Understanding the effects of oxytocin receptor variants on OXT-OXT receptor binding: A mathematical model.

Approximately half of U.S. women giving birth annually receive Pitocin, the synthetic form of oxytocin (OXT), yet its effective dose can vary significantly. This variability presents safety concerns due to unpredictable responses, which may lead to adverse outcomes for both mother and baby. To address the need for improved dosing, we developed a data-driven mathematical model to predict OXT receptor (OXTR) binding. Our study focuses on five prevalent OXTR variants (V45L, P108A, L206V, V281M, and E339K) and their impact on OXT-OXTR binding dynamics in two distinct cell types: human embryonic kidney cells (HEK293T), commonly used in experimental systems, and human myometrial smooth muscle cells, containing endogenous OXTR. We parameterized the model with cell-specific OXTR surface localization measurements. To strengthen the robustness of our study, we conducted a comprehensive meta-analysis of OXT- OXTR binding, enabling parameterization of our model with cell-specific OXT-OXTR binding kinetics (myometrial OXT-OXTR K d = 1.6 nM, kon = 6.8 × 10 5 M -1 min -1 , and koff = 0.0011 min -1 ). Our meta-analysis revealed significant homogeneity in OXT-OXTR affinity across experiments and species with a K d = 0.52 - 9.32 nM and mean K d = 1.48 ± 0.36 nM. Our model achieves several valuable insights into designing dosage strategies. First, we predicted that the OXTR complex reaches maximum occupancy at 10 nM OXT in myometrial cells and at 1 µM in HEK293T cells. This information is pivotal for guiding experimental design and data interpretation when working with these distinct cell types, emphasizing the need to consider effects for specific cell types when choosing OXTR-transfected cell lines. Second, our model recapitulated the significant effects of genetic variants for both experimental and physiologically relevant systems, with V281M and E339K substantially compromising OXT-OXTR binding capacity. These findings suggest the need for personalized oxytocin dosing based on individual genetic profiles to enhance therapeutic efficacy and reduce risks, especially in the context of labor and delivery. Third, we demonstrated the potential for rescuing the attenuated cell response observed in V281M and E339K variants by increasing the OXT dosage at specific, early time points. Cellular responses to OXT, including Ca 2+ release, manifest within minutes. Our model indicates that providing V281M- and E339K-expressing cells with doubled OXT dose during the initial minute of binding can elevate OXT-OXTR complex formation to levels comparable to wild-type OXTR. In summary, our study provides a computational framework for precision oxytocin dosing strategies, paving the way for personalized medicine.

Dietary risk factors for hypertensive disorders of pregnancy.

OBJECTIVE: To assess whether diet quality and specific dietary components are associated with hypertensive disorders of pregnancy (HDP). STUDY DESIGN: Nested case control study in a prospectively collected cohort of 450 participants with singleton pregnancies who completed the National Institutes of Health Diet Health Questionnaire II (DHQ-II) in the third trimester or within 3 months of delivery. Patients with fetal anomalies, conception by in-vitro fertilization, and deliveries at outside hospitals were excluded from the original prospective cohort study. Cases were patients diagnosed with HDP and controls were patients without HDP. Cases and controls were matched by BMI class in a 1:2 ratio. Exposures of interest were HEI-2015 score components and other DHQ-II dietary components including minerals, caffeine, and water. These dietary components were compared between cohorts using univariate analyses. MAIN OUTCOME MEASURES: HEI-2015 total scores representing diet quality, component scores, and objective background data between patients with HDP and patients without HDP. RESULTS: 150 patients with HDP were matched to 300 controls without HDP. Baseline demographics were similar between groups, including BMI. Patients with HDP were less likely to have high quality diets (HEI ≥ 70) than controls (7.3 % v 15.7 %, P = 0.02). HDP were associated with significantly higher dairy, saturated fat, and sodium intake compared to controls. Other components were similar between groups. CONCLUSION: Patients with HDP are more likely to have lower diet quality and higher consumption of sodium, dairy, and saturated fats. These results can be used to study antenatal diet modification in patients at high risk of HDP.

Quantification of surface-localized and total oxytocin receptor in myometrial smooth muscle cells.

Oxytocin acts through the oxytocin receptor (OXTR) to modulate uterine contractility. We previously identified OXTR genetic variants and showed that, in HEK293T cells, two of the OXTR protein variants localized to the cell surface less than wild-type OXTR. Here, we sought to measure OXTR in the more native human myometrial smooth muscle cell (HMSMC) line on both the cell-surface and across the whole cell, and used CRISPR editing to add an HA tag to the endogenous OXTR gene for anti-HA measurement. Quantitative flow cytometry revealed that these cells possessed 55,000 ± 3200 total OXTRs and 4900 ± 390 cell-surface OXTRs per cell. To identify any differential wild-type versus variant localization, we transiently transfected HMSMCs to exogenously express wild-type or variant OXTR with HA and green fluorescent protein tags. Total protein expression of wild-type OXTR and all tested variants were similar. However, the two variants with lower surface localization in HEK293T cells also presented lower surface localization in HMSMCs. Overall, we confirm the differential surface localization of variant OXTR in a more native cell type, and further demonstrate that the quantitative flow cytometry technique is adaptable to whole-cell measurements.

Risk of pre-term birth as a function of sleep quality and obesity: prospective analysis in a large Prematurity Research Cohort.

