Acute pain pathways: protocol for a prospective cohort study.

INTRODUCTION: Opioid analgesics are often used to treat moderate-to-severe acute non-cancer pain; however, there is little high-quality evidence to guide clinician prescribing. An essential element to developing evidence-based guidelines is a better understanding of pain management and pain control among individuals experiencing acute pain for various common diagnoses. METHODS AND ANALYSIS: This multicentre prospective observational study will recruit 1550 opioid-naïve participants with acute pain seen in diverse clinical settings including primary/urgent care, emergency departments and dental clinics. Participants will be followed for 6 months with the aid of a patient-centred health data aggregating platform that consolidates data from study questionnaires, electronic health record data on healthcare services received, prescription fill data from pharmacies, and activity and sleep data from a Fitbit activity tracker. Participants will be enrolled to represent diverse races and ethnicities and pain conditions, as well as geographical diversity. Data analysis will focus on assessing patients' patterns of pain and opioid analgesic use, along with other pain treatments; associations between patient and condition characteristics and patient-centred outcomes including resolution of pain, satisfaction with care and long-term use of opioid analgesics; and descriptive analyses of patient management of leftover opioids. ETHICS AND DISSEMINATION: This study has received approval from IRBs at each site. Results will be made available to participants, funders, the research community and the public. TRIAL REGISTRATION NUMBER: NCT04509115.

Racial, Ethnic, and Geographic Disparities in Cardiovascular Health Among Women of Childbearing Age in the United States.

Background In the United States, large disparities in cardiovascular health (CVH) exist in the general population, but little is known about the CVH status and its disparities among women of childbearing age (ie, 18-49 years). Methods and Results In this cross-sectional study, we examined racial, ethnic, and geographic disparities in CVH among all women of childbearing age in the United States, using the 2011 to 2019 Behavioral Risk Factor Surveillance System. Life's Simple 7 (ie, blood pressure, glucose, total cholesterol, smoking, body mass index, physical activity, and diet) was used to examine CVH. Women with 7 ideal CVH metrics were determined to have ideal CVH. Among the 269 564 women of childbearing age, 13 800 (4.84%) had ideal CVH. After adjusting for potential confounders, non-Hispanic Black women were less likely to have ideal CVH (odds ratio, 0.54; 95% CI, 0.46-0.63) compared with non-Hispanic White women, and with significantly lower odds of having ideal metrics of blood pressure, blood glucose, body mass index, and physical activity. No significant difference in CVH was found between non-Hispanic White and Hispanic women. Large geographic disparities with temporal variations were observed, with the age- and race-adjusted ideal CVH prevalence ranging from 4.05% in the District of Columbia (2011) to 5.55% in Maine and Montana (2019). States with low ideal CVH prevalence and average CVH score were mostly clustered in the southern United States. Conclusions Large racial, ethnic, and geographic disparities in CVH exist among women of childbearing age. More efforts are warranted to understand and address these disparities.

Association of Inadvertent 9-Valent Human Papillomavirus Vaccine in Pregnancy With Spontaneous Abortion and Adverse Birth Outcomes.

