleep duration or 52.5% for those with normal sleep duration, P = 0.002. CONCLUSIONS: Shift work and sleep duration are both associated with adverse pregnancy outcomes. Further research on the impact of sleep disturbance on pregnancy outcomes is warranted.

Human immune globulin treatment controls Zika viremia in pregnant rhesus macaques.

There are currently no approved drugs to treat Zika virus (ZIKV) infection during pregnancy. Hyperimmune globulin products such as VARIZIG and WinRho are FDA-approved to treat conditions during pregnancy such as Varicella Zoster virus infection and Rh-incompatibility. We administered ZIKV-specific human immune globulin as a treatment in pregnant rhesus macaques one day after subcutaneous ZIKV infection. All animals controlled ZIKV viremia following the treatment and generated robust levels of anti-Zika virus antibodies in their blood. No adverse fetal or infant outcomes were identified in the treated animals, yet the placebo control treated animals also did not have signs related to congenital Zika syndrome (CZS). Human immune globulin may be a viable prophylaxis and treatment option for ZIKV infection during pregnancy, however, more studies are required to fully assess the impact of this treatment to prevent CZS.

Documented ß-Lactam Allergy and Risk for Cesarean Surgical Site Infection.

Objective: To examine the relationship between documented ß-lactam allergy and cesarean delivery (CD) surgical site infection (SSI). Study Design. We conducted a retrospective cohort analysis of women who underwent CD at Ben Taub Hospital and Texas Children's Pavilion for Women (Houston, TX) from August 1, 2011, to December 31, 2019. The primary exposure was a documented ß-lactam allergy, and the second exposure of interest was the type of perioperative antibiotic received. The primary outcome was the prevalence of SSI. Maternal characteristics were stratified by the presence or absence of a documented ß-lactam allergy, and significance was evaluated using Pearson's chi-squared test for categorical variables and t-test for continuous variables. A logistic regression model estimated odds of SSI after adjusting for possible confounders. Results: Of the 12,954 women included, 929 (7.2%) had a documented ß-lactam allergy while 12,025 (92.8%) did not. Among the 929 women with a ß-lactam allergy, 495 (53.3%) received non-ß-lactam perioperative prophylaxis. SSI occurred in 38 (4.1%) of women who had a ß-lactam allergy versus 238 (2.0%) who did not (p ≤ 0.001). ß-Lactam allergy was associated with higher odds of SSI compared to no allergy (adjusted odds ratio (aOR) = 1.97; 95%confidence interval (CI) = 1.24-3.14; p = 0.004) after controlling for age, race, ethnicity, insurance status, delivery body mass index (BMI), tobacco use, intra-amniotic infection in labor, duration of membrane rupture, preterm delivery, delivery indication, diabetes, hypertension, group B Streptococcus colonization, and type of perioperative antibiotic received. Conclusion: The presence of a ß-lactam allergy is associated with increased odds of developing a CD SSI after controlling for possible confounders, including the type of perioperative antibiotic received.

Weight gain in pregnancy: can metformin steady the scales?