Study Objective: To investigate whether poor sleep quality is associated with pre-term birth (PTB) risk, overall and independent of sleep apnea and habitual snoring. Methods: We used longitudinal data from the Washington University Prematurity Research Cohort to investigate the association between poor sleep quality (defined as a Pittsburgh Sleep Quality Index > 5) and PTB, overall and independent of sleep apnea and snoring (defined by the Berlin questionnaire and prior sleep clinic attendance). Associations were investigated for sleep quality early and throughout pregnancy. Stratified analyses were performed by factors previously shown to modify associations between sleep and PTB (race, pre-pregnancy obesity). Results: Of the 976 eligible participants, 50.1% experienced poor sleep quality early in pregnancy (<20 completed weeks) and 14.2% delivered pre-term (n = 50 without and 89 with poor sleep quality). In multivariable-adjusted analyses, poor sleep quality early in pregnancy was associated with increased PTB risk (hazard ratio [HR] = 1.48, 95% confidence interval [CI] = 1.02-2.14). This association persisted after further adjustment for sleep apnea and snoring (HR = 1.50, 95% CI = 1.02-2.20) and in analyses stratified by race. It varied, however, by pre-pregnancy obesity. Among individuals without obesity, no association was observed between poor sleep and PTB (HR = 1.08, 95% CI = 0.65-1.79), whereas among those with obesity, a positive association was observed (HR = 2.94, 95% CI = 1.52-5.69, p-interaction = .05). This association was limited to individuals with obesity who experienced poor sleep both earlier and later in pregnancy (HR = 3.94, 95% CI = 1.56-9.99). Conclusion: Our findings suggest that improving sleep quality early in pregnancy may be important for PTB prevention, particularly among individuals with obesity.

Diabetes Group Prenatal Care: A Systematic Review and Meta-analysis.

OBJECTIVE: To estimate the effect of diabetes group prenatal care on rates of preterm birth and large for gestational age (LGA) among patients with diabetes in pregnancy compared with individual diabetes prenatal care. DATA SOURCES: We searched Ovid Medline (1946-), Embase.com (1947-), Scopus (1823-), Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov. METHODS OF STUDY SELECTION: We searched electronic databases for randomized controlled trials (RCTs) and observational studies comparing diabetes group prenatal care with individual care among patients with type 2 diabetes mellitus or gestational diabetes mellitus (GDM). The primary outcomes were preterm birth before 37 weeks of gestation and LGA (birth weight at or above the 90th percentile). Secondary outcomes were small for gestational age, cesarean delivery, neonatal hypoglycemia, neonatal intensive care unit admission, breastfeeding at hospital discharge, long-acting reversible contraception (LARC) uptake, and 6-week postpartum visit attendance. Secondary outcomes, limited to the subgroup of patients with GDM, included rates of GDM requiring diabetes medication (A2GDM) and completion of postpartum oral glucose tolerance testing (OGTT). Heterogeneity was assessed with the Cochran Q test and I2 statistic. Random-effects models were used to calculate pooled relative risks (RRs) and weighted mean differences. TABULATION, INTEGRATION, AND RESULTS: Eight studies met study criteria and were included in the final analysis: three RCTs and five observational studies. A total of 1,701 patients were included in the pooled studies: 770 (45.3%) in diabetes group prenatal care and 931 (54.7%) in individual care. Patients in diabetes group prenatal care had similar rates of preterm birth compared with patients in individual care (seven studies: pooled rates 9.5% diabetes group prenatal care vs 11.5% individual care, pooled RR 0.77, 95% CI, 0.59-1.01), which held for RCTs and observational studies. There was no difference between diabetes group prenatal care and individual care in rates of LGA overall (four studies: pooled rate 16.7% diabetes group prenatal care vs 20.2% individual care, pooled RR 0.93, 95% CI, 0.59-1.45) or by study type. Rates of other secondary outcomes were similar between diabetes group prenatal care and individual care, except patients in diabetes group prenatal care were more likely to receive postpartum LARC (three studies: pooled rates 46.1% diabetes group prenatal care vs 34.1% individual care, pooled RR 1.44, 95% CI, 1.09-1.91). When analysis was limited to patients with GDM, there were no differences in rates of A2GDM or postpartum visit attendance, but patients in diabetes group prenatal care were significantly more likely to complete postpartum OGTT (five studies: pooled rate 74.0% diabetes group prenatal care vs 49.4% individual care, pooled RR 1.58, 95% CI, 1.19-2.09). CONCLUSION: Patients with type 2 diabetes and GDM who participate in diabetes group prenatal care have similar rates of preterm birth, LGA, and other pregnancy outcomes compared with those who participate in individual care; however, they are significantly more likely to receive postpartum LARC, and those with GDM are more likely to return for postpartum OGTT. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42021279233.

Intrapartum electronic fetal monitoring features associated with a clinical diagnosis of nonreassuring fetal status.