Importance: The 9-valent human papillomavirus (9vHPV) vaccine is recommended for individuals through age 26 years and may be administered to women up to age 45 years. Data on 9vHPV vaccine exposures during pregnancy are limited. Objective: To evaluate the associations between 9vHPV vaccine exposures during pregnancy or peripregnancy and selected pregnancy and birth outcomes (spontaneous abortion [SAB], preterm birth, small-for-gestational age [SGA] birth, and major structural birth defect). Design, Setting, and Participants: This cohort study analyzed data from 7 participating health systems in the Vaccine Safety Datalink. The cohort comprised pregnancies among girls and women aged 12 to 28 years that ended between October 26, 2015, and November 15, 2018. Singleton pregnancies that ended in a live birth, stillbirth, or SAB were included. Exposures: Vaccine exposure windows were distal (9vHPV or 4vHPV vaccine administered from 22 to 16 weeks before last menstrual period [LMP]), peripregnancy (9vHPV vaccine administered from 42 days before LMP until LMP), and during pregnancy (9vHPV vaccine administered from LMP to 19 completed weeks' gestation). Primary comparisons were (1) girls and women with 9vHPV vaccine exposures during pregnancy vs those with 4vHPV or 9vHPV distal vaccine exposures, (2) girls and women with vaccine exposures peripregnancy vs those with 4vHPV or 9vHPV distal vaccine exposures, and (3) girls and women with 9vHPV vaccine exposures during pregnancy or peripregnancy vs those with 4vHPV or 9vHPV distal vaccine exposure. Main Outcomes and Measures: Spontaneous abortions were confirmed based on medical record review and adjudication. Preterm and SGA births were identified from electronic health record and birth data. Major structural birth defects were based on diagnostic codes using a validated algorithm. Inverse probability weighting was used to balance the covariates. Time-dependent covariate Cox proportional hazards regression models and Poisson regression were used to estimate the associations between 9vHPV vaccine exposures and pregnancy and birth outcomes. Results: The final cohort included 1493 pregnancies among girls and women with a mean (SD) maternal age of 23.9 (2.9) years. Of these pregnancies, 445 (29.8%) had exposures to the 9vHPV vaccine during pregnancy, 496 (33.2%) had exposures to the 9vHPV vaccine peripregnancy, and 552 (37.0%) had 4vHPV or 9vHPV distal vaccine exposures. The 9vHPV vaccine administered during pregnancy was not associated with increased risk for SAB (hazard ratio, 1.12; 95% CI, 0.66-1.93) compared with distal vaccine exposures. Findings were similar for 9vHPV vaccine exposures peripregnancy (relative risk [RR], 0.72; 95% CI, 0.42-1.24). Among live births (n = 1409), 9vHPV vaccine exposures during pregnancy were not associated with increased risks for preterm birth (RR, 0.73; 95% CI, 0.44-1.20) or SGA birth (RR, 1.31; 95% CI, 0.78-2.20). Results were similar regarding the association between 9vHPV vaccine exposures peripregnancy and preterm birth (RR, 0.72; 95% CI, 0.45-1.17) and SGA birth (RR, 1.10; 95% CI, 0.65-1.88). Birth defects were rare in all exposure groups, occurring in about 1% of live births with available infant data. Conclusions and Relevance: This study found that 9vHPV vaccine exposures during or around the time of pregnancy were uncommon and not associated with SABs or selected adverse birth outcomes. These findings can inform counseling for inadvertent 9vHPV vaccine exposures.

Antenatal N-acetylcysteine to improve outcomes of premature infants with intra-amniotic infection and inflammation (Triple I): randomized clinical trial.

BACKGROUND: Intrauterine infection and/or inflammation (Triple I) is an important cause of preterm birth (PTB) and adverse newborn outcomes. N-acetylcysteine (NAC) is a Food and Drug Administration (FDA)-approved drug safely administered to pregnant women with acetaminophen toxicity. METHODS: We conducted a single-center, quadruple-blind, placebo-controlled trial of pregnant women with impending PTB due to confirmed Triple I. Participants (n = 67) were randomized to an intravenous infusion of NAC or placebo mimicking the FDA-approved regimen. Outcomes included clinical measures and mechanistic biomarkers. RESULTS: Newborns exposed to NAC (n = 33) had significantly improved status at birth and required less intensive resuscitation compared to placebo (n = 34). Fewer NAC-exposed newborns developed two or more prematurity-related severe morbidities [NAC: 21% vs. placebo: 47%, relative risk, 0.45; 95% confidence interval (CI) 0.21-0.95] with the strongest protection afforded against bronchopulmonary dysplasia (BPD, NAC: 3% vs. placebo: 32%, relative risk, 0.10; 95% CI: 0.01-0.73). These effects were independent of gestational age, birth weight, sex, or race. Umbilical cord plasma NAC concentration correlated directly with cysteine, but not with plasma or whole blood glutathione. NAC reduced the placental expression of histone deacetylase-2, suggesting that epigenetic mechanisms may be involved. CONCLUSIONS: These data provide support for larger studies of intrapartum NAC to reduce prematurity-related morbidity. IMPACT: In this randomized clinical trial of 65 women and their infants, maternal intravenous NAC employing the FDA-approved dosing protocol resulted in lower composite neonatal morbidity independent of gestational age, race, sex, and birthweight. Administration of NAC in amniocentesis-confirmed Triple I resulted in a remarkably lower incidence of BPD. As prior studies have not shown a benefit of postnatal NAC in ventilated infants, our trial highlights the critical antenatal timing of NAC administration. Repurposing of NAC for intrapartum administration should be explored in larger clinical trials as a strategy to improve prematurity-related outcomes and decrease the incidence of BPD.