OBJECTIVE: Metformin has been associated with modest weight reduction in the non-pregnant population. Our hypothesis is that metformin exposure will lead to a higher incidence of appropriate weight gain during pregnancy. STUDY DESIGN: This was a retrospective cohort study in a single center between 2009 and 2019. We included all pregnant women with type 2 diabetes or prediabetes. We compared women exposed to metformin in any trimester. The primary outcome was appropriate weight gain defined by the Institute of Medicine guidelines. Secondary outcomes included excessive weight gain, weight loss, suspected fetal growth restriction (FGR), and mean birth weight. Adjusted odds ratios or group differences were calculated using logistic or linear regression, controlling for confounders. RESULTS: Of 41,472 deliveries during the study period, 511 pregnancies met inclusion criteria. 284 pregnancies had no metformin exposure; 227 did have metformin exposure, of which 169 (72.2%) were initiated on metformin in the first trimester. Women exposed to metformin in any trimester were statistically not more likely to have appropriate weight gain (aOR 1.53 (95% CI 1.00-2.34, p = .048), but did have less excess weight gain (aOR 0.45, 95% CI 0.30-0.66, p < .001), and more maternal weight loss (aOR 2.17, 95% CI 1.18-3.98, p = .012) than the unexposed group. Women exposed to metformin in the first trimester of pregnancy were less likely to have excess weight gain (aOR 0.39, 95% CI 0.25-0.61, p < .001) and more likely to have maternal weight loss (aOR 2.56, 95% CI 1.30-5.07, p = .007) than the unexposed cohort. There was no difference in FGR (5.3% vs 2.5% p = .094) or mean birth weight (3235.6 vs 3352.4 gm p = .122) in the metformin exposed group vs non-exposed groups, respectively. CONCLUSIONS: Metformin exposure in pregnancy was associated with less excess weight gain and a higher rate of weight loss. There was no difference in FGR or mean birth weight in metformin exposed neonates. This suggests that metformin may help avoid excess weight gain and its associated comorbidities.

The impact of preexisting maternal anxiety on pain and opioid use following cesarean delivery: a retrospective cohort study.

BACKGROUND: Anxiety disorders are the most common mental health condition. They are associated with negative pain experiences and can hinder rehabilitation in the hospital setting. Anxiety has been shown to be predictive of increased postoperative pain in patients undergoing nonobstetrical surgery. OBJECTIVE: To evaluate the impact of preexisting maternal anxiety disorders on average self-reported pain scores and opioid use in the first 24 hours following cesarean delivery STUDY DESIGN: This was a single-center retrospective cohort study of cesarean deliveries between January 1, 2016 and December 31, 2017. The primary outcome was average pain, calculated by averaging all documented self-reported pain scores (0-10 scale) during the first 24 hours postdelivery. The secondary outcome included the oral morphine milligram equivalents used in the first 24 hours postdelivery. Analysis of the impact of anxiety disorders on these outcomes was performed using multivariable linear regression to control for confounding variables. RESULTS: A total of 2228 cesarean deliveries were analyzed, of which 578 (25.9%) had an anxiety disorder documented. Women with a diagnosis of anxiety had higher average pain scores (3.9 vs 3.5; P<.001) and morphine milligram equivalents use (110.4 mg vs 102.2 mg; P<.001) than women without anxiety. CONCLUSION: Patients with preexisting anxiety diagnoses reported higher average pain scores and opioid pain medication use in the first 24 hours following cesarean delivery.

Postoperative Respiratory Compromise following Cesarean Birth: The Impact of Obesity and Systemic Opioids.

Objective The aim of this study was to measure the effect of obesity and systemic opioids on respiratory events within the first 24 hours following cesarean. Methods Opioid-naive women undergoing cesarean between January 2016 and December 2017 were included in this retrospective cohort study. The primary outcome was the proportion of women experiencing at least one composite respiratory outcome (oxygen saturation less than 95% lasting 30+ seconds or need for respiratory support) within 24 hours of cesarean. The impact of obesity and total systemic opioid dose in 24 hours (measured in morphine milligram equivalents [MMEs]) on the composite respiratory compromise outcome were evaluated. Results Of 2,230 cesarean births, 790 women had at least one composite respiratory event. Predictors of the composite respiratory outcome included body mass index (BMI) as a continuous variable (odds ratio = 1.063 for every one unit increase in BMI [95% confidence interval (CI): 1.021-1.108], p = 0.003), and MME (odds ratio = 1.005 [95% CI: 1.002-1.008], p = 0.003), adjusting for magnesium sulfate use. The interaction between obesity and opioid dose demonstrated an odds ratio of 1.000 (95% CI: 0.999-1.000, p = 0.030). Conclusion The proportion of women experiencing respiratory events following cesarean birth increases with the degree of obesity and opioid dose. Key Points Respiratory events increase with obesity.Respiratory events increase with systemic opioid use.Odds ratio of respiratory events is 1.063/unit BMI increase.