BACKGROUND: Nonreassuring fetal status detected by continuous electronic fetal monitoring accounts for almost 1 in 4 primary cesarean deliveries. However, given the subjective nature of the diagnosis, there is a need to identify the electronic fetal monitoring patterns that are clinically considered nonreassuring. OBJECTIVE: This study aimed to describe which electronic fetal monitoring features are most commonly associated with first-stage cesarean delivery for nonreassuring fetal status, and to evaluate the risk of neonatal acidemia following cesarean delivery for nonreassuring fetal status. STUDY DESIGN: This was a nested case-control study in a prospectively collected cohort of patients with singleton pregnancies at ≥37 weeks' gestation, admitted in spontaneous labor or for induction of labor from 2010 to 2014 at a single tertiary care center. Patients with preterm pregnancies, multiple gestations, planned cesarean delivery, or nonreassuring fetal status in the second stage of labor were excluded. Cases were identified as having nonreassuring fetal status on the basis of what was documented in the operative note by the delivering physician. Controls were patients without nonreassuring fetal status within 1 hour of delivery. Cases were matched to controls in a 1:2 ratio by parity, obesity, and history of cesarean delivery. Electronic fetal monitoring data were abstracted by credentialed obstetrical research nurses for the 60 minutes before delivery. The primary exposure of interest was the incidence of high-risk category II electronic fetal monitoring features in the 60 minutes before delivery; in particular, the incidence of minimal variability, recurrent late decelerations, recurrent variable decelerations, tachycardia, and >1 prolonged deceleration were compared between groups. We also compared neonatal outcomes between cases and controls, including fetal acidemia (umbilical artery pH <7.1), other umbilical artery gas analytes, and neonatal and maternal outcomes. RESULTS: Of the 8580 patients in the parent study, 714 (8.3%) underwent cesarean delivery for nonreassuring fetal status in the first stage of labor. Patients diagnosed with nonreassuring fetal status requiring cesarean delivery were more likely to have recurrent late decelerations, >1 prolonged deceleration, and recurrent variable decelerations compared with controls. More than 1 prolonged deceleration was associated with 6 times increased rate of nonreassuring fetal status diagnosis resulting in cesarean delivery (adjusted odds ratio, 6.73 [95% confidence interval, 2.47-8.33]). Rates of fetal tachycardia were similar between groups. Minimal variability was less common in the nonreassuring fetal status group compared with controls (adjusted odds ratio, 0.36 [95% confidence interval, 0.25-0.54]). Compared with control deliveries, cesarean delivery for nonreassuring fetal status was associated with nearly 7 times higher risk of neonatal acidemia (7.2% vs 1.1%; adjusted odds ratio, 6.93 [95% confidence interval, 3.83-12.54]). Composite neonatal morbidity and composite maternal morbidity were more likely among patients delivered for nonreassuring fetal status in the first stage (3.9% vs 1.1%; adjusted odds ratio, 5.70 [2.60-12.49]; and 13.3% vs 8.0%; adjusted odds ratio, 1.99 [1.41-2.80]). CONCLUSION: Although multiple category II electronic fetal monitoring features have been traditionally linked to acidemia, the presence of recurrent late decelerations, recurrent variable decelerations, and prolonged decelerations seemed to concern obstetricians enough to surgically intervene for nonreassuring fetal status. A clinical intrapartum diagnosis of nonreassuring fetal status in the setting of these electronic fetal monitoring features is also associated with increased risk of acidemia, suggesting clinical validity to the diagnosis of nonreassuring fetal status.

Heterogeneity in management of category II fetal tracings: data from a multihospital healthcare system.

BACKGROUND: Electronic fetal monitoring is widely used to identify and intervene in suspected fetal hypoxia and/or acidemia. Category II fetal heart rate tracings are the most common class of fetal monitoring in labor, and intrauterine resuscitation is recommended given the association of category II fetal heart rate tracings with fetal acidemia. However, limited published data are available to guide intrauterine resuscitation technique selection, leading to heterogeneity in the response to category II fetal heart rate tracings. OBJECTIVE: This study aimed to characterize approaches to intrauterine resuscitation in response to category II fetal heart rate tracings. STUDY DESIGN: This was a survey study administered to labor unit nurses and delivering clinicians (physicians and midwives) across 7 hospitals in a Midwestern healthcare system spanning 2 states. The survey posed 3 category II fetal heart rate tracing scenarios (recurrent late decelerations, minimal variability, and recurrent variable decelerations) and asked participants to select first- and second-line intrauterine resuscitation management strategies. The participants were asked to quantify the level of influence certain factors have on their choice using a scale from 1 to 5. Intrauterine resuscitation strategy selection was compared by clinical role and hospital type (nurses vs delivering clinicians and university-affiliated hospital vs non-university-affiliated hospital). RESULTS: Of 610 providers invited to take the survey, 163 participated (response rate of 27%): 37% of participants from university-affiliated hospitals, 62% of nurses, and 37% of physicians. Maternal repositioning was the most selected first-line strategy, regardless of the type of category II fetal heart rate tracing. First-line management varied by clinical role and hospital affiliation for each fetal heart rate tracing scenario, particularly for minimal variability, which was associated with the most heterogeneity in the first-line approach. Previous experience and recommendations from professional societies were the most influential factors in intrauterine resuscitation selection overall. Of note, 16.5% of participants reported that published evidence did not influence their choice at all. Participants from a university-affiliated hospital were more likely than participants from a non-university-affiliated hospital to consider patient preference when selecting an intrauterine resuscitation technique. Nurses and delivering clinicians differed significantly in the rationale for management choices: nurses were more often influenced by advice from other healthcare providers on the team (P<.001), whereas delivering clinicians were more influenced by literature (P=.02) and ease of technique (P=.02). CONCLUSION: There was significant heterogeneity in the management of category II fetal heart rate tracing. In addition, motivations for choice in intrauterine resuscitation technique varied by hospital type and clinical role. These factors should be considered when creating fetal monitoring and intrauterine resuscitation protocols.

The Impact of Cervical Effacement at Time of Amniotomy in Patients Undergoing Induction of Labor.

OBJECTIVE: There is evidence to suggest that early amniotomy during induction of labor is advantageous. However, following cervical ripening balloon removal, the cervix remains less effaced and the utility of amniotomy in this setting is less clear. We investigated whether cervical effacement at the time of amniotomy impacts outcomes among nulliparas undergoing induction of labor. STUDY DESIGN: This was a secondary analysis of a prospective cohort of singleton, term, nulliparous patients at a tertiary care center undergoing induction of labor and amniotomy. The primary outcome was completion of the first stage of labor. Secondary outcomes were vaginal delivery and postpartum hemorrhage. Outcomes were compared between patients with cervical effacement ≤50% (low effacement) and >50% (high effacement) at time of amniotomy. Multivariable logistic regression was used calculate risk ratios (RR) to adjust for confounders including cervical dilation. Stratified analysis was performed in patients with cervical ripening balloon use. A post hoc sensitivity analysis was performed to further control for cervical dilation. RESULTS: Of 1,256 patients, 365 (29%) underwent amniotomy at low effacement. Amniotomy at low effacement was associated with reduced likelihood of completing the first stage (aRR: 0.87 [95% confidence interval, CI: 0.78-0.95]) and vaginal delivery (aRR: 0.87 [95% CI: 0.77-0.96]). Although amniotomy at low effacement was associated with lower likelihood of completing the first stage in all-comers, those who had amniotomy performed at low effacement following cervical ripening balloon expulsion were at the highest risk (aRR: 0.84 [95% CI: 0.69-0.98], p for interaction = 0.04) In the post hoc sensitivity analysis, including patients who underwent amniotomy at 3- or 4-cm dilation, low cervical effacement remained associated with a lower likelihood of completing the first stage of labor. CONCLUSION: Low cervical effacement at time of amniotomy, particularly following cervical ripening balloon expulsion, is associated with a lower likelihood of successful induction. KEY POINTS: · Low cervical effacement at amniotomy was associated with lower rates of complete dilation.. · Effacement at amniotomy is especially important for patients who had a cervical ripening balloon.. · Providers should consider cervical effacement when timing amniotomy for nulliparous term patients..