Drug use associated tricuspid valve infective endocarditis in pregnancy.

BACKGROUND AND AIM: We report a case of intravenous drug use associated tricuspid valve endocarditis in a 28-year-old pregnant female at 26-week gestation. METHODS: Patient management required a multidisciplinary collaboration between cardiac surgery, obstetrics and gynecology, and neonatal critical care. RESULTS: Despite appropriate intravenous antibiotics, the patient developed life-threatening complications and underwent planned cesarean delivery at 28 weeks 6 days gestation followed by interval tricuspid valve replacement 1 week later. CONCLUSIONS: Both the patient and her infant were successfully managed through the perioperative period.

Optimal maternal and neonatal outcomes and associated hospital characteristics.

BACKGROUND: This study aims to examine hospital variation in both maternal and neonatal morbidities and identify institutional characteristics associated with hospital performance in a combined measure of maternal and neonatal outcomes. METHODS: Using the California Linked Birth File containing data from birth certificate and hospital discharge records, we identified 1 322 713 term births delivered at 248 hospitals during 2010-2012. For each hospital, a risk-standardized rate of severe maternal morbidities and a risk-standardized rate of severe newborn morbidities were calculated after adjusting for patient clinical risk factors. Hospitals were ranked based on combined information on their maternal and newborn morbidity rates. RESULTS: Risk-standardized severe maternal and severe newborn morbidity rates varied substantially across hospitals (10th to 90th percentile range = 67.5-148.2 and 141.8-508.0 per 10 000 term births, respectively), although there was no significant association between the two (P = 0.15). Government hospitals (non-Federal) were more likely than other hospitals to be in worse rank quartiles (P value for trend = 0.004), whereas larger volume was associated with better rank among hospitals in the first three quartiles (P = 0.004). The most prevalent morbidities that differed progressively across hospital rank quartiles were severe hemorrhage, disseminated intravascular coagulation, and heart failure during procedure/surgery for mothers, and severe infection, respiratory complication, and shock/resuscitation for neonates. CONCLUSIONS: Hospitals with low maternal morbidity rates may not have low neonatal morbidity rates and vice versa, highlighting the importance of assessing joint maternal-newborn outcomes in order to fully characterize a hospital's obstetrical performance. Hospitals with smaller volume and government ownership tend to have less desirable outcomes and warrant additional attention in future quality improvement efforts.

Risk of Spontaneous Abortion After Inadvertent Human Papillomavirus Vaccination in Pregnancy.

OBJECTIVE: To evaluate the risk of spontaneous abortion after quadrivalent human papillomavirus (4vHPV) vaccination before and during pregnancy across seven integrated health systems within the Vaccine Safety Datalink. METHODS: Within a retrospective observational cohort, we compared risks for spontaneous abortion after 4vHPV in three exposure windows: distal (16-22 weeks before the last menstrual period [LMP]), peripregnancy (within 6 weeks before the LMP), and during pregnancy (LMP through 19 weeks of gestation). Women 12-27 years of age with a pregnancy between 2008 and 2014, with continuous insurance enrollment 8 months before and through pregnancy end, and with a live birth, stillbirth, or spontaneous abortion were included. Pregnancies were identified through validated algorithms. Spontaneous abortions and stillbirths were verified by chart review with spontaneous abortions adjudicated by clinical experts. We excluded multiple gestations, spontaneous abortions before 6 weeks of gestation, and women using medications increasing risk of spontaneous abortion. Spontaneous abortion risk after 4vHPV during pregnancy was compared with distal vaccination using time-dependent covariate Cox models. Spontaneous abortion risk for peripregnancy compared with distal vaccination was evaluated with standard Cox models. RESULTS: We identified 2,800 pregnancies with 4vHPV exposure in specified risk windows: 919 (33%) distal, 986 (35%) peripregnancy, and 895 (32%) during pregnancy. Mean age was 22.4 years in distal and peripregnancy groups compared with 21.4 years among women vaccinated during pregnancy. Among women with distal 4vHPV exposure, 96 (10.4%) experienced a spontaneous abortion. For peripregnancy and during pregnancy exposures, spontaneous abortions occurred in 110 (11.2%) and 77 (8.6%), respectively. The risk of spontaneous abortion was not increased among women who received 4vHPV during pregnancy (adjusted hazard ratio 1.10, 95% CI 0.81-1.51) or peripregnancy 1.07 (0.81-1.41). CONCLUSION: Inadvertent 4vHPV exposure during or peripregnancy was not significantly associated with an increased risk of spontaneous abortion.

