Understanding the Effects of the COVID-19 Pandemic on Infant Development - The Preterm Problem

As the COVID-19 pandemic nears the end of another year, it makes sense to wonder about the effect on children conceived and born in its shadow. Some of the consequences can be seen in the increasing rates of COVID-19 among infants and young children, particularly among those with comorbid medical conditions. But less obvious sequelae also should be considered: are infants born during the pandemic at greater risk for behavioral or neurodevelopmental problems, either due to exposure to maternal SARS-CoV-2 infection or to the more global effects of trauma and stress? Pregnant women and their infants are vulnerable to the effects of disasters, and evidence suggests that disasters affect maternal mental health and some perinatal health outcomes, particularly among highly exposed women. Prenatal exposure to some viral infections, such as rubella and HIV, increases the risk of neurobehavioral problems in children, and some have hypothesized that SARS-CoV-2 infection could have a similar outcome via in utero exposure to maternal fever, hypoxia, or inflammation

Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose Mortality

OBJECTIVE: Previous studies examining opioid dose and overdose risk provide limited granularity by milligram strength and instead rely on thresholds. We quantify dose-dependent overdose mortality over a large spectrum of clinically common doses. We also examine the contributions of benzodiazepines and extended release opioid formulations to mortality. DESIGN: Prospective observational cohort with one year follow-up. SETTING: One year in one state (NC) using a controlled substances prescription monitoring program, with name-linked mortality data. SUBJECTS: Residential population of North Carolina (n = 9,560,234), with 2,182,374 opioid analgesic patients. METHODS: Exposure was dispensed prescriptions of solid oral and transdermal opioid analgesics; person-years calculated using intent-to-treat principles. Outcome was overdose deaths involving opioid analgesics in a primary or additive role. Poisson models were created, implemented using generalized estimating equations. RESULTS: Opioid analgesics were dispensed to 22.8% of residents. Among licensed clinicians, 89.6% prescribed opioid analgesics, and 40.0% prescribed ER formulations. There were 629 overdose deaths, half of which had an opioid analgesic prescription active on the day of death. Of 2,182,374 patients prescribed opioids, 478 overdose deaths were reported (0.022% per year). Mortality rates increased gradually across the range of average daily milligrams of morphine equivalents. 80.0% of opioid analgesic patients also received benzodiazepines. Rates of overdose death among those co-dispensed benzodiazepines and opioid analgesics were ten times higher (7.0 per 10,000 person-years, 95 percent CI: 6.3, 7.8) than opioid analgesics alone (0.7 per 10,000 person years, 95 percent CI: 0.6, 0.9). CONCLUSIONS: Dose-dependent opioid overdose risk among patients increased gradually and did not show evidence of a distinct risk threshold. There is urgent need for guidance about combined classes of medicines to facilitate a better balance between pain relief and overdose risk

Rotavirus Vaccine Schedules and Vaccine Response Among Infants in Low- and Middle-Income Countries: A Systematic Review

Rotavirus vaccine schedules may impact vaccine response among children in low- and middle-income countries (LMICs). Our objective was to review the literature evaluating the effects of monovalent (RV1) or pentavalent rotavirus vaccines schedules on vaccine response

Timing and predictors of severe rotavirus gastroenteritis among unvaccinated infants in low- and middle-income countries

Delays in rotavirus vaccine schedule could improve performance in low- and middle-income countries (LMICs). However, delaying the first dose could be detrimental if infants experience severe rotavirus gastroenteritis (RVGE) early in life. Our objective was to describe the timing and predictors of severe RVGE in unvaccinated children in LMICs. We analysed the placebo arms from two clinical trials (cohort 1: NCT00241644; cohort 2: NCT00362648). We estimated the rate, cumulative incidence (per 1000 infants) and age distribution of severe RVGE episodes. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals (CI) for the association between baseline factors and severe RVGE. Cumulative incidence at 6 months of age was 23/1000 (95% CI 15-30) in cohort 1 and 6/1000 (95% CI 3-8) in cohort 2. Early antibiotic use (compared with no use) was associated with 2.03 (95% CI 1.18-3.48) and 1.41 (95% CI 0.80-2.51) times the rate of severe RVGE in cohorts 1 and 2, respectively. The cumulative incidence of severe RVGE was low at 6 months of age, suggesting that a 4-week delay in the vaccination schedule may not result in a large number of severe RVGE episodes prior to vaccine receipt. Copyright © Cambridge University Press 2018