The relationship between maternal anemia and electronic fetal monitoring patterns.

BACKGROUND: Anemia is a commonly diagnosed comorbidity in pregnancy that is associated with increased risk of maternal and neonatal complications. Recent data demonstrate that maternal anemia is associated with higher umbilical artery and umbilical vein O2 content at the time of delivery. OBJECTIVE: This study aimed to examine the relationship between maternal anemia and electronic fetal monitoring patterns associated with fetal hypoxia. STUDY DESIGN: This is a secondary analysis of a prospective cohort study of singleton term deliveries with cord gases and universal complete blood count collected on admission between 2010 and 2014. Maternal anemia was defined as hemoglobin ≤11.0 g/dL on admission. The primary outcome was a composite of high-risk category 2 electronic fetal monitoring features in the last 60 minutes before delivery (recurrent late and/or variable decelerations, minimal variability, tachycardia, or >1 prolonged deceleration); secondary outcomes were total deceleration area and total deceleration area >90th percentile. Of the 8580 patients in the original study, 8196 were included in the analysis. Outcomes were compared between patients with and without anemia. Multivariable logistic regression was used to adjust for potentially confounding factors, including hypertensive disorders of pregnancy and induction of labor. RESULTS: Of the 8196 patients with complete blood count on admission and fetal monitoring data, 2672 (32.6%; 2672/8196) were anemic and 5524 (67.4%; 5524/8196) were not. Patients with anemia were significantly less likely to have composite high-risk category 2 features on electronic fetal monitoring (34.2% vs 32.0%; adjusted risk ratio, 0.93; 95% confidence interval, 0.86-0.99). Women with anemia also had decreased total deceleration area and were less likely to have total deceleration area >90th percentile (18.7% vs 16.2%; adjusted risk ratio, 0.85; 95% confidence interval, 0.77-0.94). CONCLUSION: Patients with anemia are less likely to have high-risk category 2 electronic fetal monitoring features associated with fetal hypoxia. This finding is consistent with the association between maternal anemia and increased umbilical cord O2 content, and suggests that maternal anemia may be protective against intrapartum fetal hypoxia.

Sphingosine 1-Phosphate Activates S1PR3 to Induce a Proinflammatory Phenotype in Human Myometrial Cells.

One of the common mechanisms responsible for obstetric complications, affecting millions of women every year, is abnormal uterine contractility. Despite the critical importance of this process for women's health, the mechanisms of uterine contraction regulation remain poorly understood. The initiation of uterine smooth muscle (myometrial) contraction is an inflammatory process, accompanied by upregulation of proinflammatory genes and cytokine release. In this study, we show that sphingolipid metabolism is activated during human labor and that sphingosine 1-phosphate (S1P), the main bioactive sphingolipid, may modify the myometrial proinflammatory phenotype. Our data in both primary and immortalized human myometrial cells show that exogenous S1P induces a proinflammatory gene signature and upregulates the expression of known inflammatory markers of parturition, such as IL8 and COX2. Using expression of IL8 as a readout for S1P activity in myometrial cells, we established that these S1P effects are mediated through the activation of S1P receptor 3 (S1PR3) and downstream activation of ERK1/2 pathways. Inhibition of S1PR3 in human myometrial cells attenuates upregulation of IL8, COX2, and JUNB both at the mRNA and protein levels. Furthermore, activation of S1PR3 with a receptor-specific agonist recapitulated the effects seen after treatment with exogenous S1P. Collectively, these results suggest a signaling pathway activated by S1P in human myometrium during parturition and propose new targets for development of novel therapeutics to alter uterine contractility during management of preterm labor or labor dystocia.

Video Instruction for Pushing in the Second Stage: a randomized controlled trial.