A standardized post-cesarean analgesia regimen reduces postpartum opioid use.

BACKGROUND: Optimal post-cesarean pain control is important. With the rising opioid epidemic it is imperative to maximize non-opioid based primary approaches to post-cesarean pain control. In 2018, we implemented a standardized post-cesarean analgesia regimen. OBJECTIVE: To determine if implementation of a standardized postoperative analgesic regimen decreases opioid use following cesarean birth. STUDY DESIGN: A standardized postoperative analgesia protocol was implemented in June 2018, which included scheduled oral acetaminophen (975 mg every 6 h) and nonsteroidal anti-inflammatory drugs (NSAIDs) (ketorolac 15 mg IV every 6 h for 5 doses followed by ibuprofen 600 mg oral every 6 h) with opioids available for breakthrough pain. There was no prior standardized protocol. A before-and-after study design was used to compare oral morphine milligram equivalents (MME) for nine months prior to and nine months after this protocol was implemented, excluding the two month period of protocol rollout. Women with opioid use disorder or postoperative intubation were excluded. The primary outcome was the cumulative MME used in the first 72 h postoperatively. Total dose at 12, 24, and 48 h were also compared. RESULTS: Of 2340 women who underwent cesarean birth during the study period (1 July 2017 - 30 April 2019), 2001 women met inclusion criteria (914 before 10 April 2018 (pre-protocol) and 1087 after 17 June 2018 (post-protocol)). Baseline characteristics of the two groups were similar, including gestational age at delivery, maternal body mass index (BMI), planned versus unplanned cesarean birth, and type of intraoperative anesthesia used. The cumulative opioid dose in the first 72 h postoperatively was 216.3 ± 84.3 MME prior to implementation compared to 171.5 ± 91.5 MME following implementation (p < .001). The average cumulative MME use was higher in the pre-protocol period compared to post-protocol at all time periods: 12 h (57.3 ± 23.8 vs 48.6 ± 26.2 MME, p < .001), 24 h (98.1 ± 34.1 vs 82.1 ± 38.8 MME, p < .001), and 48 h (165.8 ± 58.3 vs 134.9 ± 66.2 MME, p < .001). The average pain scores were lower in the pre-protocol group (3 vs 3.3, p < .001). CONCLUSION: Scheduled administration of acetaminophen and NSAIDs following cesarean birth significantly decreased the cumulative dose of opioids used in the first 72 h postoperatively.

Gestational Intermittent Hypoxia Induces Sex-Specific Impairment in Endothelial Mechanisms and Sex Steroid Hormone Levels in Male Rat Offspring.

Obstructive sleep apnea (OSA) is highly prevalent during gestation and is linked with adverse fetal outcomes. We examined whether gestational intermittent hypoxia (GIH), the main feature of OSA, leads to sex-specific alterations in cardiovascular function and vascular mechanisms in the offspring. Pregnant rats exposed to intermittent hypoxia or ambient air from gestation days 10 to 21 and their offspring were used for the study. GIH exposure did not affect water and food intake in dams. Compared to controls, the male and female offspring born to GIH dams were smaller in weight by 14% and 12%, respectively, and exhibited catch-up growth. Cardiac function was not affected in either GIH males or females. At 12 weeks of age, blood pressure was increased in GIH males, but not GIH females, compared to their control counterparts. While mesenteric arterial contractile responses to phenylephrine and endothelin were unaffected in GIH males and females, relaxation response to acetylcholine was reduced in GIH males but not GIH females. Relaxation to sodium nitroprusside was unaffected in both GIH males and females. Total eNOS expression was not affected, but phospho(Ser1177)-eNOS levels were decreased in GIH males. eNOS expression and its phosphorylation status were unaffected in GIH females. Serum testosterone and estradiol levels were higher in GIH males but were unaltered in GIH females. Together, these findings suggest that GIH leads to a sex-specific increase in blood pressure in adult male offspring with blunted endothelium-mediated relaxation, decreased eNOS activity, and elevated sex steroid hormone levels.