How subgroup analyses can miss the trees for the forest plots: A simulation study

Objectives: Subgroup analyses of clinical trial data can be an important tool for understanding when treatment effects differ across populations. That said, even effect estimates from prespecified subgroups in well-conducted trials may not apply to corresponding subgroups in the source population. While this divergence may simply reflect statistical imprecision, there has been less discussion of systematic or structural sources of misleading subgroup estimates. Study Design and Setting: We use directed acyclic graphs to show how selection bias caused by associations between effect measure modifiers and trial selection, whether explicit (e.g., eligibility criteria) or implicit (e.g., self-selection based on race), can result in subgroup estimates that do not correspond to subgroup effects in the source population. To demonstrate this point, we provide a hypothetical example illustrating the sorts of erroneous conclusions that can result, as well as their potential consequences. We also provide a tool for readers to explore additional cases. Conclusion: Treating subgroups within a trial essentially as random samples of the corresponding subgroups in the wider population can be misleading, even when analyses are conducted rigorously and all findings are internally valid. Researchers should carefully examine associations between (and consider adjusting for) variables when attempting to identify heterogeneous treatment effects

Long-Term Outcomes after Midurethral Mesh Sling Surgery for Stress Urinary Incontinence

Objectives: Although midurethral mesh slings are the criterion standard surgical treatment for stress urinary incontinence (SUI), limited data exist regarding long-term outcomes. Thus, our objectives were to evaluate the long-term risk of sling revision and the risk of repeat SUI surgery up to 15 years after the initial sling procedure and to identify predictors of these outcomes. Methods: Using a population-based cohort of commercially insured individuals in the United States, we identified women aged 18 years or older who underwent a sling procedure between 2001 and 2018. For sling revision, we evaluated indications (mesh exposure or urinary retention). We estimated the cumulative risks of sling revision and repeat SUI surgery annually using Kaplan-Meier survival curves and evaluated predictors using Cox proportional hazards models. Results: We identified 334,601 mesh sling surgical procedures. For sling revision, the 10-year and 15-year risks were 6.9% (95% confidence interval [CI], 6.7–7.0) and 7.9% (95% CI, 7.5–8.3), with 48.7% of sling revisions associated with mesh exposure. The 10-year and 15-year risks of repeat SUI surgery were 14.5% (95% CI, 14.2–14.8) and 17.9% (95% CI, 17.3–18.6). Women aged 18–29 years had an elevated risk for both sling revision (hazard ratio, 1.20; 95% CI, 1.15–1.25) and repeat SUI surgery (hazard ratio, 1.30; 95% CI, 1.25–1.37) compared with women 70 years and older. Conclusions: In our study population, the 15-year risk of sling revision was 7.9%, with nearly half of revisions due to mesh exposure. These findings provide critical long-term data to support informed decisions for women and health care providers considering midurethral mesh slings

Postsurgical Opioid Prescriptions and Risk of Long-term Use: An Observational Cohort Study Across the United States