BACKGROUND: The second stage of labor requires active patient engagement. Previous studies suggest that coaching can influence the second stage of labor duration. However, a standardized education tool has not been established, and patients face many barriers to accessing childbirth education before delivery. OBJECTIVE: This study aimed to investigate the effect of an intrapartum video pushing education tool on the second stage of labor duration. STUDY DESIGN: This was a randomized controlled trial of nulliparous patients with singleton pregnancies ≥37 weeks of gestation admitted for induction of labor or spontaneous labor with neuraxial anesthesia. Patients were consented on admission and block randomized in active labor to 1 of 2 arms in a 1:1 ratio. The study arm viewed a 4-minute video before the second stage of labor on what to anticipate in the second stage of labor and pushing techniques. The control arm received the standard of care: bedside coaching at 10 cm dilation from a nurse or physician. The primary outcome was second stage of labor duration. The secondary outcomes were birth satisfaction (using the Modified Mackey Childbirth Satisfaction Rating Scale), mode of delivery, postpartum hemorrhage, clinical chorioamnionitis, neonatal intensive care unit admission, and umbilical artery gases. Of note, 156 patients were needed to detect a 20% decrease in the second stage of labor duration with 80% power, 2-sided alpha level of .05, and 10% loss after randomization. Funding was provided by the Lucy Anarcha Betsy award from the division of clinical research at Washington University. RESULTS: Of 161 patients, 81 were randomized to standard of care, and 80 were randomized to intrapartum video education. Among these patients, 149 progressed to the second stage of labor and were included in the intention-to-treat analysis: 69 in the video group and 78 in the control group. Maternal demographics and labor characteristics were similar between groups. The second stage of labor duration was statistically similar between the video arm (61 minutes [interquartile range, 20-140]) and the control arm (49 minutes [interquartile range, 27-131]) (P=.77). There was no difference in mode of delivery, postpartum hemorrhage, clinical chorioamnionitis, neonatal intensive care unit admission, or umbilical artery gases between groups. Although the overall birth satisfaction score on the Modified Mackey Childbirth Satisfaction Rating Scale was similar between groups, patients in the video group rated their "level of comfort during birth" and "attitude of the doctors in birth" significantly higher or more positively than patients in the control group (P<.05 for both). CONCLUSION: Intrapartum video education was not associated with a shorter second stage of labor duration. However, patients who received video education reported a higher level of comfort and a more favorable perception of their physician, suggesting that video education may be a helpful tool to improve the birth experience.

Efficacy of Postpartum Pharmacologic Thromboprophylaxis: A Systematic Review and Meta-analysis.

OBJECTIVE: To evaluate the effectiveness of pharmacologic venous thromboembolism (VTE) prophylaxis in postpartum patients. DATA SOURCES: On February 21, 2022, a literature search was conducted on Embase.com , Ovid-Medline All, Cochrane Library, Scopus, and ClinicalTrials.gov using terms postpartum period AND thromboprophylaxis AND antithrombin medications including heparin and low molecular weight heparin. METHODS OF STUDY SELECTION: Studies that evaluated the outcome of VTE among postpartum patients exposed to pharmacologic VTE prophylaxis with or without a comparator group were eligible for inclusion. Studies of patients who received antepartum VTE prophylaxis, studies in which this prophylaxis could not be definitively ruled out, and studies of patients who received therapeutic dosing of anticoagulation for specific medical problems or treatment of VTE were excluded. Titles and abstracts were independently screened by two authors. Relevant full-text articles were retrieved and independently reviewed for inclusion or exclusion by two authors. TABULATION, INTEGRATION, AND RESULTS: A total of 944 studies were screened by title and abstract, and 54 full-text studies were retrieved for further evaluation after 890 studies were excluded. Fourteen studies including 11,944 patients were analyzed: eight randomized controlled trials (8,001 patients) and six observational studies (3,943 patients). Among the eight studies with a comparator group, there was no difference in the risk of VTE between patients who were exposed to postpartum pharmacologic VTE prophylaxis and those who were unexposed (pooled relative risk 1.02, 95% CI 0.29-3.51); however, six of eight studies had no events in either the exposed or unexposed group. Among the six studies without a comparator group, the pooled proportion of postpartum VTE events was 0.00, likely due to five of six studies having no events. CONCLUSION: The current literature provided an insufficient sample size to conclude whether postpartum VTE rates differ between those exposed to postpartum pharmacologic prophylaxis and those unexposed, given the rarity of VTE events. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42022323841.

Association between Elevated Intrauterine Resting Tone during Labor and Neonatal Morbidity.

OBJECTIVE: Internal contraction monitoring provides a quantitative assessment of intrauterine resting tone. During the course of labor, elevated intrauterine resting tone may be identified. We hypothesized that elevated intrauterine resting tone could lead to compression of the spiral arteries, thus limiting uterine blood flow and resulting in neonatal compromise. Therefore, our objective was to assess the association between elevated resting tone during labor and neonatal morbidity. STUDY DESIGN: This was a secondary analysis of a prospective cohort study of singleton deliveries at ≥37 weeks of gestation. Patients with ruptured membranes and an intrauterine pressure catheter in place for at least 30 minutes prior to delivery were included. Intrauterine resting tone was calculated as the average baseline pressure between contractions during the 30 minutes prior to delivery. The study group had elevated intrauterine resting tone, defined as intrauterine resting tone ≥75th percentile (≥12.3 mm Hg). Primary outcome was composite neonatal morbidity: hypoxic-ischemic encephalopathy, hypothermia treatment, intubation, seizures, umbilical arterial pH ≤7.1, oxygen requirement, or death. Secondary outcomes included umbilical artery pH <7.2, lactate ≥4 mmol/L, and rates of neonatal intensive care unit admission. RESULTS: Of the 8,580 patients in the cohort, 2,210 (25.8%) met the inclusion criteria. The median intrauterine resting tone was 9.7 mm Hg (interquartile range: 7.3-12.3 mm Hg). Elevated resting tone was associated with a shorter median duration of the first stage of labor (10.0 vs. 11.0 hours, p < 0.01) and lower rates of labor induction and oxytocin augmentation (p < 0.01). Neonatal composite morbidity was higher among patients with elevated intrauterine resting tone (5.1 vs. 2.9%, p = 0.01). After adjusting for chorioamnionitis and amnioinfusion, elevated intrauterine resting tone was associated with increased risk of neonatal morbidity (adjusted odds ratio: 1.70, 95% confidence interval: 1.06-2.74). CONCLUSION: Our findings suggest that elevated intrauterine resting tone is associated with increased risk of neonatal composite morbidity. KEY POINTS: · Higher intrauterine resting tone is associated with increased risk of neonatal morbidity.. · Elevated intrauterine tone can negatively impact umbilical artery pH and lactate levels.. · If elevated intrauterine pressure is noted, we recommend close monitoring of fetal status..

Vaginal cleansing before unscheduled cesarean delivery to reduce infection: a randomized clinical trial.