Maternal and Infant Outcomes After Human Papillomavirus Vaccination in the Periconceptional Period or During Pregnancy.

OBJECTIVE: To evaluate whether quadrivalent human papillomavirus vaccine (4vHPV) administered during the periconceptional period or during pregnancy was associated with increased risks for adverse obstetric events, adverse birth outcomes, or selected major structural birth defects. METHODS: We conducted a retrospective, observational cohort study using administrative and health care data from the Vaccine Safety Datalink. Insured women 13-27 years old with singleton pregnancies and a live birth from January 1, 2007, through September 1, 2013, who received 4vHPV during the periconceptional period (2 weeks before to 2 weeks after their last menstrual period), during pregnancy, or during both periods combined were compared with women who had a live birth during the same time period and received 4vHPV 4-18 months before their last menstrual period. We examined risks of gestational diabetes, hypertensive disorders of pregnancy, chorioamnionitis, preterm birth, small-for-gestational-age birth, and selected major structural birth defects in offspring. We estimated relative risks associated with receipt of 4vHPV during the periconceptional period, during pregnancy, and both exposure periods combined using a generalized linear model with Poisson distribution including a propensity score that included relevant maternal demographic and pregnancy characteristics. RESULTS: Of 92,579 potentially eligible pregnant women, 720 received 4vHPV during the periconceptional period, 638 received 4vHPV during pregnancy, and 8,196 received 4vHPV during the comparison period. Administration of 4vHPV during pregnancy was not associated with increased risk of adverse obstetric events, birth outcomes. Preterm birth occurred in 7.9% of pregnancies with vaccine exposures during pregnancy compared with 7.6% of pregnancies with vaccination in the comparison period (adjusted relative risk 0.97, 95% CI 0.72-1.3). Major structural birth defects were diagnosed in 2.0% of pregnancies with vaccine exposure during pregnancy compared with 1.8% of pregnancies with vaccine exposure during the comparison period (adjusted prevalence ratio 1.0, 95% CI 0.52-1.9). Results were similar for 4vHPV exposure during the periconceptional period. CONCLUSION: Quadrivalent HPV vaccine inadvertently administered in pregnancy or during the periconceptional period was not associated with adverse pregnancy or birth outcomes.

Limiting the Exposure of Select Fetuses to Intrauterine Infection/Inflammation Improves Short-Term Neonatal Outcomes in Preterm Premature Rupture of Membranes.

BACKGROUND: To improve neonatal outcomes in pregnancies at heightened risk for early-onset neonatal sepsis (EONS), there is a need to identify fetuses that benefit from expectant management as opposed to early delivery. Detectable haptoglobin and haptoglobin-related protein (Hp&HpRP switch-on status) in cord blood has been proposed as a biomarker of antenatal exposure to intra-amniotic infection and/or inflammation (IAI), an important determinant of EONS. SUBJECTS AND METHODS: We analyzed 185 singleton newborns delivered secondary to preterm premature rupture of membranes (PPROM). In 123 cases, amniocentesis was performed to exclude amniotic fluid (AF) infection. Delivery was indicated for 61 cases with confirmed infection. Women without AF infection (n = 62) and those without amniocentesis (n = 62) were managed expectantly. Interleukin 6 and Hp&HpRP switch-on status were evaluated by ELISA and Western blot. Newborns were followed prospectively for short-term outcomes until hospital discharge or death. RESULTS: Newborns exposed antenatally to IAI had an increased risk of adverse neonatal outcome [OR: 3.0 (95% CI: 1.15-7.59)]. Increasing gestational age [OR: 0.61 (95% CI: 0.52-0.70)] and management with amniocentesis [OR: 0.37 (95% CI: 0.14-0.95)] lowered the newborn's risk of developing adverse outcomes. DISCUSSION: In the setting of PPROM and IAI, early delivery benefits a select subgroup of fetuses that have not yet progressed to Hp&HpRP switch-on status.

Modulation of amniotic fluid activin-a and inhibin-a in women with preterm premature rupture of the membranes and infection-induced preterm birth.