Objective: The aim of this study was to evaluate differences in risk of longterm opioid therapy after surgery among an opioid-naive population using varying cutoffs based on days supplied (DS), total morphine milligram equivalents (MME) dispensed, and quantity of pills (QTY) dispensed. Background: In response to the US opioid crisis, opioid prescription (Rx) limits have been implemented on a state-by-state basis beginning in 2016. However, there is limited evidence informing appropriate prescribing limits, and the effect of these policies on long-term opioid therapy. Methods: Using the MarketScan claims databases, we identified all opioidnaive patients undergoing outpatient surgery between July 1, 2006 and June 30, 2015. We identified the initial postsurgical opioid prescribed, examining the DS, total MME, and QTY dispensed.We used Poisson to estimate adjusted risk differences and risk ratios of long-term opioid use comparing those receiving larger versus smaller volume of opioids. Results: We identified 5,148,485 opioid-naive surgical patients. Overall, 55.5% received an opioid for postoperative pain, with median days supply =5 and median total MME = 240. The proportion of patients receiving prescriptions above 7 DS increased from 11% in 2006 to 19% in 2015. Among those receiving postoperative opioids, 8% had long-term opioid use, and risk of long-term use was 1.16 times [95% confidence interval (CI), 1.10-1.25] higher among those receiving >7 days compared with those receiving ≤7 days. Those receiving >400 total MME (15% of patients) were at 1.17 times (95% CI, 1.10-1.25) the risk of long-term use compared with those receiving ≤400 MME. Conclusions: Between 2005 and 2015, the amounts of opioids prescribed for postoperative pain increased dramatically, and receipt of larger volume of opioids was associated with increased risk of long-term opioid therapy

Trends in the Surgical Management of Stress Urinary Incontinence

To estimate the rates of stress urinary incontinence (SUI) surgery from 2000-2009 by type of procedure, year, age, and region of the country

Nondifferential Treatment Misclassification Biases Toward the Null? Not a Safe Bet for Active Comparator Studies

Active comparator studies are increasingly common, particularly in pharmacoepidemiology. In such studies, the parameter of interest is a contrast (difference or ratio) in the outcome risks between the treatment of interest and the selected active comparator. While it may appear treatment is dichotomous, treatment is actually polytomous as there are at least 3 levels: no treatment, the treatment of interest, and the active comparator. Because misclassification may occur between any of these groups, independent nondifferential treatment misclassification may not be toward the null (as expected with a dichotomous treatment). In this work, we describe bias from independent nondifferential treatment misclassification in active comparator studies with a focus on misclassification that occurs between each active treatment and no treatment. We derive equations for bias in the estimated outcome risks, risk difference, and risk ratio, and we provide bias correction equations that produce unbiased estimates, in expectation. Using data obtained from US insurance claims data, we present a hypothetical comparative safety study of antibiotic treatment to illustrate factors that influence bias and provide an example probabilistic bias analysis using our derived bias correction equations

Persistent Opioid Use after Hysterectomy in the United States, 2005-2015

OBJECTIVE:To assess variables associated with opioid prescriptions filled perioperatively after hysterectomy and the risk of prolonged opioid use through 1 year after hysterectomy.METHODS:In this retrospective cohort study, we used the 2005-2015 IBM MarketScan databases to identify women aged at least 18 years who underwent hysterectomy. For opioid use, we identified filled prescriptions for opioid medications. We excluded women with prevalent opioid use, defined as an opioid prescription filled 180 to 30 days preoperatively or at least two prescriptions filled in the 30 days before surgery. We defined perioperative opioid use as any opioid prescription filled within 30 days before or 7 days after surgery. We used log-binomial regression to identify independent predictors of perioperative opioid prescription fill. To assess the risk of long-term opioid use, we estimated the proportion of women with ongoing monthly opioid prescriptions through 12 months after surgery and the proportion of women with any opioid prescription 3-6 months after surgery, mimicking published estimates.RESULTS:Among 569,634 women who underwent hysterectomy during the study period, 176,537 (30.9%) were excluded owing to prevalent opioid use. We found that 331,322 (84.3%) women filled a perioperative opioid prescription, with median quantity of 30 pills (interquartile range 25-40), and that younger (adjusted risk ratio [adjRR]18-24 0.91) and older (adjRR65-74 0.84; adjRR75+ 0.70) patients were less likely to receive a perioperative prescription compared with women aged 45-54. The proportion of women with continuous monthly fills of opioids through 2, 3, 6, and 12 months after surgery was 1.40%, 0.34%, 0.06%, and 0.02%, respectively.CONCLUSION:Most women who underwent hysterectomy in the United States from 2005 to 2015 filled a perioperative opioid prescription with a median quantity of 30 pills. The risk of prolonged opioid use through 6 months is quite low, at 0.06% or 1 in 1,547