BACKGROUND: Cesarean delivery is the most performed major surgery among women, and surgical-site infections following a cesarean delivery are a significant source of postoperative morbidity. It is unclear if vaginal cleansing before a cesarean delivery decreases post-cesarean delivery infectious morbidity. OBJECTIVE: This study aimed to evaluate if preoperative vaginal cleansing with povidone-iodine among women undergoing a cesarean delivery after labor decreases postoperative infectious morbidity. STUDY DESIGN: This randomized clinical trial was conducted from August 3, 2015 to January 28, 2021, with 30 days of follow-up and the final follow-up completed on February 27, 2021. Patients met the inclusion criteria if they underwent a cesarean delivery after regular contractions with cervical dilation, rupture of membranes, or any cesarean delivery performed at >4 cm dilation. Participants were randomly assigned in a 1:1 ratio to either abdominal cleansing plus vaginal cleansing with 1% povidone-iodine or abdominal cleansing alone. The primary outcome was composite infectious morbidity including surgical-site infection, fever, endometritis, and wound complications within 30 days after the cesarean delivery. Secondary outcomes included individual components of the composite, length of hospital stay, postoperative hospitalization or outpatient treatment related to infectious morbidity, and empirical treatment for neonatal sepsis. RESULTS: A total of 608 subjects (304 vaginal cleansing group, 304 control group) were included in the intention-to-treat analysis. Patient characteristics were similar between groups. There was no significant difference in the primary composite outcome between the 2 groups (11.8% vs 11.5%; P=.90; relative risk, 1.0; 95% confidence interval, 0.7-1.6). Individual components of the composite and secondary outcomes were also not significantly different between the groups. Similar findings were observed in the as-treated analysis (11.3% vs 11.8%; P=.9; relative risk, 1.0; 95% confidence interval, 0.7-1.6). CONCLUSION: Vaginal cleansing with povidone-iodine before an unscheduled cesarean delivery occurring after labor did not reduce the postoperative infectious morbidity. These findings do not support the routine use of vaginal cleansing for women undergoing a cesarean delivery after labor.

Association between Maternal Serum Lipids and Intrapartum Oxytocin Requirements during Labor Induction and Augmentation.

OBJECTIVE: This study aimed to investigate the relationship between maternal serum lipid parameters and oxytocin requirements among women with term vaginal deliveries. STUDY DESIGN: In this secondary analysis of a prospective cohort study, women who presented for delivery at ≥37 weeks' gestation and received oxytocin during their labor were included. Maternal serum was collected intrapartum. The cohort was stratified into two groups based on maximum oxytocin infusion dose during labor. Primary outcomes were maternal total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride levels. Generalized linear regression models were used to assess the association between lipid parameters and maximum oxytocin dose requirements while controlling for potential confounders. For secondary analyses, the cohort was stratified by HDL-C into two groups. Multivariable logistic regression was used to evaluate the relationship between low maternal HDL-C and additional intrapartum oxytocin parameters. RESULTS: There were no differences in maternal total cholesterol, LDL-C, or triglyceride values between high and low maximum oxytocin groups. Median serum HDL-C was significantly lower among women in the high oxytocin group compared with those in the low oxytocin group (56 vs. 62 mg/dL, p < 0.01). For every 0.26 mg/dL lower HDL-C, women had 1 mU/min higher maximum oxytocin infusion dose during labor. Women with low serum HDL-C were also more likely to require maximum oxytocin doses above the 75th percentile (adjusted odds ratio [aOR]: 1.99, 95% confidence interval [CI]: 1.06-3.75) and above the 90th percentile (aOR: 2.47, 95% CI: 1.10-5.54). Among women undergoing induction of labor, low serum HDL-C was also associated with longer duration of oxytocin infusion (aOR: 2.07, 95% CI: 1.02-4.20). CONCLUSION: Low maternal HDL-C levels at term are associated with higher maximum oxytocin infusion doses among women undergoing labor induction or augmentation. Given the growing prevalence of metabolic syndrome in the United States and persistently high rates of cesarean delivery, HDL-C or its components may present a new target for predicting and improving labor outcomes. KEY POINTS: · Serum HDL-C at term is inversely correlated with oxytocin infusion doses at term.. · Low maternal serum HDL-C is associated with higher oxytocin requirements during labor induction or augmentation.. · No association between maternal serum total cholesterol, LDL-C, or triglyceride levels and oxytocin requirements in labor..

One-Step Compared With Two-Step Gestational Diabetes Screening and Pregnancy Outcomes: A Systematic Review and Meta-analysis.

OBJECTIVE: To estimate short-term maternal and neonatal outcomes with one-compared with two-step testing for gestational diabetes mellitus (GDM). DATA SOURCES: A systematic review of randomized controlled trials (RCTs) and observational studies comparing one-step and two-step GDM testing strategies before September 2021 was conducted. We searched Ovid Medline (1946-), EMBASE (1947-), Scopus (1960-), Cochrane Central, and ClinicalTrials.gov . The primary outcome was rate of large-for-gestational age (LGA) neonates. Secondary outcomes were clinically relevant outcomes for GDM that were selected a priori. METHODS OF STUDY SELECTION: Titles, abstracts, and manuscripts were screened, selected, and reviewed by the first two authors. Four RCTs (24,966 patients) and 13 observational studies (710,677 patients) were analyzed. TABULATION, INTEGRATION, AND RESULTS: Pooled relative risks (RRs) were calculated with 95% CIs using random-effects models and were plotted graphically with forest plots. Study heterogeneity was evaluated using Cochran Q and Higgins I 2 tests. The quality of studies that met the inclusion criteria was evaluated with the Downs and Black checklist. Publication bias was assessed by using asymmetry of funnel plots and Harbord's test. There was no difference in the rate of LGA neonates (pooled RR 0.95; 95% CI 0.88-1.04) by testing strategy among RCTs, but patients who underwent one-step testing were more likely to be diagnosed with GDM (pooled RR 2.13; 95% CI 1.61-2.82) and treated with diabetes medications (pooled RR 2.24; 95% CI 1.21-4.15). One-step testing was associated with higher rates of neonatal intensive care unit (NICU) admission (pooled RR 1.12; 95% CI 1.00-1.26) and neonatal hypoglycemia (pooled RR 1.23; 95% CI 1.13-1.34). In analysis of high-quality RCTs and observational studies, one-step testing was associated with a lower rate of LGA neonates (pooled RR 0.97; 95% CI 0.95-0.98), but higher rates of GDM diagnosis, treatment, NICU admission, and neonatal hypoglycemia. CONCLUSION: Despite a significant increase in GDM diagnosis and treatment with one-step testing, there is no difference in rate of LGA neonates compared with two-step testing among RCTs. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42021252703.