PROBLEM: Activins and inhibins are important modulators of inflammatory processes. We explored activation of amniotic fluid (AF) activin-A and inhibin-A system in women with intra-amniotic infection and preterm premature rupture of the membranes (PPROM). METHOD OF STUDY: We analyzed 78 AF samples: '2nd trimester-control' (n=12), '3rd trimester-control' (n=14), preterm labor with intact membranes [positive-AF-cultures (n=13), negative-AF-cultures (n=13)], and PPROM [positive-AF-cultures (n=13), negative-AF-cultures (n=13)]. Activin-A levels were evaluated ex-vivo following incubation of amniochorion and placental villous explants with Gram-negative lipopolysaccharide (LPS) or Gram-positive (Pam3Cys) bacterial mimics. Ability of recombinant activin-A and inhibin-A to modulate inflammatory reactions in fetal membranes was explored through explants' IL-8 release. RESULTS: Activin-A and inhibin-A were present in human AF and were gestational age-regulated. Activin-A was significantly upregulated by infection. Lower inhibin-A levels were seen in PPROM. LPS elicited release of activin-A from amniochorion, but not from villous explants. Recombinant activin-A stimulated IL-8 release from amniochorion, an effect that was not reversed by inhibin-A. CONCLUSION: Human AF activin-A and inhibin-A are involved in biological processes linked to intra-amniotic infection/inflammation-induced preterm birth.

Stillbirth at term in women of advanced maternal age in the United States: when could the antenatal testing be initiated?

We sought to determine if advanced maternal age (AMA) is a risk factor for intrauterine fetal demise (IUFD). We used a U.S. Centers for Disease Control and Prevention database and analyzed outcomes in women 15 to 44 years of age with term singleton gestations. Cox proportional hazards models and Cochran-Mantel-Haenszel tests were used. Results were controlled for maternal race and smoking. After excluding congenital anomalies and medical complications, 6,239,399 singleton term deliveries were identified. When compared with women 25 to 29 years of age, the risk of IUFD increased with advancing age: 30 to 34 years, odds ratio [OR] = 1.24 (95% confidence interval [CI], 1.13 to 1.36); 35 to 39 years, OR = 1.45 (95% CI, 1.21 to 1.74), and 40 to 44 years, OR = 3.04 (95% CI, 1.58 to 5.86). The risk of IUFD for women 40 to 44 years of age at 39 weeks is comparable with that of 42 weeks in those 25 to 29 years of age. We concluded that AMA is an independent predictor of IUFD, and a strategy of antenatal testing in those > or = 40 years of age beginning at 38 weeks may be considered.

Maternal obesity and diabetes as risk factors for adverse pregnancy outcomes: differences among 4 racial/ethnic groups.

OBJECTIVES: We examined associations between obesity, diabetes, and 3 adverse pregnancy outcomes--primary cesarean delivery, preterm birth, and low birth-weight (LBW)--by racial/ethnic group. Our goal was to better understand how these associations differentially impact birth outcomes by group in order to develop more focused interventions. METHODS: Data were collected from the 1999, 2000, and 2001 New York City birth files for 329,988 singleton births containing information on prepregnancy weight and prenatal weight gain. Separate logistic regressions for 4 racial/ethnic groups predicted the adverse pregnancy outcomes associated with diabetes. Other variables in the regressions included obesity, excess weight gain, hypertension, preeclampsia, and substance use during pregnancy (e.g., smoking). RESULTS: Chronic and gestational diabetes were significant risks for a primary cesarean and for preterm birth in all women. Diabetes as a risk for LBW varied by group. For example, whereas chronic diabetes increased the risk for LBW among Asians, Hispanics, and Whites (adjusted odds ratios=2.28, 1.69, and 1.59), respectively, it was not a significant predictor of LBW among Blacks. CONCLUSIONS: In this large, population-based study, obesity and diabetes were independently associated with adverse pregnancy outcomes, highlighting the need for women to undergo lifestyle changes to help them control their weight during the childbearing years and beyond.

Acquired von Willebrand disease: management of labor and delivery with intravenous dexamethasone, continuous factor concentrate, and immunoglobulin infusion.

Acquired von Willebrand disease is a rare bleeding disorder that can lead to complete absence of clotting factor 8 and von Willebrand factor. Recently, the hematologic literature has reported continuous infusion of factor concentrates and intravenous immunoglobulin as an improved therapy for active bleeding and prophylaxis in patients who are anticipating surgery with congenital von Willebrand disease. We describe the first case of a pregnant woman with acquired von Willebrand disease who underwent the described therapy during delivery.