Fetal membrane extracellular vesicle profiling reveals distinct pathways induced by infection and inflammation in vitro.

PROBLEM: Fetal inflammatory signals can be propagated to maternal tissues to initiate labor via exosomes (extracellular vesicles; 30-150 nm). We tested the hypothesis that fetal membrane cells exposed to infectious and inflammatory mediators associated with preterm birth (PTB) produce exosomes with distinct protein cargo contents indicative of underlying pathobiology. METHODS OF STUDY: Fetal membrane explants (FM) as well as primary amnion epithelial (AEC) and mesenchymal cells (AMC), and chorion cells (CC) from term deliveries were maintained in normal conditions (control) or exposed to LPS 100 ng/mL or TNF-α 50 ng/mL for 48 hours. Exosomes were isolated from media by differential centrifugation and size exclusion chromatography and characterized using cryo-electron microscopy (morphology), nanoparticle tracking analysis (size and quantity), Western blot (markers), and mass spectroscopy (cargo proteins). Ingenuity pathway analysis (IPA) determined pathways indicated by differentially expressed proteins. RESULTS: Irrespective of source or treatment, exosomes were spherical, had similar size, quantities, and markers (ALIX, CD63, and CD81). However, exosome cargo proteins were different between FM and individual fetal membrane cell-derived exosomes in response to treatments. Several common proteins were seen; however, there are several unique proteins expressed by exosomes from different cell types in response to distinct stimuli indicative of unique pathways and physiological functions in cells. CONCLUSIONS: We demonstrate collective tissue and independent cell response reflected in exosomes in response to infectious and inflammatory stimuli. These cargoes determined underlying physiology and their potential in enhancing inflammation in a paracrine fashion.

Multimodal Pain Management for Cesarean Delivery: A Double-Blinded, Placebo-Controlled, Randomized Clinical Trial.

OBJECTIVE: Our objective was to evaluate the efficacy of perioperative multimodal pain management in reducing opioid use after elective cesarean delivery (CD). STUDY DESIGN: A single-center, double-blinded, placebo-controlled randomized trial of women undergoing elective CD. Participants were allocated 1:1 to receive the multimodal protocol or matching placebos. The multimodal protocol consisted of a preoperative dose of intravenous acetaminophen, preincision injection of subcutaneous bupivacaine, and intraoperative injection of intramuscular ketorolac. Primary outcome was total opioid intake at 48 hours postoperatively. Secondary outcomes were pain scores, time to first opioid intake, neonatal outcomes, and total outpatient opioid intake on postoperative day (POD) 7. Data were analyzed using parametric and nonparametric tests and quantile regression as appropriate. RESULTS: A total of 242 women were screened with 120 randomized, 60 to the multimodal group and 60 to control group. There was no significant difference in the primary outcome of opioid use nor in the secondary outcomes. Smokers and patients with a history of drug use had higher median postoperative opiate use and earlier administration. On POD 7, only 40% of prescribed opioids had been used, and there was no difference between the groups. CONCLUSION: This perioperative multimodal pain regimen did not reduce opioid use in 48 hours after CD. Patients who smoke or with a history of drug use required more opioids in the postoperative period. Providers significantly overprescribed opioids after CD.

Effects of medication intake in early pregnancy on the fetal fraction of cell-free DNA testing.

OBJECTIVES: To determine the association between medications intake in early pregnancy and variation in the fetal fraction (FF) in pregnant women undergoing cell-free DNA (cfDNA) testing. METHODS: We performed a retrospective cohort study of women (n = 1051) undergoing cfDNA testing at an academic center. The exposed group included women taking medications (n = 400; 38.1%), while the nonexposed group consisted of women taking no medications (n = 651; 61.9%). Our primary outcome was FF. We performed univariate and multivariate analyses as appropriate. RESULTS: The FFs were 8.8% (6.6-12.1), 8.7% (6.3-11.6), and 7.7% (5.1-9.3) among women taking 0, 1, and two or more medications, respectively (P < 0.01). Using multivariable linear mixed effects model, the mean FF was significantly lower among those taking two or more medications compared with the nonexposed group. FF was directly correlated with gestational age at the time of cfDNA testing and inversely correlated with maternal obesity. Exposure to metformin was associated with 1.8% (0.2-3.4) lower mean FF when compared with the nonexposed group (P = 0.02). Obesity and intake of two or more medications were associated with higher hazard ratio of having a low FF less than 4%. CONCLUSIONS: Exposure to metformin or two or more medications was associated with decreased FF, and obesity is associated with delay in achieving adequate FF percentage. These findings should be considered while counseling patients on test limitations.

The Effect of Distraction during Labor Induction on Timing of Analgesia Request: A Randomized Clinical Trial.

OBJECTIVE: To assess whether distraction using music and/or video games influences timing of analgesia request and improves pain outcomes in women undergoing labor induction. STUDY DESIGN: A total of 219 pregnant women with singleton gestation undergoing labor induction with a Foley bulb (FB) at term were randomized to distraction with music and video games via iPod (n = 109) or no iPod (n = 110). The primary outcome was the time from FB placement to request for pain medication. Secondary outcomes included number of patients requesting pain medication within 6 and 12 hours, type of pain medication received, pain visual analog scale scores, and patient satisfaction. Mann-Whitney's, chi-square, Kaplan-Meier's curves, and Pearson's product moment correlation were used for statistical analysis (significance: p < 0.05). RESULTS: Baseline characteristics were similar between the two groups. There was no difference in the time from FB placement until pain medication request between the groups. There were no significant differences in secondary outcomes. Increased per cent time of iPod use correlated with a longer time until pain medication request (R 2 = 0.22, p = 0.03). CONCLUSION: We were not able to show that distraction using music and video games delays timing of analgesia request or improve pain outcomes in pregnant women undergoing mechanical labor induction at term.

Digoxin Therapy of Fetal Superior Ventricular Tachycardia: Are Digoxin Serum Levels Reliable?

BACKGROUND: Despite its seldom occurrence, fetal tachycardia can lead to poor fetal outcomes including hydrops and fetal death. Management can be challenging and result in maternal adverse effects secondary to high serum drug levels required to achieve effective transplacental antiarrhythmic drug therapy. CASE: A 33-year-old woman at 33 weeks of gestation with a diagnosis of a fetal sustained superior ventricular tachycardia developed chest pain, shortness of breath, and bigeminy on electrocardiogram secondary to digoxin toxicity despite subtherapeutic serum drug levels. She required supportive care with repletion of corresponding electrolyte abnormalities. After resolution of cardiac manifestations of digoxin toxicity, the patient was discharged home. The newborn was discharged at day 9 of life on maintenance amiodarone. CONCLUSION: We describe an interesting case of digoxin toxicity with cardiac manifestations of digoxin toxicity despite subtherapeutic serum drug levels. This case report emphasizes the significance of instituting an early diagnosis of digoxin toxicity during pregnancy, based not only on serum drug levels but also on clinical presentation. In cases of refractory supportive care, digoxin Fab fragment antibody administration should be considered. With timely diagnosis and treatment, excellent maternal and perinatal outcomes can be achieved.