Etiology and evaluation of stillbirth in patients with obesity.

OBJECTIVE: Maternal obesity is a risk factor for stillbirth, but whether or not the etiology of stillbirth differs in gravidas with and without obesity is unknown. We categorized stillbirths in a contemporary cohort to test the hypothesis that the etiology of stillbirth is different in gravidas with and without obesity. METHODS: This retrospective cohort study included all gravidas with a stillbirth ≥20 weeks' gestation between 2010 and 2017 and a normal mid-trimester anatomic survey by ultrasound assessment at a large academic institution. Pregnancies were excluded if delivery data were unavailable, a multifetal gestation was present, or there was an antenatally diagnosed fetal structural or genetic anomaly. Our primary exposure was maternal obesity, defined as a body mass index (BMI) ≥ 30 kg/m2 at the time of anatomic survey. Our primary outcome was stillbirth etiology, as classified by the initial causes of fetal death tool from the Stillbirth Collaborative Research Network and includes maternal, obstetric, hematologic, fetal, infectious, placental, other, or unexplained categories. Our secondary outcomes included the evaluation performed on each stillbirth, compliance with the recommended stillbirth evaluation by the American College of Obstetricians and Gynecologists (ACOG), and the percentage of abnormal results for each of the tests ordered for stillbirth evaluation. RESULTS: Of 118 stillbirths meeting the inclusion criteria, 44 (37.3%) occurred in gravidas with obesity and 74 (62.7%) were in patients without obesity. An obstetric complication was the most commonly identified etiology for stillbirth, found in 40.9% of cases with obesity versus in 29.7% of cases without obesity (aOR 1.09, 95% CI 0.47-2.66). The likelihood of any specific etiology of stillbirth was not significantly different in gravidas of the two weight groups, after controlling for confounders. However, assignment to the unexplained stillbirth category was significantly less common in women with obesity, compared to those without obesity (aOR 0.18, 95% CI 0.05-0.67). There was no difference in testing performed on each stillbirth between the groups. Compliance with the ACOG-recommended diagnostic evaluation for stillbirth was similar in the two groups but was only performed in 10.2% of all cases of stillbirth. Placental pathology was the test most likely to yield an abnormal result in both groups, but the percentage of abnormal results for this and all other tests was the same in the presence and absence of obesity. CONCLUSION: There is no specific etiology of stillbirth seen in gravidas with obesity, compared to those without obesity, after controlling for maternal confounders. We surmise that the evaluation recommended for stillbirth assessment in the general population is appropriate for stillbirth evaluation in gravidas with obesity. Testing pursued was similar between groups, but compliance with ACOG recommendations for testing after stillbirth was deficient in the cohort. Future work should aim to identify and address barriers to completing the recommended stillbirth evaluation.

Clinical significance of umbilical artery intermittent vs persistent absent end-diastolic velocity in growth-restricted fetuses.

BACKGROUND: Umbilical artery absent end-diastolic velocity indicates increased placental resistance and is associated with increased risk of perinatal demise and neonatal morbidity in fetal growth restriction. However, the clinical implications of intermittent vs persistent absent end-diastolic velocity are unclear. OBJECTIVE: We compared umbilical artery Doppler velocimetry changes during pregnancy and neonatal outcomes between pregnancies with fetal growth restriction and intermittent absent end-diastolic velocity and those with persistent absent end-diastolic velocity. STUDY DESIGN: In this retrospective study of singletons with fetal growth restriction and absent end-diastolic velocity, umbilical artery Doppler abnormalities were classified as follows: intermittent absent end-diastolic velocity (<50% of cardiac cycles with absent end-diastolic velocity) and persistent absent end-diastolic velocity (≥50% of cardiac cycles with absent end-diastolic velocity). The primary outcome was umbilical artery Doppler progression to reversed end-diastolic velocity. Secondary outcomes included sustained umbilical artery Doppler improvement, latency to delivery, gestational age at delivery, neonatal morbidity composite, rates of neonatal intensive care unit admission, and length of neonatal intensive care unit stay. Outcomes were compared between intermittent absent end-diastolic velocity and persistent absent end-diastolic velocity. Multivariate logistic regression was used to adjust for confounders. A receiver operating characteristic curve was generated to assess the sensitivity and specificity of the percentage of waveforms with absent end-diastolic velocity in predicting the neonatal composite. The Youden index was used to calculate the optimal absent end-diastolic velocity percentage cut-point for predicting the neonatal composite. RESULTS: Of the 77 patients included, 38 had intermittent absent end-diastolic velocity and 39 had persistent absent end-diastolic velocity. Maternal characteristics, including age, parity, and preexisting conditions did not differ significantly between the 2 groups. Progression to reversed end-diastolic velocity was less common in intermittent absent end-diastolic velocity than in persistent absent end-diastolic velocity (7.9% vs 25.6%; odds ratio, 0.25; 95% confidence interval, 0.06-0.99). Sustained umbilical artery Doppler improvement was more common in intermittent absent end-diastolic velocity than in persistent absent end-diastolic velocity (50.0% vs 10.3%; odds ratio, 8.75; 95% confidence interval, 2.60-29.5). Pregnancies with intermittent absent end-diastolic velocity had longer latency to delivery than those with persistent absent end-diastolic velocity (11 vs 3 days; P<.01), and later gestational age at delivery (33.9 vs 28.7 weeks; P<.01). Composite neonatal morbidity was less common in the intermittent absent end-diastolic velocity group (55.3% vs 92.3%; P<.01). Neonatal death occurred in 7.9% of intermittent absent end-diastolic velocity cases and 33.3% of persistent absent end-diastolic velocity cases (P<.01). The differences in neonatal outcomes were no longer significant when controlling for gestational age at delivery. The percentage of cardiac cycles with absent end-diastolic velocity was a modest predictor of neonatal morbidity, with an area under the receiver operating characteristic curve of 0.71 (95% confidence interval, 0.58-0.84). The optimal percentage cut-point for fetal cardiac cycles with absent end-diastolic velocity observed at the sentinel ultrasound for predicting neonatal morbidity was calculated to be 47.7%, with a sensitivity of 65% and specificity of 85%. CONCLUSIONS: Compared with persistent absent end-diastolic velocity, diagnosis of intermittent absent end-diastolic velocity in the setting of fetal growth restriction is associated with lower rates of progression to reversed end-diastolic velocity, higher likelihood of umbilical artery Doppler improvement, longer latency to delivery, and higher gestational age at delivery, leading to lower rates of neonatal morbidity and death. Our data support using an absent end-diastolic velocity percentage cut-point in 50% of cardiac cycles to differentiate intermittent absent end-diastolic velocity from persistent absent end-diastolic velocity. This differentiation in growth-restricted fetuses with absent end-diastolic velocity may allow further risk stratification.

Severity of intrapartum fever and neonatal outcomes.

BACKGROUND: The few studies that have addressed the relationship between severity of intrapartum fever and neonatal and maternal morbidity have had mixed results. The impact of the duration between reaching maximum intrapartum temperature and delivery on neonatal outcomes remains unknown. OBJECTIVE: To test the association of severity of intrapartum fever and duration from reaching maximum temperature to delivery with neonatal and maternal morbidity. STUDY DESIGN: This was a secondary analysis of a prospective cohort of term, singleton patients admitted for induction of labor or spontaneous labor who had intrapartum fever (≥38°C). Patients were divided into 3 groups according to maximum temperature during labor: afebrile (<38°C), mild fever (38°C-39°C), and severe fever (>39°C). The primary outcome was composite neonatal morbidity (umbilical artery pH <7.1, mechanical ventilation, respiratory distress, meconium aspiration with pulmonary hypertension, hypoglycemia, neonatal intensive care unit admission, and Apgar <7 at 5 minutes). Secondary outcomes were composite neonatal neurologic morbidity (hypoxic-ischemic encephalopathy, hypothermia treatment, and seizures) and composite maternal morbidity (postpartum hemorrhage, endometritis, and maternal packed red blood cell transfusion). Outcomes were compared between the maximum temperature groups using multivariable logistic regression. Cox proportional-hazards regression modeling accounted for the duration between reaching maximum intrapartum temperature and delivery. RESULTS: Of the 8132 patients included, 278 (3.4%) had a mild fever and 74 (0.9%) had a severe fever. The incidence of composite neonatal morbidity increased with intrapartum fever severity (afebrile 5.4% vs mild 18.0% vs severe 29.7%; P<.01). After adjusting for confounders, there were increased odds of composite neonatal morbidity with severe fever compared with mild fever (adjusted odds ratio, 1.93 [95% confidence interval, 1.07-3.48]). Severe fevers remained associated with composite neonatal morbidity compared with mild fevers after accounting for the duration between reaching maximum intrapartum temperature and delivery (adjusted hazard ratio, 2.05 [95% confidence interval, 1.23-3.43]). Composite neonatal neurologic morbidity and composite maternal morbidity were not different between patients with mild and patients with severe fevers. CONCLUSION: Composite neonatal morbidity correlated with intrapartum fever severity in a potentially dose-dependent fashion. This correlation was independent of the duration from reaching maximum intrapartum temperature to delivery, suggesting that clinical management of intrapartum fever, in terms of timing or mode of delivery, should not be affected by this duration.

Pharmacological chaperones for the oxytocin receptor increase oxytocin responsiveness in myometrial cells.

Oxytocin is a potent uterotonic agent administered to nearly all patients during childbirth in the United States. Inadequate oxytocin response can necessitate Cesarean delivery or lead to uterine atony and postpartum hemorrhage. Thus, it may be clinically useful to identify patients at risk for poor oxytocin response and develop strategies to sensitize the uterus to oxytocin. Previously, we showed that the V281M variant in the oxytocin receptor (OXTR) gene impairs OXTR trafficking to the cell surface, leading to a decreased oxytocin response in cells. Here, we sought to identify pharmacological chaperones that increased oxytocin response in cells expressing WT or V281M OXTR. We screened nine small-molecule agonists and antagonists of the oxytocin/vasopressin receptor family and identified two, SR49059 and L371,257, that restored both OXTR trafficking and oxytocin response in HEK293T cells transfected with V281M OXTR. In hTERT-immortalized human myometrial cells, which endogenously express WT OXTR, treatment with SR49059 and L371,257 increased the amount of OXTR on the cell surface by two- to fourfold. Furthermore, SR49059 and L371,257 increased the endogenous oxytocin response in hTERT-immortalized human myometrial cells by 35% and induced robust oxytocin responses in primary myometrial cells obtained from patients at the time of Cesarean section. If future studies demonstrate that these pharmacological chaperones or related compounds function similarly in vivo, we propose that they could potentially be used to enhance clinical response to oxytocin.